Gene Markers Confirmed For Fluorouracil-Related AE Severity

Patients carrying variant forms of a gene involved in fluorouracil metabolism may be at increased risk of severe side effects from the drug

medwireNews: The risk of severe adverse events (AEs) in colon cancer patients undergoing fluorouracil -based chemotherapy is linked to carriage of two variant forms of the dihydropyrimidine dehydrogenase gene (DPYD), researchers say.

Grade 3 or greater fluorouracil AEs occurred in 60.8% of the 199 patients carrying the V732I variant of DPYD and 85.7% of the 21 patients who carried the D949V variant,compared with 49–50% of the overall group of 1545 patients given FOLFOX4 alone or alongside cetuximab .

There was an absolute difference in the risk of grade 3 or more severe haematological AEs in V732I and D949V carriers of 15% and 37%, respectively. And the at-risk alleles were estimated to contribute to 29% and 48% of the haematological AEs in these two patient groups, respectively, report Valérie Boige, from Institut Gustave Roussy in Villejuif, France, and co-investigators.

After adjusting for confounding factors, the V732I and D949V variants were associated with a 1.7- and 6.3-fold increased risk of grade 3 or more severe fluorouracil-associated AEs, respectively, with corresponding odds ratios (ORs) of 1.9 and 5.2 for grade 3 or greater haematological AEs.

The secondary analysis of this PETACC-8 randomised trial for stage III colon cancer confirms earlier smaller studies suggesting a link between DPYD single nucleotide polymorphisms that alter fluorouracil metabolism and the variability of side effects via dihydropyrimidine dehydrogenase enzyme activity, the authors write in JAMA Oncology.

Steven Offer and Robert Diasio, from the Mayo Clinic in Rochester, Minnesota, USA, observe in an accompanying comment that V732I may only contribute indirectly to fluorouracil toxicity, via another linked genetic factor or in the context of certain DPYD haplotypes.

But they write: “Regardless of whether the effect on toxicity is direct or indirect, the present study indicates that p.V732I may be a predictive marker of fluorouracil-related toxic effects to FOLFOX4 chemotherapy.”

The significant impact of V732I – although not D949V – was confirmed in a validation cohort of 339 patients with metastatic colorectal cancer given FOLFOX4 in a second clinical trial, with an OR of 2.7 for any grade 3 or greater fluorouracil side effect and an OR of 3.8 for grade 3 or above haematological AEs.

“Before genetic testing can be used in clinical practice, there is a need to identify and characterize additional fluorouracil AE variants in larger patient cohorts and to investigate the potential associations between combinations of rare and common DPYD variants and severe AEs, which may provide a more comprehensiveDPYDvariant model for fluorouracil AE prediction”, explain the authors.

“Such variants should be added to the panel of polymorphisms identified in our study so as to develop a genetic test that might well make it possible to closely monitor patients who are at increased risk of experiencing AEs.

“It would be worth demonstrating whether such a strategy would be cost-effective.”

References

Boige V, Vincent M, Alexandre P, et al. DPYD genotyping to predict adverse events following treatment with fluorouracil-based adjuvant chemotherapy in patients with stage III colon cancer. A secondary analysis of the PETACC-8 randomized clinical trial. JAMA Oncol 2016; Advance online publication 21 January.doi:10.1001/jamaoncol.2015.5392

Offer SM, Diasio RB. Biomarkers of fluorouracil toxicity. Insight from the PETACC-8 trial.JAMA Oncol 2016; Advance online publication 21 January.doi:10.1001/jamaoncol.2015.5463

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