Mayo 1

SYMPOSIUM
SOLID
TUMORS
PREVENTION ANDON
DIAGNOSIS
OF BREAST
CANCER
A Multidisciplinary Approach to the Management of Breast Cancer, Part 1:

Prevention and Diagnosis
SANDHYA PRUTHI, MD; KATHLEEN R. BRANDT, MD; AMY C. DEGNIM, MD; MATTHEW P. GOETZ, MD;
EDITH A. PEREZ, MD; CAROL A. REYNOLDS, MD; PAULA J. SCHOMBERG, MD; GRACE K. DY, MD;
AND JAMES N. INGLE, MD
Breast cancer is the most common cancer among women in the
United States, with an estimated 200,000 new cases diagnosed
annually. A multidisciplinary focus that entails prevention, diagnosis, and treatment has led to significant strides in the reduction of
breast cancer incidence and mortality. Additionally, breast cancer
management has become increasingly complex, requiring comprehensive assessment and review of multiple issues that include the
role of genetic testing, imaging and breast magnetic resonance
imaging, surgical and reconstructive options, and a variety of new
adjuvant therapies. It has become more evident that a multidisciplinary team approach that involves a spectrum of breast
experts is necessary to provide optimal care to patients. This
team includes medical oncologists, breast radiologists, breast
pathologists, surgical breast specialists, radiation oncologists,
geneticists, and primary care physicians. Furthermore, patient
knowledge has increased use of the Internet, and more patients
are seeking a multidisciplinary approach to treatment. This review
considers information for health care professionals who will facilitate optimal patient care for women at increased risk for or
presenting with a new diagnosis of breast cancer. The multidisciplinary team of authors, representing the different disciplines,
has selected important state-of-the-art issues that arise in their
daily practices for consideration, rather than summarizing what is
already available in textbooks.
Mayo Clin Proc. 2007;82(8):999-1012

AI = aromatase inhibitor; AJCC = American Joint Committee on Cancer;
CAD = computer-aided detection; CI = confidence interval; DCIS =
ductal carcinoma in situ; FDA = Food and Drug Administration; FISH =
fluorescence in situ hybridization; HR = hazard ratio; LCIS = lobular
carcinoma in situ; MAP-3 = Mammary Prevention 3; MRI = magnetic
resonance imaging; NSABP = National Surgical Adjuvant Breast and
Bowel Project; RR = relative risk; SERM = selective estrogen receptor
modulator; SLNB = sentinel lymph node biopsy
reast cancer is a common disease in women. Approximately one third of cancers in women arise in the
breast, making it by far the most commonly diagnosed
cancer when basal and squamous cell skin cancers are
excluded. In the United States, the American Cancer Society estimates that 180,510 cases of invasive breast cancer
and 62,030 cases of breast carcinoma in situ will be diagnosed in 2007,1 resulting in a woman receiving a diagnosis
of breast cancer approximately every 2 minutes. In addition
to breast cancer being a diagnostic reality for many women,
it is a concern for all women. This emphasizes the importance of knowledge of the disease for all health care professionals who are responsible for the care of women. As more
attention has shifted to both primary and secondary prevention of breast cancer, patients are seeking education and
Mayo Clin Proc.
information from their primary care physicians about

breast cancer risk and options for risk reduction. Primary
care physicians who care for women have an important role
in addressing breast cancer prevention. With the advent of
improved efforts at prevention, screening, and adjuvant
therapies, breast cancer mortality has declined.2
PREVENTION
RISK OF DEVELOPING BREAST CANCER
Breast cancer is a complex disease, resulting from the
interaction of multiple environmental, hormonal, and lifestyle risk factors with the individuals
genome. Although inherited risk fac- For editorial
tors are not modifiable, most lifestyle comment,
factors are modifiable and are opportu- see page 915
nities for breast cancer risk reduction
for many women. Application of breast cancer risk prediction models in clinical practice and their role in defining
who is at high risk is paramount in targeting management
options to match the individuals underlying risk. Management options for high-risk women include chemoprevention, risk-reducing surgical interventions, and clinical
trials. Newer modalities to prevent breast cancer are on the
horizon, and clinical trials that evaluate these modalities
are promising in their ability to positively impact breast
cancer incidence and mortality.
The role of endogenous and exogenous exposure to
estrogens in the induction and promotion of breast carcinoFrom the Breast Diagnostic Clinic, Division of General Internal Medicine
(S.P.), Department of Radiology (K.R.B.), Department of Surgery (A.C.D.),
Department of Oncology (M.P.G., G.K.D., J.N.I.), Department of Laboratory
Medicine and Pathology (C.A.R.), and Department of Radiation Oncology
(P.J.S.), Mayo Clinic, Rochester, Minn; and Division of Hematology/Oncology,
Mayo Clinic, Jacksonville, Fla (E.A.P.).
Dr Goetz is a consultant for F. Hoffman-La Roche Ltd and DNA Direct. Dr
Perez serves on an advisory board for Genentech, Inc, sanofi-aventis,
GlaxoSmithKline, and Novartis and receives research support from
GlaxoSmithKline. Dr Ingle receives honoraria from AstraZeneca Pharmaceuticals LP, Novartis, and Pfizer Inc.
Address correspondence to Sandhya Pruthi, MD, Division of General Internal
Medicine, Mayo Clinic, 200 First St SW, Rochester, MN 55905 (e-mail: pruthi
.sandhya@mayo.edu). Individual reprints of this article and a bound reprint of
the entire Symposium on Solid Tumors will be available for purchase from our
Web site www.mayoclinicproceedings.com.
2007 Mayo Foundation for Medical Education and Research
August 2007;82(8):999-1012
www.mayoclinicproceedings.com
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
999
PREVENTION AND DIAGNOSIS OF BREAST CANCER
genesis has become an increasingly important risk factor

for breast cancer. The mechanism of carcinogenesis is
believed to be the result of estrogen stimulation of tissue
growth and potentially serum estrogens metabolism to
genotoxic metabolites.3
The cumulative exposure to endogenous estrogen can be
associated with reproductive factors, such as early menarche and late menopause. In the postmenopausal state,
ongoing estrogen synthesis is secondary to the conversion
of androgens (androstenedione and testosterone) via
aromatase activity in breast and peripheral adipose tissue.
Postmenopausal obesity has been shown to increase breast
cancer risk by 50%, and this risk factor is thought to
contribute to carcinogenesis on the basis of the presence of
increased serum estrone and estradiol concentrations in
these patients.4 Conversely, weight loss or maintenance of
ideal body weight (body mass index, 19-25 kg/m2 [calculated as weight in kilograms divided by the square of height
in meters]) and moderate physical activity have been
clearly shown to reduce the risk of breast cancer in adult
women by approximately 30%.5,6 Two prospective placebo-controlled trials were conducted by the Womens
Health Initiative in which either estrogen alone (conjugated
equine estrogen) or estrogen and medroxyprogesterone
were administered and compared with placebo in women
with and without an intact uterus, respectively. Although
administration of estrogen and medroxyprogesterone increased the incidence of invasive breast cancer by 26% or
an excess of 8 cases per 10,000 women-years of follow-up
in the women receiving the hormonal therapy and increased the risk of thromboembolism, stroke (41%), and
cardiovascular events (29%),7 administration of estrogen
alone was associated with a trend toward a decreased incidence of breast cancer (hazard ratio [HR], 0.80; P=.09).8
Findings of epidemiological studies that evaluated oral
contraceptives have evolved as a result of changes in hormonal formulations and doses. Although older formulations of oral contraceptives, which contained higher dosages of estrogen and progestins, appeared to increase the
risk of breast cancer (among women who used these drugs
before 1975),9 more recent studies have shown that current
and former oral contraceptive use is not associated with a
significantly increased risk of breast cancer.10 Similarly, a
study of BRCA1 carriers who first took oral contraceptives
before 1975, who took them before the age of 30 years, or
who took them for 5 or more years may have an increased
risk of breast cancer. Although data on BRCA2 carriers
were limited, oral contraceptive use did not appear to be
associated with risk of breast cancer.11
Overall, these studies suggest that estrogen alone is not
sufficient for carcinogenesis, and they point to the importance of progestin as an important environmental exposure
1000
Mayo Clin Proc.
that increases risk. Increasing knowledge of the role of

genetically inherited variation in the pathways that convert
estrogen into genotoxic metabolites and pathways involved
in conjugation of estrogens may clarify the role of estrogen
in breast carcinogenesis.
Age and sex are the most significant nonhormonal risk
factors. One in 8 women will develop breast cancer during
an expected lifetime of 80 years.12 A personal history of
prior breast biopsies, specifically the finding of atypical
hyperplasia, is associated with a 4-fold increase in the risk
of breast cancer during a 15-year period.13 Lobular neoplasia defines a spectrum of histologic changes from atypical
lobular hyperplasia to lobular carcinoma in situ (LCIS) that
carries a 4-fold to 10-fold increased risk of breast cancer.14
Women with a strong family history of breast cancer or
family members with a known or suspected genetic predisposition to breast cancer are at significant risk for developing this disease. Although only 5% to 10% of breast cancers are associated with a hereditary pattern for these
women, the lifetime risk of developing breast cancer in
these women is 40% to 80%. Another 15% to 20% of breast
cancers have a familial pattern but without a readily identifiable inheritance mechanism. As with any cancer, breast
carcinogenesis results from a complex combination of environmental factors that interact with the host genome and
influence the bodys response to DNA and cellular damage.15 Radiation exposure is a classic example, wherein
women with Hodgkin lymphoma previously treated with
thoracic radiation have a significantly higher risk of breast
cancer.16 Although breast density as noted on mammography carries a 4- to 6-fold increase in breast cancer risk, the
underlying genetic factors that confer this risk are unknown.17
Modifiable risk factors associated with lifestyle may
include alcohol consumption and dietary fat intake. Although multiple cohort studies have reported that consumption of 1 or more alcoholic drinks per day results in an
increased risk of breast cancer by approximately 26%,18,19
no prospective trials have been performed to determine
whether the omission of alcohol reduces risk. More recently a study of a low-fat diet among postmenopausal
women did not result in a statistically significant reduction
in invasive breast cancer risk.6 Although a low-fat diet
during later years did not reduce the risk of breast cancer,
such a diet initiated earlier in life may play a role in
preventing breast cancer.
DEFINING BREAST CANCER RISK
Targeting preventable management interventions is based
for the most part on the degree of risk. Breast cancer risk
can be categorized as low to average, high, and very high.
Women at low to average risk have risk factors that confer
August 2007;82(8):999-1012
no greater than a 1.5-fold relative risk of developing breast

cancer.20 Elevated or high risk includes women with a Gail
model 5-year risk score of 1.66% or higher (defined subsequently), prior history of atypical hyperplasia, or family
history that includes 1 affected first-degree relative. Very
high-risk women include BRCA1 or BRCA2 gene mutation
carriers and those with a history of LCIS, ductal carcinoma
in situ (DCIS), or irradiation before the age of 20 years.
Breast Cancer Risk Assessment. To properly assess a
womans risk of breast cancer, clinicians must take an
accurate history, use validated tools to assess the individuals risk of breast cancer, and understand when to
apply risk management strategies based on the degree of
risk. The informed decision-making process requires open
dialogue and may occur during multiple visits. This process is not urgent but is complicated by a spectrum of
options; it is a time-intensive and ongoing process that requires periodic risk reassessment during a womans lifetime. Decision aids provide graphical information about
breast cancer risk, but the results need to be interpreted in
the context of the individuals overall health, beliefs, attitudes, and personality characteristics and factor in the average risk of the population.
Risk Prediction Models. The 2 most common breast
cancer risk prediction models are the Gail model and Claus
model. These models are used to estimate risk and are not
absolute indicators of who will develop breast cancer. In
contrast, likelihood models are used to predict the probability of BRCA1 or BRCA2 gene mutation in a given patient or
family. These likelihood models take into account a more
extensive family history and include both ovarian and
breast cancer; examples include the Myriad model, Couch
model, and BRCAPRO model. All risk assessment models
have strengths and limitations, and no model is comprehensive enough to stand alone as predictive of breast cancer
risk. The clinical scenario dictates how to interpret the
information and risk estimates. Furthermore, communication and understanding of the perceived risk vs the actual
risk are important as part of the decision-making process.
The Breast Cancer Detection Demonstration Project led
by Gail et al21 was instrumental in defining significant and
validated predictors of lifetime risk of breast cancer risk.
The National Cancer Institute modified this into a computerized risk assessment tool that calculates the 5-year and
lifetime risk of breast cancer as a percentage. A Gail model
score of 1.66% or higher is considered high risk and takes
into account the following factors: age (model valid only
for women >35 years), age at menarche, number of breast
biopsies and history of atypical hyperplasia, number of
first-degree relatives with breast cancer (mother, sister, or
daughter), age at first live birth, and race. The Gail model is
available online at www.bcra.nci.nih.gov/brc/ and can be
Mayo Clin Proc.
used by the clinician during the office visit. This model

does well in predicting the absolute risk of developing
breast cancer for women as a group and stratified by various risk factors but does not address the issue of individual
risk prediction. This model has other limitations; for example, it is not appropriate for women with a history of
breast cancer, LCIS, or DCIS or women who do not undergo annual screening mammography. Also, this model
can result in an underestimation of risk in those with an
extensive family history of breast cancer, and it does not
take into account the paternal side or age of onset of affected relatives. Although the Gail model has limitations
and research is needed to identify models with better discriminatory power, it is the model currently approved for
use to determine eligibility for tamoxifen therapy for breast
cancer risk reduction.
The Claus model is another risk prediction model that
incorporates a more extensive family history (first- and
second-degree relatives, maternal or paternal, affected by
breast cancer and age of affected individuals). The model
predicts a womens absolute risk of developing breast cancer in 10-year increments (between 29 and 77 years of age),
culminating in a lifetime risk.22
The 3 likelihood models were developed for use by
genetic counselors for evaluating women with a strong
family history of breast cancer, and each has strengths and
limitations. Genetic counselors use these models to determine the probability of an individual patient carrying a
genetic mutation. Features of a family history suggestive of
a predisposition to hereditary breast cancer include known
BRCA1 or BRCA2 mutation, breast or ovarian cancer
within a family of Ashkenazi Jewish ancestry, relatives
with bilateral breast cancer, multiple relatives with onset of
breast or ovarian cancer at a young age, and male relatives
with breast cancer.
Clinicians are advised to refer at-risk women or those
with pertinent familial patterns to an established breast clinic
or program for risk assessment, counseling, and education.
Genetic consultation is a critical component of the evaluation that facilitates discussion regarding risks, benefits, and
limitations before proceeding directly to genetic testing.
MOLECULAR EPIDEMIOLOGY
The field of epidemiology has traditionally evaluated
whether lifestyle factors (eg, fat intake) are associated with
cancer risk. However, with an increased understanding of
the molecular processes that underlie carcinogenesis in the
context of the mapping of the human genome, the field of
molecular epidemiology has emerged. In this discipline,
researchers study whether inherited variation in genes that
regulate cellular homeostasis affects cancer risk and identify newer molecular markers of exposure to make connec-
August 2007;82(8):999-1012
1001
tions between lifestyle and cancer risk. The ultimate goal of

molecular epidemiology is to personalize risk assessment,
allowing a more precise estimate of which patients are at
higher risk of development of breast cancer. In these patients, more intensive screening, chemoprevention, or prophylactic surgery may ultimately reduce morbidity and
mortality associated with breast cancer.
The intraductal approach is a new area of investigation
assessing the microenvironment of the breast and tumor
biology of breast cancer. This approach encompasses modalities such as nipple fluid aspiration to provide physiologic fluid that can be assessed for novel proteomics,
estrogen metabolites, DNA adducts, and other biochemical
assays to help identify newer biomarkers.23 The development of biomarkers may help facilitate more accurate
short-term risk assessment and predict response to prevention treatment.
RISK-REDUCING STRATEGIES
A variety of primary and secondary preventive strategies
are available to clinicians who care for high-risk women.
Secondary preventive strategies include the combination of
clinical breast examinations and breast imaging modalities
to detect disease at an earlier stage of progression. Primary
preventive strategies include lifestyle modification, chemoprevention, and risk-reducing surgery.
Surveillance. The American Cancer Society guidelines
for early detection of breast cancer in average risk, asymptomatic women include the following: clinical breast examination as part of the periodic health examination for
women in their 20s and 30s to continue annually beginning
at the age of 40 years, annual mammography beginning at
the age of 40 years, and awareness of new breast symptoms
and prompt reporting of changes to their primary care
physician. Enhanced surveillance is important in women at
high or very high risk and includes having a clinical breast
examination performed every 6 to 12 months and annual
mammography. In these women, the age at which to initiate mammography should begin 5 to 10 years earlier
than the youngest affected relative or at the age of 40
years, whichever is earlier. Studies that assess contrastenhanced breast magnetic resonance imaging (MRI) as a
screening tool for very high-risk women report a very
high sensitivity for detecting invasive breast cancer. However, given that the specificity ranges from 37% to 97%,
the risks, benefits, and limitations of this study must be
thoroughly discussed.24
The American Cancer Society recently issued guidelines, after review of the evidence, for breast screening with
MRI as an adjunct to mammography for specific levels of
risk. On the basis of this review, screening MRI is recommended for women with a strong family history of breast
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Mayo Clin Proc.
and ovarian cancer, carriers of the BRCA mutation, women

with a history of chest radiation between the ages of 10 and
30 years for Hodgkin disease, and women with a lifetime
risk greater than 20% to 25% as defined by risk predication
models dependent on family history. Risk groups for which
evidence is insufficient to recommend for or against
screening include women with a personal history of invasive or in situ breast cancer, atypical hyperplasia, and extremely dense breasts on mammography.25
Risk-Reducing Surgery. Risk-reducing mastectomy,
although considered an aggressive option, is a reasonable
and effective option in very high-risk women (hereditary
predisposition to carrying a genetic mutation or BRCA1 or
BRCA2 gene mutation carriers). Hartmann et al26 first reported that in high-risk women (those with a family history
of breast cancer), prophylactic mastectomy reduced the
incidence of breast cancer by 90%. In contrast, prophylactic oophorectomy decreases ovarian cancer by at least 95%
and breast cancer risk by 50% if performed before the age of
40 years.27 Prophylactic oophorectomy is more often the
initial choice for risk reduction because it is not associated
with alteration in body image and self-esteem, as can occur
after prophylactic mastectomy. Women who spend the necessary time exploring their options and share information
with family members and friends are more accepting of their
decision to have risk-reduction surgery in the long term.
CHEMOPREVENTION
Tamoxifen. Tamoxifen, a first-generation selective estrogen receptor modulator (SERM), has both estrogenic
and antiestrogenic properties, and its mechanism of action
against breast cancer is estrogen receptor blockade. In
1998, the Food and Drug Administration (FDA) approved
the use of tamoxifen, 20 mg/d for 5 years, for breast cancer
risk reduction in high-risk individuals.
A placebo-controlled trial of tamoxifen as adjuvant
therapy showed a reduction in contralateral breast cancer.28
Subsequently, 4 randomized trials that prospectively evaluated tamoxifen and 1 meta-analysis (involving the National
Surgical Adjuvant Breast and Bowel Project [NSABP] P-1,
the International Breast Cancer Intervention Study, a Royal
Marsden Hospital study, and an Italian study) led to further
support of tamoxifen as a risk-reducing drug.29-33 The
NSABP P-1 trial was the first and largest (N=13,388) of the
randomized studies that compared tamoxifen to placebo.
Eligibility for this trial included women older than 35 years
and those at high risk based on a Gail model 5-year risk
score of 1.66% or higher, prior LCIS, or history of atypical
ductal or lobular hyperplasia. After 41/2 years of treatment
with tamoxifen, a 42% reduction in breast cancer occurred
(relative risk [RR], 0.58; 95% confidence interval [CI],
0.38-0.84), and the risk reduction benefit was seen across
August 2007;82(8):999-1012
all age groups. In women with LCIS, a 56% reduction was

seen, and in those with atypical hyperplasia, an 86% reduction was seen. Noninvasive breast cancer was reduced by
50%, and estrogen receptorpositive tumors were decreased by 69%. The meta-analysis, including the 4 trials
aforementioned, reported a 38% reduction in breast cancer
with tamoxifen (odds ratio, 0.62; 95% CI, 0.42-0.89).33
However, none of the 4 trials showed a mortality benefit
with tamoxifen use. Furthermore, women need to be informed of the adverse effects of tamoxifen, which include
hot flashes, vaginal discharge, and other significant risks,
such as endometrial cancer (2 per 1000 women per year),
stroke (2-fold increased risk), and life-threatening thromboembolic disease (2- to 3-fold increased risk). These risks
appear to be less pronounced in premenopausal women and
increase significantly in postmenopausal women and those
with other medical comorbidities.29
Raloxifene. Raloxifene is a second-generation SERM
with estrogen antagonist properties similar to tamoxifen
but with a less agonistic effect on the endometrium.
Raloxifene increases bone mineral density in postmenopausal women and reduces the risk of vertebral fracture; it
is approved by the FDA for the prevention and treatment of
osteoporosis. The MORE (Multiple Outcomes of Raloxifene Evaluation) trial was a study of postmenopausal
women with osteoporosis who were randomized to raloxifene or placebo in which a secondary aim of breast cancer
incidence was predefined. This trial (N=7705) found that the
incidence of breast cancer was reduced by 72% after 4 years
and was the first study, to our knowledge, to show a possible
breast cancer risk reduction effect with raloxifene therapy.34
The CORE (Continuing Outcomes Relevant to Evista)
trial, completed in 2004, was designed to evaluate the
efficacy of an additional 4 years of raloxifene therapy in
preventing invasive breast cancer. During the 8 years of
both trials, the incidence of estrogen receptorpositive invasive breast cancer was reduced by 66% (HR, 0.34; 95%
CI, 0.22-0.50) and 76% (HR, 0.24; 95% CI, 0.83-5.70),
respectively. No new safety concerns related to raloxifene
therapy were identified during this trial.35
Raloxifene, in these trials, appeared to have a similar
side effect profile as tamoxifen in terms of increased risk of
thromboembolic disease (2-fold increased risk) and stroke
and exacerbation of vasomotor symptoms. However, unlike tamoxifen it does not result in an increased risk of
endometrial cancer. With regard to heart disease, the
RUTH (Raloxifene Use for The Heart) trial reported no
significant reduction in cardiovascular disease among
women with multiple cardiac risk factors or prior history of
cardiovascular disease. However, an increased risk of fatal
stroke and venous thromboembolism was found in this
high-risk group.36
Mayo Clin Proc.
An important prevention study was the NSABP P-2

STAR (Study of Tamoxifen and Raloxifene) trial, a prospective, randomized, double-blind study of 19,747 postmenopausal (mean age, 58.5 years) high-risk women
(eligibility similar to NSABP P-1).37 The NSABP investigators found that raloxifene was as effective as tamoxifen
in reducing the risk of invasive breast cancer (RR, 1.02;
95% CI, 0.82-1.28). Interestingly, the occurrence of noninvasive breast cancer was lower with tamoxifen (RR,
1.40; 95% CI, 0.98-2.00) although the reason is not entirely
clear. Thromboembolic events and cataracts were significantly less among women taking raloxifene compared with
tamoxifen. Among women taking raloxifene, fewer cases
of uterine hyperplasia occurred, but the uterine cancer risk
was similar between both groups. With regard to quality of
life and patient-reported outcomes and symptoms, women in
the tamoxifen arm reported more vasomotor symptoms, leg
cramps, and gynecological problems but better sexual function. Those taking raloxifene reported more dyspareunia,
weight gain, and musculoskeletal problems.38 On the basis of
the findings from the STAR trial, it appears that raloxifene
represents an alternative to tamoxifen in women who want to
take a SERM and who are willing to accept the potential
adverse effects of this therapy. Raloxifene is not recommended for treatment in premenopausal women.
Aromatase Inhibitors. Aromatization of androgens
(androstenedione or testosterone) by the aromatase enzyme
in peripheral tissues such as fat and muscle is a major
source of estrogens in postmenopausal women. Aromatase
inhibitors (AIs) include first-, second-, and third-generation drugs and significantly reduce the amount of estrogen
in breast tissue. Third-generation drugs, unlike the firstand second-generation drugs, do not alter cortisol or aldosterone plasma levels. Third-generation drugs include
anastrozole and letrozole, which are both nonsteroidal AIs
and bind to the P-450 site of the aromatase complex, and
exemestane, a steroidal AI that binds to the substrate-binding
pocket, resulting in aromatase inactivation. All 3 have comparable degrees of estrogen suppression (96%-99%) and
lower estrogen levels in the breast and in other tissues.39
To date no completed randomized clinical trials have
evaluated AIs in breast cancer prevention. The 3 AIs have
been studied in adjuvant breast therapy trials (compared
with tamoxifen) and have consistently shown a benefit in
reducing contralateral breast cancer. These studies have led
the way for new chemoprevention trials39 that will define
the benefit-risk ratio of these agents.
American Society of Clinical Oncology Technology
Assessment: Chemoprevention 2002. This ongoing comprehensive literature review of evidence-based chemopreventive strategies for breast cancer reduction has to date
highlighted that placebo controls are appropriate for breast
August 2007;82(8):999-1012
1003
cancer risk reduction since no intervention has demonstrated a favorable net impact on overall health or survival.
The tamoxifen trials have not shown that the drug in the
chemoprevention setting provides an overall benefit or increased survival.40
Women with a defined 5-year projected breast cancer
risk score of 1.66% or higher may be offered tamoxifen at
20 mg/d for 5 years to reduce their risk of breast cancer.
The risk-benefit models suggest that the greatest clinical
benefit with the fewest adverse effects derived from
tamoxifen use is observed in younger (premenopausal)
women who are less likely to have thromboembolic sequelae and uterine cancer or in women who have had a
hysterectomy. Tamoxifen use should be discussed as part
of an informed decision-making process with careful consideration of individually calculated risks and benefits.41
Ongoing Prevention Trials. The National Cancer Institute of Canada is conducting a prevention trial comparing exemestane to placebo in a study known as MAP-3
(Mammary Prevention 3) that involves postmenopausal
women. The 5-year study has a projected accrual of 4500
women. Eligibility for this trial includes a Gail model
5-year risk score of 1.66% or higher, age 60 years and
older, prior atypical ductal or lobular hyperplasia, or DCIS
treated with mastectomy alone. This multicenter study includes sites in the United States, Canada, and Spain.42
The International Breast Cancer Intervention 2 trial began in Europe in February 2003 and is comparing anastrozole to placebo in 6000 postmenopausal women at increased risk of breast cancer with a secondary aim of
assessing osteoporosis incidence. This trial has similar
high-risk entry criteria as were aforementioned for the
MAP-3 trial with the addition of increased mammographic
density. A second complementary study will address the
role of anastrozole vs placebo in women with DCIS.42
A third study, the Aromasin Prevention Study, is under
way in Italy and is evaluating exemestane vs placebo in
BRCA1 and BRCA2 gene mutation carriers during 5 years.
The primary aim includes the incidence of breast cancer,
and secondary aims involve the incidence of LCIS, DCIS,
toxicity, bone mineral density, and quality of life.42
DIAGNOSIS
The multidisciplinary approach to the work-up of newly
diagnosed breast cancer includes a team of breast experts,
including internal medicine (primary care and nursing), radiology, pathology, surgery, and medical oncology specialists.
BREAST IMAGING
Mammography is the most established method for imaging
the breast and is the primary tool for breast disease evalua1004
Mayo Clin Proc.
tion. Asymptomatic women undergo screening mammography, which entails 2 views of each breast: the craniocaudal view and the medial lateral oblique view. Women
with symptoms such as a palpable abnormality, skin
changes, or nipple discharge undergo diagnostic mammography, which is also used for further evaluation of abnormal findings on a screening mammogram. Besides the
standard 2 views of each breast, diagnostic mammography
may include additional mammographic magnification
views or spot compression views. Ultrasonography is frequently used as an adjunct to diagnostic mammography.
Most women with a palpable abnormality will undergo a
focused ultrasonographic examination involving the area
of clinical concern. Additionally, ultrasonography is often
used to further characterize a mammographic abnormality
and is a common guide for breast intervention.
A meta-analysis of randomized trials studying the effectiveness of screening mammography demonstrates reductions of 20% to 35% in mortality due to breast cancer for
women aged 50 to 69 years.43 The benefit of screening
women in their 40s is slower to appear and is somewhat
less than that for women older than 50 years.44 The goal of
screening mammography is to detect breast cancer early
before it becomes symptomatic and before it spreads to
lymph nodes. The American College of Radiology has
established that more than 50% of breast cancers diagnosed
in a successful mammography practice should be stage 0 or
1 and more than 30% should be invasive cancers that are 1
cm or smaller or DCIS.45 The prevalence of breast cancer
found on first-time screening mammograms is between 6
and 10 per 1000 women. The incidence of cancers found on
follow-up screening mammography is between 2 and 4 per
1000 women.45
The widely accepted definition of a false-negative mammogram is a negative mammogram within the year before
the breast cancer diagnosis. This number is used to calculate
the sensitivity of mammography.45 The overall sensitivity of
mammography for breast cancer detection is approximately
85%.46,47 However, studies that evaluate only women with
BRCA mutations and dense breasts report sensitivities of
only 38% to 55%.48,49 Breast cancer often has the same
density as normal fibroglandular tissue, making detection
more difficult in dense breasts. The American College of
Radiology Breast Imaging and Reporting Data System divides breast density into 4 categories. A density of 1 represents
breasts that are composed of less than 25% dense tissue,
whereas a density of 4 signifies that more than 75% of the
breast is composed of dense tissue.45 Breast density is a known
limitation of mammography and one reason that other methods for screening women with dense breasts are desirable.
Digital mammography may provide improved cancer
detection in women with dense breasts. In a recent study,
August 2007;82(8):999-1012
42,760 women at 33 centers underwent both digital and

film mammography. In the population as a whole, the
diagnostic accuracy of film and digital mammography was
similar. However, digital mammography was significantly
more accurate in women with dense breasts.50 The advantage of digital mammography seems to be the ability to
manipulate image contrast during interpretation to enhance
the visibility of subtle lesions. Currently, digital mammography is not widely available, and the cost is prohibitive for
many breast centers.
In recent years, computer-aided detection (CAD) systems have been approved by the FDA for screening and
diagnostic mammography. The CAD systems are designed
to serve as a second reader, prompting review of marked
areas. The interpreting radiologist determines whether action needs to be taken on a CAD marker. A study that
evaluated CAD found a 7.6% increase in cancer detection,
and 5 of 8 cancers detected only by CAD in that study were
DCIS presenting as microcalcifications. The CAD system
did not mark 24% of the cancers that were detected by the
radiologist.51
The utility of whole breast screening ultrasonography is
currently being investigated in a large multi-institutional
study. Published single-institution studies indicate that
the cancer detection rate of screening ultrasonography in
women with a negative mammogram and clinical breast
examination is 2.7 to 4.6 per 1000 women.52-54 Although
painless and relatively inexpensive, ultrasonography is
highly operator dependent and has a high false-positive
rate. In screening studies, the positive predictive value of
an ultrasonography-detected lesion that undergoes biopsy
is approximately 10% compared with 35% for a mammography-detected lesion.55
Breast MRI is another imaging modality that is used as
an adjunct to diagnostic mammography. It is also a screening tool in select high-risk women. Similar to ultrasonography, the effectiveness of MRI is not limited by breast
density. The sensitivity for invasive cancer is 77% to 100%
in published series, and the negative predictive value is
very high in problem-solving situations.56-58 Preoperative
MRI in women with a new diagnosis of breast cancer can
assess tumor extent more accurately than mammography
and detect additional sites of unsuspected ipsilateral cancer
in 6% to 34% of cases.59-62 Unsuspected contralateral malignancy, detected only with MRI, is found in 3% to 5% of
women with a new diagnosis of breast carcinoma.63,64
Specificity is a limitation of breast MRI, primarily because
of overlap in the appearance of malignant and benign disease, leading to additional work-ups, biopsies, and anxiety
for MRI-detected benign disease.65 The cost, time, and
false-positive result issue make it unlikely that MRI will
become a screening tool in the general population. In the
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high-risk patient, investigators consistently find a higher

sensitivity with MRI than mammography.24,57 However, the
impact on survival has not been demonstrated, and randomized studies have not been performed.
Core needle biopsy with ultrasonography, stereotactic
(mammographic), or MRI guidance is routinely performed
for diagnosing indeterminate breast lesions. Core needle
biopsy with imaging or pathology correlation is very accurate.66,67 The positive predictive value for cancer diagnosis
with core needle breast biopsy is 25% to 40%.45 For women
with a benign lesion at core biopsy, surgery is unnecessary.
For those with cancer, the core biopsy results are useful for
therapeutic planning.
BREAST PATHOLOGY AND SURGICAL MANAGEMENT
The pathologists primary responsibility is to establish the
histologic diagnosis and anatomic extent of the tumor.
Determining whether the breast carcinoma is in situ or
invasive is an important factor. Pathologists closely examine and report the gross, histologic, and molecular characterization of the breast tumor. This information is then
directly used by the treating clinician to estimate prognosis,
select adjuvant therapy (eg, chemotherapy and/or hormonal therapy), and estimate benefit of therapy. Accurate
reporting of pathological test results is of the utmost importance, and strict guidelines have been set forth by the
Cancer Committee of the College of American Pathologists to accomplish this mission.68
Screening mammography programs have led to a substantial increase in the detection of DCIS, which accounts
for approximately 20% of newly diagnosed breast cancers.69,70 The hallmark of DCIS is the neoplastic proliferation of epithelial cells confined to the ductal-lobular system
without stromal invasion. In principle, DCIS has no metastatic potential. However, 1% to 2% of patients diagnosed
as having DCIS will eventually develop distant metastases.71 This phenomenon is explained by occult invasion not detected in the original lesion or progression of the
residual DCIS lesion to invasive carcinoma. Treatment
options available for patients diagnosed as having DCIS
include breast-conserving surgery with radiation (with or
without adjuvant tamoxifen therapy) or total mastectomy.
The consideration for adjuvant radiation and/or hormonal
therapies is based on data from multiple randomized controlled trials showing that radiotherapy consistently reduces the risk of local recurrence by approximately 50%
and that the addition of tamoxifen to lumpectomy and
radiotherapy significantly reduces the incidence of cancer
events in estrogen receptorpositive tumors.72-75 Prognosis
for patients diagnosed as having DCIS is associated with
tumor size, nuclear grade, distance to the surgical resection
margin, estrogen receptor status, and age, with margin
August 2007;82(8):999-1012
1005
status proving to be a significant indicator of local tumor

control.76,77
Given the fact that more women are choosing breastconserving surgery over mastectomy, the question of what
constitutes an adequate pathological excision margin still
remains. We know that among patients treated with or
without radiation therapy, significantly higher local recurrence rates were observed when the surgical resection margins were positive than when the surgical resection margins
were negative.78 Therefore, achieving negative margins in
patients treated with breast-conserving surgery is clinically
important. To evaluate the status of the resection margins,
the specimen is inked many times with different-colored
inks that designate various margins before sectioning. Numerous studies have been conducted to address the best
method (shaved vs perpendicular vs separate cavity sampling) of margin assessment and the ideal distance to the
resection margin to obtain good clinical outcome.79-81 No
single best accepted method for margin assessment has
been identified, and the choice of the method used may
depend in part on the clinical circumstance. Moreover,
several studies have shown that the local recurrence rate
decreases as margin width increases.77,82 For that reason,
the question has been raised about whether there is a subset
of patients diagnosed as having DCIS who have a low risk
of recurrence such that wide excision alone is sufficient
treatment. The hypothesis that small low-grade DCIS lesions excised with margins of at least 1.0 cm may not need
the addition of radiotherapy has been suggested. Unfortunately, given the current evidence, no such subset of patients has been identified,77,83,84 although a prospective
clinical trial of surgery alone has been performed and published results are awaited.
Multiple factors have been proven to be of prognostic
importance and useful in the clinical management of patients with invasive carcinoma. Tumor size, presence or
absence of lymph nodes, and histological grade are the 3
factors considered to be the gold standards by which novel
prognostic factors are judged. The size of the tumor is one
of the most powerful predictors of tumor behavior in breast
cancer.85,86 Accurate assessment of tumor size is important
to stratify patients properly, especially since screening
mammography has resulted in a larger number of smaller
tumors. The tumor is staged on the basis of the largest
dimension of the invasive component. When 2 or more
distinct invasive tumors are present, staging is based on the
size of the largest tumor; the tumors sizes are not added
together to create a single larger measurement.68
The histological grade and histological type of invasive
tumor also allow risk stratification within a given tumor
stage and thus are important determinants of prognosis.87
The Nottingham combined histological grade (Elston-Ellis
1006
Mayo Clin Proc.
modification of the Scarff-Bloom-Richardson grading system) has been validated and is widely accepted.88-90 This
grading system is based on 3 morphologic features: tubule
formation (glandular differentiation), nuclear pleomorphism, and mitotic activity. The importance of this grading
system is endorsed in the 6th edition of the AJCC [American Joint Committee on Cancer] Cancer Staging Manual,
and this system is considered mandatory.91 The most common type of invasive carcinoma is ductal or no special type
and comprises approximately 60% to 75% of all invasive
tumors. The reported frequency of invasive lobular carcinoma varies considerably and ranges from 1% to 15%.92
The remaining histological types are considered special
types (eg, tubular carcinoma, mucinous carcinoma), and
most are associated with favorable prognosis.
Estrogen receptor and progesterone receptor testing
should be performed on all primary invasive carcinomas93
and intraductal carcinomas based on the recent findings
from the NSABP Protocol B-24.94 The presence or absence
of estrogen and progesterone receptors determines clinical
response to hormonal therapy and thus is used in the routine management of patients with breast cancer.68,95 Immunohistochemical analysis is the current choice for estrogen
assessment, and its predictive value has been shown to be
superior to that of biochemically based ligand-binding assays.96 New treatment recommendations presented at the
ninth St Gallen (Switzerland) consensus conference emphasized the importance of endocrine responsiveness in
choosing appropriate adjuvant systemic treatments for the
patient with invasive breast carcinoma.97 Therefore, the
percentage or proportion of tumor cells that express estrogen and progesterone receptors ideally should be specified
in the pathology report.
erbB2 (HER2-neu) is overexpressed and/or amplified in
20% to 30% of invasive breast carcinomas.98 The 2 most
common commercially available assays use immunohistochemical analysis and fluorescence in situ hybridization
(FISH) and have been approved by the FDA. The issue of
whether immunohistochemical analysis or FISH is a superior determinant of HER2-neu status remains a topic of
debate. The commercial kit for immunohistochemical testing uses a 4-part grading system (0-3+) based on quantitative and staining intensity. Scores of 0 to 1+ are considered
negative, whereas scores of 3+ are considered positive.
Poor correlation exists between weak positivity (2+) by
immunohistochemical analysis and gene amplification by
FISH; therefore, an algorithm has been proposed that all
tumors with weak positivity by immunohistochemical
analysis also be evaluated by FISH before making a decision to recommend anti-HER therapy.99
The most important predictor of disease-free and overall
survival in breast cancer has been axillary lymph node
August 2007;82(8):999-1012
status.100 A correlation has been found between the number

of positive lymph nodes and patient prognosis, with worse
prognosis associated with an increased number of positive
lymph nodes.101
The most important surgical development in breast cancer treatment during the past 10 years has been the adoption
of the sentinel lymph node biopsy (SLNB) as the preferred
technique for axillary staging in invasive cancer.102 Before
the use of SLNB, axillary dissection was the standard procedure for both axillary staging and regional control in the
axillary basin. However, axillary dissection has substantial
attendant morbidity, including lymphedema, sensory deficits, chronic pain, motor nerve injury, depression, and reduced quality of life.103 In most node-negative women with
breast cancer, axillary dissection is a morbid technique for
proving that the nodal basin is clear of disease, and a less
invasive procedure to identify this group is valuable.
The SLNB is based on the concept that metastasis of a
primary tumor follows drainage of breast lymphatics to a
sentinel lymph node before other lymph nodes in the basin.
Therefore, if the sentinel node or nodes are negative, higher
echelon nodes are assumed to be negative, and axillary
dissection can be avoided. Multiple validation studies that
correlate findings of SLNB with concomitant axillary dissection have proven the high accuracy of this procedure,
with false-negative rates consistently less than 10% and
often less than 5%.104 In the SLNB procedure, the sentinel
nodes are located (mapped) via draining breast lymphatics
by injection of tracer agents (radioisotope, blue dye, or
both) in the breast preoperatively. At surgery, lymph nodes
that are hot, blue, or palpably suspicious for disease are
considered sentinel nodes and are removed. Although
SLNB can be performed with a single tracer, the American
Society of Breast Surgeons recommends the use of both
blue dye and isotope for optimal mapping accuracy.105 As
expected, SLNB has proven to be less morbid than axillary
dissection.106,107 Therefore, in cases in which the sentinel
lymph node or nodes are negative for metastasis, no axillary dissection is necessary, reducing surgical morbidity
for most node-negative patients. In contrast, for cases with
positive sentinel nodes, the SLNB procedure has created
some management controversies.
The removal of only a few sentinel lymph nodes allows
more careful histologic evaluation of this tissue compared
with what has been done with an axillary node excision
pathologic specimen. Furthermore, immunohistochemical
staining to detect cytokeratin-positive cells has resulted in a
subset of patients having isolated tumor cells or very small
metastases. The AJCC staging system was modified in
2000 and further stratifies nodal findings for the N1 category based on the measured size of metastasis.108 For
patients with sentinel node metastasis that measures less
Mayo Clin Proc.
than 0.2 mm (including those with isolated tumor cells), the

tumors are considered node negative and are denoted
N0(i+). These patients (a minority of those with sentinel
node findings) should be treated as node negative because
the clinical importance of these subtle histologic findings is
unclear.68 However, some evidence indicates that these
patients are being upstaged, with resulting concerns of
overtreatment and its related toxicity.109
In cases with a true-positive sentinel node (metastasis
>0.2 mm), completion axillary dissection remains the standard of care for both local control and prognostication.
Some centers use intraoperative analysis of sentinel nodes
(either frozen section or touch preparation cytologic testing) and then proceed immediately to axillary dissection,
completing all necessary surgical procedures during 1 operation.110 However, these intraoperative analyses will still
miss some sentinel node metastases found later with permanent sections, leading to the challenging postoperative
discussion with the sentinel nodepositive patient who
has not undergone an axillary dissection. For patients who
have already been staged as having node-positive disease,
many physicians question the need for axillary dissection
since these patients will receive adjuvant systemic treatments and possibly also low axillary radiation as part of
standard breast radiation with tangents. A recent randomized trial was designed to address the need for completion
axillary dissection in the event of a positive sentinel node
(ACOSOG [American College of Surgeons Oncology
Group] Z0011), but this trial closed early because of poor
accrual and has had fewer events than expected in both
treatment arms.111
Of patients with a positive sentinel node, approximately
40% to 60% have no other involved nodes and would not
be expected to benefit from axillary lymph node dissection.112 When the sentinel node is the only node with metastasis, sentinel lymphadenectomy is diagnostic and therapeutic. Therefore, some research efforts have focused on
creating predictive models to identify patients who will
have no disease in the remaining nonsentinel nodes. Early
studies noted that nonsentinel node metastasis was much
less common in patients with micrometastasis in the sentinel node.113 A model to estimate the risk of additional nodal
metastasis was developed at the Memorial Sloan-Kettering
Cancer Center on the basis of common clinicopathologic
characteristics.114 This model has been validated in other
patient populations with acceptable, but variable, performance.115-118 Although overall model performance for a
population may be good, its ability to identify patients without additional nodal disease (based on a low-risk calculation)
may not be highly reliable in that same population.115
Some node-positive patients have chosen not to undergo
a second operation for completion axillary dissection. The
August 2007;82(8):999-1012
1007
limited published literature in such cases demonstrates a

negligible rate of axillary recurrence, with follow-up ranging from 28 to 32 months.119-121 Not surprisingly, one study
has confirmed that node-positive patients who do not undergo axillary dissection are not a random subset of nodepositive patients; they are significantly different than those
who undergo axillary dissection based on multiple clinicopathologic characteristics.122 As one might expect, patients
who forgo axillary dissection are older, have smaller tumors, and have a lower burden of metastasis in the sentinel
node or nodes. These reports confirm that some patients
and clinicians in current practice judge the risk of axillary
dissection to be greater than its benefit, and axillary recurrence rates in these patients may be low enough that omission of axillary dissection is a reasonable approach for
some sentinel lymph nodepositive patients. Although axillary dissection remains the current standard of care for
patients with sentinel lymph nodepositive breast cancer,
this is a controversial issue that deserves further study.
STAGING AND PROGNOSTIC INDICATORS
Because staging systems take into account the extent of
tumor spread in the body, they serve as critical guides to
physicians in deciding appropriate treatment strategies and
in discussing an individual patients prognosis as the risk of
developing metastasis increases with the presence of lymph
node involvement and/or a larger primary tumor. The currently used TNM (representing tumor-node-metastasis)
staging system for breast cancer reflects the revisions implemented in 2003 by the AJCC to account for developments
in biomarker assays, imaging, and surgical techniques.123
It maintains the traditional dual approach of pretreatment
clinical staging complemented by postsurgical histopathologic examination. (Full details on staging are available at
http://nccn.org/professionals/physician_gls/PDF/breast.pdf.)
Careful physical examination and history taking are the key
elements in clinical staging for breast cancer, particularly
since additional imaging studies, such as computed tomography, bone scans, MRI, or positron emission tomography, are
sometimes used to investigate abnormal blood test results
(eg, elevation of liver enzyme levels, bone fraction of serum
alkaline phosphatase) and also to evaluate patients who
present with locally advanced disease. When multiple tumors are present in the same breast, only the largest is
measured to determine the T stage. Metastatic deposits
within axillary fat are considered positive axillary nodes, as
are positive intramammary nodes, even though the actual
axillary nodes are negative.108
Decision making on adjuvant treatment recommendations is a complex process that involves integration of
probabilistic estimates of risk of breast cancer recurrence
and death due to breast cancer as well as competing health
1008
Mayo Clin Proc.
risks with actuarial survival in the context of efficacy data

of available treatment. Although the TNM system is well
established as a prognostic tool, it does not reflect the
biological heterogeneity of breast cancer; thus, it fails to
account for approximately one third of women with nodenegative breast cancer who eventually develop distant metastases, whereas another one third of patients with nodal
involvement of breast cancer remain free of distant metastases 10 years after local therapy.124,125 Thus, various
prediction models, such as the validated Adjuvant! Online
tool (www.adjuvantonline.com),126 have incorporated multiple other variables (eg, tumor grade) to help individualize
risk assessments.
Studies have shown that loss of histopathological differentiation (tumor grade)87,127,128 and presence of lymphovascular invasion are associated with an increased risk of
distant recurrence, especially in node-negative breast cancer.129-131 The expression of estrogen receptor is generally132
but not consistently133 reported to be a favorable prognostic
factor. This prognostic significance is posited to be time
dependent, arising from treatment effect134,135 because of
the correlation of better response to tamoxifen in tumors
with high estrogen receptor levels.136 Outcomes among
postmenopausal women who did not receive adjuvant endocrine treatment were most favorable for those whose
tumors had intermediate expression compared with those
whose tumors had high expression of estrogen receptors.137,138 Moreover, when treated with chemotherapy
alone, premenopausal women younger than 35 years with
estrogen receptorpositive tumors seem to have significantly worse disease-free survival rates than younger patients with estrogen receptornegative tumors.139
Amplification or overexpression of HER2/neu has been
associated with poor survival outcome in patients with axillary lymph node metastases.140 Although its prognostic value
is deemed weak to moderate,141 testing for HER2/neu status
is routine because it is a predictive marker for response to
chemotherapy,142 endocrine therapy,143,144 and agents directed against HER2, such as trastuzumab and lapatinib.145,146
Conversely, the negative prognostic effect on survival
outcomes after detection of tumor cell dissemination, either
in circulation or in the bone marrow, remains controversial147,148 and must be further substantiated by standardized
detection and quantification procedures before clinical use
becomes widespread.
In recent years, mathematical algorithms based on gene
expression profiles have been added to the arsenal of prognostication tools. On the basis of unsupervised clustering
analysis, 3 biologically distinct subtypes of estrogen receptornegative and 2 of estrogen receptorpositive breast
cancers were identified that represented clinically distinct
subgroups of patients. For example, estrogen receptor
August 2007;82(8):999-1012
positive luminal A subtype tumors have the best outcome

of all subtypes.149,150
On the basis of a supervised analytical approach, different gene signatures have also been developed to harness the
prognostic and predictive power of genome-wide interrogation. A 70-gene signature (MammaPrint) was developed
based on a cohort of young patients (<55 years) with lymph
nodenegative breast cancer to assess 5-year disease relapse, although estrogen receptor status and other clinical
variables were not considered.151 The classification based
on this gene profile outperformed other risk classification
criteria and applied just as well to patients with nodal
involvement, implying that acquisition of metastatic potential is an early event in tumorigenesis.152 It is the first
multigene prognostic test that received FDA approval (in
February 2007). Using an alternative microarray platform
that accounts for estrogen receptor status, a gene expression signature of 76 genes also outperformed traditional
risk criteria in predicting 5-year distant relapse outcomes in
patients of all age groups with lymph nodenegative breast
cancer, particularly for estrogen receptorpositive subgroups.153,154 For patients with node-negative estrogen receptorpositive breast cancers who have been treated with adjuvant tamoxifen, an independently prognostic 21-gene signature profile (Oncotype DX) has been developed to generate a
recurrence score that quantifies individual risk of distant
disease in this group of patients.155 Although this information
may help patients and physicians decide on the utility of
adjuvant systemic chemotherapy depending on the recurrence risk score, this test will be of questionable value in
decision making to approximately one fifth of this group of
women who will have an intermediate score. Moreover, no
strong evidence is available on its prognostic value among
patients not receiving adjuvant systemic therapy.156-158 This
finding led to the recent opening of a large randomized
clinical trial (TAILORx [Trial Assigning IndividuaLized
Options for Treatment (Rx)]) in which patients with nodenegative, estrogen receptorpositive breast cancer with an
intermediate risk prognosis according to Oncotype DX are
randomized to either hormonal therapy alone or chemotherapy followed by hormonal therapy. The trial is powered
to establish nonsuperiority between these 2 treatment arms
but only in patients with intermediate-risk tumors. In contrast, there is no randomization in either the high- or low-risk
group. Patients with low-risk scores are offered only hormonal therapy, whereas patients with high-risk scores are
offered chemotherapy followed by hormonal therapy.
CONCLUSION
Breast cancer care requires a multidisciplinary approach.
The team of breast experts includes primary care physiMayo Clin Proc.
cians (internists, family medicine specialists, and nurses),

geneticists, breast radiologists, breast pathologists, surgical
breast specialists, and radiation and medical oncology specialists. The complexity of breast cancer has increased with
the advent of risk-reducing strategies, breast imaging technology, new drug therapies, and the integration of
genomics into the evaluation and treatment of patients. As
each member of the team focuses on his or her area of
expertise, patients benefit from the collaboration, and overall this provides optimal, quality patient care.
Part 2 of this contribution will provide a comprehensive
overview of new adjuvant therapies. The overview will
describe the role of partial breast radiation, adjuvant hormonal and systemic options, tamoxifen pharmacogenetics,
and antiHER2 therapy with the goal of providing caregivers with state-of-the-art treatment for breast cancer.
We acknowledge Jillian J. Nickell from the Office of Womens
Health, Mayo Clinic, Rochester, MN, for assistance with manuscript preparation.
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The Symposium on Solid Tumors will continue in the September issue.

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SYMPOSIUM

A Multidisciplinary Approach to the Management of Breast Cancer, Part 1:

Mayo Clin Proc. 2007;82(8):999-1012

information from their primary care physicians about

PREVENTION AND DIAGNOSIS OF BREAST CANCER

genesis has become an increasingly important risk factor

Mayo Clin Proc.

that increases risk. Increasing knowledge of the role of

PREVENTION AND DIAGNOSIS OF BREAST CANCER

no greater than a 1.5-fold relative risk of developing breast

used by the clinician during the office visit. This model

PREVENTION AND DIAGNOSIS OF BREAST CANCER

tions between lifestyle and cancer risk. The ultimate goal of

Mayo Clin Proc.

and ovarian cancer, carriers of the BRCA mutation, women

PREVENTION AND DIAGNOSIS OF BREAST CANCER

all age groups. In women with LCIS, a 56% reduction was

An important prevention study was the NSABP P-2

PREVENTION AND DIAGNOSIS OF BREAST CANCER

Mayo Clin Proc.

PREVENTION AND DIAGNOSIS OF BREAST CANCER

42,760 women at 33 centers underwent both digital and

high-risk patient, investigators consistently find a higher

PREVENTION AND DIAGNOSIS OF BREAST CANCER

status proving to be a significant indicator of local tumor

Mayo Clin Proc.

PREVENTION AND DIAGNOSIS OF BREAST CANCER

status.100 A correlation has been found between the number

than 0.2 mm (including those with isolated tumor cells), the

PREVENTION AND DIAGNOSIS OF BREAST CANCER

limited published literature in such cases demonstrates a

Mayo Clin Proc.

risks with actuarial survival in the context of efficacy data

PREVENTION AND DIAGNOSIS OF BREAST CANCER

positive luminal A subtype tumors have the best outcome

cians (internists, family medicine specialists, and nurses),

PREVENTION AND DIAGNOSIS OF BREAST CANCER

17. Harvey JA, Bovbjerg VE. Quantitative assessment of mammographic

Mayo Clin Proc.

39. Cuzick J. Aromatase inhibitors for breast cancer prevention. J Clin

PREVENTION AND DIAGNOSIS OF BREAST CANCER

Mayo Clin Proc.

89. Robbins P, Pinder S, de Klerk N, et al. Histological grading of breast

PREVENTION AND DIAGNOSIS OF BREAST CANCER

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