Miranda P Steenbeek

Pathogenesis of peritoneal high‐grade serous carcinoma after risk‐reducing surgery: a systematic review

AbstractGermline BRCA1/2 pathogenic variant carriers have an increased risk for high‐grade serous carcinoma (HGSC) and are therefore advised to have risk‐reducing salpingo‐oophorectomy around the age of 40. However, a risk of 0.9% to develop peritoneal HGSC remains in these women, which increases to 27.5% when serous tubal intraepithelial carcinoma (STIC) is detected. The pathophysiological mechanism that leads to the development of peritoneal HGSC after salpingectomy or salpingo‐oophorectomy is still largely unknown. In this systematic review, we aim to provide insights into the pathogenic pathways of peritoneal HGSC after salpingectomy or salpingo‐oophorectomy. Therefore, we performed a systematic search for studies investigating pathophysiological mechanisms related to peritoneal HGSC in PubMed and EMBASE. A total of 49 articles were included in this study. Most evidence was found on mechanisms following a tubal origin, such as clonality between STIC and peritoneal HGSC as well as molecular similarities between fallopian tube (FT) epithelium and peritoneal HGSC. Additionally, FT epithelium was shown to adhere to the ovary and could therefore stay present after isolated salpingectomy. There might be a role for the endometrium, as it was observed that serous endometrial intraepithelial carcinoma (SEIC) has a clonal relationship with extra‐uterine HGSC. The role of the ovary seems limited, although some mouse models show a role for follicular fluid in the dissemination of malignant cells on the peritoneum. In conclusion, different mechanisms might be responsible for peritoneal HGSC development after bilateral salpingectomy or salpingo‐oophorectomy. Most available evidence supports the dissemination of precursor cells originating in the FT. Also, a possible role for the endometrium was found. An ovarian origin seems less likely; however, execution of oophorectomy does not seem obsolete in clinical practice as follicular fluid might promote dissemination and residual tubal tissue can be present on the ovary after salpingectomy.

Risk of Peritoneal Carcinomatosis After Risk-Reducing Salpingo-Oophorectomy: A Systematic Review and Individual Patient Data Meta-Analysis

PURPOSE After risk-reducing salpingo-oophorectomy (RRSO), BRCA1/ 2 pathogenic variant (PV) carriers have a residual risk to develop peritoneal carcinomatosis (PC). The etiology of PC is not yet clarified, but may be related to serous tubal intraepithelial carcinoma (STIC), the postulated origin for high-grade serous cancer. In this systematic review and individual patient data meta-analysis, we investigate the risk of PC in women with and without STIC at RRSO. METHODS Unpublished data from three centers were supplemented by studies identified in a systematic review of EMBASE, MEDLINE, and the Cochrane library describing women with a BRCA-PV with and without STIC at RRSO until September 2020. Primary outcome was the hazard ratio for the risk of PC between BRCA-PV carriers with and without STIC at RRSO, and the corresponding 5- and 10-year risks. Primary analysis was based on a one-stage Cox proportional-hazards regression with a frailty term for study. RESULTS From 17 studies, individual patient data were available for 3,121 women, of whom 115 had a STIC at RRSO. The estimated hazard ratio to develop PC during follow-up in women with STIC was 33.9 (95% CI, 15.6 to 73.9), P < .001) compared with women without STIC. For women with STIC, the five- and ten-year risks to develop PC were 10.5% (95% CI, 6.2 to 17.2) and 27.5% (95% CI, 15.6 to 43.9), respectively, whereas the corresponding risks were 0.3% (95% CI, 0.2 to 0.6) and 0.9% (95% CI, 0.6 to 1.4) for women without STIC at RRSO. CONCLUSION BRCA-PV carriers with STIC at RRSO have a strongly increased risk to develop PC which increases over time, although current data are limited by small numbers of events.

TUBectomy with delayed oophorectomy as an alternative to risk-reducing salpingo-oophorectomy in high-risk women to assess the safety of prevention: the TUBA-WISP II study protocol

Risk-reducing salpingectomy with delayed oophorectomy has gained interest for individuals at high risk for tubo-ovarian cancer as there is compelling evidence that especially high-grade serous carcinoma originates in the fallopian tubes. Two studies have demonstrated a positive effect of salpingectomy on menopause-related quality of life and sexual health compared with standard risk-reducing salpingo-oophorectomy. To investigate whether salpingectomy with delayed oophorectomy is non-inferior to the current standard salpingo-oophorectomy for the prevention of tubo-ovarian cancer among individuals at high inherited risk. We hypothesize that postponement of oophorectomy after salpingectomy, to the age of 40-45 ( In this international prospective preference trial, participants will choose between the novel salpingectomy with delayed oophorectomy and the current standard salpingo-oophorectomy. Salpingectomy can be performed after the completion of childbearing and between the age of 25 and 40 ( Premenopausal individuals with a documented class IV or V germline pathogenic variant in the The primary outcome is the cumulative tubo-ovarian cancer incidence at the target age: 46 years for The sample size to ensure sufficient power to test non-inferiority of salpingectomy with delayed oophorectomy compared with salpingo-oophorectomy requires 1500 Participant recruitment is expected to be completed at the end of 2026 (total recruitment period of 5 years). The primary outcome is expected to be available in 2036 (minimal follow-up period of 10 years). NCT04294927.

Risk-reducing salpingectomy with delayed oophorectomy to prevent ovarian cancer in women with an increased inherited risk: insights into an alternative strategy

AbstractEpithelial ovarian cancer (EOC) is the most lethal type of gynaecological cancer, due to lack of effective screening possibilities and because the disease tends to metastasize before onset of symptoms. Women with an increased inherited risk for EOC are advised to undergo a risk-reducing salpingo-oophorectomy (RRSO), which decreases their EOC risk by 96% when performed within guideline ages. However, it also induces premature menopause, which has harmful consequences. There is compelling evidence that the majority of EOCs originate in the fallopian tube. Therefore, a risk-reducing salpingectomy with delayed oophorectomy (RRS with DO) has gained interest as an alternative strategy. Previous studies have shown that this alternative strategy has a positive effect on menopause-related quality of life and sexual health when compared to the standard RRSO. It is hypothesized that the alternative strategy is non-inferior to the standard RRSO with respect to oncological safety (EOC incidence). Three prospective studies are currently including patients to compare the safety and/or quality of life of the two distinct strategies. In this article we discuss the background, opportunities, and challenges of the current and alternative strategy.

TUBectomy With Delayed Oophorectomy in High Risk Women to Assess the Safety of Prevention

The aim of the project is to evaluate the risk-reducing salpingectomy with delayed oophorectomy as an alternative for risk-reducing salpingo-oophorectomy in high risk women with respect to ovarian cancer incidence.