title: Association between DPYD c.1129-5923 C>G/hapB3 and severe toxicity to 5-fluorouracil-based chemotherapy in stage III colon cancer patients: NCCTG N0147 (Alliance).
abstract: 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.
authors.affiliation: 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.
authors.forename: Adam M
authors.initials: AM
authors.lastname: Lee
authors.forename: Qian
authors.initials: Q
authors.lastname: Shi
authors.forename: Steven R
authors.initials: SR
authors.lastname: Alberts
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Sargent
authors.forename: Frank A
authors.initials: FA
authors.lastname: Sinicrope
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Berenberg
authors.forename: Axel
authors.initials: A
authors.lastname: Grothey
authors.forename: Blase
authors.initials: B
authors.lastname: Polite
authors.forename: Emily
authors.initials: E
authors.lastname: Chan
authors.forename: Sharlene
authors.initials: S
authors.lastname: Gill
authors.forename: Morton S
authors.initials: MS
authors.lastname: Kahlenberg
authors.forename: Suresh G
authors.initials: SG
authors.lastname: Nair
authors.forename: Anthony F
authors.initials: AF
authors.lastname: Shields
authors.forename: Richard M
authors.initials: RM
authors.lastname: Goldberg
authors.forename: Robert B
authors.initials: RB
authors.lastname: Diasio
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects* / Q000627:therapeutic use; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000235:genetics*; D005260:Female; D005472:Fluorouracil / Q000009:adverse effects* / Q000627:therapeutic use; D056726:Genetic Association Studies; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D020641:Polymorphism, Single Nucleotide; D011237:Predictive Value of Tests
chemical_list: D000964:Antimetabolites, Antineoplastic; D042943:Dihydrouracil Dehydrogenase (NADP); D005472:Fluorouracil