Weill Cornell Medicine researchers developed an approach that may identify more patients likely to benefit from the cancer treatments compared to current commercial methods.
Researchers at Weill Cornell Medicine and NewYork-Presbyterian have developed a whole-genome sequencing algorithm that shows early promise for identifying patients who may benefit from PARP inhibitor cancer treatments more accurately than existing commercial methods.
The study, published Jan 12 in Communications Medicine, analyzed hundreds of tumor samples to train and validate an algorithm that detects homologous recombination deficiency, a DNA-repair defect that makes tumors vulnerable to PARP inhibitors. The research was conducted as part of a precision medicine initiative involving Weill Cornell, NewYork-Presbyterian and Illumina Inc.
“A whole-genome analysis of the entire genome has advantages compared with traditional, targeted detection strategies for predicting homologous recombination deficiency,” says Juan Miguel Mosquera, MD, professor of pathology and laboratory medicine and director of research pathology at the Englander Institute for Precision Medicine at Weill Cornell and study senior author, in a release.
Algorithm Detects Broader Range of Mutations
The team used 305 samples from patients with various cancers to train the algorithm, which was developed in collaboration with medical diagnostics company Isabl Inc. The algorithm searches for genome-wide DNA defects associated with homologous recombination repair deficiency, rather than focusing primarily on BRCA1 and BRCA2 mutations as current methods do.
Researchers validated the algorithm using 556 cancer samples and tested it against commercial methods with an additional 212 tumor samples. The algorithm detected DNA-repair deficiency in 21% of breast tumors, 20% of pancreatic and bile duct tumors, and 17% of gynecological tumors.
Notably, 24% of the detected cases did not involve BRCA1 or BRCA2 mutations, highlighting the diversity of underlying genetic mutations that can cause homologous recombination deficiency.
Addressing Current Testing Limitations
Current clinical practice focuses primarily on BRCA1 and BRCA2 mutations to determine patient eligibility for PARP inhibitors. These mutations are most frequently found in patients with breast, ovarian, pancreatic and prostate cancers. However, research shows many other gene mutations can also disrupt DNA repair processes.
Tumors with homologous recombination deficiency are vulnerable to PARP inhibitors, which further disrupt DNA repair and cause cancer cells to accumulate DNA damage. Platinum-based chemotherapies also tend to work better in these cases.
The algorithm appeared to flag false negative and false positive predictions from commercial methods that didn’t match patient outcomes in several cases during testing.
The research team plans to conduct larger studies of the detection algorithm as a tool to guide cancer treatment decisions. Whole-genome sequencing has become affordable enough for routine clinical use in recent years, making the approach potentially viable for broader implementation.
We Recommend for You:
