Gene variants linked to toxicity of fluorouracil-based chemo

Last Updated: 2016-02-01

By Joan Stephenson

NEW YORK (Reuters Health) - In patients who received fluorouracil-based chemotherapy for colon cancer, two variants of the dihydropyrimidine dehydrogenase (DPYD) gene were linked with an increased incidence of severe fluorouracil toxicity.

The findings, which implicate D949V and V732I (DPYD*6), are from a pharmacogenetic substudy of a large randomized trial.

Previous research had documented a link between D949V and fluorouracil toxicity, but the effect of V732I has been unclear.

If the new findings are independently confirmed, genetic testing for V732I and other known "at-risk" DPYD variants "may be justifiable to highlight patients at risk" of adverse events caused by the fluorouracil-based FOLFOX regimen, Dr. Valerie Boige of the Institut Gustave Roussy in France and colleagues wrote.

In the PETACC-8 trial, conducted between 2005 and 2009, 2559 patients with resected stage III colon cancer were randomly assigned to receive standard FOLFOX4 (fluorouracil, leucovorin, and oxaliplatin) alone or with cetuximab for six months.

The new work was a pharmacogenetic substudy of 1,545 of those subjects (58% male, median age 60), who underwent genotyping for 25 DPYD variants.

Fluorouracil adverse events grade 3 or higher occurred in 18 of 21 (85.7%) individuals carrying the D949V variant and in 121 of 199 (60.8%) carriers of V732I variants, the researchers reported online January 21 in JAMA Oncology.

These adverse events were significantly associated with D949V (odds ratio, 6.3, p<0.001) and V732I (OR, 1.7, p<0.001) variants, after adjusting for multiple variables.

Grade 3 or greater overall hematologic adverse events were associated with D949V and V732I variants (ORs 5.2 and 1.9, respectively, p<0.001). V732I was also associated with grade 3 or greater neutropenia (OR 1.8; p<0.001).

Studies probing the association between the variants and fluorouracil toxicity in an independent cohort of 339 patients with metastatic colorectal cancer validated a significant association between V732I and grade 3 or greater adverse events (OR, 2.7, p=0.002) and for overall hematologic adverse events (OR, 3.8. p=0.002), but no link was seen for D949V.

The researchers have taken an important step forward "by investigating further the DPYD genotyping ability to predict adverse reactions following treatment with FOLFOX4 adjuvant chemotherapy," Dr. Felicia S. Falvella, of the Luigi Sacco University Hospital, in Milan, Italy, told Reuters Health by email.

The effect of V732I "is still not elucidated in full," said Dr. Falvella, who was not involved with the study. "Although the authors cannot exclude that the V732I may only be in linkage disequilibrium with the causal variants, this is the first large study revealing the association of the more common V732I variants with fluorouracil-related adverse events in stage III colon cancer patients treated with FOLFOX4 chemotherapy."

The current study confirmed the significant predictive value of D949V, but not of two other DPYD variants, DPYD*2A and I560S (DPYD*13), that have been linked with fluorouracil toxicity and are included in the 2013 Clinical Pharmacogenetics Implementation Consortium Guidelines, she noted. The guidelines recommend use of an alternative drug for homozygous carriers of these three variants and using a starting dose of 50% for heterozygous carriers (http://1.usa.gov/1PDZZbs).

However, the failure to find a link between fluorouracil toxicity and DPYD*2A or I560S may be due simply to the low allelic frequency in the study population, she said.

"Previous studies have suggested that (V732I) may not directly contribute to fluorouracil toxicity risk, but instead the observed association may be due to that of another linked genetic factor," noted Dr. Steven M. Offer and Dr. Robert B. Diasio of the Mayo Clinic in Rochester, Minnesota, in an accompanying commentary.

Whether the effect on toxicity is direct or indirect, the new study does indicate that this variant may be a predictive marker of fluorouracil-related toxicity from the FOLFOX4 regimen, they wrote.

Additional research is needed to determine whether V732I "is predictive of toxic effects in other fluorouracil combination therapies and the mechanism by which this variant may contribute to toxic effects," they wrote.

The authors did not respond to requests for comment.

The study had partial funding from Merck KGaA and Sanofi.

SOURCE: http://bit.ly/1SlYeEP and http://bit.ly/1SMJY9x

JAMA Oncol 2016.