Upfront DPYD genotyping and toxicity associated with fluoropyrimidine-based concurrent chemoradiotherapy for oropharyngeal carcinomas.

Abstract

6580 Background: The combination of carboplatin and 5-fluorouracil (5-FU) is effective when used concurrently with radiotherapy for locoregionally advanced oropharyngeal carcinomas (Calais et al. 1999). DPYD polymorphisms can be associated with an increased risk of severe toxicity to fluoropyrimidines (Deenen et al. 2016). Upfront screening for the DPYD*2A allele is available in the province of Québec, Canada since March 2017. This study aimed to determine the effect of upfront genotyping on grade ≥3 toxicities. Methods: The studied population included all consecutive cases of oropharyngeal carcinomas treated with 5-FU based chemoradiotherapy one year before and after the implementation of upfront DPYD*2A genotyping. All patients were treated at the Centre Hospitalier de l’Université de Montréal (CHUM) between March 2016 and April 2018. Clinical data were extracted from chart review. Extended screening for 3 supplemental at-risk DPYD variants was also retrospectively performed in August 2019. Results: 181 patients were included in the analysis (87 patients before and 94 patients after DPYD*2A screening implementation). 91% of patients (n = 86) were prospectively genotyped for the DPYD*2A allele. Of those screened, 2% (n = 2/87) demonstrated a heterozygous DPYD*2A mutation. Those two patients received cisplatin-based treatment and thus avoided 5-FU toxicities. Extended genotyping of DPYD*2A-negative patients later allowed for the retrospective identification of 6 additional patients with alternative DPYD variants (two c.2846A > T and four c.1236G > A allele mutations). Conclusions: The DPYD*2A, c.2846A > T and c.1236G > A polymorphisms are associated with an increased risk of G3-4 toxicity to 5-FU, as well as higher hospitalization rates. Upfront DPYD genotyping can identify patients in whom fluoropyrimidine-related toxicity should be avoided. This represents an interesting addition in terms of pharmacovigilance. [Table: see text]