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Abstract
Simple SummaryThe combination of carboplatin and 5-fluorouracil (5-FU) is effective when used concurrently with radiotherapy for locoregionally advanced oropharyngeal carcinomas. DPYD polymorphisms can be associated with an increased risk of severe toxicity to fluoropyrimidines. Upfront screening for the DPYD*2A allele has been available in the province of Québec, Canada, since March 2017. This study aimed to determine the effect of upfront genotyping on the incidence of grade ≥3 toxicities. We included 181 patients in the analysis. Extended screening for three supplemental at-risk DPYD variants was also retrospectively performed in August 2019. The DPYD*2A, c.2846A>T and c.1236G>A polymorphisms were associated with an increased risk of grade ≥3 toxicity to 5-FU. Upfront DPYD genotyping can thus identify patients in whom 5-FU-related toxicity should be avoided.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.
Highlights
Fluoropyrimidines, such as 5-fluorouracil (5-FU) and prodrug capecitabine, are pyrimidine analogs that interfere with DNA and RNA synthesis, which have shown activity in the treatment of gastrointestinal tract malignancies, as well as head and neck squamous cell carcinoma (HNSCC) [1,2,3,4]
91% (n = 86) were prospectively genotyped for the DPYD*2A allele in order to guide clinical decision-making in terms of the chemotherapy regimen
The DPYD*2A, c.2846A>T, and c.1236G>A polymorphisms are associated with an increased risk of severe toxicity to 5-FU in locally advanced oropharyngeal squamous cell carcinomas (OPSCCs) patients, as well as higher hospitalization rates when compared to DPYD-WT patients
Summary
Fluoropyrimidines, such as 5-fluorouracil (5-FU) and prodrug capecitabine, are pyrimidine analogs that interfere with DNA and RNA synthesis, which have shown activity in the treatment of gastrointestinal tract malignancies, as well as head and neck squamous cell carcinoma (HNSCC) [1,2,3,4]. The initial and rate-limiting enzyme in pyrimidine catabolism is dihydropyrimidine dehydrogenase (DPD), which inactivates more than 80% of 5-FU [8,9]. This enzyme is encoded by the DPYD gene [10]. Fluoropyrimidine toxicity has been associated with reduced DPD activity and DPYD*2A polymorphism, based on numerous reports [18,19,20,21,22,23,24], including two recent meta analyses [16,25]
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