Genomic and epigenomic ctDNA profiling in liquid biopsies from heavily pre-treated patients with DNA damage response-deficient tumors

Abstract Purpose: The development of DNA damage response (DDR)-directed therapies is a major area of clinical investigation, yet to date Poly (ADP-ribose) polymerase inhibitors (PARPi) remain the only approved therapy in this space. Major challenges to DDR-targeted therapies in the post-PARPi era are the context dependency of DDR alterations and the presence of pre-existing resistance in this heavily pre-treated population. Blood samples from patients with tumors harboring defects in DDR genes were evaluated the feasibility of liquid biopsy platform for detecting complex genomic events such as BRCA1/2 reversions, HRD signatures, PV allele status, and differentially methylated regions for accurate quantitation of TF. Patients and Methods: Overall, 173 patients enrolled in two Phase 1/2 clinical trials (TRESR; NCT04497116, ATTACC; NCT04972110) were selected. The pre-treatment circulating tumor DNA (ctDNA) samples were analyzed from these patients, harboring pathogenic variants (PVs) in DDR genes. Results: In a phase I heavily pretreated patient population with DDR defects, ctDNA can detect complex genomic alterations (HRD, biallelic loss, complex reversions) that historically require tumor tissue biopsies. Within the cohort of BRCA-associated tumor types previously treated with PARPi or platinum, HRD reversions were detected in 44% of evaluable patients and included large genomic rearrangements leading to deletion of whole or partial exons which have been underrepresented in the literature due to technological limitations. Conclusions: This study showcases the genomic complexity of DDR-altered tumors as revealed through baseline ctDNA profiling, an understanding of which is crucial for the future clinical development of novel DDR-directed therapies and combinations.