Association of uncommon DPYD polymorphisms with severe fluoropyrimidine toxicity.

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 C, p.Val586Ala, rs374527058 0% (0/1) c.557A>G, p.Tyr186Cys, rs115232898 67% (4/6) c.274C>G, p.Pro92Ala, rs143986398 100% (1/1) c.187A>G, p.Lys63Glu, rs367619008 100% (1/1)