Modifiers of risk of hereditary breast cancer.

Mutations in the BRCA1 and BRCA2 genes confer a high lifetime risk of breast and ovarian cancer. The risk varies from individual to individual, and it appears that the risk has increased in recent generations. These observations imply that non-genetic factors may modify the inherited risk. To date, the factors that appear most strongly to modify the risk include reproductive histories and exogenous hormones. Oral contraceptives are associated with a profound reduction in the risk of ovarian cancer, and with little or no increase in the risk of breast cancer. Other modifying factors include age of menarche, parity, breastfeeding and oophorectomy. The effect of parity is different in BRCA1 and BRCA2 carriers. Multiparity appears to be protective in BRCA1 carriers, but is associated with an increase in risk in BRCA2 carriers. Oophorectomy has been associated with reductions in both the risk of breast and ovarian cancer. Knowledge of these risk factors will be useful for managing risk and for developing prevention strategies.