Kelly-Anne Phillips

Hormonal Contraception and Breast Cancer Risk for Carriers of Germline Mutations in BRCA1 and BRCA2

PURPOSE It is uncertain whether, and to what extent, hormonal contraceptives increase breast cancer (BC) risk for germline BRCA1 or BRCA2 mutation carriers. METHODS Using pooled observational data from four prospective cohort studies, associations between hormonal contraceptive use and BC risk for unaffected female BRCA1 and BRCA2 mutation carriers were assessed using Cox regression. RESULTS Of 3,882 BRCA1 and 1,509 BRCA2 mutation carriers, 53% and 71%, respectively, had ever used hormonal contraceptives for at least 1 year (median cumulative duration of use, 4.8 and 5.7 years, respectively). Overall, 488 BRCA1 and 191 BRCA2 mutation carriers developed BC during median follow-up of 5.9 and 5.6 years, respectively. Although for BRCA1 mutation carriers, neither current nor past use of hormonal contraceptives for at least 1 year was statistically significantly associated with BC risk (hazard ratio [HR], 1.40 [95% CI, 0.94 to 2.08], P = .10 for current use; 1.16 [0.80 to 1.69], P = .4, 1.40 [0.99 to 1.97], P = .05, and 1.27 [0.98 to 1.63], P = .07 for past use 1-5, 6-10, and >10 years before, respectively), ever use was associated with increased risk (HR, 1.29 [95% CI, 1.04 to 1.60], P = .02). Furthermore, BC risk increased with longer cumulative duration of use, with an estimated proportional increase in risk of 3% (1%-5%, P = .002) for each additional year of use. For BRCA2 mutation carriers, there was no evidence that current or ever use was associated with increased BC risk (HR, 0.70 [95% CI, 0.33 to 1.47], P = .3 and 1.07 [0.73 to 1.57], P = .7, respectively). CONCLUSION Hormonal contraceptives were associated with increased BC risk for BRCA1 mutation carriers, especially if used for longer durations. Decisions about their use in women with BRCA1 mutations should carefully weigh the risks and benefits for each individual.

Oral Contraceptive Use in BRCA1 and BRCA2 Mutation Carriers: Absolute Cancer Risks and Benefits

Abstract Background To help BRCA1 and 2 mutation carriers make informed decisions regarding use of combined-type oral contraceptive preparation (COCP), absolute risk-benefit estimates are needed for COCP-associated cancer. Methods For a hypothetical cohort of 10 000 women, we calculated the increased or decreased cumulative incidence of COCP-associated (breast, ovarian, endometrial) cancer, examining 18 scenarios with differences in duration and timing of COCP use, uptake of prophylactic surgeries, and menopausal hormone therapy. Results COCP use initially increased breast cancer risk and decreased ovarian and endometrial cancer risk long term. For 10 000 BRCA1 mutation carriers, 10 years of COCP use from age 20 to 30 years resulted in 66 additional COCP-associated cancer cases by the age of 35 years, in addition to 625 cases expected for never users. By the age of 70 years such COCP use resulted in 907 fewer cancer cases than the expected 9093 cases in never users. Triple-negative breast cancer estimates resulted in 196 additional COCP-associated cases by age 40 years, in addition to the 1454 expected. For 10 000 BRCA2 mutation carriers using COCP from age 20 to 30 years, 80 excess cancer cases were estimated by age 40 years in addition to 651 expected cases; by the age of 70 years, we calculated 382 fewer cases compared with the 6156 cases expected. The long-term benefit of COCP use diminished after risk-reducing bilateral salpingo-oophorectomy followed by menopausal hormone therapy use. Conclusion Although COCP use in BRCA1 and BRCA2 mutation carriers initially increases breast, ovarian, and endometrial cancer risk, it strongly decreases lifetime cancer risk. Risk-reducing bilateral salpingo-oophorectomy and menopausal hormone therapy use appear to counteract the long-term COCP-benefit.

Motivators of Inappropriate Ovarian Cancer Screening: A Survey of Women and Their Clinicians

Abstract Background This study examined why women and doctors screen for ovarian cancer (OC) contrary to guidelines. Methods Surveys, based on the Theoretical Domains Framework, were sent to women in the Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer and family physicians and gynecologists who organized their screening. Results Of 1264 Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer women, 832 (65.8%) responded. In the past 2 years, 126 (15.1%) had screened. Most of these (n = 101, 80.2%) would continue even if their doctor told them it is ineffective. For women, key OC screening motivators operated in the domains of social role and goals (staying healthy for family, 93.9%), emotion and reinforcement (peace of mind, 93.1%), and beliefs about capabilities (tests are easy to have, 91.9%). Of 531 clinicians 252 (47.5%) responded; a minority (family physicians 45.8%, gynecologists 16.7%) thought OC screening was useful. For gynecologists, the main motivators of OC screening operated in the domains of environmental context (lack of other screening options, 27.6%), and emotion (patient peace of mind, 17.2%; difficulty discontinuing screening, 13.8%). For family physicians,, the strongest motivators were in the domains of social influence (women ask for these tests, 20.7%), goals (a chance these tests will detect cancer early, 16.4%), emotion (patient peace of mind, 13.8%), and environmental context (no other OC screening options, 11.2%). Conclusion Reasons for OC screening are mostly patient driven. Clinician knowledge and practice are discordant. Motivators of OC screening encompass several domains, which could be targeted in interventions to reduce inappropriate OC screening.

Bilateral Salpingo-oophorectomy and Breast Cancer Risk for BRCA1 and BRCA2 Mutation Carriers: Assessing the Evidence

Abstract Without preventive interventions, women with germline pathogenic variants in BRCA1 or BRCA2 have high lifetime risks for breast cancer and tubo-ovarian cancer. The increased risk for breast cancer starts at a considerably younger age than that for tubo-ovarian cancer. Risk-reducing bilateral salpingo-oophorectomy (rrBSO) is effective in reducing tubo-ovarian cancer risk for BRCA1 and BRCA2 mutation carriers, but whether it reduces breast cancer risk is less clear. All studies of rrBSO and breast cancer risk are observational in nature and subject to various forms of bias and confounding, thus limiting conclusions that can be drawn about causation. Early studies supported a statistically significant protective association for rrBSO on breast cancer risk, which is reflected by several international guidelines that recommend consideration of premenopausal rrBSO for breast cancer risk reduction. However, these historical studies were hampered by the presence of several important biases, including immortal person-time bias, confounding by indication, informative censoring, and confounding by other risk factors, which may have led to overestimation of any protective benefit. Contemporary studies, specifically designed to reduce some of these biases, have yielded contradictory results. Taken together, there is no clear and consistent evidence for a role of premenopausal rrBSO in reducing breast cancer risk in BRCA1 or BRCA2 mutation carriers.

Risk of Peritoneal Cancer After Risk-Reducing Bilateral Salpingo-Oophorectomy for Women With Germline BRCA Pathogenic Variants: A Cause for Concern or Potentially Avoidable?