DPYD variants as predictors of 5-fluorouracil toxicity in adjuvant colon cancer treatment (NCCTG N0147).
BACKGROUND
Previous studies have suggested the potential importance of three DPYD variants (DPYD*2A, D949V, and I560S) with increased 5-FU toxicity. Their individual associations, however, in 5-FU-based combination therapies, remain controversial and require further systematic study in a large patient population receiving comparable treatment regimens with uniform clinical data.


METHODS
We genotyped 2886 stage III colon cancer patients treated adjuvantly in a randomized phase III trial with FOLFOX or FOLFIRI, alone or combined with cetuximab, and tested the individual associations between functionally deleterious DPYD variants and toxicity. Logistic regressions were used to assess univariate and multivariable associations. All statistical tests were two-sided.


RESULTS
In 2594 patients with complete adverse event (AE) data, the incidence of grade 3 or greater 5FU-AEs in DPYD*2A, I560S, and D949V carriers were 22/25 (88.0%), 2/4 (50.0%), and 22/27 (81.5%), respectively. Statistically significant associations were identified between grade 3 or greater 5FU-AEs and both DPYD*2A (odds ratio [OR] = 15.21, 95% confidence interval [CI] = 4.54 to 50.96, P < .001) and D949V (OR = 9.10, 95% CI = 3.43 to 24.10, P < .001) variants. Statistical significance remained after adjusting for multiple variables. The DPYD*2A variant statistically significantly associated with the specific AEs nausea/vomiting (P = .007) and neutropenia (P < .001), whereas D949V statistically significantly associated with dehydration (P = .02), diarrhea (P = .003), leukopenia (P = .002), neutropenia (P < .001), and thrombocytopenia (P < .001). Although two patients with I560S had grade≥3 5FU-AEs; a statistically significant association could not be demonstrated because of its low frequency (P = .48).


CONCLUSIONS
In the largest study to date, statistically significant associations were found between DPYD variants (DPYD*2A and D949V) and increased incidence of grade 3 or greater 5FU-AEs in patients treated with adjuvant 5-FU-based combination chemotherapy.
Department of Molecular Pharmacology and Experimental Therapeutics (AML, RBD), Alliance Statistics and Data Center (QS, EP, DJS), Division of Medical Oncology (SRA, FAS, RBD), Division of Gastroenterology (FAS), Mayo Clinic Cancer Center, Rochester, MN; Cancer Prevention and Control Program, University of Hawaii Cancer Center, Honolulu, HI (JLB); Division of Medical Oncology, The Ohio State University Medical Center, Columbus, OH (RMG).
Adam M
AM
Lee
Department of Molecular Pharmacology and Experimental Therapeutics (AML, RBD), Alliance Statistics and Data Center (QS, EP, DJS), Division of Medical Oncology (SRA, FAS, RBD), Division of Gastroenterology (FAS), Mayo Clinic Cancer Center, Rochester, MN; Cancer Prevention and Control Program, University of Hawaii Cancer Center, Honolulu, HI (JLB); Division of Medical Oncology, The Ohio State University Medical Center, Columbus, OH (RMG).
Qian
Q
Shi
Department of Molecular Pharmacology and Experimental Therapeutics (AML, RBD), Alliance Statistics and Data Center (QS, EP, DJS), Division of Medical Oncology (SRA, FAS, RBD), Division of Gastroenterology (FAS), Mayo Clinic Cancer Center, Rochester, MN; Cancer Prevention and Control Program, University of Hawaii Cancer Center, Honolulu, HI (JLB); Division of Medical Oncology, The Ohio State University Medical Center, Columbus, OH (RMG).
Emily
E
Pavey
Department of Molecular Pharmacology and Experimental Therapeutics (AML, RBD), Alliance Statistics and Data Center (QS, EP, DJS), Division of Medical Oncology (SRA, FAS, RBD), Division of Gastroenterology (FAS), Mayo Clinic Cancer Center, Rochester, MN; Cancer Prevention and Control Program, University of Hawaii Cancer Center, Honolulu, HI (JLB); Division of Medical Oncology, The Ohio State University Medical Center, Columbus, OH (RMG).
Steven R
SR
Alberts
Department of Molecular Pharmacology and Experimental Therapeutics (AML, RBD), Alliance Statistics and Data Center (QS, EP, DJS), Division of Medical Oncology (SRA, FAS, RBD), Division of Gastroenterology (FAS), Mayo Clinic Cancer Center, Rochester, MN; Cancer Prevention and Control Program, University of Hawaii Cancer Center, Honolulu, HI (JLB); Division of Medical Oncology, The Ohio State University Medical Center, Columbus, OH (RMG).
Daniel J
DJ
Sargent
Department of Molecular Pharmacology and Experimental Therapeutics (AML, RBD), Alliance Statistics and Data Center (QS, EP, DJS), Division of Medical Oncology (SRA, FAS, RBD), Division of Gastroenterology (FAS), Mayo Clinic Cancer Center, Rochester, MN; Cancer Prevention and Control Program, University of Hawaii Cancer Center, Honolulu, HI (JLB); Division of Medical Oncology, The Ohio State University Medical Center, Columbus, OH (RMG).
Frank A
FA
Sinicrope
Department of Molecular Pharmacology and Experimental Therapeutics (AML, RBD), Alliance Statistics and Data Center (QS, EP, DJS), Division of Medical Oncology (SRA, FAS, RBD), Division of Gastroenterology (FAS), Mayo Clinic Cancer Center, Rochester, MN; Cancer Prevention and Control Program, University of Hawaii Cancer Center, Honolulu, HI (JLB); Division of Medical Oncology, The Ohio State University Medical Center, Columbus, OH (RMG).
Jeffrey L
JL
Berenberg
Department of Molecular Pharmacology and Experimental Therapeutics (AML, RBD), Alliance Statistics and Data Center (QS, EP, DJS), Division of Medical Oncology (SRA, FAS, RBD), Division of Gastroenterology (FAS), Mayo Clinic Cancer Center, Rochester, MN; Cancer Prevention and Control Program, University of Hawaii Cancer Center, Honolulu, HI (JLB); Division of Medical Oncology, The Ohio State University Medical Center, Columbus, OH (RMG).
Richard M
RM
Goldberg
Department of Molecular Pharmacology and Experimental Therapeutics (AML, RBD), Alliance Statistics and Data Center (QS, EP, DJS), Division of Medical Oncology (SRA, FAS, RBD), Division of Gastroenterology (FAS), Mayo Clinic Cancer Center, Rochester, MN; Cancer Prevention and Control Program, University of Hawaii Cancer Center, Honolulu, HI (JLB); Division of Medical Oncology, The Ohio State University Medical Center, Columbus, OH (RMG). diasio.robert@mayo.edu.
Robert B
RB
Diasio
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000009:adverse effects*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D001224:Aspartic Acid; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D017024:Chemotherapy, Adjuvant; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D003967:Diarrhea / Q000139:chemically induced; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000235:genetics*; D064420:Drug-Related Side Effects and Adverse Reactions / Q000235:genetics; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects*; D020022:Genetic Predisposition to Disease; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D009367:Neoplasm Staging; D009503:Neutropenia / Q000139:chemically induced; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D012720:Severity of Illness Index; D013921:Thrombocytopenia / Q000139:chemically induced; D014633:Valine; D014839:Vomiting / Q000139:chemically induced
D000964:Antimetabolites, Antineoplastic; D009944:Organoplatinum Compounds; D001224:Aspartic Acid; D042943:Dihydrouracil Dehydrogenase (NADP); D014633:Valine; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin