Data from Identification of Additional <i>DPYD</i> Polymorphisms That Increase the Risk of Severe Fluoropyrimidine Toxicity and Improve Predictive Accuracy when Combined with Previously Validated Variants

<jats:p>&lt;div&gt;Abstract Purpose:&lt;p&gt;Fluoropyrimidine (FP) chemotherapy can cause life-threatening toxicity. Four &lt;i&gt;DPYD&lt;/i&gt; polymorphisms (&lt;i&gt;DPYD&lt;/i&gt;*2A, *13, p.Asp949Val, and HapB3) are most well established to increase FP toxicity risk. This study aimed to identify additional &lt;i&gt;DPYD&lt;/i&gt; polymorphisms that increase FP severe toxicity.&lt;/p&gt; Experimental Design:&lt;p&gt;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 &lt;i&gt;DPYD&lt;/i&gt; variants was classified as uncommon (minor allele frequency &lt;0.01) or common. The genetic association with toxicity was analyzed via multivariable logistic regression.&lt;/p&gt; Results:&lt;p&gt;Among 849 eligible patients, the composite toxicity endpoint occurred in 25%. Genetic data were available for five uncommon and six common suspected deleterious &lt;i&gt;DPYD&lt;/i&gt; 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; &lt;i&gt;P&lt;/i&gt; = 0.009). None of the common deleterious variants were associated with toxicity. Toxicity prediction in the entire cohort (&lt;i&gt;n&lt;/i&gt; = 849) was slightly improved by testing the uncommon and validated variants versus testing only the validated variants (positive predictive value: 44.1% vs. 40%).&lt;/p&gt; Conclusions:&lt;p&gt;Five uncommon &lt;i&gt;DPYD&lt;/i&gt; 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.&lt;/p&gt;&lt;p&gt;&lt;a target="_blank" href="https://aacrjournals.org/clincancerres/article-abstract/doi/10.1158/1078-0432.CCR-26-0952"&gt;&lt;i&gt;See related commentary by Gaddy et al., p. 3109&lt;/i&gt;&lt;/a&gt;&lt;/p&gt;&lt;/div&gt;</jats:p>