Proteomic signature for detection of high-grade ovarian cancer in germline BRCA mutation carriers

Keren Bahar-Shany, Georgina D. Barnabas, Lisa Deutsch, Netanel Deutsch, Efrat Glick-Saar, Dan Dominissini, Stav Sapoznik, Limor Helpman, Tamar Perri, Anna Blecher, Guy Katz, Itai Yagel, Orgad Rosenblatt, Daniel Shai, Benny Brandt, Raanan Meyer, Aya Mohr-Sasson, Alexander Volodarsky-Perel, Itamar Zilberman, Shunit ArmonAriella Jakobson-Setton, Ram Eitan, Yfat Kadan, Mario Beiner, Dana Josephy, Malka Brodsky, Eitan Friedman, Liat Anafi, Yossef Molchanov, Jacob Korach, Tamar Geiger, Keren Levanon*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

No current screening methods for high-grade ovarian cancer (HGOC) guarantee effective early detection for high-risk women such as germline BRCA mutation carriers. Therefore, the standard-of-care remains risk-reducing salpingo-oophorectomy (RRSO) around age 40. Proximal liquid biopsy is a promising source of biomarkers, but sensitivity has not yet qualified for clinical implementation. We aimed to develop a proteomic assay based on proximal liquid biopsy, as a decision support tool for monitoring high-risk population. Ninety Israeli BRCA1 or BRCA2 mutation carriers were included in the training set (17 HGOC patients and 73 asymptomatic women), (BEDOCA trial; ClinicalTrials.gov Identifier: NCT03150121). The proteome of the microvesicle fraction of the samples was profiled by mass spectrometry and a classifier was developed using logistic regression. An independent cohort of 98 BRCA mutation carriers was used for validation. Safety information was collected for all women who opted for uterine lavage in a clinic setting. We present a 7-protein diagnostic signature, with AUC >0.97 and a negative predictive value (NPV) of 100% for detecting HGOC. The AUC of the biomarker in the independent validation set was >0.94 and the NPV >99%. The sampling procedure was clinically acceptable, with favorable pain scores and safety. We conclude that the acquisition of Müllerian tract proximal liquid biopsies in women at high-risk for HGOC and the application of the BRCA-specific diagnostic assay demonstrates high sensitivity, specificity, technical feasibility and safety. Similar classifier for an average-risk population is warranted.

Original languageEnglish
Pages (from-to)781-793
Number of pages13
JournalInternational Journal of Cancer
Volume152
Issue number4
DOIs
StatePublished - 15 Feb 2023

Funding

FundersFunder number
Department of Obstetrics and Gynecology at Sheba Medical Center
Israel Innovation Authority of the Israeli Ministry of Finance
Israeli Ministry of Finance
SPARK-Tel Aviv team
Israel Cancer Research Fund
University of Washington
Israel Cancer Association
Israel Science Foundation1104/17
Medizinische Universität Wien

    Keywords

    • BRCA
    • early detection biomarker
    • ovarian cancer
    • utero-tubal lavage

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