Functional Drug Screening Of Organoids From Ovarian Cancer Patients Demonstrates Clinical And Genomic Concordance And Identifies Novel Therapeutic Vulnerabilities.

Abstract Background: Clinically approved targeted therapies for ovarian cancer patients are currently limited to PARP inhibitors and bevacizumab. To improve treatment outcomes, a precision medicine approach is crucial to match effective drugs to patient-specific genetic features and vulnerabilities. This study aimed to: (1) demonstrate the feasibility of performing high-throughput drug screens on fresh patient organoids using a CLIA-approved assay, (2) assess concordance of responses with genomic and clinical information, and (3) reveal novel biomarkers of response to approved/experimental drugs and insights into ovarian cancer biology. Methods: From 2015 to 2020, 76 ovarian tumor samples were collected from 60 patients. To date, 50 evaluable samples were successfully screened at SEngine Precision Medicine. Drugs tested include a range of chemotherapies and targeted therapies that are FDA-approved or in clinical development, with an average of 61 drugs screened per assay (range: 6-135). Somatic and/or germline DNA sequencing is currently available for 30 samples. Sample collection, screening, and sequencing is ongoing. Results: The cohort included ovarian cancer patients with high grade serous (65%), low grade serous (7%), unknown grade serous (7%), clear cell (7%), carcinosarcoma (5%), stromal (5%), endometrioid (2%) subtypes, and one of unknown pathology. Whole genome mutational analysis of 5 tumor-derived organoids and their original tumors demonstrated a high degree of similarity between the tumor-organoid pairs. We present prospective and retrospective evidence from at least 18 cases that organoid drug screening can accurately predict clinical response to chemotherapy and targeted therapies. We also report a patient with platinum resistant serous carcinoma who responded to ibrutinib treatment after screening identified the drug as having excellent response in this patient's organoids. Three months into treatment, the patient's CA125 level was reduced from 250 to 125U/ml. In samples with available genomic information, we demonstrate high concordance between drug sensitivity and known biomarkers, e.g. 83% of samples with known BRCA1/BRCA2 mutation or high HRDetect showed sensitivity to a PARP inhibitor. Further, organoid screening can identify unique targets for every patient beyond established genomic biomarkers. Subsets of patients responded exceptionally to BET (41%), HDAC (28%), WEE1 (24%), and BTK (11%) inhibitors, indicating potential for these targeted therapies in ovarian cancer. Conclusions: The genomic and histopathological heterogeneity of ovarian cancer points to a need to evolve and prioritize the personalization of treatment. Our data demonstrates the utility of organoid based drug screening to nominate therapeutic options for individual patients with or without known genomic biomarkers. Citation Format: Goldie Lui, Anne Richardson, Payel Chatterjee, Madison Pollastro, Mia Lints, Danielle Peretti, Rachele Rosati, Lauren Appleyard, Grace Durenberger, Robert Diaz, Kay Gurley, Isabella Stork, Adam Whitney, Katannya Kapeli, Hallie Swan, Yasin Memari, Helen Davies, Serena Nik-Zainal, Kalyan Banda, Heidi Gray, Barbara Goff, Elizabeth Swisher, Astrid Margossian, Christopher Kemp, Carla Grandori. Functional drug screening of organoids from ovarian cancer patients demonstrates clinical and genomic concordance and identifies novel therapeutic vulnerabilities [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 534.