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Updated: Sep 14, 2025
Detection of Cell-Free DNA in Blood Plasma Samples of Cancer Patients
Published on: September 9, 2020
Genomic and Epigenomic ctDNA Profiling in Liquid Biopsies from Heavily Pretreated Patients with DNA Damage
Ian M Silverman1, Joseph D Schonoft1, Benjamin Herzberg2
1Repare Therapeutics, Cambridge, Massachusetts.
Purpose:
The development of DNA damage response (DDR)-directed therapies is a major area of clinical investigation; however, 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 profiling, an understanding of which is crucial for the future clinical development of novel DDR-directed therapies and combinations.
Insights
Liquid biopsy using circulating tumor DNA (ctDNA) effectively detects complex genomic alterations in DNA damage response (DDR) deficient tumors. This approach aids in understanding resistance mechanisms and developing new DDR-targeted therapies.
Area of Science:
- Oncology
- Genomics
- Molecular Biology
Background:
- DNA damage response (DDR) therapies are crucial in oncology, with Poly (ADP-ribose) polymerase inhibitors (PARPi) being the only approved class.
- Challenges in DDR-targeted therapy include context-dependent alterations and pre-existing resistance in heavily pre-treated patients.
Purpose of the Study:
- To evaluate the feasibility of a liquid biopsy platform for detecting complex genomic events in patients with DDR gene defects.
- To identify genomic alterations such as BRCA1/2 reversions, HRD signatures, and differentially methylated regions using circulating tumor DNA (ctDNA).
Main Methods:
- Analysis of pre-treatment ctDNA samples from 173 patients in Phase 1/2 clinical trials (TRESR, ATTACC).
- Patients selected had tumors with pathogenic variants (PVs) in DDR genes.
Main Results:
- ctDNA successfully detected complex genomic alterations (HRD, biallelic loss, complex reversions) in a heavily pre-treated DDR-deficient population.
- HRD reversions, including large genomic rearrangements, were found in 44% of evaluable BRCA-associated tumor patients previously treated with PARPi or platinum.
Conclusions:
- Baseline ctDNA profiling reveals the genomic complexity of DDR-altered tumors.
- Understanding this complexity is vital for the future development of novel DDR-directed therapies and treatment combinations.
