Women who inherit a deleterious mutation in BRCA1[27,28] or BRCA2 have an increased lifetime risk of breast cancer (which occurs at a younger age), ovarian cancer, and possibly colon cancer. Deleterious BRCA2 mutations are less common than BRCA1 mutations; BRCA2 mutations are also associated with male breast cancer, prostate cancer, pancreatic cancer, and lymphomas.
Factors Associated With Increased Risk of Breast Cancer
Exogenous hormone therapy (HT) after menopause was shown to be associated with increased breast cancer risk in 1997.
The Heart and Estrogen/Progestin Replacement Study published in 2002  included an open-label follow-up of a randomized controlled trial (RCT) of estrogen and progestin therapy in 2,763 women (mean age, 67 years) who had coronary heart disease. After a mean follow-up of 6.8 years, the relative risk [RR] for breast cancer was 1.27 (95% confidence interval [CI], 0.84–1.94). Although not statistically significant, the RR estimate is consistent with the much larger Women's Health Initiative (WHI) study.
The WHI-combined HT trial was terminated early (in July 2002) because the overall health risks exceeded benefits.
The randomized trial component of the WHI investigated the effect of hormones and dietary interventions on breast cancer risk. Women aged 50 to 79 years who had intact uteri were randomly assigned to receive combined conjugated estrogen with continuous progestin (n = 8,506) or placebo (n = 8,102). Breast cancer risk was increased with combined HT, with a hazard ratio (HR) of 1.24 (95% CI, 1.02–1.50), consistent with prior reports from observational studies. The trial was terminated early because overall health risks, including cardiovascular disease and thrombotic events, exceeded benefit. HT was also associated with a higher percentage of abnormal mammograms. The excess risk was observed in all subgroups of women for invasive breast cancer but not for in situ breast cancer. The combined HT-related cancers had similar grade, histology, and expression of estrogen receptor (ER), progesterone receptor, and HER2/neu compared with those related to placebo, with a trend toward larger size and higher incidence of lymph node metastases. Extended follow-up (mean follow-up of 11 years) of these women showed higher breast cancer-specific mortality for the HT group compared with those randomly assigned to receive placebo (25 vs. 12 deaths, 0.03% vs. 0.01% per year, HR = 1.95; 95% CI, 1.0–4.04; P = .049).