Pharmacogenetic analyses of hematotoxicity in advanced gastric cancer patients receiving biweekly fluorouracil, leucovorin, oxaliplatin and docetaxel (FLOT): a translational study of the Arbeitsgemeinschaft Internistische Onkologie (AIO).
BACKGROUND
Docetaxel-based chemotherapy regimens have demonstrated activity in advanced gastric cancer (AGC). However, a high rate of grade 3/4 hematotoxicity was reported with these regimens. Our purpose was to identify pharmacogenetic markers with potential to detect patients with increased risk to encounter severe hematotoxicity following treatment with 5-fluorouracil, leucovorin, oxaliplatin and docetaxel (FLOT).


METHODS
Polymorphisms of genes involved in DNA repair, drug transport and metabolism were determined in 50 AGC patients receiving FLOT within a phase II trial. DNA was extracted from peripheral blood. Genotyping was carried out using PCR-based techniques.


RESULTS
Patients possessing TS-group A genotypes (2R/2R, 2R/3RC, 3RC/3RC) were at increased risk for grade 3/4 hematotoxicity compared with patients harboring a TS-group B genotype (2R/3RG, 3RC/3RG, 3RG/3RG). In all, 59% (20 of 34) of patients with TS-group A genotypes developed grade 3/4 hematotoxicity compared with 25% (4 of 16) of those having TS-group B genotypes (P=0.035). Grade 3/4 neutropenia occurred in 53% (18 of 34) of TS-group A patients compared with 19% (3 of 16) in TS-group B patients (P=0.032). Multivariate analyses identified TS-group A genotypes as significant predictors of grade 3/4 overall hematotoxicity {odds ratio (OR) 4.62 [95% confidence interval (CI) 1.22; 17.44], P=0.024} and neutropenia [OR 5.74 (95% CI 1.03; 32.08), P=0.047].


CONCLUSIONS
TS-promoter polymorphisms may be associated with hematotoxicity in AGC patients receiving FLOT.
Goekkurt
E
E
Department of Internal Medicine I, University Hospital Carl Gustav Carus, University of Dresden, Dresden, Germany.
Al-Batran
S-E
SE
Mogck
U
U
Pauligk
C
C
Hartmann
J T
JT
Kramer
M
M
Jaeger
E
E
Ehninger
G
G
Stoehlmacher
J
J
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D001483:Base Sequence; D017931:DNA Primers; D004260:DNA Repair; D000077143:Docetaxel; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage; D009503:Neutropenia / Q000139:chemically induced*; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D000077150:Oxaliplatin; D010597:Pharmacogenetics; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D043823:Taxoids / Q000008:administration & dosage
D017931:DNA Primers; D009944:Organoplatinum Compounds; D043823:Taxoids; D000077150:Oxaliplatin; D000077143:Docetaxel; D002955:Leucovorin; D005472:Fluorouracil