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.

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John M. Bryant, MD, discusses how identifying germline DNA repair mutations may impact the development of targeted therapy development in PDAC. 

Dr Bryant on the Background For Investigating Germline DNA Repair Mutations in PDAC

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John Michael Bryant, MD, resident, Radiation Oncology, Moffit Cancer Center, discusses research investigating the effects of germline DNA repair mutations on radiosensitivity in patients with pancreatic ductal adenocarcinoma (PDAC).

The correlation between homologous recombination deficiency in patients with PDAC and their responsiveness to platinum-based chemotherapy underscores the importance of delving deeper into how germline DNA repair mutations impact the effectiveness of various treatments. With recent data affirming that chemotherapy alone is an acceptable standard of care to improve R0 resection in patients with PDAC, attention has shifted toward understanding the role of radiotherapy in this population. However, there is still limited comprehension regarding the connection between germline DNA repair mutations in general and radiosensitivity. Therefore, investigators launched retrospective research evaluating the association between germline mutations and the Radiosensitivity Index Gene Signature.

The investigators’ focus was on patients with PDAC who underwent genomic adjusted radiation dosing testing at Moffit Cancer Center, Bryant begins. This specific testing allows for the assessment of the inherent radiosensitivity of a tumor, providing a radiosensitivity index score, Bryant says. Analyzing a substantial cohort of surgical specimens dating back to 1999, investigators also examined how many of these patients had undergone genomic testing for germline DNA repair mutations, he adds. Bryant says that after meticulous examination, he and the other investigators established a well-matched cohort, comprising 13 patients with germline DNA repair mutations and 12 without.

The primary objective of this research was to determine whether patients with germline DNA repair mutations exhibited significant differences in their radiosensitivity scores compared with those without mutations, he expands. The findings indicate that patients with germline DNA repair mutations demonstrated increased sensitivity to radiation based on the genomic adjusted radiation dosing testing, Bryant emphasizes.

Overall, these results reveal heightened radiosensitivity in patients with germline DNA repair mutations, indicating that these cancers may exhibit greater vulnerability to DNA damage induced by radiation; however, notable limitations were imposed by the small sample size, Bryant concludes.

John Michael Bryant, MD, discusses the effects of germline DNA repair mutations on radiosensitivity in patients with pancreatic ductal adenocarcinoma.

John Michael "JM" Bryant, MD, radiation oncology resident, Moffitt Cancer Center, discusses the combination of nivolumab (Opdivo) with standard of care (SOC) in the management of patients with prostate cancer, detailing the results of the interim analysis of the phase 2 trial (NCT03543189).

The single-center, single-arm study investigated the safety and tolerability of nivolumab when given in combination with high-dose radiation and androgen deprivation therapy (ADT), and to evaluate the combination’s effectiveness in delaying disease progression. Findings presented at the 2023 AACR Annual Meeting showed that the addition of nivolumab to radiation and ADT led to an 88% reduction in the 2-year risk of metastasis vs a historical control arm that consisted of patients with grade group 5 prostate cancer treated with SOC alone at Moffitt Cancer Center from January 2013 to November 2021 who met the study’s inclusion criteria.

Moreover, biopsies taken at the time of diagnosis, prior to both factions of brachytherapy, and one month following radiation, Bryant explains. With this approach, investigators gathered genomic data and found that CD8A, STING, ANPEP, and multiple immune signatures were associated with an early major pathologic response (MPR). Additionally, the Ricketts Immunosuppression genomic signature was strongly associated with MPR, Bryant continues.

Given the clinically significant reduction in 2-year risk of metastasis observed in this interim analysis, more investigations into genomic signatures associated with MPR could help better identify which patients would most benefit from the addition of nivolumab to SOC, Bryant concludes.

John Michael "JM" Bryant, MD, discusses the combination of nivolumab with standard of care in the management of patients with prostate cancer, detailing the results of the interim analysis of the phase 2 trial.

John Michael "JM" Bryant, MD

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

Dr Bryant on the Background For Investigating Germline DNA Repair Mutations in PDAC

Dr Bryant on Utilizing Nivolumab With SOC in Grade Group 5 Prostate Cancer