Association of uncommon <i>DPYD</i> polymorphisms with severe fluoropyrimidine toxicity.

Abstract

112 Background: Fluoropyrimidine (FP) chemotherapy can cause life-threatening toxicity, especially in patients with dihydropyrimidine dehydrogenase (DPD) deficiency. Four DPYD polymorphisms ( DPYD *2A, *13, p.Asp949Val, HapB3) are validated to increase FP toxicity risk but the association for many other DPYD variants has not been demonstrated. This study aims to identify additional DPYD polymorphisms that increase FP-related toxicity. Methods: This retrospective study used genetic data from the Michigan Genomics Initiative institutional biobank, which is linked to the University of Michigan Rogel Cancer Center electronic medical record. Adults treated with standard doses of systemic FP (5-fluorouracil or capecitabine) for any tumor type with available genetic data were included. The primary toxicity 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 DPYD variants beyond the four validated variants was classified as uncommon (minor allele frequency &lt;0.01) or common. Uncommon variants were analyzed in aggregate whereas common variants were analyzed individually, excluding patients carrying validated variants. The genetic association with toxicity was analyzed via logistic regression adjusted for demographic and treatment factors. Toxicity prediction was estimated using positive (PPV) and negative (NPV) predictive values for testing the validated variants with and without the uncommon variants. Results: Among 849 eligible patients, the composite toxicity endpoint occurred in 25.1% (16.5% grade ≥3 toxicity, 23.2% treatment modification). Genetic data were available for four 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 variant (1.1% of patients; Table 1) had significantly higher risk of toxicity than non-carriers (66.7% vs. 23.7%; adjusted OR 7.36; 95% CI 1.75–38.2; p=0.009). None of the common variants were associated with toxicity (data not shown). Toxicity prediction in the entire cohort (n=849) was slightly improved by testing the uncommon and validated variants vs. testing only the validated variants (PPV= 44.1% vs. 40.0%, NPV=76.3% vs. 75.8%). Conclusions: Four uncommon DPYD variants that, in combination, increase FP toxicity risk and improve toxicity risk prediction were identified. Inclusion of these variants in DPYD testing would identify more patients with high toxicity risk who should receive adjusted FP doses to prevent severe toxicity. Incidence of toxicity among carriers of each uncommon variant. Uncommon variant Incidence of toxicity among carriers c.1757T&gt;C, p.Val586Ala, rs374527058 0% (0/1) c.557A&gt;G, p.Tyr186Cys, rs115232898 67% (4/6) c.274C&gt;G, p.Pro92Ala, rs143986398 100% (1/1) c.187A&gt;G, p.Lys63Glu, rs367619008 100% (1/1)