Role of genetic and nongenetic factors for fluorouracil treatment-related severe toxicity: a prospective clinical trial by the German 5-FU Toxicity Study Group.
OBJECTIVE
To assess the predictive value of polymorphisms in dihydropyrimidine dehydrogenase (DPYD ), thymidylate synthase (TYMS ), and methylene tetrahydrofolate reductase (MTHFR ) and of nongenetic factors for severe leukopenia, diarrhea, and mucositis related to fluorouracil (FU) treatment.


METHODS
A multicenter prospective clinical trial included 683 patients with cancer treated with FU monotherapy. Toxicity was documented according to World Health Organization grades. DPYD, TYMS, and MTHFR genotypes were determined, and DPYD was resequenced in patients with severe toxicity.


RESULTS
Grade 3 to 4 toxicity occurred in 16.1% of patients. The sensitivity of DPYD*2A genotyping for overall toxicity was 5.5% (95%CI, 0.02 to 0.11), with a positive predictive value of 0.46 (95% CI, 0.19 to 0.75; P = .01). Inclusion of additional DPYD variants improved prediction only marginally. Analysis according to toxicity type revealed significant association of DPYD with mucositis and leukopenia, whereas TYMS was associated with diarrhea. Genotype, female sex, mode of FU administration, and modulation by folinic acid were identified as independent risk factors by multivariable analysis. A previously unrecognized significant interaction was found between sex and DPYD, which resulted in an odds ratio for toxicity of 41.8 for male patients (95% CI, 9.2 to 190; P < .0001) but only 1.33 (95% CI, 0.34 to 5.2) in female patients. Homozygosity for the TYMS enhancer region double repeat allele increased risk for toxicity 1.6-fold (95% CI, 1.08 to 2.22; P = .02).


CONCLUSIONS
DPYD, TYMS, and MTHFR play a limited role for FU related toxicity but a pronounced DPYD gene/sex-interaction increases prediction rate for male patients. Toxicity risk assessment should include sex, mode of administration, and folinic acid as additional predictive factors.
Schwab
Matthias
M
Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, University of Stuttgart, Stuttgart, Germany.
Zanger
Ulrich M
UM
Marx
Claudia
C
Schaeffeler
Elke
E
Klein
Kathrin
K
Dippon
Jürgen
J
Kerb
Reinhold
R
Blievernicht
Julia
J
Fischer
Joachim
J
Hofmann
Ute
U
Bokemeyer
Carsten
C
Eichelbaum
Michel
M
D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects*; D019175:DNA Methylation; D003967:Diarrhea / Q000139:chemically induced / Q000209:etiology* / Q000235:genetics; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000235:genetics; D005260:Female; D005472:Fluorouracil / Q000009:adverse effects*; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D005858:Germany; D006720:Homozygote; D006801:Humans; D002955:Leucovorin / Q000009:adverse effects; D007970:Leukopenia / Q000139:chemically induced / Q000209:etiology* / Q000235:genetics; D016015:Logistic Models; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics; D052016:Mucositis / Q000139:chemically induced / Q000209:etiology* / Q000235:genetics; D016017:Odds Ratio; D018579:Patient Selection; D011110:Polymorphism, Genetic; D011237:Predictive Value of Tests; D011401:Promoter Regions, Genetic; D011446:Prospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D012720:Severity of Illness Index; D013940:Thymidylate Synthase / Q000235:genetics; D014803:Vitamin B Complex / Q000009:adverse effects
D000964:Antimetabolites, Antineoplastic; D014803:Vitamin B Complex; D042943:Dihydrouracil Dehydrogenase (NADP); D042965:Methylenetetrahydrofolate Reductase (NADPH2); D013940:Thymidylate Synthase; D002955:Leucovorin; D005472:Fluorouracil