Identification of Additional DPYD Polymorphisms That Increase the Risk of Severe Fluoropyrimidine Toxicity and...

Fluoropyrimidine (FP) chemotherapy can cause life-threatening toxicity. Four DPYD polymorphisms (DPYD*2A, *13, p.Asp949Val, and HapB3) are most well established to increase FP toxicity risk. This study aimed to identify additional DPYD polymorphisms that increase FP severe toxicity.

Adult patients treated with standard doses of systemic FP (5-fluorouracil/capecitabine) for any tumor type with available genetic data were included. The primary toxicity endpoint was a composite of Common Terminology Criteria for Adverse Event grade ≥3 toxicity or treatment modification due to toxicity in the first two FP cycles. A literature-curated list of suspected deleterious unvalidated DPYD variants was classified as uncommon (minor allele frequency <0.01) or common. The genetic association with toxicity was analyzed via multivariable logistic regression.

Among 849 eligible patients, the composite toxicity endpoint occurred in 25%. Genetic data were available for five uncommon and six common suspected deleterious DPYD variants. In the primary analysis of 799 patients who did not carry a validated variant, carriers of an uncommon deleterious variant (1.1% of patients) had significantly higher risk of toxicity than noncarriers (67% vs. 24%; adjusted OR, 7.36; 95% confidence interval, 1.75-38.20; P = 0.009). None of the common deleterious variants were associated with toxicity. Toxicity prediction in the entire cohort (n = 849) was slightly improved by testing the uncommon and validated variants versus testing only the validated variants (positive predictive value: 44.1% vs. 40%).

Five uncommon DPYD variants, in combination, increase FP toxicity risk and improve risk prediction. Testing these variants could identify more high-risk patients who should receive adjusted FP doses to prevent severe toxicity. See related commentary by Gaddy et al., p. 3109.