Fluoropyrimidine chemotherapy: recommendations for DPYD genotyping and therapeutic drug monitoring of the Swiss Group of Pharmacogenomics and Personalised Therapy

Abstract

Fluoropyrimidines (FPs), mainly 5-fluorouracil (5-FU) and its oral prodrug capecitabine (Cap), remain the backbone of the treatment of many different solid tumors. Despite their broad use in clinical routine, 10-40% of patients experience severe, and in rare cases (0.2-0.5%) even lethal, FP-related toxicity in early chemotherapy cycles. Today, there is a plethora of evidence that genetic variants in the gene encoding for the 5-FU catabolising enzyme dihydropyrimidine dehydrogenase (DPD, encoded by DPYD) are predictive of severe FP-related toxicities, and international clinical practice recommendations for DPYD genotype-guided FP dosing and therapeutic drug monitoring (TDM) are available. In spite of this strong evidence and DPYD genotyping becoming standard practice in other countries, it is has not been widely adopted in Switzerland to date. Here, we discuss current guidelines on genotypeguided FP dosing and TDM, and propose recommendations tailored to the situation in Switzerland to facilitate their clinical uptake for the further individualisation of FP chemotherapy.We recommend preemptive testing of four DPYD variants (c.1905+1G>A (rs3918290), c.1679T>G (rs55886062), c.2846A>T (rs67376798) and c.1129-5923C>G (rs75017182, c.1236G>A/HapB3)) in patients with an indication for FP-based chemotherapy, with the costs reimbursed through the compulsory health insurance in Switzerland. Carriers of these variants (6.5% in the Swiss population) have a 40-50% risk of developing severe early-onset toxicity when treated with standard FP doses. In these patients, we therefore recommend the use of a reduced starting dose, based on a dose adjustment scheme provided herein. Furthermore, we recommend the use of infusional 5-FU in patients with a DPYD risk genotype in order to enable TDM-based dose escalation. Only if the use of an infusional 5-FU regimen is not feasible should a slow titration of Cap, starting with the recommended reduced dose and basing further doses on monitoring of toxicity, be considered. Given that several studies have shown that TDM in 5-FU treatment improves not only the therapy's safety, but potentially also its efficacy, we also include detailed TDM-based dosing guidelines and discuss the pre-analytical aspects of 5-FU TDM.

DPYD polymorphisms c.496A>G, c.2194G>A and c.85T>C and risk of severe adverse drug reactions in patients treated with fluoropyrimidine‐based protocols

“…predicted remaining DPD activity, are provided by the Clinical Pharmacogenetics Implementation Consortium (CPIC), 15 and the Dutch Pharmacogenetics Working Group (DPWG), 14 as well the French National Network of Pharmacogenetics (RNPGx) 17 and the Swiss Group of Pharmacogenomics and Personalised Therapy. 18 They pertain to patients who are heterozygous carriers of a single DPYD variant. For homozygous DPYD variant allele carriers and for compound heterozygous DPYD variant allele carriers, dosing guidelines…”

Overcoming barriers to implementing precision dosing with 5‐fluorouracil and capecitabine

“…These recommendations are 1 of the first available using both approaches together and provide a simplified scheme to guide personalising dosing of fluoropyrimidines. 47…”

“…Recommendations for using both DPYD genotyping and TDM were recently published by the Swiss Group of Pharmacogenomics and Personalised Therapy. These recommendations are 1 of the first available using both approaches together and provide a simplified scheme to guide personalising dosing of fluoropyrimidines 47 …”

DPYD polymorphisms c.496A>G, c.2194G>A and c.85T>C and risk of severe adverse drug reactions in patients treated with fluoropyrimidine-based protocols

“…This prospective observational study was conducted at a single tertiary centre (January 2016 to December 2020) and was approved by the Institutional Ethics Committee (approval class: 8.1.-19/232-2; registration number: 02/21 AG). Consecutive adults suffering from solid organ malignancy with an indication for 5-FU/capecitabine-based chemotherapy were genotyped for DPYD polymorphisms [*2Ac.1905+1G>A , (rs3918290);c.2946A>T (rs67376798),c.1236G>A (rs56038477) and *13 c.1679T>C (rs55886062)] recommended by the actual guidelines, 14,15,17,18 (residual) enzyme activitiy score was derived (DPYD activity score), and FP doses were adjusted accordingly. Where disease course necessitated, genotyping could be completed only after the treatment commencement and doses were adjustedpost-hoc .…”

“…Preemptive screening for these DPYDvariants and subsequent genotype-guided dose individualization results in a significant reduction of severe adverse reactions and is feasible and cost-effective in daily practice 9,16 . Dosing guidelines -driven by the predicted remaining DPD activity based on the four variants -are provided by the Clinical Pharmacogenetics Implementation Consortium (CPIC) 15 , and the Dutch Pharmacogenetics Working Group (DPWG) 14 , as well the French National Network of Pharmacogenetics (RNPGx) 17 and the Swiss Group of Pharmacogenomics and Personalised Therapy 18 . They pertain to patients who are heterozygous carriers of a single DPYD variant.…”