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INTRODUCTION
Gastric cancer is one of the most common adult malignant
tumors. Gastric cancer is the fourth common type of cancer
and the second most frequent cause of death from cancer,
worldwide, with the highest incidence in China, Japan and
Eastern European countries (1). Cisplatin is commonly used
with 5-fluorouracil (5-FU) as chemotherapy doublets in the
treatment of advanced gastric cancer (2). During the last few
years additional drugs were introduced into chemotherapy
regimens for gastric cancer such as oxaliplatin, taxanes and
epirubicin. However, the response rates of these drugs or their
combinations were still less than 50% (3-5). One of the re-
maining challenges is the development of predictive marker
profiles to identify patients who will derive both minimal
toxicity and maximum benefit from certain chemotherapy.
There is a growing body of evidence suggesting that genetic
polymorphisms in genes involved in metabolism, signalling,
DNA-repair and cellular response pathways all contribute to
inter-patient variability of drug response and toxicity (6, 7).
Therefore, pharmacogenetic analyses appear to be a promis-
ing tool to develop individualized treatment plans. Individ-
ual chemotherapy based on pharmacogenetics and pharma-
cogenomics has shown a potentially predictive role to achieve
superior outcome in retrospective and perspective studies in
lung cancer (8, 9). However, little is known in gastric cancer
pharmacogenetics.
Oxaliplatin, carrying a 1,2-diamino-cyclohexane ring, leads
to platinum-DNA adducts, which are more cytotoxic than
adducts formed from other platinum agents and more effec-
tive at blocking DNA replication (10). With the wider use of
oxaliplatin in gastric cancer, predictive markers for clinical
outcome to this platinum agent may help to identify pro-
spectively those patients who are more likely to benefit from
the treatment. Resistance to platinum agents has been attri-
buted to enhanced tolerance to platinum DNA adducts, dec-
reased drug accumulation, or enhanced DNA repair (11). Vari-
able chemosensitivity to oxaliplatin may depend on detoxi-
fication pathways, including the glutathione S-transferase
(GST) family of isoenzymes (12, 13). Glutathione S-trans-
ferase P1 (GSTP1) is a member of a superfamily of dimeric
phase II metabolic enzymes that play an important role in
the cell defense system. GSTP1 directly participates in the
detoxification of platinum compounds and is an important
846
Qing-Fang Li, Ru-Yong Yao,
Ke-wei Liu, Hong-Ying Lv, Tao Jiang,
and Jun Liang
Treatment and Research Center of Oncology, The
Affiliated Hospital of Medical College of Qingdao
University, Qingdao, China
Address for Correspondence
Jun Liang, M.D.
Treatment and Research Center of Oncology, The
Affiliated Hospital of Medical College of Qingdao
University, Jiangsu Road 16, Qingdao 266003, China
Tel : +86-532-82911348, Fax : +86-532-82911999
E-mail : qfmy4812@sina.com
This work was supported in part by grants from
Shandong Province Natural Science Foundation
(Y2008C126).
J Korean Med Sci 2010; 25: 846-52 ISSN 1011-8934
DOI: 10.3346/jkms.2010.25.6.846
Genetic Polymorphism of GSTP1: Prediction of Clinical Outcome
to Oxaliplatin/5-FU-based Chemotherapy in Advanced Gastric Cancer
The aim of this study was to evaluate the predictive value of the polymorphism Glu-
tathione S-transferase P1 (GSTP1) Ile
105
Val on oxaliplatin/5-FU-based chemother-
apy in advanced gastric cancer. Patients with advanced gastric cancer accepted
oxaliplatin/5-FU-based chemotherapy as first-line chemotherapy were investigated.
GSTP1 Ile
105
Val polymorphism was detected by TaqMan-MGB probe allelic discrimi-
nation method. Response to treatment was assessed by disease controlled rate.
Time to progression, overall survival and toxicities were recorded. Final patient out-
comes were as follows: the allele frequencies of GSTP1 were
105
Ile/
105
Ile 52%,
105
Ile/
105
Val 41% and
105
Val/
105
Val 7%. For patients with
105
Ile/
105
Ile and those with at least
one
105
Val allele, disease control rate was 39% and 71% (P=0.026), respectively;
median time to progression was 4.0 and 7.0 months (P=0.002); median overall sur-
vival time was 7.0 and 9.5 months (P=0.002). Neurological toxicity was more fre-
quently occurred in patients with two
105
Ile alleles (P=0.005). In conclusion, patients
with at least one
105
Val allele have better prognosis and response to oxaliplatin/5-FU-
based regimen as first-line treatment for patients with advanced gastric cancer.
Key Words : Polymorphism; Glutathione S-Transferase pi; Oxaliplatin; Stomach Neoplasms
Received : 19 August 2009
Accepted : 23 November 2009
ⓒ2010 The Korean Academy of Medical Sciences.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial
License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use,
distribution, and reproduction in any medium, provided the original work is properly cited.
Polymorphism of GSTP1 as a Prediction of Clinical Outcome 847
mediator of both intrinsic and acquired resistance to platinum
(14). A single nucleotide substitution (A→G) at position
313 (resulting in replacing isoleucine with valine at codon
105) has been found to modify the enzyme’s activity and affin-
ity for electrophilic substrates (15). Previous studies showed
the expression level and the polymorphic Ile105Val of GSTP1
had linked with the sensitivity of cancer cells to platinum
(16). Clinical studies also have implicated GSTP1 as a pre-
dictive marker for clinical outcome in patients with cancer
treated with platinum-based chemotherapy (17, 18). How-
ever, the predictive values in advanced gastric cancer with
oxaliplatin-based chemotherapy are still not sufficient.
Given the further biochemical evidence that GSTP1 medi-
ates inactivation of platinum drugs, we analyzed the common
polymorphism in GSTP1-105 in patients with advanced gas-
tric cancer to determine whether the presence of the poly-
morphism is associated with clinical outcome to oxaliplatin/
5-FU-based first-line chemotherapy in Chinese population.
MATERIALS AND METHODS
Study subjects
From July 2006 to December 2008, 163 patients with ad-
vanced gastric cancer were treated at the Cancer Treatment
Center in the Affiliated Hospital of Medical College, Qingdao
University (China). The criteria for acceptance of the patients
were as follows: 1) all patients had bi-dimensionally measur-
able disease; 2) each participant had gastric adenocarcinoma
with stage IV disease, definitely diagnosed by histology; 3)
patients’ performance status was classified according to East-
ern Cooperative Oncology Group (ECOG) criteria, and each
patient’s ECOG status was not greater than 2; 4) patients had
not been treated with chemotherapy previously; 5) each par-
ticipant’s hemogram, hepatic function, renal function, and
electrocardiogram were normal before chemotherapy. Accord-
ing to the criteria mentioned-above, 92 patients were eligi-
ble for the study. All the 92 patients signed an informed con-
sent form before entering the study. Specimens (blood sam-
ples) of the patients were obtained before treatment.
Chemotherapy
All participants received the following oxaliplatin/5-FU-
based combination therapy regimen as first-line treatment.
All patients administered oxaliplatin plus 5-FU regimen once
every two weeks: oxaliplatin (Jiangsu Heng-rui Express, China;
H20040817) 85 mg/m2as a 2-hr infusion on day 1, and then
calcium folinate (Jiangsu Heng-rui Express) 200 mg/m2as
a 2-hr infusion on days 1-2, combined with bolus 5-FU (Tian-
jin Jin-yao Express, China; H12020959) 300 mg/m2and con-
tinuous infusion of 5-FU 600 mg/m2on days 1-2. Treatment
was continued until documented disease progression, unac-
ceptable toxic effects or patient’s refusal.
Clinical evaluation
All patients for analyses were required to have completed
at least four cycles of chemotherapy. Computed tomography
imaging was performed every 6 weeks. Objective response to
the treatment corresponded to a decrease in tumor burden
(the sum, over all measurable lesions, of the products of the
largest diameter and its perpendicular diameter) of 50% or
more for at least 6 weeks (partial response, or complete res-
ponse). And disease control includes complete response (CR),
partial response (PR) and stable disease (SD, ≤25% progres-
sion, <50% shrinkage) for at least 6 weeks. Progressive dis-
ease (PD) was defined as an enlargement in tumor burden of
25% or more (compared with the smallest measurement) or
appearance of new lesions. We calculated the disease control
rate (the percent of CR+PR+SD) to evaluate patients’ response
to chemotherapy. Time to progression (TTP) was calculated
from the time of initial treatment to disease progression. Over-
all survival (OS) was calculated from the time of initial treat-
ment to death or the last follow-up. Neuropathy was scored
according to the oxaliplatin-specific scale reported by Caus-
sanel et al. (19). On this oxaliplatin-specific scale, the grade
of cumulative neuropathy depends on the duration and inten-
sity of symptoms (grade 1, paresthesia, dysesthesia of short
duration; grade 2, paresthesia, dysesthesia persisting between
cycles; grade 3, paresthesia, dysesthesia causing functional
impairment; grade 4, paralysis). Other reliable adverse events
were evaluated using the National Cancer Institute-Common
Toxicity Criteria (NCI-CTC) version 2.0 (grade 1, mild adverse
event; grade 2, moderate adverse event; grade 3, severe and
undesirable adverse event; grade 4, life-threatening or dis-
abling adverse event).
DNA extraction and genotyping
Genomic DNA was isolated from 2 mL peripheral blood,
using Blood Genomic DNA Isolation Kit (Watson Biotech-
nologies, Inc., Taipei, Taiwan). The Ile105Val polymorphism
was analyzed with TaqMan genotyping assays, using the Roter-
gene real time 36-well polymerase chain reaction (PCR) sys-
tem (Gene Company Limited, Hong Kong, China). Probes,
primer and TaqMan universal PCR master mix were purchas-
ed from Applied Biosystems Inc. (ABI). The TaqMan assay
were performed in 25 mL reaction solution containing 1.25 mL
TaqMan SNP Genotyping Assay Mix (consisting of 20×mix
of unlabeled PCR primers and TaqMan MGB probe, FAM and
VIC dye-labeled), 12.5 mL PCR mixture reagent and 20 ng
genomic DNA. The polymerase chain reaction consisted of
an initial step at 95
℃
for 10 min and 48 cycles of denatur-
ing at 92
℃
for 15 sec and annealing 60
℃
for 1 min. SDS
allelic discrimination software provided by Gene Company
Limited was used for analysis of the PCR genotyping results.
848 Q.-F. Li, R.-Y. Yao, K.-W. Liu, et al.
30 randomly selected DNA samples were genotyped at least
twice to confirm the results.
Statistical analysis
Initially, disease controlled rate, time to progression, over-
all survival, and reliable toxicity were the end points consid-
ered in this analysis. Patients’ characteristics were compared
across genotypes using chi-square test. GSTP1 genotype dis-
tribution gained in the study was tested by the Hardy-Wein-
berg equilibrium law. The disease controlled rate were com-
pared by the chi-square test and Fisher exact test between the
patients with 105Ile/105Ile GSTP1 genotype and those with at
least one 105Val allele. The Cox proportional hazards model
was used to determine the association of TTP and OS with
the following baseline prognostic factors: histology, site of
tumor, number of metastatic sites, performance status, age
at enrollment of study, and gender. The odds ratio (OR) and
95% confidence intervals (95% CI) were calculated at the
same time. The log-rank test and Kaplan-Meier plots were
used to evaluate the association of overall survival and time
to progression with GSTP1 polymorphism. Treatment-relat-
ed toxicity was compared by the Mann-Whitney test between
the patients with GSTP1 wild genotype and patients with
GSTP1 mutant genotype at codon 105.
All Pvalues reported here were two-sided, and a probabil-
ity of 0.05 or smaller was considered statistically significant.
Statistical analyses were performed using SPSS software, Ver-
sion 16.0 (SPSS Inc., Chicago, IL, USA).
RESULTS
GSTP1 polymorphism
Ninety-seven percent (89/92) of the patients’ genetic poly-
morphism was determined successfully. GSTP1 genotype was
analyzed for 89 patients, of which 46 (52%) were homozy-
gous for the 105Ile/105Ile GSTP1 genotype, 37 (41%) were
heterozygous for 105Ile/105Val, and 6 (7%) were homozygous
for the 105Val/105Val. The allele frequency for the GSTP1 105Val
allele in our study was 48% (43/89). The allelic distribution
was in Hardy-Weinberg equilibrium (
c
2=0.156, P=0.692).
The 89 patients consisted of 25 females (28%) and 64 males
(72%), with a median age of 55 yr old (range 32 yr old to
77 yr old). No clear patterns for significant associations bet-
ween the polymorphism and any of the other demographic
(gender), clinical (performance status, site of the tumor, and
number of metastases), or pathological characteristics (tumor
differentiation) were observed (Table 1).
Response to chemotherapy
GSTP1-105 genotype analyses were successful for 89 pa-
tients of which 85 were eligible for response analyses. Four
patients withdrew from the study too early to evaluate their
response. The four patients refused to continue chemothera-
*Performance status was classified according to Eastern Cooperative
Oncology Group (ECOG) criteria.
GSTP1, Glutathione S-transferases P1.
GSTP1, Glutathione S-transferases P1; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease, OR, odds ratio; CI,
confidence intervals.
Characteristics
P
c
2
P
c
2
Chi-square test
GSTP1-
105
Ile/Ile (n)
GSTP1-105
Ile/Val+Val/
Val (n)
Sex 0.822 0.365
Male 35 29
Female 11 14
Age 2.449 0.294
≤44 5 10
45-59 23 19
>60 18 14
Site of tumor 2.613 0.455
Fundus 6 2
Body 14 18
Sinus 21 19
Other 5 4
Histology 0.182 0.670
Well/moderate 10 11
Poor 36 32
Number of metastasis 0.811 0.847
02019
11315
296
≥343
Performance status* 0.198 0.656
≤13837
=2 8 6
Table 1. Demographic, clinical, and pathological characteristics
compared between patients with different GSTP1 genotype
Response to treatment
Genotype
CR+PR+SD OR (95% CI)PD
Chi-square test Logistic regression analysis
P
GSTP1-105 Ile/Val+Val/Val 29 12 1.000
GSTP1-105 Ile/Ile 17 27 9.259 0.026 5.028 (1.750-14.446) 0.003
Table 2. Association between GSTP1 polymorphism and response to treatment
Polymorphism of GSTP1 as a Prediction of Clinical Outcome 849
py. The median cycles of chemotherapy were 5 cycles for the
remaining 85 patients. Among these 85 patients, 12 (14%)
of the patients showed PR, 34 (40%) SD, 39 (46%) showed
PD, and no patients showed CR. The association between the
response to treatment and the GSTP1 polymorphisms was
shown in Table 2.
Time to progression
The 85 patients mentioned-above were eligible for survival
analysis since the four patients took off study too early to eval-
uate their survival time. From July 2006 to April 2009, 83
patients (98%) were followed up, with a median follow-up
period of 11.6 months (range 3.5 to 23 months). The survival
time of the 2 patients who lost follow-up was treated as cen-
sored data.
Among the 85 patients, eighty-seven percent (74/85) of
the participants’ disease had progression during the follow-up
period. Then the TTP of the 9 patients without disease pro-
gression and the 2 patients with lost of follow up was censor-
ed. Compared with patients with a homozygous 105Ile/105Ile
GSTP1 genotype, patients with one or two 105Val alleles had
increased the median time to progression (MTTP). The MTTP
for patients with a homozygous 105Ile/105Ile GSTP1 genotype
was 4.0 months (95% CI 3.649-4.351), whereas that for pa-
Characteristics No.
OR (95% CI)
TTP
COX regression analysis
POR (95% CI)
OS
P
Sex
Female 23 1.000 1.000
Male 62 0.953 (0.529-1.714) 0.871 1.120 (0.584-2.145) 0.733
Age (yr) 0.123 0.318
≤44 15 1.000 1.000
45-59 40 0.458 (0.215-0.972) 0.042 0.559 (0.257-1.215) 0.142
≥60 30 0.570 (0.251-1.294) 0.179 0.685 (0.290-1.621) 0.390
Site of tumor 0.457 0.362
Fundus 7 1.000 1.000
Body 31 1.374 (0.518-3.647) 0.523 1.225 (0.458-3.276) 0.686
Sinus 39 1.208 (0.476-3.070) 0.690 1.465 (0.551-3.896) 0.444
Other 8 2.271 (0.724-7.127) 0.160 2.645 (0.809-8.644) 0.108
Histology
Well/moderate 20 1.000 1.000
Poor 65 1.582 (0.892-2.804) 0.117 2.134 (1.153-3.949) 0.016
Number of metastasis 0.153 0.010
0 36 1.000 1.000
1 27 1.080 (0.616-1.894) 0.788 1.446 (0.799-2.684) 0.242
2 15 1.753 (0.864-3.559) 0.120 2.428 (1.120-5.262) 0.025
≥3 7 2.717 (0.976-7.613) 0.058 5.088 (1.804-14.348) 0.002
Performance status*
≤1 71 1.000 1.000
=2 14 2.229 (1.096-4.534) 0.027 1.611 (0.775-3.351) 0.202
GSTP1-105 genotype
Ile/Val or Val/Val 1.000 1.000
Ile/Ile 2.359 (1.362-4.087) 0.002 2.268 (1.281-4.017) 0.005
Table 3. Association between patients’ characteristics and TTP, OS after oxaliplatin/5-FU-based chemotherapy
*Performance status was classified according to Eastern Cooperative Oncology Group (ECOG) criteria.
TTP, time to progression; OS, overall survival; OR, odds ratio; CI, confidence intervals; GSTP1, Glutathione S-transferases P1.
Fig. 1. Time to progression curves of patients with advanced gas-
tric cancer according to GSTP1 Ile105Val polymorphism.
Probability of time to progression
1.0
0.8
0.6
0.4
0.2
0.0
2.50 5.00 7.50 10.00 12.50
Time to progression (months)
GSTP1-105 lle/lle
P=0.002
GSTP1-105 lle/Val+Val/Val
Group
1
2
1-censored
2-censored
1, lle/lle
2, lle/Val+Val/Val
850 Q.-F. Li, R.-Y. Yao, K.-W. Liu, et al.
tients with one or two 105Val GSTP1 genotype was 7.0 months
(95% CI 5.360-8.640;
c
2=10.043, P=0.002) (Fig. 1).
The MTTP for all 85 patients was 5.3 months (95% CI
4.431-6.169). Homozygosity for 105Ile/105Ile GSTP1 genotype
was associated with a significantly increased risk of progres-
sion compared with at least one 105Val allele (OR 2.359; 95%
CI 1.362-4.087; P=0.002). Patients with a performance sta-
tus ECOG=2 showed an increased risk of progressing (P=
0.027) when compared with patients who showed a superi-
or performance status (ECOG 0-1). Age, sex, tumor histolog-
ic grade, metastases, as well as site of tumor was not associ-
ated with TTP in this series of patients (Table 3).
Overall survival time
Of the 85 patients, 14 patients were still alive. The survival
time of the 14 patients and the two patients with lost of fol-
low up was treated as censored data. The median overall sur-
vival (MOS) for patients with a homozygous 105Ile/105Ile GS-
TP1 genotype was 7.0 months (95% CI 5.137-8.863), where-
as that for patients with one or two 105Val GSTP1 genotype
was 9.5 months (95% CI 7.847-11.153;
c
2=9.223, P=0.002)
(Fig. 2).
The MOS for all 85 patients was 8.0 months (95% CI
6.623-9.377). Patients with 105Ile/105Ile genotype had a high-
er risk of death compared with patients with one or two 105Val
alleles (OR 2.268; 95% CI 1.281-4.017; P=0.005). Age,
sex, site of tumor, and performance status were not associat-
ed with patient survival. However, patients with more metas-
tases seemed to have a shorter survival time (P=0.010). Oth-
erwise, 65 patients with a poorly differentiated tumor also
tended to have a higher risk of death (P=0.016). The associ-
ation of demographic, clinical, and pathological characteris-
tics and clinical outcome was listed in Table 3.
Toxicity
All 85 patients were evaluated toxicity from the time of
initial chemotherapy to end of follow-up. No treatment-relat-
ed deaths occurred. The most common adverse events of the
treatment were hematological and neurological toxicity. Grade
3 or 4 cumulative peripheral neuropathy was significantly
more common in patients with 105Ile/105Ile GSTP1 genotype
(10 of 44 patients, 23%) compared with patients with 105Ile/
105Val or 105Val/105Val GSTP1 genotype (2 of 41 patients, 5%;
2=5.577, P=0.018). Meanwhile, the overall incidence of neu-
rological toxicity in patients with homozygous 105Ile/105Ile
GSTP1 genotype was significantly higher than that in patients
with one or two 105Val GSTP1 genotype (P=0.005) (Table 4).
DISCUSSION
We attempted to identify predictive genetic polymorphisms
for response and survival to oxaliplatin/5-FU chemotherapy
in patients with advanced gastric cancer. Our analysis of the
common polymorphism for the GSTP1 in patients with ad-
vanced gastric cancer demonstrates that relevant alteration
of a protein’s function can result in differences of defined clin-
ical endpoints. In this study, patients with at least one 105Val
allele had a better prognosis and response to the oxaliplatin/
5-FU-based regimen as first-line treatment for advanced gas-
tric cancer.
The identification of molecular variables that predict either
Adverse events
0 I II III IV
GSTP1-105 Ile/Ile
0 I II III IV
GSTP1-105 Ile/Val+Val/Val Mann-Whit-
ney test
P
Leucocytopenia 24 9 8 3 0 18 10 5 6 2 0.229
Neutrocytopenia 23 8 10 3 0 19 8 4 7 2 0.323
Thrombocytopenia 37 4 2 1 0 36 3 1 0 1 0.626
Erythrocytopenia 35 3 4 2 0 34 4 2 1 0 0.624
Nausea 14 15 12 3 0 18 10 11 2 0 0.399
Vomiting 22 11 9 2 0 21 11 8 1 0 0.807
Neurological toxicity 11 14 9 10 0 19 15 5 2 0 0.005
Table 4. Association between GSTP1 polymorphism and treatment-related toxicity
Fig. 2. Overall survival curves of patients with advanced gastric
cancer according to GSTP1 Ile105Val polymorphism.
Probability of survival
1.0
0.8
0.6
0.4
0.2
0.0
0.0 5.0 10.0 15.0 20.0 25.0
Overall survival time (months)
Group
1
2
1-censored
2-censored
P=0.002
GSTP1-105 lle/lle
GSTP1-105 lle/Val+Val/Val
GSTP1, Glutathione S-transferases P1.
1, lle/lle
2, lle/Val+Val/Val
Polymorphism of GSTP1 as a Prediction of Clinical Outcome 851
resistance or sensitivity to chemotherapy is of major interest
in selecting the most likely effective first-line treatment, avoid-
ing adverse side effects of a toxic but inactive therapy. Glu-
tathione S-transferases catalyze the first step in the formation
of mercapturic acids, initiating a pathway that results most-
ly in the elimination of toxic compounds. Previous studies
revealed that substitution of isoleucine with valine at codon
105 alters the function of the GSTP1 protein (20).
It is known that the allele frequencies of metabolic genes are
not equally distributed throughout the human population
but follow diverse ethnic and/or geographic-specific patterns.
An American population-based study reported, for GSTP1,
the prevalence rates of 105Ile/105Val heterozygosity and 105Val/
105Val homozygosity were found to be 30% to 51% and 7%
to 19%, respectively (15). For gastric cancer patients, a Chi-
nese study showed the rates of GSTP1 105Ile/105Val genotype
and 105Val/105Val genotype were 30.6% and 0% (21). In our
study, 41% of the participants were heterozygous for 105Ile/
105Val, and 7% were homozygous for the 105Val/105Val. This
frequency is similar to the frequencies above.
Stoehlmacher et al. (17) reported clinical response was not
statistically associated with GSTP1 genotypes in patients with
colorectal cancer. Ott et al. (18) reported GSTP1 genotypes
were not correlated with response to neoadjuvant chemother-
apy in gastric cancer. Cabelguenne et al. (22) could not observe
a correlation between GSTP1 genotypes and response to cis-
platin neoadjuvant chemotherapy in head and neck squamous
cell cancer (HNSCC) patients. While another study showed
patients possessing the GSTP1-105 Val/Val genotype showed
a significant superior response in gastric cancer (23). Our
results demonstrated patients with at least one 105Val allele
had a better disease control rate compared with patients with
homozygous 105Ile/105Ile genotype. There were some contro-
versial reports about the impact of GSTP1 on clinical res-
ponse, indicating that other potential factors may affect the
response to chemotherapy, such as ethnic background, geo-
graphic pattern or other potential genetic factors.
Our study suggested patients with GSTP1 105Val geno-
type had a better clinical outcome to oxaliplatin/5-FU-based
chemotherapy in advanced gastric cancer patients. GSTP1
Ile105Val polymorphism was studied widely in various tumors,
such as prostate cancer, colorectal cancer, breast cancer, eso-
phageal cancer and gastric cancer. Reports in colorectal can-
cer patients demonstrated a significantly improved time to
progression and overall survival for carriers of the GSTP1 105Val
allele after 5-FU/oxaliplatin chemotherapy (17, 24). Goekkurt
et al. reported that patients with GSTP1 105Val/105Val geno-
type demonstrated significant superior median survival time
after 5-FU/cisplatin chemotherapy for gastric cancer (23). In
the present study, we demonstrated that patients with two
105Ile alleles had a significantly increased risk of progression
and death. In summary, the results we report here are in strong
agreement with the current understanding of GSTP1 involve-
ment in platinum detoxification. Our findings support the
hypothesis that increased platinum sensitivity may in part
be due to impaired GSTP1 enzyme function.
Recent clinical reports provided evidence for an association
between GSTP1 genotype and cytotoxicity of chemothera-
peutic agents (25). A study reported that oxaliplatin-related
cumulative neuropathy scored grade 3 was significantly more
frequent in patients homozygous for the GSTP1 105Ile allele
than in patients homozygous or heterozygous for the GSTP1
105Val allele (OR 5.75; 95% CI 1.08-30.74; P=0.02) (26).
Another report showed Patients with GSTP1 105Ile/105Ile geno-
type had a higher risk of developing a grade >or =2 docetax-
el-induced peripheral neuropathy (25). Similarly, our study
implied patients with two GSTP1 105Ile alleles had a higher
risk of developing neurological toxicity, especially in grade 3
neuropathy. It was reported that individuals with two GSTP1
105Val alleles had a lower catalytic activity compared with indi-
viduals with two GSTP1 105Ile alleles (15). In particular, there
was in vitro evidence that GSTP1 105Val allele is much more
active than the wild-type alleles against cisplatin and carbo-
platin (27). Thus, the increasing rate of grade 3 neuropathy
in patients with 105Ile/105Ile GSTP1 genotype could be exp-
lained by the diminished capacity of detoxifying oxaliplatin.
And the involvement of GSTP1 in cellular apoptosis could
be another hypothesis to explain the protective effect of the
variant genotype.
In conclusion, we demonstrated that among patients with
gastric cancer who received 5-FU/oxaliplatin chemotherapy
as first-line treatment, those possessing the GSTP1 105Val
variant allele show a statistically significant benefit for both
time to progression and overall survival. Our results support
the hypothesis that the effects of chemotherapeutic drugs may
be altered when enzymes that could enhance the elimination
of these drugs show a reduced activity. However, more per-
spective multicentric randomized studies are required to con-
firm our preliminary results for patients with advanced gas-
tric cancer in Chinese population.
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