重篤なフルオロピリミジン毒性のリスクを高め、以前に検証されたバリアントと組み合わせた場合の予測精度を向上させる追加のDPYD多型の同定

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

Adult patients treated with standard doses of systemic FP (5-fluorouracil/capecitabine) for any cancer with available DPYD genetic data were included. The primary endpoint was a composite of CTCAE 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 uncommon deleterious variants (1.1% of patients) had significantly higher toxicity risk than non-carriers (67% vs. 24%; adjusted OR 7.36; 95% CI 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 vs. testing only the validated variants (positive predictive value: 44.1% vs. 40.0%).

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.