Germline mutations in the BRCA1/2 genes are associated with high susceptibility for breast and ovarian cancer and these mutations are highly penetrant.1 Risk-reducing salpingo-oophorectomy is the only proven surgical strategy in reducing ovarian cancer risk.2,3 Until recently, risk-reducing salpingo-oophorectomy was also thought to reduce breast cancer risk by half when performed before natural menopause2; however, this is contradicted by several recent publications.4–6
The most important disadvantage of salpingo-oophorectomy at premenopausal age is onset of premature menopause, which is known to have several short- and long-term adverse effects like vasomotor symptoms, sexual dysfunction, osteoporosis, cardiovascular disease, cognitive impairment, and increased risk of premature death.7–10 Hormone therapy alleviates most menopausal effects to greater or lesser extent but not all.7 Therefore, a risk-reducing strategy enabling preservation of the ovaries and thereby increasing quality of life may be of great advantage. Together with the growing evidence for the fallopian tube as the place of origin of ovarian carcinoma,11–14 an alternative risk-reducing strategy has been suggested.15–20 This consists of early risk-reducing salpingectomy on completion of childbearing followed by delayed risk-reducing oophorectomy several years later than currently recommended. However, data on its effects on ovarian cancer risk are lacking. We need optimal insight into ovarian cancer risks before offering this alternative risk-reducing strategy to BRCA mutation carriers. Therefore, the aim of this study is to estimate cumulative ovarian cancer risks for this alternative strategy and to compare them with risks under standard risk-reducing salpingo-oophorectomy with the ultimate goal to personalize and optimize risk communication.
MATERIALS AND METHODS
We determined three important variables in estimating cumulative ovarian cancer risks, which were included in this modeling study: 1) cumulative ovarian cancer risks for BRCA1/2 mutation carriers, 2) the ovarian cancer risk reduction attributable to risk-reducing salpingo-oophorectomy, and 3) the assumed effect of risk-reducing salpingectomy based on the distribution of the histotypes of BRCA-related ovarian carcinomas. An extensive review of the literature was performed on these variables to obtain hazard ratios as input for our risk model (Table 1). The MEDLINE database was searched for publications between 1964 and September 1, 2014 (date of our last search) using the following terms: 1) MeSH: Penetrance; Genes, BRCA1; Genes, BRCA2. Title&abstract: Meta-analysis; 2) title and abstract: Salpingo-oophorectomy; Salpingectomy; Oophorectomy; BRCA1; BRCA2; BRCA; Meta-analysis; 3) MeSH: Humans; Title&Abstract: BRCA1; BRCA2; BRCA; Ovarian Cancer; Ovarian Carcinoma; Mutation Carrier(s); Germline; Pathology; Histology; Morphology; Epithelial. Titles and abstracts of the identified 3, 10, and 171 reports, respectively, were read by one of the authors (M.G.H.) to select articles that were likely to report the requested effect sizes. Full texts of the remaining articles were scrutinized by one of the authors (M.G.H.) to further determine relevance and applicable hazard ratios were extracted from the relevant articles describing the largest patient groups as input for our model: one, two, and three articles, respectively. When available, most recent meta-analyses were considered best evidence (level I). The entire selection procedure was separately checked by one of the authors (J.A.d.H.). Whenever broad ranges in published data existed, we ran the model for the “best-case” and “worst-case” scenarios.
Chen et al1 performed a meta-analysis of 10 studies to calculate mean cumulative ovarian cancer risks for BRCA1/2 mutation carriers until the age of 70 years taking into account competing deaths (Table 2). In our opinion, this most recent meta-analysis reflects the best available evidence (ie, level I) and is worldwide frequently referred to when cumulative risks in BRCA1/2 mutation carriers are described.
Risk-reducing salpingo-oophorectomy is well established in reducing ovarian cancer risk in BRCA1/2 mutation carriers. Although various hazard ratios (HRs) were found in previous studies (HR 0.04–0.29), two meta-analyses were quite consistent and showed HRs of 0.21 and 0.19 corresponding to a risk reduction of approximately 80%.2,3
Rebbeck et al2 performed a fixed-effects meta-analysis of pooled results from three nonoverlapping publications. Among 2,840 BRCA1/2 mutation carriers, an HR of 0.21 (95% confidence interval [CI] 0.12–0.39) for ovarian cancer was found for risk-reducing salpingo-oophorectomy. A second fixed-effects meta-analysis by Marchetti et al3 included three studies, one overlapping Rebbeck et al2 and two more recent prospective cohort studies. A total of 9,192 BRCA1/2 mutation carriers were included; 46% had undergone risk-reducing salpingo-oophorectomy. They found an HR of 0.19 (95% CI 0.13–0.27) for ovarian cancer after risk-reducing salpingo-oophorectomy.3 Sufficient data are lacking to discriminate between BRCA1 and BRCA2 mutation carriers with respect to the effect of risk-reducing salpingo-oophorectomy. In conclusion, the reported HRs for the whole group of BRCA1/2 mutation carriers are close to 0.20, so we assumed an HR of 0.20 for risk-reducing salpingo-oophorectomy (ie, 80% risk reduction).
However, the HR of 0.20 might be an underestimation of the effect of risk-reducing salpingo-oophorectomy. First, the mean age at salpingo-oophorectomy was roughly 45 years in the previously mentioned studies, whereas current guidelines recommend risk-reducing salpingo-oophorectomy at age 35–40 years (BRCA1) or 40–45 years (BRCA2). Second, it was not always clear whether complete salpingo-oophorectomy or oophorectomy alone was performed, the latter performed at times until the role of the fallopian tube became illuminated. Furthermore, histologic assessment of earlier salpingo-oophorectomy specimens might have missed occult carcinomas, because the protocol for sectioning and extensively examining the fimbriated end of the fallopian tube was introduced in 2006.21,22 Follow-up of patients was continued until after the introduction of sectioning and extensively examining the fimbriated end of the fallopian tube in only two of eight studies in the meta-analyses. When metastasized disease was subsequently misdiagnosed as primary peritoneal cancer, risk reduction of salpingo-oophorectomy could be underestimated. In conclusion, inclusion of older patients who might have undergone oophorectomy only or whose fallopian tubes were not fully examined in aforementioned studies could have led to underestimation of the effect. Therefore, we decided to also run the model with the best effect of risk-reducing salpingo-oophorectomy ever reported: HR of 0.04 (95% CI 0.01–0.16), corresponding to 96% risk reduction.23
No published data on the risk-reducing effect of salpingectomy in BRCA1/2 mutation carriers are available. The theory of ovarian carcinoma arising from the fallopian tube is related to the serous histotype. Therefore, we extracted data on the proportion of the serous histotype within BRCA-related ovarian carcinoma to estimate the possible risk-reducing effect of salpingectomy. Two reviews8,24 and one original study using a large international database25 report on this. Altogether, approximately 65% of BRCA-related ovarian carcinomas are of the serous histotype (Table 3), which equals the distribution within sporadic ovarian carcinoma.24 Assuming that most serous cancers originate from the fallopian tube, we expect that the best possible HR for risk-reducing salpingectomy lies around 0.35, that is, 65% risk reduction.
However, the effect of risk-reducing salpingectomy can turn out to be greater because specimens in these large studies were not necessarily assessed or revised by a specialized gynecologic pathologist. Revision has been shown to partially reclassify former endometrioid and clear cell carcinomas as serous carcinomas, thereby slightly increasing the amount of serous carcinomas and indirectly the potential risk-reducing effect of salpingectomy.26 Furthermore, links between the fallopian tube and endometrioid and mucinous ovarian carcinomas have been described as well: through retrograde menstruation and endometriosis for the first and through Walthard cell nests, paratubal cysts and Brenner tumors for the latter.14 The effect of risk-reducing salpingectomy thus could be greater than we now assume if it is not limited to the serous histotype.
In contrast, there is still a possibility that salpingectomy does not reduce ovarian cancer risk at all and it is uncertain at what age it should be performed. Therefore, we ran scenarios with HRs of either 0.35 or 1.0 for risk-reducing salpingectomy.
Chen et al1 presented ovarian cancer risk estimates per 10-year intervals (eg, cumulative risk for ovarian cancer at age 50 years assuming no cancer at age 20 years). To transform these 10-year risks into yearly cumulative risk estimates, we used nonparametric interpolating splines. The resulting risks were used to calculate cumulative hazards for each age (t) as H(t)=−log(S[t]), where log is the natural logarithm and S(t) is the probability that cancer has not occurred at age t. Hazards h(t) for age t were calculated as the increment between H(t−1) and H(t). The hazards were multiplied with the hypothesized HRs (Table 4): if risk-reducing salpingectomy took place at age tRRS and delayed risk-reducing oophorectomy took place at age tRRO, the hazards between ages tRRS and tRRO (>tRRS and ≤tRRO) were multiplied with the assumed HR for risk-reducing salpingectomy (eg, 0.35 in case of 65% risk reduction or 1.0 in case of no risk reduction), and the hazards corresponding to ages >tRRO were multiplied with the assumed HR for risk-reducing salpingo-oophorectomy (ie, 0.04 in case of 96% risk reduction or 0.20 in case of 80% risk reduction). New cumulative risks were calculated as 1 minus the exponentiated negative sum of the appropriate hazards, that is, 1−exp(−Σhi), where i denotes the relevant ages. For example, if a 35-year-old woman presents without ovarian cancer, and risk-reducing salpingo-oophorectomy will take place at age 45 years with 80% risk reduction (HR 0.20), her estimated cumulative risk for ovarian cancer at age 70 years is based on the hazards from age 36 years up to and including age 70 years, where the hazards from age 46 years onward are multiplied with 0.20. The model design is illustrated in Figure 1.
Twenty scenarios were run for BRCA1 with five explicitly chosen combinations of risk-reducing salpingectomy (risk reduction 65% or 0%) between age 33 and 40 years and second-stage risk-reducing oophorectomy (risk reduction 96% or 80%) between age 40 and 45 years. For BRCA2, 28 scenarios were run with seven different combinations of risk-reducing salpingectomy (risk reduction 65% or 0%) between age 33 and 43 years and second-stage risk-reducing oophorectomy (risk reduction 96% or 80%) between age 45 and 50 years. More scenarios for BRCA2 were run because the interval between completion of childbearing and recommended age for risk-reducing salpingo-oophorectomy is longer in BRCA2 mutation carriers.
Because no human subjects were involved in this study, no informed consent was needed and the study was exempt from application to and approval of the institutional review board according to Dutch law.
BRCA1 mutation carriers' cumulative risks of ovarian cancer at age 70 years for several scenarios are provided in Table 5, conditional on the current age. Estimated cumulative risks assuming both 96% and 80% risk reduction by either risk-reducing salpingo-oophorectomy or delayed risk-reducing oophorectomy are displayed with corresponding 95% CIs.
Postponing oophorectomy from age 38 to 43 years, for example, will increase the point estimate of a 30-year-old BRCA1 mutation carrier's cumulative risk from 3.4% to 5.2% (assuming 96% risk reduction of risk-reducing salpingo-oophorectomy) or from 10.4% to 11.8% (assuming 80% risk reduction of salpingo-oophorectomy) in case there is no effect of previous salpingectomy. In case risk-reducing salpingectomy at age 33 years already reduces her risk by 65%, point estimates will decrease from 3.4% to 3.3% (96% risk reduction of salpingo-oophorectomy) or from 10.4% to 10.0% (80% risk reduction of salpingo-oophorectomy). Differences in risk estimates for this example assuming 96% risk reduction are displayed in Figure 2A.
In a second example, a 35-year-old BRCA1 mutation carrier considers standard risk-reducing salpingo-oophorectomy at short term or risk-reducing salpingectomy at short term with delayed oophorectomy at age 40 years. Risk estimates for this example are illustrated in Figure 2B for an assumed 96% risk reduction of salpingo-oophorectomy.
The maximum increase in point estimates (from 1.8% to 4.1%) occurs in a 40-year-old BRCA1 mutation carrier undergoing oophorectomy at age 45 years after nonprotective salpingectomy instead of salpingo-oophorectomy (96% risk reduction) at age 40 years. Assuming 65% risk reduction by salpingectomy and 96% of salpingo-oophorectomy, point estimates either increase (maximum increase from 1.8% to 2.6%) or decrease (maximum decrease from 3.4% to 3.3%) depending on current age and intervals between surgeries.
Table 6 provides cumulative risks of ovarian cancer at age 70 years for several scenarios for BRCA2 mutation carriers conditional on the current age. Estimated cumulative risks assuming both 96% and 80% risk reduction by either risk-reducing salpingo-oophorectomy or delayed risk-reducing oophorectomy are displayed with 95% CIs.
For example, postponing oophorectomy from age 40 to 45 years will increase the point estimate of a 35-year-old BRCA2 mutation carrier's cumulative risk from 1.0% to 1.7% (assuming 96% risk reduction of salpingo-oophorectomy) or from 3.6% to 4.2% (assuming 80% risk reduction of salpingo-oophorectomy) in case there is no effect of previous salpingectomy. In case risk-reducing salpingectomy at age 35 years already reduces her risk by 65%, point estimates will be equal assuming 96% risk reduction of salpingo-oophorectomy and increase from 3.5% to 3.6% assuming 80% risk reduction of salpingo-oophorectomy. Differences in risk estimates for this example assuming 96% risk reduction of salpingo-oophorectomy are displayed in Figure 2C.
In a second example, a 40-year-old BRCA2 mutation carrier considers standard risk-reducing salpingo-oophorectomy at age 43 years or risk-reducing salpingectomy at short term with delayed risk-reducing oophorectomy at age 48 years. Risk estimates for this example are illustrated in Figure 2D for an assumed 96% risk reduction of salpingo-oophorectomy.
In the worst-case scenario for BRCA2, point estimates maximally increase from 0.6% to 1.8% in 45-year-old carriers when oophorectomy is performed at age 50 years instead of risk-reducing salpingo-oophorectomy at age 45 years. Assuming 65% risk reduction of salpingectomy, and 96% of salpingo-oophorectomy, point estimates either increase (maximum increase from 1.3% to 1.5%) or decrease (maximum decrease from 1.5% to 1.3%) depending on current age and age at surgery.
In this study, cumulative risks of ovarian cancer for several risk-reducing strategies in BRCA1/2 mutation carriers are estimated by modeling data from the literature. Because risk-reducing salpingectomy with delayed oophorectomy has not been clinically studied yet, risk reduction rates for salpingectomy were estimated by combining existing data: 65% (best-case) or 0% (worst-case). In the best-case scenario, risk estimates were very similar for risk-reducing salpingo-oophorectomy at the currently recommended age and for risk-reducing salpingectomy with delayed oophorectomy 5 years beyond the currently recommended age. In the worst-case scenario (assuming no risk-reducing effect of salpingectomy), delaying oophorectomy by 5 years is estimated to maximally increase cumulative risk point estimates by 2.3 (BRCA1) and 1.2 (BRCA2) percentage points compared with risk-reducing salpingo-oophorectomy. Oophorectomy remains part of every scenario and none of the presented risk estimates are for salpingectomy alone.
Two research groups have published simulation models for risk-reducing surgery in BRCA1/2 mutation carriers since 2010.16,27 Kurian et al27 published a Monte Carlo simulation model as an online tool for cancer incidences and survival under risk-reducing mastectomy and risk-reducing salpingo-oophorectomy at different ages. For scenarios matching ours, results lie within the same range. They conclude that early mastectomy and salpingo-oophorectomy most effectively prevent cancer. However, alternative strategies resulted in similar survival rates, albeit reducing cancer incidence less substantially.
Kwon et al16 published the only model that included risk-reducing salpingectomy (at age 40 years, HR 0.40) with delayed oophorectomy (at age 50 years) besides risk-reducing salpingo-oophorectomy (at age 40 years, HR 0.20 for ovarian and HR 0.30–0.60 for breast cancer). They calculated gain in life expectancy and quality-adjusted life-years using a Markov model with Monte Carlo simulations. Risk-reducing salpingo-oophorectomy at age 40 years offered the greatest risk reduction for ovarian and breast cancer, but risk-reducing salpingectomy with delayed oophorectomy was cost-effective considering quality-adjusted life expectancy and therefore a reasonable alternative for BRCA1/2 mutation carriers who are reluctant to undergo risk-reducing salpingo-oophorectomy.
BRCA1/2 mutation carriers' choice for risk-reducing strategies is highly personal. To make an informed choice between risk-reducing salpingo-oophorectomy and risk-reducing salpingectomy with delayed oophorectomy, knowledge of estimated ovarian cancer risks under several scenarios is essential. BRCA mutation carriers should decide themselves which consequence outweighs the other: the possibility of slightly higher estimated ovarian cancer risks or the acute onset of surgical menopause and its consequences. The main strength of our model is that we provide such risk estimates for a number of potential scenarios: surgery at several ages and with various time intervals between risk-reducing salpingectomy and oophorectomy. Consequently, the risk estimates generated by our model can contribute to the decision for or against the alternative strategy. Another strength is that we have taken into account two different risk reduction rates for risk-reducing salpingo-oophorectomy: 80% (two meta-analyses) and 96% (best ever reported).2,3,23
Although halving of breast cancer risk by premenopausal risk-reducing salpingo-oophorectomy was widely communicated until recently,2 we did not include the effect of salpingo-oophorectomy on breast cancer in our model. Heemskerk-Gerritsen et al6 found no beneficial effect of risk-reducing salpingo-oophorectomy on breast cancer after applying alternative analyses to earlier large cohort studies, thereby minimizing amounts of bias. Furthermore, the effect of salpingo-oophorectomy is irrelevant for the substantial part (up to 32%) of BRCA1/2 mutation carriers having already undergone mastectomy by age 40–45 years.28
The most important limitation of our study is the uncertainty about assumptions the model was built on. First, reported penetrance of ovarian cancer at different ages in BRCA1/2 mutation carriers widely differs.1,5,29 This might be the result of methodologic differences and differences in patient populations. If penetrance appears to be higher in reality than reported by Chen et al,1 our model might underestimate absolute differences in cumulative risks. Second, given the lack of previous studies on its efficacy, risk reduction estimates for salpingectomy were totally based on the hypothesis that all serous ovarian carcinomas in BRCA1/2 mutation carriers could be prevented by salpingectomy. The 58% risk reduction of ovarian cancer after tubal ligation in BRCA1 mutation carriers could be considered indirect evidence.30
Based on the presented risk estimates, we conclude that risk-reducing salpingectomy necessarily followed by delayed oophorectomy may be offered to BRCA1/2 mutation carriers as an alternative strategy to risk-reducing salpingo-oophorectomy, preferably within a clinical trial. With current age as well as timing and type of surgeries taken into account, these ovarian cancer risk estimates are highly personalized. Providing these personal risk estimates, our model may support both patients and physicians in shared decision-making, and this may contribute to individualized health care. A decision aid might be helpful to comprehensibly present these risk estimates to patients.
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