Time Of Risk-reducing Salpingo-oophorectomy Research Articles

Effects of Hormonal Replacement Therapy and Mindfulness-Based Stress Reduction on Climacteric Symptoms Following Risk-Reducing Salpingo-Oophorectomy.

Breast Cancer Associated Susceptibility Proteins Type 1/2 (BRCA1/2) promote cellular functioning by modulating NRF2-mediated antioxidant signaling. Redox failure in women with BRCA1/2 insufficiency increases the risk for breast/ovarian/uterine cancers. Risk-reducing salpingo-oophorectomy (RRSO) is a prophylactic surgery of the reproductive organs, which is frequently conducted by the age of 40 to lower the occurrence of cancer in women with BRCA1/2 mutations. However, abrupt estrogen decline following RRSO causes ovarian failure, which implicates various cellular physiological processes, resulting in the increased release of free radicals and subsequent severe onset of menopausal symptoms. Comfort measures (e.g., hormonal replacement therapy (HRT) and mindfulness-based stress reduction (MBSR)) may improve chronological menopause-related quality of life, but their specific effects are not clear in women with gene mutations. Aiming to fill the gap, this study used path analysis to examine the effects of HRT and MBSR on menopausal symptoms among RRSO patients (N = 199, mean age = 50.5 ± 6.7 years). HRT directly alleviated the levels of urogenital symptoms (β = -0.195, p = 0.005), which mediated its indirect significant effects on the somatic-vegetative and psychological symptoms of menopause (β = -0.046, -0.067; both p values = 0.004, respectively), especially in BRCA2 carriers and in women who were currently physically active, premenopausal at the time of RRSO, had a high BMI, and had no history of breast cancer. It increased the severity of urogenital symptoms in women with a history of cancer. MBSR, on the other hand, was associated with indirect increases in the intensity of the somatic-vegetative and psychological symptoms of menopause (β = 0.108, 0.029; p = 0.003, 0.033, respectively). It exerted positive direct effects on different menopausal symptoms in multigroup analysis. The results suggest that young women undergoing recent RRSO may benefit from HRT at an individual level, while their need for extensive measures to optimize their psychological wellbeing is ongoing. The adverse effects of MBSR, which are captured in the present study, imply that MBSR may interfere with redox sensitivity associated with estradiol fluctuations in BRCA1/2 carriers. Investigations are needed to test this hypothesis and elaborate on the underlying mechanisms in these women.

BRCA Mutation Patients: Are There Other Predisposing Factors for Ovarian Cancer Occurrence? A Multicenter Retrospective Study

Objectives: The objective of this multicenter retrospective study aimed to evaluate the association of clinical variables and the incidence of ovarian cancer in patients with BRCA 1–2 mutation carriers who underwent risk-reducing salpingo-oophorectomy (RRSO). Design: Patients with a pathogenic mutation of BRCA 1–2 genes and with no evidence of disease are considered eligible. The exclusion criterion was the refusal to undergo the surgery. The retrospective study included all RRSO performed from May 2015 to April 2022 in the three gynecological Institutions of Southern Italy for were included in this retrospective study. Participants/Materials, Setting, Methods: Age, menarche age, BMI, menopause at time of RRSO, breast cancer first- and second-degree relatives, ovarian cancer first- and second-degree relatives, estroprogestin use, pregnancy normal full-term delivery, history of endometriosis, previous breast cancer and histologic type, previous abdominal/pelvic surgery, BRCA 1 or BRCA 2 status, preoperative serum CA-125 levels (IU/mL), age at time of RRSO and histological analysis were collected. Results: 184 were recruited. One was excluded. To assess cancer risk, the outcome variable was classified into three classes: no event, cancer, and other conditions excluding cancer. 14 women presented ovarian cancer and tubal intraepithelial carcinoma (STIC) on histopathologic final report. Ovarian cancer was found in 8 patients, whereas the presence of STIC was found in 6 of them. Limitations: The low incidence of patients diagnosed with ovarian cancer or STIC compared with the total number of patients undergoing RRSO is a potential bias. Conclusions: Our study did not demonstrate a correlation between clinical features and the occurrence of precancerous or cancerous lesions in BRCA mutation carrier patients.

Quality of life after risk-reducing salpingo-oophorectomy in women with a pathogenic BRCA variant.

Risk-reducing salpingo-oophorectomy (RRSO) is recommended to women with a pathogenic BRCA variant, but as a main side effect, RRSO could lead to an early onset of menopause. To evaluate the impact of RRSO and preoperative menopausal status on menopausal symptoms, sexual functioning, and quality of life (QOL). The study was conducted between November 2019 and April 2020. Women were included who tested positive for a pathogenic BRCA1/2 variant between 2015 and 2018. Depression levels, QOL, and global health status were measured and compared with those of women who opted against RRSO. Furthermore, women who underwent RRSO treatment were asked to report menopausal complaints that they experienced at 1 month postsurgery and any current complaints. RRSO had no significant impact on QOL, but women who were premenopausal at the time of surgery reported more sexual complaints than postmenopausal women. In total, 134 carriers of a BRCA mutation were included: 90 (67%) underwent RRSO and 44 (33%) did not. At the time of the survey, neither the control nor experimental group experienced significant changes in QOL (b = -0.18, P = .59). Women who underwent RRSO reported a significantly lower global health status (b = -0.66, P = .05). Women who were premenopausal at the time of surgery were bothered more by sexual symptoms (b = 0.91, P = .19) but experienced fewer vasomotor complaints (b = -1.09, P = .13) than women who were postmenopausal at the time of RRSO. The decrease of sexual functioning after RRSO should be an integral part of preoperative counseling because it is important for BRCA carriers, especially for premenopausal women. Some strengths of the present study were the long follow-up, a high response rate, and the existence of a control group, whereas defining menopausal status by last menstrual bleeding and self-report of data (eg, breast cancer history) increased the risk of errors. Our study indicated that women who underwent RRSO experienced no difference in QOL when compared with women without RRSO and that patients with premenopausal status seemed to be at higher risk to experience sexual complaints after surgery.

Endometrial Cancer and BRCA Mutations: A Systematic Review.

This systematic review identifies, evaluates, and summarises the findings of all relevant individual studies on the prevalence of BRCA mutation (BRCAm) in endometrial cancer patients and the incidence of endometrial cancer in BRCAm women patients. Consequently, the benefits and limits of a prophylactic hysterectomy at the time of the risk-reducing salpingo-oophorectomy are analysed and discussed. A systematic literature search was performed in the databases of PubMed, Cochrane, and Web of Science until May 2022; 13 studies met the eligibility criteria. Overall, 1613 endometrial cancer patients from 11 cohorts were tested for BRCA1/2 mutation. BRCA1/2m were identified in 4.3% of women with endometrial cancer (70/1613). BRCA1m was the most represented (71.4%) pathogenic variant. Alongside, a total of 209 BRCAm carriers from 14 studies were diagnosed with endometrial cancer. Only 5 out of 14 studies found a correlation between BRCAm and an increased risk of endometrial cancer. Nevertheless, two studies found a statistical difference only for BRCA1m women. The present systematic review does not provide strong evidence in favour of performing routine hysterectomy at the time of risk-reducing salpingo-oophorectomy; however, it provides epidemiological data that can be useful for counselling patients in order to offer a tailored approach.

Presentation of ovarian cancer in women with BRCA mutations

<h3>Objectives:</h3> Investigate the clinical presentation and diagnosis of ovarian cancer in women with <i>BRCA</i> mutations. <h3>Methods:</h3> Retrospective cohort study of all women in an integrated healthcare system with pathogenic mutations identified between 1/1/2003-12/31/2018 who were diagnosed with ovarian cancer (OC). Primary outcome was stage of OC; secondary outcomes included method of diagnosis in women with genetic testing before OC diagnosis, interval to diagnosis, and age at genetic testing and ovarian cancer diagnosis. <h3>Results:</h3> Of the 299 women with OC and a <i>BRCA</i> mutation, 41 women were diagnosed with OC after <i>BRCA</i> testing, with 26 (63%) diagnosed on risk-reducing salpingo-oophorectomy (RRSO), 4 (10%) diagnosed by abnormal surveillance testing, and 11 (27%) diagnosed with symptoms. Median age at OC diagnosis was 55, 54, and 58 years for the RRSO, surveillance and symptom groups respectively. Women with a known <i>BRCA</i> mutation status at the time of their OC diagnosis were more likely to have earlier stage OC compared to those who underwent genetic testing after their OC diagnosis (54% vs 15%, <i>p</i><0.001). <h3>Conclusions:</h3> In women with a known <i>BRCA</i> mutation, most OC is diagnosed in older women and at the time of RRSO. Women with a known <i>BRCA</i> mutation at the time of their OC diagnosis were more likely to have earlier stage disease compared to those who underwent genetic testing after their OC diagnosis. The late age at genetic testing of these patients, as well as the earlier stage disease seen in those with a known <i>BRCA</i> mutation, highlights the need for earlier genetic testing and RRSO. Cancers diagnosed on RRSO are more likely to be early stage. Few cancers are detected by surveillance.

Uptake and timing of risk-reducing salpingo-oophorectomy among patients with BRCA1 and BRCA2 mutations

In women with BRCA mutations, risk-reducing bilateral salpingo-oophorectomy has been shown to decrease gynecologic cancer-specific and overall mortality. The National Comprehensive Cancer Network recommends that patients with BRCA mutations undergo risk-reducing bilateral salpingo-oophorectomy between the ages of 35 and 40 years for BRCA1 mutation carriers and between the ages of 40 and 45 years for BRCA2 mutation carriers or after childbearing is complete. Currently, uptake and timing of risk-reducing bilateral salpingo-oophorectomy and reasons for delays in risk-reducing bilateral salpingo-oophorectomy are not well understood. We sought to evaluate uptake and timing of risk-reducing bilateral salpingo-oophorectomy among women with BRCA1 and BRCA2 mutations concerning the National Comprehensive Cancer Network guidelines and reasons for delays in risk-reducing bilateral salpingo-oophorectomy. In this retrospective chart review, we identified women with BRCA1 and BRCA2 mutations who discussed risk-reducing bilateral salpingo-oophorectomy with a provider between 2012 and 2021. Uptake of risk-reducing bilateral salpingo-oophorectomy was documented, and patients were classified as having timely or delay in risk-reducing bilateral salpingo-oophorectomy based on the National Comprehensive Cancer Network guidelines. For those with delay in risk-reducing bilateral salpingo-oophorectomy, reasons cited for delay were collected. Comparative statistical analyses were performed to evaluate characteristics of those with timely vs delayed risk-reducing bilateral salpingo-oophorectomy. A multivariable logistic regression model was used to evaluate the associations among factors related to timing of risk-reducing bilateral salpingo-oophorectomy. We identified 638 BRCA1 and BRCA2 mutation carriers seen between 2012 and 2021. Of these patients, 306 (48.0%) had undergone risk-reducing bilateral salpingo-oophorectomy and 332 (52.0%) had not. When evaluating the timing of risk-reducing bilateral salpingo-oophorectomy, 136 (21.3%) underwent timely risk-reducing bilateral salpingo-oophorectomy, 239 (37.5%) had delays in risk-reducing bilateral salpingo-oophorectomy, and 263 (41.2%) had not undergone risk-reducing bilateral salpingo-oophorectomy but were younger than the National Comprehensive Cancer Network age guidelines; therefore, they were neither timely nor delayed. Patients with delay in risk-reducing bilateral salpingo-oophorectomy were significantly older at the time of genetic testing than those with timely risk-reducing bilateral salpingo-oophorectomy (mean, 49.8 vs 36.3 years; P<.001). Of the 306 patients who underwent risk-reducing bilateral salpingo-oophorectomy, those with delayed risk-reducing bilateral salpingo-oophorectomy had a significantly shorter interval between BRCA identification and risk-reducing bilateral salpingo-oophorectomy than those with timely risk-reducing bilateral salpingo-oophorectomy (median, 8.7 vs 17.6 months; P<.001). Patients with delay in risk-reducing bilateral salpingo-oophorectomy were more likely to have a personal history of cancer than those with timely risk-reducing bilateral salpingo-oophorectomy (49.8% vs 37.5%; P=.028). Of the 239 women with delay in risk-reducing bilateral salpingo-oophorectomy, 188 (78.7%) had delayed BRCA mutation identification, 29 (12.1%) had menopausal concerns, 17 (7.1%) had ongoing cancer treatment, 12 (5.0%) had coordination with breast surgery, 20 (8.4%) had miscellaneous reasons, and 19 (7.9%) had no reason documented. In the multivariate model, older age at BRCA diagnosis (odds ratio, 0.73; 95% confidence interval, 0.68-0.78; P<.001) was significantly associated with delayed risk-reducing bilateral salpingo-oophorectomy timing; those with BRCA2 mutation type were 7.54 times as likely to have timely risk-reducing bilateral salpingo-oophorectomy than BRCA1 mutation carriers (odds ratio, 7.54; 95% confidence, 3.70-16.42; P<.001). Nearly 38% of BRCA1 and BRCA2 mutation carriers undergo or have yet to undergo risk-reducing bilateral salpingo-oophorectomy over the recommended National Comprehensive Cancer Network age. The most common reason for the delay in risk-reducing bilateral salpingo-oophorectomy was delayed identification of BRCA mutation, noted in 79% of patients with delayed risk-reducing bilateral salpingo-oophorectomy. Timely genetic testing for eligible patients can increase appropriately timed risk-reducing bilateral salpingo-oophorectomy for the prevention of ovarian cancer and reduction of mortality in BRCA mutation carriers.

Outcomes of incidentally detected ovarian cancers diagnosed at time of risk-reducing salpingo-oophorectomy in BRCA mutation carriers

ObjectivePrior data suggested that women with incidentally detected occult invasive ovarian cancer (OIOC) at the time of risk-reducing salpingo-oophorectomy (RRSO) for BRCA mutation may have poorer prognoses than would be expected based on disease stage. We sought to evaluate prevalence and outcomes of patients with OIOC in a tertiary referral center. MethodsPatients with BRCA mutation undergoing RRSO from 01/2005 to 05/2017 were identified, and their records reviewed. Women with incidentally detected OIOC were included; those with clinical features raising preoperative suspicion for malignancy were excluded. Results548 patients with BRCA mutation who underwent RRSO were identified. 26 (4.7%) had an OIOC (median age 55 years; range 42–75); 15(58%) patients, BRCA1; 9(34%), BRCA2; 2(8%) had a mutation in both genes. All OIOCs were high-grade serous: 10 (38%) Stage I; 8 (31%) Stage II; 8(31%) Stage III. 24(92%) patients received adjuvant platinum/taxane therapy. Of Stage III patients, 4 (50%) were identified intraoperatively; the remaining 4 (50%) had microscopic nodal disease on final pathology only. At median follow-up of 67.3 months (28–166) no Stage I patients have recurred; 2 Stage II and 6 Stage III patients recurred. 5-year progression-free survival (PFS) was 72% (95%CI, 50.2–85.7%); median PFS for the cohort was 129 months (95%CI, 75.3-not estimable). 5-year disease-specific survival (DSS) was 96% (95%CI, 76–99%); median DSS not reached. ConclusionConsistent with prior reports, almost 5% of patients had an OIOC at RRSO. The majority with early-stage disease had excellent PFS and DSS outcomes, as would be expected based on disease stage.

Commentary on Provider Adherence to Surgical Guidelines for Risk Reducing Salpingo-Oophorectomy

BRCA mutation carriers have a significantly increased lifetime risk of ovarian cancer compared to the general population. Risk-Reducing Salpingo-Oophorectomy (RRSO) is the primary evidence-based treatment to decrease that risk. The National Comprehensive Care Network (NCCN) and American College of Obstetricians and Gynecologists (ACOG) endorse a set of surgical guidelines to be completed at the time of RRSO. In the study “Provider Adherence to Surgical Guidelines for Risk Reducing Salpingo-oophorectomy”, we found that only two-thirds of all surgical providers were fully adherent to these guidelines. Gynecologic oncologists were more likely to follow surgical guidelines compared to general Obstetrician Gynecologists, and more likely to diagnose occult neoplasia despite similar patient populations. Here we discuss the reason for the surgical protocol, the clinical implications of noncompliance, and practical ways that providers can ensure full adherence to the protocol.

Precision prophylaxis: Identifying the optimal timing for risk-reducing salpingo-oophorectomy based on type of BRCA1 and BRCA2 cluster region mutations

ObjectivesCurrent risk-reducing salpingo-oophorectomy (RRSO) guidelines for individuals with BRCA1/2 mutations do not account for risk variability due to BRCA1/2 cluster region mutations that are associated with varying risks for the development of breast and ovarian cancer. We assessed whether current recommendations are appropriate for individual patients considering mutation-specific risks. MethodsUsing a hypothetical cohort of patients with BRCA1/2 mutations, we constructed Markov models allowing for the estimation of mean life expectancy based upon BRCA1/2 mutation, the presence of a cluster region mutation (Ovarian Cancer Cluster Region (OCCR), Breast Cancer Cluster Region (BCCR), or non-BCCR/OCCR), age at time of BRCA1/2 diagnosis (20–65), and age at time of RRSO (21–80). ResultsFor all BRCA1/2 mutation types, the optimal strategy was to undergo RRSO as early as possible. For BRCA1/2 carriers who delayed RRSO or who were identified with a mutation later in life, the OCCR mutation tended to be associated with lower life expectancy estimates than the BCCR and non-BCCR/OCCR mutations. Minimal delays in RRSO (i.e., neighboring 5-year intervals) were associated with minor losses in life expectancy. Variables associated with greatest impact on life expectancy included ovarian cancer risk after RRSO, breast cancer mortality rate, non-cancer mortality associated with RRSO, and breast cancer stage distribution. ConclusionsBRCA1/2 cluster regions may provide more precise estimates of life expectancy in counselling and shared decision-making. The most appropriate timing for RRSO is a complex decision and must be individualized for each patient.

Health Care Provider Adherence to Surgical Guidelines for Risk-Reducing Salpingo-Oophorectomy.

To evaluate health care provider adherence to the surgical protocol endorsed by the National Comprehensive Cancer Network and the American College of Obstetricians and Gynecologists at the time of risk-reducing salpingo-oophorectomy and compare adherence between gynecologic oncologists and obstetrician-gynecologists (ob-gyns). In this multicenter retrospective cohort study, women were included if they had a pathogenic BRCA mutation and underwent risk-reducing salpingo-oophorectomy between 2011 and 2017. Adherence was defined as completing all of the following: collection of washings, complete resection of the fallopian tube, and performing the Sectioning and Extensively Examining the Fimbriated End (SEE-FIM) pathologic protocol. Of 290 patients who met inclusion criteria, 160 patients were treated by 18 gynecologic oncologists and 130 patients by 75 ob-gyns. Surgery was performed at 10 different hospitals throughout a single metropolitan area. Demographic and clinical characteristics were similar between groups. Overall, 199 cases (69%) were adherent to the surgical protocol. Gynecologic oncologists were more than twice as likely to fully adhere to the full surgical protocol as ob-gyns (91% vs 41%, P<.01). Specifically, gynecologic oncologists were more likely to resect the entire tube (99% vs 95%, P=.03), to have followed the SEE-FIM protocol (98% vs 82%, P<.01), and collect washings (94% vs 49%, P<.01). Complication rates did not differ between groups. Occult neoplasia was diagnosed in 11 patients (3.8%). The incidence of occult neoplasia was 6.3% in gynecologic oncology patients and 0.8% in obstetrics and gynecology patients (P=.03). Despite clear surgical guidelines, only two thirds of all health care providers were fully adherent to guidelines. Gynecologic oncologists were more likely to follow surgical guidelines compared with general ob-gyns and more likely to diagnose occult neoplasia despite similar patient populations. Rates of risk-reducing surgery will likely continue to increase as genetic testing becomes more widespread, highlighting the importance of health care provider education for this procedure. Centralized care or referral to subspecialists for risk-reducing salpingo-oophorectomy may be warranted.

Development of Peritoneal Carcinoma in women diagnosed with Serous Tubal Intraepithelial Carcinoma (STIC) following Risk-Reducing Salpingo-Oophorectomy (RRSO)

IntroductionThe management of Serous Tubal Intraepithelial Carcinoma (STIC) found at the time of Risk-Reducing Salpingo-Oophorectomy (RRSO) remains unclear. We set out to analyse the incidence of peritoneal carcinomas developed after prophylactic surgery and to formulate further guidance for these patients.MethodsThis is a retrospective study of 300 consecutive RRSO performed at the Royal Marsden Hospital between January 2008 and January 2017.ResultsThe median age at RRSO was 47.8 years (range 34 to 60 years) and median BMI was 26.2 kg/m2 (range 16 to 51 kg/m2). A total of 273 patients (91%) were tested for BRCA mutations. Of these, 124 (45.4%) had a BRCA 1 mutation, 118 (43.2%) had a BRCA 2 mutation, 2 (0.7%) had both a BRCA 1 and a BRCA 2 mutation and 29 (10.6%) had no BRCA mutation detected. Isolated STIC lesions were identified in 7 cases (2.3%) and p53 signatures in 75 cases (25%). There were five (1.6%) incidental tubal carcinomas and one (0.3%) ovarian carcinoma at the time of surgery. Two (28.6%) of the 7 patients with STIC identified following RRSO had high grade serous peritoneal carcinoma diagnosed at 53 and 75 months. One (0.3%) patient from the other 287 patients from our series with no STIC diagnosis or incidental carcinomas at RRSO developed high grade serous carcinoma of peritoneal origin after 92 months.ConclusionThis study demonstrates that when a STIC lesion is identified following RRSO there is a significantly higher risk of a subsequent peritoneal cancer. Although there is no published consensus in literature, we recommend that consideration should be given for long term follow-up if a STIC lesion is identified at RRSO.

Hysterectomy at the time of risk-reducing surgery in BRCA carriers

In this study, women at risk for BRCA were surveyed to understand their choice of prophylactic surgery and associated risk of uterine cancers. The study was conducted as an anonymous online web-based survey that assessed personal and family histories and choice of prophylactic surgery. Respondents were targeted through social media groups that bring awareness to hereditary breast and ovarian cancer.The study cohort included an international group of 601 respondents. The majority were female (99.3%), in their 40s (34.2%), and had completed college or graduate school (68.8%). 87% of respondents carry BRCA gene mutation. Of 339 respondents who underwent risk-reducing salpingo-oophorectomy (RRSO), 55.8% had a hysterectomy at time of RRSO. Most common reasons for hysterectomy at time of RRSO included: 39% provider recommendation, 27.6% personal desire, 9.7% benign indications, 1.6% cancer in uterus, 1.1% precancerous uterine lesion, and 21.1% other (N = 185). In this cohort, nine were diagnosed with uterine cancer. Three were diagnosed after risk-reducing surgery. Both patients with uterine serous carcinoma were BRCA1 carriers.Two thirds of BRCA carriers surveyed had undergone RRSO. Of these, more than half had hysterectomy at time of RRSO. One third chose to have hysterectomy based on surgeon recommendation. <1% (2 out of 258) of BRCA1 gene mutation carriers reported being diagnosed with uterine serous carcinomas. While this incidence is low, it may be an underestimate based on the limitations of this study. Additional studies are needed to select which patients will benefit from concurrent hysterectomy and RRSO.

Uterine Cancer After Risk-Reducing Salpingo-oophorectomy Without Hysterectomy in Women With BRCA Mutations

The link between BRCA mutations and uterine cancer is unclear. Therefore, although risk-reducing salpingo-oophorectomy (RRSO) is standard treatment among women with BRCA mutations (BRCA+ women), the role of concomitant hysterectomy is controversial. To determine the risk for uterine cancer and distribution of specific histologic subtypes in BRCA+ women after RRSO without hysterectomy. This multicenter prospective cohort study included 1083 women with a deleterious BRCA1 or BRCA2 mutation identified from January 1, 1995, to December 31, 2011, at 9 academic medical centers in the United States and the United Kingdom who underwent RRSO without a prior or concomitant hysterectomy. Of these, 627 participants were BRCA1+; 453, BRCA2+; and 3, both. Participants were prospectively followed up for a median 5.1 (interquartile range [IQR], 3.0-8.4) years after ascertainment, BRCA testing, or RRSO (whichever occurred last). Follow up data available through October 14, 2014, were included in the analyses. Censoring occurred at uterine cancer diagnosis, hysterectomy, last follow-up, or death. New cancers were categorized by histologic subtype, and available tumors were analyzed for loss of the wild-type BRCA gene and/or protein expression. Incidence of uterine corpus cancer in BRCA+ women who underwent RRSO without hysterectomy compared with rates expected from the Surveillance, Epidemiology, and End Results database. Among the 1083 women women who underwent RRSO without hysterectomy at a median age 45.6 (IQR: 40.9 - 52.5), 8 incident uterine cancers were observed (4.3 expected; observed to expected [O:E] ratio, 1.9; 95% CI, 0.8-3.7; P = .09). No increased risk for endometrioid endometrial carcinoma or sarcoma was found after stratifying by subtype. Five serous and/or serous-like (serous/serous-like) endometrial carcinomas were observed (4 BRCA1+ and 1 BRCA2+) 7.2 to 12.9 years after RRSO (BRCA1: 0.18 expected [O:E ratio, 22.2; 95% CI, 6.1-56.9; P < .001]; BRCA2: 0.16 expected [O:E ratio, 6.4; 95% CI, 0.2-35.5; P = .15]). Tumor analyses confirmed loss of the wild-type BRCA1 gene and/or protein expression in all 3 available serous/serous-like BRCA1+ tumors. Although the overall risk for uterine cancer after RRSO was not increased, the risk for serous/serous-like endometrial carcinoma was increased in BRCA1+ women. This risk should be considered when discussing the advantages and risks of hysterectomy at the time of RRSO in BRCA1+ women.

The effect of personal medical history and family history of cancer on the uptake of risk-reducing salpingo-oophorectomy.

Women with an increased lifetime risk of ovarian cancer are advised to undergo risk-reducing salpingo-oophorectomy (RRSO) to reduce risk of adnexal cancer. We investigated the uptake of RRSO and evaluated the influence of personal medical history of (breast) cancer, risk-reducing mastectomy (RRM) and family history of ovarian and/or breast cancer on the RRSO decision. This single center retrospective observational cohort study was performed in a tertiary multidisciplinary clinic for hereditary cancer of the University Medical Centre Utrecht, the Netherlands. Women ≥35 years old with an estimated lifetime risk of ovarian cancer ≥10 %, who had completed childbearing, were eligible for RRSO. Uptake and timing of RRSO were analyzed. Influence of personal medical history and family history on RRSO decision making, were evaluated with logistic regression. The study population consisted of 218 women (45.0 % BRCA1 mutation carrier, 28.0 % BRCA2 mutation carrier, 27.0 % with familial susceptibility) with 87.2 % RRSO uptake. The median age at RRSO was 44.5 (range 28–73) years. Of the women undergoing RRSO, 78.3 % needed ≤3 consultations to reach this decision. Multivariable analysis showed a significant difference in RRSO uptake for women with a history of RRM [OR 3.66 95 % CI (1.12–11.98)], but no significant difference in women with a history of breast cancer [OR 1.38 95 % CI (0.50–3.79)], nor with a family history of ovarian and/or breast cancer [OR 1.10 95 % CI (0.44–2.76)]. We conclude that RRSO counseling, without the alternative of screening, is effective. The uptake is increased in women with a history of RRM.

Quality of life in BRCA1 and BRCA2 mutation carriers (B1/2) following risk-reducing salpingo-oophorectomy (RRSO).

1508 Background: RRSO is associated with a decreased risk of breast cancer, ovarian cancer and improved survival in B1/2. Timing of RRSO must balance the known benefits against the impact of early ...

A Major Step Forward for BRCA1/2-Related Cancer Risk Management

A Major Step Forward for <i>BRCA1/2</i>-Related Cancer Risk Management

Long term follow up of BRCA1 and BRCA2 mutation carriers with unsuspected neoplasia identified at risk reducing salpingo-oophorectomy

ObjectivesThe reported incidence of neoplasia identified at the time of risk-reducing salpingo-oophorectomy (RRSO) in germline BRCA1/2 mutation carriers ranges from 4 to 12% but long-term outcomes have not been described. We evaluated recurrence and survival outcomes of mutation carriers with neoplastic lesions identified at RRSO. MethodsWe identified BRCA1/2 mutation carriers with neoplasia at RRSO at three institutions. Data was collected on clinical variables, adjuvant treatment and follow-up. ResultsWe identified 32 mutation carriers with invasive carcinomas (n=15) or high-grade intraepithelial neoplasia (n=17) that were not suspected prior to surgery. 26 occurred in BRCA1 and 6 in BRCA2 mutation carriers. Median and mean age for carcinomas were 50years and 49.3 respectively, significantly younger than for intraepithelial neoplasm, median 53years, and mean 55years (p=0.04). For the 15 invasive carcinomas, median follow up was 88months (range 45–172months), 7 recurred (47%), median time to recurrence was 32.5months and 3 have died of disease; 1 additional patient died of breast cancer. Overall survival was 73%, disease specific overall survival was 80% and disease free survival was 66%. For the 17 high-grade intraepithelial neoplasms, median follow up was 80months (range 40–150), 4 were treated with chemotherapy. One recurred at 43months and is currently not on therapy with a normal CA125, 16months later. All patients with noninvasive neoplasia are alive. ConclusionsBRCA1 and BRCA2 mutation carriers with unsuspected invasive carcinoma at RRSO have a relatively high rate of recurrence despite predominantly early stage, small volume disease. High-grade intraepithelial neoplasms rarely recur as carcinoma and may not require adjuvant chemotherapy.

Management and clinical outcomes of women with BRCA1/2 mutations found to have occult cancers at the time of risk-reducing salpingo-oophorectomy

Objective: Risk-reducing salpingo-oophorectomy (RRSO) is of proven benefit in reducing the risk of ovarian cancer in women carrying BRCA1/2 mutations. However, occult cancers are diagnosed in up to 12% of women undergoing RRSO. It is unclear whether additional staging or adjuvant chemotherapy is necessary in patients with occult cancers. The objective of this study was to report postoperative treatment, clinical outcomes and survival in women diagnosed with an occult cancer during RRSO.

Identification of a Preneoplastic Gene Expression Profile in Tubal Epithelium of BRCA1 Mutation Carriers

Microinvasive carcinomas and high-grade intraepithelial neoplasms are commonly discovered within the fallopian tube of BRCA1 mutation carriers at the time of risk-reducing salpingo-oophorectomy, suggesting that many BRCA1-mutated ovarian carcinomas originate in tubal epithelium. We hypothesized that changes in gene expression profiles within the histologically normal fallopian tube epithelium of BRCA1 mutation carriers would overlap with the expression profiles in BRCA1-mutated ovarian carcinomas and represent a BRCA1 preneoplastic signature. Laser capture microdissection of frozen sections was used to isolate neoplastic cells or histologically normal fallopian tube epithelium, and expression profiles were generated on Affymetrix U133 Plus 2.0 gene expression arrays. Normal-risk controls were 11 women wild type for BRCA1 and BRCA2 (WT-FT). WT-FT were compared with histologically normal fallopian tube epithelium from seven women with deleterious BRCA1 mutations who had foci of at least intraepithelial neoplasm within their fallopian tube (B1-FTocc). WT-FT samples were also compared with 12 BRCA1 ovarian carcinomas (B1-CA). The comparison of WT-FT versus B1-FTocc resulted in 152 differentially expressed probe sets, and the comparison of WT-FT versus B1-CA resulted in 4079 differentially expressed probe sets. The BRCA1 preneoplastic signature was composed of the overlap between these two lists, which included 41 concordant probe sets. Genes in the BRCA1 preneoplastic signature included several known tumor suppressor genes such as CDKN1C and EFEMP1 and several thought to be important in invasion and metastasis such as E2F3. The expression of a subset of genes was validated with quantitative reverse transcription-polymerase chain reaction and immunohistochemistry.

Occult ovarian cancers identified at risk-reducing salpingo-oophorectomy in a prospective cohort of BRCA1/2 mutation carriers

Risk-reducing salpingo-oophorectomy (RRSO) is widely used for cancer risk reduction in BRCA1 or BRCA2 (BRCA1/2) mutation carriers. Occult ovarian/fallopian tube cancers (OOC) detected at the time of RRSO have been reported in several studies with wide variability in reported prevalence. We estimated the prevalence of OOC in a prospective cohort of 647 BRCA1/2 mutation carriers from 18 centers (PROSE consortium) who underwent RRSO between 2001 and 2008. OOC was detected in 16 of 647 women (2.5%). The mean age at RRSO was 51.7 in those with OOC versus 46.6 in those without OOC (P = 0.017). Twelve of the 16 OOCs (75%) were diagnosed in women with BRCA1 mutations. Thirty-eight percent of women with OOC had stage 1 cancer versus none of the women in the PROSE database diagnosed with ovarian cancer outside of screening. Among 385 women (60%) in whom pathology reports were available for central review, 246 (64%) RRSOs were performed at participating PROSE centers while 139 (36%) were performed at local sites. Ovarian and fallopian tube tissues removed at major genetics referral centers were significantly more likely to have been examined in toto compared to specimens obtained at non-referral centers (75% vs. 30%, P < 0.001). Our results confirm that OOC may be found at the time of RRSO in BRCA1/2 mutation carriers and suggest that OOC are of a more favorable stage than cancers found outside RRSO. An unacceptably high proportion of pathologic examinations did not adequately examine ovaries and fallopian tubes obtained at RRSO.