Breast cancer is a malignant proliferation of epithelial cells lining the ducts or lobules of the breast. In the year 2010, about 180,000 cases of invasive breast cancer and 40,000 deaths will occur in the United States. In addition, about 2000 men will be diagnosed with breast cancer. Epithelial malignancies of the breast are the most common cause of cancer in women (excluding skin cancer), accounting for about one-third of all cancer in women. As a result of improved treatment and earlier detection, mortality rate from breast cancer has begun to decrease very substantially in the United States. This chapter will not consider rare malignancies presenting in the breast, such as sarcomas and lymphomas, but will focus on the epithelial cancers. Human breast cancer is a clonal disease; a single transformed cell—the product of a series of somatic (acquired) or germ-line mutations—is eventually able to express full malignant potential. Thus, breast cancer may exist for a long period as either a noninvasive disease or an invasive but nonmetastatic disease. These facts have significant clinical ramifications.
Not more than 10% of human breast cancers can be linked directly to germ-line mutations. Several genes have been implicated in familial cases. The Li-Fraumeni syndrome is characterized by inherited mutations in the p53 tumor-suppressor gene, which lead to an increased incidence of breast cancer, osteogenic sarcomas, and other malignancies. Inherited mutations in PTEN have also been reported in breast cancer.
Another tumor-suppressor gene, BRCA-1, has been identified at the chromosomal locus 17q21; this gene encodes a zinc finger protein, and the product therefore may function as a transcription factor. The gene appears to be involved in gene repair. Women who inherit a mutated allele of this gene from either parent have at least a 60–80% lifetime chance of developing breast cancer and about a 33% chance of developing ovarian cancer. The risk is higher among women born after 1940, presumably due to promotional effects of hormonal factors. Men who carry a mutant allele of the gene have an increased incidence of prostate cancer and breast cancer. A fourth gene, termed BRCA-2, which has been localized to chromosome 13q12, is also associated with an increased incidence of breast cancer in men and women.
Germ-line mutations in BRCA-1 and BRCA-2 can be readily detected; patients with these mutations can be counseled appropriately. All women with strong family histories for breast cancer should be referred to genetic screening programs, particularly women of Ashkenazi Jewish descent who have a high likelihood of a specific BRCA-1 mutation (substitution of adenine for guanine at position 185).
Even more important than the role these genes play in inherited forms of breast cancer may be their role in sporadic breast cancer. A p53 mutation is present in nearly 40% of human breast cancers as an acquired defect. Acquired mutations in PTEN occur in about 10% of the cases. BRCA-1 mutation in sporadic primary breast cancer has not been reported. However, decreased expression of BRCA-1 mRNA (possibly via gene methylation) and abnormal cellular location of the BRCA-1 protein have been found in some breast cancers. Loss of heterozygosity of BRCA-1 and BRCA-2 suggests that tumor-suppressor activity may be inactivated in sporadic cases of human breast cancer. Finally, increased expression of a dominant oncogene plays a role in about a quarter of human breast cancer cases. The product of this gene, a member of the epidermal growth factor receptor superfamily, is called erbB2 (HER/2 neu) and is overexpressed in these breast cancers due to gene amplification; this overexpression can contribute to transformation of human breast epithelium and is the target of effective systemic therapy in adjuvant and metastatic disease settings.
Breast cancer is a hormone-dependent disease. Women without functioning ovaries who never receive estrogen-replacement therapy do not develop breast cancer. The female-male ratio is about 150:1. For most epithelial malignancies, a log-log plot of incidence versus age shows a single-component straight-line increase with every year of life. A similar plot for breast cancer shows two components: a straight-line increase with age but with a decrease in slope beginning at the age of menopause. The three dates in a woman's life that have a major impact on breast cancer incidence are age at menarche, age at first full-term pregnancy, and age at menopause. Women who experience menarche at age 16 years have only 50–60% of the breast cancer risk of a woman having menarche at age 12 years; the lower risk persists throughout life. Similarly, menopause occurring 10 years before the median age of menopause (52 years), whether natural or surgically induced, reduces lifetime breast cancer risk by about 35%. Women who have a first full-term pregnancy by age 18 years have a 30–40% lower risk of breast cancer compared with nulliparous women. Thus, length of menstrual life—particularly the fraction occurring before first full-term pregnancy—is a substantial component of the total risk of breast cancer. These three factors (menarche, age of first full-term pregnancy, and menopause) can account for 70–80% of the variation in breast cancer frequency in different countries. A meta-analysis has shown that duration of maternal nursing correlates with substantial risk reduction independent of either parity or age at first full-term pregnancy.
International variation in incidence has provided some of the most important clues on hormonal carcinogenesis. A woman living to age 80 years in North America has one chance in nine of developing invasive breast cancer. Asian women have one-fifth to one-tenth the risk of breast cancer of women in North America or Western Europe. Asian women have substantially lower concentrations of estrogens and progesterone. These differences cannot be explained on a genetic basis because Asian women living in a Western environment have sex steroid hormone concentrations and risks identical to those of their Western counterparts. These migrant women, and more notably their daughters, also differ markedly in height and weight from Asian women in Asia; height and ...