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 that might provide a basis for consideration of the proposed BSOR management strategy and outline the evidence for and against this potential risk-reducing intervention. Based on the evidence, 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 usefulness, particularly because delay in bilateral oophorectomy theoretically could reduce the protective effect against breast cancer that has been documented in women who have undergone RRSO.
The mapping and cloning of BRCA1 and BRCA2 , the 2 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 on which these choices are considered comprises 1 of the major scientific accomplishments in clinical cancer genetics during the past decade.
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, numerous questions regarding the timing of the procedure, post-RRSO nononcologic morbidity, and the safety of menopausal hormonal therapy (MHT) remain unresolved.
Concerns and uncertainties for at-risk women and healthcare providers regarding the frequency and severity of symptoms that are 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 childbearing. Although previous studies have suggested that short-term use of MHT after RRSO among BRCA1/2 mutation carriers does not mitigate the impact of RRSO on breast cancer risk, and the use of short-term (eg, <5 years) MHT is increasing among premenopausal women who undergo RRSO, the existing evidence must be confirmed; many providers and patients remain wary of the potential adverse effects of postsurgical MHT.
The suggestion regarding a potentially new treatment 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, which was 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.
The rationale
This question arose as an unexpected nexus of a discussion that centered on 2 important clinical observations. First, bilateral tubal ligation has been suggested to be associated with a reduction in the risk of both sporadic and hereditary ovarian cancer, particularly among BRCA1 mutation carriers. However, this risk reduction has not been observed consistently. Although Narod et al showed that bilateral tubal ligation was associated with a 61% reduction in ovarian cancer risk among BRCA1 mutation carriers, this observation was not replicated in a larger study. There has been considerable speculation regarding the physiologic basis for this association, which includes 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 compelling anatomically, because the ovarian blood supply typically is not altered by tubal ligation. The second (most notably in the form of the “talc hypothesis” of ovarian carcinogenesis) remains controversial, despite being observed in multiple studies. Regardless of the mechanism, the association between interruption of the fallopian tubes and ovarian cancer risk reduction is potentially substantial. However, tubal ligation seldom is raised as a treatment option among young women who are mutation carriers.
Second, the increasingly wide-spread application of RRSO as a treatment strategy in high-risk women, coupled with more careful histopathologic scrutiny of the fallopian tubes that were obtained at the time of surgery, has shown that a significant proportion of the clinically occult malignancies that were detected in these pathologic specimens originated in the fallopian tube rather than the ovary. We now know that the fallopian tube is a target for BRCA1/2 -related malignancies, which is an insight that has resulted in the routine incorporation of bilateral salpingectomy into the surgical treatment of women with BRCA1/2 mutations.
Furthermore, these findings have led several groups of investigators to evaluate more carefully the role of the fallopian tube in ovarian carcinogenesis. A potential paradigm-altering hypothesis has emerged from their work (ie, that a significant proportion of what has been classified historically as ovarian cancer is actually cancer of fallopian tube origin. Thus, the term pelvic serous carcinoma (PSC) may be a more precise over-arching concept that subsumes the site-specific entities of ovarian, fallopian tube, and primary peritoneal malignancies. This new terminology acknowledges the difficulty that is related to the determination of the precise site of initial malignant transformation among these morphologically and clinically similar neoplasms. The full spectrum of proliferative and neoplastic lesions that is 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 premenopausal women who have completed their planned family but who are not yet ready to undergo bilateral oophorectomy.
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