Pharmacogenetic profiling and clinical outcome of patients with advanced gastric cancer treated with palliative chemotherapy.
OBJECTIVE
To investigate whether polymorphisms with putative influence on fluorouracil/cisplatin activity are associated with clinical outcomes of patients with advanced gastric cancer (AGC).


METHODS
Peripheral blood samples from 175 prospectively enrolled AGC patients treated with fluorouracil/cisplatin palliative chemotherapy were used for genotyping 13 polymorphisms in nine genes (TS, MTHFR, XPD, ERCC1, XRCC1, XRCC3, GSTPI, GSTTI, GSTMI). Genotypes were correlated to response and survival.


RESULTS
The overall response rate was 41%, the median progression-free survival (PFS) was 24 weeks (range, 4 to 50 weeks), and the median overall survival (OS) was 39 weeks (range, 8 to 72+ weeks). Chemoresistance and poor survival were significantly associated with TS 5'-UTR 3G-genotype (2R/3G, 3C/3G, 3G/3G) and GSTP1 105 A/A homozygous genotype. Sixty-one patients (35%) did not show any of these risk genotypes (group 0), 57 patients (32.5%) showed one of the two risk genotypes (group 1), and 57 patients (32.5%) showed both risk genotypes (group 2). Median PFS and OS in group 0 patients were 32 weeks (range, 8 to 50 weeks) and 49 weeks (range, 18 to 72+ weeks), respectively. Group 1 and group 2 patients showed significantly worse PFS (median, 26 weeks [range, 6 to 44 weeks] and 14 weeks [range, 4 to 38 weeks], respectively) and worse OS (median, 39 weeks [range, 10 to 58 weeks] and 28 weeks [range, 8 to 56 weeks]), respectively, than group 0 patients. This adverse effect was retained in multivariate analysis.


CONCLUSIONS
Specific polymorphisms may influence clinical outcomes of AGC patients. Selecting palliative chemotherapy on the basis of pretreatment genotyping may represent an innovative strategy that warrants prospective studies.
Ruzzo
Annamaria
A
Medical Oncology Unit, Hospital of Urbino, Urbino, Italy.
Graziano
Francesco
F
Kawakami
Kazuyuki
K
Watanabe
Go
G
Santini
Daniele
D
Catalano
Vincenzo
V
Bisonni
Renato
R
Canestrari
Emanuele
E
Ficarelli
Rita
R
Menichetti
Ettore Tito
ET
Mari
Davide
D
Testa
Enrica
E
Silva
Rosarita
R
Vincenzi
Bruno
B
Giordani
Paolo
P
Cascinu
Stefano
S
Giustini
Lucio
L
Tonini
Giuseppe
G
Magnani
Mauro
M
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use*; D016022:Case-Control Studies; D002945:Cisplatin / Q000008:administration & dosage; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D010166:Palliative Care; D018579:Patient Selection; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D011379:Prognosis; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D016019:Survival Analysis
D002945:Cisplatin; D005472:Fluorouracil