br Table br Monte Carlo simulation of female first
Monte Carlo simulation of 1400 female first-degree relatives of women with high-grade serous ovarian cancer diagnosed every year.
Strategy Expected events over time horizon of 50
Breast Ovarian Deaths
cancer cancer from
Universal BRCA testing 146 19 7
With at least 2000 and 20,000 women diagnosed with ovarian cancer per year in Canada and the United States respectively in the 1990's [34,35], there may be a comparable number of surviving female first-degree relatives (daughters, sisters), who would benefit from the knowledge of carrying a BRCA mutation, by subsequently undergoing risk-reducing interventions to avoid the diagnoses of ovarian and breast cancer.
The latest NCCN Guidelines (Version 1.2019) recommend BRCA mu-tation testing for “an individual with no personal history of cancer but with a close relative (first or second degree) with ovarian (epithelial, non-mucinous, including fallopian tube and primary peritoneal) can-cer” . However, in many jurisdictions, particularly in Canada, many first-degree relatives of HGSC patients whose BRCA Olaparib sta-tus is unknown still do not qualify for BRCA mutation testing, nor are they eligible for coverage through Medicaid in the United States.
Overall, female first-degree relatives of HGSC patients have an esti-mated risk of ovarian cancer that is 2–3-fold higher than the general population risk, which translates into a lifetime risk of 3–4% [37–40]. This estimate can also be derived by assuming a 20% risk of a BRCA mu-tation in HGSC patients, 50% chance of inheritance in 1st degree rela-tives, and 40% lifetime risk of ovarian cancer if BRCA1 mutation. Some of these women are being referred for RRBSO, without genetic testing, to avert the diagnosis of ovarian cancer. According to guidelines from the United Kingdom National Institute for Health and Care Excellence (NICE), RRBSO is only available to high-risk women with greater than a 10% lifetime risk of ovarian cancer, but Manchanda et al. assert that women with a 4% lifetime risk of ovarian cancer should be offered this procedure . The caveat is that compliance with HRT must be high. Our model also demonstrates effectiveness with RRBSO among women with a comparable increased risk of ovarian cancer, but only if
compliance with HRT is greater than 79.3%. This is an unrealistic as-sumption based on available data on HRT rates post-oophorectomy in premenopausal women. Approximately 60% of women who undergo RRBSO will ever use HRT, but the mean duration of use is only about 3 years, and only 35% of women use HRT for 5 years post-RRBSO [12–14].
Our model predicts that universal RRBSO for all female first-degree relatives of HGSC patients will yield a lower number of breast and ovar-ian cancer cases over a lifetime, compared to BRCA mutation testing first (and RRBSO reserved only for mutation carriers). This seems plausible, because premenopausal BSO reduces breast and ovarian cancer risks, even among non-mutation carriers , and therefore universal RRBSO for these women will yield the greatest risk reduction against these cancers. However, universal RRBSO without BRCA testing is not the ideal intervention for female first-degree relatives of HGSC patients for 2 reasons. Firstly, most of these women are never destined to de-velop breast or ovarian cancer, and therefore the majority of women will have surgery unnecessarily. Yet, these women who have surgery are at increased risk of mortality from downstream health conse-quences, given known compliance rates with HRT [25,43]. Secondly, without genetic testing, family members will remain uninformed about mutation status. Their first-degree relatives, both female and male, need to know that they could still carry a mutation. Men who in-herit a BRCA mutation have an increased risk of prostate cancer , and many of them will have female descendants who could have in-creased lifetime risks of breast and ovarian cancer. It is intuitive that of-fering BRCA testing to male first-degree relatives could reduce cancer rates and costs among them and their descendants. However, even if all male first-degree relatives were tested, they do not have risk-reducing interventions comparable to those for women that would sub-stantially alter their own life expectancy. The average lifetime benefit (life expectancy gain) for men is expected to be much lower, which in turn would increase the ICER. On the other hand, if female first-degree relatives are tested first and are confirmed mutation carriers, then male first-degree relatives can undergo targeted testing, which is much less costly and time-consuming, given the known mutation and the 50% probability of carrying that mutation.