Additional DPYD Variants Associated with Fluoropyrimidine-Related Toxicity Identified

Researchers suggest a fluoropyrimidine dose reduction for patients with the c.1679T>G and c.1236G>A/HapB3 variants of the dihydropyrimidine dehydrogenase encoding DPYD gene

medwireNews: The risk of severe fluoropyrimidine-associated toxicity is elevated in patients harbouring the c.1679T>G and c.1236G>A/HapB3 variant alleles of the DPYD gene, according to a meta-analysis of individual patient data.

“Upfront screening for these variants, in addition to the established variants DPYD*2A and c.2846A>T, is recommended to improve the safety of patients with cancer treated with fluoropyrimidines”, the researchers write in The Lancet Oncology.

They explain that the DPYD gene encodes dihydropyrimidine dehydrogenase (DPD), the deficiency of which results in the impairment of fluoropyrimidine detoxification, adding that guidelines currently recommend a 50% dose reduction for patients heterozygous for DPYD*2A.

This meta-analysis included 7365 patients treated with fluorouracil, capecitabine or tegafur-uracil (either as monotherapy or together with other anticancer drugs or radiotherapy) from eight studies, of which five were cohort studies (three prospective and two retrospective) and three were secondary analyses of randomised controlled trials.

The c.1679T>G variant was evaluated in five studies with a total of 5616 participants. And the 0.2% of participants heterozygous for the allele had a significantly increased risk of grade 3 or worse global fluoropyrimidine-related toxicity relative to patients without the allele, with an adjusted relative risk (RR) of 4.40.

Among the 4261 patients from six studies included in the analysis for the c.1236G>A/HapB3 polymorphism, the risk was a significant 1.59 times higher for the 4.1% of heterozygous and 0.1% of homozygous polymorphic patients than for noncarriers.

Both the c.1679T>G and c.1236G>A/HapB3 variants were consistently associated with severe gastrointestinal and haematological side effects, but not with hand–foot syndrome, report Jan Schellens, from Netherlands Cancer Institute in Amsterdam, and co-workers.

By contrast, there was no significant correlation between the c.1601G>A polymorphism – assessed in five studies with 3900 patients, of whom 4.7% were heterozygous and 0.1% were homozygous – and either severe global toxicity or any of the individual types of toxicities.

On the basis of their findings and available functional data, the study authors suggest a 50% reduction in fluoropyrimidine dose for individuals with the c.1679T>G variant and a 25% dose reduction for those heterozygous for c.1236G>A/HapB3.

In a linked commentary, Joseph Ciccolini, from La Timone University Hospital of Marseille, France, writes that the study is “rather ironically” published exactly 30 years after the first report of a fatal outcome with fluorouracil in a DPD-deficient patient.

However, DPD testing is still not officially recommended by health agencies, he says, probably owing to difficulties in identifying the most relevant DPYD polymorphisms associated with severe toxicities and lack of consensus on the best strategy to assess DPD phenotype.

But “timely initiatives” such as the recommendations of the Clinical Pharmacogenetics Implementation Consortium have aided clinical decision making, Joseph Ciccolini comments, adding that the current meta-analysis merits praise as it should further assist clinicians.

“[Thirty] years after the initial clinical report, it might be time to stop playing Russian roulette when administrating standard fluorouracil to patients with cancer”, he concludes.

References

Meulendijks D, Henricks LM, Sonke GS, et al. Clinical relevance of DPYD variants c.1679T>G, c.1236G>A/HapB3, and c.1601G>A as predictors of severe fluoropyrimidine-associated toxicity: a systematic review and meta-analysis of individual patient data.Lancet Oncol 2015; Advance online publication 22 October. doi: dx.doi.org/10.1016/S1470-2045(15)00286-7

Ciccolini J. DPD deficiency in patients treated with fluorouracil. Lancet Oncol 2015; Advance online publication 22 October. doi: dx.doi.org/10.1016/S1470-2045(15)00360-5

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