Henricks LM, et al. - As up to 30% of patients may experience fluoropyrimidine treatment-related severe toxicity which is often the result of reduced activity of the key metabolic enzyme dihydropyrimidine dehydrogenase (DPD), mostly caused by genetic variants in the gene encoding DPD (DPYD), researchers evaluated the influence of prospective screening for the four most relevant DPYD variants (DPYD*2A [rs3918290, c.1905+1G>A, IVS14+1G>A], c.2846A>T [rs67376798, D949V], c.1679T>G [rs55886062, DPYD*13, I560S], and c.1236G>A [rs56038477, E412E, in haplotype B3]) on patient safety and subsequent DPYD genotype-guided dose individualisation in daily clinical care. Observations suggest that in routine clinical practice, prospective DPYD genotyping is feasible, and DPYD genotype-based dose reductions promote patient safety of fluoropyrimidine treatment.

Methods

• In 17 hospitals in the Netherlands, researchers performed a prospective, multicentre, safety analysis; the study population was comprised of adult patients (≥18 years) with cancer who were intended to start on a fluoropyrimidine-based anticancer therapy (capecitabine or fluorouracil as single agent or in combination with other chemotherapeutic agents or radiotherapy).
• Eligible patients were those for which fluoropyrimidine-based therapy was considered in their best interest.
• For DPYD*2A, c.2846A>T, c.1679T>G, and c.1236G>, a prospective genotyping was performed.
• They performed an initial dose reduction of 25% (c.2846A>T and c.1236G>A) or 50% (DPYD*2A and c.1679T>G) among heterozygous DPYD variant allele carriers, and treated DPYD wild-type patients according to the current standard of care.
• The frequency of severe (National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03 grade ≥3) overall fluoropyrimidine-related toxicity across the entire treatment duration was assessed as the primary endpoint of the study.
• They performed a comparison of toxicity incidence between DPYD variant allele carriers and DPYD wild-type patients on an intention-to-treat basis.
• Comparison of relative risks (RRs) for severe toxicity was also performed between the current study and a historical cohort of DPYD variant allele carriers treated with full dose fluoropyrimidine-based therapy (derived from a previously published meta-analysis).

Results

• A total of 1181 patients were enrolled between April 30, 2015, and Dec 21, 2017.
• Researchers considered 78 patients as non-evaluable, because they were not meeting inclusion criteria, did not start fluoropyrimidine-based treatment, or were homozygous or compound heterozygous DPYD variant allele carriers.
• Eighty five (8%) were heterozygous DPYD variant allele carriers, and 1018 (92%) were DPYD wild-type patients among the 1103 evaluable patients.
• In DPYD variant carriers, fluoropyrimidine-related severe toxicity was higher (33 [39%] of 85 patients) than that observed in wild-type patients (231 [23%] of 1018 patients; p=0·0013).
• For severe fluoropyrimidine-related toxicity, the observed RR was 1·31 (95% CI 0·63–2·73) for genotype-guided dosing compared with 2·87 (2·14–3·86) in the historical cohort for DPYD*2A carriers, no toxicity compared with 4·30 (2·10–8·80) in c.1679T>G carriers, 2·00 (1·19–3·34) compared with 3·11 (2·25–4·28) for c.2846A>T carriers, and 1·69 (1·18–2·42) compared with 1·72 (1·22–2·42) for c.1236G>A carriers.