Severe (grade≥3) adverse events (AEs) to 5-fluorouracil (5-FU)-based chemotherapy regimens can result in treatment delays or cessation, and, in extreme cases, life-threatening complications. Current genetic biomarkers for 5-FU toxicity prediction, however, account for only a small proportion of toxic cases. In the current study, we assessed DPYD variants suggested to correlate with 5-FU toxicity, a deep intronic variant (c.1129-5923 C>G), and four variants within a haplotype (hapB3) in 1953 stage III colon cancer patients who received adjuvant FOLFOX±cetuximab. Logistic regression was used to assess multivariable associations between DPYD variant status and AEs common to 5-FU (5FU-AEs). In our study cohort, 1228 patients (62.9%) reported any grade≥3 AE (overall AE), with 638 patients (32.7%) reporting any grade≥3 5FU-AE. Only 32 of 78 (41.0%) patients carrying DPYD c.1129-5923 C>G and the completely linked hapB3 variants c.1236 C>G and c.959-51 T>C showed at least one grade≥3 5FU-AE, resulting in no statistically significant association (adjusted odds ratio=1.47, 95% confidence interval=0.90–2.43, P=0.1267). No significant associations were identified between c.1129-5923 C>G/hapB3 and overall grade≥3 AE rate. Our results suggest that c.1129-5923 C>G/hapB3 have limited predictive value for severe toxicity to 5-FU-based combination chemotherapy.
aDepartment of Molecular Pharmacology and Experimental Therapeutics (MPET), Mayo Clinic Cancer Center
bAlliance Statistics and Data Center
cDivision of Medical Oncology
dDivision of Gastroenterology, Mayo Clinic, Rochester, Minnesota
eDepartment of Surgery, Cancer Prevention and Control Program, University of Hawaii Cancer Center, Honolulu, Hawaii
fDepartment of Medicine, Center for GI Oncology, The University of Chicago Medicine, Chicago, Illinois
gDivision of Hematology Oncology, Vanderbilt-Ingram Cancer Center, Nashville, Tennessee
hSurgical Oncology Associates of South Texas, San Antonio, Texas
iDepartment of Hematology Oncology, Lehigh Valley Health Network, John and Dorthy Morgan Cancer Center, Allentown, Pennsylvania
jDepartment of Oncology, Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, Michigan
kDepartment of Hematology/Oncology, Division of Medical Oncology, The Ohio State University Medical Center, Columbus, Ohio, USA
lDepartment of Medicine, Division of Medical Oncology, University of British Columbia, British Columbia Cancer Agency, Vancouver, British Columbia, Canada
* Adam M. Lee and Qian Shi contributed equally to the writing of this article.
Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (www.pharmacogeneticsandgenomics.com).
Initial results from this study were presented as an abstract at the 2015 American Society of Clinical Oncology Gastrointestinal Cancers Symposium; 17 January 2015; San Francisco, California.
Correspondence to Robert B. Diasio, MD, Department of Molecular Pharmacology and Experimental Therapeutics (MPET), Mayo Clinic Cancer Center, 200 1st Street SW, Rochester, MN 55905, USA Tel: +1 507 266 4997; fax: +1 507 538 6674; e-mail: email@example.com
Received August 24, 2015
Accepted November 17, 2015