Cancer Chemother Pharmacol DOI 10.1007/s00280-012-2067-8
ORIGINAL ARTICLE
XRCC1 and GSTP1 polymorphisms and prognosis of oxaliplatin-based chemotherapy in colorectal cancer: a meta-analysis Fanghui Ye • Zhenfang Liu • Aihua Tan • Ming Liao • Zengnan Mo • Xiaobo Yang
Received: 10 November 2012 / Accepted: 19 December 2012 Ó Springer-Verlag Berlin Heidelberg 2013
Abstract Purpose Genetic variations are related to individual differences of DNA repair ability and drug metabolism, which can greatly influence prognosis of antineoplastic agents, such as oxaliplatin. The aim was to explore the influences of X-ray repair cross-complementing 1(XRCC1) and Glutathione S-transferase P1 (GSTP1) genetic variants on prognosis of oxaliplatin-based chemotherapy in colorectal cancer patients. Methods We performed a meta-analysis including 13 original studies with a total number of 1,234 patients in advanced or metastatic colorectal cancer. Tumor responses [complete response, partial response, stable disease (SD)
The authors Fanghui Ye and Zhenfang Liu contributed equally to this work. F. Ye A. Tan M. Liao Z. Mo X. Yang (&) Center for Genomic and Personalized Medicine, Guangxi Medical University, Nanning 530021, Guangxi, China e-mail:
[email protected] Z. Liu Department of Hematology, The First Affiliated Hospital, Guangxi Medical University, Nanning, Guangxi, China A. Tan Department of Chemotherapy, The Affiliated Tumor Hospital, Guangxi Medical University, Nanning 530021, Guangxi, China Z. Mo Institute of Urology and Nephrology, The First Affiliated Hospital, Guangxi Medical University, Nanning, Guangxi, China X. Yang Department of Occupational Health and Environmental Health, School of Public Health, Guangxi Medical University, Nanning, Guangxi, China
and progressive disease (PD)] and progression-free survival were estimated. Results Our results showed that XRCC1 Arg399Gln polymorphism was significantly associated with tumor chemotherapy when SD or PD was considered as nonresponse [risk ratio (RR) = 1.29; 95 % confidence intervals (CI): 1.05–1.60; P = 0.02]. No significant association was found between GSTP1 Ile105 Val polymorphism and tumor response (RR = 0.63; 95 % CI: 0.35–1.14; P = 0.13). In addition, our results also showed that there was no significant association between XRCC1 codon 399 Arg/Gln or Gln/Gln genotypes and hazard ratio for progression-free survival (Hazards ratio = 1.04 and 1.92; 95 % CI: 0.75–1.43 and 0.62–1.37; P = 0.826 and 0.677, respectively). Conclusion In our meta-analysis, XRCC1 Arg399Gln polymorphism may be a valuable genetic marker for oxaliplatin-based chemotherapy in colorectal cancer, and the results still need further confirmation. Keywords Oxaliplatin Colorectal cancer XRCC1 GSTP1 Genetic polymorphisms
Introduction Pharmacogenetics play an important role in the cancer chemotherapy today, and its prognosis can be explained with the genetic background or individual influence [11]. In the term of associations between cancer prognosis and genetic markers, they are still regarded as great challenges to explore in the field of tumor chemotherapy sensitivity. The widely used antineoplastic agent oxaliplatin mainly makes a contribution to inhibit the DNA replication caused by the formed DNA damage or macromolecular adducts.
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For colorectal cancer, the success of oxaliplatin chemotherapy was remarkable either in advanced colorectal cancer (aCRC) or metastatic colorectal cancer (mCRC) [5, 23]. However, the drug resistance related to genetic variations is now one of the main causes of treatment failure [11, 12, 23, 25]. It is expected that the pharmacogenetic markers may benefit individual cancer patients in prognosis [1]. X-ray repair cross-complementing 1(XRCC1) gene repairs single-strand breaks by encoding a protein that defends breaks while repairs base excision by interacting with specific enzymes [16, 19]. The DNA replication inhibition caused by oxaliplatin chemotherapy could be influenced by XRCC1 variations because XRCC1Arg399Gln polymorphism in exon 10 can lead to the decreased DNA repair activity [17]. Previous studies reported that it is a notable impact on prognosis in oxaliplatin-based chemotherapy [8, 16, 22], especially when the Arg399Gln polymorphism exists in the genomic region [22]. Meanwhile, Glutathione S-transferase P1 (GSTP1) gene plays a crucial role in detoxification in cell [20, 27] and Ile105 Val polymorphism in exon 5 leads to the decreased activity [7], and GSTP1 was also identified as a mediator of the resistance to platinum by protecting cells from the damage [23]. The strength of DNA repair as well as the drug metabolism will influence the efficacy of oxaliplatin chemotherapy due to resistance [1]. Though previous studies have demonstrated the XRCC1 Arg399Gln and GSTP1 Ile105 Val polymorphisms may relate to prognosis of platinum both in aCRC and mCRC, the conclusion was inconsistent in those original works [1, 2, 11, 19, 23, 28]. In order to investigate the influence of these two genetic markers on prognosis of oxaliplatinbased chemotherapy, a meta-analysis was performed in view of the key genes of DNA repair and metabolism.
Materials and methods Study search strategy We searched relevant studies published before July 15, 2012, in PubMed and HuGE. The following terms were allowed: colorectal cancer, colon cancer, rectal cancer, polymorphisms, variants, oxaliplatin, OXA and OXP. We evaluated all the studies by titles and abstracts initially and made further evaluation for some of them. Two reviewers (ZL, ML) assessed studies for eligibility independently and discrepancies were finally resolved by consensus.
systematic review. Meanwhile, the subjects of all the included studies should be humans. All the included original studies had to meet the following criteria: (a) cancer should be confirmed as aCRC or mCRC; (b) chemotherapy was XELOX (oxaliplatin plus capecitabine) or FOLFOX (oxaliplatin plus 5-FU/leucovorin). In addition, oxaliplatin plus an oral fluorouracil was a treatment that conformed to this meta-analysis; (c) genetic polymorphisms were in detail; (d) studies should contain the necessary information of outcomes about tumor response and/or PFS. Neither the country of origin nor the sample size was restricted. The proportion of gender and the average ages of patients in each original study were not taken into account. The method how to detect polymorphisms was not limited, and the evaluation criteria of tumor response was accepted in public (the WHO criteria or the Evaluation Criteria in Solid Tumors criteria). In terms of the definition of tumor response, two different standards were allowed and they were based on the evaluation mentioned above. If some studies did not obtain the crucial information of drug response and/or state of survival, we would write to the corresponding authors in order to ask for detailed data. Statistical methods The risk ratio (RR) for tumor response [complete response (CR) ? partial response (PR) versus stable disease (SD) ? progressive disease (PD) or CR ? PR ? SD versus PD, adopting the WHO criteria or the Evaluation Criteria in Solid Tumors criteria [3]] was estimated after accepting the chemotherapy mentioned above. Especially, progression-free survival (PFS) was only for XRCC1 Arg399Gln polymorphism because of the limited information and that was performed with the univariate Cox proportional hazard regression model based on the information of hazards ratios (HRs) and 95 % confidence intervals (CI) for PFS, which were provided in those published articles. The heterogeneity between-study [30] was evaluated with I2 and 50 % in I2 was regarded as the threshold. The finally included studies were performed by a fixed model initially and the random model was used just when the heterogeneity was significant (I2 [ 50 %). We judged the publication bias with the funnel plot and the Egger’s test (if P \ 0.10, publication bias was significant), and the influence analysis was also taken into account. All the P values were two-sided, and analysis was completed by STATA version 9.0 and Revman version 5.0.
Inclusion criteria and data extraction Results We searched for studies without any language limitation. However, some types of original studies were not eligible to this meta-analysis, such as review, case report and
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A total number of 13 original studies including 1,234 patients were finally eligible to our meta-analysis
Evaluation criteria: tumor response adopting to RECIST criteria or WHO criteria, HR for PFS is the inclusion criteria of the three identified studies b
Study is present with the first author and with the number of references followed
(Table 1). The process of selection and exclusion (Fig. 1) as well as the results for tumor response and PFS (Figs. 2, 3) were shown, respectively. Some studies were finally excluded because no enough data information was available, even though we tried to make contacts with the corresponding authors [11, 23]. In terms of tumor response among these included studies, either SD or PD was considered of non-response [2, 9, 10, 13, 19] while others were not [14, 25, 28]. It is notable that two standards were available for one study because additional data information was provided by the corresponding author [1], and the other study was provided different standards for two genes [12]. In addition, necessary information for the HR for PFS was available [4, 21, 24] and one of the three original studies included two different treatments, which were both fit for the inclusion criteria though with a relatively small sample size [21].
a
LDR ligation detection reaction, SSCP single-strand conformation polymorphism, mFOLFOX modified FOLFOX, FOLFOX 5-FU ? oxaliplatin ? leucovorin, OXA oxaliplatin, S-1 an oral fluorouracil, TS inhibitor 5-FU or other agents with the same mechanism, XELOX capecitabine ? oxaliplatin, TR tumor response, PFS progression-free survival, OS overall response, TTP time to treatment failure, DCR disease-control rate, mCRC metastatic colorectal cancer, aCRC advanced colorectal cancer, PCR–RFLP PCR-restriction fragment length polymorphism
TR, survival, toxicity R399Q HR for PFS FOLFOX
PFS I105 V, R399Q HR for PFS FOLFOX-4
Fluorescent SSCP 115
mCRC
166
Australia Chua [4]
Ruzzo [24]
Italy
aCRC
PCR–RFLP
TR, PFS, OS
PFS, DCR R399Q HR for PFS XELOX or FUOX PCR–RFLP 95 Martinez-Balibrea [21]
Spain
mCRC
I105 V, R399Q RECIST FOLFOX-4
TR, TTP R399Q WHO mFOLFOX-4 or XELOX
PCR–RFLP
aCRC 55
157
China Lv [19]
Huang [10]
Taiwan
mCRC
TaqMan-MGB
TR, survival
TR
R399Q
R399Q
WHO
WHO
FOLFOX
OXA ? 5-FU
PCR
PCR–RFLP
mCRC 51
61
Korea
Stoehlmacher [28]
Suh [25]
USA
aCRC
TR
R399Q WHO
TR, OS
I105 V, R399Q WHO FOLFOX-4 LDR CRC 73
113
China
Liang [14]
Chai [1]
China
mCRC
PCR
mFOLFOX-4 or XELOX
Response, toxicity
TR, OS, PFS, toxicity
I105 V
I105 V
RECIST
WHO
FOLFOX-4
TS inhibitor ?OXA
PCR–RFLP
PCR–RFLP 59
mCRC 166 Taiwan
Le Morvan [13]
Chen [2]
France
mCRC
TR, survival
TR, PFS, OS, toxicity
I105 V, R399Q
I105 V, R399Q
RECIST
RECIST
mFOLFOX-6
OXA ? S-1
Direct sequencing
PCR–RFLP
mCRC
mCRC
72
51
Spain
Korea Hong [9]
Lamas [12]
Outcomes Polymorphism Evaluation criteriab Chemotherapy Methods Tumor Sample size Country Study (publication year)a
Table 1 Characteristics of the studies on oxaliplatin-based chemotherapy for XRCC1 Arg399Gln and GSTP1 Ile105 Val polymorphisms about colorectal cancer identified in the meta-analysis
Cancer Chemother Pharmacol
Tumor response of XRCC1 Arg399Gln polymorphisms (non-response: SD or PD) Four studies were finally included in a dominant model with a total sample size of 336 patients. Data showed that the Arg to Gln substitution was likely associated with tumor response in this analysis (Gln/Arg ? Gln/Gln versus Arg/Arg: RR, 1.29; 95 % CI, 1.05–1.60; P = 0.02). No significant heterogeneity between-study was observed in initial fixed model so that a random model was no need to perform (I2 = 23 %). In addition, no publication bias was detected with a P value of 0.594 in Egger’s test, and no significant outcome of influence analysis was observed (data were not shown). Tumor response of XRCC1 Arg399Gln polymorphisms (non-response: PD) Five studies were finally included in a dominant model with a total sample size of 370 patients. Data showed that the Arg to Gln substitution was not associated with tumor response in this analysis (Gln/Arg ? Gln/Gln versus Arg/Arg: RR, 1.02; 95 % CI, 0.62–1.85; P = 0.95). Significant heterogeneity between-study was observed in initial fixed model and then a random model was performed (I2 = 54 %). In addition, no publication bias was detected with a P value of 0.861 in Egger’s test, and no significant outcome of influence analysis was observed (data were not shown). Tumor response of GSTP1 Ile105 Val polymorphisms (non-response: SD or PD) Five studies were finally included in a dominant model with a total sample size of 415 patients. Data showed that the Ile105 Val substation was not significantly associated
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Relevant studies XRCC1 (n = 138)
Relevant studies GSTP1 (n = 159)
Studies were evaluated by titles and abstracts˖review, systematic review, case reports, letters etc. were excluded
substitution of Arg to Gln was associated with HRs for PFS. For those patients who carried Arg/Gln: HR, 1.04; 95 % CI, 0.75–1.43; P = 0.826. Besides, for those subjects with Gln/Gln: HR, 0.92; 95 % CI, 0.62–1.37; P = 0.677. In addition, significant publication bias was detected with a P value of 0.054 in people who carried Arg/Gln in Egger’s test. However, the publication bias was not obvious at all in the other variation (P value was 0.603 in Egger’s test).
Discussion n = 114
n = 132
Studies were under further evaluation and met the following criteria at the same time: (a) cancer should be confirmed as aCRC or mCRC; (b) chemotherapy was XELOX (oxaliplatin plus capecitabine/5-FU/leucovorin/an oral fluorouracil) (c) genetic polymorphisms (Arg399Gln or Ile105Val) were in detail; (d) necessary information of outcomes about tumor response and/or PFS.
n = 11
n=5
n = 13 Fig. 1 The progression of studies inclusion and extraction for XRCC1 and GSTP1 and the concise reasons for all selections
with tumor response in this analysis (Val/Val ? Ile/Val versus Ile/Ile: RR, 0.63; 95 % CI, 0.35–1.14; P = 0.13) (Fig. 2c). Significant heterogeneity between-study was observed in initial fixed model and then a random model was performed (I2 = 79 %). In addition, no publication bias was detected with a P value of 0.163 in Egger’s test, and no significant outcome of influence analysis was observed (data were not shown). Hazards ratios for progression-free survival of XRCC1 Arg399Gln polymorphisms Three studies were finally included in this analysis with four eligible chemotherapy including oxaliplatin with a total sample size of 376 patients (Tables 2, 3). The
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In this meta-analysis of 13 original studies with 1,234 patients, we found that XRCC1 Arg399Gln polymorphism was significantly associated with oxaliplatin-based chemotherapy in response in colorectal cancer when SD or PD was defined as non-response, although the association was not significant when only PD was considered as nonresponse. Platinum-based agents are commonly used in several solid tumors with successful achievements, which induces DNA adducts and make a contribution to the death of tumor cells [1]. However, the genetic variations that influence the tolerance to DNA adducts, function of DNA repair and drug metabolism will do harm to prognosis of platinum-based chemotherapy [2, 12, 19, 23, 26]. In order to explore the influence of genetic variation on prognosis of oxaliplatinbased chemotherapy both in view of DNA repair and drug metabolism, XRCC1 Arg399Gln and GSTP1 Ile105 Val polymorphisms were widely studied about their influence on prognosis of colorectal cancer, but those conclusions were inconsistent each other [1, 14, 22, 28]. The XRCC1 Arg399Gln polymorphism was considered of increasing chemotherapy sensitivity, which not only reduced the function of DNA repair but also leaded to the effect of increased DNA damage and mutation induction followed [19]. It has been demonstrated that cells with a switch from arginine to glutamine, such as the Arg/Gln or Gln/Gln will make a negative effect on the DNA repair activity [17, 18]. Theoretically, cells with substitution of arginine to glutamine would show larger amounts of DNA damage, and the therapeutic effect of oxaliplatin-based chemotherapy should be turn better [17]. However, our result showed the tumor response rate was significantly lower in patients who carried Arg/Gln ? Gln/Gln than Arg/Arg polymorphisms in XRCC1 when SD or PD was regarded as non-response, which was opposite to the previous study [18] but consistent with other original studies [10, 28]. In fact, more interactions of genetic variations may be also attributable to the prognosis in terms of XRCC1, such as the linkage disequilibrium with other genes with these similar mechanisms so that the combination with other polymorphism could result in a
Cancer Chemother Pharmacol
Fig. 2 Meta-analysis for XRCC1 and GSTP1 polymorphism in view of drug response. The ‘‘event’’ means non-response and point was to estimate the risk ratio and the 95 % CI. For a, the non-response was
stable disease (SD) or progressive disease (PD) while for b only means PD. For c, the non-response was SD or PD
significant difference [19] or unknown region which contributed to the potential mechanism of XRCC1Arg399Gln polymorphism [25]. Additionally, the tumor description, such as the classification and stages, may also be an impact factor on account for those inconsistent results [25], for both aCRC and mCRC were accord with this meta-
analysis. In terms of survival, we failed to demonstrate that the influence of XRCC1 polymorphisms on PFS was significant. Those data of previous studies were contradictory in patients with different cancer in view of survival [6, 15]. Besides, the classification of tumor may be a key impact factor leading to the inconsistent results.
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Cancer Chemother Pharmacol Fig. 3 Meta-analysis for hazards ratio (HR) for progression-free survival (PFS) in XRCC1 polymorphism, which was performed with univariate Cox proportional hazard regression model. For a, subjects were in this comparison group contained only one minor variant A allele. For b, subjects were in this comparison group contained two minor variant A allele. The included studies were shown with the first authors. The point was to estimate the HR and the 95 % CI
Table 2 Univariate Cox proportional hazards regression for progression-free survival (PFS) of XRCC1 Arg399Glnpolymorphisms Study (publication year)a
No. of patients
Chemotherapy
Arg/Arg
Arg/Gln
HR
HR
HR (95 % CI) 95 % CI
Martinez-Balibrea [21]
47
XELOX
1.00
0.82
0.39–1.71
0.82 (0.39–1.71)
Martinez-Balibrea [21]
48
FUOX
1.00
0.85
0.42–1.73
0.83 (0.42–1.73)
Ruzzo [24]
166
FOLFOX-4
1.00
1.67
0.90–2.41
1.67 (0.90–2.41)
Chua [4]
115
FOLFOX
1.00
0.57
0.28–1.19
0.57 (0.28–1.19)
Total
376
1.04 (0.75–1.43)
XELOX capecitabine ? oxaliplatin, FOLFOX 5-FU ? oxaliplatin ? leucovorin, FUOX 5-FU ? oxaliplatin, RR risk ratio a
Study is present with the first author
GSTP1 is one member of glutathione S-transferase (GST) superfamily in cellular defense function [9], and the substitution of Ile to Val at codon 105 would lead to the decreased ability of defending [29], and hence increase the sensitivity of oxaliplatin-based chemotherapy. The inconclusive results of some previous studies may be due to the characteristic of these patients, for example, the influence of ethnicity subgroups [1, 2, 13, 30]. In the present metaanalysis, our results did not show a significant relationship between tumor response and GSTP1 polymorphism, which
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may be attributable to the definition of tumor response with SD or PD, however, the significant results also might appear when only PD was considered as non-response if enough data information existed. There were several limitations in our meta-analysis. Firstly, the total sample size was still small and subgroup analysis could not be performed, for example, the ethnicity classification was not considered in the present metaanalysis. Secondly, significant heterogeneity betweenstudy was still obtained in spite of WHO criteria, and the
Cancer Chemother Pharmacol Table 3 Univariate Cox proportional hazards regression for progression-free survival (PFS) of XRCC1 Arg399Gln polymorphisms Study (publication year)a
No. of patients
Chemotherapy
Arg/Arg
Gln/Gln
HR
HR
HR (95 % CI) 95 % CI
Martinez-Balibrea [21]
47
XELOX
1.00
0.65
0.25–1.66
0.65 (0.25–1.66)
Martinez-Balibrea [21]
48
FUOX
1.00
0.96
0.31–3.00
0.96 (0.31–3.00)
166
FOLFOX-4
1.00
0.99
0.57–1.71
0.99 (0.57–1.71)
Chua [4]
115
FOLFOX
1.00
1.01
0.39–2.60
1.01 (0.39–2.60)
Total
376
Ruzzo [24]
0.92 (0.62–1.37)
XELOX capecitabine ? oxaliplatin, FOLFOX: 5-FU ? oxaliplatin ? leucovorin, FUOX 5-FU ? oxaliplatin, RR risk ratio a
Study is present with the first author
RECIST criteria were comparable to each other in evaluation of tumor response in colorectal carcinoma [3]. Thirdly, our study was lack of information to perform a recessive model and investigate the adverse effect of oxaliplatin-based chemotherapy, and the difference of mixed regimens of chemotherapy may be also an impact factor to the results of this study.
5.
6.
Conclusion 7.
Overall, our meta-analysis revealed that XRCC1 Arg399Gln polymorphism was likely to be one prospective genetic marker in oxaliplatin-based chemotherapy in colorectal cancer of tumor response. However, larger sample size studies are needed to make a further confirmation to our finding and the support in application is indispensable.
8.
Acknowledgments We thank Dr. Haihui Sheng for providing additional data to our study kindly. This study was partially supported by grants from the National Natural Science Foundation of China (81160072), Guangxi Science Fund for Distinguished Young Scholars (2012jjFA40011).
10.
Conflict of interest
9.
None. 11.
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