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eMedicine Specialties > Oncology > Carcinoma of the Breast

Breast Cancer

Rachel Swart, MD, PhD, Assistant Professor of Medicine, Department of Hematology and

Oncology, Arizona Cancer Center, University of ArizonaLeona Downey, MD, Assistant Professor of Internal Medicine, Section of Oncology and

Hematology, University of Arizona, Arizona Cancer Center; Julie Lang, MD, AssistantProfessor of Surgery and the BIO5 Institute, Director of Breast Surgical Oncology, University of

Arizona; Patricia A Thompson, PhD, Assistant Professor, Department of Pathology, Universityof Arizona, Tucson; Robert B Livingston, MD, Professor of Clinical Medicine and Director,

Clinical Research Shared Services, Arizona Cancer Center; Alison T Stopeck, MD, AssociateProfessor of Medicine, Arizona Cancer Center, University of Arizona Health Sciences Center;

Director of Clinical Breast Cancer Program, Arizona Cancer Center; Medical Director ofCoagulation Laboratory, University Medical Center; Director of Arizona Hemophilia and

Thrombosis Center

Updated: Nov 15, 2010

Introduction

Worldwide, breast cancer is the most frequently diagnosed life-threatening cancer in women andthe leading cause of cancer death among women. Over the last two decades, breast cancer

research has lead to extraordinary progress in our understanding of the disease, resulting in moreefficient and less toxic treatments. Increased public awareness and improved screening have led

to earlier diagnosis at stages amenable to complete surgical resection and curative therapies.Consequently, survival rates for breast cancer have improved significantly, particularly in

younger women. This article addresses the etiology, clinical presentation, diagnosis, surgical andmedical treatment, and prognosis of breast cancer.

For patient education resources, visit eMedicine's Cancer and Tumors Center, Women's Health

Center, and Imaging Center. eMedicine also has pertinent patient education articles on BreastCancer, Mastectomy, Breast Lumps and Pain, Breast Self-Exam, Mammogram, and

OvarianCancer.

Epidemiology

The American Cancer Society estimated nearly 1.4 million new cases of invasive breast cancer

worldwide in 2008. Female breast cancer incidence rates for 2002 varied internationally by more


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than 2.5-fold, ranging from 3.9 cases per 100,000 in Mozambique to 101.1 cases per 100,000 inthe United States. Over the past 25 years, breast cancer incidence rates have risen globally, with

the highest rates occurring in the westernized countries. Reasons for this trend include change inreproductive patterns, increased screening, dietary changes, and decreased activity. Although

breast cancer incidence is on the rise globally, breast cancer mortality has been decreasing,

especially in industrialized countries.

In the United States, an estimated 192,370 new cases of invasive breast cancer will occur in

women in 2009, along with 1,910 cases in men. After two decades of increasing incidence rates,the number of new female breast cancers decreased by 2.2% per year from 1999 to 2005. This

decrease is thought to reflect reduced use of hormone replacement therapy (HRT) following thepublication of the Womens Health Initiative in 2002, which linked HRT use to an increased risk

of heart disease and breast cancer. In addition to invasive breast cancer, 62,280 new cases of insitu breast cancer are expected to occur among women in 2009. Approximately 85% of these are

expected to be ductal carcinoma in situ (DCIS). Rates of DCIS have stabilized since 2000.[1 ]

The current lifetime risk of breast cancer in the United States is estimated at 12.7% for allwomen, 13.3% for non-Hispanic whites, and 9.98% for African American women. Overall, the

annual incidence rates in African American women (119.4 out of every 100,000) andHispanic/Latina women (89.9 out of every 100,000) have been stable since the early 1990s and

are lower than the annual incidence of breast cancer in white women (141.1 out of every100,000). However, African American women are more likely than white women to be

diagnosed with larger, advanced stage tumors (>5 cm). Incidence rates among Asian and PacificIslander women have continued to increase at 1.5% per year (89 out of every 100,000) but are

still significantly lower than white women.

Death rates from breast cancer have steadily decreased in women since 1990. An estimated

40,610 breast cancer deaths (40,170 women, 440 men) are expected in 2009. The largestdecrease in mortality has been seen in women younger than 50 years (3.3% per year) versus

those aged 50 years and older (2.0% per year). The decrease in breast cancer death rates isthought to represent progress in both earlier detection and improved treatment modalities.

[2 ]

Etiology

The current understanding of breast tumorigenesis is that invasive cancers arise through a series

of molecular alterations at the cellular level, resulting in the outgrowth and spread of breastepithelial cells with immortal features and uncontrolled growth. Genomic profiling has

demonstrated the presence of discrete breast tumor subtypes with distinct clinical behavior (eg, 4

subclasses: luminal A, luminal B, basal, and HER2+). The exact number of disease subtypes andmolecular alterations from which these subtypes derive remains to be fully elucidated, but theygenerally align closely with the presence or absence of hormone receptor and mammary

epithelial cell type (luminal or basal).

The figure below summarizes the current general understanding of breast tumor subtypes,prevalence, and the major associated molecular alterations. This view of breast cancer, not as aset of stochastic molecular events, but as a limited set of separable diseases of distinct molecular


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and cellular origins, has altered thinking about breast cancer etiology, type-specific risk factors,prevention, and treatment strategies.


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Intrinsic subtypes of breast cancer.

Risk factors

Epidemiological studies have identified many risk factors, which increase the chance of a woman

developing breast cancer (see Table 1, below). Many of these factors form the basis for breast

cancer risk assessment tools. The common denominator for many of these risk factors is theireffect on the level and duration of exposure to endogenous estrogen. Early menarche, nulliparity,

and late menopause increase lifetime exposure to estrogen in premenopausal women, whileobesity and hormone replacement therapy increase estrogen levels in postmenopausal women.

A family history of breast cancer in a first-degree relative is the most widely recognized breast

cancer risk factor. Risk is approximately 5 times greater in women with 2 or more first-degreerelatives with breast cancer and is also greater among women with a single first-degree relative,

particularly if diagnosed at an early age (age 50 years or younger). A family history of ovariancancer in a first-degree relative, especially if the disease occurred at an early age (< 50 years

old), has also been associated with a doubling of risk of breast cancer.

One of the most widely studied risk factors in breast cancer is the use of exogenous hormones in

the form of oral contraceptives (OCs) and hormone replacement therapy (HRT). The overallevidence suggests a modest 1.25 increased risk among current users of oral contraceptives. The

risk appears to decrease with age and time from oral contraceptive discontinuation. Breast cancerrisk returns to that of the average population after approximately 10 years following cessation of

oral contraceptives.

Consistent epidemiologic data support an increased risk of breast cancer incidence and mortality(2003) with the use of postmenopausal HRT. Risk is directly associated with length of exposure,

with the greatest risk observed for the development of hormonally responsive lobular (relativerisk [RR]=2.25, 95% confidence interval [CI]= 2.00-2.52), mixed ductallobular (RR=2.13, 95%

CI= 1.68-2.70), and tubular cancers (RR=2.66, 95% CI= 2.16-3.28).

The risk is greater in women taking combination estrogen plus progestin formulations comparedto estrogen-only formulations (HR 0.77 for unopposed estrogen vs placebo), but missed

statistical significance (p=0.06). Published results of a randomized trial, the Womens HealthInitiative (WHI), of estrogen-only and combination-HRT for the prevention of chronic disease

indicate that the adverse outcomes associated with long-term use outweigh the potential diseaseprevention benefits particularly for women older than 65 years. Conversely, late menarche,

anovulation, and early menopause (spontaneous or induced) are protective, owing to their effecton lowering endogenous estrogen levels or shortening the duration of estrogenic exposure.

Table 1. Risk Factors for Breast Cancer

Risk Factors Estimated Relative Risk

Advanced age >4


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Family history

Two or more relatives (mother, sister)One first-degree relative

Family history of ovarian cancer in women 5>2

>2

Personal history

Personal historyPositiveBRCA1/BRCA2 mutationBreast biopsy with atypical hyperplasia

Breast biopsy with LCIS or DCIS

3-4>44-5

8-10

Reproductive historyEarly age at menarche (30 y)/nulliparity

Use of combined estrogen/progesterone HRTCurrent or recent use of oral contraceptives

2

1.5-22

1.5-21.25

Lifestyle factors

Adult weight gainSedentary lifestyle

Alcohol consumption

1.5-21.3-1.5

1.5

Risk assessment models

There has been a concerted effort by several groups to develop multivariate methods to derive a

Breast Cancer Risk Assessment Tool using sets of risk factors (genetic and other) that areinformative for estimating the risk of breast cancer. Two types of risk models have been

developed that are clinically relevantthose that estimate a womans absolute risk of developingbreast cancer over time and those that determine the likelihood that an individual is a carrier of a

BRCA1,BRCA2, or unknown gene mutation (ie,BRCA1/2 probability models).

The most commonly used BRCAPRO model identifies approximately 50% of mutation-negativefamilies but fails to screen 10% of mutation carriers. The BRCAPRO model, along with others

(ie, Myriad I and II, Manchester, Breast and Ovarian Analysis of Disease Incidence and CarrierEstimation Algorithm[BOADICEA], and Ontario Family History Assessment Tool [FHAT])

were developed using mutation rates in Ashkenazi Jewish families and families of Europeandescent but have recently been validated in African American and Hispanic populations. The

U.S. Preventive Services Task Force (USPSTF) does not specifically endorse any of thesegenetic risk assessment models because of insufficient data to evaluate their applicability to

asymptomatic, cancer-free women. The USPSTF does support the use of a greater than 10% riskprobability for recommending further evaluation with an experienced genetic counselor for

decisions regarding genetic testing.

In contrast to BRCA probability tools, risk prediction models are designed to derive individual

risk estimates for the development of breast cancer over time. The Gail Model was originallydeveloped in 1989 from data derived from the Breast Cancer Detection and Demonstration


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Project (BCDDP). It was developed to estimate the probability of developing breast cancer overa defined age interval and was originally intended to improve screening guidelines. The model

was subsequently revised (Gail Model 2) and validated to predict risk of invasive breast cancerincluding information on the history of first-degree affected family members. The Gail Model 2

has been used extensively in clinical practice and has served as the basis of eligibility for a

number of the breast cancer prevention trials.

At present, the U.S. FDA guidelines use the National Surgical Adjuvant Breast and Bowel

Projects (NSABP) modified Gail model as the basis for eligibility for the prophylactic use oftamoxifen. Tamoxifen is approved for women aged 35 years and older who have a 5-year Gail

risk of breast cancer of 1.67% or more. The Gail Model 2 also forms the basis of the U.S.National Cancer Institutes Breast Cancer Risk Assessment Tool.

The Gail Model 2 is most accurate for non-Hispanic White women who receive annual

mammograms, but the model tends to overestimate risk in younger women who do not receiveannual mammograms. The model also demonstrates reduced accuracy in populations with

demographics (age, race, screening habits) that differ from the population on which it was built.At the individual level, the model lacks adequate discrimination in predicting risk and has been

challenged on its generalizability across populations.

To address concerns regarding applicability of the Gail Model to African American women, Gail

and colleagues have derived a CARE Model using data from a large case control study ofAfrican American women participating in the Womens Contraceptive and Reproductive

Experiences (CARE) Study. The CARE Model demonstrated high concordance between thenumbers of breast cancer predicted and the number of breast cancers observed among African

American women when validated in the WHI cohort.

Improvements in risk prediction and clinical tools are likely to emerge in the next few years withthe addition of such factors as breast density, mammographic density change across exams, use

of HRT, and a variety of other factors such as weight, age at birth of first live child, and numberof first-degree relatives with breast cancer. Going forward, it is likely that there will be models

specifically for risks of premenopausal versus postmenopausal cancers and for specific breastcancer subtypes (luminal versus basal).

Genetic factors

While 20-30% of women with breast cancer have at least one relative with a history of breastcancer, only 5-10% of women with breast cancer have an identifiable hereditary predisposition.

BRCA1 andBRCA2 mutations are responsible for 3-8% of all cases of breast cancer and 15-20%of familial cases. Rare mutations are seen in thePTEN, TP53, MLH1, MLH2, and STK11 genes.

TheBRCA1 andBRCA2 gene mutations, on chromosome 17 and 13, respectively, account for

the majority of autosomal dominant inherited breast cancers. Both genes are believed to be tumorsuppressor genes whose products are involved with maintaining DNA integrity and

transcriptional regulation.


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Mutation rates may vary by ethnic and racial groups. ForBRCA1 mutations, the highest ratesoccur among Ashkenazi Jewish women (8.3%) followed by Hispanic women (3.5%), non-

Hispanic white women (2.2%), African American women (1.3%), and Asian American women(0.5%). Moreover, 95% of Ashkenazi Jews with aBRCA gene mutation will have one of the 3

founder mutations (185delAG, 538insC inBRCA1 and 6174delT inBRCA2). Women who

inherit a mutation in theBRCA1 orBRCA2 gene have an estimated 50-80% lifetime risk ofdeveloping breast cancer.

Specifically,BRCA1 mutations are seen in 7% of families with multiple breast cancers and 40%

of families with breast and ovarian cancer. People with aBRCA1 mutation have a lifetime risk of

40% for developing ovarian cancer and are also at a higher risk of colon cancer and prostatecancer. Breast cancer that develops inBRCA1 mutation carriers are more likely to be high-grade,

and ER, PR, and HER-2/neu negative (triple negative) or basal-like subtype.

BRCA2 mutations are identified in 10-20% of families at high risk for breast and ovarian cancersand in only 2.7% of women with early-onset breast cancer. Women with aBRCA2 mutation have

approximately 10% lifetime risk of ovarian cancer.BRCA2 mutation carriers who develop breastcancer are more likely to have a high grade, ER+/PR+, and HER-2/neu negative cancer (luminal

type).BRCA2 is also a risk factor for male breast cancer.

Other cancers associated withBRCA2 mutations include prostate, pancreatic, fallopian tube,

bladder, non-Hodgkin lymphoma, and basal cell carcinoma.

Li-Fraumeni syndrome, caused by TP53 mutations, is associated with multiple cancers,including the SBLLA syndrome (sarcoma, breast and brain tumors, leukemia, and laryngeal and

lung cancer). Cancer susceptibility is transmitted in an autosomal dominant pattern, with alifetime risk of breast cancer of 90%. Li-Fraumeni syndrome is responsible for approximately

1% of cases of familial breast cancer. Bilateral breast cancer is noted in up to 25% of patients.

Cowden disease is a rare genetic syndrome caused byPTENmutations. It is associated withintestinal hamartoma, cutaneous lesions, and thyroid cancer. The prevalence rate of breast cancer

in women with this disease is approximately 30%. Benign mammary abnormalities (eg,fibroadenomas, fibrocystic lesions, ductal epithelial hyperplasia, and nipple malformations) are

also common. Other rare genetic disorders, such as Peutz-Jeghers and hereditary nonpolyposiscolorectal carcinoma (HNPCC), are associated with an increased risk of breast cancer.

Breast cancer screening

Early detection remains the primary defense available to patients in preventing the development

of life-threatening breast cancer. Breast tumors that are smaller or nonpalpable are more treatablewhen detected and thus have a more favorable prognosis. The survival benefit of early detection

with mammography screening has been demonstrated. Therefore, early detection is widelyendorsed by organizations that issue clinical recommendations for breast cancer care. For women

younger than 40 years, monthly breast self-examination practices and clinical breast exams every3 years are recommended, beginning at age 20 years.

The most widely recommended approach in the United States has been annual screening


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mammography beginning at age 40 years.[3 ]

In November 2009, however, the U.S. PreventiveServices Task Force (USPSTF) issued updated breast cancer screening guidelines that

recommend against routine mammography before age 50 years. Instead, for women 40 to 49years of age, the USPSTF suggests that the decision to start regular screening mammography be

individualized and should include the patient's values regarding specific benefits and harms

(Grade C recommendation).

[4 ]

In addition, rather than annual screening, the USPSTF guidelines recommend that screening

mammography be performed biennially (Grade B recommendation). The USPSTF concludesthat there is currently insufficient evidence to assess the additional benefits and harms of

screening mammography in women 75 years or older and thus recommends stopping screeningat age 74 years.

[4 ]

In response, the American College of Obstetricians and Gynecologists (ACOG) has stated that

while it is evaluating the USPSTF guidelines in detail, for the present it continues to recommendadherence to current ACOG guidelines. These include screening mammography every 1-2 years

for women aged 40-49 years and screening mammography every year for women age 50 orolder.[5 ]

The ACOG notes, however, that because of the USPSTF downgrading, some insurers

may no longer cover some of these studies.

Breast self-examination (BSE) and clinical breast examination (CBE)

Both breast self-examination and clinical breast examination involve inexpensive andnoninvasive procedures for the regular examination of breasts (ie, monthly for breast self-

examination and annually for clinical breast examination). Evidence supporting the effectivenessof breast self-examination and clinical breast examination are controversial and largely inferred.

Even with appropriate training, breast self-examination has not been found to reduce breast

cancer mortality. However, with increasing improvements in treatment regimens for early,localized disease, breast self-examination and clinical breast examination, particularly among

women younger than 40 years, continues to be recommended. Most recently, randomized clinicaltrial results support combining clinical breast examination with mammography to enhance

screening sensitivity, particularly in younger women in whom mammography may be lesseffective and in women who receive mammograms every other year as opposed to annually.

In 2002, the USPSTF found that there was inadequate evidence to make a recommendation on

teaching or performing BSE. The 2009 USPSTF guidelines recommend against teaching womenhow to perform BSE (Grade D recommendation), based on studies that found that teaching BSE

did not reduce breast cancer mortality but instead resulted in additional imaging procedures andbiopsies.[4 ]At present, however, the ACOG continues to recommend counseling patients that

BSE has the potential to detect palpable breast cancer and can be performed.[5 ]

Mammography

Mammography has been demonstrated to be an effective tool for the prevention of advanced

breast cancer in women at average risk. Mammography is currently the best available


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population-based method to detect breast cancer at an early stage when treatment is mosteffective. Mammography often reveals a lesion before it is palpable by clinical breast

examination and, on average, 1-2 years before noted by breast self-examination. Recentadvances in mammography include the development of digital mammography and the increased

use of computer-aided diagnosis (CAD) systems. CAD systems have been developed to help the

radiologist identify mammographic abnormalities. Digital mammography allows the image to berecorded and stored. Using computer technology, digital mammogram images can be magnifiedand the image modified to improve evaluation of specific areas in question.

The USPSTF estimates the benefit of mammography in women aged 50-74 years to be a 30%

reduction in risk of death from breast cancer. For women aged 40-49 years, the risk of death isdecreased by 17%. Although mammography guidelines have been in place for over 30 years, 20-

30% of women still do not undergo screening as indicated. The two most significant factors for awoman to undergo mammography are physician recommendation and access to health insurance.

Non-white women and those of lower socioeconomic status remain less likely to obtainmammography services and more likely to present with life-threatening, advanced-stage disease.

Alternative screening modalities and future directions

While mammography remains the most cost-effective approach for breast cancer screening, thesensitivity (67.8%) and specificity (75%) are not ideal. As reported, mammography combined

with clinical breast examination slightly improves sensitivity (77.4%) with a modest reduction inspecificity (72%). Comparisons between recently introduced digital mammography and screen-

film mammography suggest that the sensitivity of full-field digital mammography is superior toscreen film mammography in certain subsets of women. For example, digital mammography

demonstrates improved detection rates for younger women and for women with more densebreasts. Improved imaging modalities with greater sensitivity are of particular benefit for women

at the highest risk and for women whose breast images are difficult to interpret.

Ultrasound has become a widely available and useful adjunct to mammography in the clinicalsetting. Ultrasound is generally used to assist the clinical examination of a suspicious lesion

detected via mammogram or physical examination. As a screening device, the ultrasound islimited by a number of factors, but most notably by the failure to detect microcalcifications and

poor specificity (34%).

In an effort to overcome the limitations of mammography and ultrasound, magnetic resonanceimaging (MRI) has been explored as a modality for detecting breast cancer in women at high risk

and in younger women. A combination of T-1, T-2, and 3-D contrast-enhanced MRI techniqueshas been found to be highly sensitive (approximating 99% when combined with mammogram

and clinical breast examination) to malignant changes in the breast.

MRI has been demonstrated to be an important adjunct screening tool for women withBRCA1 or

BRCA2 mutations identifying cancers at earlier stages. However, breast MRI has limited use as ageneral screening tool with a 10-fold higher cost than mammography and poor specificity (26%),

resulting in significantly more false-positive reads that generate significant additional diagnostic


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costs and procedures. Below are the criteria for using breast MRI screening per the AmericanCancer Society (ACS).

[6 ]

y Recommend annual breast MRI screening (evidence based, evidence fromnonrandomized trials and observational studies)

oBRCA mutation

o First-degree relative ofBRCA carrier, but untestedo Lifetime risk approximately 20-25% or greater as defined by BRCAPRO or other

risk modelsy Recommend annual breast MRI screening (based on evidence of lifetime risk of breast

cancer)o Radiation to chest when aged 10-30 yearso Li-Fraumeni syndrome and first-degree relativeso Cowden and Bannayan-Riley-Ruvalcaba syndromes and first-degree relatives

y Insufficient evidence to recommend for or against MRI screeningo Lifetime risk 15-20%, as defined by BRCAPRO or other risk modelso

Lobular carcinoma in situ or atypical lobular hyperplasia (ALH)o Atypical ductal hyperplasia (ADH)o Heterogeneously or extremely dense breast on mammographyo Women with a personal history of breast cancer, including ductal carcinoma in

situ

The American Cancer Society does not recommend the use of breast MRI in women who haveless than 15% lifetime risk. Among those with average risk, a combination of clinical breast

examinations and yearly mammograms is recommended.

Pharmacologic breast cancer risk reduction

Two selective estrogen receptor modulators (SERMs), tamoxifen and raloxifene, are approvedfor reduction of breast cancer risk in high-risk women. Two National Surgical Adjuvant Breast

and Bowel Project (NSABP P1 and P2) trials showed that tamoxifen reduced the risk of ductalcarcinoma in situ (DCIS) and invasive breast cancer by 30-50%. In the NSABP P2 prevention

trial, raloxifene was as effective as tamoxifen in reducing the risk of invasive breast cancer butwas 30% less effective than tamoxifen in reducing the risk of DCIS.

The American Society of Clinical Oncology (ACOG) has updated their practice guidelines

regarding pharmacologic intervention (eg, tamoxifen, raloxifene, aromatase inhibition) for breastcancer risk reduction.

[7 ]Some of the highlights of the expert panel's literature review are as

follows:

y Tamoxifen use for 5 years reduces risk for at least 10 years in premenopausal women,particularly estrogen receptor (ER) positive invasive tumors.

o Women 50 years or younger have few adverse effects with tamoxifen.o Vascular/vasomotor adverse effects do not persist post treatment.

y Tamoxifen and raloxifene are equally effective in reducing risk of ER-positive breastcancer in postmenopausal women.


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o Raloxifene is associated with lower rates of thromboembolic disease, benignuterine conditions, and cataracts than tamoxifen.

o Evidence does not exist regarding whether either agent decreases mortality frombreast cancer.

y Recommendationso

For women with increased risk for breast cancer, offer tamoxifen (20 mg/d for 5y) to reduce risk of invasive ER-positive breast cancer.o In postmenopausal women, raloxifene (60 mg/d for 5 y) may also be considered.o Aromatase inhibitors (eg, anastrozole, exemestane, letrozole), fenretinide, or other

SERMs are not recommended outside of a clinical trial.

Presentation

Breast cancer is often first detected as an abnormality on a mammogram before it is felt by the

patient or health care provider. Mammographic features suggestive of malignancy includeasymmetry, microcalcifications, a mass, or architectural distortion. If any of these features are

identified, a diagnostic mammogram along with a breast ultrasound should be performed prior toobtaining a biopsy. In certain cases, a breast MRI may be warranted. Larger tumors may present

as a painless mass. Only 5% of patients with a malignant mass present with breast pain. Othersymptoms include immobility, skin changes (ie, thickening, swelling, redness) or nipple

abnormalities (ie, ulceration, retraction, spontaneous bloody discharge). See Breast CancerEvaluation.

Workup

Diagnostic Procedures

Percutaneous vacuum-assisted large gauge core biopsies with image guidance are therecommended diagnostic approach for newly diagnosed breast cancers. Image guided breast

biopsy may be performed with ultrasound, stereotactic, or MRI guidance. Core biopsies spare theneed for operative intervention (and subsequent scarring), often providing pathological results

quicker than surgical excisions. Additionally, excisional biopsy, as the initial operative approach,has been shown to increase the rate of positive margins. Thus, core biopsies for diagnosing

breast cancer can eliminate the need for additional surgeries for definitive margin control andassessment of nodal status.

In some cases, a breast mass may be palpable but not correlate with imaging by either ultrasoundor mammogram. Under this circumstance, palpation directed core biopsy, fine needle aspiration,

or open excisional biopsy may be required to diagnose a suspicious palpable breast mass.Typically, patients who undergo a core needle biopsy, whether directed by imaging studies or

palpation, have a titanium marker clip placed at the biopsy site. These clips are particularlyhelpful when planning a lumpectomy for non-palpable breast lesions that require preoperative

image-guided wire-localization or for patients who undergo neoadjuvant chemotherapy, resultingin a pathological complete response. Complications of a diagnostic core or excisional biopsy

include hematoma, infection, scarring, re-operation, and sampling error resulting in inaccuratediagnosis.


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Histologic Findings

Ductal carcinoma in situ (DCIS)

Increased use of screening mammography has resulted in a dramatic increase in the detection of

DCIS. Approximately 64,000 cases of DCIS are diagnosed annually in the United States. Today,90% of DCIS cases are identified on mammography as suspicious calcifications, linear,clustered, segmental, focal, or mixed distribution. DCIS is divided into comedo (ie, cribriform,

micropapillary, solid) and noncomedo subtypes, which provides additional prognosticinformation regarding likelihood of progression or local recurrence.

Table 3. Ductal Carcinoma in Situ Subtypes

DCIS Characteristic Comedo Noncomedo

Nuclear grade High Low

Estrogen receptor Negative Positive

HER2/neu overexpression Present Absent

Distribution Continuous Multifocal

Necrosis Present Absent

Local recurrence High Low

Prognosis Worse Better

However, mammography often underestimates the multifocality and extent of DCIS. This has ledto the use of breast MRI for the detection and staging of DCIS. Several studies, however, have

demonstrated high sensitivity and low specificity for MRI in the detection of DCIS leading tounnecessary biopsies and more aggressive surgeries. Currently, the standard treatment of DCIS is

surgical resection with or without radiation. Adjuvant radiation and hormonal therapies are oftenreserved for younger women, patients undergoing lumpectomy, or comedo subtype.

Approximately 30% of women with DCIS in the United States are treated with mastectomy withor without reconstruction, 30% with conservative surgery alone, and 40% with conservative

surgery followed by whole-breast radiation therapy. Axillary or sentinel lymph node dissection isnot routinely recommended for patients with DCIS. Current studies have identified metastatic

disease to the axillary node in 10% of patients. In DCIS, whole-breast radiotherapy is deliveredover 5-6 weeks after surgery, reducing the local recurrence rate by approximately 60%. Roughly

50% of local recurrences are invasive breast cancer. Meta-analyses of randomized controlledtrials comparing radiation therapy versus observation after surgery for DCIS have demonstrated

slightly higher rates of contralateral breast cancer after radiation therapy (3.85% vs 2.5%).Studies comparing accelerated partial breast radiation given over 5 days to standard whole breast

radiotherapy are currently underway.

Tamoxifen is the only hormonal therapy currently approved for adjuvant therapy in patientstreated with breast-conserving surgery and radiation for DCIS. Currently, a clinical trial

evaluating the role of the aromatase inhibitor anastrozole as adjuvant therapy in DCIS has met its


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accrual and results are anticipated.

Lobular carcinoma in situ (LCIS)

LCIS arises from the terminal duct apparatus and shows a rather diffuse distribution throughout

the breast, which explains its presentation as a non-palpable mass in most cases. Over the last 25years, LCIS incidence has doubled and is now 2.8% per 100,000 women. The peak incidence isin women aged 40-50 years. Because LCIS is nonpalpable, it has no consistent features on breast

imaging and is most often an incidental finding associated with a breast biopsy performed for anunrelated mammographic abnormality. Approximately, 10-20% of women with LCIS develop

invasive breast cancer within 15 years from their LCIS diagnosis. Thus, LCIS is considered abiomarker of increased breast cancer risk. Treatment options for LCIS include chemoprevention

with a SERM, bilateral mastectomy with or without reconstruction, and close observation.

Other invasive breast cancer histology

y Medullary carcinoma: Medullary carcinoma is relatively uncommon (5%) and generallyoccurs in younger women. Most patients present with a bulky palpable mass with axillarylymphadenopathy. Diagnosis of this type of breast cancer depends on a histologic triad of

(1) sheets of anaplastic tumor cells with scant stroma, (2) moderate or marked stromallymphoid infiltrate, and (3) histologic circumscription or a pushing border. DCIS may be

observed in the surrounding normal tissues. ER, PR, and HER2/neu are typicallynegative, and TP53 is commonly mutated. Roughly 30% of patients have lymph node

metastasis. Typical or classic medullary carcinomas are often associated with a goodprognosis despite the unfavorable prognostic features associated with this type of breast

cancer. However, a recent analysis of 609 medullary breast cancer specimens fromvarious stage I and II NSABP protocols indicate that overall survival and prognosis are

not as good as previously reported.y Mucinous carcinoma: Mucinous carcinoma is another rare histologic type seen in fewer

than 5% of invasive breast cancer cases. It usually presents during the seventh decade oflife. It often presents as a palpable mass or mammographically as a poorly defined tumor

with rare calcifications. Mucin production is the histologic hallmark with 2 main forms,type A and B, with AB lesions possessing features of both. Type A mucinous carcinoma

represented the classic variety with larger quantities of extracellular mucin, whereas typeB is a distinct variant with endocrine differentiation. DCIS is not a frequent occurrence,

though it may be found. Most cases are ER and PR positive, but HER2/neuoverexpression is rare. Additionally, these carcinomas predominantly express

glycoproteins MUC2 and MUC6. Overall, patients with mucinous carcinoma have anexcellent prognosis (>80% 10-year survival).

y Tubular carcinoma: Tubular carcinoma of the breast is an uncommon histologic typeinvolving 1-2% of all breast cancers. Characteristic features of this type include a singlelayer of epithelial cells with low-grade nuclei and apical cytoplasmic snoutings arranged

in well-formed tubules and glands. Tubular components comprise more than 90% of puretubular carcinomas and at least 75% of mixed tubular carcinomas. This type of breast

cancer has a low incidence of lymph node involvement and a very high overall survivalrate. Because of its favorable prognosis, patients are often treated with only breast-

conserving surgery and local radiation therapy.


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y Papillary carcinomao Papillary carcinoma of the breast encompasses a spectrum of histological

subtypes. There are two common types: cystic (noninvasive form) andmicropapillary ductal carcinoma (invasive form). This form of breast cancer is

usually seen in women older than 60 years and accounts for approximately 1-2%

of all breast cancers. Papillary carcinomas are centrally located in the breast andcan present with bloody nipple discharge. They are strongly ER and PR positive.o Cystic papillary carcinoma has a low mitotic activity, which results in a more

indolent course and good prognosis. However, invasive micropapillary ductalcarcinoma has a more aggressive phenotype even though approximately 70% of

cases are ER positive. A retrospective review of 1400 cases of invasive carcinomaidentified 83 cases (6%) with at least one component of invasive micropapillary

ductal carcinoma. Additionally, lymph node metastasis is frequently seen in thissubtype (70-90% incidence), and the number of lymph nodes involved appears to

correlate with survival.y Metaplastic breast cancer (MBC)

oMBC accounts for less than 1% of breast cancer cases. It is characterized by acombination of adenocarcinoma plus mesenchymal and epithelial components. A

wide variety of histological patterns include spindle-cell carcinoma,carcinosarcoma, squamous cell carcinoma of ductal origin, adenosquamous

carcinoma, carcinoma with pseudosarcomatous metaplasia, and matrix-producingcarcinoma. This diverse group of malignancies is identified as a single entity

based on a similarity in clinical behavior. When compared with infiltrating ductalcarcinoma, metaplastic breast cancer tumors are larger, more rapidly growing,

commonly node negative, and typically ER, PR, and HER-2 negative. The diseasetends to occur in older women with an average age of onset in the sixth decade

and has a higher incidence in African Americans.o The majority of published case series have demonstrated a worse prognosis for

metaplastic breast cancer as compared to infiltrating ductal carcinoma, even whenadjusted for stage, with a 3-year overall survival rate of 48-71% and 3-year

disease-free survival rate of 15-60%. In most case series, large tumor size andadvanced stage have emerged as predictors of poor overall survival and prognosis.

Nodal status does not appear to impact survival in metaplastic breast cancer.o Surgery is used to treat up to 95% of women with metaplastic breast cancer. Few

data support the effectiveness of systemic chemotherapy in patients withmetaplastic breast cancer and its use has been extrapolated from the treatment of

more common types of breast cancer. A review of chemotherapy and response ina series of 27 patients with metaplastic breast cancer found only one partial

response with a doxorubicin-containing regimen in the setting of metastaticdisease. As in soft-tissue sarcomas, metaplastic breast cancer shows a tendency

for local recurrence and for hematogenous spread to lung, liver, and bone.y Mammary Paget disease (MPD)

o MPD is relatively rare, comprising 1-4% of all breast cancers. Peak incidence isseen in the sixth decade of life (mean age 57 y). This adenocarcinoma is localized

within the epidermis of the nipple-areola complex and composed of the histologichallmark, Paget cells, within the basement membrane. Paget cells are large, pale


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epithelial cells with hyperchromatic, atypical nucleus, dispersed between thekeratinocytes as a single or cluster of cells. Lesions are predominantly unilateral

developing insidiously as a scaly, fissured, oozing, or erythematous nipple-areolacomplex. Retraction or ulceration of the nipple is often noted, along with

symptoms of itching, tingling, burning, or pain.o

Mammary Paget disease is associated with an underlying breast cancer in 75% ofcases. Standard treatment of mammary Paget disease is surgical excision(modified radical mastectomy with lymph node excision). Breast conserving

surgery can achieve satisfactory results, but at the risk of local recurrence.Adjuvant chemotherapy with tamoxifen may increase survival in premenopausal

patients with lymph node metastasis. Poor prognostic factors include a palpablebreast tumor, lymph node involvement, histological type, and patient younger

than 60 years. The overall 5-year and 10-year survival rates are 59% and 44%,respectively.

Prognostic and predictive factors

Numerous prognostic and predictive factors for breast cancer have been identified by the College

of American Pathologists to guide the clinical management of women with breast cancer. Breastcancer prognostic factors include the following:

y Axillary lymph node statusy Tumor sizey Lymphatic/vascular invasiony Patient agey Histologic gradey Histologic subtypes (eg, tubular, colloid [mucinous], papillary)y

Response to neoadjuvant therapyy Estrogen receptor/progesterone receptor statusy Her2/neu gene amplification and/or overexpressiony Breast cancer predictive factors include the following:y Estrogen receptor/progesterone receptor statusy Her2/neu gene amplification and/or overexpressiony Lymph node status: Fluid from the breast tissue normally drains into the lymph nodes

located in the axilla. Cancerous involvement of these nodes is an indication of the

likelihood that the breast cancer has spread to other organs. Axillary nodal involvementand survival have been evaluated relative to the number and sites in breast cancer

patients. For any given number of positive nodes, survival was independent of the levelof involvement but directly related to the number of involved nodes. Patients with node-

negative disease have an overall 10-year survival rate of 70% and 5-year recurrence rateof 19%. As the number of positive nodes increase, so does the probability of relapse.

With 1-3 positive nodes, the recurrence rate at 5 years is 30-40%. Four to 9 positivenodes have a recurrence rate of 44-70%. Patients with more than 10 positive lymph nodes

have a recurrence rate of 72-82%.y Hormone receptor status: Estrogen receptor (ER) and progesterone receptor (PR) assays

are routinely performed by pathologists on tumor material. Immunohistochemistry (IHC)


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is a semiquantitative technique that is observer and antibody dependent. In general,hormone-positive tumors have a more indolent course and are responsive to hormonal

therapy.y HER2

o Eighteen to twenty percent of invasive breast cancers overexpress HER2, whichhas both prognostic and predictive implications. Prior to the routine use ofadjuvant trastuzumab therapy, HER2 overexpression was associated with a moreaggressive tumor phenotype and worse prognosis (higher rate of recurrence and

mortality) especially in patients who do not receive adjuvant chemotherapy.Additionally, HER2 status has been shown to be predictive for response to certain

chemotherapeutic agents (ie, doxorubicin, and HER2 targeted therapies,trastuzumab, a monoclonal antibody, and lapatinib, a small molecule oral tyrosine

kinase inhibitor) directed specifically to the HER2 receptor. Retrospectivelyanalyzed results from clinical trials have shown HER2-positive patients benefit

from anthracycline-based regimens secondary to the co-amplification oftopoisomerase II with HER2. Preliminary data also suggest that HER2 may

predict response and benefit from paclitaxel in the adjuvant setting.o A recent phase III, double-blind, randomized study evaluated the efficacy of

lapatinib in HER2-negative and HER2 uncharacterized metastatic breast cancer.The study concluded that while patients with HER2-negative or HER2-untested

metastatic breast cancer did not experience benefit from the addition of lapatinibto paclitaxel, first-line therapy with paclitaxel-lapatinib significantly improved

clinical outcomes in patients who were HER2-positive.[8 ]

o Several methods for HER2 testing have been developed. Since approximately

20% of current HER2 testing may be inaccurate, the American Society of ClinicalOncology and the College of American Pathologists have recommended

guidelines in HER2 testing to ensure accuracy. Breast cancer specimens shouldinitially undergo HER2 testing by a validated immunohistochemistry assay (ie,

DAKO Hercep Test [DAKO Cytomation]) for HER2 protein expression.[9 ]Thescoring method for HER2 expression is based on the cell membrane staining

pattern and is listed below. 3+: Positive HER2 expression - Uniform intense membrane staining of

more than 30% of invasive tumor cells 2+: Equivocal for HER2 protein expression Complete membrane

staining that is either nonuniform or weak in intensity but hascircumferential distribution in at least 10% of cells

0 or 1+: Negative for HER2 protein expressiono Breast cancer specimens with equivocal immunohistochemistry should undergo

validation using a HER2 gene amplification method (ie, fluorescence in situhybridization [FISH]). More centers are relying on FISH alone for determining

HER2 status. In general, FISH testing is thought to be more reliable, but it is moreexpensive than immunohistochemistry. Newer methodologies for establishing

HER2 status including RT-PCR and CISH (chromogenic in situ hybridization)have not yet been validated. Equivocal immunohistochemistry results can be seen

in 15% of invasive breast cancers. The interpretation for HER2 FISH testing(HER2/CEP17 ratio and gene copy number) is given below.


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PositiveHER2 amplification: FISH ratio greater than 2.2 orHER2 genecopy greater than 6.0

EquivocalHER2 amplification: FISH ratio 1.8-2.2 orHER2 gene copy4.0-6.0

Negative HER2 amplification: FISH less than 1.8 orHER2 gene copy lessthan 4.0

o Discordant results (IHC3+/FISH negative or IHC less than 3+/FISH positive)have been observed in approximately 4%. EquivocalHER2 FISH results are seen

in less than 3% of invasive breast cancer specimens and had previously beenconsideredHER2 positive. Currently, no data support excluding this group from

treatment with trastuzumab.y Oncotype DX

o The Oncotype Dx assay (Genomic Health, San Francisco, Calif) is a reversetranscriptase-polymerase chain reaction (RT-PCR)-based assay of 21 genes (16

cancer genes and 5 reference genes) performed on paraffin-embedded breasttumor tissue. Using a formula based on the expression of these genes, a

recurrence score (RS) can be calculated that correlates with the likelihood ofdistant recurrence at 10 years. Breast tumors with a recurrence score of less than

18 are considered low risk, recurrence score of 18-30 intermediate-risk, and morethan 30 are high risk. Currently, Oncotype Dx has been validated and FDA

approved in women with early-stage, ER-positive, node-negative breast cancertreated with tamoxifen where the recurrence score correlated with both relapse-

free interval and overall survival. Furthermore, the Oncotype Dx assay has beenshown to predict benefit from chemotherapy and hormonal therapy in hormone-

sensitive, node-negative tumors retrospectively in the NSABP B-14 and B-20studies.

o Women with low recurrence score showed a significantly higher improvement indisease-free survival (DFS) with the addition of tamoxifen versus chemotherapy.

Whereas, women with a high recurrence score had a significant improvement indisease-free survival by adding chemotherapy. Among women with 1-3 node-

positive, hormone receptor-positive disease, the Oncotype Dx recurrence scorewas a significant predictor of recurrence, with a 21% decrease in recurrence risk

for each 10-point drop in recurrence score. In general, results from these studieswould indicate a selective group of node-positive, hormone receptor-positive

patients with a low recurrence score would not benefit from an anthracyclinebased regimen. The benefit of adding chemotherapy to hormonal therapy in

tumors with an intermediate score is still controversial, and a large prospective,randomized phase III study (TAILORx Trial) is addressing this important

question.

Staging

The American Joint Committee on Cancer staging system groups patients based on the tumorsize (T), lymph node status (N), and distant metastasis (M) into 4 stages.

y Primary tumor (T)


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o Tx: Primary tumor cannot be assessedo T0: No evidence of primary tumoro Tis: (DCIS) Carcinoma in situo Tis: (LCIS) Carcinoma in situo Tis: Paget disease of the nipple with no tumor (Paget disease associated with a

tumor is classified according to the size of the tumor.)o T1: Tumor 2 cm or smaller in greatest diameter

T1mic: Microinvasion 0.1 cm or less in greatest dimension T1a: Tumor >0.1 but not >0.5 cm in greatest diameter T1b: Tumor >0.5 but not >1 cm in greatest diameter T1c: Tumor >1 cm but not >2 cm in greatest diameter

o T2: Tumor >2 cm but not >5 cm in greatest diametero T3: Tumor >5 cm in greatest diametero T4: Tumor of any size, with direct extension to (a) the chest wall or (b) skin only,

as described below T4a: Extension to the chest wall, not including the pectoralis muscle

T4b: Edema (including peau dorange) or ulceration of the skin of thebreast or satellite skin nodules confined to the same breast

T4c: Both T4a and T4b T4d: Inflammatory disease

y Regional lymph nodes (N)o Nx: Regional lymph nodes cannot be assessed (eg, previously removed)o N0: No regional lymph node metastasiso N1: Metastasis in movable ipsilateral axillary lymph node(s)o N2: Metastasis in ipsilateral axillary lymph node(s) fixed or matted, or

in clinically apparent ipsilateral internal mammary nodes in the absence

of clinically evident axillary lymph node metastasis N2a: Metastasis in ipsilateral axillary lymph nodes fixed to one another or

to other structures N2b: Metastasis only in clinically apparent ipsilateral internal mammary

nodes and in the absence of clinically evident axillary lymph nodeso N3: Metastasis in ipsilateral infraclavicular or supraclavicular lymph node(s) with

or without axillary lymph node involvement, or clinically apparent ipsilateralinternal mammary lymph node(s) and in the presence of axillary lymph node

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)

y Distant metastasiso Mx: Distant metastasis cannot be assessedo M0: No distant metastasiso M1: Distant metastasis

Table 2. TNM Staging System for Breast Cancer


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Stage TumorNode Metastases

Stage 0 Tis N0 M0

Stage I T1 N0 M0

Stage IIA T0

T1T2

N1

N1N0

M0

M0M0

Stage IIB T2

T3

N1

N0

M0

M0

Stage IIIA T0T1

T2T3

N2N2

N2N1-2

M0M0

M0M0

Stage IIIB T4

T4T4

N0

N1N2

M0

M0M0

Stage IIIC Any T N3 M0

Stage IV Any T Any N M1

Five-year survival rates are highly correlated with tumor stage, 99-100% for stage 0, 95-100%

for stage I, 86% for stage II, 57% for stage III, and 20% for stage IV. This prognosticinformation can guide physicians in making therapeutic decisions. Pathologic review of the

tumor tissue for histological grade along with the determination of estrogen/progesteronereceptor (ER/PR), HER2 status, and lymph node involvement as determined by sentinel lymph

node biopsy or axillary lymph node dissection is necessary for determining prognosis.

See also the Best Evidence rated reference, Trends in survival over the past two decades among

white and black patients with newly diagnosed stage IV breast cancer.[10 ]

The National Cancer Center Network (NCCN) guideline recommends a history and physicalexamination followed by laboratory studies (CBC with differential, liver and renal function tests,

and calcium levels) for all asymptomatic women with early stage breast cancer (Stage I and II).Women with stage III (locally advanced or inflammatory breast cancer) or symptomatic disease

should have a chest x-ray or CT scan of the chest, CT scan of the abdomen and pelvis, and bonescan for evaluation of distant metastasis. Tumor markers (CEA and CA15.3 or CA27.29) may

also be obtained in these patients.[11 ]

Currently, the use of positron emission tomography (PET) or PET/CT is not indicated in thestaging of clinical stage I, II, or operable stage III breast cancer; however, the use of PET/CT

scans for staging locally advanced and inflammatory breast cancer to assist in identification ofnonaxillary lymph node metastasis (ie, internal mammary or supraclavicular lymph nodes) prior

to starting neoadjuvant therapy is appropriate.

Treatment


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Medical Therapy

TREATMENT OF INVASIVE BREAST CANCER

Surgery is considered primary treatment for breast cancer, as many early stage patients are cured

with surgery alone. The goals of breast cancer surgery include complete resection of the primarytumor with negative margins to reduce the risk of local recurrences and pathologic staging of thetumor and axillary lymph nodes for providing necessary prognostic information. Several

different types of operations are available for the treatment of breast cancer.

Lumpectomy

Lumpectomy is defined as complete surgical resection of a primary tumor with a goal ofachieving widely negative margins (ideally a 1 cm margin around the lesion). Other terms

synonymous for lumpectomy include partial mastectomy, segmental mastectomy, and tylectomy.A quadrantectomy is a type of lumpectomy that is defined as complete removal of the entire

affected breast quadrant. Lumpectomies may be performed with palpation guidance or withimage guidance.

Variations on the theme of image guidance include 1) wire localization of nonpalpable imagedetected lesions via ultrasound, stereotactic, or MRI guidance; 2) hematoma ultrasound guidance

by the operating surgeon; or 3) radioactive seed localization. Patients who undergo alumpectomy for calcifications should always be advised to have a mammogram following their

lumpectomy to establish definitively that all calcifications were successfully removed. Thismammogram should occur prior to the administration of any radiation therapy.

In general, 2 mm or greater is a reasonable definition of a clear margin. Patients with margin

widths less than 2 mm are often advised to return to the operating room for re-excision toimprove local recurrence rates. The rate of surgical re-excision after lumpectomy ranges from

20-60% in the published literature. Contraindications to lumpectomy include multicentricdisease, adverse tumor-to-breast ratio, large primary tumor, repeated positive margins, and

inability to undergo radiation therapy for invasive disease.

The NSABP-B6 was a prospective trial in which 2,163 breast cancer patients were randomizedto modified radical mastectomy (the standard of care at that time), lumpectomy, and whole breast

radiation therapy, or lumpectomy without radiation. All patients underwent axillary lymph nodedissection. At 20-year follow-up, no significant difference was seen in overall survival, disease-

free survival, or distant disease-free survival among the 3 treatment groups. However, the

NSABP-B6 did find a significant difference in the rate of local recurrence between the 3treatment arms. Patients in the lumpectomy alone without radiation therapy group had asignificantly higher local recurrence rate than patients undergoing lumpectomy plus radiation

therapy (39.2% vs 14.3%, respectively). Patients who underwent modified radical mastectomyhad a 10.2% risk of chest wall recurrence. This landmark study established breast-conserving

surgery with radiation therapy to be equivalent to modified radical mastectomy.


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Oncoplastic surgery is a rapidly advancing field that uses local tissue rearrangement toreconstruct a partial mastectomy defect. Options include fasciocutaneous local tissue

advancement flaps, breast parenchymal local flaps or latissimus dorsi myocutaneous flaps. Theselection of aesthetically appropriate incisions also impacts the overall cosmetic result after

lumpectomy. Silverstein et al reported a variety of options for oncoplastic approaches to breast

conservation.

[12 ]

Kronowitz et al reported that partial mastectomy reconstruction producessuperior aesthetic results and lower complication rates when performed prior to radiationtherapy.

[13 ]

Mastectomy

A total mastectomy is defined as complete removal of all breast tissue to the clavicle superiorly,

the sternum medially, the inframammary crease inferiorly, and the anterior axillary line laterallywith en bloc resection of the fascia of the pectoralis major. The nipple-areolar complex (NAC) is

resected along with a skin paddle to achieve a flat chest wall closure when performing a totalmastectomy. A total mastectomy does not refer to removal of any axillary nodes but may be

performed in conjunction with a sentinel or axillary node dissection. A modified radicalmastectomy is defined as a total mastectomy with axillary lymph node dissection. In contrast, a

radical mastectomy is defined as a total mastectomy plus en bloc resection of the pectoralismajor and axillary lymph node dissection. Extended radical mastectomy refers to a radical

mastectomy with resection of the internal mammary lymph nodes.

Two modern variations of the total mastectomy include the skin-sparing total mastectomy (SSM)

and the nipple-sparing total mastectomy (NSM). These operations refer to surgical approachesdesigned for patients who elect to have immediate reconstruction. Both SSM and NSM are

minimally invasive surgical approaches that are technically more difficult and, thus, more time-consuming than traditional mastectomy. SSM and NSM result in preservation of the patients

skin envelope and maintain the position of the infra-mammary fold. However, both SSM andNSM are intended to be complete total mastectomies with the same extent of resection as a

traditional total mastectomy.

These operations may not be appropriate for cancers near the skin or nipple. Additionally, SSMor NSM are not appropriate for locally advanced or inflammatory breast cancer. Multiple

retrospective single institution studies have reported excellent results with SSM and NSM. Norandomized clinical trials compare survival results for SSM, NSM, and total mastectomy.

However, most surgical oncologists accept that as long as SSM and total mastectomy arecarefully performed and patients are carefully selected, these are reasonable oncologic choices

for prophylactic mastectomy and for the treatment of selected early stage breast cancers.Complications after total mastectomy include risk of local recurrence (5-10%), wound infection,

seroma, mastectomy skin flap necrosis, hematoma, chronic pain, incisional dog ears,lymphedema, and fibrosis.

Breast Reconstruction

Breast reconstruction for mastectomy may be performed in the immediate or the delayed setting.Most patients undergoing mastectomies for prophylaxis or early stage breast cancer are


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candidates for reconstruction. Immediate reconstruction, when feasible, generally providessuperior cosmetic results because a SSM or NSM may be offered to selected patients, resulting in

preservation of the native skin envelope and infra-mammary crease. However, whenpostmastectomy radiation is likely or a reconstructive surgeon is unavailable, delayed

reconstruction following all adjuvant therapies may be recommended.

Reconstruction may be performed via implant-based methods, autologous tissue-based (termedflaps) method, or a combination of the two. Implant-based approaches include tissue expanders

and saline or silicone implants. Tissue-based approaches include the transverse rectus abdominusmyocutaneous flap (TRAM), latissimus dorsi flap, and the deep inferior epigastric perforator flap

(DIEP).

Although federal law protects the rights of patients to have reconstruction by mandating thatinsurance companies support reconstruction, most patients undergoing mastectomy do not

undergo breast reconstruction. Reasons for this include provider biases, patient preferences andlack of available specialty services. Patients and physicians should have realistic expectations for

breast reconstruction. Although excellent results may be achieved, often multiple operations arerequired for revisions, symmetry procedures, and nipple reconstruction. Complications related to

reconstruction include infected prosthetic implant, implant rupture, capsular contracture, flapnecrosis, flap loss, fat necrosis, asymmetry, and scarring.

Management of the Contralateral Breast

Patients diagnosed with breast cancer that are not known carriers of a deleteriousBRCA mutationare predicted to have a 0.7% annual risk of contralateral breast cancer. Patients who are known

BRCA mutation carriers have a 3% annual risk of a contralateral breast cancer. The decision forcontralateral prophylactic mastectomy (CPM) is a personal decision for the patient and impacted

by cancer stage, desire for symmetry, comorbidities, histologic risk factors, family history,potential difficult surveillance, and degree of risk aversion. Patients with locally advanced breast

cancers should be discouraged from a contralateral prophylactic mastectomy, as potentialsurgical complications could compromise their oncologic treatments. Mastopexy and reduction

mammoplasty for the contralateral breast are potential alternatives to contralateral prophylacticmastectomy as symmetry procedures.

Sentinel Lymph Node Dissection

Sentinel lymph node (SLN) dissection is a minimally invasive procedure designed to stage theaxilla in breast cancer patients who have clinically negative nodes. Sentinel nodes are the first

node or first group of nodes that drain from the breast to the axilla. Lymphatic mapping may beperformed with radioisotope (technetium99 sulfur colloid) alone or radioisotope plus a patent blue

dye (Lymphazurin or methylene blue). With sentinel lymph node dissection, typically 1-3 lymphnodes are removed and tested for nodal metastasis with hematoxylin and eosin (H&E) stain and

immunohistochemistry (IHC) with an anticytokeratin cocktail.

Sentinel lymph nodes may be checked intraoperatively by imprint touch preparation, frozensection, or RT-PCR. Intraoperative evaluation allows for immediate axillary lymph node


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dissection to be performed if the sentinel lymph node is unequivocally positive for nodalmetastasis. The American Society of Clinical Oncology (ASCO) Guideline Recommendations

for Sentinel Lymph Node Biopsy in early stage breast cancer recommends axillary lymph nodedissection after detection of a positive sentinel lymph node. However, isolated tumor cells

detected by specialized techniques such as immunohistochemistry and RT-PCR remain of

uncertain significance. When sentinel lymph node mapping is not successful, complete axillarylymph node dissection is recommended. Absolute contraindications for sentinel lymph nodedissection include clinically suspicious axillary nodes, which should be evaluated by ultrasound-

guided (FNA), and biopsy-proven node-positive disease.

A recent study evaluated the accuracy of 4 nomograms in patients with sentinal lymph node-positive breast cancer. The authors found the Memorial Sloan-Kettering Cancer Center

nomogram to be more predictive than the other nomograms.[14 ]

Axillary Lymph Node Dissection

Axillary lymph node dissection for breast cancer is a complete en bloc removal of the level I andII lymph nodes. level I nodes are lateral to the pectoralis minor, level II are beneath the pectoralis

minor, and level III are medial to the pectoralis minor. The level III nodes are not removedsurgically unless there is suspicious or palpable adenopathy present. Skip metastasis to the

axillary apex of level III without lower axillary involvement is very rare. Axillary lymph nodedissection removes all nodal tissue defined by the borders of the axillary vein superiorly, the

latissimus dorsi muscle laterally, the medial border of the pectoralis minor muscle medially, andthe subscapularis muscle posteriorly.

Care is taken to preserve the long thoracic and thoracodorsal nerves along their course throughthe axilla. Injury to the long thoracic nerve results in a winged scapula, while injury to the

thoracodorsal nerve compromises internal rotation and abduction of the arm beyond 90 degrees.The median and lateral pectoral nerves may also be injured during axillary lymph node

dissection. The antecostobrachial nerves run directly through the resection specimen and aretypically sacrificed, resulting in a predictable pattern of cutaneous numbness in the inner arm

region for most patients after this procedure.

Axillary lymph node dissection was previously considered to be the standard of care for allpatients diagnosed with invasive breast cancer. However, axillary lymph node dissection carries

a high rate of surgical morbidity (lymphedema rates of about 25%, shoulder dysfunction, woundinfection, seroma, nerve damage, numbness, chronic pain, and, rarely, brachial plexus injury).

Lymphedema is the abnormal accumulation of protein-rich edema fluid in the upper extremityfollowing axillary lymph node dissection. This occurs because a portion of the lymphatics that

drain from the breast to the axilla, and those that drain from the arm are shared within the axilla.Early detection of lymphedema is paramount as lymphedema is potentially reversible when

treated in its earliest stage. Compression garments and physical therapy with lymphatic massageare still the backbone for the treatment of lymphedema.

Patients who have an axillary lymph node dissection should be cautioned about the risk oflymphedema and should take precautions to avoid breaks in the skin or infections in the affected


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extremity. Lymphedema may develop at any time after lymph node dissection but mostcommonly occurs within the first 2 years of the surgery. Risk factors for developing

lymphedema include obesity and radiation therapy. Although patients are commonly advised toavoid taking blood pressures or inserting IVs in the affected arm after axillary lymph node

dissection, no level I or level II evidence supports that recommendation.

Breast-Conserving Radiation Therapy (RT)

The purpose of radiation therapy following breast-conserving surgery is to eradicate localsubclinical residual disease while reducing local recurrence rates by approximately 75%. Based

on results from several randomized controlled studies, radiation to the intact breast is consideredstandard of care even in the lowest risk disease with the most favorable prognostic features.

There are two general approaches used to deliver radiation therapy: conventional external beamradiotherapy (EBRT) and partial breast irradiation (PBI). Whole breast radiotherapy (WBRT) is

comprised of EBRT delivered to the breast at a dose of 50-55 Gy over 5-6 weeks. This is oftenfollowed by a boost dose specifically directed to the area in the breast where the tumor was

removed.

Common side effects of radiation therapy include fatigue, breast pain, swelling, and skin

desquamation. Late toxicity (lasting 6 mo or longer following treatment) may include persistentbreast edema, pain, fibrosis, and skin hyperpigmentation. In a quality-of-life study that was part

of the START (Standardisation of Breast Radiotherapy) trials, Hopwood et al found that at 5years after radiotherapy for early breast cancer, up to 40% of women reported moderate or

marked changes to the breast, and arm and shoulder pain affected up to a third of patients. Breastsymptoms and body image concerns reduced over time. Adverse change in skin appearance was

significantly lower for patients who received hypofractionated therapy, with 39 Gy delivered in13 fractions over 5 weeks or 40 Gy in 15 fractions over 3 weeks, compared with a global

standard of 50 Gy in 25 fractions.

[15 ]

Rare side effects of radiation therapy include rib fractures,pulmonary fibrosis, cardiac disease (left breasttreatment),andsecondarymalignancies such as

radiation-induced sarcoma (0.5%).

Partial breast irradiation is employed in early stage breast cancer following breast-conservingtherapy as a way of delivering larger fraction sizes while maintaining a low risk of late effects.

Several techniques that can deliver this therapy include interstitial brachytherapy (multiplecatheters placed through the breast) and intracavitary brachytherapy (a balloon catheter inserted

into the lumpectomy site [ie, MammoSite]). Treatment is typically for 5 days, twice daily. Thesetechniques have shown low local recurrence rates comparable to EBRT in several

nonrandomized studies. The American Society of Breast Surgeons recommends the followingselection criteria when considering patients for treatment with accelerated partial breast

irradiation.

y Age 45 years and oldery Invasive ductal carcinoma or DCISy Total tumor size (invasive and DCIS) 3 cm or smallery Negative microscopic surgical margins of excisiony Axillary lymph node/sentinel lymph node negative


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Potential complications of partial breast irradiation are catheter placement followed by removalsecondary to inadequate skin spacing, infection, seroma, fibrosis, chronic pain, or disease

recurrence.

Postmastectomy Radiation Therapy

Clinical practice guidelines developed by the American Society of Clinical Oncology along withseveral prospective randomized clinical trials recommend postmastectomy radiation therapy be

performed using the following criteria.

y Positive postmastectomy marginsy Primary tumors larger than 5 cmy Involvement of 4 or more lymph nodes

Patients with more than 4 positive lymph nodes should also undergo prophylactic nodal radiation

therapy at doses of 4500-5000 cGy to the axillary and supraclavicular regions. For patients who

undergo axillary lymph node dissection and are found to have no lymph node involvement,axillary radiation therapy is not recommended. Meta-analyses have shown postmastectomycombined with regional nodal radiation therapy significantly decrease the rate of local relapse

and breast cancer mortality. Currently, the benefit of radiation therapy for women with 1-3positive axillary lymph nodes is uncertain and studies are ongoing.

ADJUVANT THERAPY FOR BREAST CANCER

The breast cancer mortality rate fell 24% between the years 1990 and 2000 for women aged 30-79 years. This improvement in breast cancer mortality is thought to have resulted from both

improvements in early detection through screening and from advances in adjuvant treatment.

Depending on the model of risk reduction, adjuvant therapy has been estimated to be responsiblefor 35-72% of that reduction. Adjuvant treatment of breast cancer is designed to treat micro-metastatic disease, or breast cancer cells that have escaped the breast and regional lymph nodes

but have not yet established an identifiable metastasis. Treatment is aimed at reducing the risk offuture recurrence, thereby reducing breast cancer-related morbidity and mortality.

Adjuvant Chemotherapy

Combination chemotherapy regimens are standardly recommended in the adjuvant setting. The

most commonly used regimens are shown below.

Table 4. Adjuvant Chemotherapy Regimens for Breast Cancer

Regimen Dose and Schedule Frequency Cycles

TAC (Martin et al, Eur J Cancer 2(suppl):70, 2004)

Taxotere (Docetaxel) 75 mg/m IV day 1 Every 21 days 6

Adriamycin 50 mg/m IV day 1

Cyclophosphamide 500 mg/m IV day 1


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AC => T (conventional regimen)[ 16 ]

Adriamycin 60 mg/m IV day 1 Every 21 days 4


Followed by

Paclitaxel 175 mg/m IV

day 1 Every 21 days 4Dose-Dense

Adriamycin 60 mg/m IV day 1 Every 14 days 4


Followed by

Paclitaxel 175 mg/m IV day 1 Every 14 days 4

Metronomic regimen

Adriamycin 20 mg/m IV day 1 Every week 12

Cyclophosphamide 50 mg/m PO Every day

Followed by

Paclitaxel 80 mg/m IV day 1 Every week 12

AC => T + H (Trastuzumab)[ 17 ]

4 mg/kg IV load then 2 mg/kg weekly with Paclitaxel then give 6 mg/kg IV every 3 weeks for 40

weeks; NOTE Trastuzumab to be added to a weekly Paclitaxel regimen in HER2-positive breastcancer patients

FEC-100[ 18 ]

5-FU 500 mg/m IV day 1 Every 21 days 6

Epirubicin 100 mg/m IV day 1


FAC[ 19, 20 ]

5-FU 600 mg/m IV day 1 Every 21 days 4

Adriamycin 60 mg/m IV day 1


5-FU 500 mg/m IV days 1 and 8 Every 28 days 6

Adriamycin 30 mg/m IV days 1 and 8

Cyclophosphamide 100 mg/m PO days 1-14

CMF (Bonadonna regimen)[ 21 ]

Cyclophosphamide 100 mg/m PO days 1-14 Every 28 days 6

Methotrexate 40 mg/m IV days 1 and 85-FU 600 mg/m IV days 1 and 8

Metronomic regimen[ 22 ]

Cyclophosphamide 50 mg/m PO days 1-7 Weekly 24

Methotrexate 15 mg/m IV

5-FU 300 mg/m IV


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TC[ 23 ]

Taxotere 75 mg/m IV day 1 Every 21 days 4


TCH[ 24 ]

Taxotere (Docetaxel) 75 mg/m IV

day 1 Every 21 days 6Carboplatin AUC 6 IV day 1

Trastuzumab 4 mg/kg loading dose IV followed

by2 mg/kg/wk X 18 then q3wk X 12

A comparison of major Cancer and Leukemia Group B (CALGB) chemotherapy clinical trialsfrom the last few decades including C8541 compared various doses of CAF, 9344 (which added

paclitaxel to standard dose AC) and 9741 (which compared q3wk dosing to q2wk dosing inestrogen receptor-positive and -negative patients). In all cases, chemotherapy was enormously

better in terms of improving disease-free and overall survival in patients with estrogen receptor-

negative disease.

When the inferior arm of C8541 was compared to the dose dense arm of C9741, a remarkable63% (CI 43-76%) improvement in disease-free and 59% (CI 34-74%) improvement in overall

survival was observed in patients with estrogen receptor-negative disease compared to 32% (CI -7-56%) improvement in disease-free and 18% (CI -41-53%) improvement in overall survival in

patients with estrogen receptor-positive disease. Overall, the advantages of chemotherapy,particularly in estrogen receptor-negative disease, were observed across all 3 trials irrespective of

the chemotherapy regimen used.

Role of taxanes

Taxanes are amongst the most active and commonly used chemotherapeutic agents used to treatearly stage breast cancer. However, questions have lingered as to whether taxanes are the mosteffective chemotherapeutic agent to use in this setting and if so, what is the best dosing schedule.

A recent Cochrane meta-analysis including 12 studies and more than 21,000 patients evaluatedthe role of taxanes in the adjuvant treatment of operable breast cancer (stage I-III). The results

showed a statistically significant overall survival (HR 0.81, p< 0.00001) and disease-freesurvival (HR 0.81, p< 0.00001) for the taxane-containing regimens compared with the nontaxane

regimens. This meta-analysis did not identify any subgroups of patients within the evaluatedstudies in which a taxane-containing regimen would be more efficacious.

The CALGB 9344 was one of the largest trials evaluating taxanes in the adjuvant setting forearly stage breast cancer, with more than 3,000 women with node-positive breast cancer. Thisstudy demonstrated a survival benefit for the sequential use of paclitaxel following AC

chemotherapy. In a recent retrospective analysis of CALGB 9344 testing for HER2 status using1,322 original participant tumor blocks, HER2 positivity irrespective of estrogen receptor status

predicted a significant benefit from paclitaxel in terms of reduced disease recurrence (HR 0.59,p= 0.01). Patients with estrogen receptor-positive, HER2-, node-positive breast cancer did not

seem to benefit from the addition of a taxane.


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However, the National Cancer Institute of Canada MA.21 and UK TACT trials, which usedtaxane and nontaxane-based chemotherapeutic regimens in early stage breast cancer patients, did

not demonstrate a benefit in using taxanes. Although the precise role of adjuvant taxane therapyremains controversial, the optimal scheduling of taxane administration has been determined.

The Eastern Coast Oncology Group (ECOG) 1199 randomized 4,950 women with lymph node-positive or high-risk lymph node-negative early stage breast cancer to 4 cycles of AC followedby 4 different taxane regimens: 1) paclitaxel at 175 mg/m

2q3wk; 2) paclitaxel at 80 mg/m

2

weekly; 3) docetaxel at 100 mg/m2

q3wk; and 4) docetaxel 35 mg/m2

weekly. After a 64-monthmedian follow-up, paclitaxel weekly and docetaxel every 3 weeks were superior to the other two

regimens in terms of disease-free survival.

Similarly, the TAX 311 trial performed by the US Oncology group showed that every 3 weekdocetaxel at 100 mg/m2 improved time to progression (TTP) and overall survival when

compared to paclitaxel at 175 mg/m2

given every 3 weeks. Thus, taxane-based regimens stillhave use in the treatment of early stage breast cancer and should be considered in treating

women especially with HER2+ disease using either the weekly paclitaxel or every-3-weekdocetaxel dosing schedules.

Role of anthracyclines

Anthracycline-containing adjuvant chemotherapy regimens have been used in the treatment of

early stage breast cancer for decades, although concerns regarding anthracycline-associatedcardiotoxicity or leukemogenic potential remain. In the 2000 Early Breast Cancer Trialists

Collaborative Group (EBCTCG) overview, anthracycline-based regimens were associated withan annual risk of cardiac mortality of 0.08% per year as compared with 0.06% per year in

patients treated with nonanthracycline-based regimens. However, the question of long-termcardiac safety remains, particularly for older women with early stage breast cancer.

The US Oncology 9735 trial randomized 1,016 women with operable breast cancer (stages I-III)to 4 cycles of TC versus 4 cycles of standard dose AC. After a median of 7 years follow-up, both

disease-free survival (81% vs 75%; HR, 0.74; p= 0.033) and overall survival (87% vs 82%; HR0.69; p= 0.032) were superior in the TC arm. Grade 5 cardiotoxicity (resulting in death) was seen

in 6 patients treated with AC (4 from myocardial infarction; 2 from congestive heart failure)versus 2 (myocardial infarction) in the TC group. This trial established TC as a viable option for

treating women with early stage breast cancer, especially those at high risk of cardiotoxicity orrequiring only 12 weeks of therapy.

Additionally, a recent meta-analysis of 8 trials comprised of 6,564 women with early stage breast

cancer to anthracycline versus nonanthracycline-based regimens suggested a benefit withanthracycline administration only in patients with HER2+ disease. Biologically, anthracyclines

inhibit topoisomerase IIa, whose gene (TOP2A) lies adjacent to theHER2 gene on chromosome17 and is coamplified in approximately 35% ofHER2 -overexpressing breast cancers.

The original trials demonstrating superiority of anthracycline-based regimens over CMF did notinclude TOP2A orHER2 testing. The BCIRG 006 trial, which randomized women with HER2+


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disease to AC followed by T, AC followed by TH, or TCH, did test forTOP2A andHER2coamplification.

[24 ]This group comprised only approximately 8% of the total breast cancer

population and may be the only subgroup to benefit from anthracycline administration. The roleofTOP2A as a predictive marker of response to anthracyclines needs further validation. Until

then, patients should not be deprived anthracycline-based adjuvant chemotherapy if their risk

assessment so determines it.

A recent study compared the effectiveness of oral uracil-tegafur (UFT) with that of CMF given

as a postoperative adjuvant to women with node-negative, high-risk breast cancer. Risk-freesurvival and overall survival were similar in the 2 groups, but the quality of life scores were

higher for patients given UFT than those given CMF. The study concluded that for women withnode-negative, high-risk breast cancer, UFT is a promising alternative to CMF.

[25 ]

An anthracycline followed by or concurrent with a taxane is the most optimal therapy for "triple-

negative" breast cancer patients with no medical contraindications. However, it remains unclearwhat the optimal combination chemotherapy regimen is for ER+, HER2 tumors. Currently,

CMF, TC, or an anthracycline-based regimen may all be reasonable options.

Adjuvant Therapy forHER2+ Breast Cancer

Overexpression of HER2 occurs in approximately 20% of breast cancers and previouslycorrelated with a more aggressive phenotype and worse prognosis prior to the development of

HER2 targeted therapies. The advent of trastuzumab, a monoclonal antibody (mAb) targeting theextracellular domain of the receptor, has changed the treatment paradigm for HER2-positive

breast cancer. Trastuzumab has a powerful synergism with a variety of chemotherapeutics, yetlacks the side-effects (with the notable exception of cardiotoxicity, which means it should not

generally be given with anthracyclines).

To date, results are available from 5 studies (HERA, FinHer, NSABP B-31, BCIRG006, N9831)that randomized 11,650 women with early-stage HER2+ breast cancer to trastuzumab versus

non-trastuzumab-based adjuvant chemotherapy. All 5 trials have demonstrated that the inclusionof trastuzumab produces roughly a 50% improvement in disease-free survival and 33%

improvement in overall survival regardless of the chemotherapy regimen or sequence oftrastuzumab delivery. Based on these trials trastuzumab was FDA approved for the treatment of

HER2+ disease in the adjuvant setting. Whether the combination of two anti-HER2 targetedtherapies with chemotherapy will prove beneficial in early stage disease is currently being tested

in the phase III ALTTO (Adjuvant Lapatinib and/or Trastuzumab Treatment Options) trial aswell as the similar NeoALTTO (Neoadjuvant Lapatinib and/or Trastuzumab TreatmentOptimization) trial.

Adjuvant Hormonal Therapy

In estrogen-receptor positive early stage breast cancer, hormonal therapy plays a main role in

adjuvant treatment, either alone or in combination with chemotherapy. Hormonal treatmentsfunction to decrease estrogens ability to stimulate existing micro-metastases or dormant cancer

cells. Adjuvant hormonal therapy can reduce the relative risk of distant, ipsilateral, and


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contralateral breast cancer recurrence by up to 50% in tumors with high ER expression. FDA-approved endocrine therapies for adjuvant treatment of breast cancer includes tamoxifen and the

aromatase inhibitors (anastrozole, letrozole, exemestane[26 ]

).

Tamoxifen

Tamoxifen is a selective estrogen receptor modulator (SERM), which binds to and inhibitsestrogen receptor signaling in the breast. As a receptor antagonist, it is effective in both

premenopausal and postmenopausal women. It has ER-stimulating effects in other tissues,including bone (resulting in preservation of bone density) and endometrium (leading to a 2- to 4-

fold increased risk of endometrial cancer). Tamoxifen has been approved for breast cancertreatment since the early 1980s. It has been shown in multiple studies to decrease breast cancer

associated mortality and recurrence. In an analysis of 55 trials evaluating tamoxifen versusplacebo in the adjuvant treatment of breast cancer, 5 years of tamoxifen therapy resulted in a

47% reduction in recurrence and a 22% reduction in mortality.

The EBCTCG meta-analysis demonstrates that the risk reduction from adjuvant tamoxifen issimilar (or even superior) in older versus younger women, with a relative risk of recurrence of0.49 in patients older than 70 years, 0.55 in patients aged 60-69 years, 0.66 in patients aged 50-

59 years, 0.71 in patients aged 40-49 years. Common side effects associated with tamoxifen useinclude hot flashes (up to 80%), vaginal bleeding (2-23%), discharge (13-55%) or dryness

(


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concurred that until more data are available, these patients should avoid concomitant use ofSSRIs.

[27,28,29 ]

Aromatase inhibitors (AIs)

AIs function by inhibiting aromatase, the enzyme (found in body fat, adrenal glands, and breasttissue as well as tumor cells) responsible for converting other steroid hormones into estrogen.Aromatase is the sole source of estrogen in postmenopausal women and likely the underlying

reason that obesity (larger volume of body fat produces more estrogen) has been associated witha higher risk of breast cancer in postmenopausal patients. As the AIs have no effect on ovarian

estrogen production, they are only effective in postmenopausal women. Common side effects ofAIs include hot flashes (12-36%), arthralgia/arthritis (17%), headache (9-13%), vaginal dryness

(2%), and mood changes (19%).

Several large randomized trials including BIG1-98 and ATAC have shown aromatase inhibitorsto be superior to tamoxifen with regard to disease-free

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