Breast cancer is the most common malignancy in women, accounting for 31% of all female cancers. Breast cancer also is responsible for 15% of cancer deaths in women, making it the number-two cause of cancer death. An estimated 182,460 new invasive breast cancer cases will be diagnosed in women in the United States in 2008, and 40,480 women will die of this cancer. There are approximately 2 million breast cancer survivors in the United States.

This chapter provides an overview of breast cancer, with discussions of epidemiology, etiology and risk factors, genetic cancer risk assessment, signs and symptoms, screening and diagnosis, prevention (including lifestyle changes and chemoprevention), staging, and prognosis. The three chapters to follow focus on the management of stages 0 and I, stage II, and stages III and IV breast cancers.

Epidemiology

Gender Breast cancer is relatively uncommon in men; the female-to-male ratio is approximately 100:1. It accounts for < 1% of all cancer cases in men, and an estimated 450 men will die of the disease in 2008. 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. BRCA mutations are associated with an increased risk for breast cancer in men.

The most common presentation in men is asymmetric gynecomastia, often related to a single effect of drug therapy (such as from digoxin) or liver failure. All palpable masses in men should be carefully examined. Based upon the findings on physical examination, 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 uncommon 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 African-American women; however, this difference is not apparent until age 50 and is marked only after menopause. The incidence of breast cancer in American Asian and Hispanic women is approximately half that in American Caucasian 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 among 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 may be related, in some way, 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.

Disease site 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 contralateral breast cancer in women with BRCA mutations is approximately 40% at 10 years after theinitial diagnosis of breast cancer. This risk is higher in BRCA1 than BRCA2 mutation carriers and those first diagnosed at age < 50.

Risk for breast cancer may be reduced in women who take tamoxifen. It may also be reduced in women who undergo bilateral salpingo-oophorectomy (BSO), 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.

Survival Survival rates for patients with nonmetastatic breast cancer have improved in recent years (Table 1). These improvements may be secondary to advances in adjuvant chemotherapy and 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

Numerous risk factors have been associated with the development of breast cancer, 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 risk factors.

Genetic factors Hereditary forms of breast cancer constitute only 5% to 7% 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 (BRCA1, BRCA2, and p53) associated with a high risk for breast cancer development.

Elevated risk for breast cancer is also associated with mutations in the PTEN gene in Cowden’s syndrome (described later), and a modest increased risk (relative risk of 3.9–6.4) may be seen in women who are heterozygous for a mutation in the ATM gene, which is associated with the recessive disease ataxia-telangiectasia in the homozygous state. A moderately increased risk for breast cancer (2-fold for women and 10-fold for men) has been associated with a variant (1100 delC) in the cell-cycle checkpoint kinase gene, CHEK2, among families without BRCA gene mutations.

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

BRCA2 gene The BRCA2 gene was localized to chromosome 13. BRCA2 is approximately twice as large as BRCA1 and 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). Increased risk for ovarian cancer, pancreatic cancer, prostate cancer, and melanoma has also been reported. Together, BRCA1 and BRCA2 account for 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, only 9.4% of women < 35 years of age at the time of diagnosis and 12.0% 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.

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 p53 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. Given the rarity, diversity of tumor types, and age at risk spanning both child and young adulthood, coherent screening strategies beyond those for the early-onset breast cancer risk are difficult to find.

Cowden’s 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 GI polyps 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.

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.