Dr Bryant on the Influence of Germline DNA Repair Mutations on Therapeutic Development in PDAC

John M. Bryant, MD, resident, Radiation Oncology, Moffit Cancer Center, discusses how the identification of germline DNA repair mutations influencing radiosensitivity may impact the development of targeted therapies in pancreatic ductal adenocarcinoma (PDAC), as well as highlights next steps planned for this area of research.

Prior investigations in this arena have identified a correlation between homologous recombination deficiency (HRD) and the responsiveness of patients with pancreatic ductal adenocarcinoma (PDAC) to platinum-based chemotherapy, indicating the need for an improved understanding of how germline DNA repair mutations affect treatment efficacy. To elucidate whether individuals with germline DNA repair mutations exhibited notable differences in radiosensitivity scores vs those without mutations, a retrospective analysis was conducted in patients with PDAC who underwent genomic adjusted radiation dosing (GARD) testing at Moffit Cancer Center. Results demonstrated that patients with germline DNA repair mutations displayed heightened sensitivity to radiation based on GARD testing.

Although this study was intended to be hypothesis-generating, it will be important to clinically validate these findings, particularly as germline testing for pancreatic cancer becomes increasingly prevalent, Bryant begins. The insights gleaned from this research could potentially inform treatment decisions by guiding and tailoring the dosing of radiation doses to specific patient populations, he says. Bryant adds that this personalized approach aims to optimize treatment outcomes while minimizing the associated toxicity of radiation therapy.

As the field progresses and a deeper understanding of PDAC biology and biomarkers emerges, there is a growing emphasis on tailoring therapies to individual patients, Bryant continues. This personalized approach not only ensures that patients receive the most appropriate treatments but also seeks to mitigate adverse effects, he explains. In the context of borderline or locally advanced disease, optimizing therapeutic regimens can have significant implications for treatment outcomes, including decisions regarding surgical intervention, Bryant notes.

Ultimately, the potential clinical applications of these findings, if validated, are vast, Bryant emphasizes. Continued research and validation efforts are essential to further elucidate the clinical utility of these findings and pave the way for personalized treatment strategies in pancreatic cancer, he concludes.