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

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.

High incidence of gynecologic sarcomas in Israel-A comparison to European and American reports: Gynecologic Sarcoma in Israel.

OBJECTIVE: Gynecologic Sarcomas are rare, aggressive tumors. The aim of this study was to explore the incidence and outcomes of gynecologic sarcomas in a large national data registry and to compare them with reports from other countries. STUDY DESIGN: Records of gynecologic sarcomas diagnosed in Israel (1980-2014) were extracted from the National Cancer Registry and classified according to International Classification of Diseases for Oncology-3 and characterized according to anatomical site, morphology and demographics. Age-standardized incidence rates and 1, 3, 5 and 10-year relative survival rates were calculated for 3 time periods (1980-1994, 1995-2001 and 2005-2014) according to patient age, stage and years of diagnosis. RESULTS: During 1980-2014, 1271 new gynecologic sarcomas were diagnosed in Israel, with incidence slightly increasing in 1980-2004, to an age-standardized incidence rate of 13 per million women. The most common histologic diagnosis was leiomyosarcoma (48%) and the most common anatomical site was the uterus (89%). The age-standardized incidence rate for uterine sarcoma is higher in Israel (10.55 per million) than in England (7.4 per million) and Germany (5.8 per million) respectively. The 5-year overall survival was significantly poorer in patients >70-years, as compared to younger patients (p<0.001) and in those with leiomyosarcoma compared to endometrial stromal sarcoma (p<0.001). The survival rate of patients with leiomyosarcoma in Israel are comparable to survival rates reported by other studies, although substantially lower regarding endometrial stromal sarcoma. CONCLUSIONS: Uterine leiomyosarcoma was the most common gynecologic sarcoma found in the Israeli, European and American registries. Older patients and those with leiomyosarcoma have the worst prognoses. Histological and anatomical variations in Israel are comparable with global statistics, but the incidence in Israel seems higher than in Europe.

Microvesicle Proteomic Profiling of Uterine Liquid Biopsy for Ovarian Cancer Early Detection.

High-grade ovarian cancer (HGOC) is the leading cause of mortality from gynecological malignancies, because of diagnosis at a metastatic stage. Current screening options fail to improve mortality because of the absence of early-stage-specific biomarkers. We postulated that a liquid biopsy, such as utero-tubal lavage (UtL), may identify localized lesions better than systemic approaches of serum/plasma analysis. Further, while mutation-based assays are challenged by the rarity of tumor DNA within nonmutated DNA, analyzing the proteomic profile, is expected to enable earlier detection, as it reveals perturbations in both the tumor as well as in its microenvironment. To attain deep proteomic coverage and overcome the high dynamic range of this body fluid, we applied our method for microvesicle proteomics to the UtL samples. Liquid biopsies from HGOC patients (n = 49) and controls (n = 127) were divided into a discovery and validation sets. Data-dependent analysis of the samples on the Q-Exactive mass spectrometer provided depth of 8578 UtL proteins in total, and on average ∼3000 proteins per sample. We used support vector machine algorithms for sample classification, and crossed three feature-selection algorithms, to construct and validate a 9-protein classifier with 70% sensitivity and 76.2% specificity. The signature correctly identified all Stage I lesions. These results demonstrate the potential power of microvesicle-based proteomic biomarkers for early cancer diagnosis.