Breast Cancer Overview: Risk Factors, Screening, Genetic Testing, and Prevention

June 1, 2015

Article

This management guide covers the risk factors, symptoms, screening, diagnosis, prevention, and staging of breast cancer.

Overview

Breast cancer is the most common malignancy in women, accounting for 29% of all female cancers; it accounts for < 1% of all cancer cases in men. Breast cancer also is responsible for 15% of cancer deaths in women, making it the number-two cause of cancer death. An estimated 234,190 new breast cancer cases will be diagnosed in women and 2,350 new cases will be diagnosed in men in the United States in 2015, and 40,290 women and 440 men will die of this cancer. As of 2014, there were more than 2.8 million women breast cancer survivors in the United States.

Epidemiology

Gender

Breast cancer is relatively uncommon in men; the female-to-male ratio is approximately 100:1. The incidence of breast cancer in men has remained relatively stable over the past decades, except in Africa, where, for unclear reasons, the incidence is rising. BRCA2 mutations are associated with an increased risk of breast cancer in men. The most common presentations of breast cancer in men are asymmetric gynecomastia or a palpable mass. All palpable masses in men should be carefully examined. Based on the physical examination findings, mammography and breast ultrasonography should be considered. Fine-needle aspiration (FNA) or core biopsy can be used to distinguish between gynecomastia and breast cancer. Core biopsy may be performed if the FNA is nondiagnostic.

Age

The risk of developing breast cancer increases with age. The disease is less common in women younger than 40 years of age; only about 0.8% of breast cancers occur in women < 30 years old, and approximately 6.5% develop in women between 30 and 40 years old.

Race

Caucasian women have a higher overall rate of breast cancer than do African-American women; however, this difference is not apparent until age 50 and is marked only after menopause. There is a higher incidence in young African-American women when compared to young Caucasian women. In the United States, the incidence of breast cancer in Asian and Hispanic women is approximately half that in white women. Breast cancer risk is extremely low in Native-American women.

Geography

There is at least a fivefold variation in the incidence of breast cancer reported in different countries, although this difference appears to be narrowing. The incidence of breast cancer is significantly lower in Japan, Thailand, Nigeria, and India than in Denmark, the Netherlands, New Zealand, Switzerland, the United Kingdom, and the United States. Women living in North America have the highest rate of breast cancer in the world. It has been suggested that these trends in breast cancer incidence somehow may be related to dietary influences, particularly dietary fat consumption (see section on “Etiology and risk factors”).

Socioeconomic Status

The incidence of breast cancer is higher in women of higher socioeconomic background. This relationship is most likely related to lifestyle differences, such as age at first birth and dietary fat intake.

TABLE 1: Survival of women with breast cancer, according to stage, without chemotherapy

Survival

Survival rates for patients with nonmetastatic breast cancer have improved in recent years (Table 1). These improvements may be secondary to advances in screening, systemic therapy, and locoregional radiation therapy. The contribution of screening mammography to breast cancer–specific survival is variable, favoring a reduction in breast cancer mortality of up to 25% in some series. Its impact on overall survival is less certain.

Etiology and Risk Factors

The development of breast cancer has been associated with numerous risk factors, including genetic, environmental, hormonal, and nutritional influences. Despite all of the available data on breast cancer risk factors, 75% of women with this cancer have no readily identifiable risk factors.

Genetic Factors

Hereditary forms of breast cancer constitute only 5% to 10% of breast cancer cases overall. However, the magnitude of the probability that a woman will develop cancer if she inherits a highly penetrant cancer gene mutation justifies the intense interest in predictive testing. Commercial testing is available for several genes, including BRCA1, BRCA2, tumor protein 53 gene (TP53), and the PTEN gene in Cowden Syndrome (described later in this chapter), associated with a high risk of breast cancer development. Economical next-generation sequencing technologies have prompted in part the development of multigene panels including these high penetrance and multiple lower penetrance genes.

For example, a modest increased risk (relative risk of 3.9 to 6.4) may be seen in women who are heterozygous for a mutation in the ataxia-telangiectasia mutated gene (ATM gene), which is associated with the recessive disease ataxia-telangiectasia in the homozygous state. A moderately increased risk of breast cancer (2-fold for women and 10-fold for men) has also been associated with a variant (1100 delC) in the cell-cycle checkpoint kinase gene, CHEK2.

BRCA1 gene

The BRCA1 gene is located on chromosome 17. This gene is extremely large and complex, and there are more than 1,000 different possible mutations. BRCA1 mutations are inherited in an autosomal-dominant fashion and are associated with an increased risk of breast, ovarian, and, to a lesser degree, prostate cancers. A BRCA1 mutation carrier has a 56% to 85% lifetime risk of developing breast cancer and a 15% to 45% lifetime risk of developing ovarian cancer.

BRCA2 gene

The BRCA2 gene is located on chromosome 13. BRCA2 is approximately twice as large as BRCA1 and is similarly complex. Alterations in BRCA2 have been associated with an increased incidence of breast cancer in both women (similar to BRCA1) and men (6% lifetime risk). BRCA2 mutations are also associated with an increased risk of ovarian cancer, pancreatic cancer, prostate cancer, and melanoma. Together, mutations of BRCA1 and BRCA2 have been linked to most hereditary breast and ovarian cancer families and approximately half of hereditary breast cancer families.

The incidence of BRCA gene mutations in the general breast cancer population is unknown, since most of the data have come from studies of high-risk populations. In one population-based study of women with breast cancer, 9.4% of women < 35 years of age at the time of diagnosis and 12% of women < 45 years old who also had a first-degree relative with breast cancer had germline BRCA1 or BRCA2 mutations. However, a 40-year-old woman of Ashkenazi Jewish ancestry who has breast cancer has a 20% to 30% probability of bearing one of three founder BRCA gene mutations, based on data from high-risk clinics, testing vendors, and Israeli series. BRCA probability models are discussed below.

Li-Fraumeni syndrome

This rare syndrome is characterized by premenopausal breast cancer in combination with childhood sarcoma, brain tumors, leukemia, and adrenocortical carcinoma. Tumors frequently occur in childhood and early adulthood and often present as multiple primaries in the same individual. Germline mutations in the TP53 gene on chromosome 17p have been documented in persons with this syndrome. Inheritance is autosomal dominant, with a penetrance of at least 50% by age 50. Although the rarity of this syndrome, the diversity of tumor types, and the fact that the age of patients at risk spans from childhood to young adulthood makes coherent screening strategies beyond those for early-onset breast cancer risk difficult to find, a recent pilot study with 18-fluorodeoxyglucose positron emission tomography/CT scanning was promising. Gonzalez et al have reported on the largest experience with clinical TP53 testing published thus far. In all, 91 of 525 patients had a deleterious mutation. The investigators derived user-friendly mutation-probability tables based upon presenting features of individuals and families, with the highest yield noted among children with choroid plexus tumors. Testing for TP53 mutations in BRCA-negative women diagnosed with breast cancer under 30 years old was cited in the 2009 National Comprehensive Cancer Network (NCCN) guidelines.

Cowden syndrome

This syndrome is inherited as an autosomal-dominant trait and is notable for a distinctive skin lesion (trichilemmoma) and mucocutaneous lesions. Patients with this uncommon syndrome have a high incidence of hyperplastic gastrointestinal polyps, early-onset uterine cancer, and thyroid disorders; lifetime estimates for breast cancer among women with this syndrome range from 25% to 50%. Germline mutations in the PTEN gene, located on chromosome 10q23, are responsible for this syndrome. The key issues for management include screening for breast, thyroid, and uterine cancers.

Family History

The overall relative risk of breast cancer in a woman with a positive family history in a first-degree relative (mother, daughter, or sister) is 1.7. Premenopausal onset of the disease in a first-degree relative is associated with a threefold increase in breast cancer risk, whereas postmenopausal diagnosis increases the relative risk by only 1.5. When the first-degree relative has bilateral disease, there is a fivefold increase in risk. The relative risk for a woman whose first-degree relative developed bilateral breast cancer prior to menopause is nearly 9.

Proliferative Breast Disease

The diagnosis of certain conditions on a breast biopsy is also associated with an increased risk for the subsequent development of invasive breast cancer. They include moderate or florid ductal hyperplasia and sclerosing adenosis, which pose only a slightly increased risk of breast cancer (1.5–2 times); atypical ductal or lobular hyperplasia, which moderately increases risk (4–5 times); and lobular carcinoma in situ (LCIS), which markedly increases risk (8–11 times; see more detailed discussion of LCIS in the “Stages 0 and I Breast Cancer” chapter). Patients who have a family history of breast cancer along with a personal history of atypical epithelial hyperplasia have an 8-fold increase in breast cancer risk when compared with patients with a positive family history alone and an 11-fold increase in breast cancer risk when compared with patients who do not have atypical hyperplasia and have a negative family history.

Disease Site and Personal Cancer History

The left breast is involved slightly more frequently than the right, and the most common locations of the disease are the upper outer quadrant and retroareolar region. The risk of a second primary breast cancer is highest in BRCA1 and BRCA2 mutation carriers and in women whose first breast cancer was diagnosed at age < 50. The risk is approximately 0.5% per year after the first diagnosis in the setting of sporadic disease. The risk of contralateral breast cancer in women with a mutation of a breast cancer gene (BRCA) is approximately 3% to 5% per year or about 40% at 10 years after the initial diagnosis of breast cancer, with a cumulative lifetime risk of up to 64% in high-risk cohorts.

Tamoxifen reduces the risk of breast cancer and is an effective chemopreventive agent. Bilateral salpingo-oophorectomy (BSO) also reduces breast cancer risk, especially when this procedure is performed in women younger than age 50. The protective effect of BSO is pronounced among women who develop breast cancer premenopausally. Exemestane was recently shown to significantly reduce the risk of invasive breast cancer in high-risk postmenopausal women. It is another option for chemoprevention.

A personal history of breast cancer is a significant risk factor for the subsequent development of a second, new primary breast cancer. This risk has been estimated to be as high as 1% per year from the time of diagnosis of an initial sporadic breast cancer. Women with a history of endometrial, ovarian, or colon cancer also have a higher likelihood of developing breast cancer than do those with no history of these malignancies.

Menstrual and Reproductive Factors

Early onset of menarche (< 12 years old) has been associated with a modest increase in breast cancer risk (twofold or less). Women who undergo menopause before age 30 have a twofold reduction in breast cancer risk when compared with women who undergo menopause after age 55. A first full-term pregnancy before age 30 appears to have a protective effect against breast cancer, whereas a late first full-term pregnancy or nulliparity may be associated with a higher risk. There is also a suggestion that lactation protects against breast cancer development.

Radiation Exposure

An increased rate of breast cancer has been observed in survivors of the atomic bomb explosions in Japan, with a peak latency period of 15 to 20 years. It has also been noted that patients with Hodgkin lymphoma who are treated with mantle irradiation, particularly women who are younger than age 20 at the time of radiation therapy, have an increased incidence of breast cancer.

Exogenous Hormone Use

In regard to hormone replacement therapy (HRT) or postmenopausal hormone use, results from the Women’s Health Initiative (WHI) showed that the overall risks of estrogen plus progestin outweigh the benefits. This large randomized clinical trial sponsored by the National Institutes of Health (NIH) included more than 16,000 healthy women. Results from the WHI trial were published in 2002, after an average 5.6 years of follow-up, and included a 26% increase in risk of invasive breast cancer among women taking estrogen plus progestin, as compared with women taking placebo. In addition, in women taking these hormones, there were increased risks of heart disease, stroke, and blood clots.

The NIH stopped the estrogen-alone arm of the WHI trial in March 2004. No increase in breast cancer risk was observed in the estrogen-alone arm during the study period (7 years of follow-up). The NIH concluded that estrogen alone does not appear to increase or decrease a woman’s risk of heart disease, although it does appear to increase her risk of stroke and decrease her risk of hip fracture.

Following the publication of the WHI trial results, the use of HRT in the United States declined by almost 40% from 2002 to 2003. During approximately the same period, there was a 6.7% decline in the age-adjusted incidence of breast cancer. Furthermore, the decrease was evident only among women 50 years of age and older and primarily among those with estrogen receptor–positive breast cancers.

Alcohol

Moderate alcohol intake (two or more drinks per day) appears to modestly increase breast cancer risk.

High-Fat Diet

Diets that are high in fat have been associated with an increased risk for breast cancer. Women who have diets high in animal fat from high-fat dairy foods have an increased risk of developing breast cancer. Whether the increase in breast cancer risk is associated with the fat content or an unknown carcinogen in these foods is unclear. There is no association between the consumption of red meat and an increased risk of breast cancer.

Obesity

Alterations in endogenous estrogen levels secondary to obesity may enhance breast cancer risk. Obesity appears to be a factor primarily in postmenopausal women.

In late 2007, the relative risks of cancer incidence and mortality from the Million Women Study were reported. The study analyzed data on 1.2 million women in the UK (age from 1996-2001, 50-64 years) who were followed for an average of 5.4 years for cancer incidence and 7 years for cancer mortality. In all, 45,037 incident cancers and 17,203 deaths from the disease occurred during follow-up. An increased incidence of breast cancer with increasing body mass index (BMI) was noted. For breast cancer, the effect of BMI on risk differed significantly according to menopausal status (relative risk in postmenopausal women = 1.40). Calculations were adjusted for BMI, age, geographic region, socioeconomic status, age at first birth, parity, smoking status, alcohol use, physical activity, number of years since menopause, and use of HRT.

Genetic Cancer Risk Assessment

Genetic testing clearly has the potential to benefit carefully selected and counseled families. Education and adequately trained health care professionals are key elements in the successful integration of genetic cancer-risk assessment into clinical practice.

The genetic risk assessment process begins with an evaluation of perceived risk and the impact of cancer on the patient and family. This information forms the framework for counseling.

Comprehensive Personal and Family Histories

Detailed information regarding personal, reproductive, and hormonal risk factors is noted. Family history, including age at disease onset, types of cancer, and current age or age at death, is obtained for all family members going back at least three generations.

Documentation of Cancer Cases

Documentation is crucial to accurate risk estimation. Pathology reports, medical record notes, and death certificates may all be used in determining the exact diagnosis.

Pedigree Construction and Evaluation

The family pedigree is then constructed and analyzed to determine whether a pattern of cancer in the family is consistent with genetic disease. Sometimes, small family structure or lack of information about the family limits assessment of a hereditary trait; other times, clues such as ancestry or early age at diagnosis influence risk assessment and the usefulness of genetic testing.

Individual Risk Assessment

Several models are used to estimate the likelihood that a detectable BRCA1 or BRCA2 mutation is responsible for the disease in the family. The BRCA PRO computer program is a cancer risk–assessment tool that uses a family history of breast or ovarian cancer in first- and second-degree relatives to calculate the probabilities that either a BRCA1 or BRCA2 mutation is responsible for the disease. It includes a Bayesian calculation (of conditional probability) to account for age-specific penetrance differences. If genetic testing is not performed or results are uninformative, the empiric breast cancer risk is estimated by the phenotype as well as the Claus model (derived from the Cancer and Hormone Study, which uses age at onset of breast cancer among first- and second-degree relatives) or Gail model (which uses a combination of family, menstrual, reproductive, and breast pathology information). Personal and family characteristics that are associated with an increased likelihood of a BRCA1 or BRCA2 mutation are summarized in Table 2.

TABLE 2: Features indicating an increased likelihood of a

BRCA

mutation

Education

Patients should be given information about the principles of genetics and hereditary cancer patterns and the application of genetic testing (appropriateness, limitations, advantages, and disadvantages).

Genetic Counseling and Testing

Informed consent is obtained before genetic testing is performed. For individuals who decide to undergo testing, a post-test counseling session is scheduled to disclose and explain the results in person.

TABLE 3: Risk management options for

BRCA

mutation carriers

Customized Screening and Prevention Recommendations

Regardless of whether or not a woman undergoes genetic testing, a customized management plan is delineated, with the goal of preventing or detecting malignancy early, within the context of the patient’s personal preferences and degree of risk (Table 3).

Laboratory Methods and Limitations

Several techniques/strategies for detecting mutations in cancer genes have been adopted by different researchers and commercial vendors. The number of vendors offering BRCA gene testing has expanded rapidly as a result of a recent Supreme Court decision invalidating many patents held by the previously exclusive US vendor.

Directed assays are available for specific founder or ancestral mutations that are common in a given population. Among Ashkenazi Jews, 1 in 40 individuals bears one of three founder mutations (185delAG and 5382insC in BRCA1 and 6174delT in BRCA2); these mutations account for 25% of early-onset breast cancer in this population. Moreover, 95% of Ashkenazi Jews with a BRCA gene mutation will have one of the three founder mutations. However, complete gene sequencing can be performed if a patient does not test positive for a founder mutation.

Large genomic rearrangements of the BRCA genes account for approximately 10% of all deleterious mutations and are not detectable by the standard sequenceing test. The NCCN guidelines recently defined BRCA testing as full sequencing of the translated exons and full screening for large rearrangements (aka BART, per one commercial vendor).

Limitations

All of the approaches to detecting mutations have limitations. In general, discovery of an inactivating or “deleterious” mutation of either BRCA1 or BRCA2 indicates a high probability that a person will develop breast and/or ovarian cancer.

One of the greatest challenges is the interpretation of missense mutations. These mutations are more likely to be significant if located in an evolutionarily conserved or functionally critical region of the protein. In the absence of a clear disease association, it is often difficult to exclude the possibility that a given missense alteration simply represents a rare polymorphism. Using advanced methods, a recent study was able to characterize 133 of 1,433 variants as likely polymorphisms and 43 as likely deleterious; the majority would still be designated as “genetic variants of uncertain significance.”

Although less common, mutations in other genes besides BRCA1 and BRCA2 (eg, CHEK2 and TP53) may predispose patients to breast cancer. Clinical characteristics such as macrocephaly and/or uterine and thyroid cancer may direct the diagnostic strategy to the genes, such as PTEN associated with Cowden syndrome.

Testing Strategies

In general, testing should be initiated with the youngest affected individual in a given family. Even if one is convinced that a family has hereditary breast and ovarian cancers based on clinical criteria, there is only a 50% chance that an offspring or sibling of an affected patient will have inherited the deleterious allele. Therefore, only a positive test result (detection of a known or likely deleterious mutation) is truly informative. There are no established guidelines regarding when to deploy multigene panel testing, but such an approach may be valuable if the family cancer phenotype implicates more than one genetic syndrome (eg, colon cancer or pancreatic cancer in a breast cancer patient’s family), or when BRCA gene testing is uninformative in a very high risk patient/family.

Until the “familial mutation” is known, a negative test result could mean either that the unaffected person being tested did not inherit the cancer-susceptibility mutation or that the person inherited the disease-associated gene but the mutation was not detectable by the methods used.

In many cases, no affected family members are available for testing. In such circumstances, one may proceed with genetic testing of an unaffected person, but only after that individual has been thoroughly counseled regarding the risks, benefits, and limitations of testing.

Unless there is a suggestive family history, cancer-susceptibility testing is not considered appropriate for screening unaffected individuals in the general population. However, it may be reasonable to test unaffected persons who are members of an ethnic group in which specific ancestral mutations are prevalent and whose family structure is limited (ie, the family is small, with few female relatives or no information due to premature death from noncancerous causes).

Impact of Genetic Cancer Risk Status on Management

Data from the Breast Cancer Linkage Consortium suggest that the cumulative risk of developing a second primary breast cancer is approximately 65% by age 70 among BRCA gene mutation carriers who have already had breast cancer. A large, retrospective cohort study of BRCA mutation carriers with a history of limited-stage breast cancer indicated up to a 40% risk of contralateral breast cancer at 10 years. A subsequent study of the same cohort noted almost a 13% risk for ovarian cancer in the same interval and reported that ovarian cancer was the cause of cancer death in 25% of stage I breast cancer patients with BRCA mutations.

Thus, knowledge of the genetic status of a woman affected with breast cancer might influence the initial surgical approach (eg, bilateral mastectomy might be recommended for a mutation carrier instead of a more conservative procedure). Moreover, since ovarian cancer risk may be markedly increased in women with BRCA1 mutations (and to a lesser degree with BRCA2 mutations), additional measures, such as surveillance for presymptomatic detection of early-stage tumors or consideration of oophorectomy, may be warranted.

According to data from BRCA-mutated carriers who underwent risk-reduction salpingo-oophorectomy (RRSO), breast cancer risk is also decreased following bilateral oophorectomies, as is all-cause mortality.

Rebbeck et al performed a meta-analysis of published studies of RRSO in BRCA-mutation carriers and confirmed the magnitude of breast cancer risk reduction associated with the procedure. Critically, their findings firmly established a significant risk reduction for BRCA1 carriers (hazard ratio [HR] = 0.49; 95% confidence interval [CI], 0.35–0.64), who are predisposed to ER-negative tumors in particular.

Both retrospective and prospective data have demonstrated the efficacy (> 90% risk reduction) of bilateral mastectomy in women who are at high risk for the disease based upon BRCA genetic status. Women who opt for risk-reduction mastectomy should be offered reconstruction. Skin-sparing mastectomy may enhance the cosmetic results of reconstruction and should be discussed with the patient’s surgeon. This procedure entails removing the breast tissue (including the nipple-areolar complex). Women who develop breast cancer despite prophylactic mastectomy may develop it in the locoregional areas such as the chest wall or skin or lymph nodes; in rare instances, it may present as a metastasis at a distant site.

The efficacy of bilateral risk-reduction mastectomy has been confirmed in a large prospective study of 483 women with BRCA mutations. With a mean follow-up of 6.4 years, risk-reduction mastectomy reduced the risk of breast cancer by 90% (95% in women who also underwent RRSO).

Potential Benefits and Risks of Genetic Testing

The ability to identify individuals at highest risk for cancer holds the promise of improved prevention and early detection of cancers. Patients who are not at high risk can be spared anxiety and the need for increased surveillance. Recent studies suggest a better emotional state among at-risk relatives who undergo testing than among those who choose not to know their status. The patient’s perception of risk is often much higher than risk estimated by current models.

Potential risks

Potential medical, psychological, and socioeconomic risks must be addressed in the context of obtaining informed consent for genetic testing.

Concerns about insurance. Fear about adverse effects of testing on insurability remains the premier concern among patients. Close behind that is concern about the cost of analyzing large complex genes, though the cost of genetic analyses is decreasing quickly.

Legal and privacy issues. The legal and privacy issues surrounding genetic testing are as complex as the testing technologies. Although several state laws regarding the privacy of medical information, genetic testing, and insurance and employment discrimination have been passed, they vary widely.

The 1996 Health Insurance Portability and Accountability Act (US public law 104-191), governing group medical plans, stipulates that genetic information may not be treated as a preexisting condition in the absence of a diagnosis of the condition related to such information. It further prohibits basing rules for eligibility or costs for coverage on genetic information. However, the law did not address genetic privacy issues and does not cover individual policies. Many states have laws addressing genetic discrimination, but concerns about gaps remain. Recent Federal legislation expanded protection against genetic discrimination to include individual policies. The Genetic Information Nondiscrimination Act of 2008 (GINA) prohibits health insurers and employers from discriminating against individuals on the basis of genetic information.

Recommendations for Genetic Testing

Guidelines from the American Society of Clinical Oncology (ASCO) recommend that cancer predisposition testing be offered only in the following situations: (1) if a person has a strong family history of cancer or early onset of disease; (2) if the test can be adequately interpreted; and (3) if the results will influence the medical management of the patient or family member. ASCO updated its policy statement regarding genetic testing to extend commentary on the lack of documented clinical utility of commercially available genomic tests relying on single nucleotide polymorphism markers with very modest relative risk for breast cancer.

NCCN practice guidelines for genetics/familial high-risk cancer screening are updated annually and published at www.nccn.org.

Weitzel et al characterized the impact of family structure on the prevalence of BRCA gene mutations among 306 women who developed breast cancer before the age of 50 years and who had no first- or second-degree relatives with breast or ovarian cancer. BRCA mutations were detected in 13.7% of women with limited family structure (ie, fewer than two first- or second-degree relatives surviving beyond age 45 years in either lineage) and 5.2% of those having adequate family structure. Family structure, therefore, apparently is a strong predictor of mutation status (odds ratio = 2.8; 95% CI, 1.19–6.73, P = .019). The NCCN genetic testing guidelines are more inclusive for single cases of breast cancer when family structure is limited.

Signs and Symptoms

Mammographic Findings

A large proportion of breast malignancies are being discovered in asymptomatic patients through the use of screening mammography. Mammographic features suggestive of malignancy include asymmetry, microcalcifications, a mass, or an architectural distortion.

When these features are identified on a screening mammogram (see Figures 1–5), they should, in most cases, be further evaluated with a diagnostic mammogram (and, in some cases, with a breast ultrasonographic image or, in highly selected cases, with MRI [Figure 6]) prior to determining the need for a tissue diagnosis. Often, pseudolesions, such as those caused by a summation artifact, dust on the mammographic cassettes, and dermal calcifications, are correctly identified in this manner. All mammographic lesions (and the examinations themselves) must be unambiguously categorized according to one of the six Breast Imaging Reporting Data System (BI-RAD) classifications developed by the American College of Radiology (ACR) (Table 4). The ACR released the 5th edition of its BI-RADS Atlas in late 2013.

TABLE 4: BI-RAD classification of mammographic lesions

Breast Lump

When signs or symptoms are present, the most common presenting complaint is a lump within the breast. The incidence of this complaint can range from 65% to 76%, depending on the study.

Inflammatory Breast Cancer

Inflammatory breast cancer is particularly aggressive, although relatively uncommon, accounting for about 5% of all breast cancers. On breast palpation, there often is no definite mass, but the breast appears to be enlarged, with erythema, skin edema (peau d’orange), and skin ridging. A short trial of antibiotics or, on rare occasions, ultrasonography, may be helpful in differentiating mastitis from inflammatory breast cancer. If the problem does not resolve with the antibiotic treatment, a workup and biopsy are necessary.

Paget Disease

This condition has been associated with intraductal carcinoma involving the terminal ducts of the breasts and may have an associated invasive component. It presents as an eczematoid change in the nipple, a breast mass, or bloody nipple discharge. Cytology may be helpful in establishing the diagnosis; however, negative cytologic results should not preclude a biopsy.

Other Local Symptoms

Breast pain is the presenting symptom in about 5% of patients; breast enlargement, in 1%; skin or nipple retraction, in about 5%; nipple discharge, in about 2%; and nipple crusting or erosion, in 1%.

Screening and Diagnosis

Screening

Breast self-examination

The role of breast self-examination is controversial. The American Cancer Society (ACS) no longer recommends monthly self-breast examinations. However, all women should learn about the potential benefits, limitations, and harms (false-positive results) of breast self-examinations. Women should receive instructions regarding proper technique for breast self-exams and then individually may choose to perform them monthly, occasionally, or never. Other groups have suggested that routine breast self-examination may lead to more false-positive results and therefore more benign biopsies. One meta-analysis of 12 studies involving a total of 8,118 patients with breast cancer correlated the performance of breast self-examination with tumor size and regional lymph node status. Women who performed breast self-examination were more likely to have smaller tumors and less likely to have axillary node metastases than those who did not. A multicenter study from Memorial Sloan-Kettering Cancer Center and the University of Virginia attempted to measure the benefits and costs of adding clinical breast exams to yearly screening mammography. These exams detected an additional 14 breast cancers, or 0.02% of the 60,027 exams performed, and the cost for each additional cancer detected was $122,598. Based on this report, the benefit of clinical breast exams appears to be marginal.

A major problem with breast self-examination as a screening technique is that it is rarely performed well. Only 2% to 3% of women do an ideal examination a year after instruction has been provided.

FIGURE 1: Malignant calcifications (comedocarcinoma) in a classic linear dot-and-dash configuration (BI-RAD 5 lesion). BI-RAD = Breast Imaging Reporting Data System.

FIGURE 2: Left panel: A dense mass with partially unsharp margins (BI-RAD 4 lesion), which proved to be a fibroadenoma. Right panel: A small, spiculated mass (BI-RAD 5 lesion), which has engulfed a coarse, benign calcification.

FIGURE 3: Left panel: This focal mass with truly nonsharp margins (BI-RAD 4 lesion) was diagnosed as a tubular carcinoma on stereotactic core biopsy. Right panel: A well-circumscribed lesion containing fat (BI-RAD 2 lesion), which is pathognomonic for a breast hamartoma (fibroadenolipoma).

FIGURE 4: Focal architectural distortion may be difficult to see, but, if confirmed, it has the highest positive predictive value for breast carcinoma. This BI-RAD 4 lesion proved to be an invasive lobular carcinoma, which often has a subtle mammographic appearance.

FIGURE 5: This breast ultrasonographic image demonstrates a hypoechoic, solid mass, which exhibits posterior shadowing and is taller than it is wide. This BI-RAD 4 lesion proved to be an invasive ductal carcinoma, not otherwise specified.

FIGURE 6: A 42-year-old woman presents with axillary adenopathy, which was positive on fine-needle aspiration. Results of a clinical breast exam, mammography, and ultrasonography were normal. A 7-mm enhancing cancer is clearly seen on this MRI of the breast.

FIGURE 7: In addition to an obvious palpable tumor laterally, a selected slice from a tomosynthesis image also demonstrated a second tumor located more centrally (arrow), which was occult to mammography and ultrasound.

Clinical breast examination

Beginning at age 40, the clinical breast examination should be timed to occur near or prior to screening mammography. If the clinician detects an abnormality, the patient should then undergo diagnostic imaging rather than screening. Clinical breast examination should be performed and a complete breast history obtained when a woman presents for routine health care. The clinical examination should include inspection and palpation of the breast and regional lymph nodes. Between 14% and 21% of breast cancers are detected by clinical breast examination.

Mammography

Despite conflicting coverage in the lay press, the benefits of screening mammography have been well established by the findings of 11 large-scale evidence-based clinical trials. The ACS, the ACR, and the American Medical Association have updated their guidelines since 1997 and recommend annual mammography beginning at age 40. The National Cancer Institute (NCI) also updated its guidelines in 1997, recommending that women undergo screening mammography every 1 to 2 years beginning in their 40s. In November 2009, the US Preventive Services Task Force (USPSTF) released a comprehensive review of multiple aspects of breast cancer screening. The Task Force issued five controversial recommendations, which would have revolutionized current practices, including recommendations against yearly mammography (at any age), clinical breast exams, and teaching breast self-examinations, as well as mammography starting at age 50 and a mammogram every other year. There is little, if any, support for implementing these wide-ranging recommendations from the medical specialists involved, including strong pushback from the breast imaging community. However, there is evidence that participation in mammographic screening programs dropped nationwide after the release of the Task Force review, perhaps because its credibility was higher among primary care physicians, compared with their breast cancer consultants. The USPSTF has updated its guidelines and now recommends mammography every 2 years, alone or with clinical breast examination, for women aged 50 and older who are at average risk for breast cancer.

Screening mammography

Screening mammography is performed in the asymptomatic patient to detect an occult breast cancer. This contrasts with diagnostic mammography, which is performed in a patient with a breast abnormality (palpable mass, bloody nipple discharge, or some other clinical finding) to further identify the etiology of the problem.

Physical examination and mammography are complementary. Mammography has a sensitivity of 85% to 90% and, thus, would miss 10% to 15% of clinically evident tumors while detecting the majority of cases an average of 2 years prior to any perceptible clinical signs or symptoms.

Screening recommendations for average-risk patients. No upper age limit has been suggested, and screening should continue in women who are in good health and would be candidates for breast cancer treatment. The benefits of screening begin to accrue 5-plus years after the screen, so clinicians should assess the need for screening the geriatric population in light of any signficant comorbidities.The previous recommendation for a “baseline” mammogram between the ages of 35 and 40 has been withdrawn. Thus, both the ACS and the NCCN recommend annual mammography starting at age 40 for women at average risk of breast cancer. The USPSTF currently recommends yearly screening mammograms starting at age 50.

Screening recommendations for high-risk patients. Based on epidemiologic evidence that premenopausal familial breast cancer often presents at similar ages among affected family members, many breast imaging centers recommend that yearly screening for such high-risk individuals begin approximately 10 years prior to the youngest age at which a first-degree relative was diagnosed with breast cancer. For example, according to this algorithm, a woman whose mother developed breast cancer at age 45 could begin yearly screening at age 35, in addition to biannual clinical breast examinations. These commonly used screening algorithms are not based on formal studies but have arisen based on the natural history of the disease. They are, however, in keeping with the recommendations of the NCCN guidelines. Screening for women at genetic risk may begin at age 25. There are numerous studies supporting the use of breast MRI in women at genetic risk, all of which indicated that sensitivity for breast MRI screening is > 80%.

Digital mammography

Digital mammography was approved by the FDA in 2000 and is rapidly being adopted by leading breast cancer centers worldwide. Initial trials indicate a comparable sensitivity to film-based mammography, with the benefit of a reduced risk of women called back from screening for additional workup. The FDA also approved computer-aided detection (CAD) systems for mammography beginning in 2001. Mammograms are scanned by a computer, and possible lesions are marked for further review by a radiologist. A number of studies have shown a reduced risk of “missed cancers” when computer-aided diagnosis is thus employed. Although some physicians are skeptical about the benefits of such CAD systems for mammography, many investigators in the field continue to support their use. For example, Lindfors et al published data showing that these systems increased the effectiveness of mammographic screening by 29%, with a comparable increase in screening cost.

Screening ultrasonography

Sensitivity of mammography is diminished when the breast tissue is dense. There have been recent reports in the literature concerning the role of screening breast ultrasonography in women with dense breasts on mammography and normal mammography and clinical breast examination. The results from a multicenter trial of leading breast imagers, ACR Imaging Network (ACRIN) 6666, showed that the addition of ultrasound to mammography increased detection of breast cancer, when compared with mammography alone among women at increased risk of breast cancer who also had dense breast tissue. However, there was also a large increase in the number of benign biopsies.

Pending further investigation, screening ultrasonography of the breast is not sanctioned or approved, and, unlike high-risk MRI screening, it does not constitute the standard of care. However, screening breast ultrasound may have some value in high-risk women with dense breast tissue on mammography. It is currently available at a few institutions and may be offered to selected women who meet the aforementioned criteria. Many leading breast centers do not perform screening ultrasonography, based on the lack of any randomized trials demonstrating population-based benefit and risk.

In August 2012, New York became the fourth state to enact legislation mandating that all breast imagers notify their patients with dense breast parenchyma in writing. There is similar pending legislation in 13 other states, and Representative Rosa DeLauro (D-Connecticut) has introduced HR 3012 in this 112th Congress to extend the mandate nationally. Highly dense breast tissue reduces the sensitivity of routine mammographic screening, and is, in itself, a significant risk factor for breast cancer. The density notification is intended to promote the utilization of “supplemental screening tests” in women with dense breast tissue, which in most cases would be nontargeted ultrasound breast screening. However, there is significant resistance by many in the breast imaging community to using widespread ultrasound screening for the many millions of American women who would become eligible based on this legislation. Ultrasound breast cancer screening has not undergone a single randomized trial of efficacy which uses the gold standard of disease-specific-mortality reduction, and in small-scale trials like ACRIN 6666 (with the participation of the leading experts in breast ultrasound) led to additional cancer detection with a very low positive predictive value (with less than half the specificity of mammography, and thus involving many additional “unnecessary” breast biopsies). This is in contrast to screening mammography, which had demonstrated statistically significant disease-specific mortality reduction in six out of seven randomized large-scale population trials, involving millions of women studied over several decades.

Magnetic resonance imaging

This is a sensitive diagnostic tool for detecting occult breast cancer foci. Owing to its limited specificity and high cost, MRI is not likely to become a screening tool for women at average risk. However, the role of breast MRI screening for detecting breast cancer in very-high-risk women, such as carriers of a BRCA gene mutation, has now been well established. More controversial are guidelines from the ACS, which recommend that a screening breast MRI be performed in women having at least a 20% lifetime risk for breast cancer, including women having a history of radiotherapy when they were 10 to 30 years of age; or harboring a mutation of BRCA1, BRCA2, TP53, or PTEN; or having a first-degree relative who harbors one of these mutations.

Several major studies have demonstrated the increased sensitivity of MRI for detecting cancers in women with inherited susceptibility to breast cancer compared with clinical breast examination, mammography, or ultrasonography. The sensitivity of breast MRI is > 75%; in contrast, the sensitivities of mammography and ultrasonography both are < 40%. The combined sensitivity of MRI plus mammography is about 95%, suggesting that it may be a viable strategy for screening young women at high risk for breast cancer. A recent prospective study documented that the performance of regular breast MRI was associated with earlier stage at breast cancer diagnosis among BRCA mutation carriers.

Breast tomosynthesis

Digital breast tomosynthesis is a rapidly advancing three-dimensional (3D) imaging technology which creates cross-sectional images of the breast. Conventional digital mammography can have low sensitivity rates, particularly for women with dense breast tissue. In addition, the recall rates for screening mammography can be greater than 10%. Overlapping breast tissue is a common reason for recalls with screening mammography and may obscure an underlying breast cancer. Clinical trials have repeatedly demonstrated a significantly reduced “call-back” rate with tomography-based breast screening (perhaps by 30% to 40%), and a modestly increased cancer detection rate (on the order of 10%).

In February 2011, the US Food and Drug Administration (FDA) approved for clinical use the Hologic Selenia Breast Tomosynthesis Mammography system. The General Electric SenoClaire tomography system was also approved by the FDA in August 2014. This new breast imaging modality creates cross-sectional images of the breast, similar to CT slices, from a modified digital mammography unit, utilizing approximately the same x-ray dose as conventional two-dimensional mammography. A number of other manufacturers have submitted paperwork on their breast tomosynthesis units for FDA approval, including Siemens, which has a large installed tomosynthesis base in Europe.

In May 2013, Hologic won FDA approval for C-View 2D images, in which mammographic images in the standard projections are electronically reconstructed from the 3D tomosynthesis data set. The FDA had originally mandated that routine 2D mammographic images had to be obtained in addition to the tomosynthesis projections, which approximately doubled the radiation dose. However, the FDA now permits substitution of the C-View 2D computed image, and the dose used in a screening tomosynthesis study can therefore be reduced to approximately the same as that used in a conventional 2D study. Early clinical trials suggest that the synthesized 2D images are comparable in diagnostic quality to conventional 2D mammographic images.

Evaluation of a Cystic Mass

FNA

When a dominant breast mass is present and the history and physical examination suggest that it is a cyst, the mass can simply be aspirated with a fine needle. Aspiration of a simple benign breast cyst should yield nonbloody fluid and result in complete resolution of the lesion.

Ultrasonography

Ultrasound examination can also be used to determine whether a mass is solid or cystic and whether a cyst is simple, complicated, or complex. Simple cysts are anechoic and oval, with thin walls; if asymptomatic, a simple cyst may be treated as an incidental finding. Complicated cysts are similar, except that low-level echoes are present in the cyst lumen. In many instances, complicated cysts may be managed conservatively, unless a worrisome feature or history prompts aspiration. To evaluate complex masses (previously termed complex cysts) that demonstrate a mixed cystic and solid lesion and that occasionally have thickened walls or septa, a biopsy (positive predictive value, 25%) is typically necessary.

Biopsy

A biopsy should be considered in the setting of an aspiration that is bloody or for a persistent solid component. Cytologic examination of the fluid is not routinely indicated, as the yield for positive cytology is low. Cystic carcinoma accounts for < 1% of all breast cancers. However, an intraluminal solid mass is a worrisome sign suggesting (intra) cystic carcinoma, and it should be biopsied.

Evaluation of a Solid Mass

A solid, palpable mass can be evaluated in a variety of ways. The decision to observe a patient with a solid breast mass that appears to be benign should be made only after careful clinical and radiologic examinations. Either FNA for cytology or percutaneous core biopsy should also be performed.

Mammography

A mammogram is used to assess the radiologic characteristics of the mass and is important for evaluation of the remainder of the ipsilateral breast as well as the contralateral breast.

FNA

This technique is a simple, easy-to-perform method for obtaining material for cytologic examination. The overall incidence of false-positive results ranges from 0% to 2.5% (0.7% when performed by experienced technicians), and the incidence of false-negative results varies from 3% to 27% (ranging from 3% to 9% in experienced hands). Reasons for false-negative readings include less-than-optimal technique in preparing the cytologic material, a missed lesion on aspiration, tumor necrosis, and incorrect cytologic interpretation. FNA is limited in its ability to distinguish invasive from noninvasive cancers. For these reasons, the trend at leading breast centers has been to replace FNA with core biopsy.

Biopsy

In the past, an excisional biopsy of a small breast mass or an incisional biopsy of a larger breast mass was performed to establish a histologic diagnosis of breast cancer. Recently, excisional biopsies for diagnosis have been replaced by percutaneous procedures. For a suspected malignancy, core biopsy has become the preferred diagnostic tool. With a core biopsy, the surgeon can plan for the cancer surgery, allowing for definitive surgical management in a single procedure. Core biopsy is also more advantageous than FNA because it allows evaluation of architectural and cellular characteristics.

Image-guided core biopsy

Ultrasound-guided core biopsies have been shown to offer increased targeting accuracy when compared with freehand core biopsy sampling. In certain limited clinical scenarios, use of vacuum-assisted, large-core needles may help to reduce sampling error.

Evaluation of Nonpalpable Mammographic Abnormalities

Excisional biopsy

Prior to 1991, almost all nonpalpable mammographic lesions were excised using surgical excision. This technique has become less prevalent with the availability of image-guided percutaneous biopsy techniques.

Stereotactic and ultrasonography-guided core biopsies

These methods have revolutionized the management of nonpalpable breast lesions, and, currently, the majority of biopsies can be performed percutaneously, which is quicker, less invasive, and less expensive than excisional biopsy. Tissue acquisition is performed with automated core needles or directional vacuum-assisted biopsy probes. Guidance for percutaneous biopsy is usually provided by stereotaxis, ultrasonography, and, more recently, MRI.

Numerous studies comparing the sensitivity and specificity of stereotactic biopsy versus surgical biopsy have consistently found the two procedures to be statistically equivalent. The long-term false-negative rate for stereotactic biopsy is 1.4%, which equals best published results with surgical biopsy.

Up to 80% of patients with nonpalpable mammographic lesions are candidates for stereotactic core biopsy. Lesions near the chest wall or immediately behind the nipple often cannot be reached on the stereotactic table. Diffuse lesions, such as scattered calcifications or a large asymmetric density, are subject to undersampling with the percutaneous approaches. Some patients are unable to lie prone on the stereotactic table for the duration of the examination. Finally, stereotactic units and trained personnel are not universally available.

Ultrasonography-guided core biopsy is another accurate percutaneous technique, useful for lesions best imaged by ultrasonography. Since the biopsy gun is handheld and guided in real time by the ultrasound imager, its use is related to more variability in performance, depending on the experience and skill of the practitioner. The overall reported accuracy rate of ultrasonography-guided biopsy is comparable to rates achieved with stereotactic and surgical biopsies.

Ultrasonography-guided or stereotactic FNA

This biopsy option is somewhat less invasive than core biopsy, but FNA provides only cytologic (not histologic) pathology results. This technique can result in both false-positive and false-negative results, whereas a false-positive result has not been reported to date for core breast biopsies. FNA is most successful in centers that have an experienced cytopathologist, who, ideally, is available on site to review smears for adequacy during FNA procedures.

Breast MRI

This modality is currently used to search for an occult primary tumor in the setting of known metastasis, evaluate the extent of disease in a biopsy-proven breast carcinoma (useful if breast conservation is being considered), and assess lesions in implant-augmented breasts. It is also useful for screening high-risk women, as described previously. Its role in screening women with dense breasts or for evaluating borderline lesions has not been established, and these indications typically are not reimbursable. Breast MRI has a high sensitivity, and clinical developments have improved its specificity. Breast MRI examinations have recently been facilitated by the development of computer-aided detection software, which can help to streamline the interpretation of these images and produce a more uniform result.

Breast surgeons are increasingly using breast MRI for surgical planning. In a 2003 study reported by Bedrosian et al (a retrospective review of 267 patients who had preoperative MRI prior to undergoing definitive surgery), preoperative breast MRI changed the planned surgical approach in 26% of cases, including 16.5% of cases of breast conservation switched to mastectomy. Imaging centers across the United States have a varying degree of expertise in performing, interpreting, and providing a standard reporting nomenclature for breast MRI. The ACR has developed an accreditation program in breast MRI (available on their website) to address this issue.

Ultrasonography

In investigating ultrasonographic features of solid masses that suggest benign or malignant disease, Stavros et al described such factors as sharp margins (benign) and taller-than-wide lesions (malignant). Although these features are useful for clinical decision-making, their utility in increasing the specificity of the breast lesion workup has not been verified.

Molecular breast imaging

Molecular breast imaging has demonstrated excellent specificity and sensitivity in new industry-sponsored trials using high-definition, breast-specific gamma cameras. Both technetium sestamibi–based scanning and breast-specific PET scanning have shown promise. However, their utility has not yet been demonstrated in large-scale clinical trials.

Prevention

Lifestyle Changes

There is increasing evidence that lifestyle changes may alter an individual’s breast cancer risk.

Physical activity

Exercise has been associated with a reduction in breast cancer risk. The benefit was greatest in younger, premenopausal women. The activity can be related to leisure or work-time activities.

Women who exercise 3.5 to 4 times per week may have a reduced incidence of breast cancer, when compared with women who do not exercise. The protective effect of exercise may be associated with a reduction in the frequency of ovulatory cycles and in circulating estrogen and progesterone levels.

Alcohol consumption

Numerous studies of the effects of alcohol consumption on breast cancer risk and the results of a cohort study addressing this issue have been published. When compared with nondrinkers, women who consumed 2.3 to 4.5 bottles of beer per day, 2.5 to 5.6 glasses of wine per day, or 2 to 4 shots of liquor per day had a 41% higher risk of developing invasive breast cancer. Some reports indicate that the consumption of a moderate amount of alcohol (red wine) may decrease the risk of breast cancer, although these results are not conclusive. The biologic basis for the association between alcohol consumption and an increased risk of breast cancer is unclear. It has been proposed that there is a positive correlation between alcohol and estrogen levels.

Alterations in diet and tobacco use

A reduced incidence of breast cancer has been observed in countries where the diet is typically low in fat. However, no reduction in breast cancer risk has been observed in the United States when women followed low-fat diets.

Prentice et al randomly assigned postmenopausal women without prior breast cancer to an intervention designed to reduce total daily fat consumption to a minimum of 20% or to no dietary intervention. They found no statistically significant reduction in invasive breast cancer risk over a period of approximately 8 years of follow-up. However, women consuming a high-fat diet at baseline showed a significant reduction in breast cancer risk (P = .04). The authors also noted an effect that varied by hormone receptor status of the tumor.

There appears to be an association between cigarette smoking and breast cancer risk. It is not clear whether the risk for breast cancer decreases when someone stops smoking.

Lactation

Although it has been suggested that lactation may protect against breast cancer, there are conflicting studies. A recent study failed to demonstrate any breast cancer risk reduction in women who breastfed and showed no dose-response effect in women who breastfed for longer periods. A retrospective study showed reduction in breast cancer risk associated with breastfeeding among BRCA carriers.

Chemoprevention

The NIH and NCI have publicized the results of the National Surgical Adjuvant Breast and Bowel Project (NSABP) Breast Cancer Prevention Trial (BCPT). Women who had a risk of developing breast cancer equivalent to that of women 60 years of age (1.67% in 5 years, based on Gail model 2) qualified as participants in this double-blind, randomized trial. A total of 13,388 women were randomized to receive tamoxifen or placebo.

TABLE 5: Number of events among participants in the NSABP Breast Cancer Prevention Trial

Benefits of therapy

The summary results indicated that tamoxifen prevented about half of both invasive and noninvasive breast cancers in all age groups. A secondary benefit of tamoxifen appeared to be a reduction in the incidence of hip fracture (Table 5). At present, no survival advantage has been shown for participants in this trial.

Side effects

Tamoxifen-treated women younger than age 50 had no apparent increase in side effects. However, women older than age 50 experienced serious side effects, including vascular events and endometrial cancer. Particularly worrisome was the increased incidence of endometrial cancer in the tamoxifen-treated patients (Table 5). In addition, a significant increase in pulmonary embolism and deep vein thrombosis was noted, especially in women older than age 50 (Table 5).

Current recommendations

Based on results of the BCPT, the FDA has approved tamoxifen for use in women at high risk (> 1.67% chance of getting breast cancer in the next 5 years, based on Gail model 2) of breast cancer.

The NCI and NSABP are in the process of developing risk profiles based on age, number of affected first-degree relatives with breast cancer, number of prior breast biopsies, presence or absence of atypical hyperplasia or LCIS, age at menarche, and age at first live birth. These risk profiles may help guide women in making the decision as to whether or not to take tamoxifen.

An ASCO working group published an assessment of tamoxifen use in the setting of breast cancer risk reduction. All women older than 35 years of age with a Gail model 2 risk of > 1.67% (or the risk equivalent to that of women 60 years of age) should be considered candidates for this treatment strategy. Comorbid conditions, such as a history of deep vein thrombosis, must be a part of the consent process and treatment decision.

Although the BCPT results establish tamoxifen as the standard of care for the primary chemoprevention of breast cancer in high-risk women, concern over the side effects of tamoxifen prompted a search for an agent that displays a more desirable efficacy/toxicity profile. Raloxifene (Evista), approved for the prevention of osteoporosis in postmenopausal women, and for the reduction in risk of invasive breast cancer in postmenopausal women with osteoporosis, displays antiestrogenic properties in the breast and endometrium and estrogenic effects in the bone, making it an attractive candidate for comparison with tamoxifen.

The STAR (Study of Tamoxifen and Raloxifene) trial (or NSABP P-2) began in July 1999 at almost 400 centers in North America. A total of 19,747 postmenopausal women, or women > 35 years old at increased risk of breast cancer by Gail criteria, were randomized to receive either tamoxifen (20 mg/d) or raloxifene (60 mg/d) for 5 years. Study endpoints included invasive and noninvasive breast cancers, cardiovascular disease, endometrial cancer, bone fractures, and vascular events.

There were 163 cases of invasive breast cancer in women assigned to tamoxifen and 168 of those assigned to raloxifene (incidence, 4.30 per 1,000 vs 4.41 per 1,000; risk ratio, 1.02; 95% CI, 0.82–1.28). There were fewer cases of noninvasive breast cancer in the tamoxifen group (57 cases) than in the raloxifene group (80 cases); (incidence, 1.51 vs 2.11 per 1,000; risk ratio, 1.40; 95% CI, 0.98–2). There were 36 cases of uterine cancer with tamoxifen and 23 with raloxifene (risk ratio, 0.62; 95% CI, 0.35–1.08). The risk of other cancers, fractures, ischemic heart disease, and stroke is similar for both drugs. There was no difference in the total number of deaths (101 for tamoxifen vs 96 for raloxifene) or in causes of death. The authors concluded that raloxifene is as effective as tamoxifen in reducing the risk of invasive breast cancer and carries a lower risk of thromboembolic events and cataracts but a nonstatistically significant higher risk of noninvasive breast cancer.

Sidebar:Long-term follow-up results of the IBIS-I breast cancer prevention trial were presented at the 2014 San Antonio Breast Cancer Symposium. With a median follow-up of 16 years, results showed a long-term benefit of 5 years of tamoxifen for preventing breast cancer. The effects seen were larger for women not taking hormone replacement therapy during the trial (38% vs 12%,P= .04). The number needed to treat to prevent an estrogen receptor–positive invasive breast cancer is 29. The impact of tamoxifen use on overall mortality is uncertain. (Cuzick J et al: Presented at SABCS 2014: Abstract S3-07).

The MAP3 trial investigated the role of an aromatase inhibitor, exemestane, in the prevention of breast cancer. In this randomized, double-blind trial, 4,560 postmenopausal women who were at moderately increased risk for breast cancer were randomly assigned to either exemestane or placebo. At a median follow-up of 35 months, 11 invasive breast cancers were detected in those given exemestane and in 32 of those given placebo, with a 65% relative reduction in the annual incidence of invasive breast cancer (0.19% vs 0.55%; HR = 0.35; 95% CI, 0.18–0.70; P = .002). The annual incidence of invasive plus noninvasive (ductal carcinoma in situ) breast cancers was 0.35% on exemestane and 0.77% on placebo (HR = 0.47; 95% CI, 0.27–0.79; P = .004). Adverse events occurred in 88% of the exemestane group and 85% of the placebo group (P = .003), with no significant differences between the two groups in terms of skeletal fractures, cardiovascular events, other cancers, or treatment-related deaths. During a median follow-up period of 3 years, exemestane was associated with no serious toxic effects and only minimal changes in health-related quality of life.

Vitamin D is a regulator of cellular growth and differentiation. In a prospective Canadian study, vitamin D levels in women newly diagnosed with breast cancer (T1-3, N0-1, M0) more than 10 years before the study began were assessed in archived blood samples taken after surgery and prior to systemic therapy (n = 512). Vitamin D deficiency was associated with an increased risk of distant recurrence (independent of age, BMI, insulin level, and T and N stage, and not significantly modified by ER status, or use of adjuvant chemotherapy or tamoxifen) and death, while patients with insufficient vs sufficient vitamin D levels had similar outcomes. These early findings raise the question of whether vitamin D supplementation might improve breast cancer–specific survival.

Staging and Prognosis

TABLE 6: TNM staging system for breast cancer

Staging System

The most widely used system to stage breast cancer is the American Joint Committee on Cancer (AJCC) classification, which is based on tumor size, the status of regional lymph nodes, and the presence of distant metastasis (Table 6).

Clinical staging

Assessment of clinical stage is performed initially and is determined after the physical examination and appropriate radiologic studies have been performed.

Pathologic staging

Pathologic stage is determined following surgery for operable breast cancer. Pathologic tumor size may differ from clinical tumor size. In addition, axillary nodal metastases that were not clinically evident may be detected after pathologic examination. With the advent of powerful molecular techniques, isolated tumor cells (ITCs) can be identified in histologically negative nodes. In the current AJCC staging, pathologic staging of nodes for detection of ITCs was included to obtain more information and, it is hoped, gain insight into the biologic significance of these ITCs.

Prognostic Factors

Numerous prognostic factors for breast cancer have been identified.

Lymph node status

Axillary nodal metastasis is the most important prognostic factor in patients with breast cancer. Survival was examined relative to the number of nodes involved and the location of nodes that contained metastatic deposits. For any given number of positive nodes, survival was independent of the level of involvement but was directly related to the number of involved nodes.

Overall, patients who have node-negative disease have a 10-year survival rate of 70% and a 5-year recurrence rate of 19%. As the number of positive nodes increases, so does the likelihood of relapse. Patients with > 10 positive lymph nodes have a recurrence rate of 72% to 82%. The majority of patients who develop recurrence after initial curative treatment of early-stage breast cancer will have distant metastases.

Hormone-receptor status

In general, hormone receptor–positive tumors have a more indolent course than do hormone receptor–negative tumors.

Other factors

Other considerations used to predict outcome are tumor size, histologic grade, lymphovascular permeation, S-phase fraction, and ploidy. Well-differentiated breast cancers have a better prognosis than moderately or poorly differentiated cancers. Likewise, smaller tumors are more favorable than larger ones and the absence of lymphovascular invasion is better than its presence.

More recently, molecular prognostic factors have been evaluated to determine their utility in predicting outcome. They include the growth factor receptors (epidermal growth factor receptor and human epidermal growth factor receptor 2 [HER2]), tumor suppressor genes (TP53), proteolytic enzymes that may be associated with invasion of disease and metastasis (cathepsin D), and metastasis suppressor genes (NME1). Of these molecular markers, HER2 is probably the most widely studied in breast cancer to date.

All breast cancers should be evaluated by immunohistochemistry (IHC) staining for estrogen and progesterone receptor status and HER2 overexpression. The presence of the estrogen receptor (ER) and/or the progesterone receptor (PR) imparts a more favorable prognosis. In addition, these receptors are predictive of response to hormonal therapy. HER2, also referred to as HER2/neu or ErbB2, is a 185-kd transmembrane tyrosine kinase that regulates cell growth, survival, migration, differentiation, and adhesion. Overexpression of HER2 leads to dimerization of the receptors, which causes activation of the tyrosine kinase. HER2 overexpression is seen in approximately 20% to 30% of all breast cancers and is associated with a more aggressive and less favorable disease with reduced disease-free and overall survival. However, the development of biologic agents such as trastuzumab has revolutionized the treatment of this type of breast cancer. A HER2 IHC score of 0–1+ is considered negative, 2+ is equivocal, and 3+ is positive. Equivocal HER2-positive tumors undergo fluorescence in situ hybridization (FISH) analysis for evaluation of HER2 gene amplification. Despite ASCO-CAP (College of American Pathologists) guidelines classifying tumors with amplification 1.8 to 2.2 as equivocal, a HER2 amplification score of 2 or greater is sufficient for a patient to be considered eligible for anti-HER2 therapy (ie, trastuzumab).