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.