The average discounted costs, life expectancy, quality-adjusted life expectancy, and incremental cost-effectiveness ratios for women with BRCA1 and BRCA2 mutations are provided in Table 2. Bilateral salpingo-oophorectomy at age 40 years was the dominant strategy for both BRCA1 and BRCA2 carriers, because it was least costly and most effective in terms of overall life expectancy. Prophylactic salpingectomy at age 40 years followed by delayed oophorectomy at age 50 years had the highest quality-adjusted life expectancy with favorable incremental cost-effectiveness ratios of $37,805 and $89,680 per quality-adjusted life-year gained for BRCA1 and BRCA2 mutation carriers, respectively, relative to salpingectomy alone.
Our results were stable over a wide range of costs, including estimates for breast and ovarian cancer treatment that would be relevant in the U.S. health care system. Our results were also stable over a plausible range of utilities representing quality of life. Figure 1 illustrates a sensitivity analysis on the utility of prophylactic bilateral salpingo-oophorectomy at age 40 years. The utility of prophylactic bilateral salpingo-oophorectomy had to exceed 0.93 for this intervention to yield a higher quality-adjusted life expectancy than prophylactic salpingectomy followed by delayed oophorectomy. In our base case, prophylactic bilateral salpingo-oophorectomy had a utility of 0.82, implying that a year of life after prophylactic bilateral salpingo-oophorectomy is considered equivalent to 0.82 of a year in perfect health without prophylactic bilateral salpingo-oophorectomy.
We conducted a Monte Carlo simulation to estimate the total number of breast and ovarian cancers associated with each of the strategies as well as the excess number of cardiovascular deaths secondary to premenopausal bilateral salpingo-oophorectomy. In Canada there are approximately 231,600 women between the ages of 30 and 39 years.54 Assuming a population frequency of BRCA1 and BRCA2 germline mutations of 0.32% and 0.69%, respectively,55 there are an estimated 700 BRCA1 and 1,600 BRCA2 mutation carriers in this age group. By simulating this cohort, bilateral salpingo-oophorectomy at age 40 years offers the greatest risk reduction against breast and ovarian cancer with at least a 20% lower risk of ovarian cancer and up to a 40% lower risk of breast cancer compared with salpingectomy alone. Although there are more deaths from cardiovascular disease after bilateral salpingo-oophorectomy compared with the other two strategies, the overall mortality rate is less than 1%. These results are summarized in Table 3.
The results of this analysis suggest that bilateral salpingectomy followed by delayed oophorectomy may be a reasonable option for BRCA mutation carriers when quality of life is taken into account and bilateral salpingo-oophorectomy is considered unacceptable. Salpingectomy by itself does not appear to be an appropriate recommendation, because it has no effect on breast cancer risk nor does it appear to provide the same magnitude of benefit as bilateral salpingo-oophorectomy in reducing ovarian cancer risk. Salpingectomy followed by delayed oophorectomy appears to improve quality-adjusted life expectancy compared with bilateral salpingo-oophorectomy alone; however, quality of life after bilateral salpingo-oophorectomy could be improved with short-term use of hormone therapy, which does not appear to increase breast cancer risk in these high-risk women.56,57 In our base case analysis, we assumed that women who had prophylactic bilateral salpingo-oophorectomy did not use hormone therapy; therefore, we may have underestimated their quality-adjusted life expectancy. According to the Prevention and Observation of Surgical End Points Study Group, approximately 60% of women use hormone therapy after prophylactic bilateral salpingo-oophorectomy.57 Our analysis suggests that, if the utility of bilateral salpingo-oophorectomy is increased to 0.93 (possibly after hormone therapy), the quality-adjusted life expectancy of bilateral salpingo-oophorectomy exceeds that of prophylactic salpingectomy followed by delayed oophorectomy. Finally, oophorectomy appears to reduce breast cancer risk in both premenopausal and postmenopausal women,58 which implies a net health benefit of this intervention regardless of age.
Several studies have reported the identification of either invasive high-grade serous carcinomas of the fallopian tube or serous tubal intraepithelial carcinomas in prophylactic bilateral salpingo-oophorectomy specimens from women with BRCA germline mutations with the majority of pathologic abnormalities attributable to fallopian tube carcinomas or precursor lesions.9–20 However, there is still uncertainty about the true proportion of BRCA-associated ovarian cancers that arise primarily in the fallopian tube, because reported findings have ranged considerably from 18.8% to 100%.9–11,13,15,17,18,20,36 There also remain limited data on short- and long-term outcomes of salpingectomy. There are no studies directly comparing prophylactic salpingectomy with bilateral salpingo-oophorectomy for these high-risk women. The only published data on this topic to date include an editorial from Greene et al,59 who suggest that “bilateral salpingectomy with ovarian retention” be considered “an investigational risk management option of unproven clinical usefulness,” an opinion article from Dietl et al,60 who propose that bilateral salpingectomy “is likely to reduce the risk for pelvic carcinomas,” and a feasibility study by Leblanc et al,61 in which radical fimbriectomy is postulated as a reasonable risk-reducing intervention in BRCA mutation carriers who are reluctant to undergo bilateral salpingo-oophorectomy. A clinical trial led by Leblanc et al62 is currently recruiting young BRCA mutation carriers for radical fimbriectomy (NCT016808074), but it is not expected to be complete until 2019.
The advantage of this analysis is that we can promptly estimate the costs and benefits of different risk-reducing strategies among women with BRCA mutations, which would be difficult to evaluate in the context of a clinical trial. The major disadvantage is that it simulates a hypothetical cohort, and there is uncertainty relating to various parameters such as the extent of risk reduction from salpingectomy, quality of life after different surgical strategies, and health care costs. However, we have accounted for these uncertainties with extensive sensitivity analyses and evaluated these parameters within a wide range of estimates. It is important to note that these results apply only to BRCA mutation carriers and not to 1) untested relatives of carriers; 2) those with uninformative testing; or 3) those with a family history to suggest increased risk. We also did not model BRCA mutation carriers with a history of breast cancer, although these women may still be at risk for ovarian cancer and they comprise almost 25% of all referrals to our Hereditary Cancer Program.46 Many of these women would have received anthracycline- and taxane-based chemotherapy, but the likelihood of premature ovarian failure appears to be low, particularly for women younger than age 40 years,63–65 so there may still be a role for salpingectomy as a risk-reducing strategy. However, there seems to be less ambivalence about bilateral salpingo-oophorectomy after their previous cancer diagnosis, because a greater proportion of these women undergo this procedure than unaffected carriers.6 We did model BRCA1 and BRCA2 mutation carriers separately because of the different cancer phenotypes. BRCA2 carriers have a lower lifetime risk of ovarian cancer66 and therefore have a lower proportion of ovarian cancer cases and cancer-related deaths. Any reduction in cancer incidence and mortality (eg, from delayed oophorectomy after salpingectomy) will appear small when averaged over the entire cohort at risk (compared with BRCA1 carriers). The smaller the average incremental benefit, the higher the incremental cost-effectiveness ratio. Salpingectomy with delayed oophorectomy yields incremental cost-effectiveness ratios of $37,805 and $89,680 per quality-adjusted life-year for BRCA1 and BRCA2 carriers, respectively, compared with salpingectomy alone. Despite the discrepancy, the incremental cost-effectiveness ratios are still less than $100,000 per quality-adjusted life-year, so this intervention would be considered cost-effective for both BRCA1 and BRCA2 carriers.
It is important to emphasize that the standard of care for women inheriting germline mutations in BRCA1 or BRCA2 still remains prophylactic bilateral salpingo-oophorectomy after completion of childbearing or around the age of 40 years.2 It offers the greatest risk reduction in breast and ovarian cancer compared with salpingectomy with or without delayed oophorectomy. However, a significant proportion of women do not undergo bilateral salpingo-oophorectomy,6,45 and many choose surveillance alone for ovarian cancer despite the limited benefit of existing screening methods.67–71 Ovarian cancer drives the mortality rate among BRCA mutation carriers,4 and therefore any intervention that reduces ovarian cancer risk is likely better than no intervention at all. Although it remains to be validated prospectively, bilateral salpingectomy with delayed oophorectomy may be a reasonable alternative to bilateral salpingo-oophorectomy, especially for those who are reluctant to undergo the latter procedure because of the potential effect on quality of life.
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