Barbara Norquist

Adoption of Universal Testing in Endometrial Cancers for Microsatellite Instability Using Next-Generation Sequencing

Lynch syndrome screening by NGS in endometrial cancer allows concurrent molecular classification with one test.

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 METHODS Unpublished data from three centers were supplemented by studies identified in a systematic review of EMBASE, MEDLINE, and the Cochrane library describing women with a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.

Joint IARC/NCI International Cancer Seminar Series Report: expert consensus on future directions for ovarian carcinoma research

Abstract Recently, ovarian cancer research has evolved considerably because of the emerging recognition that rather than a single disease, ovarian carcinomas comprise several different histotypes that vary by etiologic origin, risk factors, molecular profiles, therapeutic approaches and clinical outcome. Despite significant progress in our understanding of the etiologic heterogeneity of ovarian cancer, as well as important clinical advances, it remains the eighth most frequently diagnosed cancer in women worldwide and the most fatal gynecologic cancer. The International Agency for Research on Cancer and the United States National Cancer Institute jointly convened an expert panel on ovarian carcinoma to develop consensus research priorities based on evolving scientific discoveries. Expertise ranged from etiology, prevention, early detection, pathology, model systems, molecular characterization and treatment/clinical management. This report summarizes the current state of knowledge and highlights expert consensus on future directions to continue advancing etiologic, epidemiologic and prognostic research on ovarian carcinoma.

Uterine Lavage Identifies Cancer Mutations and Increased TP53 Somatic Mutation Burden in Individuals with Ovarian Cancer

Current screening methods for ovarian cancer have failed to demonstrate a significant reduction in mortality. Uterine lavage combined with TP53 ultradeep sequencing for the detection of disseminated ovarian cancer cells has emerged as a promising tool, but this approach has not been tested for early-stage disease or non-serous histologies. In addition, lavages carry multiple background mutations, the significance of which is poorly understood. Uterine lavage was collected preoperatively in 34 patients undergoing surgery for suspected ovarian malignancy including 14 patients with benign disease and 20 patients with ovarian cancer [6 non-serous and 14 high-grade serous-like (serous)]. Ultradeep duplex sequencing (∼3,000×) with a panel of common ovarian cancer genes identified the tumor mutation in 33% of non-serous (all early stage) and 79% of serous cancers (including four early stage). In addition, all lavages carried multiple somatic mutations (average of 25 mutations per lavage), more than half of which corresponded to common cancer driver mutations. Driver mutations in KRAS, PIK3CA, PTEN, PPP2R1A, and ARID1A presented as larger clones than non-driver mutations and with similar frequency in lavages from patients with and without ovarian cancer, indicating prevalent somatic evolution in all patients. Driver TP53 mutations, however, presented as significantly larger clones and with higher frequency in lavages from individuals with ovarian cancer, suggesting that TP53-specific clonal expansions are linked to ovarian cancer development. Our results demonstrate that lavages capture cancer cells, even from early-stage cancers, as well as other clonal expansions and support further exploration of TP53 mutation burden as a potential ovarian cancer risk factor. Significance: Cancer driver mutations are found in uterine lavage DNA in all individuals, but driver TP53 mutations presented as significantly larger clones and with higher frequency in lavages from individuals with ovarian cancer. This suggests that TP53-specific clonal expansion plays a role in tumorigenesis and presents opportunities for early detection.