Genomic and Epigenomic ctDNA Profiling in Liquid Biopsies from Heavily Pretreated 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; how-ever, to date, PARP inhibitors (PARPi) remain the only approved therapy in this space. Major challenges to DDR-targeted therapies in the post-PARPi therapy era are the context dependency of DDR alterations and the presence of preexisting resistance in this heavily pretreated population. Blood samples from patients with tumors harboring defects in DDR genes were used to evaluate the feasibility of a liquid biopsy platform to detect complex genomic events such as BRCA1/2 reversions, homologous recombination deficiency (HRD) signatures, pathogenic variant allele status, and differentially methylated regions for accurate quantitation of tumor fraction. Experimental Design: Pretreatment ctDNA samples from 173 patients enrolled in two phase 1/2 clinical trials (TRESR; NCT04497116 and ATTACC; NCT04972110) were selected for analysis. Results: In a phase I heavily pretreated patient population with DDR defects, complex genomic alterations (HRD, biallelic loss, and complex reversions) that historically require tumor tissue biopsies could be detected in ctDNA. Within the cohort of BRCA-associated tumor types previously treated with PARPi or platinum therapy, 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 because of technological limitations. Conclusions: This study showcases the genomic complexity of DDR-altered tumors as revealed through baseline ctDNA pro-filing, an understanding of which is crucial for the future clinical development of novel DDR-directed therapies and combinations.