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