This article is more than 5 years old. Information may no longer be current.
Rare gene variants may predict chemotherapy-related AEs in colon cancer
Rare dihydropyrimidine dehydrogenase gene variants appeared to significantly increase the incidence of high-grade fluorouracil-related adverse events among patients with stage III colon cancer, according to a secondary analysis of a randomized trial.
Previous studies have shown an association between dihydropyrimidine dehydrogenase gene (DPYD) variants and fluorouracil-based adverse events, according to study background.
However, conflicting results necessitated the study of this association in a uniformly treated prospective dataset, according to the researchers.
Thus, Valérie Boige, MD, PhD, professor of medical oncology at Institut Gustave Roussy in France, and colleagues sought to determine the impact of DPYD variants on treatment-related adverse events in 1,545 patients (median age, 60 years; range, 19-75; 57.6% men) with stage III colon cancer, treated with FOLFOX4 chemotherapy on the phase 3 Pan-European Trials in Alimentary Tract Cancer (PETACC)-8 randomized clinical trial.
Patients enrolled in the PETACC-8 trial were randomly assigned to receive standard adjuvant FOLFOX4 alone (n = 780) or with cetuximab (Erbitux, Lilly; n = 765) for 6 months following surgical resection.
The association between DPYD variants and grade 3 or higher fluorouracil-based adverse events served as the primary endpoint of this analysis. Patients underwent genotyping for 25 DPYD variants.
Overall, grade 3 or worse fluorouracil-related adverse events occurred in 49% (n = 380) of patients assigned FOLFOX4 alone and 50% (n = 385) of patients assigned FOLFOX4 with cetuximab.
The researchers found that patients with certain variants appeared at an increased risk for grade 3 or worse fluorouracil-based adverse events.
Twenty-one patients harbored the D949V variant, of whom 85.7% (n = 18) had grade 3 or worse fluorouracil-based adverse events. Further, 60.8% (n = 121) of 199 patients with V732I variants experienced grade 3 or worse adverse events.
In multivariate models adjusted for relevant clinical covariates, the occurrence of grade 3 or worse fluorouracil-related adverse events appeared significantly associated with the D949V (OR = 6.3; 95% CI, 2-27) and V732I variants (OR = 1.7; 95% CI, 2-16).
Further, both variants appeared associated with grade 3 or worse hematologic adverse events (D949V, OR = 5.2; 95% CI, 2-16; V732I, OR = 1.9; 95% CI, 1.4-2.6). V732I also appeared to increase the incidence of grade 3 or worse neutropenia (OR = 1.8; 95% CI, 1.3-2.4).
To validate these findings, the researchers evaluated data from an independent cohort of 339 patients with metastatic colorectal cancer enrolled in the Fédération Francophone de Cancérologie Digestive 2000-05 trial.
In this dataset, researchers again observed an association between V732I variants and increased incidence of grade 3 or worse fluorouracil-based adverse events (OR = 2.7; 95% CI, 1.2-6.7) and hematologic adverse events (OR = 3.8; 95% CI, 1.6-9.2).
However, the association with D949V could not be replicated.
“The FOLFOX regimen is the most frequently used regimen in the treatment of colon cancer both in adjuvant and metastatic settings worldwide, thus highlighting the need to identify high-risk patients,” Boige and colleagues wrote. “To our knowledge, our study is the first to test and reveal the V732I at-risk allele in a prospective large randomized clinical trial using this regimen. Further studies are warranted to confirm and quantitate these associations in additional data sets.”
In an accompanying editorial, Steven M. Offer, PhD, and Robert B. Diasio, MD, both of Mayo Clinic in Rochester, Minnesota, highlighted the need for continued research into predictive biomarkers for chemotherapy response.
“The identification of clinically relevant predictors of toxic effects is critical to the individualization of fluorouracil-based chemotherapies,” Offer and Diasio wrote. “Additional studies are needed to determine whether this variant is predictive of toxic effects in other fluorouracil combination therapies and the mechanism by which this variant may contribute to toxic effects.” – by Cameron Kelsall
Disclosure: Boige reports honoraria and research funding from and/or consultant roles with Amgen, Bayer, Merck Sereno and Sanofi. Please see the full study for a list of all other researchers’ relevant financial disclosures. Offer and Diasio report no relevant financial disclosures.