In considering contraceptive options and preventive actions, the potential impact of oral contraceptive use upon the risk of both breast and ovarian cancer, in addition to other health-related effects of oral contraceptives, needs to be considered. A number of important issues remain unresolved including the potential differences between BRCA1/BRCA2 mutation carriers, age and duration of exposure, and formulation.
Level of evidence: 3aii
Hormone replacement therapy
Both observational and randomized clinical trial data suggest an increased risk of breast cancer associated with HRT in the general population.[101,102,103,104] The Women's Health Initiative (WHI) is a randomized controlled trial of approximately 160,000 postmenopausal women investigating the risks and benefits of strategies that may reduce the incidence of heart disease, breast and colorectal cancer, and fractures, including dietary interventions and two trials of hormone therapy. The estrogen-plus-progestin arm of the study, which randomized more than 16,000 women to receive combined hormone therapy or placebo, was halted early because health risks exceeded benefits.[103,104] One of the adverse outcomes prompting closure was a significant increase in both total (245 vs. 185 cases) and invasive (199 vs. 150) breast cancers (RR = 1.24; 95% CI, 1.02-1.50, P <.001) in women randomized to receive estrogen and progestin. Results of a follow-up study suggest that the recent reduction in breast cancer incidence, especially among women aged 50 to 69 years, is predominantly related to decrease in use of combined estrogen plus progestin HRT. HRT-related breast cancers had adverse prognostic characteristics (more advanced stages and larger tumors) compared with cancers occurring in the placebo group, and HRT was also associated with a substantial increase in abnormal mammograms.
Breast cancer risk associated with postmenopausal HRT has been variably reported to be increased [106,107,108] or unaffected by a family history of breast cancer;[83,109,110] risk did not vary by family history in the meta-analysis. The WHI study has not reported analyses stratified on breast cancer family history, and subjects have not been systematically tested for BRCA1/BRCA2 mutations. Short-term use of hormones for treatment of menopausal symptoms appears to confer little or no breast cancer risk in the general population.
Hormone replacement therapy in BRCA1/BRCA2 mutation carriers
The effect of HRT on breast cancer risk among carriers of a BRCA1 or BRCA2 mutation has been examined in two studies. In a prospective study of 462 BRCA1 or BRCA2 mutation carriers, bilateral risk-reducing salpingo-oophorectomy (RRSO) (n = 155) was significantly associated with breast cancer risk reduction overall (HR = 0.40; 95% CI, 0.18-0.92). Using mutation carriers without bilateral RRSO or HRT as the comparison group, HRT use (n = 93) did not significantly alter the reduction in breast cancer risk associated with bilateral RRSO (HR = 0.37; 95% CI, 0.14-0.96). In a matched case-control study of 472 postmenopausal women with BRCA1 mutations, HRT use was associated with an overall reduction in breast cancer risk (odds ratio [OR] = 0.58; 95% CI, 0.35-0.96, P = .03). A nonsignificant reduction in risk was observed both in women who had undergone bilateral oophorectomy and in those who had not. Women taking estrogen alone had an OR of 0.51 (95% CI, 0.27-0.98, P = .04), while the association with estrogen and progesterone was not statistically significant (OR = 0.66; 95% CI, 0.34-1.27, P = .21). Especially given the differences in estimated risk associated with HRT between observational studies and the WHI, these findings should be confirmed in randomized prospective studies, but they suggest that HRT in BRCA1/BRCA2 mutation carriers neither increases breast cancer risk nor negates the protective effect of oophorectomy.