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Risk-reducing salpingo-oophorectomy (RRSO) is the most definitive surgical intervention for ovarian cancer risk reduction among BRCA1/2 mutation carriers. For women who have completed child-bearing but who are not ready for RRSO, bilateral salpingectomy with ovarian retention (BSOR) might serve as a temporary measure while definitive risk-reducing surgery is being contemplated. Here we summarize recent insights into the pathogenesis of hereditary ovarian cancer which might provide a basis for considering the proposed BSOR management strategy and outline the evidence for and against this potential risk-reducing intervention. Based on the evidence presented, we suggest that there may be sufficient merit in this proposed intervention to consider evaluating it formally, perhaps through an intergroup-based clinical trial. In the meanwhile, we believe that BSOR should be considered an investigational risk management option of unproven clinical utility, particularly since delay in bilateral oophorectomy could theoretically reduce the protective effect against breast cancer that has been documented in women undergoing RRSO.
The mapping and cloning of BRCA1 and BRCA2, the two major breast/ovarian cancer susceptibility genes, and the subsequent widespread application of clinical germline mutation testing of these genes as the basis for cancer risk assessment and management in familial breast/ovarian cancer kindred, have presented providers and patients with many challenging clinical decisions. The steady accumulation of evidence upon which these choices are considered comprises one of the major scientific accomplishments in clinical cancer genetics during the past decade.1
Nonetheless, there remain some clinical scenarios for which we do not yet have sufficient data for evidence-based decision-making. The complexities involved in considering when a premenopausal BRCA1/2 mutation carrier should undergo risk-reducing salpingo-oophorectomy (RRSO) are among the most daunting. Although it is increasingly clear that RRSO in this setting is associated with the largest currently-available reductions in the risks of ovarian, fallopian tube, and breast carcinoma,2 numerous questions regarding the timing of the procedure, post-RRSO non-oncologic morbidity, and the safety of menopausal hormonal therapy (MHT) remain unresolved.
Concerns and uncertainties for at-risk women and health care providers regarding the frequency and severity of symptoms related to premature menopause are among the greatest deterrents to more widespread acceptance of RRSO as the routine risk management strategy for BRCA1/2 mutation carriers who have completed child-bearing. Although previous studies suggested that short-term use of MHT post-RRSO among BRCA1/2 mutation carriers does not mitigate the impact of RRSO on breast cancer risk,3, 4 and use of short-term (e.g., <5 years) MHT is increasing among pre-menopausal women who undergo RRSO, the existing evidence needs to be confirmed and many providers and patients remain wary of the potential adverse effects of post-surgical MHT.
The suggestion regarding a potentially new management option for mutation carriers who are not yet prepared to undergo premature menopause and its consequences emerged during a discussion at the 24th Annual Ella T. Grasso Ovarian Cancer Symposium, held at Yale University, in November 2008. We consider whether bilateral salpingectomy with ovarian retention (BSOR) represents a potentially useful risk-reducing strategy as a temporary, short-term intermediate step towards eventual bilateral oophorectomy in this group of women. The following discussion outlines the rationale for, and reviews the potential risks and benefits of, such a strategy, to open this novel idea for debate. We emphasize that this commentary is not intended to encourage or support ad hoc application of this unproven strategy.
This question arose as an unexpected nexus of a discussion that centered on two important clinical observations. First, bilateral tubal ligation has been suggested to be associated with a reduction in the risk of both sporadic5 and hereditary6 ovarian cancer, particularly among BRCA1 mutation carriers. However, this risk reduction has not been consistently observed. Although Narod and colleagues showed that bilateral tubal ligation was associated with a 61% reduction in ovarian cancer risk among BRCA1 mutation carriers,7 this observation was not replicated in a larger study.8 There has been considerable speculation regarding the physiologic basis for this association, including putative compromise of ovarian blood supply and mechanical interruption of the transport of environmental carcinogens from the lower female reproductive tract to the ovaries. The former is not anatomically compelling, since the ovarian blood supply is typically not altered by tubal ligation.9-11 The second – most notably in the form of the “talc hypothesis” of ovarian carcinogenesis – remains controversial despite being observed in multiple studies.12, 13 Regardless of the mechanism, the association between interruption of the fallopian tubes and ovarian cancer risk reduction is potentially substantial. However, tubal ligation is seldom raised as a treatment option among young mutation carriers.
Second, the increasingly wide-spread application of RRSO as a management strategy in high-risk women, coupled with more careful histopathologic scrutiny of the fallopian tubes obtained at the time of surgery,14 has shown that a significant proportion of the clinically-occult malignancies detected in these pathology specimens originated in the fallopian tube rather than the ovary.15 We now know that the fallopian tube is a target for BRCA1/2-related malignancies,16-22 an insight that has resulted in the routine incorporation of bilateral salpingectomy into the surgical management of women with BRCA1/2 mutations.
Furthermore, these findings have led several groups of investigators to more carefully evaluate the role of the fallopian tube in ovarian carcinogenesis.23-28 A potential paradigm-altering hypothesis has emerged from their work, i.e., that a significant proportion of what has historically been classified as ovarian cancer is actually cancer of fallopian tube origin.15, 29 Thus the term “pelvic serous carcinoma” (PSC) may be a more precise over-arching concept which subsumes the site-specific entities of ovarian, fallopian tube, and primary peritoneal malignancies. This new terminology acknowledges the difficulty related to determining the precise site of initial malignant transformation among these morphologically and clinically similar neoplasms. The full spectrum of proliferative and neoplastic lesions seen in most other epithelial malignancies in adults (but conspicuously absent in the ovaries themselves) has now been observed in the fallopian tube mucosa of BRCA1/2 mutation carriers. This then raises the question of whether there might be significant risk-reduction associated with a strategy of bilateral salpingectomy, followed later by definitive risk-reducing bilateral oophorectomy, in pre-menopausal women who have completed their planned family but who are not yet ready to undergo bilateral oophorectomy.
The potential advantages for a BSOR strategy are based on three assumptions: a) a clinically meaningful proportion of all BRCA-related PSC arises in the fallopian tube; b) these fallopian tube cancers (FTC) can be prevented by bilateral salpingectomy; and c) any risks associated with delaying menopause among genetically-predisposed women are offset by benefits related to removal of the tubes at a younger age than might otherwise be the case.
Within this framework, potential advantages to BSOR as a short-term, intermediate bridge to risk-reducing bilateral oophorectomy (RRBO) include:
The following constitutes a summary of the potential problems or difficulties involved in considering a BSOR strategy:
Although the rationale supporting the potential utility of BSOR as an interim, short-term measure while awaiting definitive ovarian cancer risk-reducing surgery seems reasonable, we have no objective data at present to prove that it is safe and effective, when all the risks and benefits are taken into account.
Weighing the complex set of pros and cons related to BSOR above, it seems that there may be sufficient merit in this proposal to consider evaluating it in a formal fashion. In summary, it appears that:
If a consensus emerges that BSOR is an interim, short-term management option worthy of serious consideration by women desirous of deferring bilateral oophorectomy, it would be desirable to undertake a formal clinical research protocol. One could register eligible mutation carriers at the time they complete their planned family, and offer standard RRSO to everyone. Those declining RRSO would be offered BSOR. Some women would choose one of the surgical options, although some would likely defer surgical intervention to a later time. The surgical procedure would be stipulated per protocol, and the following outcomes would be obtained:
A simplified, streamlined study design would make it feasible for an Inter-Group study, thus permitting relatively rapid accrual of the large number of participants required to achieve adequate statistical power. We await the response of care-providers and consumers with interest.
We cannot emphasize enough that the complexities related to a reliable risk/benefit assessment of the BSOR strategy we have described clearly show that there is opportunity for this approach to be seriously flawed. We propose that, pending additional data, BSOR should be considered an investigational procedure of unproven utility, which would be most safely evaluated on the basis of carefully-designed clinical trials. A pilot study of BSOR is currently under consideration by the Gynecologic Oncology Group.
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Mark H. GREENE, Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD 20852.
Phuong L. MAI, Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD 20852.
Peter E. SCHWARTZ, Division of Gynecologic Oncology, Yale University School of Medicine, New Haven, CT 06520.