T

ONCOLOGIC MANAGEMENT OF
BREAST CANCER
OBJECTIVES
To answer the questions frequently asked by our colleagues
regarding systemic therapy and radiotherapy in breast
cancer

Expectations of an oncologist from surgeons and
pathologists in breast cancer

QUESTIONS
What are the indications of chemotherapy and radiotherapy in
early breast cancer?
What is hormone therapy? Should tamoxifen be given to all
patients?
What is neoadjuvant and adjuvant therapy. Indications of
chemotherapy/radiation therapy before and/or after surgery in
locally advanced breast cancer?
In which patients no systemic/radiation therapy should be given?
QUESTIONS

Is axillary radiation as effective as axillary lymph node
dissection?
What is immunotherapy? What is Her-2 neu and Herceptin?
What specific parameters are assessed while planning
chemo/radiotherapy?
What is the role of chemotherapy/hormone therapy in cases of
LCIS/DCIS?
In inflammatory carcinoma breast, is pre-op
chemotherapy/radiotherapy indicated?

TERMINOLOGIES
Neoadjuvant therapy
Treatment given prior to the primary treatment in order to
make the tumor amenable to primary treatment (usually
surgery or radiation)
Adjuvant therapy
Additional therapy given for the possibility of subclinical and
subradiological metastasis that would not otherwise be treated
by the primary treatment modality
Salvage therapy
After failure of other treatments (surgery, radiation or
chemotherapy), salvage treatment is used to control disease or
provide palliation
Hormonal therapy
Therapy to induce response in a tumor by altering the hormonal
environment

TERMINOLOGIES
Ductal carcinoma in situ DCIS
Malignant cells are confined to the lumen of the duct and do not
breach the basement membrane
Lobular carcinoma in situ LCIS
Malignant cells are confined to the lumen of the lobule and do not
breach the basement membrane
Invasive ductal carcinoma
Malignant cells arising from the duct system breach the basement
membrane
Invasive lobular carcinoma
Malignant cells arising from the lobules breach the basement
membrane
Inflammatory Carcinoma
characterized by diffuse brawny induration of the skin with an
erysipeloid edge, usually with no underlying mass.

GLOBAL ISSUE
BREAST CANCER INCIDENCE &
MORTALITY
aaaaaaaaa
PAKISTANI STATISTICS
Count %age of total
Breast 5119 21.26%
TOP MALIGNANCY SEEN AT SKMH&RC AMONG ALL AGE GROUPS &
BOTH SEXES COMBINED FROM DEC 1994 TO DEC 2004
TOP MALIGNANCY SEEN AT SKMH&RC AMONG FEMALES ALL AGE
GROUPS COMBINED FROM DEC 1994 TO DEC 2004

Count %age of total
Breast 5060 42.37%
Hameed S, etal, http://www.shaukatkhanum.org.pk/pdf/Cancer%20Registry%20Report
%20-1994-2004_10%20years_.pdf
BREAST CANCER DEMOGRAPHICS
Anderson WF et al. Breast Cancer Res Treat 2002; 76: 2736
24.9
56.9
35.7
64.3

41.4
50.1
8.5

75.1
63.3
20.1
79.9

28.8
65.1
6.1
ER-positive ER-negative
Proportion of patients (%)
Mean age (years)
Age at diagnosis (%)
<50
50
Tumour size (%)
>2.0 cm
2.0 cm
unknown
Patients (n=82,488)
ER = oestrogen receptor
RISK FACTORS
Risk factor Category at risk
Older age Older than 50
Country of residence North America or northern Europe
Germ-line mutation With BRCA1 or BRCA2 mutations
Personal history of breast cancer With history of invasive breast
carcinoma
High radiation exposure to chest
area
With high radiation exposure to
chest
Atypical hyperplasia in breast biopsy With atypical hyperplasia
Cytological findings (fine-needle
aspiration; nipple aspiration fluid
Proliferation with atypia
Established Risk Factors
RISK FACTORS
Risk factor Category at risk
Family history of breast cancer With one or more close relatives
with breast cancer
Early menarche Menarche before age 12
Late menopause Menopause after age 55
Older age at first full-term birth Older than 30 years when first child
was born
Using menopausal hormone therapy With hormone treatment after
menopause
Obesity after menopause Obese after menopause
Established Risk Factors
RISK FACTORS
Risk factor Category at risk
Using birth control pills Current use
Tall height Taller than 5 ft 9 inches
Regular alcohol consumption Regularly consume alcoholic
beverages
Breast-feeding None
Postmenopausal body mass index
(BMI)
Higher BMI
Jewish heritage Yes
Other reported risk factors
RISK FACTORS
Risk factor Category at risk
High-density breasts on
mammograms
With high-density mammograms
High socioeconomic position Have high socioeconomic position
Physical activity Lower
Dietary factors High-fat, low-fiber diet
Possible risk
WHO SHOULD BE OFFERED GENETIC
TESTING (BRCA1 & BRCA2 MUTATIONS)
ASCO Recommendations
The individual has personal or family history features suggestive of
a genetic cancer susceptibility condition,

The test can be adequately interpreted, and

The results will aid in diagnosis or influence the medical or surgical
management of the patient or family members at hereditary risk
of cancer

BREAST CANCER SCREENING
Age Group ACR ACS NCI
2039
BSE optional; CBE
every 3 years.
Monthly BSE; CBE
every 3 years.
No
recommendation.
4049
Annual
mammography and
CBE from 40 years.
Annual
mammography and
CBE from 40 years.
Mammography
every 12 years.
>49
Annual
mammography and
CBE as long as a
woman is in
reasonably good
health.
Annual
mammography and
monthly CBE as
long as a woman is
in reasonably good
health.
Mammography
every 12 years.
BREAST CANCER SCREENING
Age Group ACR ACS NCI
At
increased
risk
Consult with their
doctors about the
benefits and
limitations of
starting
mammography
screening earlier,
having additional
tests (i.e., breast
ultrasound and
MRI), or having
more frequent
examinations.
Consult with their
physician about
beginning
mammography
screening before
age 40.
Seek expert
medical advice
about whether they
should begin
screening before
age 40 and the
frequency of
screening.
SYMPTOMS
Painless Breast Mass 65%
Painful Breast Mass 12%
Nipple Discharge 7%
Skin Dimpling 4%
Nipple Retraction 3%
Local Edema 3%
DIAGNOSIS
Triple assessment
Clinical Imaging Pathology
Age
Examination
Ultrasound
Mammography
FNA
Core-cut biopsy
Confident diagnosis in 95% cases
DIAGNOSTIC WORKUP
General
History with emphasis on presenting symptoms, menstrual status,
parity, family history of cancer, other risk factors
Physical examination with emphasis on breast, axilla,
supraclavicular area, abdomen

Special tests
Biopsy (core biopsy directed by physical examination, ultrasound,
or mammography as indicated, or needle localization)

Radiologic studies
Before biopsy
Mammography/ultrasonography
Chest radiographs
Magnetic resonance imaging of breast (selected cases)
DIAGNOSTIC WORKUP
Radiological studies
After positive biopsy
Bone scan (when clinically indicated, for stage II or III disease or
elevated serum alkaline phosphatase levels)
Computed tomography of chest, abdomen and pelvis for stage II
or III disease and/or abnormal liver function tests

Laboratory studies
Complete blood cell count, blood chemistry
Urinalysis
Other studies
Hormone receptor status (ER, PR)
HER2/neu status
Consider genetic counseling/BRCA testing in selected cases



DIAGNOSTIC ACCURACY OF
VARIOUS MODALITIES
Test Sensitivity Specificity
CBE 60-89 % 60-99 %
Mammography 83-93 % 73-97 %
Ultrasound 89-91 % 97-98 %
FNAC 65-98 % 93-99 %
Combined 99-100 % 99-100 %
AJCC AND UICC CANCER STAGING
SYSTEM
Tx
Primary tumor cannot be assessed
To
No evidence of primary tumor
Tis
Carcinoma in situ
Tis(DCIS)
Ductal carcinoma in situ
Tis(LCIS)
Lobular carcinoma in situ
Tis Pagets
Pagets disease of nipple with no tumor
T1
Tumor 2cm in greatest dimension
T1mic
Microinvasion 0.1cm or less in greatest dimension
T1a
Tumor >0.1cm but not >0.5cm in greatest dimension
T1b
Tumor >0.5cm but not >1cm in greatest dimension
T1c
Tumor >1cm but not >2cm in greatest dimension

T2
Tumor >2cm but not >5cm in greatest dimension
T3
Tumor >5cm un greatest dimension
T4
Tumor of any size with direct extension to skin or chest wall,
only as described below
T4a
Extension to chest wall not including pectoralis muscle
T4b
Edema including peau de orange or ulceration or satellite skin
nodules confined to same breast
T4c
Both T4a and T4b
T4d
Inflammatory carcinoma
STAGING SYSTEM
Nx
Regional lymph nodes cannot be assessed
No
No regional lymph node metastasis
N1
Metastasis to movable ipsilateral axillary lymph node(s)
N2a
Metastasis to ipsilateral matted axillary lymph node(s) or fixed
to other structures
N2b
Metastasis in clinically apparent ipsilateral internal mammary
lymph nodes in absence of clinically evident ipsilateral axillary
lymph node metastasis
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)
STAGING SYSTEM
pNo
No regional lymph node metastasis
pN1
Metastasis to 1 to 3 positive axillary lymph node(s)
pN2
Metastasis to 4 to 9 positive axillary lymph nodes
pN3
Metastasis to 10 or more positive axillary lymph nodes
Mx
Distant metastasis cannot be assessed

Mo
No distant metastasis

M1
Distant metastasis

Stage Tumor (T) Node (N) Metastasis (M)
Stage 0 Tis N0 M0
Stage 1 T1 N0 M0
Stage IIA
T0 N1 M0
T1 N1 M0
T2 N0 M0
Stage IIB
T2 N1 M0
T3 N0 M0
Stage IIIA
T0 N2 M0
T1 N2 M0
T2 N2 M0
T3 N1, N2 M0
Stage IIIB
T4 any N M0
any T N3 M0
Stage IV any T any N M1
CLINICAL STAGING OF BREAST
CANCER
Stage IV Stage III Stage II Stage I
Metastatic Localized (early) disease
Locally
advanced
disease

AJCC HISTOPATHOLOGIC
CLASSIFICATION
In situ carcinomas
NOS
Intraductal (in situ)
Paget's disease and intraductal

Invasive carcinomas
NOS
Ductal
Inflammatory
Medullary, NOS
Medullary with lymphoid stroma
Mucinous
Papillary (predominantly micropapillary pattern)
Tubular
Lobular
Paget's disease
Undifferentiated
Squamous cell
Adenoid cystic
Cribriform

INFILTRATING DUCTAL CARCINOMA
70% to 75% of all breast
cancers (most common
type)
Arises from the milk ducts
Stony hard on palpation
Commonly spreads to the
lymph nodes = poor
prognosis

5% to 10% of all breast cancers
Arises from the lobules of the breast
Tendency toward multicentric & bilateral
involvement
Generally poor prognosis
INFILTRATING LOBULAR CARCINOMA
INFLAMMATORY CARCINOMA

1% and 4% of all breast cancers
Characterized by red (inflamed) breast
skin - pitted appearance looks like an
orange peel (peau d'orange)
Symptoms may mimic a mastitis,
without fever or signs of infection.
Generally associated with a poor
prognosis.
Long-term remission possible with
aggressive treatment
PAGET'S DISEASE OF THE NIPPLE

3% of all breast cancers
Unique type of ductal cancer
Characterized by a rash, itching,
scaliness or redness on the nipple
and an underlying ductal
carcinoma
Frequently noninvasive

SPECIAL TYPES
Medullary cancer - good prognosis
Tubular breast cancers slow growing;
small ones rarely involve the lymph nodes

Mucinous (or colloid) breast cancer -
characterized by mucin around the tumor cells.
The more mucinous the tumor, the more slow
growing it is
PROGNOSTIC FACTORS FOR SURVIVAL
AND METASTASIS
TUMOR SIZE
AXILLARY NODAL STATUS
TUMOR TYPE
Favourable prognosis : Tubular, mucinous, medullary, papillary
subtypes compared to invasive ductal or lobular carcinoma

Poor prognosis : Metaplastic, Undifferentiated subtypes

TUMOR GRADE
Nottingham prognostic grade
Based on percentage of tubule formation, degree of nuclear
pleomorphism, accurate mitotic count
Grade I better survival
Grade II & III worse survival

ESTROGEN AND PROGESTERONE HORMONAL RECEPTORS IN TUMOR
CELLS

LYMPHATIC AND VASCULAR INVASION Increase risk of recurrence
ESTROGEN AND PROGESTERONE HORMONAL RECEPTORS IN
TUMOR CELLS
HER-2/neu
HER-2/neu proto-oncogene (also called c-erbB-2) located on
chromosome 17 codes for a transmembrane glycoprotein has
tyrosine kinase activity

Amplified or overexpressed in up to 30% of in human breast
carcinoma

Overexpression of the protein is associated with tumor
aggressiveness and decreased disease-free survival in node-
positive patients, with variable prognostic significance among
node-negative patients

AGE
Although clearly not as valid as tumor size and nodal status, young
age may be considered in combination with other prognostic
factors in clinical decision making as a potential negative
prognostic factor
OBESITY/BODY MASS INDEX
On multivariate analysis, recurrent disease developed in 32% of
obese patients compared with 19% of nonobese women

SMOKING
The RRs for smokers and exsmokers, compared with those who
had never smoked, is 1.44 and 1.13

PREGNANCY
No strong evidence to suggest that subsequent pregnancy will
increase the risk of recurrence

TUMOR LOCATION
No sufficient evidence to support any independent prognostic
significance of tumor location
Medial tumor location may lead to the underestimation of axillary
lymph node involvement
DUCTAL CARCINOMA IN SITU (DCIS)
Stage 0, Tis No Mo
Average age at diagnosis 54- 56 yrs
Presenting signs/symptoms: mass, breast pain, bloody nipple
discharge
Mammography: microcalcifications
Pathology: Less likely to be bilateral and approximately 30%
incidence of multicentricity; Comedo and non-comedo variant.
Comedo has higher proliferative rate, over expression of HER-
2/neu and higher incidence of local recurrence and microinvasion.
Risk of invasive cancer: 25-50 yrs within 10yrs of diagnosis.
Virtually all are ductal, ipsilateral and generally in the same
quadrant.
DCIS considered direct precursor of invasive cancer.

MANAGEMENT OF DCIS
LOBULAR CARCINOMA IN SITU (LCIS)
Stage 0 Tis No Mo
Peak age 45 50yrs
Non palpable
No consistent mamographic features. Often incidental finding
after biopsy performed for another reason.
Pathology: multifocal, multicentric and bilateral
Risk of invasive cancer 20 25% within 15yrs of diagnosis.
Mostly ductal in origin with both breasts at risk
LCIS considered a marker for risk of invasive cancer.
Management options:
Close follow up
Chemoprevention trial
Counselling regarding risk reduction with tamoxifen
in premenopausal women or with tamoxifen or
raloxifene for post menopausal women
In special circumstances bilateral mastectomy
reconstuction

MANAGEMENT OF INVASIVE
DISEASE
SURGICAL MANAGEMENT
BREAST CONSERVING SURGERY (BCS)
For early breast cancer
Partial mastectomy, lumpectomy/tylectomy, and quadrantectomy
Re-excision under frozen section control in patients with +ive
margins
RT may be used for focally +ive margins
For diffuse involvement, dose of RT high increase toxicity
Large T2/T3 tumors neoadjuvant chemo followed by BCS

SKIN SPARING MASTECTOMY

NIPPLE SPARING MASTECTOMY

BCS is followed by RT
Patient should be educated that mastectomy does not totally
eliminate the need for RT in EBC

SURGICAL MANAGEMENT OF AXILLARY
LYMPH NODES
30-40% of breast cancer metastases to ALN
60-80 % of patients are lymph node negative
Unnecessary surgery?
Sentinel lymph node biopsy can spare the potential morbidity of
ALND
SURGICAL MANAGEMENT OF AXILLARY
LYMPH NODES
AXILLARY LYMPH NODE DISSECTION
ALND Clearance of level I and II axillary lymph nodes
Minimum of 16 axillary lymph nodes need to be sampled
to clearly follow current guidelines regarding RT to axilla
and supraclavicular lymph nodes
Sampling of ONLY clinically enlarged lymph nodes
wrong practice
Distribution of Axillary lymph node involvement:
Level I 58%
Level I & II 22%
Level I, II & III 16%
Skip metastasis 4%
SURGICAL MANAGEMENT OF AXILLARY
LYMPH NODES
SLNB - SLN is the first lymph node to receive lymphatic
drainage from a tumor
Axillary dissection if SLNB +ive
Identification rate > 90 %
False negative rate < 5 %
Learning curve 30 - 50 cases (SLNB + ALND)

MASTECTOMY VS BCS
Local Recurrence
(%)
Survival
(%)
Study
No.
Cases
MRM BCS MRM BCS
FU
(Years)
NSABP 1219 8 10 59 63 12
Milan 701 4 7 65 65 18
NCI 237 6 16 75 77 10
EORTC 874 9 13 61 54 8
IGR 179 14 9 65 73 15
Danish 904 6 5 82 79 6
MASTECTOMY VS BCS
BREAST CONSERVING TREATMENT
INDICATIONS
Typically less than 5 cm lesion
No multicentric disease
Must have negative margins (>1mm) this includes DICS
No scleroderma/ autoimmune disease
Breast /tumor proportion cosmetic outcome

CONTRAINDICATIONS
Absolute
Prior RT to the breast or chest wall
RT during pregnancy (1
st
and 2
nd
trimester)
Diffuse suspicious or malignant appearing microcalcifications
Widespread disease that cannot be incorporated by local excision
through a single incision that achieves negative margins with a
satisfactory cosmetic result
Positive pathologic margin


BREAST CONSERVING TREATMENT
CONTRAINDICATIONS
Relative
Active connective tissue disease involving the skin (especially
scleroderma and lupus)
Tumors > 5 cm
Focally positive margin
Have an increased risk of ipsilateral breast recurrence or
contralateral breast cancer with breast conserving therapy
Prophylactic bilateral mastectomy for risk reduction may
be considered
Women 35 y or premenopausal women with a known
BRCA 1/2 mutation



RT PRODUCES ITS GREATEST EFFECT
ON LR IN WOMEN AT MOST RISK
5 Year LR
BCS
5 Year LR
BCT+RT
5 Year
Gain
N- 20.1% 5.7% 14.4%
N+/Nx 34% 8.9% 25.1%
EBCTCG, Lancet (2005)366, 2087;Harris, Breast Cancer: Current Controversies
and New Horizons, July 12, 2007, Boston

ROLE OF RADIOTHERAPY FOR BREAST
CANCER
Adjuvant
Loco-regional
Neoadjuvant
Palliative
Local and metastatic
disease control

INDICATIONS FOR ADJUVANT
RADIOTHERAPY

Breast/Chest wall irradiation
Breast Conserving Surgery
> 2 positive axillary lymph nodes
Matted lymph nodes
Tumor > 5cm. (T3, any T4)
Extracapsular extension
Positive or close margins (less than 3 mm)
Any skin, fascial or skeletal muscle involvement
Poorly differentiated tumors
Lymphatic permeation
INDICATIONS FOR ADJUVANT
RADIOTHERAPY

Lymphatic irradiation
Fewer than 9 lymph nodes sampled
Two or more metastatic axillary lymph nodes
Lymph nodes larger than 2.5cm
Involvement of apex of axilla
Gross extracapsular tumor extension
SURGICAL AXILLARY DISSECTION VS RT
SYSTEMIC THERAPY
Chemotherapy
Hormonal Therapy
Adjuvant therapy
Neoadjuvant therapy
Palliative therapy
Biologic Therapy
ST. GALEN CONSENSUS
Definition of Risk Categories for Patients with Operated
Breast Cancer
Low risk Node negative AND all of the following features:
pT 2 cm, AND
Grade 1, AND
Absence of peritumoral vascular invasion, AND
HER2/neu gene neither overexpressed nor amplified,
AND
Age 35 years
Intermediate
risk
Node negative AND at least one of the following
features:
pT >2 cm, OR
Grade 2-3,OR
Presence of peritumoral vascular invasion,OR
HER2/neu gene overexpressed or amplified,OR
Age <35 years
Node positive (13 involved nodes) AND
HER2/neu gene neither overexpressed nor amplified
ST. GALEN CONSENSUS
Definition of Risk Categories for Patients with Operated
Breast Cancer
High risk Node positive (13 involved nodes) AND
HER2/neu gene overexpressed or amplified
Node positive (4 or more involved nodes)
ST. GALEN CONSENSUS
Expert Consensus on the Therapy of Breast Cancer
Risk Category Endocrine
Responsive
Endocrine
Response
Uncertain
Endocrine
Nonresponsive
Low risk ET ET Not Applicable
Intermediate
risk
ET alone, or
CT ET
(CT + ET)
CT ET
(CT + ET)
CT
High risk CT ET
(CT + ET)
CT ET
(CT + ET)
CT
ET Endocrine therapy
CT - Chemotherapy
ST. GALEN CONSENSUS
BENEFIT OF ADJUVANT
CHEMOTHERAPY
Decreased recurrence rate ~ 20-40%
Decreased mortality rate ~ 10-40%

DEVELOPMENT OF ADJUVANT
CHEMOTHERAPY IN BREAST CANCER
Before anthracyclines
CMF, CMFVP
With anthracyclines
Combinations: AC, FAC, AVCMF,
FEC, CEF
Sequence and Alternating (Milan A
& B)
Dose intensity,dose density, HDCT
Taxanes (Paclitaxel/Docetaxel)
Sequential: A T C or AC T
Combinations: TA, TAC
Targeted Agents
Integration in chemotherapy
strategies

1970s
1980s
1990s
2000s
NEOADJUVANT / PRIMARY CHEMOTHERAPY
Advantages
- Assessment of tumor response to
chemotherapy
- Prompt treatment of the micrometastases
- May downstage the primary tumor
- Increases the likelihood of BCS
Disadvantages
- Loss of prognostic information-ALN status
- Delayed local or regional therapy
- Induction of drug resistance

Core biopsy should always be performed prior to neoadjuvant
chemotherapy to obtain sufficient tissue to identify histologic subtype,
ER/PR status and Her2 Neu status
NEOADJUVANT / PRIMARY CHEMOTHERAPY
Indications
1. Locally advanced breast cancer
- Stage IIIB, T4 or N3 cancer
- Stage IIIA inoperable cancer
2. T2 or T3 tumors, to make BCS feasible

NEOADJUVANT / PRIMARY CHEMOTHERAPY
Advantages
- Assessment of tumor response to
chemotherapy
- Prompt treatment of the micrometastases
- May downstage the primary tumor
- Increases the likelihood of BCS
Disadvantages
- Loss of prognostic information-ALN status
- Delayed local or regional therapy
- Induction of drug resistance

Core biopsy should always be performed prior to neoadjuvant
chemotherapy to obtain sufficient tissue to identify histologic subtype,
ER/PR status and Her2 Neu status
ROLE OF HORMONAL THERAPY
Adjuvant Hormonal Therapy
Primary Hormonal Therapy
Palliative Hormonal Therapy
Prevention of Breast Cancer

Nucleus
Cytoplasm
Breast Cancer Cell
E
2
E
2
PgR mitosis
E
2
ER
ER
+
E
2
=

Estradiol

ER = Estrogen receptor
E
2
ER = Estradiol-receptor complex
PgR = Progesterone receptor
HORMONE-DEPENDENT BREAST
CARCINOMA
Chromatin
RNA
TYPE OF HORMONAL THERAPY
GnRH-Agonists
- Goserelin, Leuprolide
Antiestrogens
- Tamoxifen, Toremifen, Droloxifen,
Faslodex, 3rd Generation SERMs
Antiprogestins
- Mifepristone, Onapristone
Aromatase Inhibitors
- Glutethimides, Steroidal AI
- Letrozole (Femara), Anastrozole (Arimidex)

HORMONAL THERAPY
Tamoxifen
Aromatase
Inhibitors
AROMATASE INHIBITOR
HORMONAL THERAPY
Since 1980 Tamoxifen has been the gold standard in first-line
treatment of pre menopausal with breast cancer ER/PR +ve

The third generation aromatase inhibitors, letrozole and
anastrozole first-line therapy in postmenopausal women

The selective aromatase inhibitors may prove to be the more
effective/better tolerated drugs in the neo-adjuvant setting as
well

Endocrine therapy is recommended for at least 5 years

PREVENTION OF BREAST CANCER
BCPT Results: Summary
Tamoxifen reduced incidence of invasive breast cancer by 49%
(p<0.00001)

Reduction seen in women of all age groups ( 35 years of age) and
at all levels of breast cancer risk

Fisher et al. J Natl Cancer Inst 1998;90:1371-1388.
Prevention data
13,388 women
0 1 2 3 4 5
Years on study
DCIS
1804 women
0 1 2 3 4 5
Years on study
Contralateral BC
2818 women
0 1 2 3 4 5 6
Years on study
Adjuvant, node negative
5217 women
0 1 2 3 4 5 6
Years on study
Adjuvant, node positive
2210 women
0 1 2 3 4 5 6
Years on study
Placebo
Tamoxifen
BREAST CANCER CONTINUUM: CONSISTENCY OF
RESULTS ON 5 YEARS OF TAMOXIFEN
Improved Outlook in Early Breast Cancer:
Indirect Comparison of ATAC data with EBCTCG 1995 Overview
1
(Hormone Receptor +ve Patients >50 Years)

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100
80
0
0 1 2 3 4 5+ years
90
70
84.6%
70.5%
3-year event-free rate:

90%
92%
*ATAC data truncated at 42 months
1
EBCTCG. The Lancet 1998; 351: 14511467
Anastrozole (ATAC data)
Tamoxifen (ATAC data)
Tamoxifen (EBCTCG overview)
Control (EBCTCG overview)
HER FAMILY: RECEPTORS AND LIGANDS
HER1 HER2 HER3 HER4
H
R
G

(
N
R
G
1
)

Tyrosine
kinase
domain
Ligand
binding
domain
Transmembrane
Herbst. Int J Radiat Oncol Biol Phys. 2004;59(suppl):21; Roskoski. Biochem Biophys Res Commun. 2004;319:1;
Rowinsky. Annu Rev Med. 2004;55:433.
POTENTIAL CONSEQUENCES OF HER
DYSREGULATION
Signaling
cascades
HER family
PI3K
MAPK
Nucleus
Gene activation
Cell cycle progression
M
G
1
S
G
2
Myc
Fos
Jun
P
P
Adapted from Roskoski. Biochem Biophys Res Commun. 2004;319:1-11; Rowinsky. Annu Rev Med. 2004;55:433-457.
Survival
Angiogenesis
Invasion
Apoptosis
Metastasis Proliferation
Normal (1X)
~20,000-50,000
HER2 receptors
Overexpressed HER2 (10-100X)
Up to ~2,000,000 HER2 receptors
Excessive cellular division
HER2 OVEREXPRESSION
IN BREAST CANCER

Pegram et al. Cancer Treat Res. 2000;103:57.
Ross and Fletcher. Am J Clin Pathol. 1999;112(suppl 1):S53.
Slamon et al. Science. 1987;235:177.
HER2 is overexpressed in
~25% of breast cancers
Wolff et al. JCO 25: 118 (2007); nccn.org
HER2 TESTING
HER2 evaluation in all invasive breast cancer case at diagnosis
Labs with greater experience have fewer false-positives
FISH and IHC are both appropriate testing methods when high
concordance is established
New ASCO-CAP 2006 and NCCN Task force recommendations
available:
Guidelines for testing
Definitions of Pos\Neg\Intermediate results
FISH retest of IHC 2+
Repeat FISH or perform IHC for FISH 1.8-2.2



ANTI-HER TARGETED APPROACHES
Anti-EGFR
blocking
antibodies
(eg, trastuzumab,
cetuximab)
Anti-ligand
blocking
antibodies
Tyrosine
kinase
inhibitors
(eg, erlotinib,
gefitinib,
lapatinib)
Ligand-
toxin
conjugates (eg, TP-38,
DAB
389
EGF, scFv-14e1-
ETA fusion toxin)
HER dimerization
inhibitors
(eg, pertuzumab)
TOXIN
Adapted from Noonberg and Benz. Drugs. 2000;59:753.
TARGETING THE HER FAMILY:
EXAMPLES OF THERAPIES
Agent
Mechanism
of Action
Target
Mode of
Administration
Trastuzumab MoAb HER2 IV
Cetuximab MoAb HER1 IV
Pertuzumab MoAb
HER1/HER2/HER3
/HER4
IV
Gefitinib,
Erlotinib
TKI HER1 PO
Lapatinib TKI HER1/HER2 PO
MoAb = monoclonal antibody; TKI = tyrosine kinase inhibitor
SURVIVAL RATES
5-year Survival by Age
Younger than 45
Ages 45-64
Ages 65 & older
81%
85%
86%
95%
85%
50%
20%
2-5%
98%
90%
70%
50%
15%
0
I
II
III
IV
10-year survival 5-year survival
Stage
Survival by Stage
85%
71%
57%
52%
After 5 years
After 10 years
After 15 years
After 20 years
Overall Survival Rate
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