br There are several limitations of our study Firstly
There are several limitations of our study. Firstly, our results are only generalizable to those without additional risk factors for carrying a BRCA mutation. We recognize that this may be an oversimplified model, as there are many other scenarios in which there are first-degree relatives of HGSC patients with an unknown BRCA AZD-2281 status, such as a family history of more than one HGSC, a family history of both HGSC and pre-menopausal breast cancer, or Ashkenazi Jewish ethnicity. However, all of these scenarios increase the pre-test probability of a BRCA mutation, and these women should currently be eligible for genetic testing. Further-more, we did not consider other germline mutations that are associated with ovarian cancer such as RAD51C or BRIP1, therefore panel testing in-stead of BRCA mutation testing alone would be more comprehensive and identify a greater number of first-degree relatives at risk for an inherited predisposition to cancer. However, one of the main objectives of this model was to highlight the importance of genetic testing first, rather than pursuing risk-reducing surgery in the absence of this information.
Secondly, although women with a personal history of breast cancer were excluded from this analysis, they should still be eligible for BRCA testing if they have a first-degree relative with HGSC; moreover their pre-test probability of a BRCA mutation is expected to be higher. These women are probably less likely to use HRT given their breast cancer his-tory, and therefore RRBSO should only be offered if truly indicated for a confirmed BRCA mutation, or metastatic or recurrent ER+ breast cancer for which an aromatase inhibitor may be indicated. RRBSO has the poten-tial to be harmful if offered to premenopausal women with early ER+ breast cancer in the absence of a known BRCA mutation, who are subse-quently unable to use HRT . We did not include non-hormonal inter-ventions for premature menopause after RRBSO in this model, as there are limited data on their efficacy in this context.
Third, we may have overestimated the mortality associated with RRBSO in the absence of HRT. This risk estimate was extrapolated from the subgroup of women under age 50 who underwent oophorectomy without HRT in the Nurses' Health Study . After a median follow-up of 28 years, the number needed to harm (NNH) was 8, which translates into a mortality risk of 1/8 (12.5%) attributable to oophorectomy without HRT. Although these women are arguably different from female first-degree relatives of HGSC patients, the point is that they are often young when they have this surgical procedure (under age 50) and based on cur-rent life expectancy estimates for women in Canada and the United States [46,47], they should survive another 40 years. Unfortunately, some of them will die prematurely as a result of early menopause after RRBSO, be-cause HRT or other interventions are not consistently used. Breast cancer risk appears to be the main reason why these women choose not use HRT post-RRBSO, but a significant proportion also report that they do not dis-cuss HRT concerns with their health care provider . A recent system-atic review revealed that these patients benefit from HRT post-RRBSO, without an increased risk of breast cancer . Greater efforts are re-quired to counsel women about the potential harms of premenopausal RRBSO, and the importance of HRT afterwards.
In conclusion, women with high-grade serous ovarian cancer have up to a 20% risk of carrying a BRCA mutation, and their female first-degree relatives are subsequently at risk of carrying a mutation and de-veloping breast and ovarian cancer. When BRCA mutation status is un-known among these ovarian cancer patients, their first-degree relatives should be recognized by their front-line health care providers as being at risk for carrying a mutation. They should be allowed the op-portunity for genetic counseling, and BRCA mutation testing, irrespec-tive of personal cancer history, additional family history, or ethnicity. This is cost-effective compared to the current policy (no testing unless specific cancer history and ethnicity), and less costly and more effective than risk-reducing surgery alone without BRCA testing. Confirmation of BRCA mutation status will inform these women and their family mem-bers of their cancer risks, and will facilitate personal decisions relating to cancer prevention strategies.
Dr. Tinker has received funding from Astra Zeneca to conduct re-search relating to ovarian cancer detection and a Phase I trial in recur-rent ovarian cancer. None of the other authors have any potential conflicts of interest to disclose.