Abstract 4716: Functional precision medicine: Uncovering high actionability in rare cancers beyond genomics

Background: Precision medicine relies on mutational profiling, but clinical actionability remains limited for many cancer patients. We evaluated the feasibility and actionability of ex-vivo drug sensitivity testing across solid tumors, focusing on rare cancers. This study uses the PARIS® CLIA-certified test, assessing patient-derived tumor cells (PDTCs) responses to a broad oncology drug panel. Methods: Tumor specimens (biopsies, fluids, or surgical samples) were shipped to our laboratory to arrive within 48h and cultured in either 3D or 2D with cancer type specific protocols to generate short term tumor cell cultures. PDTCs were tested with a panel of oncology drugs (up to 42 drugs /sample), customized for each patient based on cancer type, oncologist recommendations, and genomic features. Reports, ranking drug responses, were sent to oncologists within ∼3 weeks on average. Results: 86 patients with diagnosis of rare cancers (occurring in fewer than 15 out of 100,000 people each year) were consented to the SEngine IRB protocol and had a successful PARIS® test. The overall actionability was 85%, defined by one or more drugs exhibiting exceptional/good responses based on absolute and relative metrics of drug responses in our database. The cohort included biliary tract cancers (n=26), sarcomas (n=15), low grade serous ovarian cancers (n=15), cancer of unknown primary (n=4), appendiceal cancers (n=4), esophageal and gastric cancers (n=6), brain and nervous system cancers (n=2). Notably, targeted therapies showed the strongest drug sensitivities, often revealing actionable insights beyond genomic predictions. In the LGSOC cohort in the recurrent setting the results demonstrated that the PARIS® test recapitulates the clinical resistance of LGSOC to most chemotherapies but can identify multiple targeted treatments for nearly all patients. Importantly, few of these agents wouldn't have been chosen based on standard molecular testing, and multiple patients have demonstrated months to years of disease stabilization, biomarker remission and good quality of life with PARIS® -informed therapies (Gray et al., NPJ 2023, and unpublished data). As an example, one LGSOC case, which did not present any actionable biomarkers and had progressed after standard chemotherapy, achieved disease stabilization with 29 months duration, no hospitalizations, following a PARIS®-informed therapy with regimens including Lapatinib, Everolimus, Trametinib and Letrozole. Currently, the patient has biomarker remission demonstrated by ctDNA and CA-125. Cases from other cancer types will be presented. Conclusions: The PARIS® test offers an unbiased ex-vivo measurements of oncology-drug responses and can identify responders to targeted therapies also in cases lacking biomarker-drug matches, particularly in rare tumors with complex genomics or gene fusions without targeted drugs and limited on-label treatment options. Citation Format: Rachele Rosati, Payel Chatterjee, Alex C. Rajewski, Marwah Al-Aloosi, Lauren R. Appleyard, Vaishnavi Pallem, Shalini Pereira, Robert L. Diaz, Christopher J. Kemp, Ryan Jones, Brady Bernard, Pashtoon M. Kasi, Kiran Turaga, Michael Castro, Tara Seery, Arun Singh, Sameek Roychowdhury, Melind Javle, Jill Alldredge, Soledad Jorge, Kathryn Pennington, Barbara A. Goff, Heidi J. Gray, Elizabeth M. Swisher, Carla Grandori. Functional precision medicine: Uncovering high actionability in rare cancers beyond genomics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4716.