Homologous Recombination deficiency classification and PARP inhibitor response of reference-free colorectal cancer samples

PARP inhibitors (PARPi) are recognized for their ability to induce synthetic lethality in tumors exhibiting homologous recombination deficiency (HRD), commonly referred to as "BRCAness”. While BRCAness is a well-established feature in breast, ovarian, prostate and pancreatic carcinomas, our recent findings indicate that up to 15% of colorectal cancers (CRC) also harbor defects in the HR pathway, presenting promising opportunities for innovative therapeutic strategies in CRC patients. We developed a new tool called HRDirect, which builds upon the HRDetect algorithm and is able to predict HRD from reference-free tumor samples. We initially validated HRDirect using matched breast and colorectal cancer patient samples. Subsequently, we assessed its efficacy in predicting response to the PARP inhibitor (PARPi) olaparib by comparing it with two other commercial assays: AmoyDx HRD by Amoy Diagnostics and the TruSight Oncology (TSO) 500 HRD panel by Illumina NGS technology. While all three approaches successfully identified the most PARPi-sensitive CRC models, HRDirect demonstrated superior precision in distinguishing resistant models compared to AmoyDX and TSO500-HRD, which exhibited overlapping scores between sensitive and resistant cells. Furthermore, we propose the integration of HRDirect scoring with ATM immunohistochemical analysis as part of our "composite biomarker approach" to enhance the identification of HRD tumors, with an immediate translational and clinical impact for CRC personalized treatment.