Abstract 525: Assessment of the RAD51 assay as homologous recombination deficiency surrogate in a large cohort of hormone-dependent cancer PDXs.

Abstract The assessment of homologous recombination deficiency (HRD) is increasingly recognized as a critical determinant of therapeutic sensitivity in solid tumors, particularly in the context of PARP inhibition. Among emerging functional biomarkers, the RAD51 foci formation assay has gained prominence as a direct and dynamic measure of homologous recombination (HR) competence in cancer cells. Unlike genomic scar-based tests, which capture historical HRD, the RAD51 assay reflects current DNA repair functionality and therefore may more accurately predict therapeutic vulnerabilities. In this study, the RAD51 assay was applied across a diverse panel of patient-derived xenografts (PDXs), including 21 breast, 6 ovarian, 2 endometrial, 1 fallopian tube, and 1 prostate cancer models. These PDXs encompass a spectrum of molecular backgrounds and treatment histories, enabling comprehensive evaluation of RAD51 foci as a functional biomarker. Quantitative variables derived from the assay—such as RAD51 foci counts and BRCA1 foci number—were systematically correlated with extensive molecular annotations, including whole-exome sequencing (WES)-based mutational profiles, RNA-sequencing-based transcriptional features, and curated patient treatment histories. This integrated approach provides insights into how genomic alterations affecting HR pathway components converge on functional RAD51 phenotypes. In addition, clinical data from originating patients and in vivo PDX treatment responses to PARP inhibitors enable examination of whether RAD51-defined HRD states correspond to observed therapeutic outcomes. Together, these results illustrate how functional HR proficiency measured through RAD51 foci formation aligns with genomic predictors of HRD, historical treatment exposures, and PARP inhibitor sensitivity in preclinical models. By linking RAD51 assay performance to multi-omic and pharmacologic data across multiple cancer types, this work underscores the value of the RAD51 assay as a robust surrogate for tumor homologous recombination status. Citation Format: Hsiu-Wen Tsai, Marianna Zipeto, Michael Ritchie, Sebastian Brabetz, Markus Hippich, Daniel Ciznadija, Stefano Cairo. Assessment of the RAD51 assay as homologous recombination deficiency surrogate in a large cohort of hormone-dependent cancer PDXs 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 525.