Implications of Homologous Recombination Deficiency for Neoadjuvant Platinum-Based Chemotherapy in Pancreatic Cancer:...

Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal malignancy, with a 5 year survival rate of approximately 13%. Survival is extended for the few patients who undergo surgical resection with curative intent, whereas most patients succumb to distant disease recurrence. Neoadjuvant platinum-based chemotherapy has emerged as a promising strategy to improve resectability rates and survival outcomes for PDAC patients. However, treatment-related toxicities, unpredictable clinical responses, and associated risk of tumor progression during neoadjuvant therapy may delay or preclude curative resection.As a result, predictive biomarkers are needed to identify patients most likely to benefit from neoadjuvant platinum-based chemotherapy.

Alterations in the homologous recombination (HR) DNA repair pathway are reported in 3.0-19.5% of PDAC patients. These types of alterations can sensitize tumors to platinum-based chemotherapy in PDAC as well as other cancers including ovarian, colorectal, and prostate cancers. Retrospective and prospective studies in locally advanced/metastatic PDAC demonstrate higher response rates and longer survival outcomes among HR-deficient (HRD) patients receiving platinum-based chemotherapy. A growing body of evidence in the neoadjuvant setting suggests a potential benefit for HRD-PDAC patients in terms of enhanced tumor downstaging, higher resectability, and improved survival outcomes compared with HR-proficient patients. However, prospective ad hoc studies are still warranted to confirm these findings CONCLUSIONS: Homologous recombination deficiency represents a promising biomarker to guide patient selection for neoadjuvant platinum-based chemotherapy in PDAC. Incorporation of HR deficiency-testing into neoadjuvant treatment schemes will enable a more personalized therapeutic approach, supporting the implementation of precision oncology for early-stage PDAC patients.