Family History of Breast Cancer. The greatest risk is for individuals with multiple affected first-degree relatives with early-onset breast cancer. In most families, it is thought that various combinations of low penetrance, “weak” cancer genes are responsible for increased risk. However, approximately 5% to 10% of breast cancers occur in persons who inherit highly penetrant germline mutations in tumor suppressor genes (discussed later). For these individuals, the lifetime risk of breast cancer may be greater than 90%.
Geographic Factors. Significant differences in the incidence and mortality rates of breast cancer have been reported in various countries. The risk is significantly higher in the Americas and Europe than in Asia and Africa. For example, the incidence and mortality rates are five times higher in the United States than in Japan. Some risk factors must be modifiable because migrants from low-incidence to high-incidence areas tend to acquire the rates of their new home countries. Diet, reproductive patterns, and breastfeeding practices are thought to be involved. In line with this, breast cancer rates appear to be rising in parts of the world that are adopting Western habits.
Race/Ethnicity. The highest rate of breast cancer is in women of European descent, largely because of a higher incidence of ER-positive cancers. Hispanic and African American women tend to develop cancer at a younger age and are more likely to develop aggressive tumors. Such disparities are thought to result from a combination of differences in genetics, social factors, and access to health care and are an area of intense study.
Reproductive History. Early age of menarche, nulliparity, absence of breastfeeding, and older age at first pregnancy are all associated with increased risk, probably because each increases the exposure of “at-risk” breast epithelial cells to estrogenic stimulation.
Ionizing Radiation. Radiation to the chest increases the risk of breast cancer if exposure occurs while the breast is still developing. For example, breast cancer develops in 25% to 30% of women who underwent irradiation for Hodgkin lymphoma in their teens and 20s, but the risk for women treated later in life is not elevated.
Other Risk Factors. Postmenopausal obesity, postmenopausal hormone replacement, mammographic density, and alcohol consumption also have been implicated as risk factors. The risk associated with obesity probably is due to exposure of the breast to estrogen produced by adipose tissue. In keeping with this, obesity is only associated with an increased risk of tumors that express ER.
The three major subtypes of breast cancer defined by differential expression of hormone receptors and HER2 arise through more-or-less distinct pathways that involve the stepwise acquisition of driver mutations in the epithelial cells of the duct/lobular system (
Fig. 19.27 ). Factors that contribute directly to the development of breast cancer can be grouped into genetic, hormonal, and environmental categories.
Genetic. Driver mutations in cancer genes that contribute to breast carcinogenesis can be divided into those that are inherited and those that are acquired. The major germ-line mutations conferring susceptibility to breast cancer affect genes that regulate genomic stability or that are involved in progrowth signaling pathways. BRCA1 and BRCA2 are classic tumor suppressor genes, in that cancer arises only when both alleles are inactivated or defective (Chapter 6). BRCA1 and BRCA2 encode proteins that are required for repair of certain kinds of DNA damage. They are normally expressed in many different cells and tissues, and why germline mutations in these genes lead mainly to an increased risk of breast and serous ovarian cancer (discussed earlier) remains mysterious. The degree of penetrance, age of onset, and susceptibility to other types of cancers differ among the many BRCA1 and BRCA2 germ-line mutations, but most carriers develop breast cancer by the age of 70 years, as compared to about 12% of women with an average risk of breast cancer. For unclear reasons, BRCA2 mutations are primarily associated with ER-positive tumors, whereas BRCA1 mutations show a strong association with triple-negative cancers (