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2009 14:21 Uhr Seite 724

Original article S W I S S M E D W K LY 2 0 0 9 ; 1 3 9 ( 4 9 – 5 0 ) : 7 2 4 – 7 2 8 · w w w . s m w . c h 724

Peer reviewed article

Genetic polymorphisms of GSTP1 related

to response to 5-FU-oxaliplatin-based
chemotherapy and clinical outcome in
advanced colorectal cancer patients
Liang Jun, Zhang Haiping, Yin Beibei
Department of Oncology, The Affiliated Hospital of Medical College, Qing Dao University, Qingdao,
P. R. China

Summary
Objective: To determine whether genetic poly- 60.0% compared to 25.89% in patients harboring
morphisms of GSTP1 Ile105Val (A→G) predict at least one GSTP1-105 Ile allele (p = 0.032).
chemosensitivity and clinical outcome in patients GSTP1-105 Val/Val patients demonstrated a sig-
with advanced colorectal cancer, treated by 5-FU/ nificant superior median survival time of 20.4
oxaliplatin-based chemotherapy. months (95% CI: 11.85 to 28.95) compared to 6.5
Methods: In this retrospective study, the popu- months (95% CI: 4.26 to 8.74) in patients with
lation consisted of 122 advanced colorectal cancer 105 Ile/Ile genotype and 10.3 months (95% CI:
patients (III stage 51, IV stage 71). Patients were 7.05 to 13.55; p <0.01) in patients with GSTP1
treated with 5-FU-oxaliplatin-based chemother- 105 Ile/Val genotype.
apy, and their response was evaluated after at least Conclusion: The GSTP1 105Val/105Val geno-
two cycles of treatments; all patients (122) were type is associated with a higher clinical response
evaluated for median survival time (MST). rate to oxaliplatin-based chemotherapy and with
GSTP1 genotypes were detected by TaqMan- increased survival of patients with advanced colo-
MGB probe methods. rectal cancer, receiving 5-FU/oxaliplatin chemo-
Results: 75 patients (61.47%) were Ile/Ile therapy.
genotype, 10 (8.2%) were Val/Val genotype, and
37 (30.33%) were Ile/Val genotype. Patients Key words: colorectal neoplasms/genetics; polymor-
possessing the glutathione S-transferase P1-105 phisms; alleles; oxaliplatin/drug therapy; Glutathione
Val/Val genotype showed a response rate of S-transferase P1/genetics

Introduction
Pharmacogenetics is becoming an increas- zymes determine the cytotoxicity of a variety of
ingly important field in the study of cancer chemotherapeutic drugs. The mammalian cytosolic
chemotherapy. Genetic factors affecting the me- GSTs are divided into five subfamilies (Alpha, Mu,
tabolism and transport of drugs partly explain Pi, Theta and Zeta) on the basis of similarity in pri-
inter-individual variability in drug response, both mary structure [1]. The subclass GSTP1 is widely
in terms of efficacy and safety. Polymorphisms in expressed in normal human epithelial tissues and
genes encoding specific drug-metabolizing en- has been shown to be highly over-expressed in
zymes can result in individuals in the general pop- colon cancer [2]. Drug-resistant tumors were found
ulation being characterized as low, rapid, or even to contain increased levels of GSTP1. GSTP1 di-
ultrarapid metabolizers. One of the remaining rectly participates in the detoxification of platinum
challenges is to identify markers that dramatically compounds and is an important mediator of both
influence clinical outcome to specific chemother- intrinsic and acquired resistance to platinum [3]. A
apeutic agents. single nucleotide substitution (A→G) at position
The glutathione S-transferase (GST) family 313 of the GSTP1 gene, which results in replacing
consists of a group of important drug-metabolizing isoleucine with valine, substantially diminishes
No conflict of enzymes that catalyze the conjugation of reduced GSTP1 enzyme activity [4].
interest in relation
to this article.
glutathione with a variety of electrophilic com- Oxaliplatin is an innovative, third-generation,
pounds. Growing evidence indicates that GST en- platinum compound with powerful antineoplastic
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competence, a lack of cross drug resistance with cancer [7, 8], and the preliminary results of several
cisplatin, a synergistic effect with 5-FU, and a sat- recent studies indicate that various combinations
isfactory safety profile [5, 6]. Oxaliplatin is an of oxaliplatin and 5-FU may be as effective in gas-
alkylating agent that inhibits DNA replication by tric cancer [9–11]. Given the biochemical evi-
forming adducts between adjacent guanines or dence that GST mediates inactivation of plat-
guanine and adenine. Moreover, these oxaliplatin inum drugs, this study retrospectively analyzed
adducts appear to be more effective than those of the common polymorphisms of GSTP1 gene in
cisplatin with regard to inhibiting DNA synthesis. 122 previously treated patients with metastatic
In addition, oxaliplatin has a more favorable toxi- colorectal cancer, to determine whether the pres-
city profile than cisplatin. The oxaliplatin/5-FU ence of polymorphisms is associated with the clin-
combination has proven to be an effective first- or ical outcome to 5-FU/oxaliplatin chemotherapy.
second-line treatment for advanced colorectal

Subjects and methods

Eligible subjects and chemotherapy PCR mixture contained DNA 20 ng, 12.5 μl Taqman
134 patients with advanced colorectal cancer en- Universal PCR Master Mix (Applied Biosystems, Foster
rolled in this study and were treated between January City, CA, USA), 1.25 μl 20 Taqman SNP Genotyping
2006 and March 2008, at the Oncology Department of Assay Mix (Applied Biosystems, Foster City, CA, USA),
the Affiliated Hospital, Medical College, Qingdao Uni- 9.25 μl ultrapure water. The PCR conditions were as fol-
versity. Eligibility criteria for patient recruitment in- lows: 95 °C for 10 min, followed by 40 cycles at 92 °C for
cluded histological confirmation of advanced colorectal 15s, 60 °C for 1 min, 72 °C for 1 min, followed by 1 cycle
cancer and less than two prior other chemotherapy regi- at 72 °C for 7 min. Sequences of primers and probes were
mens. The ethnic backgrounds were all Chinese Han designed by Applied Biosystems (Lot Number 480524
nationality. Patients’ performance status was classified Assay ID c-622564-10). The DNA extraction and the
according to Eastern Cooperative Oncology Group genotyping success rate were 93.3% (125 cases) and
(ECOG) criteria; eligible patients were required to have 98.4% (123 cases) respectively. A minimum of 32 ran-
an ECOG Status 0 to 2 and an estimated life expectation domly selected DNA samples was genotyped at least
of at least eight weeks. All participants gave their written twice to confirm the results. Discrepancies were seen in
informed consent prior to entering the study. Patients one of the samples. Those with discordant results from
were required to have bi-dimensionally measurable dis- two analyses were excluded from the final data analysis.
ease at the time of protocol entry. To evaluate response to
therapy, response evaluation was assessed according to Statistical analysis
Response Evaluation Criteria in Solid Tumours (RE- The purpose of this analysis was to evaluate the asso-
CIST) criteria. 95 cases were administered with modified ciation between the polymorphisms and demographic
FOLFOX4 regiment and 39 with Xelox regiment. The data, pretreatment characteristics, response to chemo-
modified FOLFOX4 chemotherapy consisted of oxali- therapy and survival time. The clinical data and speci-
platin 130 mg/m2 as a 2-hour intravenous drip infusion mens were evaluated retrospectively. Survival was calcu-
on day 1, followed by infusion of 5-fluorouracil 300 lated as the time from the start of treatment until death
mg/m2, leucovorin 130 mg/m2, respectively on day 1 to 5. from any cause, or until last contact if the patient was
Xelox regiment consisted of oxaliplatin 130 mg/m2 as a 2- known to be alive. Patients who were alive at the last fol-
hour intravenous drip infusion on day 1, plus capecitabine low-up or who were taken out of the study or who died
for oral use at a dose of 1250 mg/m2/day in two divided before progression, were censored at the time that they
doses on day 1 to 14 of each 3-week cycle. were taken out of the study. Contingency tables and
Fisher’s exact test were used for the categorical variables
Genotyping to evaluate the association of the expression of markers
Blood samples were obtained from each patient be- and the response to chemotherapy, where appropriate.
fore chemotherapy for DNA isolation and determination The log-rank test and Kaplan-Meier plots were used to
of genotypes. DNA was extracted from these samples evaluate the association of genotypes and overall survival.
using Blood Genomic DNA Isolation Kit (ShangHai, Also the Cox proportional hazards model, after adjust-
Watson). GSTP1 Ile105Val polymorphisms were as- ment for patients’ clinical characteristics, was performed.
sessed by nuclease allelic discrimination assay (TaqMan- Statistical analyses were carried out using SPSS for Win-
MGB) using fluorescent temperature cycler (Rotor-Gene dows (Version 13.0). All p values cited were two-sided and
3000A Real Time PCR System, Australia). Briefly, the 25 μl p values <0.05 were judged as statistically significant.

Results
Patient characteristics extraction or failure with genotyping. Character-
In the end, 122 of 134 patients registered istics of the 122 eligible patients are listed in
from January 2006 to March 2008 were eligible table 1. These patients included 56 (45.91%)
for further data analysis in this study. The 12 women and 66 (54.09%) men. The median age
dropouts were either because of failure with DNA was 58 years (range 34–80 years).
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Genetic polymorphisms of GSTP1 related to response to 5-FU-oxaliplatin-based chemotherapy 726

GSTP1 genotyping Association among GSTP1-105 polymor-

GSTP1 genotype was assessed for 122 pa- phisms, chemotherapy response and survival
tients, of which 10 (8.20%) were homozygous For association analysis of genotype and re-
for the 105Val/105Val GSTP1 genotype, 37 sponse to chemotherapy, patients with complete
(30.33%) were heterozygous (105Ile/105Val), and disappearance of the disease (CR) and at least
75 (61.47%) were homozygous for the 105Ile/ 50% reduction in tumor load of the lesions (PR)
105Ile GSTP1 genotype. The genotype frequen- were determined “responders”. Patients with sta-
cies of the GSTP1 105 Ile→Val variation were in ble disease (≤25% progression, <50% shrinkage,
Hardy-Weinberg equilibrium. The current ob- SD) and cancer progression (size enlargement
served allele frequency for the GSTP1 105 Val al- >25% or appearance of new lesions, PD) were re-
lele was 0.23 (57/244) and was similar to previous ferred to as ‘nonresponders’. Patients were also
findings which report that frequency in healthy divided into a favorable (homozygous GSTP1-
Chinese and in colorectal cancer patients. No as- 105Val) and an unfavorable genotype group (het-
sociation was observed between the demographic erozygous and homozygous GSTP1-105Ile) ac-
characteristics of the study participants (age, cording to their genotypes. Of 122 patients, those
gender) and the GSTP1 genotypes. Pathologic possessing the GSTP1-105 Val/Val genotype
(differentiation, number of metastases, site of showed a significantly superior response rate of
metastasis) characteristics were not statistically 60.0% (6/10) compared to only 25.89% (29/112)
associated with GSTP1 genotypes. in patients harboring at least one GSTP1-105 Ile
allele (P = 0.032, Fisher’s exact test) (table 2).
Compared with patients with one or two 105 Ile
Table 1 Characteristics Cases (%)
alleles, patients with a homozygous 105Val/
Characteristics Gender
of 122 colorectal 105Val GSTP1 genotype had an increased sur-
cancer patients. Male 66 (54.09%) vival time, with a median survival time of 20.4
Female 56 (45.91%) months (95% confidence interval (CI): 11.85 to
Median age (range) 58 (34–80) 28.95). Meanwhile, the median survival time
≤50 24 (19.67%)
for patients with a homozygous 105Ile/105Ile
GSTP1 genotype was 6.5 months (95% CI: 4.26
51–69 68 (55.72%)
to 8.74), whereas for patients with a heterozygous
≥70 30 (24.51%)
105Ile/105Val GSTP1 genotype was 10.3 months
Original tumor site (95% CI: 7.05 to 13.55). The log-rank test re-
Colon 52 (42.62%) sulted in significant p values of 0.008 (χ2 = 9.56,
Rectum 70 (57.18%) with Ile/Ile and Ile/Val as separated group, fig. 1)
Differentiation
and 0.007 (χ2 = 7.38, with Ile/Ile and Ile/Val as a
combined group, fig. 2), respectively. In the Cox
Well-differentiated 12 (9.82%)
proportional hazards model, adjusted for stage,
Moderately differentiated 68 (55.72%)
Poorly differentiated 42 (34.46%) Figure 1

Stage Association between GSTP1-105 genotypes (Ile/Ile and

Ile/Val as separated group) and overall survival in patients
IIIA 32 (26.24%) with metastatic colorectal cancer receiving 5-FU/oxaliplatin
chemotherapy. The vertical hash marks denote the time of
IIIB 19 (15.57%)
last follow-up for those patients who were still alive at the
IV 71 (58.19%) time of the data analysis.

PS score Survival Functions

genotypes
0~1 79 (64.75%) 1.0
Val/Val
Ile/Val
2 43 (34.25%) Ile/Ile
0.8 Val/Val-consored
Ile/Val-consored
Chemotherapy regimens Ile/Ile-consored
Cum survival

L-OHP+CF+5-Fu 89 (72.96%) 0.6

L-OHP+Xeloda 33 (27.04%)
0.4
Number of organs involved
0.2
1 48 (39.34%)
2 31 (25.41%) 0.0
3 40 (32.79%) 0.0 5.0 10.0 15.0 20.0 25.0 30.0
4 3 (2.46%) time

Table 2 Ile 105 Val Genotypes Case [n (%)] Chi-Square Test Cox regression analysis
Response to Responder Non responder c2 p HR 95%CI
chemotherapy
according to GSTP1 Val/Val 6 (60.0%) 4 (40.0%)
genetic poly-
5.22 0.032 3.42 1.076–10.85
Ile/Ile+Ile/Val 29 (25.89%) 83 (74.11%)
morphisms.
Total 35 (28.69%) 87 (71.31%)
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Figure 2
Survival Functions
performance status, and chemotherapy regimen,
Association between
genotypes
GSTP1 Ile/Ile and Ile/Val genotypes were both
GSTP1-105 genotypes 1.0
(Ile/Ile and Ile/Val as a
Val/Val
Ile/Val+Ile/Ile
genetic factors significantly associated with an in-
combined group) and 0.8
Val/Val–consored
Ile/Val+Ile/Ile– creased risk of dying (HR = 4.89; 95% CI,
overall survival in pa- consored
1.51~15.84; and HR = 2.28; 95% CI, 0.69~7.52,
tients with metastatic
respectively).
Cum survival
colorectal cancer 0.6
receiving 5-fluo-
rouracil/oxaliplatin 0.4
chemotherapy. The
vertical hash marks
denote the time of 0.2
last follow-up for
those patients who 0.0
were still alive at the
time of the analysis 0.0 5.0 10.0 15.0 20.0 25.0 30.0
time
of the data.

Discussion
In this retrospective study, it was observed that breast cancer patients, although there is no direct
among colorectal cancer patients who received F- evidence of GSTP1 in relation to survival, in their
FU/oxaliplatin-based chemotherapy, those pos- study. It seems that GSTP1, through the Ile→Val”
sessing the GSTP1 105 Val variant allele showed polymorphisms, may reduce its effect on the inac-
statistically significant increased sensitivity of can- tivation of toxic and carcinogenic electrophones.
cer to 5-FU/oxaliplatin-based chemotherapy and The opposite results related to survival in colorec-
reduction in the risk of dying, and the trends in- tal cancer patients may be due to the different char-
creased with the number of GSTP1 105 Val alleles. acteristics of patients included in the two studies.
These results were independent of other clinical or Oxaliplatin, like cisplatin, is inactivated by be-
pathologic prognostic markers such as tumor dif- ing reacted with glutathione, a reaction catalyzed
ferentiation, performance status, and side of tumor by GST. Few biochemical studies and clinical re-
location. Thus the authors may postulate that ports provide strong evidence of the direct in-
GSTP1 may be a key player in the metabolism of volvement of GSTP1 in resistance to platinum
5-FU/oxaliplatin-based regimen. compounds. GSTP1, however, is directly involved
The GSTP1 enzyme can mediate the detoxifi- in the detoxification of cisplatin via the formation
cation of numerous chemicals including of cisplatin-glutathione adducts, which indicates
chemotherapy agents. Recent experiments from that GSTP1 plays a role in the acquisition of re-
some laboratories [12] suggest that the 105Val al- sistance to this platinum compound [16]. Clinical
lele was associated with lower GSTP1 enzyme ac- reports on head and neck cancers also reflect the
tivity in colorectal cancer tissue samples. Increased important role of GSTP1 enzymes in the metabo-
expression of GSTP1 in tumors has been hypoth- lism of platinum drugs [17]. The majority of pa-
esized to play a role in the drug resistance seen in tients who showed low GST protein expression lev-
many cancers, and this phenomenon has been ob- els in tumor tissues responded to a platinum-based
served in cancers of the breast, head and neck, and treatment and showed better survival than patients
skin and in acute leukemia [13]. Stoehlmacher et al. with high GSTP1expression levels.
[14] demonstrated that the GSTP1 Ile→Val poly- Due to GSTP1’s potential role in detoxifying
morphisms was associated in a dose-dependent carcinogenic compounds, it is plausible that indi-
manner with increased survival of patients with ad- viduals with GSTP1 105 Val alleles may be at in-
vanced colorectal cancers receiving 5-FU/oxali- creased risk of cancer from exposure to chemicals
platin chemotherapy. They suggest that the effect detoxified by the GSTP1 enzyme.Harries et al.[18]
of certain chemotherapeutic drugs might be altered found an association between GSTP1 105 Val ho-
when enzymes that could enhance the elimination mozygosity and a risk of bladder and testicular can-
of these drugs show a reduced activity. cers, but they observed no statistically significant
In contrast, other studies found that patients association with breast cancer risk. The study by
with GSTP1 Val-type had a worse prognosis than Harries et al. compared a cancer case patient series
the patients with GSTP1 Ile-type, even after ad- with an infirmary-based control group and pro-
justment for gender, age, tumor location, Dukes’ vided no information on basic characteristics of the
stage and differentiation. A study in breast cancer control groups such as age and sex. In a study of men
found that a significantly higher proportion of with lung cancer, hydrophobic DNA adduct levels
breast cancer patients with a GSTP1 Val-type had were higher among the patients with the GSTM1
more frequency of p53 mutations and loss of het- null genotype who were heterozygous or homozy-
erozygosity at the TP p53 gene locus, compared gous for the 105 Val GSTP1 allele [19]. Le Morvan
with GSTP1 Ile-type [15]. It has been widely ac- et al. and Kweekel et al. reported that GSTP1
cepted that altered p53 predicts a poor prognosis in codon 105 polymorphism is not associated with ox-
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Genetic polymorphisms of GSTP1 related to response to 5-FU-oxaliplatin-based chemotherapy 728

aliplatin efficacy or toxicity, in advanced colorectal A recent report also points to the importance of
cancer patients [20, 21].Thus, future investigations GSTP1 in the metabolism of TLK286, a promis-
would benefit from stronger study designs. ing new anticancer agent [22]. The current study
Clinical studies have implicated GSTP1 as a suggests that GSTP1 genotyping of individual
predictive marker for clinical outcome in cancer colorectal cancer patients might contribute to
patients treated with platinum-based chemother- improving therapy planning. However, only a rel-
apy. Results from the current study support the pre- atively small number of patients were evaluated,
dictive value of GSTP1 in platinum-based who all received an identical platinum-based
chemotherapy, but biochemical studies are needed chemotherapy. Furthermore, an association be-
to definitively demonstrate that GSTP1 is directly tween the GSTP1 genotype and the response to
involved in the detoxification of oxaliplatin. More- chemotherapy could not be determined conclu-
over, the patients in the current study received sively. Additionally, we did not evaluate the toxic-
combination chemotherapy of 5-FU and oxali- ity data for the difficulties of extracting the data di-
platin. Although strong biochemical evidence is rectly from patients’ files. Therefore, this data
lacking for a detoxification of 5-FU by GSTP1, should be considered as preliminary results, and
from the current study we cannot attribute the ben- randomized clinical trials with different treatment
eficial effect of reduced GSTP1 function to an al- arms are needed to confirm a survival benefit for
teration of the activity of the platinum compound patients who possess the 105Val/105Val GSTP1
alone. genotype and who are being treated with platinum
In recent years, a growing number of novel drugs.
anticancer agents for the treatment of colorectal
cancer have been developed. Oxaliplatin is one ex-
ample. Coupled with the variety of options, the Correspondence:
ability to identify patients who will be more sensi- Liang Jun M.D.
tive or resistant to a specific chemotherapeutic Department of Oncology
agent carries important clinical implications. Ge- The Affiliated Hospital of Medical College
netic profiles of individual cancer patients have the Qing Dao University, CN – Qingdao 266003
potential to aid in making treatment decisions. E-Mail: [email protected]

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