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

Abstract

Purpose: The Clinical Pharmacogenetics Implementation Consortium (CPIC) recommends screening for four common DPYD 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 and methods: Patients were grouped into four variant categories (DPYD*2A [c.1905+1G>A], DPYD*13 [c.1679T>G], c.2846A>T [p.D949V], c.1236G>A/HapB3 [p.E412E]) and a DPYD 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.

Results: Twenty-six wild-type controls and 34 DPYD 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 (DPYD*2A) and c.1679T>G (DPYD*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.

Conclusion: 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 DPYD variants to achieve optimal 5-FU exposure.

FIG 1.

Study flow. ^aWe detected n = 95 DPYD variants in n = 92 patients. One patient was heterozygote for the p.E412E/p.D949V variants and two patients were homozygous for p.E412E. CAP, capecitabine.

FIG 2.

Box plots of U/DHU ratios measured at t = 120 minutes after ingestion of 1,000 mg uracil, displayed for each of the four most common DPYD variants and DPYD wild types. Patients with a U/DHU ratio under 2.4 are rated as normal metabolizer and from 2.4 and above as poor metabolizers. DHU, dihydrouracil; U, uracil.

FIG 3.

Box plots of 5-FU AUC_0-46h values displayed for the four most common DPYD variants and DPYD wild types after dose escalation during four consecutive cycles. 5-FU, 5-fluorouracil.

FIG 4.

(A) Box plots of 5-FU dose intensity in % of the standard dose displayed for the four most common DPYD variants and DPYD wild types during cycles 1-4. (B) Combined CTCAEv5 toxicity scores displayed for the four most common DPYD variants and DPYD wild types after dose escalation during four consecutive cycles. CTCAE, Common Toxicity Criteria for Adverse Events; 5-FU, 5-fluorouracil.