Abstract 2447: Epigenomic liquid biopsy-based biomarkers of platinum and PARP inhibitor response in patients with germ line BRCA-associated PDAC: A pilot study

Abstract Background: Despite favorable overall response, pancreatic ductal adenocarcinoma (PDAC) patients with germline BRCA mutations show varied response to platinum-based chemotherapy and PARP inhibitor treatment. While some patients demonstrate long term response, others develop acquired resistance after an initial durable response and a third group are refractory to first-line platinum-based therapy. 5-hydroxymethylation (5hmC) analysis of plasma-derived cell-free DNA (cfDNA) of PDAC patients present a non-invasive approach to investigate treatment response biomarkers. Here, we investigated 5hmC profiles of plasma-derived cfDNA obtained from PDAC patients prior to treatment and while on treatment. Additionally, samples were evaluated for response by CA19-9 measurements and the Avantect Pancreatic Cancer Test (Avantect, a non-invasive, blood-based assay designed to detect PDAC using epigenomics and genomics biomarkers. Methods: A total of 80 blood samples were collected in EDTA tubes from 32 PDAC patients pre-treatment or while on-treatment, with 2-5 timepoints for each patient. Blood samples were processed to obtain plasma. Cell-free DNA extracted from plasma were analyzed using Avantect. Germline BRCA1/2 mutations were confirmed for all study subjects. Results: Of the 32 patients included in the study, 6 were refractory, 14 developed acquired resistance and 12 were long term responders to platinum/PARP-inhibitor treatment. Differential 5hmC analysis at the earliest available timepoint for each patient revealed refractory patients to have distinct cfDNA profiles relative to both acquired resistance and long-term responders. Analysis with Avantect showed that the refractory group exhibited the highest cancer scores when compared to the acquired resistance and long-term responder groups (p value 0.001). Stratification of stage IV patients according to Avantect test results revealed that cancer signal-detected patients have poor overall survival relative to cancer signal not-detected patients (9.3 months vs 25.9 months, Hazard ratio 4.17, p = 0.017). Furthermore, evaluation of on-treatment timepoints demonstrated that Avantect detected disease progression in 78.6% (11/14) of PDAC patients who developed acquired resistance. Conclusions: cfDNA 5hmC analysis revealed clear differences between long-term responders and patients with resistance, highlighting potential blood-based biomarkers of treatment durability and mechanisms of resistance.​ Cancers with worse response to therapy were detected at a higher rate by the Avantect test. These findings suggest that larger studies using Avantect can be performed to identify patient subpopulations with limited treatment response and to monitor treatment response. Citation Format: Maria Raitses-Gurevich, Gulfem Guler, Yuhong Ning, Ceyda Coruh, Micah Collins, Shimul Chowdhury, Samuel Levy, Talia Golan. Epigenomic liquid biopsy-based biomarkers of platinum and PARP inhibitor response in patients with germ line BRCA-associated PDAC: A pilot study abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2447.