DPYD Genotyping in Patients Receiving Capecitabine: An exploratory analysis from the D-TORCH study

Hemavathi Baskarane¹Mohit Divakar¹Akhil Santhosh¹Kriti Pallavi¹Vishakha Hooda¹Vamsi Krishna Yenamandra²Saran Kumar³Vrajesh Shetty¹Jahnavi Banotra¹Ishaan Gupta³Shilpi Minocha³PRANAY TANWAR¹Atul Sharma¹Payal Vasudeva¹Akash Kumar¹Chethan R.¹SAMEER BAKHSHI¹Atul Batra^1*

• ¹All India Institute of Medical Sciences, New Delhi, India
• ²Indian Institute of Science, Bengaluru, India
• ³Indian Institute of Technology Delhi, New Delhi, India

Background: Fluoropyrimidines, such as 5-fluorouracil (5-FU) and capecitabine, are widely used chemotherapeutic agents in the treatment of gastrointestinal, head and neck, and breast cancers.(1–5) These drugs are known to cause early-onset severe or life-threatening toxicities, including myelosuppression, mucositis, hand-foot syndrome, and diarrhea, in about 10 to 30% of patients, with reported mortality rates ranging from 0.5% to 1%]. (6–13) The enzyme dihydropyrimidine dehydrogenase (DPD), which is coded by DPYD gene, is the rate-limiting enzyme involved in the 5-FU metabolism (14). Partial or complete deficiency of DPD activity is associated with life-threatening side effects among patients undergoing 5–FU– based treatment (15,16). More than 450 DPYD polymorphisms have been associated with fluoropyrimidine-induced toxicity, and incidence of DPD deficiency has been estimated at 3%–7% in the Caucasian population (15–17). Routine testing for four DPYD variants that are commonly found—DPYD2A (c.1905+1G>A), DPYD13 (c.1679T>G), c.2846A>T, and c.1129-5923C>G/hapB3 is recommended by the European Medicines Agency before the initiation of 5-FU chemotherapy (16). These mutations play a role in the interindividual variability of 5-FU toxicity. The current guidelines of the Clinical Pharmacogenetics Implementation Consortium (CPIC) include 82 known DPYD variants, of which 21 are classified as poor metabolizers (no DPYD enzyme function), six as intermediate metabolizers (reduced function), and the rest as normal metabolizers or with limited evidence (17). The CPIC guidelines suggest avoiding 5-FU in poor metabolizers and a 25%–50 % dose reduction in intermediate metabolizers. (16,17) While fluoropyrimidine toxicity profiles are comparable between populations, the prevalence and distribution of DPYD variants differ. (18) Certain variants which are common in Europeans have not been reported in the African, Chinese, or Japanese populations, whilst other clinically relevant variants may be unique to non-Caucasians. Routine DPYD genotyping is not commonly practiced in India, and information on DPYD polymorphisms in the Indian population is scarce. Previously published data from India utilized PCR or Sanger sequencing to examine known polymorphisms in most cases, including healthy volunteers or patients with grade 3 toxicities (19,20). To address these gaps, we conducted a single-center study using next-generation sequencing to evaluate the prevalence of DPYD variants in capecitabine-treated patients and their associated toxicity profiles.