Diseases of the

Breast

    

 
 -   
 
 
   
Anatomy
Anatomy
 DIAGNOSIS OF BREAST
DISEASE
• History
• Physical Examination
• Fine-Needle Aspiration
• Biopsy is done when:
(1) needle aspiration produces no cyst fluid and a
solid mass is diagnosed
(2) cyst fluid produced is thick and blood tinged
(3) mass fails to resolve completely
(4) frequent or rapid (<2 weeks) reappearance of
the cyst in the same location
Common Physical Findings during
Breast Examination
 BREAST IMAGING
• to detect small, nonpalpable breast
abnormalities

• to evaluate clinical findings

• to guide diagnostic procedures.

 BREAST IMAGING
Mammography
• most sensitive and specific imaging
test currently available
• 10% to 15% false negative for
cancer
Ultrasonography
• to evaluate a breast mass
 Breast Imaging Reporting
and Data System (BI-RADS)
Category Definition
0 Incomplete assessment
need additional imaging evaluation
1 Negative; routine screening recommended
2 Benign finding
3 Probably benign finding; short-term
follow-up suggested (PPV = 2.55%)
4 Suspicious abnormality; biopsy should
be considered (PPV = 30%)
5 Highly suggestive of malignancy
(PPV = 94%)
 BREAST IMAGING
Computed tomography
• to image internal mammary nodes
• to evaluate the chest and axilla after
mastectomy
Magnetic resonance imaging
• to evaluate implant rupture
• to identify the primary site of cancer
in malignant axillary adenopathy
 Nonpalpable Mammographic
Abnormalities
Needle Localization Breast Biopsy
• permanent surgical scar on the breast skin
• a cosmetic contour change to the breast
• 2% chance of not excising the site in question
• 75% have a benign finding
• Of 25% diagnosed with a breast cancer, the
majority require a second breast surgery

Large-Core Needle Biopsy (LCNB)

The diagnostic method of choice to histologically
evaluate nonpalpable mammographic
abnormalities
 Large-Core Needle Biopsy

• 65% have a benign diagnosis

• 25% are found to have malignancy
• 10% have inconclusive histology
(1) atypical cells on pathology
(2) discordant results from mammography
(3) increased cellularity within a fibroadenoma
(4) inadequate sampling of the site (calcifications
do not appear)
Risk Factors for Breast Cancer
• Age
the most important risk factor that clinicians use in everyday
clinical practice

• Hormonal Risk Factors

- >5 years of combined estrogen/ progesterone
hormone replacement therapy
- Age at menarche <12
- Nulliparity
- Age at firstborn >30
- Age at menopause >55
- Obesity in postmenopausal women
- No cancer risk associated with induced abortion

* Reproductive risk factors alone are insufficient to

place a woman in the “high-risk” category
Risk Factors for Breast Cancer
• Histologic risk factors
- history of mammary cancer in one breast (1% per
year in young patients to 0.2% in older patients)
- LCIS
probability of developing carcinoma = 21.4% in
35 years
40% were purely in situ lesions
invasive cancers were predominantly ductal in
histology
half occurred in the contralateral breast
- atypical ductal or lobular hyperplasia (RR = 4.4)
Risk of Future Invasive Breast Carcinoma
Based on Histology from Biopsies

No Increase Slightly Increased (RR 1.5–2)

• Adenosis • Moderate or florid hyperplasia,
solid or papillary
• Apocrine metaplasia
• Duct papillomas with
• Cysts, small or large
fibrovascular core
• Mild hyperplasia
• Sclerosing lesion-radial scar
• Duct ectasia
• Fibroadenoma Moderately Increased (RR 4–5)
• Fibrosis • Atypical hyperplasia, ductal or
• Mastitis, inflammatory lobular
• Periductal mastitis
• Squamous metaplasia
Risk Factors for Breast Cancer
• Chronic consumption of alcohol, high fat diet
• Thoracic Radiation Before Age 30
- Hodgkin’s
- Infant thymus radiation
- Frequent fluoroscopy for TB
- Multiple x-rays for scoliosis
• Family History—Three Generations Maternal and
Paternal
– Known or suspected gene mutation
– Early age onset <40
– Bilateral breast cancer
– Breast and/or ovarian cancer
– Male breast cancer
– Ethnicity, e.g., Jewish ancestry with family history
– Cluster of rare tumors in a biological family
 Genetic Risk Factors
for Breast Cancer
• cause 5% to 10% of breast cancer cases
• 25% of cases in women < 30 years of age

BRCA1
• Tumor suppressor gene inherited in an autosomal
dominant fashion
• Long arm of chromosome 17 (17q21)
• 40% of familial breast cancer syndromes
• For women, increased risk for ovarian cancer (15%
to 45%) and colon cancer
• For men, increased risk for prostate cancer
• Tumors are high grade, hormone receptor negative
 Genetic Risk Factors
for Breast Cancer
BRCA2
• tumor suppressor gene inherited in an autosomal
dominant fashion
• chromosome 13q
• 30% of familial breast cancer syndromes
• For women, increased risk for ovarian cancer (20%
to 30%) and pancreatic cancer
• For men, increased risk for breast and prostate
cancer
• tumors are most commonly hormone receptor
positive and well differentiated

Life-long rates of breast cancer between 50% and

70% for carriers of BRCA1 or BRCA2 mutations
 Management of
the High-Risk Patient
Features associated with > 10% probability of
BRCA1/BRCA2 mutation carriers
• Personal history of breast cancer diagnosed ≤40 or ovarian
cancer
• Family history of breast cancer ≤40 in 1st degree relative
• Family history of breast cancer ≤40 in paternal 2nd degree
relative
• Family history of breast cancer in two 1st degree relatives,
at least one diagnosed ≤50
• Family history of ovarian cancer and breast cancer in one
1st or 2nd degree relative or in close relatives in the same
lineage
• One or more male relatives with breast cancer
 Management of
the High-Risk Patient

• Close surveillance with clinical breast

examination, mammography, and
possibly breast MRI

• Chemoprevention using tamoxifen

• Bilateral prophylactic mastectomies

BENIGN BREAST TUMORS AND
RELATED DISEASES
• Breast Cysts
- Palpable cyst develops in 1 of every 14 women
- 50% of cysts are multiple or recurrent
- Most new cyst formation first seen after the age of
35 and rarely before the age of 25
- Management of palpable cysts is needle aspiration
- Submission of cyst fluid for cytology if bloodstained
or residual solid part
- Surgical removal indicated if the cytology is
suspicious or the cyst recurs multiple times
BENIGN BREAST TUMORS AND
RELATED DISEASES
Nipple Discharge
• whether the discharge comes from one breast or
from both breasts

• whether it comes from multiple duct orifices or

from just one

• whether the discharge is grossly bloody or

contains blood
BENIGN BREAST TUMORS AND
RELATED DISEASES
Nipple Discharge
• Nipple discharge that comes from a single duct
and contains blood must be investigated further.

• The most common cause of spontaneous nipple

discharge from a single duct is a solitary
intraductal papilloma.
BENIGN BREAST TUMORS AND
RELATED DISEASES
• Fibroadenoma
- The second most common solid tumor in the
breast
- The most common tumor in women age < 30
years
- Not considered to have a malignant potential
- Small (< 1 cm) = normal, 1-3 cm = disorder,
> 3 cm or multiple (>5 lesions in one breast) =
disease
BENIGN BREAST TUMORS AND
RELATED DISEASES
• Fibroadenoma
- Most of carcinomas in preexisting fibroadenomas
are LCIS (50%)
- Giant fibroadenoma: fibroadenoma that attains an
unusually large size, typically greater than 5 cm
- Juvenile fibroadenoma: rapid growing fibroadenoma
in adolescents and young adults
BENIGN BREAST TUMORS AND
RELATED DISEASES
• Treatment of fibroadenoma
- Observe if
1) typical on examination and young patient
2) confirmed by core needle biopsy
- Excision
1) cosmetic incisions around the areola
2) removing minimal amount of adjacent tissue
3) frozen section is rarely used
BENIGN BREAST TUMORS AND
RELATED DISEASES
• Sclerosing Adenosis
- can simulate carcinoma both grossly and
histologically
- the most common pathologic diagnosis in
patients undergoing needle-directed biopsy of
microcalcifications
- one of the component lesions of fibrocystic
disease
- has no malignant potential
BENIGN BREAST TUMORS AND
RELATED DISEASES
• Radial Scar – complex sclerosing lesions
- can simulate carcinoma mammographically and on
physical examination
- contain microcysts, epithelial hyperplasia, adenosis,
and a prominent display of central sclerosis
- can produce skin dimpling by traction on surrounding
fibrous bands
- women with a history of radial scars had a risk of
breast cancer almost twice the risk in women without
radial scars
- the risk of radial scar was independent of atypical
hyperplasia
Classification of Primary Breast Cancer

Noninvasive Epithelial Cancers

Lobular carcinoma in situ (LCIS)
Ductal carcinoma in situ (DCIS) or
intraductal carcinoma
- Papillary
- Cribriform
- Solid
- Comedo
Noninvasive Breast Cancer
Lobular Carcinoma In Situ

Mean age at diagnosis = 44-47 yr

No clinical or mammographic signs

Multicentricity 60-90%; bilaterality = 50-70%

Incidence of subsequent carcinoma = 25-35% on

both breasts and ductal histology in 65%

Regarded as a marker of increased risk for

invasive breast cancer

No treatment required
Ductal Carcinoma In Situ

Mean age at diagnosis = 54-58 yr
Clinical evident DCIS presented with

a palpable mass

asymmetrical thickening

nipple discharge

Paget’s disease of the nipple

In women undergoing annual mammography, DCIS represents

20% to 40% of newly diagnosed breast cancers and
presents as

clustered calcifications without an associated density 75%

calcifications coexisting with an associated density 15%

density alone 10%
Ductal Carcinoma In Situ
Treatment recommendations based on:

Extent of disease within the breast

Existence of multicentricity

Occult invasive cancer coexisting with the in situ lesion

Natural history after treatment by BCT

Multifocal refers to disease within the vicinity or same quadrant

as the dominant lesion
Multicentric refers to disease in distant sites or quadrants
within the same breast
Occult invasive cancer, or microinvasion, is defined as invasive
disease 1 mm or less in dimension
Ductal Carcinoma In Situ
Treatment options include:

Total (simple) mastectomy

Wide excision with radiation

Wide excision alone

Adjuvant Tamoxifen in breast conservation

Risk of multicentric disease depends on:

size and pathologic extent of the primary cancer
(<10 % in tumor <2 cm, >80 % in tumor > 5 cm)

histologic type of intraductal tumor
(Micropapillary histology was associated with the highest rate of
multicentricity (80%) > papillary and comedo > solid and
cribriform)
Indications for Mastectomy
in Ductal Carcinoma In Situ

• mammographically identified multicentric disease

• diffuse suspicious mammographic calcifications

suggestive of extensive in-breast disease

• persistent positive margins after reexcision(s)

• unacceptable cosmesis to obtain negative

margins

• a patient not motivated to preserve her breast

 Indications for Sentinel Node
Mapping/Level I Dissection in DCIS

• Large tumor size (> 45 mm)

• Multicentric/diffuse/extensive disease

• Diagnosis of DCIS by a core needle biopsy

• Intermediate (6%) or high grade (28%) in core bx

Risk Factors for Local Recurrence
after Lumpectomy and Irradiation
for DCIS

• presence of positive margins

• comedo necrosis

• a mass on physical examination

• a patient 50 years of age and younger

 Paget’s Disease
• Presents as nipple erythema and mild
eczematous scaling and flaking, progressing to
nipple crusting, skin erosions, and ulceration

• Spreads outward off the nipple and onto the

areola and surrounding skin

• Paget’s cells do not invade through the dermal

basement membrane and therefore are a form of
carcinoma in situ
 Paget’s Disease
• Diagnosed by nipple-scrape cytology or biopsy

• More than 97% have an underlying breast

carcinoma.

• Paget’s may present with (54%) or without

(46%) a mass. Invasive breast cancer coexists
with Paget’s disease in 93% of patients with a
mass and in 38% of patients without a mass.
Classification of Primary Breast Cancer
Invasive Epithelial Cancers (percentage of total)
Invasive lobular carcinoma (10–15)
Invasive ductal carcinoma
Invasive ductal carcinoma, NOS (50–70)
Tubular carcinoma (2–3)
Mucinous or colloid carcinoma (2–3)
Medullary carcinoma (5)
Invasive cribriform (1–3)
Invasive papillary (1–2)
Adenoid cystic carcinoma (1)
Metaplastic carcinoma (1)
Mixed Connective and Epithelial Tumors
Phyllodes tumors, benign and malignant
Carcinosarcoma
Angiosarcoma
Classification of Primary Breast Cancer
Invasive Epithelial Cancers (percentage of total)
Invasive lobular carcinoma (10–15)
Invasive ductal carcinoma
Invasive ductal carcinoma, NOS (50–70)
Tubular carcinoma (2–3)
Mucinous or colloid carcinoma (2–3)
Medullary carcinoma (5)
Invasive cribriform (1–3)
Invasive papillary (1–2)
Adenoid cystic carcinoma (1)
Metaplastic carcinoma (1)
Mixed Connective and Epithelial Tumors
Phyllodes tumors, benign and malignant
Carcinosarcoma
Angiosarcoma
Invasive Breast Cancer
SURGICAL TREATMENT FOR
BREAST CANCER
• Radical mastectomy – removal of the breast,
pectoralis major and minor m. and Level I-III axillary
nodes

• Modified radical mastectomy – removal of breast and

Level I or Level I and II nodes

• Simple mastectomy – removal of breast

• Skin-sparing mastectomy – mastectomy with removal

of nipple-areolar complex, but with preservation of the
rest of the breast skin
Total mastectomy with and
without axillary dissection
Radical Mastectomy Offers No
Advantage (NSABP-04)

Fisher et al. NEJM 2002

• Variations in local and regional treatments that involve total
mastectomy do not alter the frequency or pattern of distant
treatment failures. Although local treatment failures are
influenced, overall survival is unaffected

• The mode and time of treatment of axillary nodes do not

alter disease-free survival or overall survival. Immediate
removal, delayed removal, or radiation produced equivalent
clinical results

• 25% of distant recurrences occurred and 50% of

contralateral breast cancers were detected after 5 years

• The location of the primary tumor in the breast does not

influence outcome. Furthermore, there was no justification
for irradiation of internal mammary nodes solely based on
the medial location of the breast cancer.
Modified Radical Mastectomy
(MRM)
Advantages over radical mastectomy

Good postoperative cosmetic appearance

Maintain motor activity in the arm

Low rate of postoperative arm edema

Easy postoperative breast reconstruction

Modified Radical Mastectomy
(MRM)
Patey: removal of pectoralis minor muscle to
allow Level III node dissection

Madden and Auchincloss: preservation of both

pectoralis major and minor; only level I-II
dissection

Reduce arm swelling

Higher chance of medial pectoral nerve

preservation

Only 2% of patients benefit by removal of the
highest-level nodes
Randomized clinical trial comparing level II and
level III axillary node dissection in addition to
mastectomy for breast cancer

Tominaga et al. Br J Surg 2004

Patient Selection and
Evaluation

• History and physical examination

• Mammography

• Histological assessment of the

resected breast specimen

• Assessment of the patient’s needs

and expectations
Absolute Contraindications
for BCT
= Absolute indications for mastectomy
• Multicentricity
• Diffuse malignant-appearing
microcalcifications
• History of prior therapeutic irradiation
to the breast region
Relative Contraindications
for BCT

Persistent positive margins after reasonable surgical

attempts (>2)

Pregnancy (first or second trimester)

Large tumor in a small breast not responding to or
unable to receive induction chemotherapy

Tumor size (> 4-5 cm)

Breast size (very large or pendulous breasts)

Active collagen vascular disease (scleroderma or SLE)

Multifocality
? Indications for Mastectomy

Prophylactic mastectomy for familial or

high risk women

Cost and inconvenience of irradiation

Attitude of patient/relatives/friends

Because the doctors say so

Breast-conserving Surgery
 Breast Conservation

Negative margins for lumpectomy specimen is required

Axillary dissection vs sentinel node bx

Whole-breast irradiation 45-50 Gy with boost to tumor bed

The appearance of cancer in the treated breast (recurrence
+ new tumors) is 1% per year over many years after
treatment

Cure rate from breast conservation is equal to mastectomy

Complication rates from radiation are low (2-5%) and
include spontaneous rib fracture, transient pericarditis for
left-sided cancers, and added distortion of the breast
 Postsurgical Radiation
Therapy
Chest wall and nodal irradiation after
mastectomy

Large cancers (T3-T4)

Aggressive histology (e.g., diffuse vascular
invasion)

Multiple positive nodes (e.g., >3 nodes positive)

Extranodal extension
 Sentinel Lymph Node
Biopsy
To minimize the complications and side effects that may occur
with axillary dissection
- lymphedema
- shoulder dysfunction
- intercostobrachial nerve injury
- injury to the long thoracic or thoracodorsal motor nerves
- axillary vein thrombosis

With acceptable low false-negative rate (< 5%)

 Nodal Metastases
At least 10 lymph nodes evaluated by the pathologist
accurately stage the axillary nodes

macrometastases if the tumor deposit > 0.2 cm

micrometastases if the deposit is < 0.2 cm

The ability to identify a nodal metastatic deposit is directly

proportional to the number of sections

Bisecting a node and examining a single slice will identify
metastases > 0.5 cm, but 14-40% of smaller
macrometastases may be missed

Node is sliced every 0.2-0.3 cm and examined with H&E
stain, all macrometastases are detected though
micrometastases may be missed
(The College of American Pathology Recommendation)
 Male Breast Cancer
• 0.8% of all breast cancers
• The median age at diagnosis is 68, 5 years older
than for women
• Risk factors
- old age
- abnormalities in estrogen/androgen balance
(testicular diseases, infertility, obesity, cirrhosis)
- radiation exposure
- genetic predisposition (Klinefelter’s syndrome,
family history, Jewish ancestry,BRCA2 mutation)
 Male Breast Cancer
• 90% are invasive, with most being ductal
carcinomas
• 80% are estrogen receptor positive
• 75% progesterone receptor positive
• 35% over express HER2/neu

• 10% are DCIS with 75% of papillary subtype

• lobular carcinoma, both invasive and in situ, is

rarely seen
 Angiosarcoma
• Lymphatic (lymphangiosarcoma)
• Capillary endothelium (hemangiosarcoma)
• Primary or secondary based on the absence or presence of a
previous breast cancer diagnosis
• Interval between breast cancer diagnosis and subsequent upper
extremity angiosarcoma is 5-10 years
• Post-treatment sarcomas can occur
- in an arm afflicted by lymphedema after radical mastectomy
(Stewart-Treves syndrome)
- in the chest wall following mastectomy and radiation
- in the breast following breast-conserving surgery and radiation
• Risk factors for the development of soft tissue sarcomas following
breast cancer include postmastectomy lymphedema
 Angiosarcoma
• Radiation is not a risk factor for the development of
angiosarcoma but is a risk factor for the development of
nonangiosarcoma sarcomas
• Clinical presentation is a cutaneous or subcutaneous bluish
nodule, erythema within edematous skin and painful,
hematoma-filled cyst
• Metastasis to regional nodes is rare; the usual mode of
spread is hematogenous, most commonly to the lungs and
bone
• Within 2 years after diagnosis, there is a 90% mortality
• Prognosis is dependent on the histologic grade (I to III) and
size of the tumor
• High-grade lesions (grade 3) are the most lethal of all
primary breast cancers
 Phyllodes Tumor
(Cystosarcoma Phyllodes)
• A phyllodes tumor is differentiated from the fibroadenoma by
the presence of stromal overgrowth
• Metastases occur in 20% of “malignant” lesions and in less
than 5% of “benign” lesions
• The diagnosis is suggested by the larger size, a history of
rapid growth, and the occurrence in older patients
• The diagnosis is usually made by excisional biopsy followed
by careful pathologic review
• For benign lesions, excision with a 1-cm minimum negative
margin is advocated
• For malignant tumors, if adequate margins are achieved with
breast-conserving surgery, mastectomy is not required
• Formal axillary dissection is unnecessary
 Systemic Therapy for
Breast Cancer
• Pure non-invasive carcinomas (stage 0)

• Operable, locoregional invasive carcinoma

(clinical stage I, II and some stage IIIA)

• Inoperable, locoregional invasive carcinoma

(clinical stage IIIB, IIIC and some IIIA)

• Metastatic or recurrent carcinoma (stage IV)

 Invasive Breast Cancer

• Size of primary tumor correlates with DFS and

OS
• Nodal status is the most important prognostic
factor
• Distant metastasis is the most common cause of
death
• Common sites are: bone, lung, pleura, soft
tissue, and liver
 Systemic Therapy for
Breast Cancer

• Invasive breast cancer = systemic disease

• Systemic therapy:
- chemotherapy
- hormonal therapy
- target therapy

• Neoadjuvant vs Adjuvant
 Early Invasive Breast Cancer
• Clinical stage
Stage I T1 N0 M0
Stage IIA T0 N1 M0 Stage IIB T2 N1 M0
T1 N1 M0 T3 N0 M0
T2 N0 M0
Stage IIIA T3 N1 M0

• Locoregional treatment + Adjuvant treatment

• Preop chemotherapy in T2-T3 for breast conservation
Overview of Adjuvant Chemotherapy from Early
Breast Cancer Trialists’ Collaborative Group

• Benefit is similar for node positive and node negative

patients, although absolute differences are smaller for
patients at lower risk for recurrence or death.
• All ages (up to 70 years) benefit, although younger patients
receive more benefit.
• 3-6 months of adjuvant treatment is similar to longer
durations.
• Anthracycline-containing regimens are more effective than
CMF esp in node positive.
• For young women, those with both ER–negative and ER–
positive tumors benefit; for older women, there is more
benefit for those with ER–negative cancers.
St Gallen Expert Consensus on
the Primary Therapy of Early
Breast Cancer 2005
• Endocrine responsiveness

• Menopausal status

• Risk categories
St Gallen Expert Consensus

• Endocrine responsiveness

- Endocrine responsive
- Endocrine responsive uncertain
- Endocrine non-responsive
 Features indicative of
uncertainty of endocrine
responsiveness
• Low levels of steroid hormone receptor
immunoreactivity (<10% of cells positive)

• Lack of progesterone receptors (PgR)

• Features suggesting potential resistance

to particular endocrine therapies (e.g.
HER2/neu overexpression and tamoxifen)
 Features indicative of
uncertainty of endocrine
responsiveness
• A high number of involved lymph nodes

• High tumor levels of uPA/PAI-1

• Increased proliferation markers

 Risk Categories
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
 Risk Categories

Intermediate risk
Node negative AND at least one of the
followings:
• pT > 2 cm, OR
• Grade 2–3, OR
• Presence of peritumoral vascular invasion, OR
• HER2/neu gene overexpressed or amplified,
OR
• Age < 35 years
 Risk Categories

High risk
• Node positive (1–3 involved nodes)
AND
HER2/neu gene overexpressed or
amplified

• Node positive (4 or more involved

nodes)
Choice of Treatment
Modalities 2005
Adjuvant Systemic Treatment
Regimens
Adjuvant Systemic Treatment
Regimens
Adjuvant Systemic Treatment
Regimens
Factors influencing treatment

• Unfavorable features:
- angiolymphatic invasion
- high nuclear grade
- high histologic grade
- HER-2 overexpression
- hormone receptor - negative
National Comprehensive Cancer
Network Clinical Practice
Guideline 2004
National Comprehensive Cancer
Network Clinical Practice
Guideline 2004
 Locally Advanced Invasive
Breast Cancer
• Clinical stage
Stage IIIA T0 N2 M0 Stage IIIB T4 N0 M0
T1 N2 M0 T4 N1 M0
T2 N2 M0 T4 N2 M0
T3 N2 M0
Stage IIIC any T N3 M0

• Preop chemo + locoregional treatment +

adjuvant Rx
National Comprehensive Cancer
Network Clinical Practice
Guideline 2004
 Endocrine Agents for
Breast Cancer
• Antiestrogens • Progestins
– Tamoxifen – Megestrol acetate
– Toremifene – Medroxyprogesterone acetate
– Fulvestrant • Estrogens
• Aromatase – Estradiol
inhibitors – DES
– Anastrozole • Androgens
– Letrozole – Fluoxymesterone
– Exemestane • LHRH analogs
– Goserelin
– Leuprolide
– Buserelin
DES = diethylstilbestrol; LHRH = luteinizing hormone-releasing hormone.
 Risk Reduction in Early Breast Cancer
in Estrogen Receptor−Positive Patients
Recurrence as First Event Mortality From Any Cause
100 100
Tamoxifen 91.8 Tamoxifen
87.4
90 (~5 y) 90 (~5 y)
Control 89.3 78.9 Control
79.2
80.1
80 74.9 Tamoxifen 80 Tamoxifen
(~5 y) Node -ve (~5 y)
% Recurrence-free

Node -ve 73.3

70 75.6 64.3 Control 70 74.2 Control
61.4
60 60

% Alive
59.7 Node +ve
58.3 Node +ve
50 50
50.5

40 44.5 40
30 30
Absolute Recurrence Reduction Absolute Mortality Reduction
20 20
Node -ve: 14.9% SD 1.4: 2P<0.00001 Node -ve: 5.6% SD 1.3: 2P<0.00001
10 Node +ve: 15.2% SD 2.5: 2P<0.00001 10 Node +ve: 10.9% SD 2.5: 2P<0.00001

0 0
0 5 10+ 0 5 10+
Years Years
Reprinted from The Lancet, vol 351, Early Breast Cancer Trialists’ Collaborative Group, 1451, 1998,
with permission from Elsevier Science.
 Breast Cancer−Specific Survival
by Joint Hormone Receptor
Expression (SEER Data)
Joint ER/PR Phenotype
1.00
Cumulative proportion surviving

ER+PR+ (n=12,811)
0.95 ER+PR- (n=2,436)
ER-PR+ (n=663)
0.90
ER-PR- (n=3,631)

0.85

0.80
Node-negative patients
with T1-T3 tumors

0.75
0 10 20 30 40 50 60 70 80
Survival (mo)
Anderson et al. Tumor variants by hormone receptor expression in white patients with node-negative breast
cancer from the surveillance, epidemiology and end results database. J Clin Oncol. 2001;19:18. Reprinted
with permission from the American Society of Clinical Oncology.
 NSABP B-14 Trial: 10 Years
of Tamoxifen vs Stopping
Placebo
Disease-free survival (%)

100
P=0.03

80 Tamoxifen

60
Patients rerandomized after 5 years of tamoxifen

40
0 1 2 3 4
Year after second randomization
Number at Risk
TAM 570 560 433 250 176
Stop 583 567 411 251 163
Fisher et al. J Natl Cancer Inst. 2001;93:684, by permission of Oxford University Press.
 Tamoxifen in Early
Breast Cancer
• Adjuvant tamoxifen is indicated for
– Receptor-positive patients regardless of age
– Pre- and postmenopausal women
– All nodal status
– Any tumor size
• Exceptions may include
– Premenopausal patients with tumor <1 cm, to
avoid
side effects
– Postmenopausal patients with a history of
thromboembolism
NIH Consensus Statement. 2000;17:1.
 Adjuvant Tamoxifen in
Postmenopausal Women
Advantages Disadvantages
• Established • Effectiveness
efficacy – Partial agonist
in reducing risk of – Mortality only reduced
recurrence and by 1/3 at 10 years
death – Resistance/dependence
for at least 10 • Toxicities
years – Endometrial cancer
• Bone and lipid – Thromboembolic effects
benefits – Hot flushes
– Vaginal/urinary
symptoms
 Rationale for Adjuvant Therapy
With Aromatase Inhibitors
• 2/3 of “at-risk” ER+ patients die of breast cancer
despite adjuvant tamoxifen
• Relapses continue for 15+ years
• Alternative SERM has not replaced tamoxifen
• Aromatase inhibitors
– Effective after tamoxifen
– Better than tamoxifen first line
– Well tolerated
– Mechanism of estrogen suppression may avoid
tamoxifen “resistance”
– Not likely to cause thromboembolism or
endometrial cancer