Whole-Genome Sequencing Algorithm Outperforms Standard Tests for Predicting PARP Inhibitor Response
核心洞察
A whole-genome sequencing-based classifier demonstrated superior performance compared to standard assays in predicting homologous recombination deficiency (搜索) across multiple cancer types.
The algorithm detected HRD in 21% of breast cancers, 20% of pancreaticobiliary cancers, and 17% of gynecologic cancers, with 24% of cases occurring in patients without BRCA1 (搜索)/2 mutations.
The study identified additional genomic mechanisms including biallelic mutations in FANCF (搜索), XRCC2 (搜索), and FANCC (搜索) that contribute to HRD phenotype.
A whole-genome sequencing-based classifier has demonstrated superior performance in predicting homologous recombination deficiency (搜索) (HRD) across cancer types compared to standard assays, potentially improving patient selection for PARP inhibitor therapy. The findings, published in Communications Medicine, represent a collaboration between Weill Cornell Medicine, NewYork-Presbyterian, and medical diagnostics company Isabl, Inc.
Enhanced Detection Across Cancer Types
The study analyzed 580 tumor and normal paired samples from 453 patients using whole-genome sequencing to examine genome-wide signatures associated with HRD phenotype. Researchers used a proprietary HRD classifier from Isabl Inc (搜索). for training on the Weill Cornell Medicine cohort, with algorithm validation performed on a dataset from the International Cancer Genome Consortium.
The algorithm detected HRD phenotype in 21% of breast cancers, 20% of pancreaticobiliary cancers, 17% of gynecologic cancers, 9% of prostate cancers, 2% of upper gastrointestinal cancers, and 1% of other cancer types including one case of carcinoma of unknown primary.
Beyond BRCA1/2 Mutations
A significant finding was that 24% of HRD instances occurred in patients with BRCA1 (搜索)/2 wild-type disease, highlighting the diversity of underlying genetic mechanisms. The study identified additional genomic mechanisms contributing to the HRD phenotype, including biallelic mutations in FANCF (搜索), XRCC2 (搜索), and FANCC (搜索).
"A comprehensive analysis of the entire genome has advantages compared with traditional, targeted detection strategies for predicting homologous recombination deficiency (搜索)," said study senior author Juan Miguel Mosquera, MD, MSc, Professor of Pathology and Laboratory Medicine and Director of Research Pathology at the Englander Institute for Precision Medicine at Weill Cornell Medicine.
Clinical Performance Advantages
The algorithm demonstrated superior predictive capability compared to traditional assays and identified discrepancies in existing commercial methods. In several cases, the algorithm flagged false negative and false positive results from commercial methods where patient outcomes did not match expected results.
The research team used 305 samples from Weill Cornell and NewYork-Presbyterian patients with various cancers to train the algorithm, then validated it using a cohort of 556 cancers and tested it against commercial methods using an additional 212 tumor samples.
Treatment Implications
Tumors with HRD are vulnerable to PARP inhibitors (搜索), which further disrupt DNA repair mechanisms, causing cancer cells to accumulate DNA damage and die. Platinum-based chemotherapies (搜索) also tend to work better in these cases. Until now, clinicians have focused primarily on BRCA1 (搜索) and BRCA2 (搜索) mutations to determine PARP inhibitor eligibility, but this approach may miss patients who could benefit from treatment.
The study represents part of a precision medicine initiative involving Weill Cornell, NewYork-Presbyterian, and Illumina, Inc., utilizing whole-genome sequencing technology that has become affordable enough for routine clinical use. The research team plans to conduct larger studies of the detection algorithm as a general tool to guide cancer treatment decisions.