Should Risk-Reducing Surgery in Women from Hereditary Breast Ovarian Cancer Families be Confined to Removal of the Fallopian Tubes with Ovarian Conservation?

“Prophylactic mastectomy and risk-reducing salpingo-oophorectomy during the fourth decade of life have proven to be the most effective approach for reducing all cancer risk and mortality in mutation carriers”

Cancers attributed to ovarian origin are relatively uncommon in the USA general population, accounting for only 2.6% of cancers in women [1]. Yet, this disease is responsible for 14.2% of the cancer deaths in American women [1]. Over 21,000 women are expected to be diagnosed in the USA with ovarian cancer during the next year [1].

When detected and treated in its earliest stage, those who may be diagnosed with ovarian cancer have relatively good prognosis for survival; however, the majority of ovarian cancers have not been diagnosed until quite advanced when the outlook for relapse-free survival has been gravely disappointing [1,2]. Thus far, available methods of screening for ovarian cancer, including serial serum CA-125 tests, transvaginal ultrasound scans and bimanual pelvic examinations have not been effective for reducing morbidities and mortality caused by ovarian cancer in general populations or in women at high hereditary risk for the disease [1,3–5]. Therefore, most clinicians do not recommend screening general populations where the risk for ovarian cancer, particularly in asymptomatic women, is only approximately 1.5%, and routine screening of women at high risk remains in question [4,5].

Women referred for cancer genetics counseling from hereditary breast ovarian (HBOC) syndrome families linked to cancer-associated mutations in the genes BRCA1 and BRCA2, often are recommended to have genetic tests to determine whether they may carry one of the deleterious mutations, which, being autosomal dominant, are inherited by half of the offspring of affiliated individuals, male or female. The risk for breast cancer in female mutation carriers from HBOC syndrome families is 56–84% [6]. Albeit, mammography screening in general populations increases the diagnosis of early stage breast cancers and reduces mortality, the effectiveness of breast cancer screening, even with the latest technics, for improving survival in women with high genetic risk is at best controversial [7–9].

Women found to carry cancer-linked mutations in BRCA1 are at 36–54% risk for developing ovarian cancer, and BRCA2 mutation carriers are at 10–27% risk [6,10]. While fewer than 3% of ovarian cancers in BRCA1 and BRCA2 mutation carriers have been diagnosed before age 35 years, as many as 52% of ovarian cancers in BRCA1 mutation carriers were diagnosed by age 50 years. Although the life-time risk for ovarian cancer in BRCA2 mutation carriers is significant, most of these cancers are diagnosed after age 50 years [5,10–11].

Because of their increased risks and the younger ages of breast and ovarian cancers in BRCA1 and BRCA2 mutation carriers occurring during their fifth and sixth decades of life, along with the inadequacies of screening, women who inherit these mutations should be thoroughly advised and offered prophylactic surgery intended to reduce their risks for early-age breast cancer and advanced ovarian cancer [4–5,7–9]. Prophylactic bilateral mastectomy is the most effective intervention against breast cancer in mutation carriers, reducing incidence by at least 90% and reducing breast cancer mortality nearly this much [8–9,12]. However, many women are reluctant to undergo this surgery, and postsurgical effects are long-lasting if they do occur [8–9,13]. On the other hand, salpingo-oophorectomy has been shown in meta-analysis not only to reduce the risk of ovarian cancer by at least 80% in BRCA1 and BRCA2 mutation carriers, but also the operation is associated with a 50% reduction in breast cancer. [6]. Subsequent publications report even more impressive prophylaxis against breast and ovarian cancers in mutation carriers with risk-reducing salpingo-oophorectomy (RRSO) [7–8,11–12]. Moreover, there is evidence that RRSO significantly reduces overall mortality; whereas, bilateral mastectomy alone may not [7,11–12]. The greatest impact of RRSO on breast cancer risk reduction in mutation carriers was found when the operation was performed prior to age 40 years, and little prophylactic effect against breast cancer was demonstrable if surgery was delayed beyond the sixth decade [11–14]. Of course, this procedure deprives premenopausal women of most endogenous estrogen production, because their ovaries are removed. In spite of that, more mutation carriers find RRSO an acceptable alternative and at younger ages than prophylactic mastectomy [13].

“During the past decade, it is becoming clear that many, if not most of these cancers arise in fallopian tube endothelium, particularly the fimbria and ampulla…”

Acute symptoms attributable to estrogen deprivation following surgical menopause in mutation carriers, hot flushes, night sweats, sexual problems, etc., are alleviated by short-term estrogen replacement therapy in mutation carriers without impairing the reduction of breast cancer risk that is associated with early RRSO [15–18]. In aging women with no known hereditary risks for cancer who underwent premenopausal oophorectomy before age 50 years and did not use hormone replacement, there may be significant increases in serious long-term sequelae, including cardiovascular disease, osteoporotic fractures and cognitive impairment against which exogenous estrogens may be protective [18,19]. Though long-term follow-up studies after RRSO in BRCA1 and BRCA2 mutation carriers are not available, it is expected that these women are also susceptible to these same adverse effects after premature surgical menopause. So, though still controversial, given the evident protection of estrogen replacement and present expectation of at least short-term safety in premenopausal women, the intended positive effects should be weighed against possible untoward effects in decisions to prescribe and use exogenous estrogens until the age of natural menopause of approximately 50 years in young mutation carriers who undergo RRSO [18,19].

The protective effects of tubal ligation and hysterectomy against ovarian cancer have been known for some while, and recent studies indicate that this trend extends to mutation carriers from HBOC syndrome families and for serous as well as endometrioid carcinomas [20–23]. The epithelial derivatives of the embryologic müllerian system have long been implicated as primary sites for malignant transformation to high-grade serous carcinomas in BRCA1 and BRCA2 mutation carriers previously assigned to ovarian and/or peritoneal origin and often associated with widespread intra-abdominal carcinomatosis. During the past decade, it is becoming clear that many, if not most of these cancers arise in fallopian tube endothelium, particularly the fimbria and ampulla, and perhaps some arise from preinvasive neoplasms of the endometrium and transit through the fallopian tubes to implant upon the ovaries and disseminate throughout the peritoneal cavity [24–26]. Thorough surgical pathological studies have revealed unexpected occult preinvasive and invasive serous carcinomas involving the ovaries, fallopian tube endothelium and endometrium in operative specimens from salpingo-oophorectomies and hysterectomies intended to reduce the risk of gynecological cancers in BRCA1 and BRCA2 mutation carriers [24–25,27–34]. A recent review of pooled studies of BRCA1 and BRCA2 mutation carriers who underwent risk-reducing surgery found an overall 3% rate of serous tubal intraepithelial carcinoma (STIC) in 2035 RRSOs and 2.7% rate of invasive cancers in 3030 RRSOs [34]. Examination of 93 occult preinvasive and invasive carcinoma cases, reported during the past 5 years since the extra-ovarian origin of many gynecologic serous carcinomas has been recognized, finds that 66% involved only fallopian tube fimbria or lumen, 15% involved both fallopian tube and ovary, and 19% involved only ovary [25,28–33]. One report that included hysterectomy in the risk-reducing surgery found two endometrial serous carcinomas in BRCA1 mutation carriers [25]. Positive peritoneal cytology and even omental metastases accompanying preinvasive and microscopic invasive carcinomas in the ovaries and fallopian tubes removed by intended RRSO are not uncommon findings [25,28,32].

Accumulating translational and molecular evidence supporting the important role of malignant transformation of fallopian tube endothelium in the genesis of aggressive pelvic-abdominal serous carcinomas that characterize the HBOC syndrome and the demonstration of significant risk reduction for ovarian cancer after salpingectomy in general population studies, have recently led to speculation that elected prophylactic surgery in young premenopausal BRCA1 and BRCA2 mutation carriers reasonably might be confined to removal of the fallopian tubes with ovarian conservation [24,35–36]. General population data analyzed from the Swedish Board of Health and Welfare concluded that previous hysterectomy and bilateral salpingo-oophorectomy reduced almost completely the risk for ovarian cancer (HR: 0.06; 95% CI: 0.02–0.24); while bilateral salpingectomy significantly reduced the risk (HR: 0.39; 95% CI: 0.18–0.87) for 10 or more years after surgery [35]. In spite of the efficacy of premenopausal RRSO by age 40 years or when childbearing is complete for lowering the risks of breast and ovarian cancers, studies show that a major obstacle to this decision is the loss of ovarian hormones [37,38]. Randomized prospective studies of younger than 40 years mutation carriers with no desire for future childbearing and prior bilateral mastectomy have been proposed to compare RRSO with bilateral salpingectomy and delayed oophorectomy after 5–15 years [37,39]. In the meanwhile, making many assumptions, others have developed and tested a Markov Monte Carlo simulation modeling prophylactic salpingectomy at age 40 years and oophorectomy at 50 years versus RRSO at age 40 years [40]. This found an expected 22.6% reduction of breast cancer and 22.8% reduction of ovarian cancer with RRSO in BRCA1 mutation carriers compared with just 0.4% reduction of breast cancer and 14.6% reduction of ovarian cancer with salpingectomy and delayed oophorectomy; and the reduction of breast cancer was 39.7% and ovarian cancer 20.5% with RRSO in BRCA2 mutation carriers compared with 1.1% breast cancer reduction and 13.1% ovarian cancer reduction with salpingectomy and delayed oophorectomy [40]. At the same time, the model expected five cardiovascular deaths in BRCA1 and ten in BRCA2 mutation carriers with RRSO, but none in mutation carriers who delayed oophorectomy until age 50 years, and delaying oophorectomy provided higher quality-adjusted life expectancy. The authors noted that their model did not assume hormone therapy in those undergoing RRSO at age 40 years and acknowledged that including estrogen replacement might improve quality-adjusted life-expectancy beyond that found with delayed oophorectomy [40]. In closing, they emphasized that the standard of care for BRCA1 and BRCA2 mutation carriers “remains prophylactic bilateral salpingo-oophorectomy after completion of childbearing or around the age of 40 years” [40].

It is important to stress that the objective of patient care is to avoid and relieve suffering. Prophylactic mastectomy and RRSO during the fourth decade of life have proven to be the most effective approach for reducing all cancer risk and mortality in mutation carriers [6–9,12–14]. For those who refuse and/or delay mastectomy and choose breast screening, RRSO before the age of 40 years convincingly reduces the risk for breast cancer and pelvic-abdominal serous carcinoma and decreases overall mortality [6–8,11–12]. Because present evidence is that short-term estrogen replacement does not adversely affect the reduction of breast or ovarian cancer risks associated with RRSO and can mitigate the acute symptoms while offering protection against some of the deleterious chronic systemic effects of estrogen deprivation, replacement therapy may be considered in mutation carriers without breast cancer [19]. The proven results achieved with RRSO for breast and ovarian cancer risk reduction and the frequency with which occult cancerous involvement of ovaries is found in mutation carriers speak against ovarian conservation when cancer prevention is intended. Until definite, assuring data from carefully designed, controlled studies are available to test the effectiveness of prophylactic salpingectomy and delayed oophorectomy for cancer prevention and improved quality-adjusted life expectancy in BRCA1 and BRCA2 mutation carriers, this approach should be reserved only for premenopausal mutation carriers who refuse the options of prophylactic mastectomy and/or RRSO [37,40–41]. Finally, it should be noted that the question remains whether BRCA1 and BRCA2 mutation carriers may be afflicted by special susceptibility to carcinomas arising from the endometrium, another Müllerian derivative [26]. An unusual prevalence of endometrial high-grade serous and serous mixed carcinomas are diagnosed in mutation carriers on one hand, and on the other hand BRCA1 and BRCA2 germline mutations have been found in relatively high proportions of patients with endometrial serous carcinomas [25,26]. Furthermore, mutation carriers who have undergone premenopausal RRSO may be treated with unopposed exogenous estrogen, and others may have received tamoxifen chemoprophylaxis or treatment against breast cancer, regimens which increase risks for endometrioid and possibly high-grade serous carcinomas [26]. Whether preinvasive or invasive, fallopian tube carcinomas involve the endometrium or whether endometrial precursor lesions or cancer cells transit to and through the fallopian tubes these routes of malignant extension will be eliminated by hysterectomy and bilateral salpingo-oophorectomy. Removal of the uterus as well as the fallopian tubes and ovaries is an option that should maximize risk-reduction against gynecologic cancers and simplify decisions regarding hormone replacement therapy for BRCA1 and BRCA2 mutation carriers following prophylactic surgery.

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The contents of this paper are solely the responsibility of the authors and do not necessarily represent the official views of the State of Nebraska or the Nebraska Department of Health and Human Services.