Current recommendations for young women who are carriers of a BRCA germline mutation include bilateral salpingo-oophorectomy by the age of 40 years or on completion of childbearing to reduce their risk of ovarian cancer.1,2 This intervention has been proven to decrease the risk of ovarian cancer by approximately 80–90%, risk of breast cancer by 50%,3 and cancer-related mortality by approximately 60%.4 Despite this widespread recommendation, many of these women are reluctant to have prophylactic or risk-reducing bilateral salpingo-oophorectomy at an early age, because of the consequences relating to estrogen deficiency, including vasomotor symptomatology, urogenital atrophy, risk of osteoporosis, and cardiovascular disease. In fact, among BRCA mutation carriers, the proportion undergoing prophylactic bilateral salpingo-oophorectomy is estimated to be only 60–70%.5–7
It has long been recognized that the vast majority of ovarian cancers diagnosed in BRCA mutation carriers are high-grade serous carcinomas.8 However, there is increasing evidence that these cancers do not exclusively arise in the ovary. A high proportion of these carcinomas identified incidentally at prophylactic bilateral salpingo-oophorectomy are invasive high-grade serous carcinomas of the fallopian tube or serous tubal intraepithelial carcinomas.9–20 This observation challenges the existing recommendation for prophylactic bilateral salpingo-oophorectomy, and it raises the possibility that prophylactic bilateral salpingectomy may be sufficient to reduce the risk of fallopian tube carcinoma while obviating the need for oophorectomy and its inherent consequences of estrogen deficiency. Prophylactic salpingectomy would not be expected to reduce breast cancer risk in this population, but it may reduce risk of premature death secondary to cardiovascular disease in women who have been rendered menopausal as a result of prophylactic bilateral salpingo-oophorectomy. It is unlikely that a randomized trial will ever be feasible to compare prophylactic bilateral salpingo-oophorectomy with prophylactic salpingectomy in this high-risk population. However, decision-analytic modeling can compare the costs, risks, and benefits of prophylactic salpingectomy with prophylactic bilateral salpingo-oophorectomy in a hypothetical cohort of women with BRCA germline mutations. Our objective was to compare the costs and benefits of salpingectomy with bilateral salpingo-oophorectomy among BRCA mutation carriers.
MATERIALS AND METHODS
This study was approved by the research ethics board of the University of British Columbia and the British Columbia Cancer Agency. We developed a Markov Monte Carlo simulation model to estimate the costs and benefits of three risk-reducing strategies in BRCA mutation carriers who have not yet had breast or ovarian cancer: 1) bilateral salpingo-oophorectomy at age 40 years (reference strategy, as per the American College of Obstetricians and Gynecologists)2; 2) bilateral salpingectomy at age 40 years; and 3) bilateral salpingectomy at age 40 years followed by bilateral oophorectomy at age 50 years. The benefit for each strategy was calculated in years of life gained as well as quality-adjusted years of life gained relative to an alternate strategy. Average lifetime costs were estimated in Canadian dollars in the year 2012. All direct and indirect costs were estimated for services rendered through the British Columbia Medical Services Plan21 and surgical treatment and outpatient chemotherapy costs through the Canadian Institute for Health Information22 and the British Columbia Cancer Agency. Opportunity costs were estimated from employment time lost based on average hourly wages from Statistics Canada.23 The primary outcome measure was the incremental cost-effectiveness ratio defined as the additional cost divided by the incremental health benefit compared with an alternate strategy. A strategy was strongly dominated if it was more costly and less effective than an alternate strategy. A strategy was considered cost-effective if its incremental cost-effectiveness ratio was between $50,000 and $100,000 per year of life gained.24 As per the U.S. Panel on Cost-effectiveness in Health and Medicine, we adopted a societal perspective and discounted all costs and benefits at a rate of 3% per year.25
Women with BRCA 1 or BRCA2 mutations comprise a hypothetical cohort residing in one of five Markov health states: 1) well; 2) at risk for breast and ovarian cancer; 3) breast cancer; 4) ovarian cancer; and 5) dead. They enter the model at age 30 years in the health state “at risk for breast cancer and ovarian cancer.” In the base case for this model, all women undergo the assigned risk-reducing intervention. Women diagnosed with breast or ovarian cancer transition to the “breast cancer” or “ovarian cancer” state, respectively, and in this state, they are subject to cancer-related mortality risks as well as age-dependent competing mortality risks according to Canadian life tables.26 We assumed that BRCA-associated ovarian cancer could arise in either the fallopian tube or ovary and that the presentation, treatment, and outcomes were comparable regardless of site of origin. Women with breast cancer remain at risk for recurrent or new breast cancer for up to 25 years if they have undergone breast-conserving surgery,27–31 but if they undergo bilateral mastectomy, this risk is reduced by 95%. If they have survived ovarian cancer for longer than 10 years, they transition to the “well” state because their mortality risks are estimated to be comparable with age-matched women without cancer. This process continues in yearly cycles until all women in the cohort reach the “dead” state because of cancer or other causes.
Because the cancer phenotype is different for BRCA1 and BRCA2 mutation carriers (ovarian cancer risk is higher and average age at diagnosis is lower in BRCA1 compared with BRCA2, and “triple-negative” breast cancers are more likely in BRCA1 than BRCA2),4,32,33 we calculated separate incremental cost-effectiveness ratios for each gene. We assumed that ovarian cancer risk reduction from prophylactic bilateral salpingo-oophorectomy at age 40 years was 80% in both BRCA1 and BRCA2 mutation carriers3,34,35 and 60% with prophylactic salpingectomy based on the assumption that the fallopian tube represents the primary site in 60% of BRCA-associated ovarian cancers.9–11,13,15,17,18,36 We assumed a 40% and 70% reduction in breast cancer risk from prophylactic bilateral salpingo-oophorectomy at age 40 years in BRCA1 and BRCA2 mutation carriers, respectively,3,4 but with an increased risk of premature death from cardiovascular disease according to outcomes from the Nurses’ Health Study.37 We assumed that salpingectomy did not reduce breast cancer risk.38
We assumed that quality of life in women undergoing prophylactic bilateral salpingo-oophorectomy at age 40 years would be compromised compared with those undergoing prophylactic salpingectomy alone. Quality-adjusted life-years were calculated by applying utilities to health states, which represent patient preferences for a year of life under specific conditions, for example, a year of life at age 40 years after having prophylactic bilateral salpingo-oophorectomy or a year of life after being diagnosed with ovarian cancer. Although prophylactic bilateral salpingo-oophorectomy at age 40 years has a utility of 0.82,39 there is no available literature on utilities for salpingectomy. Assuming a postoperative complication rate of 1.5–5%,40,41 and that ovarian function remains largely unaffected after salpingectomy,42–44 we arbitrarily assigned a utility of 0.99 for this procedure. We estimated that 30% of women would choose to undergo prophylactic mastectomy, ranging from 21% between the ages of 25 and 60 years45 to 34% between the ages of 23 and 64 years in our population based on data provided by the British Columbia Cancer Agency Hereditary Cancer Program high-risk clinic, which includes approximately 450 women with confirmed BRCA mutations.46 We assumed that these women were eligible for reconstruction with a transverse rectus abdominis myocutaneous flap with a utility of 0.87.47
We assumed that 50% of women diagnosed with breast cancer would choose bilateral mastectomy, and the other half would choose breast-conserving surgery (lumpectomy with sentinel node biopsy).48–51 Accordingly, those who had breast-conserving surgery received adjuvant radiotherapy. We assumed that these women would receive adjuvant chemotherapy as per British Columbia Cancer Agency protocol for high-risk young women comprised of four cycles of doxorubicin and cyclophosphamide followed by 12 weekly cycles of paclitaxel.52 We assumed that all women diagnosed with ovarian cancer would undergo laparotomy, hysterectomy, bilateral salpingo-oophorectomy, and staging or tumor debulking. We estimated that they would receive adjuvant chemotherapy comprised of six cycles of intravenous carboplatin and paclitaxel (and intraperitoneal chemotherapy for optimally debulked advanced-stage disease).53
We conducted a Monte Carlo simulation to estimate the number of subsequent breast and ovarian cancer cases expected with each strategy as well as the number of excess cardiovascular deaths attributed to premature menopause from bilateral salpingo-oophorectomy. Extensive sensitivity analyses were done to account for uncertainty around various parameters, including costs of treatment (to approximate costs in the United States), the proportion of BRCA-associated ovarian cancers arising in the fallopian tube and extent of risk reduction from prophylactic salpingectomy, and the ages and utilities associated with the different surgical strategies. Selected data for the base case of our model are provided in Table 1. The model was programmed using TreeAge Pro 2011.
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.
Our results were sensitive to variations in the age at prophylactic surgery. Figure 2 illustrates a two-way sensitivity analysis on the ages at salpingectomy and delayed oophorectomy to estimate whether earlier age thresholds for these procedures would be comparable to bilateral salpingo-oophorectomy at age 40 years with respect to life expectancy as the net health benefit. The sensitivity analysis demonstrates that when women have salpingectomy at 35 years of age followed by oophorectomy by the age of 46 years, costs and life expectancy are favorable compared with bilateral salpingo-oophorectomy at age 40 years given a willingness-to-pay threshold of $100,000 per year of life gained. Prophylactic salpingectomy at age 36 years followed by oophorectomy at age 42 years yields favorable costs and life expectancy compared with bilateral salpingo-oophorectomy at age 40 years.
Our results were also sensitive to varying estimates of the proportion of BRCA-associated ovarian cancers arising in the fallopian tube and the relative risk of these cancers after prophylactic salpingectomy. Assuming a higher proportion of these cancers arising in the fallopian tube, there is a higher magnitude of risk reduction from salpingectomy. Figure 3 illustrates that as the magnitude of risk reduction increases (and relative risk of ovarian cancer after salpingectomy decreases), the smaller the benefit of additional oophorectomy in terms of net health benefit, which increases the incremental cost-effectiveness ratio. Conversely, the lower the proportion of BRCA-associated ovarian cancers arising in the fallopian tube, the lower the risk reduction after salpingectomy. This translates into a greater benefit of additional oophorectomy compared with salpingectomy alone, which subsequently reduces the incremental cost-effectiveness ratio. In our base case, prophylactic salpingectomy and bilateral salpingo-oophorectomy reduced BRCA-associated ovarian cancer risks by 60% and 80%, respectively (relative risks of 0.40 and 0.20, respectively, compared with a reference risk of 1.0 without surgery). The benefit of additional oophorectomy after salpingectomy yields an incremental cost-effectiveness ratio that is well under $100,000 per quality-adjusted life-year gained compared with salpingectomy alone. When the relative risk of ovarian cancer from salpingectomy is increased to 0.30 in a sensitivity analysis (while keeping the relative risk unchanged at 0.20 for bilateral salpingo-oophorectomy), the incremental cost-effectiveness ratio is higher because magnitude of benefit from additional oophorectomy is lower, but it is still under $100,000 per quality-adjusted life-year gained.
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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