DPYD genotyping in patients receiving capecitabine: an exploratory analysis from the D-TORCH study

Introduction: Deficiency of the dihydropyrimidine dehydrogenase enzyme can result in capecitabine-related toxicity due to genetic alterations in the DPYD gene, leading to complete or partial DPD deficiency and poor or intermediate metabolizer phenotypes. The distribution of DPYD variants varies across populations. While routine DPYD genotyping is recommended in Western populations, data from India, particularly from next-generation sequencing (NGS)-based studies, remain limited. Methods: This exploratory analysis was conducted within the D-TORCH trial, a randomized, double-blind, placebo-controlled study evaluating topical diclofenac for prevention of capecitabine-induced hand-foot syndrome. Germline whole-exome sequencing was performed in consenting patients prior to capecitabine initiation. DPYD variants were identified using an NGS pipeline, annotated via ANNOVAR and PharmGKB, and classified according to CPIC guidelines. Results: Seventy-six patients underwent DPYD sequencing; 54 (71%) carried at least one variant and 22 (29%) were wild-type. Thirteen coding or splice-site variants were identified, including three (3.9%) associated with an intermediate metabolizer phenotype; no poor metabolizers were detected. The most common variants were classified as normal metabolizers. Grade 2 toxicity occurred in 63.6% of variant carriers and 55.6% of wild-type patients, with diarrhea and mucositis being most frequent. No significant association was observed between DPYD variant status and toxicity. Discussion: This first NGS-based DPYD report from India highlights the low prevalence of clinically actionable variants. Larger studies are required to validate these findings and guide population-specific fluoropyrimidine dosing strategies.