DPYD Variants May Predict Fluorouracil-related Adverse Events in Colon Cancer

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Increased incidence of grade 3 or higher fluorouracil adverse events were linked with dihydropyrimidine dehydrogenase gene DPYD variants.
Increased incidence of grade 3 or higher fluorouracil adverse events were linked with dihydropyrimidine dehydrogenase gene DPYD variants.

Increased incidence of grade 3 or higher fluorouracil adverse events were linked with dihydropyrimidine dehydrogenase gene DPYD variants in patients with resected stage 3 colon cancer treated with adjuvant fluorouracil-based combination chemotherapies, according to a study published in JAMA Oncology.1

Investigators sought to determine the prognostic significance of DYPD variants on fluorouracil-related adverse events in patients treated with the FOLFOX4 regimen (fluorouracil, leucovorin, and oxaliplatin), in a secondary analysis of the PETACC-8 randomized clinical trial.

A total of 1545 patients were genotyped on 25 DPYD variants and were randomly assigned to receive standard adjuvant FOLFOX4 alone or FOLFOX4 plus cetuximab for 6 months.

Results showed that carriers of D949V and V732I (DPYD*6) had an incidence of grade 3 or higher fluorouracil adverse events of 85.7% 60.8% patients, respectively. Researchers adjusted for multiple variables and associations were found between grade 3 or higher fluorouracil adverse events and both D949V and V732I variants (odds ratio [OR], 6.3; 95% CI, 2.0 – 27.0; P < .001; and OR 1.7; 95% CI, 1.3 – 2.4; P < .001, respectively).

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Participants with V732I and D949V variants experienced greater grade 3 or higher overall hematologic adverse events (OR, 1.9; 95% CI, 1.4 – 2.6; and OR, 5.2; 95% CI, 2.0 – 16.0, respectively).

Participants with V732I variants experienced higher rates of grade 3 or higher neutropenia (OR, 1.8; 95% CI, 1.3 – 2.4). The association of V732I and the occurrence of grade 3 or higher hematologic events related to fluorouracil were validated in an independent cohort of 399 patients.

The authors concluded that further studies are needed to confirm and quantitate the associations.   

Reference

  1. Boige V, Vincent M, Alexandre P, et al. DPYD genotyping to predict adverse events following treatment with flourouracil-based adjuvant chemotherapy in patients with stage III colon cancer: a secondary analysis of the PEDTACC-8 randomized clinical trial [published online ahead of print January 21, 2016]. JAMA Oncol. doi: 10.1001/jamaoncol.2015.5392.

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