Upfront DPYD Genotyping and Toxicity Associated with Fluoropyrimidine-Based Concurrent Chemoradiotherapy for Oropharyngeal Carcinomas: A Work in Progress.

Background : 5-FU-based chemoradiotherapy (CRT) could be associated with severe treatment-related toxicities in patients harboring at-risk DPYD polymorphisms. Methods : The studied population included consecutive patients with locoregionally advanced oropharyngeal carcinoma treated with carboplatin and 5-FU-based CRT one year before and after the implementation of upfront DPYD*2A genotyping. We aimed to determine the effect of DPYD genotyping on grade ≥3 toxicities. Results : 181 patients were analyzed (87 patients before and 94 patients following DPYD*2A screening). Of the patients, 91% ( n = 86) were prospectively genotyped for the DPYD*2A allele. Of those screened, 2% ( n = 2/87) demonstrated a heterozygous DPYD*2A mutation. Extended genotyping of DPYD*2A -negative patients later allowed for the retrospective identification of six additional patients with alternative DPYD variants (two c.2846A>T and four c.1236G>A mutations). Grade ≥3 toxicities occurred in 71% of the patients before DPYD*2A screening versus 62% following upfront genotyping ( p = 0.18). When retrospectively analyzing additional non- DPYD*2A variants, the relative risks for mucositis (RR 2.36 [1.39-2.13], p = 0.0063), dysphagia (RR 2.89 [1.20-5.11], p = 0.019), and aspiration pneumonia (RR 13 [2.42-61.5)], p = 0.00065) were all significantly increased. Conclusion : The DPYD*2A , c.2846A>T, and c.1236G>A polymorphisms are associated with an increased risk of grade ≥3 toxicity to 5-FU. Upfront DPYD genotyping can identify patients in whom 5-FU-related toxicity should be avoided.