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Editors: DeVita, Vincent T.; Lawrence, Theodore S.; Rosenberg, Steven A.

Title: Devita, Hellman & Rosenberg's Cancer: Principles & Practice of Oncology, 8th Edition Copyright 2008 Lippincott Williams & Wilkins > Table of Contents > Volume Two > Part 3 - Practice of Oncology > Chapter 43 - Cancer of the Breast Chapter 43 Cancer of the Breast Section 1: The Molecular Biology of Breast Cancer Suzanne D. Conzen Tatyana A. Grushko Olufunmilayo I. Olopade The past 20 years have witnessed a dramatic increase in our understanding of multistep carcinogenesis and the central role of genetic alterations in the diagnosis, treatment, and prevention of breast cancer. Advances in DNA microarray technology and other methods of large-scale gene expression analysis have been adopted for both biological characterization and more recently, for therapeutic decision making in breast cancer treatment. Increasing our understanding of the molecular biology and gene expression signatures of breast cancer continues to improve prevention, detection, and treatment strategies for breast cancer patients. For example, the discovery of a physiological role for the estrogen receptor (ER) in breast cancer by Nobel Prize winner Charles Huggins, paved the way for antiestrogen therapy. Similarly, amplification of the HER2 oncogene has proven to be the major determinant of sensitivity to treatment with the anti-HER2 humanized monoclonal antibody, trastuzumab. Thus, targeting specific signaling pathways in breast cancer treatment has proven value. Although many molecular abnormalities relating to growth factor signaling in breast cancers have been recently described, the specific genes causing more than half of inherited breast cancers remain largely unknown (Fig. 43.1.1). Interestingly, most of the known the genes implicated in inherited breast cancer are involved in DNA repair pathways. For example, deleterious mutations in the BRCA1 and BRCA2 account for most inherited breast cancer; they are implicated in about 40% of all familial breast cancers. In this chapter, both acquired and inherited determinants of breast cancer are reviewed, with the goal of placing molecular biology in a clinically relevant context. Genetics of Breast Cancer Genetic Predisposition Breast cancer is an extremely heterogeneous disease caused by interactions of both inherited and environmental risk factors that lead to progressive accumulation of genetic and epigenetic changes in breast cancer cells. Although epidemiological evidence supports the existence of certain risk factors (e.g., age, obesity, alcohol intake, lifetime estrogen exposure, and mammographic density), a family history of breast cancer remains the strongest risk factor for the disease. Familial forms comprise approximately 20% of all breast cancers and appear to have a distinctive pathogenesis dependent on the particular susceptibility gene involved (Fig. 43.1.1).1,2 Although the genes responsible for most familial breast cancers have yet to be identified, approximately half of familial cancers are caused by germline mutations in tumor suppressor genes (TSGs), most of which have functions implicated in preserving genome fidelity. These genes include (1) BRCA1 and BRCA2, (2) other TSGs that are associated

with rare familial cancer syndromes such as p53, PTEN, and ATM, and (3) additional lowto moderate-risk genes such as CHEK2, BRIP1, PALB2, NBS1, RAD50, and the mismatch repair genes MSH2 and MLH.3 Recently, genome-wide association studies that examine genetic variation (single nucleotide polymorphisms) in the context of familial breast cancer and case control studies of breast cancer have uncovered common low penetrance genetic variations in at least 120 candidate genes. Interestingly, among these candidate genes, the main contributors to an association with breast cancer risk are genes involved in cell cycle control, steroid hormone metabolism, and cell signaling pathways. Common susceptibility alleles of CASP8, TGFB1, FGFR2, TNC9, MAP3K1, and LSP1 have repeatedly shown the strongest and most consistent evidence for an association with breast cancer.4,5,6,7 A summary of known and emerging genes associated with breast cancer susceptibility is provided in Table 43.1.1. BRCA1 and BRCA2 BRCA1 and BRCA2 are located on chromosomes 17q12-21 and 13q12-13, respectively, and are considered classic TSGs because P.1596 one inherited defective copy of the gene is sufficient for cancer predisposition, but the loss of the wild-type allele is required for tumorigenesis.8

Figure 43.1.1. Genetics of breast cancer. The majority of breast cancers are sporadic, occur randomly, and carry somatic genetic alterations. Hereditary cancer occurs in multiple family members due to germline mutations in high-risk genes which are inherited in autosomal dominant pattern. BRCA1 and BRCA2 are two major high-risk genes associated with hereditary breast cancer. Mutations in CHEK2 contribute to a substantial fraction of familial breast cancer. Carriers of TP53 mutations develop Li-Fraumeni syndrome and are at high risk of developing early onset breast cancer, but these mutations are very rare. Susceptibility alleles in other genes, such as PTEN, ATM, STK11/LKB1, and MSH2/MLH1 are also very rare causes of breast cancer. The majority of familial clustering of breast cancer is unexplained. The susceptibility to breast cancer in this group is presumed to be due to either additional high-penetrance susceptibility genes (which remain

to be identified) or variants at many low-penetrance loci, each conferring a moderate risk of the disease (polygenic susceptibility). BRCA1 and BRCA2 encode large multifunctional proteins with multiple sites of proteinprotein interactions. BRCA1 has three major functional domains but has also been found in multiple protein complexes. In fact, it remains unclear which of the many functions contribute to its specific role as a major breast and ovarian cancer susceptibility gene. First, an amino-terminal RING finger domain forms heterodimers with the BRCA1associated ring domain 1 (BARD1) protein. This association results in BRCA1 possessing E3 ubiquitin ligase activity. Recent data relate ubiquitin modification of BRCA1 to DNA damage response and to the control of centrosome dynamics.9 A second important region contains two nuclear localization signals and a binding region for P53, MYC, Rb, as well as the zinc-finger and BRCA1-interacting protein with a CRAB domain 1 (ZBRK1), which cooperates with BRCA1 to repress transcription. Third, a large region located in the Cterminal half of the protein is required for cell cycle control, chromatin modification, and DNA-repair-related functions. The DNA-binding domain in the central part of this region forms the BRCA1-associated surveillance complex with a number of proteins including MSH2-MSH6, MRE11-RAD50-NBS1, BLM, MDC1, ATM, ATR, CDK2, CHK2, and RAD51. SQ-cluster domains are sites phosphorylated by ATM/ATR. A pair of BRCA1 Cterminal (BRCT) domains possess phosphopeptide binding motifs with a high affinity for phosphoserine and phosphothreonine residues. BRCT domains are found in many proteins involved in the DNA repair pathway. BRCT domains of BRCA1 bind to the histone deacetylase (HDAC) complex, chromatin remodeling factors SWI/SNF, RNA polymerase II, p300, BACH1, CtIP, and BRCA2 and contain second-binding sites for P53 and Rb. Interaction of BRCT repeats of BRCA1 with CHK1 and Polo-like kinase (PLK1) regulates the G2/M and G1/S checkpoints and control apoptosis. In summary, it is apparent that in complex with other proteins, BRCA1 contributes to many cellular processes including homologous recombination, DNA damage response, cell cycle checkpoint control, ubiquitination, transcriptional regulation, chromatin modification, centrosome duplication, and X-chromosome inactivation.10,11,12,13,14 Although BRCA2 also contains two nuclear localization signals, the presence of RAD51binding motifs within eight central BRC repeats supports the hypothesis that BRCA2 plays a role in double-strand break repair and both mitotic and meiotic recombination. The Cterminal DNA-binding domain of BRCA2 is a region that binds to both single-stranded DNA and to a DSS1 protein. This region contains an additional RAD51-binding motif that is distinct from the BRC repeats and regulated by CDK-dependent phosphorylation. This complex formation is important for properly controlled recombination and centrosome duplication. Although there is no sequence similarity, BRCA1 and BRCA2 are functionally related. Functions so far ascribed to BRCA2 are DNA recombination and homologous repair, transcription, chromatin remodeling, centrosome duplication, and cytokinesis. Both BRCAs are in the class of so-called caretaker genes, which through the multiple functions discussed above use a variety of pathways to ensure genomic stability.8,10,11 P.1597

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Table 43.1.1 Breast Cancer Susceptibility Genes Associated Breast Syndrome, Cancer Locatio Protein Cancer Risk Gene Abbreviation n Function Predisposition Range BRCA1AD BReast CAncer 17q12- DNA repair, RHereditary 60%85 gene 1 21 transactivatio breast/ovarian % n (lifetime); cancer Bilateral/multifo 15%40 cal breast tumor;% risk of risk of prostate ovarian colon, liver, and cancer bone cancer AD BRCA2 BReast CAncer 13q12- DNA repair, RHereditary 37%84 gene 2 13 transactivatio breast/ovarian % (by age n 70), cancer D1 60%85 Fanconi Anemia (caused % by biallelic (lifetime), mutations) Male 15%40 breast cancer; % risk of risk of pancreas, ovarian gall bladder, cancer pharynx, stomach, melanoma, and prostate cancer TP53AD Tumor Protein 53 17p13. Cell cycle Li-Fraumeni 50%89 1 regulation, syndrome % (by age DNA repair, RBreast cancer, 50), 90% apoptosis soft tissue in Lisarcoma, CNS- Fraumeni tumors, syndrome adrenocortical survivors cancer, leukemia, prostate cancer risk hCHK2/CHEK2AD Cell-cycle22q12. DNA damage Li-Fraumeni Twofold CHeckpoint 1 response, cell syndrome(?) in women, M Kinase 2 cycle Breast cancer, tenfold in regulation male breast men cancer: risk of prostate and colorectal cancer PTEN1/MMAC1/TEP1 Phosphatase and 10q23. Protein 25%50 Cowden

AD

TENsin homolog 3 deleted on chromosome TEN

MSH2 MLH1AD

MutS Homolog protein 2 MutL Homolog protein1

2p2221 3p21.3

STK11/LKB1AD

Serine/Threonine 19p13. Protein Kinase 11 3

ATMAR

AtaxiaTelangiectasia Mutated

11q22. 3

BRIP1

BRCA1 17q22Interacting Protein q24 C-terminus helicase 1 Partner and Localizer of BRCA2 16p12. 1

PALB2AR

tyrosine % syndrome phosphatase R30%50% (lifetime) incidence of breast cancer; hamartoma, thyroid, oral mucosa, endometrial, and brain tumor DNA MMR Muir-Torre 12% (lifetime) syndrome DNA MMR Breast and colorectal carcinoma, gastrointestinal, genitourinary, and skin tumors Serine/threoniPeutz-Jeghers 29%54 ne kinase % syndrome R Breast, ovary, (lifetime) cervical, uterine, testicular, and colon carcinoma, hamartous polips DNA repair AtaxiaTwofold telangiectasia (higher in M Breast and women ovarian cancer, >50), 15% leukemia, of lymphomas, monoalleli immunodeficien c carriers cy, inconclusive will data on develop stomach, breast pancreas, and cancer bladder cancer DNA repair, FA-J Fanconi Twofold checkpoint Anemia (caused (higher in control by biallelic women mutations) <50) R Breast cancer DNA repair FA-N Fanconi Twofold Anemia (caused (higher in by biallelic women mutations) <50)

RAD50

NBS1

CASP8

TGFB1

predispose to childhood malignancies, including Wilms tumor and medulloblastom a, risk of prostate cancer R Breast cancer, bilateral and male breast cancer RAD50 homolog 5q31 DNA repair Nijmegen Fourfold (S. cerevisiae) Breakage syndrome (NBS) and lymphomas (caused by hypomorphic mutations) R Breast, ovarian and prostate cancers, leukemia, malignant melanoma Nijmegen 8q21 DNA repair Nijmegen Twofold Breakage Breakage Syndrome 1 syndrome (nibrin) (NBS) and lymphomas (caused by hypomorphic mutations) R Breast, gynecologic, stomach, and prostate cancers, leukemia, malignant melanoma M-F CASPase 8 2q33- Apoptosis Breast cancer 0.3% (Cysteineq34 (caused by (familial ASpartic acid genetic variants) risk) Protease 8) Transforming 19q13. Proliferation, FBreast cancer 0.2% Growth Factor 1 apoptosis (caused by (familial

Beta 1 FGFR2

Breast cancer 16% (caused by genetic variants) Crouzon syndrome, Pfeiffer syndrome, craniosynostosi s, Apert syndrome, Jackson-Weiss syndrome, BeareStevenson cutis gyrata syndrome, SaethreChotzen syndrome, and syndromic craniosynostosi s (caused by mutations) TNRC9/TOX3 TriNucleotide 16q12. Transcription Breast cancer 0.1% Repeat containing 1 (caused by (familial 9/TOX high genetic variants) risk) mobility group box family member/Hypothet ical protein MAP3K1/MEKK Mitogen5q11.2 Mitogenesis, Breast cancer 0.1% Activated Protein metabolism, (caused by (familial kinase kinase cell signaling genetic variants) risk) Kinase 1 LSP1/WP34/pp52/leuf Lymphocyte11p15. Cytoskeleton, Breast cancer 0.1% actin Specific Protein 1 5 adhesion, (caused by signal genetic variants) transduction CNS, central nervous system; AD, autosomal dominant; AR, autosomal recessive mode of inheritance; MMR, mismatch repair; R, rare, <1% population frequency; M, moderate, 1%5%; F, frequent >5%; bold indicates associated syndrome. P.1599

differentiatio n Fibroblast Growth 10q26 Mitogenesis, Factor Receptor 2 differentiatio n

genetic variants) risk)

More than 1,000 mutations have been identified in BRCA1 and BRCA2, and most of them result in the truncation of these proteins (catalogued mutations can be viewed at http://research.nhgri.nih.gov/bic/ or http://archive.uwcm.ac.uk/uwcm/mg/hgmd0.html). Genetic testing techniques for detecting BRCA1 and BRCA2 mutations are now well established,3 and a variety of assays for defective protein function have also been developed.15 Mutations in BRCA1 and BRCA2 cause genomic instability, which leads to alterations in additional key genes including TSGs and/or oncogenes (Table 43.1.2).8 When compared to sporadic breast cancers, familial breast cancers appear to have distinct phenotypes.16 Recent studies using comparative genomic hybridization and DNA microarray analyses in combination with immunohistochemistry (IHC) and fluorescence in situ hybridization suggest distinct genetic and immunophenotypic characteristics of these tumors as listed in Table 43.1.2. The pathology and molecular biology of tumors from BRCA1 versus BRCA2 mutation carriers differ from one another. Mutant BRCA1associated tumors display aggressive features, including early age of onset, high tumor grade, ER and progesterone receptor (PR) negativity, and a high proliferation rate.17,18,19 The BRCA1 phenotype is defined by markers of basal-like or triple negative breast cancer based on gene expression profiles. BRCA1-associated tumors are characterized by specific chromosomal gains and losses, overexpression of certain oncogenes (C-MYC and CMYB), cell-cycle proteins (cyclin E) and IHC markers of the basal epithelial phenotype (basal cytokeratins, epidermal growth factor receptor [EGFR], P-cadherin). Other important characteristics include loss of TP53, down-regulation of p27, and HER2 negativity (Table 43.1.2). Typical mutant BRCA2-associated tumors exhibit ER/PR pleomorphism and molecular features that are similar to those found in sporadic breast cancers. Nevertheless, the BRCA2 phenotype can also be characterized by specific chromosomal gains and losses, distinct gene expression profiles, and overexpression of the Aurora A oncogene (Table 43.1.2). Both BRCA1 and BRCA2 mutant breast cancers overexpress the TBX2 oncogene and generally exhibit a higher tumor grade than sporadic breast cancers. BRCA1, BRCA2, and DNA Repair Some breast cancers have a high degree of genomic instability; this instability is characterized by aneuploidy, large chromosomal gains and losses, microsatellite instability, chromosomal aberrations, DNA and centrosome amplification, and micronuclei formation. These DNA alterations occur due to the changes in molecular pathways regulating cell proliferation, differentiation, apoptosis, and DNA repair. Interestingly, DNA double-strand break repair occurs following error-free homology-directed recombination using a network of proteins that are also implicated in breast cancer syndromes, including ATM/ATR, TP53, CHK2, NBS1, BRCA1, and BRCA2. This suggests that defects in DNA doublestrand break repair are associated with a genetic predisposition to breast cancer. The association of BRCAs with DNA repair was first established by the seminal observation that BRCA1 colocalizes with the homologous recombinase RAD51 in subnuclear foci.20 Subsequent genetic analyses indicated that BRCA1 associates with protein complexes that participate in DNA repair pathways. Cells that lack BRCA1 or BRCA2 are unable to (1) sense DNA damage properly, (2) transmit and process the damage response signal, or (3) repair DNA damage by homology-directed recombination. Instead, such cells utilize nonconservative, error-prone, and potentially mutagenic mechanisms of nonhomologous end joining and single-strand annealing. This genomic instability most likely underlies the cancer predisposition caused by loss-of-function mutations in BRCA1 and BRCA2.21

There are convincing data showing that BRCA1 is an integral part of the repair process itself. A significant impairment of homology-directed recombination and increase in frequency of nonhomologous end joining has been observed in Brca1-deficient mouse embryonic stem cells and conditional mutants.14,22 This impairment can be corrected by reexpression of wild-type BRCA1. Mouse Brca1-deficient and human BRCA1-deficient tumor cells both exhibit significant genomic instability, gross chromosomal aberrations, and centrosome amplifications. Both BRCA1 and BRCA2 proteins are part of the Fanconi anemia (FA) protein complex. FA is a rare hereditary disorder characterized by bone marrow failure, compromised genomic stability, and increased incidence of cancer. The FA protein complex executes a specific pathway of homology-directed repair of DNA lesions that block replication forks. BRCA2 is the same as Fanconi anemia protein D1 (FANCD1). In response to DNA damage, a nuclear complex of five FA proteins (A, C, E, F, and G) interact with FANCL and cause ubiquitination of FANCD2. Ubiquitinated FANCD2 colocalizes with the BRCA2/RAD51/BRCA1 complex in DNA damage nuclear foci. The disruption of the FABRCA pathway due to defects in participating proteins results in an impaired response to DNA damage and increased cancer susceptibility.23 Tumor cells deficient in BRCA and FA genes (1) repair DNA damage by utilizing single strand annealing and non-homologous end joining mechanisms and (2) are particularly sensitive to interstrand crosslinks following treatment with interstrand crosslinkgenerating drugs (e.g., Mitomycin-C, cis-platinum, and its analogues). These pathways have been targeted for therapy (Table 43.1.3).24 DNA crosslinks caused by Mitomycin-C and the cis-platinum family of drugs block DNA replication and lead to stalled replication forks. Furthermore, poly(ADP-ribose) polymerase 1 (PARP1) inhibitors dramatically reduce repair of single-strand breaks and double-strand breaks in BRCAdeficient tumors, resulting in increased tumor sensitivity to DNA damaging agents such as cis-platinum.25 In normal cells heterozygous for BRCA the wild type BRCA allele is active and its protein product can repair double-strand breaks by error-free homology-directed recombination. As a result, treatment with PARP inhibitors is expected to be highly specific for cancer cells and yet nontoxic for healthy tissues. A number of clinical trials with PARP inhibitors have been initiated, including a phase II study of the efficacy and safety of the PARP inhibitor KU-0059436 for the treatment of BRCA-associated breast cancer. Epigenetics In addition to inherited mutations, sporadic breast cancers exhibit epigenetic mechanisms for inactivating several important DNA repair genes including BRCA1, ATM, CHK2, and P53. Epigenetics describes chromatin and DNA modifications that alter gene expression but do not involve changes in the underlying DNA sequence.25 This is in contrast to genetics, whereby alterations in the DNA sequence can cause a P.1600

P.1601 change in gene expression and/or encode an altered protein product. In cancer, the main epigenetic mechanisms underlying abnormal gene expression include aberrant CpG-islandpromoter methylation of specific TSGs, global changes in genomic DNA methylation, and

alterations in histone modification (deacetylation and methylation). These abnormalities can be reversed by inhibitors of both DNA methyltransferases and HDACs.25 Table 43.1.2 Molecular Alterations in Hereditary and Sporadic Breast Cancers Alteration (destination or frequency) Feature Modification Sporadic BRCA1-Mutated BRCA2-Mutated STEROID HORMONES AND GENES INVOLVED IN ENDOCRINE SIGNALING ER- Amplification/Expressi 21%/70%85% Unknown/20% Unknown/High, on 30% similar to sporadic PR Expression High, 56% Low, 20% High, similar to sporadic PS2 Expression High Low High AR Expression High, 66%80% Unknown Unknown GROWTH FACTOR RECEPTORS AND PROLIFERATION MARKERS EGFR Overexpression Low, 11%21% High, 60%70% Low, 8% HER2 Amplification/Overexp 15%/15%30% Rare, 0%/0%3% or ression 0%/0%3% similar to sporadica IGF-1R Overexpression 50%93% High Unknown Ki-67 Expression 22%48% High, 56%83% Low or similar to sporadica GLOBAL GENETIC LESIONS Ploidy Aneuploidy 4965% High, 87%95% 62% or similar to sporadica Chromoso Specific gains 1q, 5p, 8q, 16p, 3q23.3-24.2, 6p, 7p, 8q22-24, mal 19q, 20q 10p, 17q22-24 9p23-24, 17q24aberrations ter, 17q23.3-24.2, 20q13 Specific losses 1p, 3p, 6q, 7q, 11p, 3p, 3q, 4p, 4q, 5q, 6q, 9p, 11q, 13q 13q, 16q, 17p, 17q, 12q 18q, 22q Centrosom Amplification 10% (murine 25%30% 44%65% e model) (murine model) (murine model) aberrations Gene Up-regulation/DownSpecific set of Specific set of expression regulation 9176 genes 11176 genes profiles ONCOGENES C-MYC Amplification 5%30% High, 53% Up to 62% or similar to sporadica C-MYB Amplification 2% High, 29% Low, similar to sporadic C-MET Overexpression 20%60% Unknown Unknown TBX2 Amplification/Overexp 8% High, 46%62% 15%85% ression EMSY Amplification 13% Unknown Unknown

Aurora Amplification 10%22% Unknown High, 70% A/STK15/B TAK PI3KCA Mutation/Activation/E 24%/18%40%/7Unknown Unknown xpression 9% pAKT Activation/Expression 49%58% Unknown Unknown SGK-1 Expression 48% Unknown Unknown TUMOR SUPPRESSOR GENES, CELL CYCLE AND APOPTOTIC PROTEINS TP53 Mutation/Inactivation 17%35%/14% 42%68%/37% 29%64%/7% 35% 77% 45% or similar to sporadica Rb Inactivation 42% Low, 13% High, 40% RAD51 Loss 20% High, 42% 20% E-cadherin Expression 41% 50% 79% P-cadherin Expression Low, 0%26% High, 70%79% Similar to sporadic CHEK2 Expression Low, 11% High, 41% High, 40% PTEN Inactivation 27%48% Not reported Not reported P16 Expression 40% Similar to High, 87% or sporadic similar to sporadica P21 Expression 10% 35% or similar to 23% or similar to sporadica sporadica P27 Expression 41%60% Low, 20%a High, 72%80%a Cyclin A Overexpression 8% High, 20% Moderate, 15% or similar to sporadica Cyclin D1 Amplification/Overexp 10%15%/26% Unknown/Low, Unknown/High, ression 100% 0%33% 27%70% Cyclin D3 Overexpression 12% Low, 3% High, 30% or similar to sporadica Cyclin E Amplification/Overexp 9%27% High, 16%71% Low, 8%35% ression or similar to sporadica CDK4 Overexpression 28% Low, 7% High, 47% or similar to sporadica E2F-6 Expression 5% 25% 12% Active Expression 3% High, 32% Similar to caspase 3 sporadic Bcl-2 Overexpression 39%90% Low, 11%30% High, either or similar to 43%56% or a sporadic similar to sporadica MARKERS OF LUMINAL PHENOTYPE

Cytokerati Expression High Low High n 8/18 MARKERS OF BASAL/MYOEPITHELIAL PHENOTYPE P63 Expression Low High Low Cytokerati Expression Low, 3%8% High, 12%65% Low, 7%15% ns 5/6 Cytokerati Expression Low, 12% High, 61% Low, 24% n 14 Cytokerati Expression Low, 10% High, 53% Low, 7% n 17 Vimentin Expression Low, 6% High, 37% Low, similar to sporadic Osteonecti Expression Low, 19% High, 43% Low, 24% n Fascin Overexpression Low, 25% High, 83% Low, 17% Caveolin 1 Expression Low, 4% 22% 10%, similar to sporadic ER, estrogen receptor; PR, progesterone receptor; PS2, breast cancer estrogen-regulated protein, member of trefoil family of proteins; AR, androgen receptor; EGFR, epidermal growth factor receptor; IGF-1R, insulin-like growth factor-1 receptor. a Data conflicting. It has been postulated that promoter methylation may serve as the second hit in the Knudson two-hit model through inactivation of the normal allele of a TSG.26 Hypermethylation of BRCA1 at promoter CpG islands occurs in a subset of sporadic breast tumors27 and may serve as a first hit by inactivating one BRCA1 allele followed by loss of the second BRCA1. BRCA1 methylation in sporadic breast cancer appears to result in a similar tumor phenotype as that seen in tumors of BRCA1 mutation carriers.26,27,28,29 In contrast, BRCA2 loss of expression via aberrant promoter methylation does not appear to occur in sporadic cancers. Table 43.1.3 Biomarkers Used in Breast Cancer Treatment Class/Pathway Biomarker AbbreviationTherapeutic Opportunity Nuclear receptor Estrogen ER- Selective ER modulators (SERMs) pathways receptoralpha (tamoxifen) Histone deacetylase (HDAC) inhibitors (vorinostat) Progesterone PR Progesterone antagonists receptor Androgen receptor AR Androgen hormone Growth factor receptor Epidermal growth EGFR Abs, TKIs (gefitinib, lapatinib) pathways factor receptor HER2 Abs (trastuzumab), TKIs, HER2 Epidermal growth intracellular domain (ICD) peptidefactor receptor based vaccine type 2 Insulin-like growthIGF-1R Abs, TKIs factor-1 receptor DNA repair pathways Breast cancer gene BRCA1/2 Poly(ADP)-ribose polymerase 1 1 and 2 (PARP1) inhibitors, interstrand

Phosphatidylinositol Mammalian target mTOR 3-kinase (PI3K) of rapamycin pathway Angiogenesis Vascular VEGF Abs (bevacizumab), TKIs, endothelial growth zoledronic factor Abs, antibodies; TKIs, tyrosine kinase inhibitors. Both inherited and sporadic breast cancers can also exhibit variable ER- expression. Interestingly, ER- coding region mutations appear to be quite rare,30,31 although there is convincing evidence that ER- is an epigenetically regulated gene P.1602

crosslinksgenerating drugs (Mitomycin-C, cis-platinum, and its analogues), lovastatin mTOR inhibitors (rapamycin, CCI799)

that can undergo promoter methylation in a significant proportion of breast cancers.32 An alternative epigenetic mechanism underlying loss of ER- expression has been suggested by the results of cell-based assays analyzing histone function as a determinant of gene expression. Restoration of ER- expression by HDAC inhibitors suggests that reorganizing the heterochromatin-associated proteins, without demethylation per se, can restore functional ER- expression.33 This possibility is being explored clinically in an ongoing phase II trial of a new generation HDAC inhibitor, vorinostat (Table 43.1.3). The investigators of this trial will determine whether or not, following vorinostat treatment, a tumor becomes sensitive to hormonal therapy and/or exhibits increased expression of ER. In addition, there have recently been a number of phase I and II trials initiated to investigate combining different classes of HDAC inhibitors with traditional therapies for the treatment of breast cancer.34 It has been observed that DNA methylation of certain genes (e.g., RASSF1A, CYP26A1, KCNAB1, SNCA, HIN-1, TWIST, and Cyclin D2) occurs in both premalignant lesions, such as atypical hyperplasia, and carcinoma of the breast.35,36 These findings suggest that epigenetic changes occur early in breast tumorigenesis and may serve as potential markers for early detection or risk assessment. Moreover, specific epigenetic changes may have prognostic and/or predictive value.37 These observations are being translated into clinical care. For example, the National Cancer Institute is sponsoring a study of women at high risk for developing breast cancer who, following surgical resection for stage I to III invasive breast cancer, are treated with simvastatin. Simvastatin belongs to the statin family; these agents have a theoretical role in chemoprevention through down-regulating Ras, up-regulating p27, and altering ER levels. The change in methylation status across a panel of genes (ER- and ER-, cyclin D2, RAR-, Twist, RASSF1A, and HIN-1) that are known to be frequently and specifically hypermethylated in breast cancer will be evaluated and correlated with changes in C-reactive protein, lipid profile, contralateral breast density, and estrogen concentration. Breast Cancer Signaling Pathways Growth Factor Receptor Pathways Growth factor receptors play an essential role in initiating both proliferative and cell survival pathways in breast as well as other epithelia. In breast cancer biology, the EGFRs and insulin-like growth factor receptors have been studied most extensively. These

receptors have an extracellular ligand-binding region, a transmembrane region, and a cytoplasmic tyrosine kinasecontaining domain that can activate downstream signaling cascades. Growth factor receptors can be constitutively activated by either excessive ligand levels, activating mutations, or gene amplification/overexpression that ultimately leads to inappropriate kinase activity and growth promoting second messenger activation. EGFR (HER1, ErbB1) and HER2 (EGFR2 or ErbB2) appear to be particularly relevant receptors in breast cancer biology. For example, HER2 amplification and/or protein overexpression (found in 20% to 30% of invasive breast cancers) is clearly associated with accelerated cell growth and proliferation as well as an increased risk of disease recurrence with shortened overall patient survival.38 At a molecular level, HER2 amplification is associated with deregulation of G1/S phase cell cycle control via up-regulation of cyclins D1, E, and cdk6, as well as p27 degradation.39 HER2 also interacts with important second messengers including SH2 domain-containing proteins (e.g., Src kinases) that provide potential additional targets for breast cancer therapy. In several studies, HER2 amplification/overexpression in metastatic breast cancer has been shown to be an independent marker of response to the monoclonal anti-HER2 antibody, trastuzumab (Herceptin). In the adjuvant setting, five independent randomized studies have shown that the addition of trastuzumab to chemotherapy reduces the rate of recurrence by half among women with HER2-positive breast cancer.40 Interestingly, the reduction in risk of recurrence appears to be independent of hormone receptor status. Trastuzumab inhibits at least three major pathways regulating tumor growth. First, trastuzumab disrupts heterodimeric interaction of HER2 with other EGFR family members. Second, trastuzumab appears to modulate host immunity, activating natural killer cells involved in antibody-dependent cellular cytotoxicity. In animal models, mice bearing BT474 HER2-overexpressing xenografts exhibit a tumor regression rate of 96% when treated with trastuzumab, whereas mice lacking the Fc receptor (FcR /) lose much of the trastuzumab benefit, with only 29% inhibition.41 Furthermore, in 22 individuals treated with trastuzumab for metastatic disease, those patients showing objective clinical responses exhibited more frequent (P = .004) and larger (P = .006) treatment-associated anti-HER2 antibody responses.42 Third, trastuzumab also appears to decrease tumor-associated microvessel density,43 and in vitro, trastuzumab reduces endothelial cell migration, an important process for angiogenesis.44 HER2 receptors can also form heterodimers with other EGFRs, and, therefore, targeting HER2 and EGFR1 simultaneously may provide therapeutic synergy (Table 43.1.3).45 For example, tyrosine kinase inhibitors such as lapatinib compete with adenosine triphosphate to bind to the activation loop of target kinases, thereby inhibiting their activity. Lapatinib inhibits the tyrosine phosphorylation of both EGFR and HER2 and in turn inhibits activation of the pro-proliferative kinases ERK1/2 and AKT. Recently, a phase III trial evaluated the administration of the oral 5-fluorouracil prodrug capecitabine, with or without lapatinib, in the treatment of patients with HER2-positive locally advanced or metastatic breast cancer that was refractory to trastuzumab.48 This study showed a highly significant benefit to adding lapatinib to capecitabine, suggesting that resistance to specific HER2 inhibition can be overcome by inhibiting activation of both EGFR and HER2. In addition to activation of the EGFR pathway, signaling via insulin-like growth factor-1 (IGF-1) and its receptor (IGF-1R) can result in phosphorylation and activation of a variety of oncogenic kinases including PI3-K and HER2.22 IGF-1R is the primary response mediator of IGF and is expressed in all epithelial cell types.47 Adaptor molecules such as

insulin receptor substrate-1 mediate signaling of IGF-1 via tyrosine phosphorylation of the IGF-1R. Elevated IGF-1 levels have been implicated in breast cancer risk.48 P.1603

The IGF-1R has also been shown to be an effective target in several preclinical trials, and clinical trials examining IGF-1R inhibitors are currently under way. Two different antibodies against the IGF-1R are currently being evaluated in phase I trials. Monoclonal antibodies directed against the IGF-1R can initiate receptor internalization, effectively down-regulating IGF-1R levels on the cell surface.49 Thus, antibodies against IGF1-R provide inhibition of both IGF and insulin signaling in cancer cells.50 In addition, anti-IGF1R small molecule inhibitors have been developed, some of which, although not very specific, appear to be highly effective in preclinical studies (Table 43.1.3). In fact, inhibition of IGF-1R and the EGFRs may prove to be a useful combination. Hormonal Regulation The degree of exposure to estrogen is a well-established risk factor for developing ERpositive breast cancer. Estrogen is a steroid hormone that has a profound proliferative effect on normal human mammary epithelium through its activation of ER-, a classic nuclear hormone receptor. ER- is overexpressed in as many as 70% of breast cancers; amplification of the ER- gene appears to be a prominent mechanism,51 although it does not account for all cases of ER- overexpression. Today, ER- remains a very effective biologic target for breast cancer treatment and prevention, and antiestrogens are incorporated into the recommended treatment of all ER--expressing tumors (Table 43.1.3). Estrogen exerts its actions through both genomic and nongenomic mechanisms. Genomic action refers to the transcriptional regulation of specific target genes by the ligand bound and dimerized ER-. Activated ER- dimers direct selective gene expression through binding to regulatory regions known as estrogen response elements. These regions direct the estrogen-mediated transcription of several growth-promoting genes including cyclin D1 and MYC. In contrast to the genomic actions of ER-, its nongenomic actions of ER- are extremely rapid (within seconds to minutes of estrogen exposure) and are believed to result from the hormone-dependent activation of membrane-bound and/or cytosolic ERs. These nonnuclear ER actions result in very rapid phosphorylation and activation of important growth regulatory kinases including EGFRs, IGF-1R, c-Src, Shc, and the p85- regulatory subunit of PI3-K.52 This crosstalk between ER- and growth factor receptors is bidirectional: constitutive HER2, for example, can increase ER- signaling to the point where it is unresponsive to antiestrogen treatments. This experimental finding suggests a role for HER2/IGF-1R/EGFR activation in both acquired and de novo resistance to treatment with antiestrogens.53 Tamoxifen is a selective ER modulator that binds to ER- and prevents its coactivator recruitment to DNA. However, de novo and acquired tamoxifen resistance is quite common. Predicting the likelihood of response to tamoxifen on the basis of a tumor's molecular characteristics is an area of intense interest; this issue is perhaps particularly relevant to women with ER--positive breast cancer for whom the question of whether or not to add toxic chemotherapy to their antiestrogen-based treatment plan is often difficult. Recently, the first breast cancer multigene expression assay (which uses real-time reverse-

transcriptase polymerase chain reaction to evaluate a panel of 21 genes implicated in breast cancer biology) was approved by the U.S. Food and Drug Administration (FDA) for women with ER--positive, early stage invasive breast cancer.54 The combined results of the quantitative reverse transcriptase-polymerase chain reactions generate a likelihood of recurrence score. This score has prognostic value regarding the overall risk of breast cancer recurrence and also has a specific predictive value regarding the likely benefit from adding adjuvant chemotherapy to tamoxifen therapy. In addition, to the 21-gene test described above, several other gene-expression tests are in various stages of clinical development as molecular prognostic and predictive tests for breast cancer.55 For example, recently the FDA approved a 70-genebased MammaPrint test that helps predict breast cancer recurrence. A major ongoing European trial is now examining whether or not a 70gene expression test is a valid predictor for adjuvant chemotherapy benefit in node-negative breast cancer.56 PI3-K Pathway The phosphatidylinositol 3-kinase (PI3-K) pathway is activated in response to a number of events that result in increased breast cancer cell growth and proliferation. Activating mutations in the gene encoding the p110- catalytic subunit of PI3-K (PI3CKA) may be an important contributing factor to mammary tumor progression.57 Activating mutations of the AKT gene family are rare. PTEN dephosphorylates, and therefore inactivates, the p110 catalytic domain of PI3-K and is either mutated or underexpressed (e.g., via methylation) in many breast cancers. Activation of the PI3-K pathway, in turn, results in the 3-phosphoinositide-dependent kinase-mediated activation of several known kinases including AKT1, AKT2, and AKT3. Interestingly, activated AKT1 appears to be antiapoptotic but also plays an anti-invasive role in tumor formation.58 In addition to the AKTs, downstream proliferative effectors of the PI3-K pathway also include the mTOR complex 1 (TORC1), which consists of mTOR, Raptor, and mLst8. It is currently believed that TORC1 mediates its progrowth effects through the activation of S6kinase1 and suppression of 4E-BP1, an inhibitor of cap-dependent translation.59 These observations all point to mTOR-Raptor as a critical target in cancer therapy, and indeed, mTOR inhibitors known as rapamycin analogues (CCI-779, RAD001, AP23576) are currently undergoing clinical trials for the treatment of breast cancer (Table 43.1.3). However, recent data suggest that inhibition of mTOR in cancer cell lines and in patient tumors is associated with induction of insulin receptor substrate-1 activity that can, in turn, be prevented by IGF-IR inhibition. IGF-I antagonizes the antiproliferative effects of rapamycin in serum-free medium, and IGF-IR inhibitors sensitize cancer cell lines to rapamycin's antiproliferative effects. This has led to current phase II trials examining the efficacy of combined mTOR and IGF-1R inhibition. Angiogenesis Tumor angiogenesis has become a frequent target for treatment of many cancers. In addition to endothelial cells, breast cancer cells themselves express the vascular endothelial growth P.1604 factor receptors (VEGFRs).60 VEGFRs, like EGFRs, are also tyrosine kinase receptors. VEGF-A binds to both VEGFR1 (Flt-1) and VEGFR2 (KDR/Flk1). VEGFR2 appears to mediate almost all of the known cellular responses to VEGFs, while the function of

VEGFR1 is less well-defined. Bevacizumab is a humanized monoclonal antibody directed against VEGF- and has been shown in preclinical studies to reduce angiogenesis (Table 43.1.3).61 In a randomized study, the addition of bevacizumab to paclitaxel as first-line therapy in metastatic breast cancer increased the overall response rate from 21.2% to 36.9%.62 Small molecular inhibitors of VEGFR tyrosine kinase activity, such as sunitinib, have proven effective in other cancers and may have clinical efficacy in breast cancer also.63 Molecular Characterization of Breast Cancer Subtypes Human mammary glands contain two distinct subtypes of epithelial cells, basal (myoepithelial) and luminal, which can be easily distinguished by the pattern of expression of certain cytokeratins. The cytokeratin pattern is largely conserved after transformation of epithelial cells, allowing determination of the cell-type origin of the primary carcinoma. Most breast cancers originate from luminal epithelium and express luminal cell-specific cytokeratins. However, 3% to 15% of all breast cancers appear to originate from basal-like epithelium because they express basal-specific cytokeratins and represent a more aggressive group of tumors.64 cDNA microarrays offer a systematic method to perform genome-wide extensive expression profiling for a single cancer specimen. Perou et al.65 and Sorlie et al.66 used cDNA microarrays followed by IHC in an attempt to classify breast cancers based on global gene-expression patterns. They found that breast cancers encompass at least five biologically distinct subtypes of tumors, including ER-negative/basal-like tumors (positive for cytokeratins 5/6 and 17), ER-negative/basal-like/HER2-positive tumors, and ERpositive/ luminal-like tumors (positive for cytokeratins 8 and 18). Following the original reports identifying signatures of gene expression for breast cancer, several other groups confirmed that individual cancers could be categorized based on their gene signature. As discussed above, current translational gene expression studies are designed to analyze tumors for their gene expression and determine which patterns represent breast cancers that are likely to respond to chemotherapy. Given that BRCA1-associated tumors are negative for both ER and HER267,68 and that 80% have a basal-like gene-expression profile,28,69 it has been suggested that such tumors have a myoepithelial, rather than luminal, epithelial cell origin. Several groups have used IHC to confirm that the expression of cytokeratins 5/6 is significantly associated with BRCA1mutated breast cancers.70,71 The analysis of tumors from BRCA2 mutation carriers suggests that these tumors are of luminal epithelial origin (Table 43.1.2).69,71,72 Conventional histopathologic and molecular studies of breast cancers with the basal/myoepithelial pattern have shown that these tumors are often high-grade, lymph nodenegative, medullary type, have areas of necrosis, show a distinct pattern of genetic alterations, and have a distinct population-based distribution.47,73 Subsequent efforts have been directed toward the development of a precise set of basal markers that define this type of carcinoma. In addition to basal and luminal subtypes, breast cancer stem cells have been identified within human breast cancers. Breast stem cells are multipotent and can self-renew, which are key characteristics of stem cells, and a single cell enriched with cell surface markers has the ability to grow into a fully functional mammary gland in vivo.74 How stem cells differentiate into specific subtypes of breast epithelium, and in turn may be precursors to diverse breast cancer subtypes, is the subject of intense investigation. Conclusions

In the 19th century, Beatson showed that estrogen has an important function in breast cancer growth. A century later, HER2 overexpression was identified in a subset of breast cancers and has been shown to be a sensitive target for inhibiting growth factor pathways via the monoclonal antibody trastuzumab. Based on these examples, it is clear that subsets of human breast cancers acquire specific and critical growth promoting pathways that can be targeted using precise interventions (Table 43.1.3). In addition to the single overexpression of a growth promoting gene, many breast cancers demonstrate a signature of gene expression that correlates with the phenotype of a particular breast cancer. These signatures are being used to determine whether chemotherapy may be an effective adjuvant to localized treatment. The use of these gene signatures is being tested in cooperative group trials, while many individual laboratories are working on identifying additional markers of breast cancer that go beyond ER and HER2. In hereditary breast cancer, the identification of additional susceptibility genes will require the collaborative efforts of research groups using high throughput methods and advanced technologies based on genome-wide association studies. In addition, the role of environment in affecting gene expression and phenotype will need to be incorporated into molecular epidemiological models. Such geneenvironment studies will require the development of novel interdisciplinary approaches and include experts in genomics, epidemiology, biology, and clinical oncology. References 1. Antoniou AC, Easton DF. Models of genetic susceptibility to breast cancer. Oncogene 2006;25(43):5898. 2. Wooster R, Weber BL. Breast and ovarian cancer. N Engl J Med 2003;348(23):2339. 3. Walsh T, King MC. Ten genes for inherited breast cancer. Cancer Cell 2007;11(2):103. 4. Cox A, Dunning AM, Garcia-Closas M, et al. A common coding variant in CASP8 is associated with breast cancer risk. Nat Genet 2007;39(3):352. 5. Easton DF, Pooley KA, Dunning AM, et al. Genome-wide association study identifies novel breast cancer susceptibility loci. Nature 2007;447(7148):1087. 6. Hunter DJ, Kraft P, Jacobs KB, et al. A genome-wide association study identifies alleles in FGFR2 associated with risk of sporadic postmenopausal breast cancer. Nat Genet 2007;39(7):870. 7. Pharoah PD, Tyrer J, Dunning AM, Easton DF, Ponder BA. Association between common variation in 120 candidate genes and breast cancer risk. PLoS Genet 2007;3:e42. 8. Couch FJ, Weber BL. Breast cancer. In: The genetic basis of human cancer. Vogelstein B, Kinzler KW, eds. New York: McGraw-Hill, NY, 2002;549581. 9. Parvin JD, Sankaran S. The BRCA1 E3 ubiquitin ligase controls centrosome dynamics. Cell Cycle 2006;5(17):1946. 10. Deng CX. BRCA1: cell cycle checkpoint, genetic instability, DNA damage response and cancer evolution. Nucleic Acids Res 2006;34(5):1416. P.1605

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53. Knowlden JM, Hutcheson IR, Jones HE, et al. Elevated levels of epidermal growth factor receptor/c-erbB2 heterodimers mediate an autocrine growth regulatory pathway in tamoxifen-resistant MCF-7 cells. Endocrinology 2003;144(3):1032. 54. Paik S, Shak S, Tang G, et al. A multigene assay to predict recurrence of tamoxifentreated, node-negative breast cancer. N Engl J Med 2004;351(27):2817. 55. Pusztai L, Cristofanilli M, Paik S. New generation of molecular prognostic and predictive tests for breast cancer. Semin Oncol 2007;34(2):S10. 56. Sotiriou C, Piccart MJ. Taking gene-expression profiling to the clinic: when will molecular signatures become relevant to patient care? Nat Rev Cancer 2007;7(7):545. 57. Bachman KE, Argani P, Samuels Y, et al. The PIK3CA gene is mutated with high frequency in human breast cancers. Cancer Biol Ther 2004;3(8):772. 58. Toker A, Yoeli-Lerner M. Akt signaling and cancer: surviving but not moving on. Cancer Res 2006;66(8):3963. 59. Fingar DC, Blenis J. Target of rapamycin (TOR): an integrator of nutrient and growth factor signals and coordinator of cell growth and cell cycle progression. Oncogene 2004;23(18):3151. 60. Nakopoulou L, Stefanaki K, Panayotopoulou E, et al. Expression of the vascular endothelial growth factor receptor-2/Flk-1 in breast carcinomas: correlation with proliferation. Hum Pathol 2002;33(9):863. 61. Kim KJ, Li B, Winer J, et al. Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo. Nature 1993;362(6423):841. 62. Wang M, Gralow J, et al. Paclitaxel plus bevacizumab versus paclitaxel along for metastatic breast cancer. N Eng J Med 2007;357(26):2666. 63. Hayes DF, Miller K, Sledge G. Angiogenesis as targeted breast cancer therapy. Breast 2007;16(Supp12):17. 64. Malzahn K, Mitze M, Thoenes M, Moll R. Biological and prognostic significance of stratified epithelial cytokeratins in infiltrating ductal breast carcinomas. Virchows Arch 1998;433(2):119. 65. Perou CM, Sorlie T, Eisen MB, et al. Molecular portraits of human breast tumours. Nature 2002;406(6797):747. 66. Sorlie T, Perou CM, Tibshirani R, et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci U S A 2001;98(19):10869. 67. Grushko TA, Blackwood MA, Schumm PL, et al. Molecular-cytogenetic analysis of HER-2/neu gene in BRCA1-associated breast cancers. Cancer Res 2002;62(5):1481. 68. Lakhani SR, Reis-Filho JS, Fulford L, et al. Prediction of BRCA1 status in patients with breast cancer using estrogen receptor and basal phenotype. Clin Cancer Res 2005;11(14):5175. 69. Sorlie T, Tibshirani R, Parker J, et al. Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci U S A 2003;100(14):8418. 70. Foulkes WD, Stefansson IM, Chappuis PO, et al. Germline BRCA1 mutations and a basal epithelial phenotype in breast cancer. J Natl Cancer Inst 2003;95(19):1482. 71. Laakso M, Loman N, Borg A, Isola J, et al. Cytokeratin 5/14-positive breast cancer: true basal phenotype confined to BRCA1 tumors. Mod Pathol 2005;18(10):1321. 72. Lacroix M, Leclercq G. The portrait of hereditary breast cancer. Breast Cancer Res Treat 2005;89(3):297.

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Section 2: Malignant Tumors of the Breast Harold J. Burstein Jay R. Harris Monica Morrow Breast cancer is a major public health problem for women throughout the world. In the United States, breast cancer remains the most frequent cancer in women and the second most frequent cause of cancer death. In 2007 it is estimated that breast cancer will account for 26% of cancer cases and 15% of cancer deaths, which translates to 176,296 new cases and 40,515 deaths.1 Breast cancer was also the most common form of cancer seen in Europe in 2006, with 429,900 new cases, representing 13.5% of all new cancers.2 Since 1990, the death rate from breast cancer has decreased in the Unites States by 24% and similar reductions have been observed in other countries.3,4 Mathematical models suggest that both the adoption of screening mammography and the availability of adjuvant chemotherapy and tamoxifen have contributed approximately equally to this improvement.5 Although breast cancer has traditionally been less common in nonindustrialized nations, its incidence in these areas is increasing. This chapter examines the salient features of breast cancer, stressing practical information of importance to clinicians and the results of prospective randomized trials that guide therapeutic decisions. Anatomy of the Breast The adult female breast lies between the second and sixth ribs and between the sternal edge and the midaxillary line. The breast is composed of skin, subcutaneous tissue, and breast tissue, with the breast tissue including both epithelial and stromal elements. Epithelial elements make up 10% to 15% of the breast mass, with the remainder being stroma. Each breast consists of 15 to 20 lobes of glandular tissue supported by fibrous connective tissue. The space between lobes is filled with adipose tissue, and differences in the amount of adipose tissue are responsible for changes in breast size. The blood supply of the breast is derived from the internal mammary and lateral thoracic arteries. The breast lymphatic drainage occurs through a superficial and deep lymphatic plexus, and more than 95% of the lymphatic drainage of the breast is through the axillary lymph nodes, with the remainder via the internal mammary nodes. The axillary nodes are variable in number and have traditionally been divided into three levels based on their relationship to the pectoralis minor muscle, as illustrated in Figure 43.2.1. The internal mammary nodes are located in the first six intercostal spaces within 3 cm of the sternal edge, with the highest concentration of internal mammary nodes in the first three intercostal spaces. Risk Factors for Breast Cancer Multiple factors are associated with an increased risk of developing breast cancer, including increasing age, family history, exposure to female reproductive hormones (both endogenous and exogenous), dietary factors, benign breast disease, and environmental factors. The majority of these factors convey a small to moderate increase in risk for any

individual woman. It has been estimated that approximately 50% of women who develop breast cancer have no identifiable risk factor beyond increasing age and female gender. The importance of age as a breast cancer risk factor is sometimes overlooked. In 2005 it is estimated that 9,510 invasive breast cancers and 1,110 breast cancer deaths occurred in U.S. women under age 40 compared to 165,460 cancers and 34,820 deaths in women aged 50 years and older.1 Familial Factors A family history of breast cancer has long been recognized as a risk factor for the disease. The majority of women diagnosed with breast cancer do not have a family member with the disease, P.1607 and only 5% to 10% have a true hereditary predisposition to breast cancer. Many women with a positive family history overestimate their risk of developing breast cancer, and women considering genetic testing have been shown to overestimate their chance of having a mutation. Overall, the risk of developing breast cancer is increased 1.5- to threefold if a woman has a mother or sister with breast cancer. Family history, however, is a heterogeneous risk factor with different implications depending on the number of relatives with breast cancer, the exact relationship, the age at diagnosis, and the number of unaffected relatives. For example, there may be a minimal elevation in breast cancer risk for a woman whose mother was diagnosed with breast cancer at an advanced age and who has no other family history of the disease. In contrast, a woman who has multiple family members diagnosed with early onset breast cancer is at a much higher risk of developing the disease. Even in the absence of a known inherited predisposition, women with a family history of breast cancer face some level of increased risk, likely from some combination of shared environmental exposures, unexplained genetic factors, or both.

Figure 43.2.1. Lymphatic drainage of the breast showing lymph node groups and levels. 1. Internal mammary artery and vein; 2. Substernal cross-drainage to contralateral internal mammary lymphatic chain; 3. Subclavius muscle and Halsted ligament; 4. Lateral pectoral nerve (from the lateral cord); 5. Pectoral branch from thoracoacromial vein; 6. Pectoralis minor muscle; 7. Pectoralis major muscle; 8. Lateral thoracic vein; 9. Medial pectoral nerve (from the medial cord); 10. Pectoralis minor muscle; 11. Median nerve; 12. Subscapular vein; 13. Thoracodorsal vein. A. Internal mammary lymph nodes; B. Apical lymph nodes; C. Interpectoral (Rotter) lymph nodes; D. Axillary vein lymph nodes; E. Central lymph nodes; F. Scapular lymph nodes; G. External mammary lymph nodes; Level I lymph nodes: lateral to lateral border of pectoralis minor muscle; Level II lymph nodes: behind pectoralis minor muscle; Level III lymph nodes: medial to medial border of pectoralis minor muscle. Inherited Predisposition to Breast Cancer Mutations in the breast cancer susceptibility genes BRCA1 and BRCA2 are associated with a significant increase in the risk of breast and ovarian carcinoma and account for 5% to 10% of all breast cancers. These mutations are inherited in an autosomal dominant fashion and have varying penetrance. As a result, the estimated lifetime risk of breast cancer development in mutation carriers ranges from 26% to 85%, and the risk of ovarian cancer from 16% to 63% and 10% to 27%, respectively in carriers of BRCA1 and BRCA2.6 More than 700 different mutations of BRCA1 and 300 different mutations of BRCA2 have been described, and the position of the mutation within the gene has been shown to influence the risk of both breast and ovarian cancers, with an increased risk of ovarian carcinoma among BRCA1 carriers with mutations in the 5 two thirds of the gene and an increased risk of ovarian carcinoma among BRCA2 carriers with mutations between nucleotides 40756503. Other cancers associated with BRCA1 or BRCA2 mutations include male breast cancer, fallopian tube cancer, and prostate cancer. Carriers of BRCA2 may also have an elevated risk of melanoma and gastric cancer. There is a great interest in the role of environmental and lifestyle factors in the modification of cancer risk among BRCA1 or BRCA2 carriers. At present, the available data are inconsistent and suggest that modifiers of risk may vary between BRCA1 and BRCA2 carriers. For example, Cullinane et al.7 demonstrated that in BRCA1 carriers pregnancy was not associated with a reduction in breast cancer risk until after four births, while each additional pregnancy after the first birth was associated with an increased breast cancer risk in BRCA2 carriers. The histologic features of cancers arising in women with BRCA1 mutations differ from those occurring sporadically, with a higher incidence of medullary features and a higher proportion of grade 3 tumors. The proportion of BRCA1 cancers expressing the estrogen (ER) or progesterone receptor (PR) is lower than is seen in sporadic cancers, and HER-2 overexpression is infrequent.8 This triple negative pattern is consistent with the basal cell phenotype. In contrast, it is not clear that the phenotype of BRCA2 cancers differs from that seen in sporadic cancers, although some studies have suggested an excess of tubular and lobular carcinomas. The presence of a BRCA1 or BRCA2 mutation may be suggested by the family history on either the maternal or paternal side of the family. The features considered by the 2005 U.S. Preventive Services Task Force9 are listed in Table 43.2.1. Less rigorous criteria for referral for genetic counseling are used for individuals of Ashkenazic Jewish ancestry because the carrier frequency of specific BRCA1 (187delAG, 5385 ins C) and BRCA2 (6174delT) mutations in this group is 1:40 compared to 1:500 in the general population. These guidelines are particularly useful for individuals not affected with breast cancer. In the

newly diagnosed breast cancer patient, young age at diagnosis (40 years or less), bilateral breast cancer, Ashkenazic ancestry, or a malignancy consistent with the BRCA1 phenotype all constitute reasons for referral to a genetic counselor, particularly in the woman with a small number of female relatives. The therapeutic implications of a BRCA1 or BRCA2 mutation in the woman with breast cancer are discussed later in this chapter. Genetic testing should be preceded by a careful evaluation of an individual's personal cancer history and family history. Models are available to estimate the likelihood of a BRCA1 or BRCA2 mutation based on family history. The implications of genetic testing for both individuals and their family members are considerable, and these issues should be discussed prior to undertaking genetic testing. Other genetic mutations have been associated with breast cancer risk, although to a much lesser extent than BRCA1 and BRCA2. TP53 and PTEN each account for fewer than 1% of cases. Mutations in low penetrance genes are thought to account for a significant number of nonBRCA1 or BRCA2 breast cancers. A specific mutation of the checkpoint kinase 2 (CHEK2) gene was found in 11.4% of families with three or more cases of breast cancer diagnosed before age 60,10 but in a large study of 10,860 unselected breast cancer patients from five countries the CHEK2 mutation was identified in only 1.9% of cases11 and 0.7% of controls (odds ratio [OR] 2.34). At this time, due to the low penetrance of this gene, genetic counseling and testing for CHEK2 is considered premature. Table 43.2.1 Factors Suggestive of BRCA1 or BRCA2 Mutation NON-ASHKENAZIC JEWISH WOMEN Two first-degree relativesa with breast cancer, one diagnosed 50 years Three or more first- or second-degree relatives with breast cancer, any age Breast and ovarian cancer among first- and second-degree relatives First-degree relative with bilateral breast cancer Breast cancer in a male relative Two or more first- or second-degree relatives with ovarian cancer ASHKENAZIC JEWISH WOMEN First-degree relative with breast or ovarian cancer Two second-degree relatives with breast or ovarian cancer a Relatives on the same side of the family. P.1608

Hormonal Factors The development of breast cancer in many women appears to be related to female reproductive hormones. Epidemiologic studies have consistently identified a number of breast cancer risk factors associated with increased exposure to endogenous estrogens. Early age at menarche, nulliparity or late age at first full-term pregnancy, and late age at menopause increase the risk of developing breast cancer. In postmenopausal women, obesity and postmenopausal hormone replacement therapy, both of which are positively correlated with plasma estrogen levels and plasma estradiol levels, are associated with increased breast cancer risk. Furthermore, in utero exposure to high concentrations of estrogen may also increase breast cancer risk. Most hormonal risk factors have a relative risk of 2.0 or less for breast cancer development.

The age-specific incidence of breast cancer increases steeply with age until menopause. After menopause, although the incidence continues to increase, the rate of increase decreases to approximately one sixth of that seen in the premenopausal period. The dramatic slowing of the rate of increase in the age-specific incidence curve suggests that ovarian activity plays a major role in the etiology of breast cancer. There is substantial evidence that estrogen deprivation via iatrogenic premature menopause can reduce breast cancer risk. Epidemiologic studies have shown that premenopausal women who undergo oophorectomy without hormone replacement have a markedly reduced risk of breast cancer later in life. Oophorectomy before age 50 decreases breast cancer risk, with an increasing magnitude of risk reduction as the age at oophorectomy decreases.12 Data from women with BRCA1 and BRCA2 mutations suggest that early oophorectomy has a substantial protective effect on breast cancer risk in this population as well.13 Age at menarche and the establishment of regular ovulatory cycles are strongly linked to breast cancer risk. Earlier age at menarche is associated with an increased risk of breast cancer; there appears to be a 20% decrease in breast cancer risk for each year that menarche is delayed. Of note, hormone levels through the reproductive years in women who experience early menarche may be higher than in women who undergo a later menarche.14 Additionally, late onset of menarche results in a delay in the establishment of regular ovulatory cycles, although there is some controversy over whether this delay confers any additional protective effect. From these data regarding menarche and menopause, it seems likely that the total duration of exposure to endogenous estrogen is an important factor in breast cancer risk. The relationship between pregnancy and breast cancer risk appears more complicated. Based on epidemiologic studies, women whose first full-term pregnancy occurs after age 30 have a two- to fivefold increase in breast cancer risk in comparison with women who have a first full-term pregnancy before approximately age 18.14,15 Nulliparous women are at greater risk for the development of breast cancer than parous women, with a relative risk of about 1.4. Breast cancer risk increases transiently after a pregnancy. The increased risk, which lasts approximately 10 years, is then associated with a more durable protective effect.15 The reason for the increased risk may be the increased proliferation that precedes terminal differentiation before lactation. Alternatively, risk may increase secondarily to the effect of high levels of hormones on subclinical cancers. Abortion, whether spontaneous or induced, does not appear to increase breast cancer risk.16 The use of combined estrogen and progestin hormone replacement therapy (HRT) also increases breast cancer risk. In the Women's Health Initiative (WHI), 16,688 postmenopausal women aged 50 to 79 years with an intact uterus were randomly assigned to receive conjugated equine estrogen (0.625 mg) and medroxyprogesterone acetate (2.5 mg) daily or placebo. When compared to placebo, the use of HRT was associated with a hazard ratio of 1.24 (P <.001) for breast cancer development.17 The effects of HRT were noted after a relatively short duration of use. An excess of abnormal mammograms was observed after 1 year of HRT use and persisted throughout the study, and an increase in breast cancer incidence was noted after 2 years. The cancers occurring in HRT users were larger and more likely to have nodal or distant metastases than those occurring in the placebo group (25.4% vs. 16%; P = .04), although they were of similar histology and grade.17 The findings of the WHI are supported by the results of the Million Women Study, an observational study of 1,084,110 women in the United Kingdom. In this study, current

use of HRT was associated with a relative risk of breast cancer development of 1.66 (P <.001) and a relative risk of breast cancer death of 1.22 (P = .05).18 Dietary and Lifestyle Factors The observation that there is a large international variation in breast cancer incidence, with countries with high fat diets having higher rates of breast cancer than those with diets lower in fat, suggested that high fat intake might be associated with increased breast cancer risk. However, pooled analysis of seven prospective epidemiologic studies failed to identify an association between fat intake and breast cancer risk in adult women in developed countries.19 There may be a moderate protective effect from high vegetable consumption, but results for fruit, fiber, and meat consumption are inconclusive. In contrast, there appears to be a positive association between alcohol and breast cancer risk, with risk increasing linearly with the amount of alcohol consumed.20 Decreased intake of nutrients such as vitamin C, folate, and -carotene may enhance the risk related to alcohol consumption. Obesity is associated with both an increased risk of breast cancer development in postmenopausal women and increased breast cancer mortality. In the placebo arm of the WHI study, women with a body mass index (BMI) of 31.1 or higher had a 2.5-fold greater risk of developing breast cancer than those with a BMI of 22.6 or lower.17 The greatest risk of postmenopausal breast cancer development appears to be associated with weight gain in adult life prior to the menopause. In premenopausal women there is actually an inverse relationship between BMI and breast cancer risk, which is thought to be due to the greater number of irregular menstrual cycles, with decreased exposure to ovarian hormones, seen in heavier premenopausal women.21 Benign Breast Disease Benign breast lesions are classified as proliferative or nonproliferative. Nonproliferative disease is not associated with an increased risk of breast cancer, whereas proliferative disease without atypia results in a small increase in risk (relative risk P.1609 [RR], 1.5 to 2.0). Proliferative disease with atypical hyperplasia is associated with a greater risk of cancer development (RR, 4.0 to 5.0).22 Dupont and Page23 found a marked interaction between atypia and a family history of a first-degree relative with breast cancer. This subgroup of patients had a risk 11-fold that of women with nonproliferative breast disease. The absolute risk of breast cancer development in women with a positive family history and atypical hyperplasia was 20% at 15 years, compared with 8% in women with atypical hyperplasia and a negative family history of breast carcinoma. Proliferative breast disease appears to be more common in women with a significant family history of breast cancer than in controls, further supporting its significance as a risk factor. Of note, however, the majority of breast biopsies done for clinical indications demonstrate nonproliferative disease. In the study of 10,000 breast biopsies by Dupont and Page,23 69% had nonproliferative changes and only 3.6% demonstrated atypical hyperplasia. No increased risk of breast cancer development has been observed in women with a diagnosis of proliferative disease who have used estrogens after breast biopsies. Table 43.2.2 Magnitude of Risk of Known Breast Cancer Risk Factors Relative Risk <2 Relative Risk 24 Relative Risk >4 Early menarche One first-degree relative Mutation BRCA1 or with BRCA2 Late menopause breast cancer LCIS

Nulliparity Estrogen plus progesterone

CHEK2 mutation Age >35 first birth

Atypical hyperplasia Radiation exposure before 40

HRT Proliferative breast disease Alcohol use Postmenopausal Mammographic breast obesity density HRT, hormone replacement therapy; LCIS, lobular carcinoma in situ. Breast Density Mammographic breast density has emerged as an important predictor of breast cancer risk, in addition to making the detection of cancer more difficult. A significant component of breast density is genetically determined, although density has also been shown to vary with the initiation and discontinuation of postmenopausal HRT. In a case control study of 1,112 case control pairs undergoing screening mammography, women with more than 75% breast density had a 4.7-fold increase in the odds of breast cancer development compared to those with less than 10% breast density (95% confidence interval [CI], 2.0 to 6.2).24 The risk was apparent even after adjustment for other risk factors. Environmental Factors Exposure to ionizing radiation increases breast cancer risk, and the increase is particularly marked for exposure at a young age. This pattern has been observed in survivors of the atomic bombings, those undergoing multiple diagnostic x-ray examinations, and in women receiving therapeutic irradiation.25 A markedly increased risk of breast cancer development has been reported in women who received mantle irradiation for the treatment of Hodgkin's lymphoma before age 15 years. Other environmental factors, including exposure to electromagnetic fields and organochlorine pesticides, have been suggested to increase breast cancer risk, but convincing documentation from well-conducted studies is lacking. A summary of the magnitude of risk associated with known breast cancer risk factors is provided in Table 43.2.2. Management of the High-Risk Patient A woman's risk of developing breast cancer is influenced by a number of factors. There is no formal definition of what constitutes high risk. Without question, women who carry mutations in either BRCA1 or BRCA2 or who have a family history consistent with genetically transmitted breast cancer are considered to be at higher risk than those in the general population. A second and much less common group of high-risk women consists of those individuals who have received mantle irradiation, usually for treatment of Hodgkin's lymphoma. Women with lobular carcinoma in situ (LCIS) or atypical hyperplasia on breast biopsy are also considered at high risk. Although a variety of hormonal factors (e.g., early menarche, late age at first full-term pregnancy) affect breast cancer risk on a population basis, these conditions have a relatively small effect on risk for any individual woman. In approaching women concerned about breast cancer risk, it is important to recognize that many women overestimate their risk of developing breast cancer. Providing women with an accurate assessment of breast cancer risk may have a number of benefits, including allaying anxiety and facilitating management decisions. The first step in determining a woman's risk of developing breast cancer is to take a thorough history, evaluating for the presence of known risk factors. Of these, family history, age, and the presence of a premalignant lesion on previous breast biopsy are probably the most significant. Because of the substantially higher risk of identifying a BRCA1 or BRCA2 mutation in women of Ashkenazic Jewish descent, ethnic background should also be established. It can be helpful to provide women

who are concerned about their breast cancer risk with a numeric risk estimate. A number of models for risk assessment are available, of which the Gail et al.26 model and a model developed by Claus et al.27 from the Cancer and Steroid Hormone Study are the most frequently used. The Gail et al. model, which calculates a woman's risk of developing breast cancer based on age at menarche, age at first live birth, number P.1610 of previous breast biopsies, the presence or absence of atypical hyperplasia, and the number of first-degree female relatives with breast cancer, has been used in the National Surgical Adjuvant Breast and Bowel Project (NSABP) breast cancer prevention trials. Efforts to validate the Gail et al. model in different settings have produced variable results. In the Nurses' Health Study cohort, the Gail et al. model was found to overestimate breast cancer risk, although in other settings it has proven to be more accurate. In the NSABP P1 prevention trial,28 the Gail et al. model performed extremely well, with a ratio of observed to predicted cancers in study participants of 1.03 (95% CI, 0.88 to 1.22). In general, the Gail et al. model is thought to underestimate risk in women with strong family histories, at least in part because it only incorporates a family history in first-degree relatives and does not include ovarian carcinoma.26 The Claus et al. model, on the other hand, takes into account both first and second-degree relatives, although it does not include other risk factors.27 Models are also available to predict the likelihood of a BRCA1 or BRCA2 mutation based on family history, although they do not assess the risk of cancer development. Although limitations of these models must be discussed with women undergoing risk assessment, they provide a useful starting point for discussions regarding genetic testing and the potential benefits of strategies to reduce breast cancer risk. Management strategies available for risk reduction in the high-risk woman include intensive surveillance, chemoprevention with selective estrogen receptor modulators (SERMs), and prophylactic surgery. Surveillance, consisting of monthly breast selfexamination, annual screening mammography, and clinical breast examinations once or twice yearly, does not clearly result in early detection in high-risk women. In the placebo arm of the NSABP P1 prevention trial where this strategy was employed, 29% of the women who developed breast cancer had axillary node metastases at diagnosis.28 In the population of women at risk due to known or suspected BRCA1 or BRCA2 mutations, an increasing body of evidence indicates that screening with magnetic resonance imaging (MRI) results in earlier detection of breast cancer than conventional surveillance strategies. Kuhl et al.29 compared the outcome of screening with mammography, ultrasound, and MRI in a cohort of 529 asymptomatic women with known or suspected BRCA mutations. After a total of 1,542 annual surveillance rounds with a mean follow-up of 5.3 years, 43 breast cancers were identified. The sensitivities of mammography, ultrasound, and MRI were 33%, 40%, and 91%, respectively. In a similar study of 236 BRCA mutation carriers that also evaluated the value of clinical breast exam (CBE), Warner et al.30 reported that of 22 cancers occurring during the study period, 17 were detected by MRI, eight by mammography, seven by ultrasound, and two by CBE. The use of all four modalities combined had a sensitivity of 95% compared to 45% for the combination of mammography and CBE. Although these studies have not demonstrated a mortality reduction with MRI screening of BRCA mutation carriers, the observation that the cancers detected in the MRI group were smaller and less likely to be associated with nodal positivity suggests that a survival benefit is likely to be present. In contrast, a study examining the benefit of MRI

screening in women at risk on the basis of atypical hyperplasia or lobular carcinoma in situ failed to find clear evidence of benefit.31 An expert panel convened by the American Cancer Society in 2007 to develop guidelines for MRI screening recommended the use of MRI in addition to mammography for a small group of women at very high risk of breast cancer development (Table 43.2.3). For women with less than a 15% risk of breast cancer development the American Cancer Society recommended against the use of MRI screening.32 In the remainder, they felt that the evidence was insufficient to recommend for or against MRI screening. Table 43.2.3 American Cancer Society Guidelines for Magnetic Resonance Imaging Screening ANNUAL MRI RECOMMENDED BASED ON EVIDENCE BRCA mutation Untested first degree relative of BRCA carrier Lifetime risk of breast cancer 20% to 25% ANNUAL MRI RECOMMENDED BASED ON EXPERT OPINION Radiation to chest between age 10 and 30 Li-Fraumeni syndrome and first-degree relatives Cowden and Bannayan-Riley-Ruvalcaba syndromes and first-degree relatives INSUFFICIENT EVIDENCE TO RECOMMEND FOR OR AGAINST MRI Lifetime breast cancer risk 15% to 20% Lobular carcinoma in situ Atypical hyperplasia (lobular or ductal) Extremely or heterogeneously dense breasts on mammogram Personal history of breast cancer, including DCIS MRI, magnetic resonance imaging; DCIS, ductal carcinoma in situ. Chemoprevention is an alternative to surveillance strategies. Two SERMs, tamoxifen and raloxifene, have been shown to reduce the incidence of ER-positive breast cancer. Four prospective, randomized trials have examined the effect of tamoxifen on breast cancer incidence. These studies and their outcomes are summarized in Tables 43.2.4 and 43.2.5.28,33,34,35 There is considerable heterogeneity in outcome among the trials, much of which can be attributed to differences in the populations studied. An Italian trial required women to have undergone a hysterectomy, but did not require an increase in breast cancer risk,34 while the Royal Marsden study used a family history of breast cancer as the determinant of risk status.33 In an overview of the four studies, tamoxifen produced a 38% reduction in breast cancer incidence (95% CI, 8% to 46%; P <.001), and a 48% reduction in the incidence of ER-positive breast cancers.36 No effect on the incidence of ER-negative cancers was seen in any of the trials, and the cancers occurring in women on tamoxifen were not found to have had more positive nodes or be larger in size than those in the placebo arm, providing reassurance that tamoxifen chemoprevention does not result in the occurrence of biologically more aggressive cancers. Table 43.2.4 A Comparison of Tamoxifen Chemoprevention Studies Family History HRT Use Lost to Follow-Up Study (Reference) Age Range (y) (%) (%) (%) Royal Marsden (33) 3070 100 26 11 N = 2,471 median 47 NSABP P1 (28) >35 76 0 1.6 N = 13,388 median NS

Italian (34) 3570 21 24.7 0.8 N = 5,408 median 51 IBIS (35) 3570 97 39.7 NS N = 7,152 median 50.8 HRT, hormone replacement therapy; NS, not stated; IBIS, International Breast Cancer Intervention Study; NSABP, National Surgical Adjuvant Breast and Bowel Project. In the largest of these studies, the NSABP P1 trial, a 49% risk reduction was seen with tamoxifen, with 43.4 cancers per 1,000 women occurring in the placebo arm compared to 22.0 per 1,000 in the tamoxifen arm.28 The benefits of tamoxifen were observed for both invasive and noninvasive carcinoma and were seen in women of all ages. A particular benefit was seen in those at risk due to atypical hyperplasia, with an 84% reduction in cancer incidence in this group. The risk reductions were similar in P.1611 those at risk on the basis of a family history of breast cancer and those at risk due to other factors. Controversy exists over the benefit of tamoxifen in BRCA mutation carriers. Only 19 of 288 women who developed breast cancer in the NSABP P1 study were found to have a BRCA1 or BRCA2 mutation. No evidence of tamoxifen benefit was seen in the eight BRCA1 carriers who received the drug. In contrast, a nonsignificant trend toward tamoxifen benefit was seen in BRCA2 carriers.37 These findings are consistent with observations that ER-positive cancers are more common in BRCA2 mutation carriers than BRCA1 mutation carriers, but the small sample size limits any conclusions. In a retrospective, case-controlled study of BRCA carriers who received tamoxifen for treatment of their initial carcinoma, Narod et al.38 reported a 50% reduction in the incidence of contralateral cancer. Benefit was seen in both BRCA1 and BRCA2 mutation carriers. These findings suggest that it is the likelihood of expressing the ER that determines the efficacy of tamoxifen as a chemopreventive rather than the presence of a BRCA mutation. The side effects of tamoxifen were well known from its use as a cancer treatment and were again observed in the prevention trials. In the combined analysis of the four studies, the relative risk of thromboembolic events in tamoxifen users was 1.9 (95% CI, 1.4 to 2.6; P <.0001) and the relative risk of endometrial cancer was 2.4 (95% CI, 1.5 to 4.0; P = .0005).36 Significant elevation in endometrial cancer and thromboembolic events was limited to postmenopausal women. Using this information, populations of women likely to have the most favorable risk-benefit ratio for tamoxifen can be identified. These include premenopausal women, younger postmenopausal women without a uterus, and those at risk on the basis of atypical hyperplasia or LCIS. In spite of this, use of tamoxifen for chemoprevention has been limited because of concerns about side effects. Table 43.2.5 Outcome of Tamoxifen Chemoprevention Studies Breast Cancer Rate (per Median 1,000 women-years) Study Follow-Up Total (Reference) (mo) Cancers Placebo Tamoxifen RR (95% CI) Royal Marsden 70 70 5.0 4.7 0.94 (ref. 33) (0.591.43) NSABP P1 (ref. 54.6 368 6.8 3.4 0.51 28) (0.390.66) Italian (ref. 34) 81.2 79 2.3 2.1 0.87 (0.622.14)

IBIS (ref. 35)

0.68 (0.500.92) RR, relative risk tamoxifen to placebo; CI, confidence interval; NSABP, National Surgical Adjuvant Breast and Bowel Project; IBIS, International Breast Cancer Intervention Study. Raloxifene is another SERM that was initially approved for the treatment and prevention of osteoporosis by the U.S. Food and Drug Administration (FDA). Studies of raloxifene in osteoporotic women demonstrated a reduction in the incidence of breast cancer, a secondary end point. Like tamoxifen, raloxifene reduces the incidence of ER-positive breast cancer and has no effect on the incidence of ER-negative breast cancer. The NSABP P2 trial, the Study of Tamoxifen and Raloxifene (STAR) directly compared the chemopreventive actions and side effects of tamoxifen and raloxifene in 19,747 postmenopausal women at increased risk of breast cancer development.39 After a mean follow-up of 3.9 years, no difference in the incidence of invasive cancer was seen between women taking tamoxifen and those taking raloxifene (RR 1.02; 95% CI, 0.82 to 1.28). More cases of noninvasive cancer were noted in the raloxifene group (RR 1.40; 95% CI, 0.98 to 2.00), with a cumulative incidence of 11.7 per 1,000 compared to 8.1 per 1,000 in the tamoxifen group at 6 years (P = .052). A more favorable side-effect profile was seen for raloxifene, with an 84% reduction in endometrial hyperplasia and a statistically significant reduction in the number of hysterectomies compared to tamoxifen. P.1612 The number of endometrial cancers was also reduced in the raloxifene group (RR 0.62; 95% CI, 0.35 to 1.08), although the difference did not reach statistical significance. Significantly fewer thromboembolic events and cataracts occurred with raloxifene. The results of this study indicate that raloxifene is a viable alternative to tamoxifen for the chemoprevention of breast cancer in postmenopausal women at increased risk for the disease. In addition, the use of raloxifene in women with osteoporosis has the potential to lower breast cancer incidence in a group of women not considered high risk. Trials of aromatase inhibitors for breast cancer prevention are ongoing based on the findings from adjuvant therapy trials (discussed later in this chapter) that show that aromatase inhibitors produce a greater reduction in contralateral breast cancer incidence than is seen with tamoxifen treatment. The reduction in cancer incidence seen with aromatase inhibitors is also limited to ER-positive cancers. At present, there are no chemopreventive agents that have been proven to be effective in reducing the incidence of ER-negative breast cancer. Prophylactic surgery, in the form of bilateral mastectomy or bilateral salpingooophorectomy, is another option for breast cancer risk reduction. The efficacy of prophylactic mastectomy has never been studied in a prospective, randomized trial. Data on the benefits of the procedure are derived from retrospective reviews and case control studies. Hartmann et al.40 identified 639 women with a family history of breast cancer who had undergone bilateral prophylactic mastectomy between 1960 and 1993. Women were characterized as high risk if their family history was suggestive of an autosomal dominant predisposition to breast cancer. The expected incidence of cancer in this group was estimated using the age-specific incidence of breast cancer in their sisters. The remaining 425 women were classified as moderate risk, and the predicted incidence of breast cancer was derived from the Gail et al. model.26 A 90% to 94% reduction in breast cancer incidence (95% CI, 71% to 99%) and an 81% to 100% reduction in breast cancer mortality were observed with prophylactic mastectomy. In a prospective study of 139 BRCA

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6.7

4.6

mutation carriers with a mean follow-up of 3 years, Meijers-Heijboer et al.41 observed no breast cancers in the group undergoing prophylactic mastectomy compared to a 2.5% per year incidence in those opting for surveillance. Rebbeck et al.42 reported a mixed retrospective and prospective study of 483 BRCA mutation carriers. In this study, prophylactic mastectomy reduced breast cancer incidence by 90% to 95%. Studies of prophylactic mastectomy are summarized in Table 43.2.6. Although bilateral prophylactic mastectomy is an effective form of breast cancer risk reduction, even in women at risk due to BRCA mutations, it is an intervention that is unacceptable to many women. Prophylactic bilateral salpingo-oophorectomy is an alternative risk-reduction strategy in women at risk on the basis of BRCA mutations, which has the added benefit of reducing the risk of ovarian carcinoma, a disease for which effective screening is not available. In a case control study of 241 women, which included 99 women who had undergone prophylactic oophorectomy at a mean age of 42 years, the risk of breast carcinoma was reduced to 0.47 (95% CI, 0.29 to 0.77) with the procedure.43 A 96% reduction in ovarian cancer incidence was also noted. In a prospective study of the benefits of prophylactic salpingo-oophorectomy in 170 BRCA mutation carriers, Kauff et al.13 observed that the hazard ratio for breast cancer was reduced to 0.32 (95% CI, 0.08 to 1.20) and that for gynecologic cancer to 0.25 (95% CI, 0.08 to 0.74) at a mean follow-up of 24 months. Table 43.2.6 Outcome of Bilateral Prophylactic Mastectomy in High-Risk Women No. of Risk Author (Reference) Population Women Follow-Up Reduction Hartmann et al. (40) Women with a family history 639 14 years 90%94% of breast cancer (median) Meijers-Heijboer et BRCA1/2 mutation carriers 139 3 years 100% al. (41) (mean) Rebbeck et al. (42) BRCA1/2 mutation carriers 105 6.4 years 90%95% (mean) Diagnosis and Biopsy The presence or absence of carcinoma in a suspicious clinically or mammographically detected abnormality can only be reliably determined by tissue sampling. The high sensitivity of MRI for cancer detection raised the possibility that this technique could replace biopsy in the evaluation of suspicious breast lesions. In a multi-institutional prospective study of 821 patients referred for breast biopsy, the sensitivity of MRI was 88.1% (95% CI, 84.6% to 91.1%) and the specificity was 67.7% (95% CI, 62.7% to 71.9%), indicating that an abnormal MRI does not reliably indicate the presence of cancer, and a nonworrisome MRI does not reliably exclude carcinoma.44 A biopsy remains the standard technique for diagnosing both palpable and nonpalpable breast abnormalities. The available biopsy techniques for the diagnosis of palpable breast masses are fine needle aspiration (FNA), core cutting needle biopsy, and excisional biopsy. The advantages and disadvantages of each are listed in Table 43.2.7. Both FNA and core biopsy are office procedures. FNA is easily performed, but requires a trained cytopathologist for accurate specimen interpretation. The sensitivity of FNA ranges from 80% to 95%, and false-positive aspirates are seen in fewer than 1% of cases in most series. False-negative results are seen in 4% to 10% of cases and are most common in fibrotic or well-differentiated tumors.45 Although an FNA diagnosis of malignant cells is sufficient to proceed with definitive treatment, FNA does not reliably distinguish invasive

cancer from ductal carcinoma in situ (DCIS), potentially leading to the overtreatment of gross DCIS. Core cutting needle biopsy has many of the advantages of FNA, but provides a histologic specimen suitable for interpretation by any pathologist. In addition, estrogen and progesterone receptor status and the presence of HER-2 overexpression can be routinely determined from core biopsy specimens, making core needle biopsy the diagnostic technique of choice for patients who will receive preoperative systemic therapy. P.1613 False-negative results due to sampling error may also occur with core cutting needle biopsy. If concordance between the core biopsy diagnosis and the clinical and imaging findings is not present, additional tissue should be obtained, usually by excisional biopsy. Table 43.2.7 Biopsy Techniques for Breast Lesions Technique Advantages Disadvantages Fine needle Rapid, painless, inexpensive. Does not distinguish invasive from in situ aspiration No incision prior to selection cancer. Markers (ER, PR, HER-2) not cytology of local therapy. routinely available. Requires experienced cytopathologist. False negatives and insufficient specimens occur. Core cutting Rapid, relatively painless, False-negative results, incomplete lesion needle biopsy inexpensive. No incision. Can characterization can occur. be read by any pathologist, markers routinely available. Excisional False-negative results rare. Expensive, more painful. Creates an incision biopsy Complete histology before to be incorporated into definitive surgery. treatment decisions. May Unnecessary surgery with potential for serve as definitive cosmetic deformity in patients with benign lumpectomy. abnormalities. ER, estrogen receptor; PR, progesterone receptor. When excisional biopsy is performed for diagnosis, a small margin of grossly normal breast should be excised around the tumor, orienting sutures should be placed, and the specimen should be inked to allow margin evaluation. This procedure allows an assessment of the completeness of the excision if carcinoma is found, sparing patients with negative margins further breast surgery and allowing re-excision to be limited to the involved margin surface(s). However, diagnosis by needle biopsy is the preferred initial method of evaluating almost all breast masses. A needle biopsy diagnosis permits a complete discussion of treatment options prior to the placement of an incision on the breast and allows the breast procedure and the axillary surgery to take place at a single operation. In addition, needle biopsy is a more cost-effective method of diagnosing benign lesions than surgical excision. Nonpalpable lesions can be biopsied with image-guided core needle biopsy or surgical excision after wire localization. Ultrasound guidance is used for lesions that are visualized with this modality; most calcifications require stereotactic mammographic guidance for biopsy. There is little role for FNA in the diagnosis of lesions detected by screening due to the high prevalence of in situ lesions. Concerns about the false-negative rate of imageguided core biopsy have been resolved with the availability of large, vacuum-assisted biopsy devices that increase the extent of lesion sampling, coupled with the development of

clearly defined indications for follow-up surgical biopsy. In a study of 318 patients with mammographic abnormalities diagnosed by core biopsy between September 1997 and December 2001, the false-negative rate was 3.3%. For radiologists who had done more than 15 biopsies, the false-negative rate was 0.6%. All of the false negatives were recognized at the time, with no delay in the diagnosis of cancer.46 Indications for surgical biopsy following core biopsy are listed in Table 43.2.8. Although the finding of atypical ductal hyperplasia on a core biopsy is uniformly accepted as an indication for surgical biopsy, the need for surgical excision of all lesions showing atypical lobular hyperplasia or lobular carcinoma in situ remains controversial (discussed in the section Lobular Carcinoma in situ below). Papillary carcinoma in situ cannot always be readily distinguished from benign papillary lesions on a core biopsy, and radial scar may be difficult to distinguish from tubular carcinoma without complete removal of the lesion. The use of core biopsy for the diagnosis of mammographic abnormalities is cost effective and increases the likelihood that the patient will be able to undergo a single surgical procedure for definitive cancer treatment. In a prospective study of 1,550 consecutive patients undergoing biopsy for mammographic abnormalities, core biopsy reduced the number of surgical procedures needed for cancers presenting as both masses and calcifications as well as in patients requiring axillary staging and those treated by mastectomy.47 In a cost analysis using patients from this data set, core biopsy resulted in cost savings for all clinical scenarios. In spite of this, in a study of 5.5 million mammograms performed in two U.S. governmentsponsored screening programs and the UK National Health Service between 1996 and 1999, 51% of the biopsies performed in the United States were surgical, compared to 23% in the United Kingdom.48 Lobular Carcinoma In Situ In 1941 Foote and Stewart published their landmark study of LCIS, describing a relatively uncommon entity characterized by P.1614 an alteration of lobular cytology. Foote and Stewart chose the name to emphasize the morphologic similarities between the cells of LCIS and those of invasive lobular carcinoma (ILC). They hypothesized that LCIS represented a precursor lesion of invasive cancer, and, based on this, mastectomy was initially recommended. Subsequent studies, discussed below, have shown that the risk of subsequent breast cancer is bilateral. More recently, the term atypical lobular hyperplasia (ALH) has been introduced to describe morphologically similar, but less well-developed lesions. Some centers use the term, lobular neoplasia (LN) to cover both ALH and LCIS. Morphologically, LN is defined as a proliferation of generally small and often loosely cohesive cells originating in the terminal duct-lobular unit, with or without pagetoid involvement of terminal ducts.49 Table 43.2.8 Indications for Surgical Biopsy after Core Needle Biopsy Failure to sample calcifications Diagnosis of atypical ductal hyperplasia Diagnosis of atypical lobular hyperplasia or lobular carcinoma in situa Lack of concordance between imaging findings and histologic diagnosis Radial scar Papillary lesions a See text.

In the past, LCIS was most frequently diagnosed in women aged 40 to 50, a decade earlier than DCIS, but recent literature indicates that the incidence in postmenopausal women is increasing.50 Determining the true incidence of LCIS is difficult since there are no specific clinical or mammographic abnormalities associated with the lesion. LCIS is typically not associated with microcalcifications on mammography. The diagnosis of LCIS is therefore often made as an incidental, microscopic finding in a breast biopsy performed for other indications. The prevalence of LN in an otherwise benign breast biopsy has been reported as between 0.5% and 4.3%.51 LCIS is both multifocal and bilateral in a large percentage of cases. In an analysis of nine separate studies evaluating outcome following a diagnosis of LCIS, 172 patients who were treated by biopsy alone were identified. On follow-up averaging about 10 years, 15% of these patients had invasive carcinoma diagnosed in the ipsilateral breast and 9.3% had invasive carcinoma in the contralateral breast.52 This corresponds to an increased rate of development of invasive carcinoma of about 1% to 2% per year, with a lifetime risk of 30% to 40%. In this study (conducted prior to effective breast imaging), 5.7% developed metastatic breast cancer. Subsequent cancers are more often invasive ductal carcinoma than ILC, but the incidence of subsequent ILC is substantially increased compared to women without LCIS. Although the risk for development of breast cancer is bilateral, subsequent ipsilateral carcinoma is more likely than contralateral breast, supporting the view that ALH and LCIS act both as precursor lesions and as risk indicators. The relative risk for development of subsequent breast cancer is lower in women diagnosed with ALH compared with LCIS. Therefore, although LN is a helpful term for collectively describing this group of lesions, specific classification into ALH and LCIS is preferable in terms of risk assessment and management. LCIS is typically positive for ER and PR staining by immunohistochemistry (IHC) and negative for HER-2/neu staining. LN (and ILC) characteristically lacks expression of Ecadherin, an epithelial cell membrane molecule involved in cellcell adhesion. Ecadherin negativity serves as a fairly reliable means of distinguishing ductal from lobular disease, both in situ and invasive. Pleomorphic LCIS is a relatively uncommon variant of LCIS characterized by medium to large pleomorphic cells containing eccentric nuclei, prominent nucleoli, and eosinophilic cytoplasm. As with classic LCIS, it is usually estrogen-receptor positive and negative for E-cadherin; it also tests positive by IHC for gross cystic disease fluid protein-15. Pleomorphic LCIS can be associated with central necrosis and may be associated with mammographic microcalcifications. It is not clear at this time whether pleomorphic LCIS has a different natural history than classic LCIS. Genetic changes in LN have been evaluated in a number of studies using comparative genomic hybridization (CGH). In one study ALH showed gain at 2p11.2 and loss at 7p11p11.1 and 22q11.1, and LCIS showed gain at 20q13.13 and loss at 19q13.2-q13.31.53 In both ALH and LCIS, there was loss at 16q21-q23.1, an altered region previously identified in invasive carcinoma. This genomic signature, common to LN and ILC, further suggests that LN is a precursor lesion in some women. Management of LN must address the bilateral risk, and options therefore include surveillance, chemoprevention, and prophylactic bilateral mastectomy. Surveillance is the strategy selected by most patients. Mammographic screening is the standard breast imaging for patients selecting surveillance. Breast MRI has been used, but there is no firm evidence supporting its efficacy; its value is being tested in a randomized clinical trial in Europe. Prophylactic mastectomy reduces breast cancer risk and mortality among high-risk women

by approximately 90%. Chemoprevention with tamoxifen in patients with LCIS has been evaluated as part of the NSABP P1 study.28 In this prospective, placebo-controlled clinical trial, with a median follow-up of 54.6 months, tamoxifen reduced the incidence of breast cancer by 49% (P <.00001). Eight hundred twenty-six of the participants had a history of LCIS, and breast cancers were detected in 18 women randomized to placebo and eight to tamoxifen, consistent with the overall reduction in breast cancer risk seen with tamoxifen. However, with the small number of events, this difference was not statistically significant. Nearly 1,200 participants had a history of atypical hyperplasia, and tamoxifen reduced the incidence of breast cancer by 86% in this group (RR = 0.14; 95% CI, 0.03 to 0.47); however, the initial report of the study did not provide results subdivided by ALH versus ADH. In the NSABP P2 (STAR) trial comparing tamoxifen and raloxifene, comparable efficacy in risk reduction was observed.39 In this study 893 participants gave a history of LCIS, and their rates of subsequent breast cancer were similar with tamoxifen and raloxifene. This benefit with tamoxifen or raloxifene needs to be weighed against the possible side effects of treatment. Although the data are conflicting, it is generally recommended to perform an excisional biopsy after detection of LN on a core needle biopsy to rule out coexisting DCIS or invasive cancer. Some have advocated a more selective approach to LCIS on core biopsy based on whether or not there is concordance between the pathology and imaging findings. With LCIS, most reported cases of malignant findings on subsequent excision occur in the setting of either a suspicious mass lesion or calcifications that prompted the biopsy initially. The recent recognition that in some cases LCIS may be a precursor lesion has led to confusion as to whether it should be treated like DCIS (i.e., excised to negative margins and irradiated). At this time, there are no data indicating that the incidence of subsequent cancer is reduced with this approach. When LCIS is seen on an excision, it is not necessary to obtain negative margins of resection, and there is no established role for radiation therapy in patients with LN. Ductal Carcinoma In Situ DCIS is defined as the proliferation of malignant-appearing mammary ductal epithelial cells without evidence of invasion P.1615 beyond the basement membrane. Prior to the widespread use of screening mammography, fewer than 5% of mammary cancers were DCIS. At present 15% to 30% of the cancers detected in mammography screening programs are DCIS, and the greatest increase in the incidence of DCIS has been seen in women aged 49 to 69. DCIS can present as a palpable mass, Paget's disease of the nipple, an incidental finding at biopsy, or a mammographically detected mass or calcifications, with calcifications being the most common presentation. A central problem in the management of DCIS is the lack of understanding of its natural history and the inability to determine which DCIS will progress to invasive carcinoma during a woman's lifetime. The concordance between risk factors for DCIS and invasive carcinoma suggests that they are part of the same disease process.54 Attempts to better characterize the natural history of DCIS on the basis of pathologic features have not been particularly successful. The traditional morphologic classification into comedo, papillary, micropapillary, solid, and cribriform types is confounded by the observation that as many as 30% to 60% of DCIS lesions display more than one histologic pattern. To overcome this difficulty, a number of classifications based on nuclear grade and the presence or absence

of necrosis have been developed. No single classification scheme has been widely adopted, and most importantly, none of the classification systems have been prospectively demonstrated to predict the risk of development of invasive carcinoma. Molecular profiling studies in DCIS have been limited by the need for histologic examination of the entire lesion to reliably exclude the presence of invasive carcinoma. The available data indicate that DCIS lesions share many of the genetic alterations of invasive carcinoma, but predictors of progression to invasion remain to be identified. Treatment of the Breast Cancer-specific survival for the woman diagnosed with DCIS exceeds 95%, regardless of the type of local therapy employed.55,56 Mastectomy, excision and radiotherapy (RT), and excision alone have all been proposed as management strategies for DCIS. The appropriate therapy for the woman with DCIS depends on the extent of the DCIS lesion, the risk of local recurrence with each form of treatment, and the patient's attitude toward the risks and benefits of a particular therapy. Table 43.2.9 Randomized Trials of Excision with or without Radiotherapy in Ductal Carcinoma in situ Ipsilateral Local Recurrence Overall Survival No. of Without With Risk P Without WithP Trial (Reference) Patients RT RT Reduction Value RT RT Value NSABP B17 (55) 813 31.7 15.7 50 <.00005 86 87 .8 12-y results EORTC 10853 1,010 26 15 47 <.0001 95 95 .53 (56) 10.5 y results UK/ANZ (60) 1,030 14 6 62 <.0001 Too few crude incidence deaths to analyze Swedish (61) 5.2 y 1,067 22 7 67 <.0001 9 deaths in results each group RT, radiotherapy; NSABP, National Surgical Adjuvant Breast and Bowel Project; EORTC, European Organization for Research and Treatment of Cancer; UK/ANZ, United Kingdom/Australia New Zealand. Total or simple mastectomy is a treatment for which all women with DCIS are eligible, and it is curative in approximately 98% of patients regardless of age, DCIS presentation, size, or grade.57 The primary medical indication for mastectomy in DCIS is a lesion too large to be excised to negative margins with a cosmetically acceptable outcome.58 The extent of DCIS is most accurately estimated preoperatively with the use of magnification mammography. Conventional two-view mammography underestimates the extent of the lesion, particularly for well-differentiated DCIS.59 Initial studies indicate that MRI both overestimates and underestimates the size of DCIS lesions and does not improve surgical planning when compared to diagnostic mammography. For women with localized DCIS, management by excision alone and excision plus RT have both been employed. Four prospective, randomized trials have directly compared these two approaches in more than 4,500 patients.55,56,60,61 In all four trials the majority of participants had mammographically detected DCIS, and in all but the Swedish trial,61 negative margins, defined as tumor filled ducts not touching an inked surface, were required. A dose of 50 Gy of radiation was delivered to the whole breast in 25 fractions, and a boost dose to the tumor bed was not required. A tumor bed boost was employed in 9% and 5% of patients in the

NSABP B1755 and European Organisation for Research and Treatment of Cancer (EORTC) 1085356 studies, respectively. The UK/ANZ (United Kingdom/Australia New Zealand) study has a two-by-two randomization that randomized patients to RT versus none and tamoxifen versus none, and institutions and patients could select to participate in one or both randomizations.60 The other studies did not allow tamoxifen. The results of these trials are summarized in Table 43.2.9. No differences in overall survival were seen between treatments arms. In all four studies, the use of RT resulted in a highly significant reduction in the risk of an ipsilateral breast tumor recurrence, with proportional risk reductions ranging from 47% in the EORTC study56 to 67% in the Swedish study.61 Consistent with observations from many retrospective studies, approximately 50% of the recurrences in both the irradiated and the nonirradiated groups were invasive P.1616 carcinoma, and a benefit for RT was seen in the reduction of both invasive and noninvasive recurrences. Subset analyses in these trials failed to identify any patient subgroups not benefitting from RT but emphasize that the magnitude of the benefit of RT varies with the risk of local recurrence.56 Patient age has emerged as an important predictor of local recurrence after excision and RT. In the NSABP B17 trial local recurrence rates ranged from 15% in women age 49 or less to 9% in those 60 years or older.56 The EORTC trial reported a relative risk of recurrence of 1.89 (95% CI, 1.12 to 3.19; P = .026) for women aged 40 and younger in multivariate analysis.56 The increased incidence of local recurrence in younger women was confirmed in the NSABP B24 trial.62 Clinical presentations of DCIS were associated with a higher rate of local failure than mammographic ones in both the EORTC trial56 and the NSABP B24 study62; and both the NSABP B17 trial and the EORTC 10853 trials found high- and intermediate-grade DCIS to be more commonly associated with local recurrence than low-grade DCIS.55,56 In spite of the clear benefit of RT seen in these four trials, considerable interest in identifying patients who could be spared the cost and inconvenience of RT has persisted. In a retrospective review, Silverstein et al.63 reported the outcome of patients with DCIS treated with and without RT and suggested that if a negative margin width of 1 cm or greater was obtained, RT was not beneficial in reducing local recurrence, regardless of the characteristics of the DCIS lesion. Wong et al.64 attempted to duplicate these findings in a prospective study of 158 patients with predominantly grade 1 and 2 DCIS who underwent excision to a negative margin greater than 1 cm. The 5-year local recurrence rate was 12%, and 31% of the recurrences were invasive, resulting in premature closure of the study prior to its planned accrual of 200 patients. The Eastern Cooperative Oncology Group (ECOG) conducted a prospective, single-arm study of the outcome of excision alone in selected patients with DCIS.65 Eligible patients included those with DCIS larger than 3 mm in size excised to a negative margin width of 3 mm or more. For patients with low- or intermediate-grade DCIS, the upper limit of lesion size was 2.5 cm or less, and for those with high-grade lesions the upper size limit was 1 cm or less. There were 579 patients with low- or intermediate-grade DCIS, with a median tumor size of 6 mm; 67% were excised to a margin of 5 mm or greater and 46% to a margin of 1 cm or greater. At a median followup of 5 years, the local recurrence rate was 6.1% (95% CI, 4.0% to 8.2%). The 101 patients with high-grade DCIS had a median tumor size of 7 mm. Seventy-five percent were excised to a margin of 5 mm or greater, and 48% had a margin of 1 cm or more. For patients with

high-grade DCIS the 5-year local recurrence rate was 14.8% (95% CI, 7.2% to 22.3%). In considering the results of excision alone in the low- and intermediate-grade group, it is worth noting that older studies that examined the 5-year results of the treatment of DCIS with excision and RT observed a significantly higher rate of local recurrence for high-grade DCIS compared to low- and intermediate-grade DCIS, but after 10 years of follow-up no differences in the rate of local failure on the basis of grade were seen.66 Additional followup of the ECOG study will be important in determining the risks of treatment with excision alone for low- and intermediate-grade DCIS. Based on the information discussed above, guidelines for breast-conserving surgery in DCIS developed by a joint committee of the American College of Surgeons, American College of Radiology, and College of American Pathologists recommend mastectomy for multicentric DCIS when there are diffuse malignant calcifications in the breast and when negative margins cannot be obtained.58 Breast-conserving surgery with radiation is recommended for those with localized DCIS excised to clear margins. Although the value of a boost has not been formally tested in patients with DCIS, it is generally recommended, particularly for young patients, based on trial results in patients with invasive breast cancer. The committee acknowledged that low local recurrence rates after wide excision of low-grade DCIS have been reported, but felt that the maximum size DCIS lesion for which RT could be safely omitted was unknown. They concluded that these cases must be evaluated individually, with the patients' attitude toward risks and benefits playing a major role in the decision to omit RT.58 Treatment of the Axilla In situ carcinoma by definition does not metastasize, so theoretically axillary staging should be unnecessary in the patient with DCIS. Many studies of axillary dissection in patients with DCIS have demonstrated axillary nodal metastases in only 1% to 2% of patients, presumably due to unrecognized microinvasion. The availability of sentinel node biopsy as a low-morbidity method of axillary staging has caused the issue of axillary staging of DCIS to be revisited. Data from the NSABP B17 and B24 studies confirm that the risk of isolated axillary recurrence with no axillary surgery is less than 0.1%, regardless of whether RT and tamoxifen are administered.67 These low rates of axillary failure do not provide justification for the routine use of sentinel lymph node biopsy in DCIS. Most investigators agree that selective use of sentinel node biopsy in patients with DCIS who are at significant risk of having coexistent invasive carcinoma is appropriate. Patients diagnosed as having DCIS with large vacuum-assisted biopsy devices are found to have invasive cancer in approximately 5% to 18% of cases after complete excision of the lesion. In patients requiring mastectomy, the opportunity for sentinel node biopsy is lost if it is not performed at the time of mastectomy, and the performance of a mastectomy is an indication for sentinel node biopsy. The diagnosis of DCIS in a palpable breast mass and pathologic interpretation of a core biopsy specimen as suspicious, but not diagnostic of microinvasion, are also circumstances where invasive cancer is frequently found when the lesion is completely examined and sentinel node biopsy should be considered. Endocrine Therapy The estrogen receptor is present in about 80% of DCIS lesions and is more frequent in noncomedo than comedo DCIS.68 Endocrine therapy has two potential benefits in women with DCIS; a reduction in local recurrence after breast-conserving therapy and the prevention of the development of new primary breast cancers in the contralateral breast. Although most of the attention in DCIS has focused on local recurrence, Solin et al.69 have

demonstrated that the 15-year risk of new ipsilateral and contralateral cancers in women with DCIS is equal to the risk of true local recurrence at the primary tumor site. Two trials have examined the use of tamoxifen in women with DCIS with somewhat conflicting results. In the NSABP B24 trial62 P.1617 1,804 patients with DCIS were treated with excision and RT and randomized to tamoxifen 20 mg daily or a placebo for 5 years. At a median follow-up of 74 months, patients in the tamoxifen arm had an 8.2% incidence of breast cancer events compared with 13.4% in the placebo group (P = .0009). Tamoxifen reduced the risk of ipsilateral invasive recurrences by 44% and reduced the risk of contralateral invasive and noninvasive cancers by 52%. Allred et al.68 reported a subset analysis of 628 patients in the study who had an ER determination. In women with ER-positive breast cancer, tamoxifen reduced the risk of any breast cancer event by 59% (RR 0.41; 95% CI, 0.25 to 0.65; P = .0002). In women with ER-negative tumors no significant benefit was seen. In contrast, no benefit for tamoxifen was demonstrated in the UK/ANZ trial.59 With a median follow-up of 52.6 months, tamoxifen did not reduce the incidence of invasive ipsilateral or contralateral events, although a 34% reduction in ipsilateral in situ recurrence was seen. The failure of this study to demonstrate any reduction in contralateral breast cancer events, a benefit of tamoxifen that is well documented in both high-risk women and women with invasive breast carcinoma, raises some questions about the overall results. Evidence that the aromatase inhibitors reduce the incidence of contralateral breast cancer to a greater extent than tamoxifen has led to interest in their use in DCIS. Several randomized trials directly comparing tamoxifen to an aromatase inhibitor are ongoing and will provide important information about whether the increased benefit in reducing contralateral carcinoma seen with the aromatase inhibitors is outweighed by the increased risk of osteoporosis associated with this drug group. In summary, patients with localized DCIS have treatment options ranging from simple excision to mastectomy, all of which have high survival rates but different risks of local recurrence. Patient preference plays a major role in treatment selection, but available evidence indicates that patients have limited understanding of the nature of DCIS. In one study, women with DCIS estimated their risk of breast cancer death to be 39%.70 Perhaps related to this, Katz et al.71 found that although patients reported that their surgeon infrequently recommended mastectomy for DCIS, greater involvement of patients in the decision-making process was associated with higher rates of mastectomy. Staging The staging system for breast cancer was last updated in 2002.72 Major changes to the staging system at that time were related to nodal classification. These included designations for micrometastases and isolated tumor cells, and separate classifications of node (N) status was based on the number of involved lymph nodes. Metastases (M) to the supraclavicular nodes were reclassified as N3 rather than M1. The staging categories are summarized below. Tumor, Node, Metastases Definitions Definitions for classifying the primary tumor (T) are the same for clinical and for pathologic classification. If the measurement is made by physical examination, the examiner will use the major headings (T1, T2, or T3). If other measurements, such as mammographic or pathologic measurements, are used, the subsets of T1 can be used.

Tumors should be measured to the nearest 0.1 cm increment. The American Joint Committee on Cancer (AJCC) TNM staging system is illustrated in Table 43.2.10. Stage IIIC breast cancer includes patients with any T stage who have pN3 disease. Patients with pN3a and pN3b disease are considered operable and are managed as described in the section on stage I, II, IIIA, and operable IIIC breast cancer. Patients with pN3c disease are considered inoperable and are managed as described in the section on inoperable stage IIIB or IIIC or inflammatory breast cancer.73 Pathology of Breast Cancer Invasive breast cancers constitute a heterogeneous group of lesions that differ with regard to their clinical presentation, radiographic characteristics, pathologic features, and biologic behavior. Historically, classification of invasive breast cancers has been based on the morphologic appearance of the cancer as seen by light microscopy.74 The most widely used such classification is that of the World Health Organization (2nd edition).75 This classification scheme is based on the growth pattern and cytologic features of the invasive tumor cells and, as currently used, is not meant to imply site of origin in the breast. Although the classification system recognizes invasive ductal and lobular carcinomas, this is not meant to indicate that the former originates in the ducts and the latter in the lobules of the breast. Most invasive breast cancers are felt to arise in the terminal duct lobular unit, regardless of histologic type. The most common histologic type of invasive breast cancer is invasive (infiltrating) ductal carcinoma. The diagnosis of invasive ductal carcinoma is a diagnosis by exclusion (i.e., this tumor type is defined as a type of cancer not classified into any of the other special categories of invasive mammary carcinoma, such as invasive lobular, tubular, mucinous, medullary, and other special types). To emphasize this point, most classification systems use the term infiltrating ductal carcinoma, not otherwise specified (NOS) or infiltrating carcinoma of no special type (NST). In practice, the terms invasive ductal carcinoma, infiltrating ductal carcinoma, and infiltrating or invasive carcinoma of no special type are used interchangeably. Infiltrating or invasive ductal cancer is the most common breast cancer histologic type and comprises 70% to 80% of cases. Special types of cancers comprise approximately 20% to 30% of invasive carcinomas, and at least 90% of a tumor should demonstrate the defining histologic characteristics of a special type of cancer to be designated as that histologic type. The following is a list of breast cancer histologic classifications.

Ductal
o o o o o o o o o o o

Invasive, NOS Invasive with predominant intraductal component Intraductal (in situ) Comedo Inflammatory Medullary with lymphocytic infiltrate Mucinous (colloid) Papillary Scirrhous Tubular Other

P.1618

P.1619

Lobular o In situ o Invasive with predominant in situ component o Invasive Nipple o Paget's disease, NOS o Paget's disease with intraductal carcinoma o Paget's disease with invasive ductal carcinoma Other o Undifferentiated carcinoma

The following are tumor subtypes that occur in the breast, but are not considered to be typical breast cancers: Table 43.2.10 American Joint Committee on Cancer Staging PRIMARY TUMOR (T) TX: Primary tumor cannot be assessed T0: No evidence of primary tumor Tis: Intraductal carcinoma, lobular carcinoma in situ, or Paget's disease of the nipple with no associated invasion of normal breast tissue Tis (DCIS): Ductal carcinoma in situ Tis (LCIS): Lobular carcinoma in situ Tis (Paget's): Paget's disease of the nipple with no tumor. [Note: Paget's disease associated with a tumor is classified according to the size of the tumor.] T1: Tumor not larger than 2.0 cm in greatest dimension T1mic: Microinvasion not larger than 0.1 cm in greatest dimension T1a: Tumor larger than 0.1 cm but not larger than 0.5 cm in greatest dimension T1b: Tumor larger than 0.5 cm but not larger than 1.0 cm in greatest dimension T1c: Tumor larger than 1.0 cm but not larger than 2.0 cm in greatest dimension T2: Tumor larger than 2.0 cm but not larger than 5.0 cm in greatest dimension T3: Tumor larger than 5.0 cm in greatest dimension T4: Tumor of any size with direct extension to (a) chest wall or (b) skin, only as described below T4a: Extension to chest wall, not including pectoralis muscle T4b: Edema (including peau d'orange) or ulceration of the skin of the breast, or satellite skin nodules confined to the same breast T4c: Both T4a and T4b T4d: Inflammatory carcinoma

REGIONAL LYMPH NODES (N) NX: Regional lymph nodes cannot be assessed (e.g., previously removed) N0: No regional lymph node metastasis N1: Metastasis to movable ipsilateral axillary lymph node(s) N2: Metastasis to ipsilateral axillary lymph node(s) fixed or matted, or in clinically apparenta ipsilateral internal mammary nodes in the absence of clinically evident lymph node metastasis N2a: Metastasis in ipsilateral axillary lymph nodes fixed to one another (matted) or to other structures N2b: Metastasis only in clinically apparenta ipsilateral internal mammary nodes and in the absence of clinically evident axillary lymph node metastasis N3: Metastasis in ipsilateral infraclavicular lymph node(s) with or without axillary lymph node involvement, or in clinically apparenta ipsilateral internal mammary lymph node(s) and in the presence of clinically evident axillary lymph node metastasis; or, metastasis in ipsilateral supraclavicular lymph node(s) with or without axillary or internal mammary lymph node involvement N3a: Metastasis in ipsilateral infraclavicular lymph node(s) N3b: Metastasis in ipsilateral internal mammary lymph node(s) and axillary lymph node(s) N3c: Metastasis in ipsilateral supraclavicular lymph node(s) PATHOLOGIC CLASSIFICATION (pN)b pNX: Regional lymph nodes cannot be assessed (e.g., not removed for pathologic study or previously removed) pN0: No regional lymph node metastasis histologically, and no additional examination for isolated tumor cells (ITC) [Note: ITCs are defined as single tumor cells or small cell clusters not larger than 0.2 mm, usually detected only by immunohistochemical (IHC) or molecular methods but that may be verified on hematoloxylin and eosin (H&E) stains. ITCs do not usually show evidence of malignant activity, e.g., proliferation or stromal reaction.]250 pN0(I-): No regional lymph node metastasis histologically, negative IHC pN0(I+): No regional lymph node metastasis histologically, positive IHC, and no IHC cluster larger than 0.2 mm pN0(mol-): No regional lymph node metastasis histologically, and negative molecular findings (RT-PCR)c pN0(mol+): No regionally lymph node metastasis histologically, and positive molecular findings (RT-PCR)c pN1: Metastasis in one to three axillary lymph nodes, and/or in internal mammary nodes with microscopic disease detected by SLN dissection but not clinically apparentc pN1mi: Micrometastasis (larger than 0.2 mm but not larger than 2.0 mm) pN1a: Metastasis in one to three axillary lymph nodes pN1b: Metastasis in internal mammary nodes with microscopic disease detected by SLN dissection but not clinically apparentb pN1c: Metastasis in one to three axillary lymph nodes and in internal mammary lymph nodes with microscopic disease detected by SLN dissection but not clinically apparent.c (If associated with more than three positive axillary lymph nodes, the internal mammary nodes are classified as pN3b to reflect increased tumor burden.) pN2: Metastasis in four to nine axillary lymph nodes, or in clinically apparentc internal mammary lymph nodes in the absence of axillary lymph node metastasis to ipsilateral

axillary lymph node(s) fixed to each other or to other structures pN2a: Metastasis in four to nine axillary lymph nodes (at least one tumor deposit larger than 2.0 mm) pN2b: Metastasis in clinically apparenta internal mammary lymph nodes in the absence of axillary lymph node metastasis pN3: Metastasis in 10 or more axillary lymph nodes, or in infraclavicular lymph nodes, or in clinically apparenta ipsilateral internal mammary lymph node(s) in the presence of one or more positive axillary lymph node(s); or, in more than three axillary lymph nodes with clinically negative microscopic metastasis in internal mammary lymph nodes; or, in ipsilateral supraclavicular lymph nodes pN3a: Metastasis in ten or more axillary lymph nodes (at least one tumor deposit larger than 2.0 mm); or, metastasis to the infraclavicular lymph nodes pN3b: Metastasis in clinically apparentd ipsilateral internal mammary lymph nodes in the presence of one or more positive axillary lymph node(s); or, in more than three axillary lymph nodes and in internal mammary lymph nodes with microscopic disease detected by sentinel lymph node dissection but not clinically apparente pN3c: Metastasis in ipsilateral supraclavicular lymph nodes DISTANT METASTASIS (M) MX: Presence of distant metastasis cannot be assessed M0: No distant metastasis M1: Distant metastasis AJCC STAGE GROUPINGS Stage 0 Stage IIIA Tis, N0, M0 T0, N2, M0 Stage I T1f, N2, M0 T1f, N0, M0 T2, N2, M0 Stage IIA T3, N1, M0 T0, N1, M0 T3, N2, M0 f T1 , N1, M0 Stage IIIB T2, N0, M0 T4, N0, M0 Stage IIB T4, N1, M0 T2, N1, M0 T4, N2, M0 T3, N0, M0 Stage IIICb Any T, N3, M0 Stage IV Any T, Any N, M1 a [Note: Clinically apparent is defined as detected by imaging studies (excluding lymphoscintigraphy) or by clinical examination or grossly visible pathologically.] b [Note: Classification is based on axillary lymph node dissection with or without sentinel lymph node (SLN) dissection. Classification based solely on SLN dissection without subsequent axillary lymph node dissection is designated (sn) for sentinel node, e.g., pN0(I+) (sn).] c [Note: RT-PCR: reverse transcriptase-polymerase chain reaction.] d [Note: Clinically apparent is defined as detected by imaging studies (excluding lymphoscintigraphy) or by clinical examination.] e [Note: Not clinically apparent is defined as not detected by imaging studies (excluding lymphoscintigraphy) or by clinical examination.]

[Note: T1 includes T1mic] (From ref. 72, with permission.)


Cystosarcoma phyllodes Angiosarcoma Primary lymphoma

Recognizing that invasive ductal carcinomas are histologically diverse with variable biologic behavior, many investigators have attempted to subclassify them based on microscopic features. The most common method to subclassify invasive ductal carcinomas has been grading, which can be based solely on nuclear features (nuclear grading) or on a combination of architectural and nuclear characteristics (histologic grading). In nuclear grading, the appearance of the tumor cell nuclei is compared with those of normal breast epithelial cells, and the tumor nuclei are classified as well differentiated, intermediately differentiated, or poorly differentiated. In current practice, histologic grading is the most commonly used method of grading. In histologic grading, breast carcinomas are categorized based on the evaluation of (1) tubule formation, (2) nuclear pleomorphism, and (3) mitotic activity. The most widely used histologic grading is that proposed by Elston and Ellis76 and is a modification of the grading system proposed by Bloom and Richardson in 1957. Tubule formation (greater than 75%, 10% to 75%, and less than 10%), nuclear pleomorphism (small and uniform, moderate variation in size and shape, and marked nuclear pleomorphism), and mitotic activity (per field area) are each scored on a scale of 1 to 3. The sum of the scores for these three parameters is the overall histologic grade. Tumors with a sum of the scores of 3 to 5 are designated grade 1 (well differentiated), those with sums of 6 and 7 are designated grade 2 (moderately differentiated), and those with sums of 8 and 9 are designated grade 3 (poorly differentiated). Histologic grading has been shown to have prognostic significance and is discussed in the section on prognostic and predictive factors. In addition, breast cancers with pure tubular, mucinous papillary or cribriform features are recognized to have a more favorable outcome than the more common types of breast cancer.74 P.1620

Local Management of Invasive Cancer The evaluation of the newly diagnosed breast cancer patient begins with a determination of operability. The presence of distant metastases at diagnosis has traditionally been considered a contraindication to surgery. Some recent studies have suggested a survival benefit for surgery of the primary tumor in the patient presenting with metastatic disease,77,78 but systemic therapy remains the initial therapeutic approach. Extensive evaluations to look for metastatic disease are not warranted in asymptomatic patients with stage I and II cancer. A review of the detection rate of staging studies in women with stage I cancer reported a 0.5% incidence of metastases found on bone scan and a 0.1% incidence on chest x-ray. For stage II disease these figures were 2.4% and 0.2%, respectively.79 The detection rate of occult metastases by computed tomography (CT) scans and positron emission tomography (PET) scans is also low, and the routine use of these tests is neither medically appropriate nor cost effective. In patients with stage III disease, occult metastases are more frequent, and staging studies are recommended by most organizations.79

Patients with T4 tumors and those with N2 nodal disease are also not candidates for surgery as the first therapeutic approach and should be treated with systemic therapy initially. Current management strategies for this group of women are discussed in the section Locally Advanced and Inflammatory Cancer. In the patient with clinical stage I, II, and T3N1 disease, the initial management is usually surgical. In these patients, the evaluation consists of a determination of their suitability for breast-conserving therapy (BCT) and a discussion of the options of mastectomy with and without reconstruction. Initial systemic therapy may be used to shrink the primary tumor to allow BCT in a woman who would otherwise require mastectomy but is not mandatory, as it is for women with locally advanced and inflammatory carcinoma. The current status of management approaches for primary operable breast cancer is discussed in detail in the following sections. Breast-Conserving Therapy The goal of BCT using conservative surgery (CS) and RT is to provide survival equivalent to mastectomy with preservation of the cosmetic appearance and a low rate of recurrence in the treated breast. Because of the wide acceptance of the Halstedian dogma, a relatively large number of randomized clinical trials were conducted comparing mastectomy and BCT, and they demonstrated equivalent survival. The long-term stability of this equivalence was confirmed by the 20-year follow-up reports of the two largest studies, the Milan I and NSABP B-06 trials.80,81 An overview of all the trials has also demonstrated comparable survival,82 indicating that survival for most breast cancer patients is not dependent on the choice of mastectomy versus BCT. In addition to the results of these trials, retrospective reports from centers in Europe and North America on the use of CS and RT with long follow-up have helped to document the time course and pattern of recurrence in the breast, factors associated with an increased risk of recurrence in the breast, and information regarding cosmetic outcomes after BCT. This information has been useful in determining the optimal approach to CS and RT, in providing guidelines for patient selection, and in providing patients treated with CS and RT with important information on their expected outcome. Despite the consistency of the evidence, the use of BCT in the United States has shown relatively slow acceptance, with considerable geographic variation.83 Potential explanations for the continued use of mastectomy in significant numbers of women include (1) large numbers of patients with contraindications to BCT, (2) patient preference for mastectomy, and (3) use of inappropriate selection criteria by physicians. Medical contraindications are not the major factor responsible for underuse of BCT.84 In a study of 432 patients with stages I and II breast cancer or DCIS who were prospectively evaluated by a multidisciplinary team, only 97 (22%) were found to have contraindications. The incidence and type of contraindications varied with tumor stage and were lowest (10%) for patients with stage I cancer and highest for those with DCIS. Contraindications to BCT (discussed below) can be readily identified with a careful history, physical examination, and detailed mammography, including magnification views of the primary site. Morrow et al.85 evaluated 263 consecutive patients using these parameters. When these parameters suggested a localized tumor, 97% were successfully treated with BCT. Thus, the available data indicate that a minority of patients have contraindications to BCT, and these are readily identified with standard clinical tools. A population-based study of patients diagnosed with breast cancer in 2002 in two large metropolitan areas (Los Angeles and Detroit) found that patient preference for mastectomy plays an important role. In this study, the majority of women (79%) reported that they made

the decision about surgical treatment or that the decision was shared with their surgeon.86 Contrary to expectation, more patient involvement in decision making was associated with a greater likelihood of undergoing mastectomy. Among white women, only 5% of patients whose surgeon made the decision underwent mastectomy compared with 17% of women who shared the decision and 27% of women who made the decision (P <.001, adjusted for other factors). This association was less pronounced among black women. Among women who perceived having a choice between surgical treatments, approximately 40% were greatly concerned about recurrence, approximately 18% about recovery, approximately 15% about radiation therapy, and approximately 10% about body/sexuality issues. Patients who were greatly concerned about recurrence and about radiation therapy were significantly more likely to undergo mastectomy, while patients who were greatly concerned about body/sexuality issues were significantly less likely to undergo mastectomy. This population-based study also found that similar patients get different treatment depending on their surgeon,87 and that the most important aspect for satisfaction with decision making is the match between the patients' preferences for decision making and their experiences regarding participation. Retrospective studies have helped to establish the incidence of local recurrence and its time course. In the 1980s and 1990s, 10-year local recurrence rates ranging from 8% to 19% were commonly reported. These rates are similar to the local recurrence rates seen in the randomized trials of CS and RT from the same era. More recent studies report lower rates of local recurrence, with 10-year actuarial rates of recurrence ranging from 2% to 7% in patients excised to negative margins. P.1621 Table 43.2.11 shows the 10-year rates of local recurrence in recent node-negative NSABP trials.88 This decrease in local recurrence rates is due to a combination of improved mammographic and pathologic evaluation and the more frequent use of adjuvant systemic therapy (discussed in detail in the section on treatment factors and local recurrence). Table 43.2.11 10-Year Local Recurrence Rates in Recent National Surgical Adjuvant Breast and Bowel Project Trials Trial Systemic Therapy ER Status 10-Year LR (%) B13 No chemo 13.3 Chemo 3.5 B14 No tamoxifen + 11.0 Tamoxifen + 3.6 B19 Chemo 6.5 B20 Tamoxifen + 4.7 B23 Chemo 4.3 Chemo, chemotherapy; LR, local recurrence; ER, estrogen receptor. (From ref. 88.) Recurrences in the breast are typically classified by their location in relation to the original tumor. Recurrences at or near the primary site (presumably representing a recurrence of the original tumor) are classified as either a true recurrence (within the boosted region) or a marginal miss (adjacent to the boosted region) or elsewhere in the breast (occurring at a distance from the original tumor and presumably representing a new primary). The time course to local recurrence in the patient undergoing BCT is prolonged. In one study, the annual incidence rate for a true recurrence/marginal miss recurrence was between 1.3% and

1.8% for years 2 through 7 after treatment and then decreased to 0.4% by 10 years after treatment. The annual incidence rate for recurrence elsewhere in the breast increased slowly to a rate of approximately 0.7% per year at 8 years and remained stable. (These results have been contrasted to those seen after mastectomy, in which most local recurrences occur in the first 3 to 5 years after surgery.) In the Milan I trial after 20 years of follow-up, the risk of any type of recurrence in the treated breast was 0.63 per 100 woman-years compared to a risk of 0.66 per 100 woman-years for contralateral cancer.81 This suggests that although whole-breast irradiation is effective at eradicating subclinical multicentric foci of breast carcinoma present at the time of diagnosis, it does not prevent the subsequent development of new cancers. Thus, patients who elect BCT require lifelong follow-up to screen for the development of new cancers in both the treated and the contralateral breast. Risk Factors for Local Recurrence Following Conservative Surgery and Radiation Therapy Risk factors for recurrence after CS and RT can be subdivided into patient, tumor, and treatment factors. Only those factors that are currently considered important are reviewed here. Patient Risk Factors The two important patient risk factors are patient age and inherited susceptibility. Patient Age (less than 35 or 40) has consistently been observed to be associated with an increased risk of local recurrence after BCT. Young patient age is associated with an increased frequency of various adverse pathologic features such as lymphatic vessel invasion, grade 3 histology, absence of ERs, and the presence of an extensive intraductal component (EIC). However, even when correction is done for the differing incidence of the pathologic features of the primary tumor between the age groups, young age is still associated with an increased likelihood of recurrence in the breast.89 Inherited Susceptibility An inherited susceptibility to breast and ovarian cancer and other cancers has been mainly linked to germ-line mutations in BRCA1 and BRCA2. Breast cancer patients with a mutation have a substantial risk of contralateral and late ipsilateral breast cancers. In a retrospective study, outcome following CS and RT was compared for 160 stage I or II breast cancer patients with germ-line BRCA1 or BRCA2 mutations and 445 age- and stagematched control patients without a mutation.90 With a follow-up time of about 7 years, there was no evidence of increased radiation sensitivity or sequelae in patients with a mutation, and actuarial rates of ipsilateral breast cancer recurrence and survival were similar at 10 years. Patients with a mutation, however, were at greater risk of contralateral breast cancer. The 10-year actuarial rate of contralateral breast cancer was 26% for patients with a mutation compared to only 3% for control patients; however, tamoxifen use significantly reduced the risk of contralateral breast cancer in mutation carriers. In addition, the time course to ipsilateral breast cancer recurrence was prolonged with many recurrences located away from the primary tumor, suggesting a new primary. In a separate study of 491 patients with stage I or II breast cancer with a known BRCA1 or BRCA2 mutation in the family, the 10-year risk of a contralateral breast cancer was 43% in BRCA1 carriers and 35% for BRCA2 carriers; however both the use of tamoxifen and bilateral oophorectomy (especially prior to age 49) was associated with reduced risk of contralateral breast cancer.91 In carriers treated with both tamoxifen and bilateral oophorectomy, the risk of contralateral breast cancer was reduced by about 90%. It is important to consider genetic testing in a newly diagnosed breast cancer patient with a personal and family history

suggestive of a BRCA1 or BRCA2 germ-line mutation. In patients with a mutation, the option of bilateral mastectomy should be considered to avoid the long-term risk of a second breast cancer in either breast. Breast cancer patients most likely to benefit from bilateral mastectomy are those who are young and have early stage disease. Given the high risk of a contralateral P.1622 breast cancer, unilateral mastectomy is generally not performed in a patient who is a candidate for BCT. The most important tumor risk factor is the margin of resection. Prior to the routine assessment of margins and detailed mammographic imaging, the presence of an EIC was shown to be a risk factor; however, in patients with negative margins of resection and resection of all suspicious mammographic calcifications, EIC is no longer a risk factor. Tumor size and nodal involvement are not prognostic factors for local recurrence after BCT, but are prognostic factors for distant recurrence. In current practice, microscopic margins of resection are the major selection factor for BCT. A negative margin is defined by absence of cancer cells at inked surfaces, but there are variations in the definitions of a close margin, with different groups using 1, 2, or 3 mm as the cutoff. The amount of cancer close to the margin is also important. Margins need to be interpreted in conjunction with the operative findings. A positive deep margin is not significant if the breast resection was carried down to the pectoral fascia; the same is true for a positive anterior margin if the resection extended to the deep dermal surface. Patients with negative margins of excision have low rates of local recurrence after treatment with CS and RT.92 The outcome of patients with close margins of resection is less clear.92 In part, this reflects variability in the definition of close margins. It seems prudent in patients with close margins to consider other factors, such as young age, involvement close to a margin along a broad front, or the presence of an EIC, in judging the need for re-excision. Close margins may also be a concern when patients receive initial chemotherapy. There is interest in identifying molecular predictors of the risk of local recurrence. One study from the Netherlands found that gene expression profiling using the wound-response signature can identify a subgroup of patients at increased risk for local recurrence.93 Preliminary data from the NSABP also showed a relationship between the results of recurrence scores from Oncotype DX (Genomic Health, Redwood City, California) and the risk of local recurrence.94 The three important treatment risk factors are the extent of breast resection, the use of a boost, and the use of adjuvant systemic therapy. The extent of breast resection has a clear association with local recurrence. The rate of local recurrence is much higher after an incisional biopsy than after an excisional biopsy. Beyond gross excision, however, controversy exists regarding the optimal extent of breast resection. In North America, a more limited resection (lumpectomy) is typically performed, and re-excision is performed if necessary to obtain clear margins, whereas in Europe a wider resection (quadrantectomy or sector resection) is more common. Increasing the volume of breast resection is associated with a decrease in the rate of local recurrence but also has an adverse effect on the cosmetic result. A boost or supplementary irradiation to the area of the primary site is generally used. It is standard in RT after lumpectomy for patients to receive 45 to 50 Gy of whole-breast irradiation followed by a 10 to 16 Gy boost to the region of the tumor bed (Fig. 43.2.2). The rationale for this treatment approach is the recognition that the vast majority of

recurrences that develop after lumpectomy (with or without adjuvant RT) are in the immediate area of the excision cavity and that a boost can be delivered safely without significantly affecting the cosmetic result. The use of a boost is supported by the large EORTC trial in which 5,318 patients with negative margins were randomized to a boost of 16 Gy or no boost following 50 Gy to the whole breast.95 With a median follow-up of 10.8 years, the cumulative incidence of ipsilateral breast recurrence was 10.2% without a boost and 6.2% with a boost (P <.0001). This 41% proportional reduction in local recurrence was similar in all age groups; however, the absolute benefit of the boost was greatest in young patients aged 40 or less (24% decreased to 14%) and was smallest in patients aged greater than 60 (7% decreased to 4%). Severe fibrosis was increased from 2% to 4% with the boost. Survival at 10 years was the same in both arms. The use of adjuvant systemic therapy is an important factor associated with recurrence in the treated breast in conjunction with CS and RT. This effect is clearly demonstrated in three randomized clinical trials. In NSABP trial B14, node-negative ER-positive patients were randomized to tamoxifen or to a placebo. Among the 1,062 patients treated with CS and RT, the 10-year rate of recurrence in the ipsilateral breast was 14.7% without tamoxifen and only 4.3% with tamoxifen.96 A similar result was seen in the Stockholm Breast Cancer Study Group among node-negative patients randomized to tamoxifen or to a placebo. Among the 432 patients treated with CS and RT, the 10-year rate of recurrence in the ipsilateral breast was 12% without tamoxifen and only 3% with tamoxifen.97 In the NSABP trial B21, patients with node-negative breast cancer measuring less than or equal to 1 cm treated with lumpectomy were randomized to tamoxifen alone, RT, or RT and tamoxifen. With a mean follow-up of 87 months, the 8-year rate of ipsilateral local recurrence was 9.3% in the patients treated with RT and 2.8% in the patients treated with RT and tamoxifen.98 Of note in these trials is that tamoxifen was given concurrently with RT; however, retrospective comparisons of concurrent versus sequential tamoxifen and RT have shown similar recurrence and survival rates. At this time, it seems that either concurrent or sequential administration of tamoxifen and RT is reasonable. Similar results are seen with adjuvant chemotherapy, but the relationship is more complex, perhaps related to sequencing. In the NSABP B13 trial, node-negative ER-negative patients were randomized to chemotherapy or to a no-treatment control group. Among the 235 patients treated with CS and RT, the 8-year rate of recurrence in the ipsilateral breast was 13.4% without chemotherapy and only 2.6% with chemotherapy given concurrently with the RT.99 Concurrent RT and chemotherapy also has the virtue of abbreviating the overall time for the course of treatment, but there is reluctance to use concurrent RT and an anthracycline. In a French phase III trial comparing concurrent versus sequential RT and chemotherapy with mitoxantrone and cyclophosphamide, local control was improved with concurrent administration, but concurrent treatment was also associated with an increased incidence of grade 2 or greater late side effects.100 The results of a prospective study of concurrent cyclophosphamide, methotrexate, and fluorouracil (CMF) chemotherapy and lower-dose breast RT showed a low rate of local recurrence with acceptable cosmetic results and few complications.101 However, an attempt to employ concurrent RT and weekly taxol following 4 doses of doxorubicin and cyclophosphamide (AC) resulted in excessive pulmonary toxicity.101 Thus, the use of concurrent breast RT and chemotherapy has appeal, but is currently not standard with RT and anthracyclines or taxanes. P.1623

Figure 43.2.2. Computed tomography simulation for a left-sided breast cancer with medial and lateral tangential fields. Left upper is the beam's eye view with the large rectangle being the treatment field. The area of the primary in the upper outer quadrant is contoured in magenta and the heart is contoured in red. Note that for the actual treatment a block was used to block irradiation of her heart, which also blocked out some breast tissue well away from the primary cancer. Right upper is an axial view of the treatment fields in the center of the treatment fields. Left lower shows (in red) the medial tangent borders on the patient's skin. Right lower shows (in green) the lateral tangent borders on the patient's skin. Updated results of our small randomized clinical trial address the question of sequencing following lumpectomy.102 In this trial 244 patients were randomized following conservative breast surgery to receive 12 weeks of CAMFP (cyclophosphamide, doxorubicin, methotrexate, fluorouracil, and prednisone) chemotherapy before radiation (CT first), or

following radiation (RT first). In the updated results, the median follow-up for surviving patients was 135 months. There were no significant differences between the CT-first and RT-first arms in time to any failure, distant metastasis, or death. Sites of first failure were also not significantly different (P = .41). However, the same trends toward greater local recurrence in the CT-first group and greater distant recurrence in the RT-group were seen. In an interaction model, there was a significant interaction between margin status and treatment sequence (P <.05). Patients with negative margins had a low rate of local recurrence as a site of first failure with either sequence; patients with positive margins had a high rate of local recurrence with both regimens. Of note, however, patients with close margins had local recurrence rate of 32% with CT first and 4% with RT first. Until safe and effective methods of concurrent anthracycline or taxol-based chemotherapy and RT are established, the standard approach is to use sequential chemotherapy and RT. Given the primary importance of preventing systemic relapse, it has been the convention to use initial chemotherapy followed by RT. Although concerns have been expressed about an increased rate of local recurrence with this approach, the results of clinical trials in patients with negative margins have not shown this to be a problem even following 4 cycles of AC followed by 4 cycles of taxol, both given every 3 weeks.103 A major goal of BCT is the preservation of a cosmetically acceptable breast. When modern treatment techniques are used, an acceptable cosmetic outcome can be achieved in almost all patients (without compromise of local tumor control) (Fig. 43.2.3) P.1624 Although treatment-related changes in the treated breast stabilize at approximately 3 years, other factors that primarily affect the untreated breast, such as change in size because of weight gain and the normal ptosis seen with aging, continue to affect the symmetry between a patient's breasts. The major factor determining the cosmetic result is the extent of surgical resection.104 A variety of factors must be considered together (the size of the patient's breast, the size of the tumor, the depth of the tumor within the breast, and the quadrant of the breast in which the tumor is located) to judge the feasibility of a cosmetically acceptable resection. For example, although the removal of a large tumor in the lower portion of the breast often results in distortion of the breast contour, this is only apparent with the arms raised and is acceptable to most women. A similar distortion in the upper inner quadrant of the breast, which is visible in most types of clothing, might not be as acceptable. Techniques such as latissimus dorsi reconstruction of the defect may be appropriate in selected patients to improve the cosmetic appearance after large resections, and the use of preoperative chemotherapy or endocrine therapy may allow resection of a smaller volume of tissue.

Figure 43.2.3. Cosmetic outcome of breast-conserving therapy. Other than the surgical scar, there is minimal difference between the treated and the untreated breast. Guidelines for Patient Selection Because of the potential options for treatment of early stage breast cancer, careful patient selection and a multidisciplinary approach are necessary. The four critical elements in patient selection for BCT are (1) history and physical examination, (2) mammographic evaluation, (3) histologic assessment of the resected breast specimen, and (4) assessment of the patient's needs and expectations. Recent (i.e., usually within 3 months) preoperative mammographic evaluation is necessary to determine a patient's eligibility for BCT. Mammographic evaluation defines the extent of a patient's disease, the presence or absence of multicentricity, and other factors that might influence the treatment decision, and evaluates the contralateral breast. If the mass is associated with microcalcifications, an assessment of the extent of the calcifications within and outside the mass should be made using magnification views. Advances in breast imaging have led some to question whether MRI should be part of the standard preoperative evaluation of the breast cancer patient; however, its benefit has not been established and might result in greater, but unwarranted use of mastectomy.105 MRI frequently identifies additional areas of involvement in the breast, but long-term clinical experience has demonstrated that the majority of this disease is controlled with RT. In addition, MRI has a substantial false-positive rate. Ideally, prospective trials demonstrating a decrease in the rate of breast recurrence in patients selected for BCT with MRI are needed before these examinations are routinely used for patient selection. The patient and her physician must discuss the benefits and risks of mastectomy compared with those of BCT in her individual case. The following factors should be discussed:

The absence of a long-term survival difference between treatments The possibility and consequences of local recurrence with both approaches

Psychological adjustment (including the fear of cancer recurrence), cosmetic outcome, sexual adaptation, and functional competence

Psychological research comparing patient adaptation after mastectomy with that after BCT shows no significant differences in global measures of emotional distress. However, women whose breasts are preserved have more positive attitudes about their body image and experience fewer changes in their frequency of breast stimulation and feelings of sexual desirability. In addition, patients treated with BCT have better physical functioning compared to patients treated with mastectomy at the end of primary treatment.106 Absolute and Relative Contraindications to Breast-Concerving Therapy In the selection of patients for BCT, there are some absolute and relative contraindications.107 Absolute Contraindications

Pregnancy is an absolute contraindication to the use of breast irradiation. However, in many cases, it may be possible to perform BCS in the third trimester and treat the patient with irradiation after delivery. Women with two or more primary tumors in separate quadrants of the breast or with diffuse malignant-appearing microcalcifications are not considered candidates for breast conservation treatment. A history of prior therapeutic irradiation to the breast region that would require retreatment to an excessively high total radiation dose to a significant volume is another absolute contraindication. Persistent positive margins after reasonable surgical attempts. The importance of a single focally positive microscopic margin needs further study and may not be an absolute contraindication.

Relative Contraindications

A history of collagen vascular disease is a relative contraindication to breast conservation treatment because published reports indicate that such patients tolerate irradiation poorly. P.1625

Most radiation oncologists will not treat patients with scleroderma or active lupus erythematosus, considering these absolute contraindications. In contrast, rheumatoid arthritis is not a relative or an absolute contraindication.

Tumor size is not an absolute contraindication to breast conservation treatment, although there is little published experience in treating patients with tumor sizes greater than 4 to 5 cm. However, a relative contraindication is the presence of a large tumor in a small breast in which an adequate resection would result in significant cosmetic alteration. In this circumstance, preoperative chemotherapy should be considered.

Breast size can be a relative contraindication. Treatment by irradiation of women with large or pendulous breasts is feasible if reproducibility of patient setup can be ensured and the technical capability exists for 6 MV or greater photon beam irradiation to obtain adequate dose homogeneity.

Nonmitigating Factors There are certain clinical and pathologic features that should not prevent patients from being candidates for breast conservation treatment. These features include the presence of clinically suspicious and mobile axillary lymph nodes or microscopic tumor involvement in axillary nodes. In addition, it is important to emphasize that it is feasible to evaluate the breast for local recurrence. The changes associated with recurrence can be detected at an early stage through the use of physical examination and mammography. The delivery of irradiation in this setting does not result in a meaningful risk of second tumors in the treated area or in the untreated breast. Tumor location is not a factor in treatment choice. Tumors in a superficial subareolar location may occasionally require the resection of the nipple/areolar complex to achieve negative margins, but this does not have an impact on outcome. Whether this is preferable to mastectomy needs to be assessed by the patient and her physician. A high risk of systemic relapse is not a contraindication for breast conservation, but rather a determinant of the need for adjuvant therapy. Preoperative Systemic Therapy for Operable Cancer Women who desire BCT but are not candidates for the procedure due to a large tumor relative to the size of the breast should be considered for preoperative or neoadjuvant therapy. This approach is not appropriate for patients with multicentric carcinoma, those with an extensive intraductal component that precludes a cosmetic resection, or those who prefer treatment by mastectomy. Patients most likely to benefit from neoadjuvant chemotherapy are those with unicentric, high-grade, ER-negative cancers. Prospective, randomized trials of patients with operable breast cancer have demonstrated that clinical response rates to neoadjuvant chemotherapy are high, ranging from 49% in the EORTC study of fluorouracil, epirubicin and cyclophosphamide (FEC)108 to 79% in the NSABP B18 study of doxorubicin (A) and cyclophosphamide (C)109 to 91% in the NSABP B27 trial examining the addition of docetaxel (T) to AC.110 Pathologic complete responses in the breast were seen in 4%, 13%, and 19% of patients, respectively, in these trials. In spite of these high response rates, only 25% to 30% of patients who were not candidates for BCT at presentation were able to undergo the procedure after preoperative therapy.108,109 This is a reflection of both the difficulty of assessing the extent of residual viable tumor after preoperative chemotherapy and the often patchy nature of cancer cell death in response to chemotherapy. This type of response significantly decreases the total number of viable tumor cells, but viable tumor remains scattered throughout the same volume of breast tissue, precluding BCT. MRI shows promise compared to mammography and ultrasound in evaluating the extent of viable tumor, but may both underestimate and overestimate the extent of residual disease. In patients who overexpress human epidermal growth factor receptor-2 (HER-2), the preoperative administration of trastuzumab in combination with chemotherapy has been associated with high rates of pathologic complete response. In a randomized study of 42 patients treated with four cycles of paclitaxel followed by four cycles of FEC or the same chemotherapy with simultaneous weekly trastuzumab for 24 weeks, the pathologic complete response rate was increased from 26% to 65% with the addition of

trastuzumab.111 In 22 additional patients assigned to chemotherapy plus trastuzumab, the pathologic complete response rate was 54.5%. A significant improvement in disease-free survival was also noted for trastuzumab treated patients after a median follow-up of 36.1 months. To date, no increase in cardiac dysfunction has been observed in the trastuzumab group.111 Although these high complete-response rates require verification in a larger cohort of patients, they are consistent with the survival benefit observed for trastuzumab when given with chemotherapy in the adjuvant setting, suggesting that this approach may increase the rate of BCT in the population of patients overexpressing HER-2. A meta-analysis of nine randomized trials of preoperative chemotherapy demonstrated no increase, or decrease, in survival with preoperative compared to postoperative treatment,112 but an elevated risk of locoregional recurrence (RR 1.22; 95% CI, 1.04 to 1.45) was noted. Some of the increase in local recurrence was due to the inclusion of studies in the metaanalysis in which patients who had a clinical complete response did not have surgery. The majority of patients with a clinical complete response do not have a pathologic complete response, and the elevated risk of local recurrence seen in the meta-analysis emphasizes the importance of surgery to minimize the residual tumor burden in the breast. Even in patients undergoing surgery an elevated risk of local recurrence has been observed. In the NSABP B18 study109 local recurrence rates were 15% in patients who required chemotherapy to undergo BCT compared to only 7% in those who were initially candidates for BCT. The increased rates of local recurrence after neoadjuvant therapy may reflect differences in the meaning of a negative excision margin in a situation where, by definition, the volume of tissue resected is smaller than the volume originally occupied by the cancer. In this setting a negative margin may still be associated with a clinically significant residual tumor burden that is unlikely to be controlled by radiotherapy. Thus, an evaluation of both surgical margins and the extent of viable tumor elsewhere in the specimen is essential and may dictate resection of additional breast tissue even when margins are apparently tumor free. Percutaneous placement of marker clips within the primary tumor prior to the initiation of chemotherapy will provide a landmark for localization and excision should a clinical and radiographic complete response occur. The lack of a survival benefit for neoadjuvant therapy and the increased complexity in determining the appropriate extent of resection P.1626 suggest that for women who are candidates for breast conservation at presentation, neoadjuvant therapy outside the context of a clinical trial offers little benefit. Table 43.2.12 Effects of Radiotherapy after Breast-Conserving Surgery 5-Y Gain in Local 15-Y Gain Breast Cancer 15-Y Gain Overall Control (%) Mortality (%) Mortality (%) BCS +/- RT: 16.1 5.1 4.6 NodeBCS +/- RT: 30.1 7.1 8.2 Node+ MRM +/- RT: 4.0 -3.6 -4.2 NodeMRM +/- RT: 17 5.4 4.4 Node+ BCS, breast-conserving treatment; RT, radiation therapy; MRM, modified radical mastectomy.

(From ref. 116.) Neoadjuvant endocrine therapy has also been used to increase rates of BCT, although there is less experience with this approach than with chemotherapy. In a randomized trial of 337 hormone-receptorpositive postmenopausal women who were not considered candidates for BCT at presentation, 35% of those who received 4 months of tamoxifen 20 mg daily and 45% of those who received letrozole 2.5 mg daily were able to undergo BCT.113 A subsequent analysis suggested that a higher response rate to letrozole was particularly likely in patients whose tumors overexpressed HER-1 or HER-2.114 In a similar study comparing 3 months of tamoxifen 20 mg daily to anastrozole 1 mg daily or the combination of the two drugs, 44% of those treated with anastrozole who were felt to require mastectomy at presentation had BCT compared to 31% of those treated with tamoxifen and 24% who received the combination (P = .23).115 These studies indicate that in postmenopausal women with hormone-receptorpositive tumors the preoperative use of an aromatase inhibitor significantly increases the likelihood of breast conservation. However, in spite of the proven survival benefit seen with endocrine therapy in the adjuvant setting, pathologic complete response is rare with the short duration of treatment used in the neoadjuvant setting. The degree of pathologic response does not appear to have the same prognostic significance as it does when neoadjuvant chemotherapy is used, and failure to achieve complete response should not be interpreted as evidence of resistance to endocrine therapy. Overall, both neoadjuvant chemotherapy and endocrine therapy are effective strategies for increasing the rate of BCT. Because neoadjuvant therapy may necessitate changes from traditional surgical and radiation therapy approaches to treatment of the breast, coupled with the more complex issues of nodal management discussed later in this chapter, this approach is best used as part of a coordinated multidisciplinary treatment effort. Conservative Surgery without Radiation Therapy An unresolved question is whether RT is necessary in all patients with invasive breast cancer after CS. It is well known that RT after CS reduces local recurrence by about 70%, but there has been uncertainty about whether this improvement in local recurrence is important to survival and whether there is a subgroup of patients with a low risk of local recurrence following CS alone. The impact of improving local control on overall long-term survival was greatly clarified with the findings of the 2005 Early Breasts Cancer Trialists Group (EBCTCG) meta-analysis.116 This study found that improvements in 5-year local control resulted in statistically significant improvements in breast cancerspecific mortality and overall survival at 15 years (Table 43.2.12). The addition of RT to CS in node-negative patients improved 5-year local control by 16.1%, 15-year breast cancer mortality by 5.1% and 15-year overall survival by 4.6%. The addition of RT to CS in nodepositive patients improved 5-year local control by 30%, 15-year breast cancer mortality by 7.1%, and 15-year overall survival by 8.2%. These data provide compelling evidence that RT after CS is not only important for local control, but also for survival. Attempts have been made to identify a subgroup of patients (based on various clinical and histologic features) who have a low risk of local recurrence after CS alone. It was not possible to identify such a subgroup within the available clinical trials. Local recurrence rates are generally lower in trials that use more extensive surgery than in those using lumpectomy and in older patients than in younger patients. The Joint Center for Radiation Therapy in Boston attempted to identify a suitable subgroup for wide excision alone in a prospective single-arm trial in which patients with a very favorable prognosis were offered the option of CS alone. The criteria for entry onto this protocol were tumor size of 2 cm or

less, histologically negative axillary nodes, absence of either lymphatic vessel invasion or an EIC in the cancer, and no cancer cells visualized within 1 cm of inked margins.117 All but one patient had a completely negative re-excision. The median age of patients in this trial was 66, 75% of cancers were detected by mammography alone, and the median pathologic size of the cancers was 9 mm. None of the patients received adjuvant endocrine therapy or chemotherapy. This trial was stopped shortly before it reached its accrual goal of 90 patients because of stopping rules ensuring against an excessively high local recurrence rate. With a median follow-up time of 86 months among the 81 eligible patients, the crude rate of local recurrence was 23%. The average local recurrence rate was 2.8% per year. Of note, of the six patients with a tubular cancer, three had a local recurrence. Examination of subsets of patients by age and tumor size did not find any statistically significant differences. Similar results were seen in a small randomized clinical trial from Finland. Based on the results of these prospective studies, it was concluded that even a highly selected group of breast cancer patients (based on patient and tumor characteristics) have a substantial risk of early local P.1627 recurrence after treatment with wide excision alone. Newer markers are needed to more reliably identify patients who can be safely treated with wide excision alone. Table 43.2.13 Trials of Tamoxifen with or without Radiotherapy after BreastConserving Therapy Study (Reference) No. of Patients: Selection FU (median months) NSABP B21 (ref. 98) 1,009: 1 cm; pN0 87 Canadian (ref. 118) 769: >50, T1,2; pN0 67 Scottish (ref. 119) 427: <70, T1,2; pN0 67 CALGB (ref. 120) 636: >70, T1; pN0 60 NSABP, National Surgical Adjuvant Breast and Bowel Project; CALGB, Cancer and Leukemia Group B; FU, follow-up. More recently, there have been four trials that have compared tamoxifen with and without RT after BCS (largely in ER-positive patients) and their details are shown in Table 43.2.13.98,118,119,120 The 5-year local recurrence rates for these trials are shown in Table 43.2.14. The 5-year results seem reasonable, but the rate of local recurrence appears increased after 5 years. In the Canadian Trial,118 local recurrence is 7.7% at 5 years, but 17.6% at 8 years. This raises the question whether tamoxifen is merely delaying local recurrence. As previously discussed, the combination of tamoxifen and RT provides a very low rate of local recurrence. Tamoxifen alone has its greatest appeal in older patients (older than 70) where competing risks of other illnesses are substantial. In elderly patients, it is critical for the clinician to assess the patient's particular cancer characteristics as well as her comorbid illnesses and individual value system in determining the advisability of adding RT. Accelerated Partial Breast Irradiation There have been a growing number of studies attempting to decrease the overall treatment time for RT after lumpectomy through the administration of larger daily doses (fraction sizes) of RT delivered only to the portion of the breast containing the primary tumor. The potential benefits of such an approach include (1) the quality of life of patients could be improved by relieving patients of the necessity of daily treatments for 5 to 6 weeks, (2) the underutilization of BCT could be reduced by making it more feasible for patients to receive

RT, (3) the integration of local and systemic therapies could be simplified, and (4) longterm complications of RT could be decreased by limiting the volume of critical structures irradiated to high dose. The scientific rationale for the delivery of whole-breast RT after lumpectomy is that many patients harbor areas of occult, residual microscopic disease in the breast after tumor excision (even with negative margins). To this end, RT has been delivered to the whole breast and the lumpectomy bed in an effort to sterilize these residual foci of cancer. However, patterns of failure after standard whole-breast RT and after excision alone demonstrate that the large majority of recurrences are in the immediate vicinity of the tumor bed.92 In addition, pathologic studies on the distribution of tumor cells in relation to the primary tumor demonstrate that for the large majority of patients the majority of tumor cells in the breast are found quite close to the primary tumor.121 This suggests that postlumpectomy RT exerts its maximal effect on eradicating residual disease in the region of the tumor bed, and that areas of occult disease in the remainder of the breast may be of little practical significance. If this hypothesis is correct, it would only be necessary to deliver RT to the region of the lumpectomy bed. By restricting the volume of tissue that requires RT, it may be possible to reduce the overall treatment time by increasing the daily dose (fraction size) of RT. These hypotheses provide the basis for the use of accelerated partial breast irradiation. Table 43.2.14 Five-Year Rates of Local Recurrence in Tamoxifen with or without Radiotherapy Trials Study (Reference) Tamoxifen (%) Tamoxifen + RT (%) End Point NSABP B21 (ref. 98) 8.4 1.1 LR Canadian (ref. 118) 7.7 0.6 LR 13.2 1.1 L-RR Scottish (ref. 119) 25.0 3.1 L-RR CALGB (ref. 120) 4 1 L-RR NSABP, National Surgical Adjuvant Breast and Bowel Project; CALGB, Cancer and Leukemia Group B; RT, radiotherapy; LR, local recurrence; L-RR, locoregional recurrence. These are a number of different techniques that can be used to achieve accelerated partial breast irradiation, and these include interstitial brachytherapy, limited external beam irradiation, intracavitary brachytherapy, and intraoperative limited RT. The field of accelerated partial breast irradiation is a rapidly moving field. At this writing, there are a variety of approaches P.1628 and few long-term data, especially from randomized clinical trials. Patient selection for this approach is still controversial. Ideal patients are older, with no or limited axillary nodal involvement, have clear margins on lumpectomy, and do not have lobular histology or ductal histology with an EIC. Successful application of this approach requires technical expertise. There is an ongoing NSABP/RTOG phase III trial comparing conventional RT versus accelerated partial breast irradiation (allowing implant or external beam techniques), and accrual to the trial has been excellent. Mastectomy Mastectomy, with or without immediate breast reconstruction, is the surgical approach for the patient with breast cancer who has contraindications to BCT or who prefers treatment with mastectomy. The mastectomy used today is a total or complete mastectomy, with removal of the breast tissue from the clavicle to the rectus abdominous and between the

sternal edge and the latissimus dorsi. A total mastectomy also removes the nipple-areolar complex, the excess skin of the breast, and the fascia of the pectoralis major muscle. When accompanied by an axillary dissection, the procedure is termed a modified radical mastectomy. Mastectomy is an extremely safe operation. The 30-day mortality in women of all ages is less than 1%. Major complications after surgery are infrequent, but there is loss of sensation on the chest wall in 100% of patients. In a population-based study of 1,884 women treated for breast cancer in 2002, 30% underwent mastectomy. This was due to contraindications to BCT in approximately half and patient choice in the remainder.86 Advances in plastic surgical technique have made immediate reconstruction an option for most patients who undergo mastectomy. Potential concerns about immediate reconstruction have included the possibility of an increased incidence of local failure, delay in the diagnosis of local failure, or delay in the administration of adjuvant therapy due to wound healing issues. More recently as indications for postmastectomy RT have expanded, the impact of RT on reconstruction has also become an issue. Immediate reconstruction can negatively impact the technical delivery of RT, possibly resulting in greater irradiation of the heart (in left-sided cancers) and lung and undercoverage of the chest wall.122 There have been no prospective trials comparing mastectomy alone to mastectomy with immediate reconstruction, but the available retrospective data do not support concerns about the incidence or detection of local recurrence in the reconstructed patient. The majority of postmastectomy recurrences occur in the skin or subcutaneous fat of the chest wall and present as palpable masses in the skin flap, so detection is not affected by the presence of the reconstruction.123 More recently, skin-sparing mastectomy in which skin excision is limited to the nippleareolar complex (NAC) and the excisional biopsy scar (if present) have been utilized to preserve the skin envelope of the breast and facilitate reconstruction. The reported rates of local recurrence after skin-sparing mastectomy are comparable to those of patients treated with conventional mastectomy.92 This finding is consistent with prior observations that the extent of skin removal in patients treated with mastectomy alone is not a major determinant of the risk of chest wall recurrence. Traditionally, skin-sparing mastectomy has included resection of the NAC. The rationale for this approach is the risk of leaving behind malignancy with nipple preservation due to the extension of ductal tissue into the nipple and the need to leave breast tissue on the NAC to provide a blood supply. Recently, however, investigators have begun to explore the safety of nipple-sparing mastectomy (NSM) in selected cases. The reported incidence of occult involvement of the NAC in patients with known breast cancer ranges from 0% to 58%.124 This wide range is due to differences in tumor stage and in the number of sections taken to evaluate the NAC specimen in different studies. Gerber et al.125 selected potential candidates for NSM who had peripherally located tumors 2 cm or less in size, no clinical evidence of nipple involvement, and clinically negative axillary nodes. In spite of this, frozen-section analysis demonstrated microscopic tumor in the subareolar tissue in 46% of 112 patients. Of the 61 patients treated by NSM, only one experienced a local recurrence in the NAC with a mean follow-up of 59 months.125 In a multi-institutional study of 123 patients undergoing NSM for treatment or prophylaxis no local recurrences in the NAC were observed after a median follow-up of 24.6 months.126 Necrosis of the nipple was seen in 11% of cases and involved less than one third of the nipple in 13 of 22 patients. Another approach to the problem of cancer recurrence in the preserved NAC has been to deliver a dose of intraoperative RT to the NAC.

These studies indicate that NSM may be a viable option in highly selected women, specifically patients with small, peripherally located, node-negative tumors with favorable histologic features. Most women in this category, however, are candidates for conventional BCT. The eligible population for NSM is further limited by the requirement that the nipple be in the appropriate position on the reconstructed breast. This is rarely the case for women with large, ptotic breasts, further limiting the application of this procedure. In summary, immediate reconstruction with preservation of the skin envelope of the breast has not been shown to alter the outcome of mastectomy or to delay the administration of systemic therapy. Immediate reconstruction has the advantages of avoiding the need for a second major operative procedure and the psychological morbidity of the loss of the breast. The two major reconstructive techniques involve the use of implants and/or tissue expanders or the use of myocutaneous tissue flaps to create a new breast mound. The advantages and disadvantages of the techniques are summarized in Table 43.2.15. Implant reconstructions are best suited for women with small to moderate sized breasts with minimal ptosis, while flap reconstructions allow more flexibility in the size and shape of the reconstructed breast (Fig. 43.2.4). In the past, most breast implants were filled with silicone gel. However, after reports from uncontrolled studies suggested an increased incidence of connective tissue disease in women with silicone implants the FDA declared a moratorium on their use. Since that time, several epidemiological studies have failed to demonstrate an increased incidence of connective tissue disorders in women with implants compared to matched control populations. Silicone implants are again available for use in breast cancer patients, but many patients opt for saline implants or flap reconstructions as a result of the adverse publicity surrounding silicone implants. Reconstructive choices may be influenced by the possible need for postmastectomy radiotherapy. As noted above, P.1629 immediate reconstruction can result in greater irradiation of heart (in left-sided cancers) and lung and undercoverage of the chest wall. There are a variety of strategies that have been proposed for selecting the type of reconstruction for a patient with a significant likelihood of requiring postmastectomy radiotherapy. There is considerable variability in outcome reported in the medical literature for the same approaches and there are no prospective studies reported to date. The use of RT in patients who have been reconstructed with implants is associated with a higher risk of encapsulation and implant loss than in nonirradiated patients. In one study, however, Cordeiro et al.127 reported that after a mean follow-up of 34 months in 68 patients reconstructed with tissue expanders or implants who received RT, 80% had good to excellent aesthetic results and 72% would have chosen the same form of reconstruction again. The figures for nonirradiated patients were 88% (P = NS) and 85%, respectively. Implant loss occurred in 11% of patients with irradiated implants and 6% of nonirradiated patients. The finding in this study that the majority of patients who require RT after implant reconstruction have good cosmesis and are satisfied with their reconstruction choice has led some to advocate insertion of an expander at the time of mastectomy, which is inflated during chemotherapy and exchanged for a permanent implant prior to RT. In patients who are satisfied with the cosmetic outcome after RT, no further surgery is required. In patients with significant cosmetic deformity, a secondary flap reconstruction is performed. This approach has the advantage of allowing preservation of the breast skin and providing the patient with a breast mound during what may be a

prolonged course of postoperative cancer therapy. However, additional favorable experience with irradiation of expanders or implants at other institutions is needed. Table 43.2.15 Common Reconstructive Options after Mastectomy Type Advantages Disadvantages Implant One stage procedure, minimal Poor symmetry if skin prolongation, hospitalization, or removed or in large ptotic recovery. breasts. Low cost. Capsular contracture, leakage, rupture possible. Tissue expander Short operative time. Multiple physician visits Hospitalization, recovery not postop. Poor symmetry large prolonged. or ptotic breasts. Low cost. Capsular contracture, leakage rupture possible. Latissimus dorsi flap Very low risk of flap loss. Donor site scar. Natural contour with autogenous Usually requires an implant. tissue. Moderate prolongation hospitalization and recovery. Transverse rectus Natural contour. Good match for Donor site scar. abdominous myocutaneous large or ptotic breasts. Fat necrosis, flap loss possible. (TRAM) flap Abdominoplasty. Abdominal wall weakness plus hernia. Significant prolongation hospitalization plus recovery. Deep inferior epigastric Natural contour. Donor site scar. perforator (DIEP) flap Muscle sparing. Need for microsurgeon. Abdominoplasty. Flap loss possible. Moderate prolongation hospitalization plus recovery. Superior gluteal artery Natural contour. Donor site scar. perforator flap Alternative donor site. Need for microsurgeon. Flap loss possible. Moderate prolongation hospitalization plus recovery.

Figure 43.2.4. Cosmetic outcome of transrectus abdominis muscle flap reconstruction after skin-sparing mastectomy. A primary flap reconstruction is another alternative for the patient who may require postmastectomy RT. Variable outcomes have been reported for patients who receive RT after transverse rectus myocutaneous flap or latissimus dorsi flap reconstruction. Complete flap loss is rare, but fat necrosis, fibrosis, and volume loss can occur. As in the native breast, the full cosmetic impact may not be evident until 3 years posttreatment. In P.1630 one study, the 5-year incidence of major complications after transverse rectus myocutaneous reconstruction was 0% (n = 35) and 5% after tissue expander/implant (n = 50) reconstruction followed by RT.128 In contrast, four of 27 (9%) patients reconstructed with flaps and six of 15 (40%) implant patients underwent major corrective surgery a median of 8 months after RT in another series.129 The extreme variability in reported results

emphasizes the need for prospective studies in this area. An alternative approach is to perform sentinel node biopsy prior to mastectomy to identify patients with nodal involvement at highest risk for requiring postmastectomy RT and delay reconstruction in this subset of women until after the completion of oncologic therapy. This is an area that continues to evolve, and multidisciplinary consultation between the oncologic surgeon, reconstructive surgeon, and radiation oncologist will help to ensure optimal patient outcomes. Management of the Axilla For many years, standard management of the axilla for patients with invasive breast carcinoma consisted of a complete axillary dissection. Initially, this was thought to be a critical component of the surgical cure of breast cancer. This changed when studies such as the NSABP B04 trial, in which clinically node-negative patients were randomized to radical mastectomy, total mastectomy with RT to the regional lymphatics, or total mastectomy with observation of the axillary nodes and delayed axillary dissection if nodal metastases developed, showed no survival benefit for the axillary surgery.130 Axillary dissection came to be regarded as a staging procedure that provided prognostic information and maintained local control in the axilla. However, the observation that 25% to 30% of long-term survivors treated with radical mastectomy alone had positive nodes,131 coupled with the decreased survival observed after inadequate axillary treatment in the Guys Hospital trial,132 suggested that for some patients with axillary nodal metastases axillary dissection was therapeutic. The technique of lymphatic mapping and sentinel node biopsy reliably identifies patients with axillary node involvement with a low morbidity operation, allowing axillary dissection to be limited to patients with nodal metastases who have the potential to benefit from the procedure. The American College of Surgeons Oncology Group (ACOSOG) Z10 trial and the NSABP B32 trial, involving 5,327 and 5,210 clinically node-negative patients, respectively, demonstrated that a sentinel node could be identified in 98.6% and 97% of patients.133 In the ACOSOG Z10 trial participating surgeons chose the method of lymphatic mapping, and no significant differences were seen in the rate of sentinel node identification with the use of blue dye alone, radiocolloid alone, or the combination of the two.133 Increasing body mass index, increasing age, and fewer than 50 patients accrued to the trial were all associated with a significant decrease in sentinel node identification rate, but a sentinel node was successfully identified in more than 95% of patients in all groups. Tumor size, histologic type, tumor location, and breast biopsy type (needle vs. surgical) were not associated with the sentinel node identification rate. Complications of sentinel node biopsy are infrequent, with anaphylaxis to Lymphazurin blue dye observed in 0.1% of patients in the ACOSOG Z10 trial134 and axillary paresthesias 6 months postoperatively in 8.6%. Lymphedema does occur after sentinel node biopsy, but at a much lower rate than after axillary dissection. In the randomized Axillary Lymphatic Mapping Against Nodal Axillary Clearance (ALMANAC) trial, the absolute incidence of lymphedema in the sentinel node biopsy group was 5% at 12 months, a relative risk of 0.37 (95% CI, 0.23 to 0.60) compared to the axillary clearance group in an intention to treat analysis.135 The majority of patients with stage I and II cancer are candidates for sentinel node biopsy. Contraindications to the procedure include pregnancy, lactation, and locally advanced breast cancer. Care should be taken to excise any palpably abnormal nodes intraoperatively since lymph nodes that contain a heavy tumor burden may not take up the mapping agent.

In the patient with clinically positive nodes, confirmation of metastases preoperatively with FNA allows an immediate axillary dissection. Caution should be used in proceeding directly to dissection without cytologic confirmation since the false-positive rate of physical examination is approximately 20%. The presence of multicentric carcinoma or a T3 primary tumor were initially thought to be contraindications to lymphatic mapping, but studies have shown that sentinel node biopsy is accurate in these circumstances.136 Controversy continues over the appropriate timing of sentinel node biopsy in patients receiving neoadjuvant chemotherapy. A retrospective analyses of 428 of 2,365 patients in the NSABP B27 trial who received chemotherapy followed by sentinel node biopsy and an axillary dissection demonstrated an 85% sentinel node identification rate and a falsenegative rate of 11%. These results are similar to those observed in patients undergoing an initial sentinel node biopsy during the same time period.137 Sentinel node biopsy after neoadjuvant therapy offers the patient the potential benefit of axillary downstaging and avoidance of axillary dissection. Further follow-up on axillary failure rates with this approach is needed. In some circumstances, knowledge of the patient's histologic nodal status prior to chemotherapy may be useful for planning RT, in which case consideration should be given to performing the sentinel node biopsy prior to the initiation of chemotherapy. The accuracy of sentinel node biopsy in patients with clinically evident axillary nodal metastases at presentation who receive neoadjuvant therapy with resolution of clinically apparent adenopathy remains uncertain. In a recent study of 61 patients with nodal metastases documented prior to chemotherapy by fine needle aspiration, a 25% falsenegative rate for sentinel node biopsy was observed.138 These findings suggest that axillary dissection should remain the standard approach for patients presenting with nodal involvement. A major concern about sentinel node biopsy has been the false-negative rate of the procedure. In most large, multi-institutional studies, false-negative rates of approximately 10%, determined by completing an axillary dissection after the sentinel node(s) were removed, have been observed even when training requirements for participating surgeons and a standard technique of lymphatic mapping were utilized.139 However, two randomized studies directly comparing the identification of axillary metastases with axillary dissection and sentinel node biopsy found no difference in the likelihood of identifying nodal disease.135,140 In the ALMANAC trial, 26% of patients undergoing sentinel node biopsy were found to have nodal metastases compared to 23% in the axillary dissection arm.135 In the study of Veronesi et al.140 these figures were 36% and 32%, P.1631 respectively. These findings emphasize that although sentinel node biopsy is associated with a false-negative rate due to failure of the surgeon to identify the correct sentinel node or all of the sentinel nodes, this is balanced by the more detailed pathology examination that can be performed on the smaller sentinel node sample. Follow-up studies of patients treated by sentinel node biopsy alone demonstrate that the rate of local recurrence in the axilla is extremely low. In one study with a median follow-up of 31 months, isolated axillary first failure was seen in only 3 of 4,008 patients (0.07%) who had a sentinel node biopsy.141 The ability to perform a more detailed examination of the sentinel node has significantly increased the identification of small tumor deposits in the axillary nodes. Registry studies have demonstrated an approximately 10% increase in the proportion of patients with

positive axillary nodes, after adjustment for other factors, in the time period since the introduction of sentinel node biopsy.142 The prognostic significance of isolated tumor cells (less than 0.2 mm deposits) and very small metastatic deposits (greater than 0.2 mm, less than 2.0 mm) is uncertain, with retrospective studies providing contradictory results. The risk of additional axillary nodal metastases and the need for completion axillary dissection in the patient with isolated tumor cells or micrometastases in the sentinel node is also uncertain.143 Prospective data from both the NSABP B32 trial and the ACOSOG Z10 trials should help to clarify this issue. Axillary dissection remains the standard approach to patients with axillary nodal metastases. Studies comparing sentinel node biopsy to axillary dissection have provided important information on the morbidity of the procedure. In the ALMANAC trial, moderate to severe lymphedema was reported by 13% of patients 12 months after axillary dissection as well as sensory loss in 31%.135 Decreases in shoulder flexion and abduction were present 1 month after surgery but resolved rapidly after that time. Axillary dissection provides excellent long-term local control, with only 1.4% of patients treated by radical mastectomy in the NSABP B04 trial130 having an isolated axillary recurrence at 10-year follow-up. The use of axillary irradiation as an alternative to axillary dissection was studied in the presentinel node era in a randomized trial in clinically node-negative patients performed at the Institute Curie. After 15 years of follow-up, the axillary failure rate was 3% in the radiated group and 1% in the surgical group (P = .03),144 indicating that this is an acceptable alternative in patients with contraindications to axillary surgery or those who refuse the procedure. Local-Regional Therapy and Survival The impact of local-regional therapy on the survival of patients with breast cancer has been debated for decades. Three viewpoints based on different hypotheses concerning the biology of breast cancer have been proposed. The Halstedian theory proposed that breast cancer is strictly a local disease, and that tumor cells spread over time in a contiguous manner away from the primary site by way of lymphatics, even to distant organs. The Halstedian theory dictated that aggressive local-regional therapy (i.e., control of disease in the breast, chest wall, and regional lymph nodes) would have a substantial impact on survival and provided justification for even more radical breast cancer surgery. As it became clear that many breast cancer patients developed distant metastases despite having their disease controlled locally, the systemic view arose in reaction to the Halstedian theory. Bernard Fisher et al. promulgated the view that breast cancer was a systemic disease, and that it could be divided into two distinct groups: those cancers that have the ability to metastasize to distant sites and those that lack this ability. According to this view, which prevailed in the last half of the 20th century, if distant metastases were destined to develop, this had already occurred at the time of the diagnosis of the cancer in the breast. This theory predicted that treatments that improved local-regional control would have little or no effect on overall survival. Randomized trials from the NSABP that studied the effect of improving local control by increasing the extent of surgery or adding RT after total mastectomy (NSABP B04)130 or breast-conserving surgery (NSABP B06)80 demonstrated comparable survival for the different treatment arms despite substantial improvement in local-regional control with additional surgery and RT. The results from these trials were widely interpreted as providing strong evidence for the systemic theory. However, in these trials there were insufficient events (in this case, deaths) to detect small, but clinically important differences in overall mortality. A third hypothesis synthesized

aspects of these two opposing views.145 This theory holds that for many breast cancers, there is a time when tumor cells have not metastasized to distant sites, but it is generally not known whether this time has passed at the point of diagnosis for any individual patient. According to this view, failure to achieve initial local control will allow some tumors to disseminate later to distant sites, reducing a patient's chance of long-term survival. Recent evidence has cast doubt on the validity of the systemic theory. First, there is strong evidence that mammographic screening reduces breast cancer mortality. The findings from a meta-analysis of randomized studies of mammographic screening demonstrate that in screened populations, the relative risk of death from breast cancer was significantly reduced (RR = 0.85; 95% CI, 0.73 to 0.99) compared to unscreened populations.146 Thus, in some patients, earlier diagnosis (with screening) can prevent the development of distant metastases. That screening decreases mortality implies that at least some breast cancers develop the propensity to spread distantly over time. Second, there is mounting evidence from randomized clinical trials supporting a link between local control and overall survival in breast cancer. A study published in 2005 from the EBCTCG presented the findings from 78 randomized clinical trials evaluating the extent of surgery and the use of RT.116 This report analyzed data from 42,000 breast cancer patients treated on trials that began by 1995 and examined more extensive versus less extensive surgery, RT versus no RT, and extensive surgery versus RT. The most striking finding from the EBCTCG study was that improved local control at 5 years resulted in a highly statistically significant improvement in both breast cancer survival and overall survival at 15 years. Further, the absolute reduction in the 5-year rate of local-regional recurrence between treatment arms was proportional to the absolute reduction in 15-year breast cancer mortality. The absolute breast cancer mortality benefit was similar for a given reduction in local-regional recurrence, regardless of the method of achieving the reduction (i.e., by more extensive surgery or by the addition of RT). For the trials in this EBCTCG meta-analysis that studied RT, the addition of RT significantly improved 15-year absolute overall P.1632 survival after breast conservation surgery by 5.3% (P = .005) (Fig. 43.2.5) and after mastectomy by 4.4% (P = .001). The survival benefits of achieving local-regional control documented in the EBCTCG meta-analysis are of similar magnitude to that for adjuvant systemic therapy, yet they have received considerably less attention.

Figure 43.2.5. The Oxford overview analysis of the impact of the reduction in local recurrence in trials of breast-conserving therapy with and without radiotherapy on breast cancer mortality and death from all causes is illustrated. For every four locoregional recurrences avoided, one breast cancer death is prevented. The impact of local therapy on survival must be considered in the context of systemic therapy. Adjuvant systemic therapy itself reduces the likelihood of both local and distant recurrence. A subset analysis in the EBCTCG meta-analysis of local therapy revealed that the use of RT after mastectomy in node-positive patients only improved 15-year survival in patients who also received adjuvant systemic therapy and not in patients who were treated with mastectomy alone. In those patients at high risk of distant metastases, such as women with positive lymph nodes, RT in the absence of systemic therapy can only improve survival in the rare patient with residual local-regional disease who has no distant dissemination. In contrast, in node-positive patients treated with mastectomy and adjuvant systemic therapy, RT will potentially contribute to survival in patients in whom systemic therapy eradicates microscopic metastases, but not residual local-regional disease. Current systemic therapy is primarily effective against micrometastatic involvement. As systemic therapies are developed that can eradicate clinically evident disease, the influence of local therapy on mortality will be reduced and possibly eliminated. These results underscore the need to routinely employ measures to achieve local control and to identify more robust predictors of local recurrence. For example, clinicians should practice careful patient selection for breast-conserving therapy, excision to negative margins, and the use of boost doses of RT, particularly in patients younger than 35 who are known to have a higher risk of local recurrence. Gene expression analyses have been used to identify patients at increased risk of distance recurrence, and it is anticipated that such molecular techniques will be helpful in identifying patients at greater risk of local recurrence. There is a need to gain a better understanding of the interplay between tumor biology, the anatomic extent of disease, the use of systemic therapy and the risk of localregional recurrence. Prognostic and Predictive Factors A prognostic factor is defined as a measurement taken at the time of diagnosis or surgery that is associated with outcome (e.g., overall survival, disease-free survival, or local control). Prog-nostic factors generally refer to a patient's anticipated outcome at the time of diagnosis in the absence of systemic therapy; however, they are sometimes useful to estimate outcome following a specific systemic therapy. Mathematically, a prognostic factor is demonstrated as a statistically (and clinically) significant separation of curves of outcome that are based on the presence or absence of the factor, in a Cox proportional hazards regression. A predictive factor is a measurement that predicts response or lack of response to a specific treatment. Mathematically, a predictive factor is modeled as an interaction between a factor and a treatment in a Cox regression. This interaction is best demonstrated in a clinical trial of treatment versus no treatment. In practice, some factors are both prognostic and predictive. Establishing the validity of a prognostic factor (biomarker) requires that the factor have biological relevance, that the methods for determining the factor be validated and reproducible (i.e., confirmed in a second independent data set) with optimal cutoff values, and that the factor be studied with adequate sample sizes without population bias. Guidelines for the evaluation and reporting of such biomarkers have been established.147

The AJCC staging system reviewed elsewhere in this chapter72 is based on established clinical and pathologic prognostic factors, and stage itself remains a major prognostic factor. The extent of axillary lymph node involvement by breast cancer is the most established and reliable prognostic factor for subsequent P.1633 metastatic disease and survival. This is not surprising since it reflects evidence of actual metastatic potential. Axillary nodal involvement has generally been stratified as the number of positive lymph nodes (e.g., 0, 1 to 3, 4 to 9, and 10 or more), although more recent analyses have stressed the percentage of positive lymph nodes, given the variability in the extent of axillary dissection between surgeons. Tumor size and histologic grading also have established prognostic significance. Tumor size is typically given as the microscopic size of the invasive cancer. Histologic grade is best determined by an established methodology, such as the Nottingham combined histologic grading system. A criticism of the value of histologic grade has been the lack of concordance among pathologists; however, this is improved by the use of an established methodology. Estrogen and progesterone receptor expression are the most important and useful predictive factors currently available. Patients with invasive breast cancer whose tumors are totally lacking in ER and PR do not derive benefit from hormonal treatment either in the metastatic or adjuvant setting. Current assays for ER and PR are performed using IHC techniques, which have the advantages of not being confounded by endogenous estrogens, can be correlated with histologic findings to eliminate the possibility that the assessment was done on noncancerous tissue, can be performed on paraffin-embedded tissues, and do not have tumor size as a limiting factor. Laboratories need to adhere to well-described techniques to ensure accurate determination of ER and PR by IHC. Since ER/PR status is critical to current management guidelines, some centers repeat the assay if the initial determination is ER negative or PR negative, particularly if there is any reason to question the result, such as in a patient with a low-grade cancer. Although there are convincing data that patients whose tumors have even as few as 1% of cells staining positively for hormone receptors derive benefit from adjuvant hormonal therapy, it is still controversial whether laboratories can reproducibly report the percentage of positive ER and PR staining.148 ER/PR status also has some prognostic value. Patients with ER/PR positive tumors have improved disease-free survival compared to similarly staged patients with ER/PR negative tumors at 5 years, but this difference is less apparent at 10 years. Using tumor size and grade, ER status, and the number of involved axillary nodes, it is possible to estimate online the prognosis of an individual patient. One such online service, which is widely used and has been validated, is Adjuvant Online (www.adjuvantonline.com).149 Patient age has also consistently been shown to be a prognostic factor. Very young breast cancer patients (35 years or less) have a poorer prognosis than older patients. The cancers in these patients tend to be higher grade, less often ER/PR positive, and more likely to have lymphovascular invasion than cancers in older patients. It is not clear whether these differences in pathologic features fully explain the worse outcome in very young patients.150,151 Approximately 20% of breast cancer patients have HER-2/neu gene amplification, which results in glycoprotein overexpression. Approximately 5% of patients have overexpression without gene amplification, but otherwise gene amplification and expression are highly

correlated. HER-2 amplification or overexpression has been associated with higher tumor grade, lack of ER receptors, higher levels of tumor proliferation, and poorer prognosis. HER-2 status is the major predictive factor for benefit from trastuzumab (Herceptin), which is discussed later in this chapter. There is some evidence that suggests that HER-2 status is predictive for benefit from anthracycline-based chemotherapy, although this relationship is not certain, particularly with the availability of trastuzumab.152 Measurements of HER-2 can be performed by either IHC or fluorescent in situ hybridization. Similar to ER, laboratories need to adhere to well-described techniques to ensure accurate determination of HER-2. A recent guideline for HER-2 testing describes these techniques and defines a positive result as IHC staining of 3+ of greater than 30% of invasive cancer cells, a fluorescent in situ hybridization result of more than six copies per nucleus, or a fluorescent in situ hybridization ratio of more than 2.2.153 Involvement of lymphovascular spaces is associated with a greater likelihood of lymph node metastases and is an independent adverse prognostic factor in both node-negative and positive patients. Rigid pathologic criteria are required for this factor to be reliable, and this includes assurance that the cancer cells are present in an area outlined by endothelium and present away from the main tumor mass. These findings allow lymphovascular invasion to be distinguished from retraction artifact. In some centers, IHC stains for endothelial cells are used. Other Factors Numerous other prognostic and predictive factors have been evaluated in patients with early breast cancer, but have not been widely adopted in routine clinical use in the United States and include (1) markers of proliferation, such as S-phase fraction, the percentage of cells labeling with thymidine or bromodeoxyuridine or cellular expression of Ki-67 or MIB-1 (which measure the percentage of cells in the G1 phase of the cell cycle), and mitotic index; (2) measures of the plasminogen activator system, such as the concentrations of urokinase plasminogen activator (u-PA) and its inhibitor, plasminogen activator inhibitor-1 (PAI-1); (3) measurements of tumor angiogenesis, such as counting the number of capillaries with IHC methods that use labeled antibodies against factor VIII in vascular endothelium; and (4) the detection of occult micrometastases in the bone marrow using IHC techniques.154 Sources are available for a more detailed discussion of these and other factors.155 Molecular and Genomic Factors Breast cancer is a heterogeneous disease, and it has long been appreciated that tumors with different biological features have different clinical outcomes and responses to therapy. At present, prognosis and treatment selection in breast cancer are based on characterization of tumor growth factor receptor statusER, PR, and HER-2. These markers can be used to define four functional groups of tumors: hormone-receptorpositive, HER-2 negative; hormonereceptornegative, HER-2 negative (triple negative tumors), and HER-2 overexpressing tumors with or without hormone-receptor expression. Recent advances in molecular biology have resulted in further refinement of these breast cancer subsets. In particular, multigene arrays and expression analyses have provided a molecular taxonomy for breast tumors, which emphasizes the underlying biological differences between tumors and provides P.1634 detailed prognostic and treatment-outcomebased information. Sorlie et al.156 and Perou

et al.157 were able to classify breast cancers into tumor subtypes that had different prognoses using complementary DNA microarrays. These studies used hierarchical clustering analysis to identify tumor subtypes with distinct gene expression patterns. The differences in gene expression patterns among these subtypes reflect basic differences in the cell biology of the tumors and are manifest in differences in clinical outcome, and clinicians are increasingly viewing these molecular subtypes as separable diseases. The subtypes are luminal A, luminal B, HER-2/neu and basal-like (or basaloid, or triple negative). The subtypes are commonly approximated using routine tumor markers, such as luminal A: ER and/or PR pos/HER-2 negative, luminal B: ER and/or PR pos/HER-2 positive; HER-2 positive: ER negative/PRnegative/HER-2 positive; and basal-like ER negative/PR negative/HER-2 negative and/or CK5/6 positive and/or epidermal growth factor (EGFR) positive. Differences in gene expression pattern affecting hundreds of genes are found between the various subgroups; these differences appear to persist through the natural life history of the breast cancer,158 and neoadjuvant treatment of breast tumors appears to have little bearing on the gene expression patterns that contribute to the intrinsic tumor subtype.157,159 In addition to defining biological tumor subsets, gene expression profiling has been used to stratify tumors as having good-risk or poor-risk prognostic signatures.160,161 One of these, MammaPrint (Agendia Br, Amsterdam, The Netherlands), a 70-gene signature developed in the Netherlands,160 was given FDA approval in February 2007. Since then, several additional poor prognosis gene expression profiles have been developed using different phenotypic characteristics of aggressive cancer biology, such as wound-response and hypoxia-response. Retrospective analyses suggest that these gene signatures contribute independent prognostic information above and beyond that achieved with use of traditional pathological markers such as tumor size, nodal status, grade, lymphovascular invasion, and hormone-receptor status. An attempt to combine three gene expression signatures did not improve the prognostic accuracy.162 One molecular test that has been shown to be of use clinically is the Oncotype DX recurrence score. The recurrence score is based on a quantitative assessment of 21 genes thought to be relevant to breast cancer biology, including hormone receptors and HER-2, among others. In contrast to gene expression profiles that classify tumors into specific subsets or dichotomize tumors into good/poor prognostic groups, the recurrence score calculates a continuous, numeric result that correlates with distant metastatic recurrence in tamoxifen-treated patients with node-negative breast cancer.163 Although the recurrence score tends to correlate with features like tumor grade, size, nodal status, and quantitative levels of hormone-receptor expression, multivariate analyses demonstrate that the score provides significant independent prognostic information. Unlike most other microarray analyses that require freshly frozen or prepared tissues, the recurrence score can be determined on paraffin-embedded tissue, allowing linkage of outcomes from clinical treatment trials to recurrence score measurements. Oncotype DX has been applied to a common clinical question: whether a node-negative, estrogen receptor-positive patient should receive chemotherapy in addition to hormonal therapy. Retrospective analyses from NSABP B20, a trial of tamoxifen alone versus tamoxifen plus chemotherapy for ERpositive, node-negative patients, demonstrated that the recurrence score was a predictive factor for benefit from chemotherapy. Patients with tumors that had a low recurrence score had a very favorable overall prognosis that was not meaningfully improved by chemotherapy, while patients with high recurrence scores derived a substantial benefit from

chemotherapy.164 Trials of preoperative chemotherapy have confirmed that a major response to treatment is more common among patients with high recurrence scores.165 Collectively, these molecular tools have led to the evolution of specific treatment algorithms based on subtype classification, and clinical trials are increasingly designed for specific tumor types. In addition, gene expression assays appear to allow for a more individualized assessment of risk based on the intrinsic biological properties of the cancer cells, with the promise of tailoring treatment programs for individual women. Adjuvant Systemic Therapy The goal of adjuvant systemic therapy is to prevent the recurrence of breast cancer by eradicating micrometastatic deposits of tumor that are present at the time of diagnosis. The rationale for adjuvant treatment stems from the systemic hypothesis of breast tumorigenesis, which argues that in the early stages of breast cancer development, tumor cells are disseminated throughout the body (discussed in detail in the section LocalRegional Therapy and Survival above). Thus, in addition to appropriate local therapy, improvements in breast cancer outcome hinge on effective systemic treatments that prevent disease recurrence as distant metastasis. To a large extent, this hypothesis has been validated through decades of clinical investigation, and approximately half of the recent decline in breast cancer mortality in the United States and Western Europe has been attributed to the widespread use of adjuvant therapy.5 In current practice, three systemic treatment modalities are widely used as adjuvant therapy for early stage breast cancer. These modalities are (1) endocrine treatments such as tamoxifen, aromatase inhibitors, or ovarian suppression, (2) anti-HER-2 therapy with the humanized monoclonal antibody, trastuzumab, and (3) chemotherapy. Selection of adjuvant treatment is determined by the biological features of the breast cancer (Table 43.2.16). Patients with tumors that are P.1635 hormone-receptor positive (either for ER, PR, or both) are candidates for adjuvant endocrine therapy; patients with tumors that are HER-2 overexpressing are candidates for trastuzumab. Chemotherapy is utilized irrespective of tumor hormone-receptor status or HER-2 status, based largely on features such as tumor size, nodal status, and the patient's other health considerations. Table 43.2.16 Overview of Adjuvant Treatment Approaches in Breast Cancer Tumor Hormone-Receptor Status Tumor HER Status Positive Negative HER-2 negative/normal Endocrine therapy chemotherapy Chemotherapy HER-2 Endocrine therapy + chemotherapy + Chemotherapy + positive/overexpressed trastuzumab trastuzumab Important progress has been made in the past 5 years, reshaping the landscape of adjuvant treatment. The introduction of taxane-based chemotherapy, aromatase inhibitors as adjuvant endocrine treatment for postmenopausal women, and the use of trastuzumab have all led to substantial improvements for breast cancer patients. Adjuvant Endocrine Therapy Tamoxifen is the agent most widely studied as adjuvant endocrine therapy for breast cancer. The Early Breast Cancer Trialists' Group has performed an overview of the randomized trials of adjuvant tamoxifen therapy.166 These results reflect data with 15 years of follow-up, from over 60 adjuvant trials including more than 80,000 women. Tamoxifen

administered for a duration of 5 years results in a 41% reduction in the annual rate of breast cancer recurrence (HR 0.59) and a 34% reduction in the annual death rate (HR 0.66) for women with ER-positive breast cancer. The gains associated with tamoxifen are achieved independent of patient age or menopausal status, with and without the use of adjuvant chemotherapy, and are durable, contributing to improved survival through at least 15 years of follow-up. Shorter durations of tamoxifen therapy are also beneficial, but appear to have less impact than a 5-year treatment duration. The optimal duration of tamoxifen therapy appears to be 5 years; extending tamoxifen therapy beyond 5 years in patients with no evidence of tumor recurrence has not led to further improvements in disease-free or overall survival.167 Consistent with its activity as a SERM, tamoxifen is not effective in preventing recurrence of hormone-receptornegative breast cancer.168,169 Based on these collective data, the National Institutes of Health Consensus Development Conference on Adjuvant Therapy for Breast Cancer in 2000 recommended the use of adjuvant tamoxifen for 5 years as adjuvant hormonal therapy for all women with hormonereceptorpositive breast cancer irrespective of age, menopausal status, tumor size, or nodal status.170 Table 43.2.17 Major Studies Comparing Adjuvant Therapy Incorporating Aromatase Inhibitors against 5 Years of Tamoxifen Hazard Ratio Absolute Difference No. of for Diseasein Disease-Free Timing/Setting Trial (Reference) AI Patients Free Survival Survival (%) Upfront; year 0 ATAC (ref. 174) ANA9,366 0.87a 2.8 @ 5 y BIG 1-98 (ref. LET 8,010 0.81 2.6 @ 5 y 175) Sequential; after IES (ref. 177) EXE 4,742 0.68 4.7 @ 3 y 23 years of TAM ARNO/ABCSG ANA3,224 0.60 3.1 @ 3 y (ref. 176) Extended; after 5 MA17 (ref. 179) LET 5,187 0.58 4.6 @ 4 y years of TAM NSABP B33 (ref. EXE 1,598 0.68 2.0 @ 4 y 180) ANA, anastrozole; LET, letrozole; EXE, exemestane; TAM, tamoxifen, AI, aromatase inhibitor a Comparison for ANA vs TAM. The third arm of the trial, combined therapy with ANA plus TAM, yielded outcomes similar to TAM alone. In the past 5 years, multiple clinical trials have examined the role of aromatase inhibitors (AIs) as adjuvant endocrine therapy for early breast cancer. Although tamoxifen works by binding to the estrogen receptor, AIs function through inhibition of the aromatase enzyme that converts androgens into estrogens.171 The result is profound estrogen depletion in postmenopausal women. AIs are not appropriate for premenopausal patients, as residual ovarian function can lead to enhanced production of aromatase and thus overcome the effects of AIs. In postmenopausal patients, where only baseline levels of aromatase activity are present, AIs effectively lower estrogen levels by 90% to nearly undetectable levels.172 A variety of clinical trials have addressed the question of whether the incorporation of an AI improves the results seen with 5 years of tamoxifen in postmenopausal women with hormone-receptorpositive breast cancer. Table 43.2.17 summarizes the major trials of

adjuvant AI therapy. AI treatment has been explored as primary or up-front therapy instead of tamoxifen,173,174,175 as sequential therapy after 2 or 3 years of tamoxifen,176,177 and as extended therapy after 5 years of tamoxifen.178,179,180 In each instance, the utilization of an AI at some point in the treatment program improved outcomes compared to the control arm, which consisted of 5 years of tamoxifen therapy. The use of an AI has led to modest improvements in disease-free survival in all of these trials, as a result of a lower risk of both distant metastasis and of in-breast recurrences and contralateral tumors. To date, significant survival differences with the use of an AI have not been reported, although in the MA17 trial of letrozole after 5 years of tamoxifen, the addition of letrozole produced a statistically significant survival benefit in the subset of node-positive women (HR 0.61; 95% CI, 0.38 to 0.98; P = .04).179 Collectively, these data argue for use of an AI in most postmenopausal women with early stage, hormone-receptorpositive breast cancer, but they leave open many critical questions about the optimal use of these agents.181 There are no data as yet comparing the up-front use of an AI against sequential treatment with tamoxifen followed by an AI, so the best timing for initiation of an AI vis- -vis tamoxifen is not clear. The Breast International Group 1-98 trial, which randomized patients to monotherapy with letrozole or tamoxifen or to a planned crossover, will eventually provide important information data on this point.175 Similarly, the appropriate duration of AI treatment is not clear. The up-front trials174,175 limited treatment to a total P.1636 of 5 years duration, and the sequential trials176,177 used AI therapy for only 2 or 3 years as part of a total of 5 years of adjuvant endocrine treatment. The studies of extended endocrine therapy beyond 5 years179,180 underscore the long natural history of hormonereceptorpositive breast cancer and demonstrate that antiestrogen treatments have ongoing benefits well beyond 5 years after diagnosis. For women who start an AI at the time of diagnosis, the appropriate duration of endocrine treatment is unknown, and studies are ongoing to address this question. Because of these uncertainties, the selection of adjuvant endocrine therapy for postmenopausal women is surprisingly complicated. Postmenopausal women should consider an AI at some point in their treatment program and anticipate receiving an AI for up to 5 years, based on current data. AIs and tamoxifen have contrasting side-effect profiles, which may inform treatment selection. Tamoxifen is associated with rare risks of thromboembolism and uterine cancer.167,174,175 AI treatment is associated with accelerated osteoporosis and an arthralgia syndrome;182 patients on AI therapy require serial monitoring of bone mineral density.183 Both treatments are associated with menopausal symptoms such as hot flashes, night sweats, and genitourinary symptoms including sexual dysfunction. Symptomatically, patients may tolerate one class of agent better than another; those intolerant of either tamoxifen or AI therapy should be offered the alternative type of treatment. Because AI therapy is only effective in postmenopausal women, tamoxifen remains the treatment of choice in women who are pre- or perimenopausal or in whom there is question of residual ovarian function. In particular, women with chemotherapyinduced amenorrhea may have recovery of ovarian function and are not suitable candidates for AI treatment.184 Despite long-standing interest in ovarian suppression as adjuvant therapy, its role in addition to tamoxifen or chemotherapy remains unclear. Early studies of ovarian

suppression were not limited to patients with hormone-receptorpositive tumors, meaning that these trials were often conducted in patients unlikely to benefit from endocrine treatment. In addition, many studies of ovarian suppression in the 1980s and 1990s failed to incorporate tamoxifen, as it was not appreciated that tamoxifen was beneficial in premenopausal women, so the benefits of ovarian suppression in addition to tamoxifen are not well understood. Finally, clinical trials that included chemotherapy for younger women were confounded by the high incidence of chemotherapy-induced menopause.185 Thus, despite the fact that multiple randomized trials have demonstrated that ovarian suppression can be effective adjuvant therapy for premenopausal women166 and have demonstrated that ovarian suppression is frequently at least as effective as adjuvant chemotherapy in preventing breast cancer recurrence,186 there remains little consensus on whether ovarian suppression adds meaningfully to results seen with tamoxifen with or without adjuvant chemotherapy. Recent observations suggest that ovarian suppression is a critical question for younger women with hormone-receptorpositive breast cancer. Very young womentypically less than age 35who do not routinely experience amenorrhea with adjuvant chemotherapy appear to have a substantially worse prognosis than patients who do enter menopause with chemotherapy.187 A randomized trial has compared chemotherapy alone, chemotherapy plus ovarian suppression and chemotherapy, and ovarian suppression plus tamoxifen as adjuvant treatment. The addition of tamoxifen clearly improved results compared to chemotherapy with or without ovarian suppression. In subset analyses, younger women (less than age 40) who were less likely to experience chemotherapy induced amenorrhea did appear to benefit from ovarian suppression in addition to chemotherapy.188 However, the study design does not directly address whether ovarian suppression would substantially add to tamoxifen-based treatment. The Adjuvant Breast Cancer Ovarian Ablation or Suppression Trial compared tamoxifen alone versus tamoxifen with ovarian suppression in premenopausal women and did not show a substantial improvement in disease-free survival with the addition of ovarian suppression.189 However, in this study, only 40% of patients were known to have estrogen-receptorpositive breast cancer, and 80% of patients additionally received adjuvant chemotherapy, profoundly limiting the interpretation of the results. Ongoing trials are specifically testing the role of ovarian suppression in addition to tamoxifen for premenopausal patients. Tamoxifen is metabolized by the cytochrome P-450 system into biologically active metabolites. Recent data have suggested that pharmacogenomic variation in P-450 alleles or the concurrent use of tamoxifen and P-450 inhibitors might affect tamoxifen metabolism, with clinically significant effects. Retrospective analyses of small adjuvant treatment trials have suggested that patients with inefficient tamoxifen metabolism owing to mutations in CYP2D6 enzyme, part of the P-450 complex, might derive less benefit from adjuvant tamoxifen than others.190,191 Patients taking certain medicines known to inhibit P-450, such as the selective serotonin reuptake inhibitors paroxetine and fluoxetine, also generate fewer active tamoxifen metabolites, which may interfere with clinical outcomes.192,193 Neither the full significance of pharmacogenomic allelic variation nor the adequacy of testing for such variation is well characterized at present. Patients on tamoxifen should probably avoid the aforementioned selective serotonin reuptake inhibitors in light of the potential pharmacological interaction. Adjuvant Chemotherapy

Adjuvant chemotherapy consisting of multiple cycles of polychemotherapy is well established as an important strategy for lowering the risk of breast cancer recurrence and improving survival. Initial studies of adjuvant chemotherapy were conducted in women with higher risk, lymph nodepositive breast cancer. Subsequent trials have extended the benefits of adjuvant chemotherapy into lower risk, node-negative patient populations.166 Long-term follow-up from the Oxford overview demonstrated benefit from chemotherapy for women irrespective of age, tumor estrogen-receptor status, or whether patients also receive adjuvant endocrine therapy.166 In addition, the overview suggests advantages for multiple cycles (four to eight) of chemotherapy compared to single-cycle regimens. The overview also supports the findings of multiple individual trials showing superiority of anthracycline-based chemotherapy compared to CMF-based, nonanthracycline regimens. Based on this collective experience, multiple cycles of adjuvant chemotherapy, typically including anthracycline-based regimens, are recommended for the majority of patients with node-positive and higher risk node-negative tumors.194,195 The current challenges in adjuvant chemotherapy treatment are to select subsets of patients that might preferentially benefit from chemotherapy or conversely be spared adjuvant chemotherapy, P.1637 to determine the role of newer agents, particularly taxanes as adjuvant treatment, and to optimize the dosing and scheduling of chemotherapy to achieve the best clinical results and improve the side-effect profile of treatment. The introduction of taxanes into early stage breast cancer treatment constitutes an important advance over the historic experience with alkylator and anthracycline-based chemotherapy. The first report on adjuvant taxane therapy was CALGB 9344, a randomized study of doxorubicin dose escalation and the incorporation of sequential paclitaxel therapy for women receiving four cycles of cyclophosphamide-doxorubicin (AC) chemotherapy.196 CALGB 9344 demonstrated that sequential paclitaxel therapy improved both disease-free and overall survival among women with node-positive breast cancer. Since that time, nearly one dozen studies have reported on breast cancer outcomes with the incorporation of taxaneseither paclitaxel or docetaxeleither as substitutes or sequential additions to anthracycline-based regimens (Table 43.2.18). Collectively, these data suggest that the use of taxanes can contribute to significant improvement in outcomes, especially among women with node-positive breast cancer, in whom the vast majority of these trials have been conducted. A randomized comparison of AC followed by either docetaxel or paclitaxel, with taxanes given either every 3 weeks or on a weekly schedule, did not show significant differences between the taxanes with respect to breast cancer recurrence.197 Ongoing studies seeking to define the best taxane regimen are comparing the three-drug regimen TAC (docetaxel/doxorubicin/5-fluorouracil) against sequential treatment with AC followed by paclitaxel given on an every 2-week schedule. Table 43.2.18 Trials of Adjuvant Taxane Therapy PACLITAXEL No. of Hazard Hazard Trial Patients Design RatioDFS RatioOS M. D. 524 FAC 8 vs. 0.7 NR Anderson P 4 FAC 8 CALGB 9344 3,121 AC 4 vs. 0.83 0.82 AC 4 P 4

ECTO GEICAM 9906 HeCOG

1,355 1,248 595

NSABP B28 3,059 DOCETAXEL

A CMF vs. 0.65 AP CMF FEC 6 vs. 0.63 FEC 4 P 8 E 4 CMF vs. 0.86 E 3 P 3 CMF 3 AC 4 vs. 0.83 AC 4 P 4

0.71 0.74 0.41

0.93

No. of Hazard Hazard Trial Patients Design RatioDFS RatioOS BCIRG 001 1,491 FAC 6 vs. 0.72 0.70 DAC 6 ECOG 2197 2,885 AC 4 vs. 0.92 0.92 AD 4 BIG 2-98 2,887 A C 4 CMF 0.86 0.92 3 vs. A 3 D 3 CMF 3 vs. AD 4 CMF 3 NSABP B27 2,411 AC 4 vs. 0.90 1.07 AC 4 D 4 PACS 01 1,999 FEC 6 vs. 0.83 0.73 FEC 3 D 3 TAXIT 216 972 E CMF vs. 0.79 0.72 E D CMF U.S. 1,016 AC 4 vs. 0.67 0.76 Oncology DC 4 DFS, disease-free survival; OS, overall survival; P, paclitaxel; D, docetaxel; F, 5fluorouracil; E, epirubicin; A, doxorubicin; C, cyclophosphamide; M, methotrexate. Chemotherapy dose and schedule considerations remain a major area of clinical investigation. Multiple studies have failed to demonstrate that dose escalation of cyclophosphamide198 or doxorubicin196 results in a lower risk of recurrence. Administration of either paclitaxel or docetaxel on an every 3-week schedule has been compared to weekly taxane administration following AC chemotherapy without contributing to statistically significant differences, although modest absolute advantages were seen with weekly paclitaxel and every 3-week docetaxel compared to the other treatment schedules.197 A neoadjuvant study reported that paclitaxel given weekly yielded P.1638 superior rates of pathological complete response compared to every 3-week paclitaxel.199 The CALGB 9741 trial compared AC followed by paclitaxel given either every 3 weeks or every 2 weeks at the same doses and schedules.200 Accelerated, every 2-week treatment led to lower risk of recurrence and improved survival. The same study also compared concurrent therapy, giving cyclophosphamide and doxorubicin together followed by

paclitaxel, or sequential chemotherapy treatment consisting of doxorubicin/paclitaxel cyclophosphamide, and showed that there was no difference between concurrent or sequential therapy. These trials suggest that chemotherapy schedule, particularly with taxanes, may have an impact on antitumor efficacy. Clinical studies have shown that chemotherapy can be of benefit to women with nodepositive and node-negative breast cancers, with tumors that are either hormone-receptor positive or negative, regardless of age or menopausal status. Retrospective analyses have even shown that chemotherapy can be beneficial to women with tumors as small as 1 cm or less, including both ER-positive and ER-negative tumors.201 Nonetheless, there is great interest in trying to determine whether specific regimens should be employed in certain groups of patients defined by clinical features or by tumor biology, and whether staging information or pathobiological tumor characteristics can identify groups of women who do not need adjuvant chemotherapy. This interest stems from several considerations. First, while the addition of chemotherapy often leads to statistically significant gains in relative risk reduction, these often translate into very small differences in the absolute risk of recurrence for patients, especially patients with earlier stage disease202 or in patients where adjuvant endocrine therapy improves outcome. Second, many chemotherapy trials, particularly those involving women with hormone-receptorpositive tumors, are confounded by the endocrine effects of chemotherapy-induced amenorrhea. Third, most clinical trial results do not take into account the existence of molecularly defined breast cancer subsets. Trials that are the benchmarks in the literature generally included patients with tumors that were not necessarily defined by hormone-receptor status, or more recently, HER-2 status. There is a concern that these all comers trials may overestimate the benefits of chemotherapy in certain subtypes of breast cancer, while underestimating the benefits in others. Finally, for patients in whom the absolute advantages of chemotherapy are modest, efforts to weigh patient preferences and directly quantify chemotherapy benefits for specific patients, as opposed to large cohorts in clinical trials, have led to further individualization of chemotherapy choices. Hormone-receptor status may be an important predictor of benefit from chemotherapy. Retrospective analyses among patients with node-negative breast cancer suggest that tumors that are low or nonexpressors of ER derive substantial benefit from the addition of chemotherapy to tamoxifen; by contrast, tumors with high quantitative levels of ER appear to not gain substantially from adding chemotherapy to endocrine therapy.169 A retrospective review of CALGB trials for node-positive breast cancer patients evaluated the gains associated with chemotherapy using a variety of anthracycline- and taxane-based treatments as a function of tumor ER status.203 Improvements in outcome due to changes in chemotherapy schedule and dosing, including the addition of taxane-based therapy, were most noticeable among patients with ER-negative tumors, while patients with ER-positive tumors derived more limited benefit from newer adjuvant chemotherapy regimens. However, not all retrospective studies have shown a clear relationship between ER status and the benefit of chemotherapy,204 and precise thresholds of ER expression and likely chemotherapy benefit are not well established. HER-2 is also a marker that has been widely studied as a predictor of benefit from adjuvant chemotherapy. Multiple retrospective analyses have suggested that HER-2 overexpression is associated with a relative benefit from anthracycline-based chemotherapy,205 and that HER-2 negative tumors do not selectively benefit from anthracyclines, as opposed to CMFtype, chemotherapy treatments. Other retrospective work based on characterizing both

HER-2 status and ER status of tumors suggests that chemotherapy with taxanes may be especially critical in tumors that either lack ER expression or express HER-2.206 However, the reported interactions between HER-2 status and type of chemotherapy are not uniform across all trials and are largely derived from unplanned, retrospective analyses. More critically, these chemotherapy trials all predate the widespread use of adjuvant trastuzumab, which may render moot the details of chemotherapy selection for HER-2 positive tumors. New molecular assays that integrate larger numbers of biomarkers may further clarify the potential role of chemotherapeutic agents in adjuvant treatment. The 21-gene recurrence score (Oncotype DX; discussed in the section Prognostic and Predictive Factors above), which incorporates hormone-receptor measurement and HER-2 expression into its numeric algorithm, has been used to predict outcome for ER-positive node-negative breast cancers treated with tamoxifen163 or tamoxifen plus chemotherapy.164 Patients with tumors with higher recurrence scores derive substantial benefit from the addition of chemotherapy to endocrine treatment, while patients with low recurrence scores have both a more favorable overall prognosis and do not appear to benefit meaningfully from the addition of chemotherapy. Investigational work with the 21-gene recurrence score and other gene expressionbased arrays suggests that pathological features such as low or no expression of hormone receptors, expression of HER-2, and high tumor grade all tend to be predictors of likely sensitivity of tumors to chemotherapy.162,207 Tumors at the other end of the molecular spectrumlow grade, high levels of hormone receptors, lack of HER-2 expressiontend to be more sensitive to endocrine therapies and less sensitive to adjuvant chemotherapy. It is widely expected that within several years sufficient clinical data will be available to allow a more precise characterization of tumor features that suggest whether or not patients should receive adjuvant chemotherapy. Critical components of decision making for adjuvant chemotherapy are a consideration of the realistic benefits and likely side effects for a given patient and involvement of the patient in the treatment selection process. Various chemotherapy regimens have distinctive side-effect profiles that can inform regimen selection for an individual patient. For example, anthracyclines are associated with a low but finite risk of cardiomyopathy and may not be appropriate for patients with previous anthracycline exposure or pre-existing cardiac disease. Taxane-based treatments are associated with neuropathy that may be worse in patients with pre-existing peripheral neuropathy. Patients and doctors may attempt to gauge the absolute gains associated with chemotherapy by considering rigorously the tumor stage, comorbid conditions, age of the patient, and the biological features of the tumor. One tool that P.1639 allows for such refinement is Adjuvant!, an online program that quantifies the benefits of adjuvant treatment.149,208 Adjuvant! integrates tumor size and biomarker information, patient age and health status, and the relative benefits of chemotherapy as measured in clinical trials, and reports in bar graph format the absolute benefits that the given patient is likely to achieve with adjuvant chemotherapy. This information, while based on computer simulation and modeling, provides quantitative estimates that may assist patients in making choices about treatment. Patient surveys, inevitably performed after patients have endured adjuvant chemotherapy, suggest that many women would prefer adjuvant chemotherapy for extraordinarily small gains (1% improvement in outcome), and most women would accept chemotherapy for modest differences on the order of a 3% to 5% improvement in chance of

recurrence.209 Nonetheless, a careful and honest appraisal of the likelihood of benefit from chemotherapy should be a part of any decision to recommend adjuvant chemotherapy treatment. Adjuvant Trastuzumab Therapy for HER-2 Overexpressing Breast Cancer HER-2 expression has historically been considered an adverse prognostic factor associated with a higher risk of recurrence, an early risk of recurrence, and relative resistance to established therapies such as CMF-based chemotherapy.210 HER-2 expressing tumors tend to express lower levels of hormone receptors than HER-2 negative tumors, contributing to relative resistance to adjuvant endocrine therapies even when hormone receptors are present.211 For these reasons, patients with HER-2 positive tumors have been a clinical challenge, contributing to a large fraction of cancer-related events in adjuvant breast cancer trials, and have been a high priority population for targeted clinical trials. In 2005 reports became available from five randomized clinical trials that examined the addition of trastuzumab, the humanized monoclonal antibody against the Her-2 protein, to chemotherapy as adjuvant treatment for HER-2 overexpressing breast cancer (Table 43.2.19).212,213,214,215,216 Although these trials used a variety of different adjuvant chemotherapy regimens and employed trastuzumab in different schedules and sequences, they all showed significant improvements in disease-free survival (reduction in risk of 50% on average) and in overall survival even after a short duration of follow-up. Subset analyses demonstrated comparable relative risk reduction regardless of tumor size, nodal status, or hormone-receptor status, resulting in the rapid incorporation of trastuzumab into standard treatment recommendations for women with HER-2 positive breast cancer. Table 43.2.19 Adjuvant Trials of Trastuzumab Trial No. of Chemotherapy Trastuzumab Hazard Hazard (Reference) Patients Regimen Regimen RatioDFS RatioOS NSABP B31 3,351 AC P One year 0.48 0.67 (212)/NCCTG beginning N9831 concurrently with P HERA (ref. 213) 3,401 Various One year 0.64 0.63 beginning sequentially after chemotherapy FinHER (ref. 232 V or D FEC 9 weeks beginning 0.42 0.41 214) concurrently with V or D BCIRG 006 (ref. 3,222 AC D One year 0.61 0.59 215) beginning concurrently with D CbDa One year 0.67 0.66 beginning concurrently with CbD DFS, disease-free survival; OS, overall survival; A, doxorubicin; C, cyclophosphamide; P, paclitaxel; D, docetaxel; Cb, carboplatin; V, vinorelbine. a In comparison to AC D chemotherapy.

Cardiomyopathy is a novel side effect of trastuzumab therapy.217 Cardiac dysfunction is more pronounced in patients receiving anthracycline-based adjuvant chemotherapy (incidence approximately 2%) than in patients who receive nonanthracycline adjuvant chemotherapy (incidence approximately 1%) in addition to trastuzumab. Other risk factors for cardiac dysfunction with adjuvant trastuzumab include pre-existing cardiac disease such as borderline normal left-ventricular ejection fraction or hypertension and age greater than 65. Because of the possibility of cardiac toxicity, all patients being considered for adjuvant trastuzumab require baseline determination of left ventricular ejection fraction and serial monitoring of cardiac function. Despite the rapidly emerging data on adjuvant trastuzumab, several key questions regarding optimal use remain. Successful determination of the HER-2 status of a tumor is a cornerstone of treatment selection as trastuzumab has only been shown to be effective in tumors with aberrant expression of HER-2.153 The duration of trastuzumab therapy is conventionally 1 year, although that length of treatment was arbitrarily chosen in the major adjuvant trials. The FinHER (Finland Herceptin) study214 used only 9 weeks of trastuzumab given concurrently with chemotherapy and showed benefit for trastuzumab despite the short treatment exposure; the HERA (Herceptin Adjuvant) trial is comparing 1 year versus 2 years of therapy, although data are not as yet available from that comparison.213 It remains unclear whether trastuzumab should be delivered sequentially after chemotherapy (as done in the HERA trial213) or concurrently with chemotherapy (as done in the NSABP B31/NCCTG [North Central Cancer Treatment Group] N9831,212 and BCIRG [Breast Cancer International Research Group] trials215). Limited direct comparisons in NCCTG N9831 suggest that for women receiving anthracyclineP.1640 and taxane-based chemotherapy, concurrent administration of trastuzumab during the taxane phase of treatment yielded superior results compared with sequential therapy. All of the adjuvant clinical trials employed chemotherapy with or without trastuzumab; there are no data on whether trastuzumab would be effective as adjuvant treatment in the absence of chemo-therapy administration. The optimal chemotherapy backbone for trastuzumab-based adjuvant treatment is uncertain. Most patients treated on the extant clinical trials received sequential anthracyclines and taxane-based treatment, with concurrent use of trastuzumab during taxane treatment. The preliminary results from BCIRG 006 suggest that the nonanthracycline trastuzumab/docetaxel/carboplatin regimen may be an acceptable alternative,215 particularly in patients with contraindications to anthracycline-based treatment. Concomitant radiation therapy and maintenance trastuzumab were delivered in most of the adjuvant trials. In short-term follow-up, combination therapy does not appear to alter the risks associated with either treatment modality. Finally, most of the patients entered onto the major trastuzumab trials had node-positive or high-risk node-negative breast cancers. The role of trastuzumab treatment for women with smaller, node-negative tumors, particularly tumors less than 1 cm, remains undetermined. Integration of Multimodality Primary Therapy Current consensus recommendations for adjuvant therapy are summarized in Table 43.2.20. The majority of women with breast cancer receive some form of adjuvant therapy, which requires integration of systemic treatments with local therapy including surgery and radiation therapy. As discussed in the section Risk Factors for Local Recurrence Following Conservative Surgery and Radiation Therapy above, in patients with negative margins of

resection, low rates of local recurrence are seen regardless of the sequence of RT and chemotherapy.102 A nonsignificant trend toward a greater risk of distant recurrence in patients receiving RT first was seen in one study,102 and because of the primary importance of preventing distant relapse, the convention has been to administer chemotherapy first. Tamoxifen therapy should not be given concurrently with chemotherapy as in one randomized study concurrent tamoxifen chemotherapy was associated with greater risk of recurrence than sequential treatment of chemotherapy followed by tamoxifen.218 There are no compelling data that the concurrent administration of tamoxifen and radiation therapy has deleterious consequences nor that it has particular advantages.219 As discussed in the section Preoperative Systemic Therapy for Operable Cancer above, the timing of surgery either before or after (neo)adjuvant chemotherapy does not alter long-term survival for women with breast cancer.112 Thus, patients may comfortably proceed in a linear fashion of treatment, receiving one therapeutic modality (surgery, radiation therapy, chemotherapy, biological therapy) after another, as they receive definitive treatment for early stage breast cancer. Table 43.2.20 Recommendations for Adjuvant Chemotherapy St. Gallen Consensus Conference National Comprehensive Cancer Network 20052007 2007 HER-2 Adjuvant chemotherapy (no specific Adjuvant chemotherapy tumors >0.5 cm positive size threshold) and/or node positive tumors HER-2 ER negative: ER negative: negative tumors adjuvant chemotherapy (no adjuvant chemotherapy for tumors specific size threshold) >1.0 cm and/or node positive; consider for tumors 0.5 to 1.0 cm if adverse prognostic factors (lymphovascular invasion, highgrade features) are present ER positive:

ER positive:

adjuvant chemotherapy if four or more lymph nodes are positive; consider if tumor >2 cm, or grade 23, or age <35, or lymphovascular invasion is present

adjuvant chemotherapy if node positive; consider if tumor >1 cm, or if tumor 0.6 to 1.0 cm and lymphovascular invasion or grade 23 features are present

Follow-Up for Breast Cancer Survivors Following initial treatment for breast cancer, patients require surveillance for local-regional tumor recurrence, contralateral breast cancer, and the development of distant metastatic disease. In addition, medical follow-up allows clinicians to monitor for late effects of chemotherapy, radiation therapy, or surgery, to gauge ongoing side effects from cancer treatments such as antiestrogen therapies, and to facilitate opportunities to update patients

on new developments that may affect their treatment plan.220 Although the greatest risk of recurrence is in P.1641 the first five years after breast cancer diagnosis, women remain at risk for many years after their treatment, especially those with hormone-receptorpositive breast cancer. These experiences justify ongoing follow-up with breast cancer specialists, although particularly in later years, follow-up is often shared with primary care physicians. Because local recurrence after BCT and contralateral primary tumors can be treated with curative intent, screening for these types of recurrences is a high priority and women should undergo regular breast examinations and annual mammography, with supplemental breast imaging as clinically indicated. By contrast, it is not clear that early detection of distant metastatic disease contributes to substantial improvement in clinically important end points. Most distant recurrences are detected following patient-reported symptoms such as bone discomfort, lymphadenopathy, chest wall/breast changes, or respiratory symptoms; asymptomatic detection through screening laboratory tests or radiology studies occurs in only a modest fraction of patients, even with intensive surveillance.221 Two randomized trials have compared vigorous surveillance with radiological imaging (chest radiography, bone scanning, and liver ultrasound) and laboratory testing (blood counts, liver function tests, and serum tumor markers) against standard care consisting of regular physical examination and mammography, with more intensive testing performed only if indicated by symptoms or physical examination.222,223 More intensive surveillance achieved modest gains in early detection of metastatic breast cancer, with a small increase in the fraction of patients diagnosed while asymptomatic, but no improvement in overall survival was noted. Based on these data, the American Society of Clinical Oncology has issued surveillance guidelines for women with early stage breast cancer,224 which are summarized in Table 43.2.21. These guidelines emphasize the importance of a careful history and examination to elicit symptoms or signs of recurrent breast cancer, but minimize the role of routine imaging studies including plain films and CT scans and do not recommend routine laboratory testing in the absence of symptoms. Patients should be encouraged to perform breast self-examination and to contact their physicians if they develop symptoms possibly suggestive of breast cancer recurrence. Understandably, patients often request additional testing to provide reassurance and to catch early recurrences. Clinical experience suggests, however, that patients respond well to discussions regarding optimal testing strategies, the role of surveillance for breast cancer recurrence, the challenges of falsepositive and false-negative test results, and the limited need for testing in the absence of symptoms or physical examination findings.225 Table 43.2.21 Breast Cancer Follow-Up RECOMMENDED FOR ROUTINE SURVEILLANCE History/physical Every 3 to 6 months for the first 3 years, every 6 to 12 months years 4 examination and 5, annually thereafter Mammography Annually, beginning no earlier than 6 months after radiation therapy Breast selfAll women should be counseled to perform monthly examination Pelvic examination Annually Coordination of Continuity of care with breast cancer specialist and appropriate other care health care providers

NOT RECOMMENDED FOR ROUTINE SURVEILLANCE Routine blood tests Complete blood cell count and liver function tests are not recommended Imaging studies Chest x-ray, bone scans, liver ultrasound, computed tomography scans, fluorodeoxyglucose-positron emission tomography scans, and breast magnetic resonance imaging are not recommended for routine breast cancer surveillance Tumor markers Cancer antigen 15-3, 27.29, and carcinoembryonic antigen are not recommended (Adapted from ref. 224.) Special Therapeutic Problems Paget's Disease Paget's disease of the breast is uncommon, accounting for about 1% of all breast malignancies. Pathologically, Paget's disease represents in situ carcinoma in the nipple epidermis. The classic pathologic finding is the presence of Paget cells (large cells with clear cytoplasm and atypical nuclei) within the epidermis of the nipple. The clinical manifestations of Paget's disease include eczematoid changes, crusting, redness, irritation, erosion, discharge, retraction, and inversion. Rarely, Paget's disease is bilateral or occurs in a male. Paget's disease may occur in the nipple (1) in conjunction with an underlying invasive cancer (staged by the invasive cancer), (2) with underlying DCIS (staged Tis), or (3) alone without any underlying invasive breast carcinoma or DCIS (also staged Tis). The associated underlying cancer may be located centrally in the breast adjacent to the nipple, or it may be located peripherally. It is uncertain whether the origin of Paget's disease is primarily an in situ intraepidermal malignancy with secondary extension to adjacent structures (intraepidermal theory) or migration of tumor cells into the nipple epidermis from an underlying carcinoma of the breast (epidermotropic theory). The age-adjusted incidence rates of female Paget's disease peaked in 1985 and have decreased yearly thereafter through 2002. From 1988 to 2002, incidence rates decreased by 45%, while the incidence of invasive cancer and DCIS increased. This decreasing incidence was greatest for Paget's disease associated with invasive cancer or DCIS.226 The explanation for this is not certain but can be interpreted as earlier detection of these lesions at a point in their evolution prior to the development of Pagetoid changes consistent with the epidermotropic theory. The work-up for the patient with Paget's disease includes mammography and physical examination of the breast, in particular to rule out an underlying invasive cancer or DCIS. In a P.1642 recent series of 40 patients with Paget's disease reported from the Mayo Clinic with a negative physical examination and mammogram, 68% had DCIS that extended beyond the nipple and only 5% (two patients) had an underlying invasive cancer.227 In patients with a negative physical examination and mammogram, breast MRI should be considered for patients who are candidates for BCT. Historically, Paget's disease has been treated with mastectomy. Prognosis is determined by the stage of the underlying malignancy if present. Several studies have focused on the potential for BCT with breast irradiation. The rationale for BCT of Paget's disease includes the success of BCT for DCIS and the earlier detection of Paget's disease with lower disease

burden at presentation. Bijker et al.228 reported on the results of a prospective trial of 61 patients treated with excision followed by radiation therapy. The 5-year local recurrence rate was 5.2%. There were four local failures; three were invasive cancer and one was DCIS only. Other small studies of BCT with excision and radiation therapy have been reported with similar results.229 In the Surveillance, Epidemiology, and End Results (SEER) data, 15-year breast cancerspecific survival is similar for patients treated with mastectomy and with BCT. BCT with radiation therapy appears to be a reasonable alternative to mastectomy, albeit with the caveats that no randomized trial has been performed and only small series of published cases have been so treated. Local excision alone, without radiation therapy, has been used to treat a small number of patients. In one of the largest series, Polgar et al.230 reported on the results of a prospective study of 33 patients treated with local excision alone. The local recurrence rate was 33% (11 of 33). Of the 11 local recurrences, ten (91%) were invasive carcinoma and one was DCIS. Six of ten patients with invasive local recurrence developed subsequent distant metastatic disease. Based on these findings, the authors recommended the addition of radiation therapy after breast-conservation surgery. Because of the small numbers of patients treated without radiation therapy and the high rate of local failure, such treatment must be considered as nonstandard at the present time. For patients treated with BCT, surgery should include excision of the full nipple-areolar complex with at least a 2-cm cone of retroareolar tissue and complete excision of any abnormal retroareolar radiologic findings. For patients with positive margins after central lumpectomy, additional surgery is indicated. Patients with negative surgical margins should undergo irradiation. The decision for axillary node surgery should be based on the presence of an invasive breast cancer; sentinel node biopsy has been used successfully in this setting. Recommendations for adjuvant systemic therapy are based on the final pathology. Occult Primary with Axillary Metastases An axillary metastases in the absence of a clinically or mammographically detectable breast tumor is an uncommon presentation of breast carcinoma seen in fewer than 1% of cases. The initial evaluation should include a detailed history and physical examination, bilateral mammogram, and a chest x-ray. At the time of the lymph node biopsy, the pathologist should be alerted to the lack of a known primary tumor so that immunohistochemical stains can be performed if needed. The presence of ER, PR, or HER-2 overexpression is strongly suggestive of metastatic breast carcinoma, although their absence does not exclude a primary breast tumor. An increasing body of evidence suggests that MRI identifies the primary tumor in the breast in a significant number of patients with a normal mammogram and breast examination. In one series of 69 patients with occult primary breast cancer seen between 1995 and 2001, MRI identified the primary breast tumor in 62%.231 In the 12 patients who did not have a tumor identified by MRI and underwent mastectomy, cancer was found in three. This experience is typical of multiple small studies of the use of MRI in this clinical circumstance. The identification of the primary tumor within the breast simplifies local management, allowing these patients to be treated with BCT or mastectomy according to standard guidelines. In cases where a primary tumor cannot be identified, treatment has traditionally been with mastectomy. This strategy was based on the observation that approximately 50% of patients who do not receive therapy to the breast will develop clinically evident disease in the breast. In addition, prior to the era of modern mammography and the availability of MRI,

the occult cancers found in the breast at mastectomy were sometimes quite large.232 More recently, radiation therapy to the whole breast has been used in these patients. Fourquet et al.232 treated 54 patients with RT to the whole breast without removal of the primary tumor. The 5- and 10-year rates of ipsilateral breast tumor recurrence were 7.5% and 20%, respectively. Other small studies antedating the use of MRI confirm that although rates of local recurrence after BCT are higher than in patients treated with excision of a known primary tumor and a boost dose of RT to the tumor bed, whole-breast irradiation with a dose of about 50 Gy is an acceptable alternative to mastectomy in this patient population. Regardless of the management approach chosen for the breast, axillary dissection should be carried out because of the limited ability of radiation to control gross axillary disease. Overall survival for women with occult primary tumors is similar to that of patients with comparable axillary involvement and a known primary tumor, and some investigators have suggested that survival is actually superior for those with occult primary tumors.233 Due to the small size of most studies of occult primary cancer, the heterogeneous treatments employed, and the variable durations of follow-up, this claim is difficult to substantiate. Systemic treatment for patients with occult primary breast cancer and axillary involvement should follow the current guidelines for patients with node-positive breast cancer. Breast Cancer and Pregnancy Breast carcinoma is one of the most commonly diagnosed malignancies during pregnancy. Older studies estimated that breast cancer developed in 2.2 per 10,000 pregnancies.234 However, the trend toward later age at first childbirth has increased the number of breast cancer cases coexistent with pregnancy, and breast cancer is now estimated to occur in 1 in 1,000 pregnancies.235 Delay in diagnosis remains a problem in women presenting with breast cancer during pregnancy. The nodularity of the breast in a pregnant woman may obscure small masses, and the presence of a breast mass may be inappropriately attributed to normal physiologic changes. Dominant breast masses developing during pregnancy require biopsy before assuming that they are benign. This can be readily accomplished with a core cutting needle P.1643 biopsy in the majority of women. If excisional biopsy is necessary, it should be undertaken; concerns about the development of a milk fistula appear to be overstated.236 Mammography is not as useful in pregnant patients as in those who are not pregnant because of the increased density in the breast parenchyma associated with pregnancy. Ultrasound may be helpful in confirming the presence of a dominant mass, but as in the nonpregnant patient, normal imaging studies should not lead to a decision to forgo biopsy in the patient with a dominant breast mass. After a diagnosis is made, the initial evaluation should include an assessment of the extent of the disease. CT and bone scans are not recommended during pregnancy because of concerns about radiation exposure to the fetus. In patients with symptoms suggestive of metastases, MRI without contrast can be used to evaluate bony sites and the intraabdominal viscera.236 Breast cancers occurring during pregnancy are usually high-grade infiltrating ductal carcinomas. In a prospective study of 38 pregnant women who developed breast cancer, 28% had ER-positive tumors and 24% PR-positive tumors.237 In general, the characteristics of cancers occurring during pregnancy are similar to those of nonpregnant women of the same age. Data from retrospective case control series suggest that after adjusting for age

and disease stage, the prognosis of women with breast cancer occurring during pregnancy differs little from that of nonpregnant patients.236 For women diagnosed in the first or second trimester, the question of pregnancy termination is inevitably raised. Although some treatment approaches are feasible during pregnancy, others are contraindicated. Depending on the patient's specific situation, continuing the pregnancy may or may not compromise the breast cancer treatment. Even when deviations from standard treatment are required, it is unclear to what extent such changes or delays affect a woman's odds of remaining free from recurrent breast cancer. The concerns about compromising care must be balanced, by the woman, her family, and her physicians, with the desire to continue the pregnancy. The woman facing these issues must also consider the possibility that if she receives chemotherapy, her ability to conceive another child could be compromised.185 There is no clear evidence that pregnancy termination changes overall survival.238 Breast surgery can be safely performed during any trimester of pregnancy. Mastectomy is the treatment that has traditionally been undertaken due to the inability to safely deliver RT to the breast without excessive fetal exposure during any trimester. The effect of delaying RT on local recurrence, in the absence of systemic therapy, is unknown and is of concern. Guidelines developed by the American College of Surgeons, American College of Radiology, and College of American Pathologists107 consider this an appropriate approach for cancers diagnosed in the third trimester and one that must be considered on a case-bycase basis for cancers diagnosed earlier in pregnancy. In the woman who will receive systemic chemotherapy, the delay in the delivery of RT is often no greater than in the nonpregnant patient. The success rate of lymphatic mapping and sentinel node biopsy in the pregnant woman is unknown. Isosulfan blue dye is not approved by the FDA for use during pregnancy. The radiation exposure to the fetus from the use of technetium has been estimated to be low, and it has been suggested that mapping with technetium alone could be discussed with patients as an appropriate management strategy.239 In the absence of definitive data on the safety and accuracy of sentinel node biopsy in the pregnant woman, axillary dissection remains the standard management strategy. The risk of congenital malformation from cytotoxic chemotherapy varies with the fetal age at exposure and the agent used. Exposure in the first trimester is associated with risks of 10% to 20%, which decline to less than 2% with exposure in the second and third trimesters.240 For this reason, chemotherapy in the first trimester should be avoided. Growth retardation may also occur, and the long-term consequences of intrauterine exposure to cytotoxic agents remain uncertain. In a prospective study of 24 pregnant women treated with fluorouracil, doxorubicin, and cyclophosphamide during the second and third trimesters of pregnancy, no complications were observed for the fetus or infant.241 Experience with the taxanes in pregnancy is very limited, but to date fetal toxicity has not been described.242 A case report of the use of trastuzumab in pregnancy documented reversible anhydramnois,243 and more information on the safety of this agent in pregnancy is needed. Methotrexate should be avoided during pregnancy because of the risk of abortion and severe fetal malformation. Similarly, tamoxifen should be withheld until after delivery since its safety is uncertain. When chemotherapy or tamoxifen is given postpartum, breastfeeding should be avoided as these agents may be excreted in the breast milk. The management of breast cancer during pregnancy is difficult since there is often a conflict between optimal therapy for the mother and the fetus. Multidisciplinary management by a team including medical, surgical, and radiation oncologists, an obstetrician, a maternal-fetal

medicine specialist, and a psychologist will facilitate the development of a strategy that optimizes the outcome for both mother and child. Male Breast Cancer The incidence of male breast cancer varies on a worldwide basis by geographic location, with the highest rates in some sub-Saharan countries. In the United States, it is estimated that in 2007, 2,030 men will be diagnosed with breast cancer (1.1% of the total for both genders) and that 450 men will die of it (1.1% of both genders).1 The risk of male breast cancer is related to an increased lifelong exposure to estrogen (as with female breast cancer) or to reduced androgen. The strongest association is in men with Klinefelter's syndrome (XXY) who have a 14- to 50-fold increased risk of developing male breast cancer and account for about 3% of all male breast cancer cases. Also, men who carry a BRCA1, or particularly a BRCA2 mutation, have an increased risk of developing breast cancer. The following conditions have been reported to be associated with an increased risk of breast cancer in men: chronic liver disorders, such as cirrhosis, chronic alcoholism, schistosomiasis; a history of mumps orchitis, undescended testes, or testicular injury; and feminization, genetically or by environmental exposure. In contrast, gynecomastia alone does not appear to be a risk factor.244 The clinical presentation of male breast cancer is similar to that of female breast cancer, but the median age of onset is later than in females (60 vs. 53 years). Since the diagnosis of breast cancer is often not considered as promptly in men and screening mammography is not used, men often present with more advanced stage than do women. All known histopathologic types of breast cancer have been described in men, with infiltrating ductal carcinoma accounting for at least 70% of P.1644 cases. However, invasive lobular carcinoma in men is rare. A majority of male breast cancers are ER/PR positive and the percentage positive is greater than for female breast cancer. As for women, stage is the predominant prognostic indicator, and most studies report that stage for stage, men with breast cancer have the same outcome following treatment as women with breast cancer. A recent study, however, from the Veterans Affairs reports a worse prognosis for men than women in early stage breast cancer.245 There appears to be a substantial negative disparity in outcome for blacks with male breast cancer compared to whites.246 Primary local treatment is typically total mastectomy. In some patients with early disease, BCT can be considered. However, the subareolar location of most male breast cancers and the small amount of breast tissue present in most men limits eligibility for BCT. The same considerations regarding nodal surgery pertain for men as for women, with sentinel node biopsy the preferred treatment in clinically node-negative patients. The use of postmastectomy radiation therapy follows the same guidelines as for female breast cancer. Similarly, the use of systemic therapy follows the same guidelines as for women with postmenopausal breast cancer. Adjuvant systemic chemotherapy is used in men, although no controlled trials have confirmed its value.247 Tamoxifen is the mainstay for adjuvant systemic therapy in ER-positive male breast cancer. There is limited experience with aromatase inhibitors in men, but they appear to be effective. Metastatic breast cancer in men is treated identically to metastatic disease in women. Phyllodes Tumor

The term phyllodes tumor includes a group of lesions of varying malignant potential, ranging from completely benign tumors to fully malignant sarcomas. Clinically, phyllodes tumors are smooth, rounded, usually painless multinodular lesions that may be indistinguishable from fibroadenomas. The average age at diagnosis is in the fourth decade. Skin ulceration may be seen with large tumors, but this is usually due to pressure necrosis rather than invasion of the skin by malignant cells. Histologically, phyllodes tumor, like fibroadenoma, is composed of epithelial elements and a connective tissue stroma. Phyllodes tumors are classified as benign, borderline, or malignant based on the nature of the tumor margins (pushing or infiltrative) and presence of cellular atypia, mitotic activity, and overgrowth in the stroma. There is disagreement about which of these criteria is most important, although most experts favor stromal overgrowth. The percentage of phyllodes tumors classified as malignant ranges from 23% to 50%. Local excision to negative margins is an appropriate management strategy for both benign and malignant phyllodes tumors if this can be accomplished with a satisfactory cosmetic outcome. The optimal margin width is not known, but wider excisions appear to reduce the risk of local recurrence. Approximately 20% of phyllodes tumors recur locally if excised with no margin or a margin of a few millimeters of normal breast tissue, regardless of whether they are benign or malignant.248 In a review of 821 patients with nonmetastatic malignant phyllodes tumors reported to the SEER registry between 1983 and 2002, 52% were treated with mastectomy and the remainder with local excision. The 10-year cause-specific survival was 89%, and no survival benefit for mastectomy was observed.249 The role of radiotherapy and systemic therapy in phyllodes tumor is unclear. Radiotherapy is not used for benign or borderline lesions but has been combined with wide excision in the management of malignant phyllodes tumors. When phyllodes tumors metastasize they tend to behave like sarcomas, with lung as the most common site. Axillary metastases are seen in fewer than 5% of cases, and axillary surgery is not indicated unless worrisome nodes are clinically evident. When systemic therapy is used for malignant phyllodes tumors, treatment is based on the guidelines for treating sarcomas. Locally Advanced and Inflammatory Breast Cancer Locally advanced breast cancer (LABC) and inflammatory breast cancer (IBC) refer to a heterogeneous group of breast cancers without evidence of distant metastases (M0) and represents only 2% to 5% of all breast cancers in the United States. Patients with these cancers include those with (1) operable disease at presentation (clinical stage T3N1), (2) inoperable disease at presentation (clinical stage T4 and/or N2-3), and (3) inflammatory breast cancer (clinical stage T4dN0-3). (All stages refer to the AJCC 6th edition, 2002.72) Subdividing patients into these three broad groups facilitates clinical management. Comparison of studies of LABC and IBC is problematic for a number of reasons. First, these patients have a high degree of heterogeneity in T and N classification, and the number of patients in each subgroup is typically small and variable between studies. Second, the definition of LABC according to AJCC staging criteria has varied over time.72 Some studies have included T3N0M0 (now stage IIB) cancers and even large T2 lesions (e.g., lesions 3 cm or larger) as LABC. Also, supraclavicular lymphadenopathy is now classified as N3 disease, although it was previously classified as M1 and therefore excluded from many studies.250 Third, the subgroups of patients included in studies vary widely. For example, patients with IBC or operable disease at presentation may or may not be combined with patients with LABC. Fourth, studies vary in the extent of diagnostic evaluation prior to treatment. Some centers, for example, have routinely employed

ultrasound evaluation of axillary and supraclavicular regions with fine needle aspiration of suspected involvement; such improved staging will improve the outcome in all stages. IBC accounts for 1% to 5% of all cases of breast cancer in the United States and is an aggressive variant of LABC. IBC is a clinicopathologic entity characterized by diffuse erythema and edema (peau d'orange) of the breast often without an underlying palpable mass. The clinical findings should involve most of the skin of the breast. IBC typically has a rapid onset and is often initially mistaken as infection and treated with antibiotics before the diagnosis is established. The clinical presentation is due to tumor emboli in the dermal lymphatics. According to the AJCC staging rules,72 IBC is primarily a clinical diagnosis. Involvement of dermal lymphatics in the absence of clinical findings does not indicate IBC. A skin biopsy may be performed to confirm the clinical impression of IBC, but the absence of dermal lymphatic involvement should not affect staging. As with all cases of breast cancer, the determination of ER, PR, and HER-2 status is critical in the management of LABC P.1645 and IBC. IBCs are more likely to be high-grade, HER-2-overexpressing, and lacking in hormone-receptor expression compared to other presentations of breast cancer. Because both LABC and IBC are associated with substantial risk of metastatic disease, these patients should undergo full work-up for distant metastases prior to initiation of therapy. Patients with LABC or IBC should be evaluated by a multidisciplinary team (ideally around the time of diagnosis). Treatment typically includes neoadjuvant chemotherapy, surgery, and radiation therapy. Prior to the use of neoadjuvant chemotherapy, long-term survival was uncommon. Long-term survival has been greatly improved with aggressive trimodality treatment. As with early stage breast cancer, biological tumor markers should affect treatment selection: patients with HER-2-positive cancers should receive trastuzumab-based therapy, and patients with hormone-receptorpositive cancers should receive adjuvant endocrine therapy. The response to neoadjuvant chemotherapy has been assessed in various studies using physical examination, mammography, ultrasonography, and MRI, but none of these methods has proven highly predictive of pathologic response. Anthracycline- and taxane-based chemotherapy regimens are appropriate as induction chemotherapy for women with LABC or IBC. The vast majority of patients will have clinical response to therapy, and roughly 15% to 25% will experience a complete pathological response. The addition of paclitaxel to anthracycline-based therapy appears to improve long-term disease outcomes for women with LABC and IBC.251 There are no studies of trastuzumab specifically for LABC/IBC; however, by extrapolation of results using trastuzumab for early stage breast cancer, it should be incorporated into the treatment of women with HER-2-positive LABC or IBC. As with other experiences using neoadjuvant chemotherapy, complete pathological eradication of the tumor predicts superior outcomes among women with LABC or IBC.252 However, even among patients with pathological complete response to neoadjuvant chemotherapy, those with LABC or IBC at baseline have a higher risk of recurrence than patients with lower stage breast cancer at baseline.253 Patients with LABC or IBC should be routinely treated with postmastectomy radiation therapy, despite a pathologic complete response to neoadjuvant chemotherapy.254 Some women with LABC may be candidates for BCT following neoadjuvant chemotherapy. In one series, local-regional control following this approach appeared to be excellent except in patients with one or more of the following features: (1) clinical N2-3

disease, (2) lymphovascular invasion, (3) residual primary pathologic size greater than 2 cm, and (4) multifocal residual disease.255 However, there is still limited experience with this approach. In a small study of 13 patients with IBC treated with preoperative chemotherapy and BCT, seven of 13 experienced local recurrence.256 This coupled with the diffuse nature of IBC indicates that BCT is contraindicated in women with this diagnosis. Although most women have a clinical response to neoadjuvant chemotherapy, some patients will experience tumor progression or remain inoperable. Such patients may be candidates for noncross-resistant chemotherapy or novel treatments. Surgery is contraindicated in IBC unless there is complete resolution of the inflammatory skin changes. In modern studies, 85% to 90% of patients become operable after initial chemotherapy.257 Radiation therapy may facilitate conversion of inoperable to operable disease. In spite of modern multimodality therapy, approximately 20% of IBC patients treated with chemotherapy, surgery, and RT will experience locoregional recurrence.257 Patients with chest wall recurrence after chemotherapy, surgery, and radiation therapy are at high risk for both extensive local-regional tumor spread and for developing metastatic disease to visceral organ sites, and are treated according to guidelines for metastatic breast cancer. Metastatic Disease Metastatic (stage IV) breast cancer is defined by tumor spread beyond the breast, chest wall, and regional lymph nodes. Tumor dissemination can occur through blood and lymphatic vessels and via direct extension through the chest wall. The most common sites for breast cancer metastasis include the bone, lung, liver, lymph nodes, chest wall, and brain. However, case reports have documented breast cancer dissemination to almost every organ in the body. Hormone-receptorpositive tumors are more likely to spread to bone as the initial site of metastasis; hormone-receptornegative and/or HER-2-positive tumors are more likely to recur initially in viscera. Lobular (as opposed to ductal) cancers are more often associated with serosal metastases to the pleura and abdomen. Most women with metastatic disease will have been initially diagnosed with early stage breast cancer, treated with curative intent, and then experience metastatic recurrence. Only about 10% of newly diagnosed breast cancer patients in the United States have metastatic disease at presentation; this proportion is far higher in areas where screening programs are not available. Symptoms of metastatic breast cancer are related to the location and extent of the tumor. Common symptoms or physical examination findings include bone discomfort, lymphadenopathy, skin changes, cough or shortness of breath, and fatigue. These clinical findings are all nonspecific, and appropriate evaluation is warranted in breast cancer patients with new or evolving symptoms. In some cases, physical examination or radiological findings will demonstrate unequivocal evidence of metastatic breast cancer. In instances when radiologic or clinical findings are equivocal, tissue biopsy is imperative. If a biopsy is performed, ER, PR, and HER-2 should be redetermined. The treatment goals in women with advanced breast cancer include prolongation of life, control of tumor burden, reduction in cancer-related symptoms or complications, and maintenance of quality of life and function. Therapy is not generally considered curative. A small fraction of patients, often those with limited sites of metastatic disease or bearing tumors with exquisite sensitivity to treatment, may experience very long periods of remission and tumor control. Treatment of advanced breast cancer, like treatment of early stage breast cancer, is based on consideration of tumor biology and clinical history. Thus,

characterization of tumor ER, PR, and HER-2 status is critical for all patients, and a detailed assessment of past treatment including timing of therapies as well as patient symptoms and functional assessment is essential. An overview of treatment for advanced breast cancer is shown in Figure 43.2.6. Patients with endocrine-sensitive tumors, particularly those with minimal symptoms and limited visceral involvement, are candidates for initial treatment with endocrine therapy alone; initial treatment using combined chemoendocrine therapy has not been shown P.1646 to improve survival compared to sequential treatment programs. Patients with hormonereceptor-negative tumors or those with hormone-receptorpositive tumors progressing despite the use of endocrine therapy are candidates for chemotherapy. If the tumor is HER2 positive, then trastuzumab treatment is employed in combination with chemotherapy.

Figure 43.2.6. Algorithm for treatment of the patient with metastatic breast cancer based on hormone-receptor status and the presence of HER-2 overexpression. ER, estrogen receptor; PR, progesterone receptor. Well-established clinical factors can inform the likelihood of response to therapy and longterm outcomes in women with metastatic breast cancer (Table 43.2.22). Patients who have received less therapy, have a longer disease-free interval since initial diagnosis, soft tissue or bone metastases, fewer symptoms and better performance status, and tumors that are hormone-receptor positive are likely to experience longer survival with metastatic disease than more heavily treated patients with shorter intervals since treatment, visceral metastases, and greater symptomatology. In clinical trials, the measured end points for defining efficacy of therapy for metastatic breast cancer are response rate, time to tumor progression, and overall survival. These landmarks are important for guiding clinical practice as well, although formal measures of response/progression are often difficult to apply owing to inconsistencies in imaging studies, the prevalence of nonmeasurable disease such as bone lesions, subcentimeter tumor deposits, and pleural effusions or ascites. The art of treating patients with metastatic breast cancer involves careful, thoughtful repetition of a process of treatment initiation, evaluation including assessment of patient functional status and symptom profile and by serial measurement of tumor burden and response to therapy, and discontinuation through multiple lines of therapy. Clinical guidelines for the management of metastatic carcinoma194 are often quite open ended, acknowledging the multiple treatment pathways

that might be legitimately pursued, arguing for judicious use of clinical decision making and treatment selection based on tumor biology, and focusing clinicians on the continuous considerations of patient preference and illness experience. Table 43.2.22 Prognostic Factors in Advanced Breast Cancer Tumor biology (grade, estrogen receptor status, HER-2 status) Performance status Cancer related symptoms Sites of recurrence Number of sites of recurrence Prior adjuvant therapy Disease-free interval Prior therapy for metastatic disease Response/duration of treatment with prior therapy for metastatic disease Endocrine Therapy for Metastatic Breast Cancer Endocrine treatment is a key intervention for women with hormone-receptorpositive, metastatic breast cancer. The first therapy for advanced breast cancer was oophorectomy, and in the 100 years since the advent of that treatment, there has been steady progress in the development of hormonal therapy for metastatic disease. Table 43.2.23 lists available endocrine drugs for treating advanced breast cancer. A variety of well-tolerated commercially available agents are now used to treat advanced breast cancer, including tamoxifen, aromatase inhibitors, fulvestrant, and progestins. Many women will be candidates for multiple types of endocrine therapy to control metastatic breast cancer. On average, first-line treatment is associated with 8 to 12 months of tumor control, and secondline treatment with 4 to 6 months. Individual patients may experience substantially longer time to progression. Sequential single-agent second- and third-line endocrine treatments are often effective, although typically for shorter durations than initial therapy. Patients with either overt tumor shrinkage or stabilization of disease in response to endocrine treatment can have equivalent long-term tumor control. Endocrine therapy can cause regression of soft tissue and bone and visceral metastases. Eventually most women with hormone-receptorpositive metastatic breast cancer will progress despite first-line endocrine therapy. Resistance to treatment does not seem to be associated with loss of hormone-receptor expression by the tumor cells. Indications for chemotherapy include symptomatic tumor progression, pending visceral crisis, or resistance to multiple endocrine therapies. Patients presenting with extensive visceral metastases or profound symptoms from breast cancer may benefit from induction chemotherapy, which should then be followed with endocrine therapy. Tamoxifen was the historic standard as treatment for ER-positive metastatic breast cancer, associated with a 50% response rate and median duration of response of 12 to 18 months among treatment-naive patients. A tamoxifen flare reaction, typically characterized by intensification of bone pain, transient tumor progression, and hypercalcemia, can arise in 5% to 10% of patients within the first days or weeks of tamoxifen P.1647 treatment. Flare reactions are often harbingers of exquisite tumor sensitivity to endocrine manipulation, but must be distinguished from overt tumor progression. Flare reactions are not frequently seen with other endocrine therapies. Table 43.2.23 Endocrine Therapies for Metastatic Breast Cancer

Ovarian suppression/ablation (premenopausal women) Selective estrogen receptor modulators (tamoxifen, toremifene) Aromatase inhibitors (anastrozole, letrozole, exemestane; postmenopausal women) Antiestrogens (fulvestrant; postmenopausal women) Progestins (megestrol and medroxyprogesterone) Other steroid hormones (high-dose estrogens, androgens; principally of historical interest) In premenopausal women with metastatic breast cancer, combined endocrine therapy with ovarian suppression and tamoxifen can improve survival compared to treatment with either tamoxifen or ovarian suppression alone.258 Thus, first intervention for premenopausal women with breast cancer recurrence is ovarian suppression or ablation, with initiation of tamoxifen treatment. Premenopausal women with metastatic tumor despite tamoxifen use are candidates for ovarian suppression/ablation and aromatase inhibitor therapy. Owing to a combination of the demographics of breast cancer, the duration of time between initial tumor diagnosis and metastatic recurrence and chemotherapy-induced amenorrhea, most women with recurrent breast cancer will be postmenopausal. Postmenopausal women are candidates for either tamoxifen, aromatase inhibitors, fulvestrant or progestational agents as palliation for metastatic breast cancer. Aromatase inhibitors appear to be the preferred initial agents for women who received prior tamoxifen treatment in the adjuvant setting.259,260 For postmenopausal women who are naive to antiestrogens, aromatase inhibitors may have modest clinical advantages over tamoxifen as initial treatment for metastatic disease.261,262 Fulvestrant appears to have comparable activity to aromatase inhibitors in women previously treated with tamoxifen.263 The optimal sequencing of endocrine therapy for postmenopausal women treated with adjuvant aromatase inhibitors is not clear, as few trials have rigorously explored different treatments among such patients. Tamoxifen, fulvestrant, progestins, and possibly different aromatase inhibitors are all reasonable options among such patients. Chemotherapy for Metastatic Breast Cancer Cytotoxic chemotherapy remains a mainstay of treatment for women with metastatic breast cancer, irrespective of hormone-receptor status, and is the backbone of many novel treatments incorporating biological therapy.264 Chemotherapy has substantial side effects, including fatigue, nausea, vomiting, myelosuppression, neuropathy, diarrhea, and alopecia. For this reason, treatment of women with chemotherapy for advanced breast cancer involves tradeoffs between cancer palliation and toxicities of therapy. Chemotherapy is used in patients with hormone-refractory or hormone-insensitive tumors (Fig. 43.2.6). Clinical trials have addressed a number of important treatment principles for use of chemotherapy in women with metastatic breast cancer. Tumor response to chemotherapy is a surrogate for longer cancer control and survival.265,266 First-line treatment is associated with higher response rates and longer tumor control than second-line and so forth. There are relatively few studies of fourth or higher lines of chemotherapy, although patients often receive many lines of treatment. Trials have demonstrated palliative benefits of chemotherapy in patients with refractory tumors receiving third-line or subsequent chemotherapy treatment, but the magnitude of such gains must be realistically weighed against the side effects of treatment. Chemotherapy treatment can be interrupted in patients who have had significant response or palliation following initiation of therapy and reintroduced when there is tumor progression or recrudescence of patient symptoms. Since the advent of chemotherapy administration for metastatic breast cancer, it has been debated whether single-agent sequential treatment or combination treatment with multiple

agents is the best strategy. Randomized studies have suggested that combination chemotherapy may be associated with higher response rates and improved time to progression compared with single-agent therapy. However, studies that have specifically planned for crossover treatment with second-line sequential therapy have not shown that combination treatment improves ultimate time to progression or survival compared to a sequential treatment program.267 Patients with extensive visceral disease or pending visceral crisis may preferentially require initiation of combination chemotherapy, but this has not been demonstrated in prospective studies. Because single-agent chemotherapy facilitates better understanding of which drugs are contributing to benefit or side effects, allowing appropriate treatment modification, and is generally associated with less toxicity, it remains the preferred approach for most women with metastatic breast cancer. A large number of chemotherapy agents and combinations are effective in treatment of metastatic breast cancer (Table 43.2.24).194 A variety of specific drugs and combinations are considered preferred based on a large historical experience, results from randomized trials, and consideration of toxicity profiles. Efforts have been made to demonstrate that one chemotherapy regimen or sequence is superior to another. For the most part, the literature does not support the idea that there is one path or algorithm for treating patients, particularly given the variety of agents and multiple lines of therapy ultimately used during the course of treating metastatic disease. Although anthracycline- and taxane-based treatments are generally considered to be among the most active in treatment of metastatic breast cancer, their utility has led to their incorporation into adjuvant chemotherapy regimens. Thus, many women with metastatic breast cancer will already have been treated with anthracyclines and or taxanes, diminishing the utility of these agents in the palliation of metastatic disease. Recent advances in chemotherapy for metastatic breast cancer are related to the development of new agents and schedules for treatment. Capecitabine is an orally available fluoropyrimidine, metabolized in tissues into 5-fluorouracil. Capecitabine has clinical activity in anthracycline- and taxane-resistant breast cancer268 and improves response and survival as first-line treatment when added to single-agent docetaxel.269 The antimetabolite gemcitabine similarly yields higher response rates and survival when paired with paclitaxel compared to paclitaxel therapy alone.270 Dose escalation of taxane therapy with paclitaxel has not been shown to result in clinically important improvements.181 However, weekly administration of paclitaxel therapy does appear to improve response rate and time to progression compared to less frequent, every 3week administration.271,272 As a strategy to overcome chemotherapy resistance, many investigators in the 1990s explored high-dose chemotherapy with autologous bone marrow or stem cell support as treatment for breast cancer. Preliminary studies suggested favorable clinical outcomes, prompting both widespread use of high-dose chemotherapy in clinical practice and randomized trials for patients with either metastatic or high-risk node-positive breast P.1648 cancer. Despite initial hopes, randomized trials did not demonstrate clinical improvement with use of high-dose chemotherapy compared to conventional chemotherapy dosing. In a randomized trial of patients with metastatic breast cancer, women received induction chemotherapy with four to six cycles of standard agents, followed by treatment with either one cycle of high-dose chemotherapy and autologous stem cell rescue or maintenance

chemotherapy at conventional doses.273 There were no differences in either progressionfree or overall survival. Table 43.2.24 Preferred Chemotherapy Agents and Combinations for Advanced Breast Cancer Single Agents Combination Regimens Anthracyclines (doxorubicin, Cyclophosphamide/anthracycline +/- 5-fluorouracil epirubicin, pegylated liposomal regimens (such as AC, EC, CEF, CAF, FEC, FAC) doxorubicin) Taxanes (paclitaxel, docetaxel, CMF albumin nano-particle bound paclitaxel) 5-fluorouracil (continuous infusion Anthracyclines/taxanes (such as doxorubicin/paclitaxel 5-FU, capecitabine) or doxorubicin/docetaxel) Vinca alkaloids (vinorelbine, Docetaxel/capecitabine vinblastine) Gemcitabine Gemcitabine/paclitaxel Platinum salts (cisplatin, Taxane/platinum regimens (such as carboplatin) paclitaxel/carboplatin or docetaxel/carboplatin) Cyclophosphamide Etoposide A, doxorubicin; C, cyclophosphamide; E, epirubicin; F, 5 fluorouracil; m, methotrexate. (Adapted from ref. 194, with permission.) Multiple randomized trials explored high-dose chemotherapy in the adjuvant setting. Among patients with ten or more positive axillary lymph nodes, six cycles of CAF (cyclophosphamide/doxorubicin/5-fluorouracil) chemotherapy was compared against CAF followed by one cycle of intensification with high-dose chemotherapy and autologous stem cell support.274 Stem cell transplant yielded small gains in relapse-free survival, no gains in overall survival, and was associated with greater risk of short- and long-term treatmentassociated mortality. A related trial of FEC with or without the addition of high-dose chemotherapy, open to women with four or more positive axillary lymph nodes, identified a subset of patients with ten or more positive nodes that showed improvement in disease-free survival with use of high-dose chemotherapy but did not suggest significant overall advantage.275 Another study compared doxorubicin followed by CMF chemotherapy against doxorubicin followed by intensified cyclophosphamide and one cycle of high-dose chemotherapy and bone marrow transplant, showing no difference in relapse-free or overall survival.276 Trials of moderately intensified adjuvant chemotherapy compared to standard chemotherapy followed by high-dose chemotherapy with autologous stem cell support disclosed no long-term clinical advantages for high-dose chemotherapy.277,278 Collectively, these studies have been interpreted as showing negligible if any benefit for use of high-dose chemotherapy in either the adjuvant or metastatic treatment setting. At present, there is no role for high-dose chemotherapy outside of a clinical trial, and it remains unclear which groups of patientsdefined by either clinical history or tumor biology might be most suitable as candidates for such studies. ANTI-HER-2 Therapy for Metastatic Breast Cancer Patients with HER-2 overexpressing breast cancer should receive trastuzumab therapy as part of their treatment program. When added to first-line chemotherapy for HER-2-positive metastatic breast cancer, trastuzumab improved response rates, time to progression, and

overall survival in two randomized trials.279,280 Cardiomyopathy is a known side effect of trastuzumab therapy, and serial determinations of left ventricular ejection fraction should be performed to screen for changes related to trastuzumab.281 For this reason, concurrent administration of trastuzumab with anthracyclines should be avoided. Neither the optimal timing for initiation of trastuzumab nor the optimal chemotherapy backbone are well characterized. Trastuzumab is generally started with chemotherapy based on data from randomized trials. In some settings, trastuzumab may be considered as single-agent therapy282 or in combination with endocrine therapy. However, it is not clear how to select patients who are suitable candidates for initial use of trastuzumab without concurrent chemotherapy administration. A variety of chemotherapy agents have shown clinical activity and safety when paired with trastuzumab, including taxanes, vinorelbine, and platinum analogs. The role of combination chemotherapy plus trastuzumab for metastatic disease remains controversial. The results of randomized studies examining the addition of platinum chemotherapy to taxanes plus trastuzumab are conflicting.283,284 The role of trastuzumab therapy for treatment beyond progression in the metastatic setting has not been studied in randomized trials. However, recent data suggest that ongoing anti-HER-2 treatment may be important for patients with tumor progression on trastuzumab. Lapatinib is a novel dual-kinase inhibitor that targets both the HER-2 and EGFR tyrosine kinase signaling pathways. Lapatinib has been studied as second-line anti-HER-2 therapy for patients progressing after chemotherapy and trastuzumab.285 In comparison with the administration of capecitabine chemotherapy alone, the combination of lapatinib plus capecitabine was associated with a longer period of tumor control and improvement in response rate, but not survival. This suggests that ongoing antiP.1649 HER-2 therapy may be effective after initial trastuzumab treatment in the metastatic setting. Antiangiogenesis Therapy for Advanced Breast Cancer Drugs that target proteins involved in tumor angiogenesis such as vascular endothelial growth factor (VEGF), VEGFR, and other receptors on tumor and endothelial cells are emerging as important agents for palliating metastatic cancer. VEGF-targeted therapies are approved for use in advanced colorectal, nonsmall cell, and renal carcinomas. Experience to date suggests that similar principles hold for patients with metastatic breast cancer. Bevacizumab, the humanized monoclonal antibody that neutralizes VEGF, is the most studied antiangiogenic agent in breast cancer. In an initial randomized trial open to patients with prior anthracycline- and taxane-based chemotherapy treatment, the addition of bevacizumab to capecitabine was not associated with improvement in time to tumor progression or survival, but did enhance response rate modestly.286 In ECOG E2100, a randomized trial of paclitaxel with or without the addition of bevacizumab as first-line treatment for metastatic breast cancer, bevacizumab did lead to clinically meaningful improvements in response rate and time to progression.287 Unique side effects of bevacizumab include hypertension, impaired wound healing, and a slightly increased risk of thromboembolism. The initial encouraging efficacy and tolerability data have led to exploration of bevacizumab as therapy for early stage breast cancer. Multiple other antiangiogenesis agents are now in clinical development for metastatic breast cancer. To date there are no specific markers that identify tumors or patients likely to benefit from antiangiogenic therapy. It is not clear how the various agents in development

compare to one another with respect to safety or utility, nor whether chemotherapy is an obligate modality for achieving benefit with these agents. Treatment of Special Metastatic Sites in Patients with Breast Cancer Specialized treatment options are available for breast cancer patients with metastases to selective anatomic sites. Patients with lytic bone metastases should receive intravenous bisphosphonate therapy such as pamidronate or zoledronic acid. These agents lessen the pain associated with bone lesions and prevent complications of skeletal metastases including fracture and hypercalcemia.288 Extended bisphosphonate therapy can be associated with osteonecrosis of the jaw, so patients should be monitored for atypical oral lesions. It is not known if the intermittent administration of bisphosphonates would compromise their efficacy or minimize the risk of osteonecrosis. Patients with focal pain at sites of skeletal metastases, pending fracture, or pathological fracture may also benefit from external beam radiation therapy at selected tumor sites, and when necessary, surgical stabilization or repair of the bone or joint. Improvements in survival in metastatic cancer seen with better chemotherapy and trastuzumab-based treatment have led to an increase in the incidence of central nervous system disease among breast cancer patients, especially those with HER-2 overexpressing or hormone-receptornegative tumors.289 This is likely a consequence of at least two clinical factors. First, the brain appears to be a relative sanctuary site for such tumors from chemotherapy and biological therapy. Second, the improved longevity of these patients who might previously have succumbed to pulmonary or hepatic metastases places them at greater jeopardy for late complications of cancer such as central nervous system metastases. Therapy for brain metastases remains inadequate, but generally includes whole brain irradiation. Patients with isolated lesions, dominant masses, or recurrence after whole brain radiation may additionally be candidates for surgical resection or stereotactic radiation therapy to specific lesions. Patients with leptomeningeal disease may achieve symptomatic improvement with whole brain irra-diation, or in some cases, intrathecal chemotherapy with methotrexate or cytarabine. Very limited clinical experience suggests that some systemic therapies, including endocrine treatments, chemotherapy agents including anthracyclines, alkylators, and capecitabine, and possibly lapatinib, may have antitumor activity in the brain. However, none of these is standard of care or a substitute for local therapy to the brain. Some breast cancer patients will have limited sites of metastatic disease, such as isolated pulmonary nodules, isolated lymph node recurrence outside of the axilla, or bone lesions. Single-institutional experience from the M. D. Anderson Cancer Center suggests that a fraction of such patients may be treated aggressively with curative intent, with favorable long-term results.290 Investigators identified cohorts of patients who had received definitive surgical treatment to the breast, had not received adjuvant anthracycline-based therapy, and who developed isolated metastatic disease that could be definitively treated with local therapy. Local therapy included surgical excision if possible, or in the case of bone lesions or other unresectable tumor sites, irradiation of the affected site. These patients were considered to be stage IVNED (no evidence of disease). Such stage IV/NED patients were treated with adjuvant type anthracycline chemotherapy and, where appropriate, endocrine therapy. Many of these patients had long periods of freedom from tumor recurrence, and 25% to 30% remained free of further recurrence through 10 years of follow-up.290

The treatment of the primary tumor in the breast in women who present with metastatic disease is another area of controversy. Historically, surgery or radiation therapy to the breast was limited to patients with local tumor complications such as pain or skin erosion, and systemic drug therapy was the primary form of treatment. An analysis of 16,023 patients presenting with stage IV disease and an intact primary tumor compared outcomes between patients having surgery of the primary tumor to negative margins or no surgery. In a multivariate analysis adjusting for known prognostic factors, surgery reduced the hazard ratio for death to 0.61 (95% CI, 0.58 to 0.65).77 A retrospective population-based study of 300 women reported similar findings.78 In the absence of a randomized trial it is impossible to exclude unrecognized selection bias as the cause of the benefit observed for surgery. However, improvements in survival for patients with metastatic breast cancer seen even prior to the era of trastuzumab78 coupled with the stage shift that is occurring due to the use of imaging technologies capable of identifying very small metastatic deposits suggest that it may be time to re-examine the role of local therapy in the patient presenting with stage IV disease and an intact primary tumor or limited metastatic P.1650 disease. At present, it is not known precisely how or when to integrate such surgical management into standard medical therapy for metastatic breast cancer or which patients in particular are most likely to benefit from such treatment. Local therapy should not be used as an initial approach to the patient with metastatic disease, but may be considered in a highly selected group of patients with a good response to systemic therapy and a limited number of metastatic sites. References 1. American Cancer Society. Breast cancer facts and figures 20052006. World Wide Web URL: www.cancer.org. 2. Ferlay J, Autier P, Boniol M, et al. Estimates of the cancer incidence and mortality in Europe in 2006. Ann Oncol 2007;18(3):581. 3. Parkin DM, Bray FI, Devesa SS. Cancer burden in the year 2000. The global picture. Eur J Cancer 2001;37(Suppl 8):4. 4. Ries L, Eisner M, Kosary CL, et al. SEER cancer statistics review, 19752001. Bethesda, MD: National Cancer Institute, 2004. 5. Berry DA, Cronin KA, Plevritis SK, et al. Effect of screening and adjuvant therapy on mortality from breast cancer. N Engl J Med 2005;353(17):1784. 6. Narod SA. Modifiers of risk of hereditary breast cancer. Oncogene 2006;25(43):5832. 7. Cullinane CA, Lubinski J, Neuhausen SL, et al. Effect of pregnancy as a risk factor for breast cancer in BRCA1/BRCA2 mutation carriers. Int J Cancer 2005;117(6):988. 8. Lakhani SR, Van De Vijver MJ, Jacquemier J, et al. The pathology of familial breast cancer: predictive value of immunohistochemical markers estrogen receptor, progesterone receptor, HER-2, and p53 in patients with mutations in BRCA1 and BRCA2. J Clin Oncol 2002;20(9):2310. 9. U.S. Preventive Services Task Force. Genetic risk assessment and BRCA mutation testing for breast and ovarian cancer susceptibility: recommendation statement. Ann Intern Med 2005;143(5):355. 10. Oldenburg RA, Kroeze-Jansema K, Kraan J, et al. The CHEK2*1100delC variant acts as a breast cancer risk modifier in non-BRCA1/BRCA2 multiple-case families. Cancer Res 2003;63(23):8153.

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