Overview of Breast Cancer

TRACO Lecture Series - 2009

Farah Zia, MD
Medical Officer, DCTD, NCI
November 9, 2009

Definition of Breast Cancer

Cancer that forms in tissues of the
breast:
Ducts: Tubes that carry milk to the
nipple
Lobules: Glands that make milk

Breast Cancer Progression

Time

Normal
Atypical
Hyperplasia

In situ
Local
Invasion

Time Points:
A. Overt non invasive carcinoma
B. Onset of local invasion
C. Onset of metastatic dissemination

Primary Tumor

Types of Breast Cancer

Ductal Carcinoma in situ

(DCIS)
Most common type of non-invasive
breast cancer.
The cancer is only in the ducts and has
not spread through the wall of the
ducts into the tissue of the breast.
Nearly all women with cancer at this
stage can be cured.
Best form of early detection is with a
mammogram (non-palpable,
asymptomatic)

Lobular Carcinoma in situ

(LCIS)
This condition begins in the milk
glands, but does not go through the
walls of the lobules into the breast
tissue.
Although not a true cancer, it does
increase a womans risk of developing
cancer later in life.
It is important that women with LCIS
have regular mammograms.

Invasive Ductal Carcinoma

(IDC)
This is the most common type of
breast ca, accounting for 8 out of 10
invasive breast cancers
Duct breaks thru duct wall
invades tissue
From there, it may enter the lymphatics
and spread to other parts of the body.

Invasive Lobular Carcinoma

(ILC)
Lobules breaks thru wall breast
tissue
It can then enter the lymphatics and

Inflammatory Breast Cancer

(IBC)
Rare, 1-5% in U.S.
Most aggressive form of breast cancer
Clinical diagnosis
diffuse erythema involving majority breast
peau d orange
erisypeloid edge
often no palpable mass

Significantly lower overall survival than

non-IBC

IBC-patient

Clinical Presentations of IBC

Inflammatory Breast Cancer

Dermal lymphatic
invasion
Stage IIIB (T4d) if
not metastatic
Compared to nonIBC, more frequently
ER/PR negative
Her2/neu positive

Key Statistics For Breast

Cancer, 2009

Chance of developing invasive breast cancer at

some point in a womans life: 1 in 8 (12%)
In 2009, 192,370 new cases of invasive breast
cancer will be diagnosed among women in the US.
Also, there will be about 62,280 new cases of
carcinoma in situ in 2009.
It is the most common cancer diagnosed among
American women
2nd leading cause of cancer death, exceeded only
by lung cancer.
In 2009, about 40,170 women will die from breast
cancer in the US

Female breast cancer by race

Relative Survival* (%)

By Cancer Site
Site

1974-6

All sites
50
Breast (female)
75
Colon
50
Leukemia
34
Lung and bronchus
13
Melanoma of the skin
80
Non-Hodgkin lymphoma 47
Ovary
37
Pancreas
3
Prostate
67

1983-5

1995-9

53
78
58
41
14
85
54
41
3
75

64
88
63
46
15
91
59
44
4
99

Breast Cancer Risk Factors

Age
Prior breast cancer
High risk pre-malignant lesion LCIS, ADH
Excess endogenous or exogenous hormones
Early menarche
Late menopause
HRT
Nulliparity or age >35 at birth of first child
History of breast biopsies
Family History, e.g. BRCA 1/2
Radiation exposure before age 40
Mammographic density
Energy balance, lifestyle factors (alcohol)

Breast Cancer
Screening Mammography
Reduces mortality by
26% in women aged 50-74,
17% in women 40-49
ACS recommends
20 or older, BSE
20-39 breast exam by physician every
three years, 40 or older every year
Mammography at age 40 and annually
thereafter

Two Major Limitations:

Mammography
Fails to detect 20% of cancer that
become palpable within 1 year
Sensitivity less in denser (younger)
breasts

Other modalities of screening in high

risk women

Digital Mammography

Overall accuracy=to film

mammograms
Better accuracy in

<50 yrs
Increased mammographic
density
Pre/peri menopause
MRI

2-6% of cancers seen only on MRI

alone
Sensitivity for MRI higher than
mammo
Specificity for MRI lower than
mammo

More false + , more biopsies

Promising technique, need longer

follow up and survival data

BREAST CANCER: Early Stage

Metastasis to ipsilateral axillary lymph node(s)
N1 = movable
N2 = fixed to one another or to other structures
M0 = no distant metastasis

BREAST CANCER
Spread to lymph nodes
Supraclavicular
Subclavicular
Distal (upper)
axillary

Mediastinal
Internal mammary

Central (middle)
axillary

Proximal (lower)
axillary

Interpectoral
(Rotters)

Systemic Therapy
Endocrine Directed (Hormone) Therapy
Chemotherapy
Biologic agents
Trastuzumab (Herceptin)
Bevacizumab (Avastin)

Hormone
Therapy

Targeting the
Estrogen
Pathway
Block receptor
SERM (selective
estrogen receptor
modulators)
Tamoxifen treatment
Raloxifene prevention
Decrease ligand
Aromatase inhibitors
Oopherectomy
GnRH analogs

EBCTCG: Tamoxifen

Tamoxifen Pharmacogenetics . A
Developing Area. JAMA, Oct. 7, 2009
The growth inhibitory effect of tamoxifen is
mediated by its metabolites:
4-hydroxytamoxifen
Endoxifen

The formation of these active metabolites is

catalyzed by the polymorphic cytochrome
P450 2D6 (CYP2D6) enzyme

CYP 2DG Variants

Approximately 100 CYP 2D6 genetic variants have
been identified.
These manifest in the population as 4 distinct
phenotypes:
Extensive (normal activity)
Intermediate (reduced activity)
Poor (no activity)
Ultra-rapid (high activity)
Thus, it can be speculated that genotype related
differences in the formation of active metabolites
influence therapeutic response to tamoxifen.

CYP 2DG VARIANTS

To investigate this relationship:
Genotyped tumor tissue DNA for CYP2D6 variations
in 1,325 breast cancer patients taking adjuvant
tamoxifen.
Women were classified as having either:
1. Extensive Metabolism (609 pts)
2. Heterozygous extensive/intermediate (637 pts)
3. Poor metabolism (79)
Researchers found clear evidence that breast cancer
was more likely to return in pts with reduced or
absent CYP 2D6 function

CYP 2DG ACTIVITY

Extensive metabolizers have a
14.9% recurrence at 9 yr FU
Heterozygotes have a 20.9%
recurrence at 9 yr FU
Poor metabolizers have a 29%
recurrence at 9 yr FU

Aromatase Inhibitors (AI):

AIs are drugs that reduce the level of
estrogen in postmenopausal women.

Aromatase Inhibitors:
Currently, 3 AIs are approved by U.S.
FDA
Anastrozole (Arimidex)
Letrozole (Femara)
Exemestane (Aromasin)

Trials of AIs in the early adjuvant setting.

In the ATAC trail patients received tamoxifen x5,
anastrozole x 5 or tamoxifen + anastrozole x 5 resulting
in a 22% improvement in DFS on anastrozole.
In the BIG I-98 trial patients received tamoxifen x 5,
letrosole x 5, tamoxifen x 2 + letrozole x 3 or tamoxifen x
3 + letroxole x 2.
In the IES trial pateients received tamoxifen x 2-3 +
tamoxifen x 2-3 or exemestane x 2-3 resulting in a 32%
improvement in DFS with exemestane.
In the ABCSGi ARNO 95 Ita trial pateints receive
tamofen x 2-3 plus tamoxifen x 2-3 or anastozole x 2-3
resulting in a 43% improvement in DFS on letrozole.

Breast cancer
Should aromatase inhibitors be
used in place of tamoxifen?
Is there a role for sequential
therapy with an AI and Tam?

SABCS 2008: Meta-analysis: Adjuvant

Aromatase Inhibitors vs Tamoxifen in
Postmenopausal Women
Data was pooled from all trials started by 2000,
prospectively comparing an AI and tamoxifen.
The large number of events properly powered the
subgroup analysis.

In the meta-analysis 9,856 breast

cancer patients received:
TAM x 5 yrs vs AI x 5 yrs
.
The 5 year recurrence with TAM or AI was
12.6% and 9.6% respectively.
The 8 year recurrence with TAX or SI was
19.2 and 15.3% respectively.

AIs reduced breast cancer recurrence.

AIs were associated with an absolute 2.9% lower
recurrence rate at 5 years, that improved to a 3.9%
gain at 8 years (15.3% vs 19.2%, P < 0.00001).
Mortality Analysis, although still early at 3.9 years fu,
showed a small, non-significant advantage to 5
years of AI mono-therapy.
Gains of 1.1 % and 0.5% for 5 and 8 year breast
cancer mortality.

AIs reduced breast cancer recurrence.

In 9015 patients treated with Tam x 2-3 years then
aldosterone x 2-3 years, the 3 years recurrence for
Tax or AI was 8.1% and 5% respectively.
Patients treated with TAX or AI, the 6 year
recurrence was 16.1% and 12.6% respectively.

Switch to an AI (after 2-3 years on TAM):

absolute gain of 3.1% lower recurrence rate
at 3 yrs after the switch and 3.5% at 6 years
after the switch (P<0.00001)
0.7% lower breast cancer mortality at 3
years and 1.6% at 6 years (P=0.02)

How Long Should You Take AIs?

Studies are ongoing
No current absolute guidelines
Adjuvant options per the oncologists
discretion include:
Primary Rx AI x 5 yrs
Primary Rx TAM x 2 or 3 yrs AI x 2 or 3
yrs
Primary Rx TAM x 5 yrs AI x 5 yrs
* Note: current standard of care = AI, Max 5 years Rx

Systemic
Adjuvant Chemotherapy

Absolute Risk Reductions of Relapse

with Polychemotherapy

Age<50

Age 50-69

Recurrence

Mortality

EBCTCG: Systemic therapy

28,000 women in 56 trials:
Meta-analysis
Impact of Polychemotherapy On
Absolute Risk Reduction at 5 years (in % )
Subgroup age < 50, Node- had a Recurrence
of 9.9% (SE 1.3).
Subgroup Age < 50, Node+ had a recurrence of
14.6% (SE 2.3).
Subgroup Age 50-69, Node- had a recurrence of 5.3
(SE 1.0).
Subgroup Age 50-69, Node + had a
recurrence of 5.9 (SE 1.0).

Adjuvant
Systemic Polychemotherapy
Polychemotherapy is more effective than
single agent
Proportional benefits not affected by
nodes, ER, menopausal status, or use of
tamoxifen
Compared with CMF, anthracyclines
produced an absolute benefit of 4% in
recurrence and survival

Adjuvant Chemotherapy
Options
Low risk/
lymph node negative

AC x 4
CMF x 6
CAF x 6
FEC-100

Lymph node positive/high risk

Dose dense AC x 4 Paclitaxel x 4 (q2wk)
AC x 4 Docetaxel x 4 (q3wk)
TAC x 6 (q3wk)

Trastuzumab if HER2 positive

Biologic Agents

ErbB2/HER2 Action in Breast CA

Member of the membrane-spanning type I
receptor tyrosine kinase family, comprising 4
closely related family members.
They dimerize upon ligand stimulation and
transduce their signals by subsequent
autophosphorylation, catalyzed by the receptor
tyrosine kinase activity.
This results in recruitment of an array of
downstream signaling cascades (survival and
mitogenic )
The incidence of ErbB2 amplification is 30% in
breast cancer Identifying it as a therapeutic
target

NRG
1
NR
G2

NR
G3

Ligand
binding
domain

HB-GF

Epi

HRG
(NRG1)

HBEG
Am F
p

-cel

Epi

EGF

F
TG

The EGFR/HER Family

4
G
NR

Transmembrane

Tyrosine
kinase
domain

erb-b1
EGFR
HER1

neu
Erb-b2
HER2

Erb-b3
HER3

Erb-b4
HER4

HER2 epitopes recognized by

hypervariable murine
antibody fragment

Human
IgG-1

HER-2: Trastuzumab
Bench to Bedside
Targets HER2 protein
High affinity (Kd = 0.1 nM)
and specificity
95% human, 5% murine
Decreases potential
for immunogenicity
Increases potential for
recruiting immune effector
mechanisms
Early-stage breast ca:
2005
- Herceptin + Chemo
OS DFS

NSABP B-31
Control: ACT
The patient receives4 treatments of
doxorubicin/cyclophosphamide (AC) 60/600 mg/m2
q 3 wk x 4 followed by 4 treatments of paclitaxel (T)
175 mg/m2 q 3 wk x 4
. Alternatively the patient receives 4 treatments of
doxorubicin/cyclophosphamide (AC) 60/600 mg/m2
q 3 wk x 4 followed by 4 treatments of paclitaxel (T)
175 mg/m2 q 3 wk x 4
followed by 4.5 treatments of trastuzumab (H)
4mg/kg LD + 2 mg/kg/wk x 51

N9831 and B-31:Disease-Free Survival

ACTH
87%
ACT

85%

75%

67%
N Events
ACT 1679 261
ACTH 1672 134

HR=0.48, 2P=3x10-12
ASCO 2005

Years From Randomization

B31/N9831

Triple Negative
Breast Cancer

Triple negative breast cancer

refers to a specific subtype of
breast cancer that does not
express the genes for:
Estrogen Receptor (ER)
Progesterone Receptor (PR)
HER2/neu

It is diagnosed more frequently in:

Younger women
African Americans
Hispanics
Women with BRCA1 mutations

Triple-negative breast ca is
clinically characterized as:
More aggressive
Less responsive to standard
chemotherapy treatment
Associated with a poorer overall
prognosis

Development of New Treatment Strategies For

Triple Negative Breast Cancer
ASCO, 2009
PARP (poly ADP-ribose polymerase) Inhibitors:
n experimental class of drugs that may have potential
for the treatment of triple-negative breast cancer.
PARP is an enzyme used by cancer cells to repair
DNA damage.
PARP inhibitors are being used to target tumors
where one pathway is already shut down.
- BRCA1/BRCA2 mutations lose a form of DNA
repair and
rely more heavily on the PARP pathway
- Tumors which are either concurrently or pretreated with

Two PARP Inhibitors

Currently in Phase I/II
Clinical Trials:
BSI 201 (IV)
Olaparib

(Oral)

BSI-201
116 women with triple-negative metastatic breast
cancer randomized to standard chemotherapy vs
standard chemo therapy + BSI-201. Median survival
of 5.7 months with standard chemotherapy versus
9.2 months with BSI-201 plus chemotherapy.
...

How can we do better?

Better selection of chemotherapy regimens
Gene expression profiling to predict response to
particular agents
Better selection of patients for treatment with
chemotherapy
Treat only those patients who are most likely to
recur AND who will therefore benefit most from
the addition of chemotherapy TAILORx Trial

Predicting Response to
Chemotherapy

Neoadjuvant (pre-surgical) chemotherapy allows for

assessment of tumor response to treatment
Allows us to identify factors associated with
response

Gene Expression Profiling to Predict

Chemotherapy Response
24 patients treated with
neoadjuvant docetaxel
therapy
Divided into responders
and non-responders
Identified 92-genes
correlated with
response to docetaxel

Molecular Portrait of Breast Cancers

Basal-like

HER-2

Normal

Luminal B

Luminal A

An Important Question in Breast

Cancer Treatment
What is the likelihood of distant
recurrence in patients with breast
cancer who have no involved
lymph nodes and estrogenreceptor positive tumors?
- These patients prognosis is poorly
defined by histopathological and
clinical measures alone

Oncotype DX A multi-step approach

was used to:

Develop an assay for the expression of tumor
related genes for use with paraffinembedded tumor tissue
To validate the assay clinically

RT-PCR method was developed to quantify gene

expression with paraffin-embedded tumor tissue.
250 candidate genes were selected from published
literature, genomic databases, and experiments
based on DNA arrays done on fresh-frozen tissue.
Data was analyzed from three independent clinical
studies of breast ca involving 447 patients to test
the relationship between expression of the 250
candidate genes and the recurrence of breast
cancer.

Three Breast Cancer Studies Used To Select 21

Gene Panel
16 Cancer and 5 Reference Genes 4. used the results of
the 3 studies to select a panel of 16 cancer related genes
and 5 reference genes.
- Best RT-PCR performance
- Most robust predictions
Designed an algorithm based on the levels of expression
of these genes to compute a recurrence score for each
tumor sample being tested.
Genes for proliferation (Ki-67, STK15, Survivin, Cyclin
B1, MUBL2), estrogen (ER, PR, Bcl2, SCUBE2), invation
(Stromolysin 3, Cathepsin L2) HER2 (GRB7, HER2),
GSTM1, VD68, BAG1 and reference (Beta-actin, GAPDH,
RPLPO, GUS, and TFRC) were studied.

Validation of Onco DX
Paraffin-embedded tissue samples from
patients previously enrolled in the NSABP B14 trial were used to validate the ability of the
21 gene RT-PCR assay and RS algorithm to
quantify the likelihood of distant recurrence
in patients with:
Node-negative, ER+, early stage breast
cancer who had been previously treated with
tamoxifen.

Kaplan-Meier Estimates of the Rate of

Distant Recurrence at 10 years, If the Onco
DX risk score is low (<18) the rate of distant
recurrance at 10 years is 6.8%. In the Onco
DX risk score is high (>31) the rate
According to the Recurrence-Score Risk
Categories. of distant recurrence at 10 years
is 30.5%.

Oncotype DX
Validated prognostic test for patients treated with
hormonal therapy. Based on this study, the
recurrence score has been validated as
quantifying the likelihood of distant recurrence in
tamoxifen-treated patients with node-negative,
ER+ breast cancer.

Oncotype Dx: Chemotherapy benefit.

Patients with tumors that have high Recurrence Scores
have a large absolute benefit of chemotherapy (similar
results with CMF and MF)
Patients with tumors that have low Recurrence Scores
derive minimal, if any, benefit from chemotherapy.
RS < 18

RS = 18-30

RS >30
1 .0

1 .0

0 .9

0 .8

0 .9

0 .8

0 .7

0 .8

0 .7

0 .6

0 .7

0 .6

0 .5

0 .6

0 .4
0 .3
0 .2

L o w R is k P a tie n ts ( R S < 1 8 )
T am + Chem o
T am

0 .1
0 .0

DRFS

0 .9

DRFS

DRFS

1 .0

0 .5

0 .4

0 .4

0 .3

0 .3

0 .2

0 .2

0 .1

In t R i s k ( R S 1 8 - 3 0 )
Tam + C hem o
Tam

0 .1

Y e a rs

10

0 .5

12
0 .0

0 .0
4

Y e a rs

10

12

H ig h R is k P a tie n ts ( R S 3 1 )
T am + C hem o
T am
0

Y e a rs

10

12

Ongoing Research: TAILORx

Landmark trial - represents the culmination of a
major initiative to integrate molecular diagnostic
testing into clinical decision making.
NCI is using Oncotype DX to identify and assign
treatment to more than 10,000 breast cancer
patients from 1,500 sites in the US, Canada, and
Peru.

Purpose:
to determine whether adjuvant hormonal therapy
is as effective as adjuvant hormonal + chemo for
women with a midrange RS.
Eligibility:
ER+ and/or PR+, Node-negative
HER2/neu-negative breast cancer
Primary Objectives:
1. Determine whether adjuvant hormonal tx is
not inferior to chemo-hormonal tx in women with a
mid-range OncoDX RS (11-25)
2. Create a tissue and specimen bank for
patients enrolled in this trial. To include: tumor
specimens, tissue microarrays, plasma, & DNA
from peripheral blood.

Schema: TAILORx
Stage I or II, ER+ and/or PR+, node-negative,
HER2/neu negative, tumor size 1.1 5.0 cm

Oncotype DX Assay
Register specimen banking

RS < 10 Hormone therapy registry

RS 11 25, Randomize
Hormone Rx vs. Chemotherapy +
Hormone Rx
RS > 25 Chemotherapy +
Hormone Rx

17

TAILORx: Key points

TAILORx will examine whether genes that are
frequently associated with recurrence for women
with early stage breast cancer can be used to assign
patients to the most appropriate and effective
treatment.
The results of this trial could eventually spare many
women the unnecessary toxicity of chemotherapy.
(currently, 10% considered low risk; with RS score, 50%).
It is one of the first trials to examine a methodology
to personalize cancer treatment!

Stage IV: Metastatic Breast Cancer

Characteristics of MBC
Median survival approximately 2 to 3 years,
with a 5-year survival of about 20%
About 10% of women present at diagnosis
with newly diagnosed metastatic breast
cancer (MBC).
Metastatic disease is considered incurable

Goals of Treatment of MBC

Prolongation of survival
Improvement of quality of life
- Improvement of symptoms
- Acceptable toxicity

Systemic Treatment Approach

for Metastatic Breast Cancer
Metastatic
Metastatic Breast
Breast Cancer
Cancer

Limited
Limited metastases
metastases (bone
(bone &
& soft
soft tissue)
tissue)
Positive
Positive hormone
hormone receptors
receptors
Hormone
Hormone responsive
responsive
Disease-free
Disease-free interval
interval 22 years
years

Extensive
Extensive metastases
metastases or
or visceral
visceral crisis
crisis
Negative
Negative hormone
hormone receptors
receptors
No
No response
response to
to hormones
hormones

Hormonal
Hormonal Therapy
Therapy
Response
Response

No
No response
response

Chemotherapy
Chemotherapy

No
No progression
progression

IfIf disease
disease progresses,
progresses, second-line
second-line hormonal
hormonal therapy
therapy

Progression
Progression of
of disease
disease

Second-line
Second-line chemotherapy
chemotherapy

Metastatic Breast Cancer: Hormonal

therapy
Selective Estrogen Receptor Modulators
Tamoxifen, toremifene
Aromatase Inhibitors (post-menopausal)
Anastrozole, letrozole, or exemestane
Selective Estrogen Receptor Downregulators
Fulvestrant
Progestins
megace 40 mg po 4 x daily
Ovarian suppression (pre-menopausal)
luteinizing hormone releasing analog
oophorectomy

Hormone positive post-menopausal

Metastatic Breast Cancer
First line: Antiestrogen or Nonsteroidal AI
Anastrozole or Letrozole.
Second line: Nonsteroidal AI or Antiestrogen.
Third line: Steroidal AI:exemestane.
Fourth line: Progestin.
Fifth line: Androgen.
If no response use chemotherapy

First - Line Chemotherapy

Agent
Docetaxel (75-100 mg/m2)
ixabepilone
Nab paclitaxel
Paclitaxel (175-250 mg/m2)
Doxorubicin (60-75 mg/m2)
Capecitabine
Vinorelbine
Gemcitabine
Carboplatin
Cisplatin
Cyclophosphamide
Flourouracil
Methotrexate

ORR (%)
48-68
42
33
29-63
43-54
35-50
30-41
25-37
7-35
9-50
36
28
26

For HER-2 positive patients

add Trastuzumab (Herceptin)
Bevacizumab (Avastin)

Bevacizumab (Avastin):
Humanized monoclonal antibody directed against
all isoforms of VEGF-A (potent vasodilator and
inducer of pathologic angiogenesis).
- binds to VEGF, inhibits VEGF receptor binding
Laboratory and clinical evidence supports the
central role of angiogenesis in the progression of
breast cancer.
Multiple angiogenic factors are expressed by
invasive breast cancers
- 121-amino-acid isoform of VEGF predominates

Bevacizumab in the First line

Treatment of Locally Recurrent or MBC
ECOG 2100 Trial
Stratify:
DFI < 24 mos. vs. > 24 mos.
< 3 vs. > 3 metastatic sites
Adjuvant chemotherapy yes vs. no
ER+ vs. ER- vs. ER unknown
Randomize and treat with paclitaxel + Bevacizumab
or paclitaxel alone

ECOG 2100: Response

O v e r a ll R e s p o n s e R a te

P<0.0001

P<0.0001

40

34.3%
28.2%

30
20

16.4%

14.2%

10
316

330

All patients

250

236

Measurable Disease

Paclitaxel
Pac + Bev

ECOG 2100:
Progression Free and Overall Survival

Bevacizumab: Future
Directions
Addition of bevacizumab to
paclitaxel
Significantly prolongs progression free survival, but
not overall survival
Increases objective response rate

Further studies are:

Exploring the role of Bevacizumab in the adjuvant
setting (BEATRICE Trial: Phase III/Triple-negative breast)
Developing methods to identify patients who are
most likely to benefit from VEGF-targeted therapies

Overview: Molecular Targets

Antireceptor
Antibodies
Toxins

Immune System
Activation (Vaccines,
Monoclonal antibodies)

Tumor Cell

Metalloproteinase
Inhibitors

Antimetabolites

Tyrosine Kinase
Inhibitors

Farnesyl
Transferase
Inhibitors

Apoptosis
Agonists

Growth
Microtubule inhibitors
Factor
Receptors

Nucleus

Intracellular
Signaling
Molecules

Hormone Agonists/
Antagonists

Matrix Degradation
(Collagenases,
Gelatinases &
Stromelysins)

Angiogenesis Inhibitors
(Angiostatin, Endostatin
& Anti-VEGF)
Antisense

Challenges for the future

Identify women more specific risk profiles
and tailor preventive interventions
Identify subsets of patients for whom
systemic therapy can be avoided
Tailor systemic therapy to individual
tumor/host characteristics
Targeted therapy: ER, HER2, EGF-R, PARP Inhib
Novel targets and pathways