Obstetrics & Gynecology:
Prophylactic Salpingectomy and Delayed Oophorectomy as an Alternative for BRCA Mutation Carriers
Kwon, Janice S. MD; Tinker, Anna MD; Pansegrau, Gary MD; McAlpine, Jessica MD; Housty, Melissa MSN; McCullum, Mary MSN; Gilks, C. Blake MD
University of British Columbia and BC Cancer Agency, Vancouver, British Columbia, Canada.
Corresponding author: Janice S. Kwon, MD, Division of Gynecologic Oncology, University of British Columbia, 2775 Laurel Street, 6th Floor, Vancouver, BC, Canada, V5Z 1M9; e-mail: firstname.lastname@example.org.
Supported by an OvCaRe internal grant.
Financial Disclosure The authors did not report any potential conflicts of interest.
OBJECTIVE: Prophylactic bilateral salpingo-oophorectomy is advised for women with BRCA mutations, but there are adverse consequences of premature menopause. The majority of BRCA-associated ovarian cancers appear to arise in the fallopian tube; therefore, salpingectomy may be an alternative to bilateral salpingo-oophorectomy. We compared the costs and benefits of salpingectomy with bilateral salpingo-oophorectomy among BRCA mutation carriers.
METHODS: We developed a Markov Monte Carlo simulation model to compare three strategies for risk reduction in women with BRCA mutations: 1) bilateral salpingo-oophorectomy; 2) bilateral salpingectomy; and 3) bilateral salpingectomy with delayed oophorectomy. Net health benefits were measured in years-of-life expectancy and quality-adjusted life-year expectancy, and the primary outcome was the incremental cost-effectiveness ratio. The model estimated the number of future breast and ovarian cancers and cardiovascular deaths attributed to premature menopause with each strategy.
RESULTS: Bilateral salpingo-oophorectomy was associated with the lowest cost and highest life expectancy compared with the other two strategies. When quality-of-life measures were included, salpingectomy followed by delayed oophorectomy yielded the highest quality-adjusted life expectancy with incremental cost-effectiveness ratios of $37,805 and $89,680 per quality-adjusted life-year for BRCA1 and BRCA2, respectively, relative to salpingectomy alone. Bilateral salpingo-oophorectomy yielded the lowest number of future breast and ovarian cancers compared with the other two strategies.
CONCLUSION: Bilateral salpingo-oophorectomy offers the greatest risk reduction for breast and ovarian cancer among BRCA mutation carriers. However, when considering quality-adjusted life expectancy, bilateral salpingectomy with delayed oophorectomy is a cost-effective strategy and may be an acceptable alternative for those unwilling to undergo bilateral salpingo-oophorectomy.
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.
Table 1-a Selected D...Image Tools
Table 1-b Selected D...Image Tools
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.
Sensitivity analysis...Image Tools
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.
Two-way sensitivity ...Image Tools
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.
Sensitivity analysis...Image Tools
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.
1. Lancaster JM, Powell CB, Kauff ND, Cass I, Chen LM, Lu KH, et al.. Society of Gynecologic Oncologists Education Committee statement on risk assessment for inherited gynecologic cancer predispositions. Gynecol Oncol 2007;107:159–62.
2. Hereditary breast and ovarian cancer syndrome. ACOG Practice Bulletin No. 103. American College of Obstetricians and Gynecologists. Obstet Gynecol 2009;113:957–66.
3. Rebbeck TR, Kauff ND, Domchek SM. Meta-analysis of risk reduction estimates associated with risk-reducing salpingo-oophorectomy in BRCA1 or BRCA2 mutation carriers. J Natl Cancer Inst 2009;101:80–7.
4. Domchek SM, Friebel TM, Singer CF, Evans DG, Lynch HT, Isaacs C, et al.. Association of risk-reducing surgery in BRCA1 or BRCA2 mutation carriers with cancer risk and mortality. JAMA 2010;304:967–75.
5. Friebel TM, Domchek SM, Neuhausen SL, Wagner T, Evans DG, Isaacs C, et al.. Bilateral prophylactic oophorectomy and bilateral prophylactic mastectomy in a prospective cohort of unaffected BRCA1 and BRCA2 mutation carriers. Clin Breast Cancer 2007;7:875–82.
6. Metcalfe KA, Birenbaum-Carmeli D, Lubinski J, Gronwald J, Lynch H, Moller P, et al.. International variation in rates of uptake of preventive options in BRCA1 and BRCA2 mutation carriers. Int J Cancer 2008;122:2017–22.
7. Bradbury AR, Ibe CN, Dignam JJ, Cummings SA, Verp M, White MA, et al.. Uptake and timing of bilateral prophylactic salpingo-oophorectomy among BRCA1 and BRCA2 mutation carriers. Genet Med 2008;10:161–6.
8. Risch HA, McLaughlin JR, Cole DE, Rosen B, Bradley L, Kwan E, et al.. Prevalence and penetrance of germline BRCA1 and BRCA2 mutations in a population series of 649 women with ovarian cancer. Am J Hum Genet 2001;68:700–10.
9. Callahan MJ, Crum CP, Medeiros F, Kindelberger DW, Elvin JA, Garber JE, et al.. Primary fallopian tube malignancies in BRCA-positive women undergoing surgery for ovarian cancer risk reduction. J Clin Oncol 2007;25:3985–90.
10. Carcangiu ML, Peissel B, Pasini B, Spatti G, Radice P, Manoukian S. Incidental carcinomas in prophylactic specimens in BRCA1 and BRCA2 germ-line mutation carriers, with emphasis on fallopian tube lesions: report of 6 cases and review of the literature. Am J Surg Pathol 2006;30:1222–30.
11. Finch A, Shaw P, Rosen B, Murphy J, Narod SA, Colgan TJ. Clinical and pathologic findings of prophylactic salpingo-oophorectomies in 159 BRCA1 and BRCA2 carriers. Gynecol Oncol 2006;100:58–64.
12. Shaw PA, Rouzbahman M, Pizer ES, Pintilie M, Begley H. Candidate serous cancer precursors in fallopian tube epithelium of BRCA1/2 mutation carriers. Mod Pathol 2009;22:1133–8.
13. Medeiros F, Muto MG, Lee Y, Elvin JA, Callahan MJ, Feltmate C, et al.. The tubal fimbria is a preferred site for early adenocarcinoma in women with familial ovarian cancer syndrome. Am J Surg Pathol 2006;30:230–6.
14. Colgan TJ, Murphy J, Cole DE, Narod S, Rosen B. Occult carcinoma in prophylactic oophorectomy specimens: prevalence and association with BRCA germline mutation status. Am J Surg Pathol 2001;25:1283–9.
15. Domchek SM, Friebel TM, Garber JE, Isaacs C, Matloff E, Eeles R, et al.. Occult ovarian cancers identified at risk-reducing salpingo-oophorectomy in a prospective cohort of BRCA1/2 mutation carriers. Breast Cancer Res Treat 2010;124:195–203.
16. Finch A, Beiner M, Lubinski J, Lynch HT, Moller P, Rosen B, et al.. Salpingo-oophorectomy and the risk of ovarian, fallopian tube, and peritoneal cancers in women with a BRCA1 or BRCA2 Mutation. JAMA 2006;296:185–92.
17. Manchanda R, Abdelraheim A, Johnson M, Rosenthal AN, Benjamin E, Brunell C, et al.. Outcome of risk-reducing salpingo-oophorectomy in BRCA carriers and women of unknown mutation status. BJOG 2011;118:814–24.
18. Powell CB, Chen LM, McLennan J, Crawford B, Zaloudek C, Rabban JT, et al.. Risk-reducing salpingo-oophorectomy (RRSO) in BRCA mutation carriers: experience with a consecutive series of 111 patients using a standardized surgical—pathological protocol. Int J Gynecol Cancer 2011;21:846–51.
19. Yates MS, Meyer LA, Deavers MT, Daniels MS, Keeler ER, Mok SC, et al.. Microscopic and early-stage ovarian cancers in BRCA1/2 mutation carriers: building a model for early BRCA-associated tumorigenesis. Cancer Prev Res (Phila) 2011;4:463–70.
20. Rabban JT, Krasik E, Chen LM, Powell CB, Crawford B, Zaloudek CJ. Multistep level sections to detect occult fallopian tube carcinoma in risk-reducing salpingo-oophorectomies from women with BRCA mutations: implications for defining an optimal specimen dissection protocol. Am J Surg Pathol 2009;33:1878–85.
24. King JT Jr, Tsevat J, Lave JR, Roberts MS. Willingness to pay for a quality-adjusted life year: implications for societal health care resource allocation. Med Decis Making 2005;25:667–77.
25. Weinstein MC, Siegel JE, Gold MR, Kamlet MS, Russell LB. Recommendations of the panel on cost-effectiveness in health and medicine. JAMA 1996;276:1253–8.
27. Brekelmans CT, Seynaeve C, Menke-Pluymers M, Bruggenwirth HT, Tilanus-Linthorst MM, Bartels CC, et al.. Survival and prognostic factors in BRCA1-associated breast cancer. Ann Oncol 2006;17:391–400.
28. Graeser MK, Engel C, Rhiem K, Gadzicki D, Bick U, Kast K, et al.. Contralateral breast cancer risk in BRCA1 and BRCA2 mutation carriers. J Clin Oncol 2009;27:5887–92.
29. Malone KE, Begg CB, Haile RW, Borg A, Concannon P, Tellhed L, et al.. Population-based study of the risk of second primary contralateral breast cancer associated with carrying a mutation in BRCA1 or BRCA2. J Clin Oncol 2010;28:2404–10.
30. Metcalfe K, Lynch HT, Ghadirian P, Tung N, Olivotto I, Warner E, et al.. Contralateral breast cancer in BRCA1 and BRCA2 mutation carriers. J Clin Oncol 2004;22:2328–35.
31. Pierce LJ, Levin AM, Rebbeck TR, Ben-David MA, Friedman E, Solin LJ, et al.. Ten-year multi-institutional results of breast-conserving surgery and radiotherapy in BRCA1/2-associated stage I/II breast cancer. J Clin Oncol 2006;24:2437–43.
32. Antoniou A, Pharoah PD, Narod S, Risch HA, Eyfjord JE, Hopper JL, et al.. Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case series unselected for family history: a combined analysis of 22 studies. Am J Hum Genet 2003;72:1117–30.
33. Atchley DP, Albarracin CT, Lopez A, Valero V, Amos CI, Gonzalez-Angulo AM, et al.. Clinical and pathologic characteristics of patients with BRCA-positive and BRCA-negative breast cancer. J Clin Oncol 2008;26:4282–8.
34. Evans DG, Clayton R, Donnai P, Shenton A, Lalloo F. Risk-reducing surgery for ovarian cancer: outcomes in 300 surgeries suggest a low peritoneal primary risk. Eur J Hum Genet 2009;17:1381–5.
35. Kauff ND, Domchek SM, Friebel TM, Robson ME, Lee J, Garber JE, et al.. Risk-reducing salpingo-oophorectomy for the prevention of BRCA1- and BRCA2-associated breast and gynecologic cancer: a multicenter, prospective study. J Clin Oncol 2008;26:1331–7.
36. Norquist BM, Garcia RL, Allison KH, Jokinen CH, Kernochan LE, Pizzi CC, et al.. The molecular pathogenesis of hereditary ovarian carcinoma: alterations in the tubal epithelium of women with BRCA1 and BRCA2 mutations. Cancer 2010;116:5261–71.
37. Parker WH, Broder MS, Chang E, Feskanich D, Farquhar C, Liu Z, et al.. Ovarian conservation at the time of hysterectomy and long-term health outcomes in the nurses' health study. Obstet Gynecol 2009;113:1027–37.
38. Rebbeck TR, Levin AM, Eisen A, Snyder C, Watson P, Cannon-Albright L, et al.. Breast cancer risk after bilateral prophylactic oophorectomy in BRCA1 mutation carriers. J Natl Cancer Inst 1999;91:1475–9.
39. Anderson K, Jacobson JS, Heitjan DF, Zivin JG, Hershman D, Neugut AI, et al.. Cost-effectiveness of preventive strategies for women with a BRCA1 or a BRCA2 mutation. Ann Intern Med 2006;144:397–406.
40. Kauff ND, Satagopan JM, Robson ME, Scheuer L, Hensley M, Hudis CA, et al.. Risk-reducing salpingo-oophorectomy in women with a BRCA1 or BRCA2 mutation. N Engl J Med 2002;346:1609–15.
41. Meeuwissen PA, Seynaeve C, Brekelmans CT, Meijers-Heijboer HJ, Klijn JG, Burger CW. Outcome of surveillance and prophylactic salpingo-oophorectomy in asymptomatic women at high risk for ovarian cancer. Gynecol Oncol 2005;97:476–82.
42. Almog B, Wagman I, Bibi G, Raz Y, Azem F, Groutz A, et al.. Effects of salpingectomy on ovarian response in controlled ovarian hyperstimulation for in vitro fertilization: a reappraisal. Fertil Steril 2011;95:2474–6.
43. Johnson N, van Voorst S, Sowter MC, Strandell A, Mol BW. Surgical treatment for tubal disease in women due to undergo in vitro fertilisation. Cochrane Database of Systematic Reviews 2010, Issue 1. Art No.: CD002125. DOI: 10.1002/14651858.CD002125.pub3.
44. Strandell A, Lindhard A, Waldenstrom U, Thorburn J. Prophylactic salpingectomy does not impair the ovarian response in IVF treatment. Human Reprod 2001;16:1135–9.
45. Metcalfe KA, Ghadirian P, Rosen B, Foulkes W, Kim-Sing C, Eisen A, et al.. Variation in rates of uptake of preventive options by Canadian women carrying the BRCA1 or BRCA2 genetic mutation. Open Med 2007;1:e92–8.
47. Thoma A, Khuthaila D, Rockwell G, Veltri K. Cost-utility analysis comparing free and pedicled TRAM flap for breast reconstruction. Microsurgery 2003;23:287–95.
48. Evans DG, Lalloo F, Hopwood P, Maurice A, Baildam A, Brain A, et al.. Surgical decisions made by 158 women with hereditary breast cancer aged <50 years. Eur J Surg Oncol 2005;31:1112–8.
49. Metcalfe KA, Lubinski J, Ghadirian P, Lynch H, Kim-Sing C, Friedman E, et al.. Predictors of contralateral prophylactic mastectomy in women with a BRCA1 or BRCA2 mutation: the Hereditary Breast Cancer Clinical Study Group. J Clin Oncol 2008;26:1093–7.
50. Schwartz MD, Lerman C, Brogan B, Peshkin BN, Halbert CH, DeMarco T, et al.. Impact of BRCA1/BRCA2 counseling and testing on newly diagnosed breast cancer patients. J Clin Oncol 2004;22:1823–9.
51. Weitzel JN, McCaffrey SM, Nedelcu R, MacDonald DJ, Blazer KR, Cullinane CA. Effect of genetic cancer risk assessment on surgical decisions at breast cancer diagnosis. Arch Surg 2003;138:1323–8; discussion 1329.
55. Risch HA, McLaughlin JR, Cole DE, Rosen B, Bradley L, Fan I, et al.. Population BRCA1 and BRCA2 mutation frequencies and cancer penetrances: a kin-cohort study in Ontario, Canada. J Natl Cancer Inst 2006;98:1694–706.
56. Eisen A, Lubinski J, Klijn J, Moller P, Lynch HT, Offit K, et al.. Breast cancer risk following bilateral oophorectomy in BRCA1 and BRCA2 mutation carriers: an international case-control study. J Clin Oncol 2005;23:7491–6.
57. Rebbeck TR, Friebel T, Wagner T, Lynch HT, Garber JE, Daly MB, et al.. Effect of short-term hormone replacement therapy on breast cancer risk reduction after bilateral prophylactic oophorectomy in BRCA1 and BRCA2 mutation carriers: the PROSE Study Group. J Clin Oncol 2005;23:7804–10.
58. Kotsopoulos J, Lubinski J, Lynch HT, Kim-Sing C, Neuhausen S, Demsky R, et al.. Oophorectomy after menopause and the risk of breast cancer in BRCA1 and BRCA2 mutation carriers. Cancer Epidemiol Biomarkers Prev 2012;21:1089–96.
59. Greene MH, Mai PL, Schwartz PE. Does bilateral salpingectomy with ovarian retention warrant consideration as a temporary bridge to risk-reducing bilateral oophorectomy in BRCA1/2 mutation carriers? Am J Obstet Gynecol 2011;204:19.e1–6.
60. Dietl J, Wischhusen J, Hausler SF. The post-reproductive Fallopian tube: better removed? Hum Reprod 2011;26:2918–24.
61. Leblanc E, Narducci F, Farre I, Peyrat JP, Taieb S, Adenis C, et al.. Radical fimbriectomy: a reasonable temporary risk-reducing surgery for selected women with a germ line mutation of BRCA 1 or 2 genes? Rationale and preliminary development. Gynecol Oncol 2011;121:472–6.
63. Minisini AM, Menis J, Valent F, Andreetta C, Alessi B, Pascoletti G, et al.. Determinants of recovery from amenorrhea in premenopausal breast cancer patients receiving adjuvant chemotherapy in the taxane era. Anticancer Drugs 2009;20:503–7.
64. Swain SM, Land SR, Ritter MW, Costantino JP, Cecchini RS, Mamounas EP, et al.. Amenorrhea in premenopausal women on the doxorubicin-and-cyclophosphamide-followed-by-docetaxel arm of NSABP B-30 trial. Breast Cancer Res Treat 2009;113:315–20.
65. Tham YL, Sexton K, Weiss H, Elledge R, Friedman LC, Kramer R. The rates of chemotherapy-induced amenorrhea in patients treated with adjuvant doxorubicin and cyclophosphamide followed by a taxane. Am J Clin Oncol 2007;30:126–32.
66. Chen S, Parmigiani G. Meta-analysis of BRCA1 and BRCA2 penetrance. J Clin Oncol 2007;25:1329–33.
67. Botkin JR, Smith KR, Croyle RT, Baty BJ, Wylie JE, Dutson D, et al.. Genetic testing for a BRCA1 mutation: prophylactic surgery and screening behavior in women 2 years post testing. Am J Med Genet 2003;118A:201–9.
68. Lerman C, Hughes C, Croyle RT, Main D, Durham C, Snyder C, et al.. Prophylactic surgery decisions and surveillance practices one year following BRCA1/2 testing. Prev Med 2000;31:75–80.
69. Lodder L, Frets PG, Trijsburg RW, Klijn JG, Seynaeve C, Tilanus MM, et al.. Attitudes and distress levels in women at risk to carry a BRCA1/BRCA2 gene mutation who decline genetic testing. Am J Med Genet 2003;119A:266–72.
70. Meijers-Heijboer EJ, Verhoog LC, Brekelmans CT, Seynaeve C, Tilanus-Linthorst MM, Wagner A, et al.. Presymptomatic DNA testing and prophylactic surgery in families with a BRCA1 or BRCA2 mutation. Lancet 2000;355:2015–20.
71. Schwartz MD, Kaufman E, Peshkin BN, Isaacs C, Hughes C, DeMarco T, et al.. Bilateral prophylactic oophorectomy and ovarian cancer screening following BRCA1/BRCA2 mutation testing. J Clin Oncol 2003;21:4034–41.
72. Rebbeck TR, Friebel T, Lynch HT, Neuhausen SL, van 't Veer L, Garber JE, et al.. Bilateral prophylactic mastectomy reduces breast cancer risk in BRCA1 and BRCA2 mutation carriers: the PROSE Study Group. J Clin Oncol 2004;22:1055–62.
73. Hartmann LC, Sellers TA, Schaid DJ, Frank TS, Soderberg CL, Sitta DL, et al.. Efficacy of bilateral prophylactic mastectomy in BRCA1 and BRCA2 gene mutation carriers. J Natl Cancer Inst 2001;93:1633–7.
74. Herrinton LJ, Barlow WE, Yu O, Geiger AM, Elmore JG, Barton MB, et al.. Efficacy of prophylactic mastectomy in women with unilateral breast cancer: a cancer research network project. J Clin Oncol 2005;23:4275–86.
75. Kaas R, Verhoef S, Wesseling J, Rookus MA, Oldenburg HS, Peeters MJ, et al.. Prophylactic mastectomy in BRCA1 and BRCA2 mutation carriers: very low risk for subsequent breast cancer. Ann Surg 2010;251:488–92.
76. El-Tamer M, Russo D, Troxel A, Bernardino LP, Mazziotta R, Estabrook A, et al.. Survival and recurrence after breast cancer in BRCA1/2 mutation carriers. Ann Surg Oncol 2004;11:157–64.
77. Rennert G, Bisland-Naggan S, Barnett-Griness O, Bar-Joseph N, Zhang S, Rennert HS, et al.. Clinical outcomes of breast cancer in carriers of BRCA1 and BRCA2 mutations. N Engl J Med 2007;357:115–23.
78. Robson ME, Chappuis PO, Satagopan J, Wong N, Boyd J, Goffin JR, et al.. A combined analysis of outcome following breast cancer: differences in survival based on BRCA1/BRCA2 mutation status and administration of adjuvant treatment. Breast Cancer Res 2004;6:R8–R17.
79. Boyd J, Sonoda Y, Federici MG, Bogomolniy F, Rhei E, Maresco DL, et al.. Clinicopathologic features of BRCA-linked and sporadic ovarian cancer. JAMA 2000;283:2260–5.
80. Cass I, Baldwin RL, Varkey T, Moslehi R, Narod SA, Karlan BY. Improved survival in women with BRCA-associated ovarian carcinoma. Cancer 2003;97:2187–95.
81. Rubin SC, Benjamin I, Behbakht K, Takahashi H, Morgan MA, LiVolsi VA, et al.. Clinical and pathological features of ovarian cancer in women with germ-line mutations of BRCA1. N Engl J Med 1996;335:1413–6.
82. Fryback DG, Dasbach EJ, Klein R, Klein BE, Dorn N, Peterson K, et al.. The Beaver Dam Health Outcomes Study: initial catalog of health-state quality factors. Med Decis Making 1993;13:89–102.
83. Grann VR, Jacobson JS, Sundararajan V, Albert SM, Troxel AB, Neugut AI. The quality of life associated with prophylactic treatments for women with BRCA1/2 mutations. Cancer J Sci Am 1999;5:283–92.
84. Sun CC, Bodurka-Bevers D, Cantor SB, Mills GB, Gershenson DM. Preferences for outcomes in women at high-risk for breast/ovarian cancer—who and how you ask matters. ASCO Proceedings 2000;2000:435a.
85. Tengs TO, Winer EP, Paddock S, Aguilar-Chavez O, Berry DA. Testing for the BRCA1 and BRCA2 breast–ovarian cancer susceptibility genes: a decision analysis. Med Decis Making 1998;18:365–75.
86. van Roosmalen MS, Verhoef LC, Stalmeier PF, Hoogerbrugge N, van Daal WA. Decision analysis of prophylactic surgery or screening for BRCA1 mutation carriers: a more prominent role for oophorectomy. J Clin Oncol 2002;20:2092–100.
87. Tengs TO, Wallace A. One thousand health-related quality-of-life estimates. Med Care 2000;38:583–637.
88. Lidgren M, Wilking N, Jonsson B, Rehnberg C. Health related quality of life in different states of breast cancer. Qual Life Res 2007;16:1073–81.
89. Lloyd A, Nafees B, Narewska J, Dewilde S, Watkins J. Health state utilities for metastatic breast cancer. Br J Cancer 2006;95:683–90.
91. BCCA. BC Cancer Agency Patient Service Fee Schedule; 2012; 2011. Available at: Retrieved April 4, 2012.
© 2013 The American College of Obstetricians and Gynecologists
What does "Remember me" mean?
By checking this box, you'll stay logged in until you logout. You'll get easier access to your articles, collections,
media, and all your other content, even if you close your browser or shut down your
To protect your most sensitive data and activities (like changing your password),
we'll ask you to re-enter your password when you access these services.
What if I'm on a computer that I share with others?
If you're using a public computer or you share this computer with others, we recommend
that you uncheck the "Remember me" box.
Looking for ABOG articles? Visit our ABOG MOC II collection. The selected Green Journal articles are free through the end of the calendar year.
ACOG MEMBER SUBSCRIPTION ACCESS
If you are an ACOG Fellow and have not logged in or registered to Obstetrics & Gynecology, please follow these step-by-step instructions to access journal content with your member subscription.
Data is temporarily unavailable. Please try again soon.
Readers Of this Article Also Read