Carriers of the genetic DPYD*2A variant, resulting in dihydropyrimidine dehydrogenase deficiency, are at significantly increased risk of developing severe fluoropyrimidine‐associated toxicity. Upfront DPYD*2A genotype‐based dose reductions improve patient safety, but uncertainty exists whether this has a negative impact on treatment effectiveness. Therefore, this study investigated effectiveness and safety of DPYD*2A genotype‐guided dosing.
A cohort of 40 prospectively identified heterozygous DPYD*2A carriers, treated with a ~50% reduced fluoropyrimidine dose, was identified. For effectiveness analysis, a matched pair‐analysis was performed where for each DPYD*2A carrier a matched DPYD*2A wild‐type patient was identified. Overall survival and progression‐free survival were compared between the matched groups. The frequency of severe (grade≥3) treatment‐related toxicity was compared to 1] a cohort of 1606 wild‐type patients treated with full dose and 2] a cohort of historical controls derived from literature, i.e. 86 DPYD*2A variant carriers who received a full fluoropyrimidine dose.
For 37 out of 40 DPYD*2A carriers, a matched control could be identified. Compared to matched controls, reduced doses did not negatively affect overall survival (median 27 months versus 24 months, P=0.47) nor progression‐free survival (median 14 months versus 10 months, P=0.54). Risk of severe fluoropyrimidine‐related toxicity in DPYD*2A carriers treated with reduced dose was 18%, comparable to wild‐type patients (23%, P=0.57) and significantly lower than the risk of 77% in DPYD*2A carriers treated with full dose (P<0.001).
This study is the first to show that DPYD*2A genotype‐guided dosing appears to have no negative effect on effectiveness of fluoropyrimidine‐based chemotherapy, while resulting in significantly improved patient safety.
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