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DR LADIPO T.A DEPARTMENT OF RADIOTHERAPY NHA

Breast cancer is one of the major diseases of public health importance. Worldwide it is the most common cancer in women. It affects about 1% of male population. Breast cancer is second only to lung cancer in mortality world wide. Incidence varies greatly around the world, being lower in less-developed countries and greatest in the more-developed countries.

Although the incidence has stabilised in developed countries, it has continued to rise in developing and other countries that had low rates. While the morbidity and mortality of the disease is declining in developed countries, its increasing in the developing countries most probably due to poverty and late presentation.( Vanderpuye et al, 2009)

A TIP OF THE ICEBERG

Breast cancer is the leading cause of death in women aged 45-50yrs. The 5yr survival is 60% overall but is greater than 80% for early disease.(Hemant singal et al,2009)

It is rarely found before the age of 25yrs except in certain familial cases. Rates are high in USA,Scotland and western Europe. Estimated new cases and deaths from breast cancer in the United States in 2008: New cases: 182,460 (female); 1,990 (male) Deaths: 40,480 (female); 450 (male) (Breast cancer.org.) At U.C.H diagnosed in 22yr old female.

Women in the US have 1 in 8 (12.5%) lifetime chance of developing invasive breast cancer and 1 in 35 (3%) chance of breast cancer causing their death.

Breast cancer affects African-American women less than white women. Black women are less likely to get the disease, but are more likely to die from it. Black women also get the disease at younger age than white women.

The rate of breast cancer is very low in Japan, India and some areas of Africa . Its the most common cancer in Nigeria accounting for 29.7% of 818 cancer cases(Ibadan cancer registry). The peak age incidence in Nigerian women is about a decade earlier than in Caucasians. It was estimated that between 7-10 thousand new cases of breast cancer developed in Nigeria in 2005.(Adebamowo et al).

Somatic mutations theory postulates the accumulation of mutations in somatic genes that progressively deregulate normal breast behavior, The cell is believed to be the epithelial cell lining the terminal duct lobular unit, Several processes predispose to mutation including exposure to mutagens e.g. radiation, mitogens such as estrogen,

Mitogens are thought to predispose to malignant transformation by increasing the risk of unrepaired DNA replication errors during stimulated cell division. Over expression of certain genes e.g. epidermal growth factor, HER-2, is associated with high nuclear grade,(25% of all B.C) Others are p53(the guardian of the genome ),cowden syndrome(PTEN),Ataxia telegiectasia(ATM)

Inheritance of high penetrance dominant mutations account for 5-10% of breast ca and typically presents with a strong family history e.g. BRCA1&2 genes. The biochemical basis of the cellular effect is a repair defect, rendering the genome prone to mutation a state referred to as genomic instability.(Treatment of cancer 4th editionPat Price&Karol Sikora).

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MAJOR Female gender(M:F 1:100) Increase age(late 30s-0.07% risk,70s-0.44%) western culture(dietary and enviromental) Family history( 1.7% and 1.4% in 1st & 2nd degree relatives respectively) Benign breast dx (proliferative benign dxs) Radiation( children & adolescent) Prior diagnosis of breast ca(10-15% in contralateral dx risk) Mutation in BRCA 1% 2( 64% & 45% respectively)

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MODERATE Early menarche/ late menopause Nulliparity / delayed full term preg. High socioeconomic status Country of residence Alcohol intake Obesity Prior diagnosis of uterine, ovarian, or colonic ca.

OTHERS; o Oral contraceptive pills o Hormone replacement therapy o High density breast mammograpy o High fat diet, o Drugs-antihypertensive(Rauwolfia cpds) (Cancer medicine 4th edition-Holland et al).

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Some risk factors associated with bilateral disease are; Young age at first onset. Positive family history. Multicentric disease in ipsilateral breast. Invasive lobular subtype

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Considering the combination of risk factors in an individual ,it is possible to predict his annual and life time risk of breast ca. Gail et al uses these epidemiological factors to derive a model for predicting breast ca risk. Commonly used by Gail are; Age at presentation Nos of 1st degree relatives Age at 1st birth Age at menarche No of biopsy & result

Based on the model people with high risk of developing breast ca.are councel to consider either prophylactic tamoxifen use or prophylactic surgery.

TAMOXIFEN ; o Reduce the incidence of invasive & non invasive by 49% & 50% respectively(Perez et al) o Decreases the incidence of contralateral breast ca(NSABP) o Individuals with high risk detected using Gail model who uses tamoxifen for 5yrs, have increase 5yrs free dx rate(Perez et al)

PROPHYLACTIC SURGERY; Results shows 89.5% decrease in risk for those that had this procedure(Mayo clinic 1993)

Lower age at first childbirth (less than 24 years maternal age), Multiparity (about 7% lowered risk per child), Breastfeeding (4% per breastfeeding year, with an average relative risk around 0.7%) Breast ca risk decreased by 7% for every 12months of breastfeeding Adebamowo CA , Campbell O B , Adenipekun A , et al ( Br J Cancer 2008) In addition, exercising three times a week for one hour each has been found to lower breast cancer by up to 40%

The (2003) World Health Organization (WHO) classification of tumors of the breast recommends the following pathological types Invasive breast carcinomas Invasive ductal carcinoma
Most are "not otherwise specified" The remainder are given subtypes:
Mixed type carcinoma Pleomorphic carcinoma Carcinoma with osteoclastic giant cells Carcinoma with choriocarcinomatous features Carcinoma with melanotic features

Invasive lobular carcinoma Tubular carcinoma Invasive cribriform carcinoma Medullary carcinoma Mucinous carcinoma and other tumors with abundant mucin
Mucinous carcinoma Cystadenocarcinoma and columnar cell mucinous carcinoma Signet ring cell carcinoma

Neuroendocrine tumors
Solid neuroendocrine carcinoma (carcinoid of the breast) Atypical carcinoid tumor Small cell / oat cell carcinoma Large cell neuroendocrine carcioma

Invasive papillary carcinoma Invasive micropapillary carcinoma Apocrine carcinoma

Metaplastic carcinomas
Pure epithelial metaplastic carcinomas
Squamous cell carcinoma Adenocarcinoma with spindle cell metaplasia Adenosquamous carcinoma Mucoepidermoid carcinoma

Mixed epithelial/mesenchymal metaplastic carcinomas

Lipid-rich carcinoma Secretory carcinoma Oncocytic carcinoma Adenoid cystic carcinoma Acinic cell carcinoma Glycogen-rich clear cell carcinoma Sebaceous carcinoma Inflammatory carcinoma

Sarcomas: -Angiosarcoma -Liposarcoma -Rhabdomyosarcoma -Leiomyosarcoma -Fibrosarcoma

Precursor lesions Lobular neoplasia


lobular carcinoma in situ(LCIS)

Intraductal proliferative lesions


Usual ductal hyperplasia Flat epithelial hyperplasia Atypical ductal hyperplasia Ductal carcinoma in situ(DCIS)

Microinvasive carcinoma

Intraductal papillary neoplasms


Intraductal papillary carcinoma Intracystic papillary carcinoma

Tumors of the nipple Paget's disease of the nipple Malignant lymphoma Metastatic tumors Tumors of the male breast Carcinoma
In situ Invasive

Multiple tumor grading systems have been proposed. The Scarff-Bloom-Richardson classification system utilizes mitotic index, differentiation, and pleomorphism, each with scores of 1 to 3. Scores of 3 to 5 are well differentiated, 6 to 7 moderately differentiated, and 8 to 9 poorly differentiated. This system is commonly employed and has been shown to be of independent prognostic significance Nottingham model.

Actual field size 150 X 100 microns) Arrow heads show the myoepithelial cells apposed to the basal lamina. Ductal cells (short arrows) are partly overlapping in this section but form a single cell layer above the myoepithelium. Long thin arrows show several of the periductal fibroblasts. These have characteristic long pointed nuclei, they show a typical orientation of their long axis parallel with the basal lamina, and they appear inactive (heterochromatic nuclei) in this duct. Mature collagen with a wavy

Figure 28: DCIS with invasive ductal carcinoma, high magnification. (Actual field size 360 X 240 microns) This is from the same patient as Figure 27, but from a different area of the biopsy. The arrow heads outline a focus of intraductal carcinoma. This DCIS has a smooth outer contour, and the extracellular matrix has a normal concentric arrangement around this duct. The fibroblasts around this duct (thin arrows) are thin, arranged in the normal parallel orientation to the duct, and they appear inactive since they do not have much euchromatin or nucleoli. In contrast, the other ductal cells are all "invasive" and show a ragged contour without an organized concentric wrap of extracelluar matrix around them. The fibroblasts near the invasive ductal cells appear highly active (thick arrows) with open chromatin and nucleoli. The products of the active fibroblasts include bubbly bluish mucopolysaccharides and young finely fibrillar collagen. To diagnose invasion, it is often essential to look at the non-neoplastic stromal cells.

(T) -Primary Tumor Tx - Primary tumor cannot be assessed. T0 - No evidence of primary tumor. Tis - Carcinoma in situ.
Tis(DCIS) - Intraductal Carcinoma in situ. Tis(LCIS) - Lobular Carcinoma in situ. Tis(Paget's) - Paget's disease of the nipple with no tumor.

T1 - Tumor 2cm or less in its greatest dimension.

T2 - Tumor more than 2.0cm but not more than 5.0cm in its greatest dimension.

T1mic - Microinvasion 0.1cm or less in greatest dimension. T1a - Tumor more then 0.1cm but not more than 0.5cm in its greatest dimension. T1b - Tumor more than 0.5cm but not more than 1.0cm in its greatest dimension. T1c - Tumor more than 1.0cm but not more than 2.0cm in its greatest dimension.

T3 - Tumor more than 5cm in its greatest dimension. T4 - Tumor of any size with direct extension to (a) chest wall or (b) skin as described below:
T4a - Extension to chest wall. T4b - Oedema (including peau d'orange) or ulceration of the breast skin, or satellite skin nodules confined to the same breast. T4c - Both T4a and T4b. T4d - Inflammatory breast cancer.

Lymph Node There are four lymph node classification values (N0, N1, N2 or N3) which depend on the number, size and location of breast cancer cell deposits in lymph nodes. Nx - regional lymph nodes cannot be assessed. Perhaps due to previous removal. N0 - no regional lymph node metastasis.

N1 - metastasis to movable regional axillary lymph nodes on the same side as the affected breast. N2 - metastasis to fixed regional axillary lymph nodes, or metastasis to the internal mammary lymph nodes, on the same side as the affected breast. N3 - metastasis to supraclavicular lymph nodes or infraclavicular lymph nodes or metastasis to the internal mammary lymph nodes with metastasis to the axillary lymph nodes

Metastases There are two metastatic classification values (M0 or M1) which depend on the presence or absence of breast cancer cells in locations other than the breast and lymph nodes (so-called distant metastases, e.g. to bone, brain, lung). M0 no distant metastasis M1 distance metastasis is present

STAGE-1 STAGE-2

STAGE-3
muscle

Tumor confined to breast and not attached to underlying muscle. no axillary LN. As in stage 1,but axillary LN are involved but mobile. I-Skin involvement beyond periphery of tumor or ll-tumor attached to underlying

lll-Axillary LN are mobile or fixed. There are no distant metastasis.

STAGE 4 l-Lymphatic spread is beyond the ipsilateral axilla. ll-Distant blood-borne metastasis

STAGE 0 1 II III IV

5yr survival(%) 99 97 83 54 16

10yr survival(%) 95 88 66 36 7

PAINLESS BREAST LUMP. .BLOOD STAINED NIPPLE DISCHARGE(DUCT CA) RETRACTION OF THE NIPPLE LYMPHEDEMA OF THE BREAST&/ARM. ECZEMA OR DERMATITIS OF THE AREOLA(PAGETS DX)

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METASTASES; Pulmonary- Cough, dyspnea. Bone deposit- bone pain, pathologic #, bony swellings of skull, ribs, clavicle. Cord compression from vertebra deposits or # may result in paraplegia. Liver -hepatomegaly,ascites. Brain metastasis-features of raised ICP.

FIBROADENOMA CYST GALATOCELE CHRONIC BREAST ABSCESS TRAUMATIC FAT NECROSIS

LOCAL INVASION LYMPHATIC SYSTEM BLOOD STREAM

Most common site-upper outer quadrant. Commoner on the left breast Unusual for both to occur simultaneously The growth travels along the duct Breaks through the basement mmb. of duct invading adjacent duct, fascia, mammary fat, spreading through breast lymphatics to peripheral lymphatics.

Common route, first to the axillary nodes(increases with tumor size) Then to other nodes-internal mammary, supraclavicular LN, Then vascular invasion by tumor & haematogenous metastasis. (Carlos Perez & Co prin. & prac. of Radiology oncology 3rd ed)

BREAST SELF EXAMINATION CLINICAL BREAST EXAMINATION MAMMOGRAPHY

Starting at 40yrs,yearly mammograpy should be done. Clinical examination by a physician every 3yrs for those in 20s and 30s and annually for those with 40yrs and above. Breast self examination monthly starting with women in there 20s. Those with high risk(family history,|)should have earlier mammograpy starting at 25yrs.US &MRI can also be done.

HISTORY-menstrual status, parity, family hx , PHYSICAL exam- breast, axillary LN (size, mobility, no), supraclavicular fossa, abdomen, spine. Excisional biopsy if lump is small Otherwise incisional biopsy Core needle biopsy
Histological diagnosis ER/PR and HER2/neu

RADIOLOGIC studies-mammography, ultrasound, CXR, abdominopelvic USS, Bone scan, MRI, CT scan. LAB studies- FBC, E/U & Cr, alkaline phosphatase, LFT. Urinalysis. Tumour markers. Oncogene assay- BRCA 1 & 2, HER-2

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INTRINSIC: Axillary nodes(1-3 ,73% 5yr survival rate) Tumor size(<1cm-88%survival rate) Tumor type(tubula,mucinous-bettter prog.) Histological grades-well differentited have better prognosis Positive estrogen receptor & progesterone receptor status. DNA- ploidy index- correlates with nuclear grade,Diploid low grade,ER+ve =better prog.

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Presence of multiple primary tumor (multicentricity). Proliferative rate (High)- mitotic index, thymidine labeling index, s-phase fractionpoor prognosis. Over expression of her-2, CA-15-3, CA2729, Epidermal growth factor Lymphovascular invasion(recurrence rate for LVI+VE -38%,LVI-VE -22%) P53-over expression-poor prognosis Tumor location medial tumors worst prog.

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EXTRINSIC Factors: Age-worse with younger age(ER-ve status,high grade dx) Race-Black women,advanced stages. Obesity-Greater risk of reoccurrence. Smoking??

Rare occurrence. Incidence <1% Similar risk factors including testicular function(e.g. klinefelter syndrome) Similar prognostic factors Strongly associated with BRCA2 in some families DCIS &L CIS are rare in men

Same histologic subtypes of invasive cancer. More rapidly infiltrates to become attached to overlying skin and thoracic wall. Distant metastasis to lungs,brain,bone&liver are common. Presents in a more advanced stage in men. Estrogen receptor tumor is more predominant in males.

Among women with breast ca 1-2% are pregnant. No evidence that pregnancy is associated with either the development or progression of breast ca. Prognosis is related to stage,worse prognosis because; -Delayed diagnosis -Reluctance with use of mammograpy -Changes in the breast during pregnancy makes cancer difficult to detect.

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This is a type of breast cancer that is clinically negative for ER/PR and HER-2 proteins. Constitute of 15% of all breast cancer in USA(medscape 2009) Its more common in; Carriers of BRCA-1 gene mutation Young women African-American women HIGHEST RISK young and african-American It is characterized by its unique molecular profile, aggressive behavior, distinct patterns of metastasis, and lack of targeted therapies.

UP to 50% of breast cancer patient in Africa have this disease.Although; o Data collection? o Screening tools? (Lisa carey et al,medscape 2009) TNBC is a traumatic diagnosis to both the clinician and patient as it doesnt respond to conventional treatment.

As opposed to other breast cancer types,its response to chemotherapy is better with Platinum compound(Effective for BRCA-1 disease) than with anthracyclines and taxanes Screening for early detection is a problem due to poor access to the facilities especially in Africa due to poverty Also some with high risk are too young for standard screening

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More researches are on the way to unveil promising treatment modalites; Antiangiogenic agents e.g intergroup E5103(early disease) PARP (ADP-ribose polymerase) inhibitors EGFR, C-KIT inhibitors MAP-kinase inhibitors Mtor inhibitors -VEGF HER/1

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