Abstract 805: RECAP (REpair CAPacity) identifies a subset of breast cancers unable to form RAD51 foci which are undetected by DNA-based BRCAness tests

Abstract Background: Germline BRCA1/2 mutation status is currently used as predictive biomarker for response to Poly-(ADP-Ribose)-Polymerase (PARP) inhibitors in breast cancer (BC) patients. However, non-germline BRCA1/2 mutated tumors and homologous recombination repair deficient (HRD) tumors with unknown etiology are probably also PARP inhibitor-sensitive. Various HRD biomarkers have been proposed and their clinical validity and utility are under investigation. We recently described the functional REpair CAPacity (RECAP) test as a real-time method to select HRD tumors based on their inability to form RAD51 foci. Here, we investigated whether this functional test defines a similar group of HRD tumors as DNA-based tests for primary and metastatic BCs. Materials and Methods: A cohort (n=71; 52 primary and 19 metastatic BCs) enriched for HRD tumors was selected based on the RECAP test, consisting of 26 RECAP-HRD (37%), 9 RECAP-HR intermediate (HRi; 13%) and 36 RECAP-HR proficient (HRP; 51%) tumors. Whole genome sequencing (WGS) was carried out on matched germline and tumor DNA samples for 38 primary BCs and the 19 metastatic lesions, for which material was available. Three samples were excluded due to a low purity score (<0.2), thus WGS data was present for 54 tumors. The tumors were subjected to DNA-based HRD tests: CHORD and BRCA1/2-like classifier algorithms. Concordance between different HRD tests was reached when a tumor was classified as HRD/HRi or HRP by both tests. Results: The RECAP test identified all bi-allelic BRCA deficient samples (n=15) in this cohort as HRD/HRi. Within the remaining non-BRCA RECAP-HRD/HRi samples, there were no pathogenic mutations in other relevant genes that could explain the HRD status of these tumors. In the RECAP-HR proficient tumors no bi-allelic BRCA1/2 deficiencies were identified. The RECAP status partially correlated with the DNA-based HRD test outcomes using the HRDetect, CHORD and BRCA1/2-like classifier algorithms (70% concordance for RECAP-CHORD and RECAP-BRCA1/2-like classifier, and 66% for CHORD-BRCA1/2-like classifier). However, RECAP identified additional samples unable to form RAD51 foci. The discordance among the tests were evenly distributed among the primary and metastatic BCs. Conclusions: The difference between RECAP and other HRD tests in BC patients is relatively large (30-34% discordance), implying that RECAP may be identifying deficiencies in other components of DNA repair which could also result in PARP inhibitor sensitivity. Therefore, direct comparison of these HRD tests in clinical trials will be required to evaluate the optimal predictive test for clinical decision making. Citation Format: Titia G. Meijer, Luan Nguyen, Arne van Hoeck, Marjolijn M. Ladan, Nicole S. Verkaik, Kirsten Ruigrok-Ritstier, Carolien H. van Deurzen, Harmen J. van de Werken, Esther H. Lips, Sabine C. Linn, Yasin Memari, Helen Davies, Serena Nik-Zainal, Roland Kanaar, John W. Martens, Edwin Cuppen, Agnes Jager, Dik C. van Gent. RECAP (REpair CAPacity) identifies a subset of breast cancers unable to form RAD51 foci which are undetected by DNA-based BRCAness tests [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 805.