A groundbreaking study led by researchers from Weill Cornell Medicine and NewYork-Presbyterian has revealed that a whole-genome sequencing approach shows significant promise over current commercial methods for identifying patients who are more likely to benefit from PARP inhibitor cancer treatments. The findings, published on January 12 in Communications Medicine, suggest that further development of this innovative approach is warranted.
The research involved analyzing hundreds of tumor samples obtained through informed consent as part of a precision medicine initiative by Weill Cornell, NewYork-Presbyterian, and Illumina, Inc., a renowned biotechnology company specializing in DNA sequencing technology. The team utilized the sequencing results to train and validate an algorithm designed to detect homologous recombination deficiency, a specific type of DNA-repair defect. Tumors with this defect are particularly susceptible to PARP inhibitors, which further impede DNA repair, leading to the accumulation of DNA damage and subsequent cancer cell death. Additionally, platinum-based chemotherapies, which also cause DNA damage, tend to be more effective in these scenarios.
Advancements in Genome Analysis
The study’s senior author, Dr. Juan Miguel Mosquera, a professor of pathology and laboratory medicine and director of research pathology at the Englander Institute for Precision Medicine at Weill Cornell, emphasized the advantages of comprehensive genome analysis over traditional, targeted detection strategies.
“A comprehensive analysis of the entire genome has advantages compared with traditional, targeted detection strategies for predicting homologous recombination deficiency,”
Dr. Mosquera stated. He is also a pathologist at NewYork-Presbyterian/Weill Cornell Medical Center and a member of the Sandra and Edward Meyer Cancer Center at Weill Cornell.
This research was conducted in collaboration with the medical diagnostics company Isabl, Inc. Until now, clinicians have primarily focused on BRCA1 and BRCA2 mutations, the most common drivers of DNA-repair defects, to determine the likelihood of patient benefit from PARP inhibitors. These mutations are most frequently found in patients with breast, ovarian, pancreatic, and prostate cancers. However, recent studies indicate that numerous other gene mutations can also disrupt this repair process. With the decreasing cost of whole-genome sequencing, detecting these broader genetic changes has become feasible for routine clinical use.
Algorithm Development and Validation
The researchers utilized 305 samples from patients at Weill Cornell and NewYork-Presbyterian with various cancers to train an algorithm developed by Isabl. This algorithm searches for a genome-wide array of DNA defects associated with homologous recombination repair deficiency. The algorithm was then validated using a cohort of 556 cancers and tested against commercial methods with an additional 212 tumor samples.
The results were promising. The algorithm detected DNA-repair deficiencies in a significant portion of the samples, identifying 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, underscoring the diversity of underlying genetic mutations. In several instances, the algorithm appeared to correct “false negative” and “false positive” predictions made by commercial methods that did not align with patient outcomes.
Future Implications and Research Directions
As the field of precision medicine continues to evolve, the implications of this study are profound. The ability to accurately identify patients who will benefit from specific cancer treatments can significantly improve treatment outcomes and reduce unnecessary side effects. The research team plans to conduct larger studies to further validate the new detection algorithm as a general tool for guiding cancer treatment.
This development follows a growing trend in the medical community to integrate advanced genomic technologies into clinical practice, potentially transforming the landscape of personalized medicine. The move represents a significant step forward in the ongoing battle against cancer, offering new hope to patients and clinicians alike.
As the research progresses, the potential for whole-genome sequencing to become a standard component of cancer diagnostics and treatment planning appears increasingly likely. The study’s findings not only highlight the importance of genomic research in understanding cancer biology but also pave the way for more effective and individualized treatment strategies.
