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BRCA1/2 Pathogenic Variant Carriers with Serous Tubal Intraepithelial Carcinoma at Risk-Reducing Salpingo-Oophorectomy are at Increased Risk of Peritoneal Carcinomatosis

The risk to develop peritoneal carcinomatosis increases over time
04 Apr 2022
Gynaecologic malignancies;  Personalised medicine

Systematic review and individual patient data meta-analysis showed an increased risk of peritoneal carcinomatosis in BRCA1/2 pathogenic variant carriers with a serous tubal intraepithelial carcinoma at risk-reducing salpingo-oophorectomy. The hazard ratio (HR) for developing peritoneal carcinomatosis in women with serous tubal intraepithelial carcinoma is 33.9 compared with women without. The 5- and 10-year risks to develop peritoneal carcinomatosis after risk-reducing salpingo-oophorectomy are 10.5% and 27.5% for women with serous tubal intraepithelial carcinoma compared with 0.3% and 0.9% for women without. It is important that women are informed about this increased risk according to Dr. Miranda P. Steenbeek of the Radboud University Medical Center, Radboud Institute for Health Sciences, Department of Obstetrics and Gynaecology in Nijmegen, the Netherlands and colleagues who published findings on 18 March 2022 in the Journal of Clinical Oncology.

Women in the general population have a lifetime risk of 1.3% to develop epithelial ovarian cancer, but this risk is, on average, 44% for women with a BRCA1 and 17% for women with a BRCA2 pathogenic variant up to age 80 years. Timely risk-reducing salpingo-oophorectomy is the most effective method of prevention, reducing epithelial ovarian cancer risk up to 96%. To optimise risk-reduction, BRCA1/2 pathogenic variant carriers are advised to undergo risk-reducing salpingo-oophorectomy at the age of 35-40 and 40-45 years. Despite the significant risk-reduction, a risk of developing peritoneal carcinomatosis persists. Currently, it is unclear which patients are most at risk to develop peritoneal carcinomatosis after risk-reducing salpingo-oophorectomy.

The authors wrote in the background that the aetiology of peritoneal carcinomatosis is not yet clarified. It was thought to derive from the pelvic peritoneum as secondary Müllerian system. However, signs for a Fallopian tube origin of peritoneal carcinomatosis accumulated as the focus on the Fallopian tube epithelium expanded after the suggestion of the non-invasive serous tubal intraepithelial carcinoma as precursor for high-grade serous carcinoma.

As serous tubal intraepithelial carcinoma lesions are rather rare, only small series describing the follow-up of BRCA pathogenic variant carriers with serous tubal intraepithelial carcinoma have been published. To elucidate the risk of peritoneal carcinomatosis for BRCA pathogenic variant carriers with a serous tubal intraepithelial carcinoma at risk-reducing salpingo-oophorectomy, the authors present a systematic review and individual patient data meta-analysis which is especially useful when analyzing time-to-event outcomes such as the risk of peritoneal carcinomatosis, as HRs and risk predictions can be calculated independent to study reporting. Furthermore, effect modifiers can be directly assessed. 

In the systematic review and individual patient data meta-analysis, the study team investigated the risk of peritoneal carcinomatosis in women with and without serous tubal intraepithelial carcinoma at risk-reducing salpingo-oophorectomy. Unpublished data from 3 centres were supplemented by studies identified in a systematic review of EMBASE, MEDLINE, and the Cochrane library until September 2020. Primary outcome was the HR for the risk of peritoneal carcinomatosis between BRCA pathogenic variant carriers with and without serous tubal intraepithelial carcinoma at risk-reducing salpingo-oophorectomy, 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.

From 17 studies, individual patient data were available for 3,121 women, of whom 115 had a serous tubal intraepithelial carcinoma at risk-reducing salpingo-oophorectomy. The estimated HR to develop peritoneal carcinomatosis during follow-up in women with serous tubal intraepithelial carcinoma was 33.9 (95% confidence interval [CI] 15.6 to 73.9, p < 0.001) compared with women without serous tubal intraepithelial carcinoma. For women with serous tubal intraepithelial carcinoma, the 5- and 10-year risks to develop peritoneal carcinomatosis were 10.5% (95% CI 6.2 to 17.2) and 27.5% (95% CI 15.6 to 43.9), 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 serous tubal intraepithelial carcinoma at risk-reducing salpingo-oophorectomy. 

None of the women with serous tubal intraepithelial carcinoma who underwent additional staging surgery or chemotherapy developed peritoneal carcinomatosis, but the data regarding additional treatment are insufficient for clinical recommendations.

The authors concluded that BRCA1/2 pathogenic variant carriers with serous tubal intraepithelial carcinoma at risk-reducing salpingo-oophorectomy are at increased risk of peritoneal carcinomatosis. This risk increases over time up to 27.5% after 10 years, whereas the corresponding risk is only 0.9% for women without serous tubal intraepithelial carcinoma at risk-reducing salpingo-oophorectomy. It is important that women are informed about this increased risk, and future research should focus on prospective data collection on serous tubal intraepithelial carcinomas, peritoneal carcinomatosis aetiology, and clinical management after serous tubal intraepithelial carcinoma diagnosis.

The study was presented previously in part at the European Society of Gynaecological Oncology congress in Prague, Czech Republic (30-31 October 2021) and at the BRCA symposium in Montreal, Canada (4-7 May 2021).

It was supported in part by the Research Council of Lithuania grant.

Reference

Steenbeek MP, van Bommel MHD, Bulten J, et al. Risk of Peritoneal Carcinomatosis After Risk-Reducing Salpingo-Oophorectomy: A Systematic Review and Individual Patient Data Meta-Analysis. Journal of Clinical Oncology; Published online 18 March 2022. DOI: 10.1200/JCO.21.02016

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