Precision Treatment of Patients With GI Cancer Using Pre-emptive <i>DPYD</i> Genotyping/Phenotyping Plus Pharmacokinetic-Guided Dosing of 5-Fluorouracil.

Abstract

The Clinical Pharmacogenetics Implementation Consortium (CPIC) recommends screening for four common <i>DPYD</i> variants to prevent severe toxicity in patients with cancer treated with fluoropyrimidines. A 50% starting dose followed by toxicity-based dose titration is advised for patients heterozygous for these variants. In this study, the appropriateness of the CPIC-recommended 5-fluorouracil (5-FU) starting dose was evaluated. Patients were grouped into four variant categories (<i>DPYD</i>*2A [c.1905+1G>A], <i>DPYD</i>*13 [c.1679T>G], c.2846A>T [p.D949V], c.1236G>A/HapB3 [p.E412E]) and a <i>DPYD</i> wild-type control group. Uracil loading tests were used for phenotyping. Variant patients started on a 50% reduced 5-FU dose. On the basis of steady-state 5-FU plasma concentrations, dose adjustments were made during cycles 2-4 until an 5-FU target AUC_0-46h of 20-30 mg × h/L was achieved, if tolerated. Twenty-six wild-type controls and 34 <i>DPYD</i> variant patients were included: 16 with c.1236G>A/HapB3, eight with c.1905+1G>A, eight with p.D949V, and two with c.1679T>G. Heterozygous carriers of c.1905+1G>A (<i>DPYD</i>*2A) and c.1679T>G (<i>DPYD*</i>13) displayed significant reduced uracil metabolism. The impact on uracil clearance was highly variable in p.D949V but only minor in c.1236G>A/HapB3 variants. In all, 65% of wild-type controls had 5-FU exposure within target range on a 100% dose (mean, 23.2; IQR, 6.6). In 97% of all variant patients, the 50% reduced dose resulted in 5-FU underexposure, with a median AUC of 10.6 mg × h/L (IQR, 3.2). Dose escalation to 70% or higher was tolerated in most patients, reaching the target AUC in 68% of patients. The current CPIC guidelines are overly conservative for c.1236G>A/HapB3 and most p.D949V variants. A 75% starting dose is more appropriate for most c.1236G>A/HapB3 carriers. We recommend 5-FU therapeutic drug monitoring in all patients with <i>DPYD</i> variants to achieve optimal 5-FU exposure.