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10.1245/s10434-006-9112-y
Annals of Surgical Oncology 13:1379-1385 (2006)
© 2006 Society of Surgical Oncology
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Original Article

Which Gene is a Dominant Predictor of Response During FOLFOX Chemotherapy for the Treatment of Metastatic Colorectal Cancer, the MTHFR or XRCC1 Gene?

Kwang Wook Suh, MD1, Joo Hyung Kim, MD1, Do Yoon Kim, MD1, Young Bae Kim, MD2, Chulho Lee3 and Sungho Choi, PhD3

1 Department of Surgery, Ajou University School of Medicine, Suwon, 442-749, Korea
2 Department of Pathology, Ajou University School of Medicine, Suwon, Korea
3 ISU ABIXIS Co., Ltd., Seoul, Korea

Correspondence: Address correspondence and reprint requests to: Kwang Wook Suh, MD; E-mail: suhkw{at}ajou.ac.kr


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Combination chemotherapy using oxaliplatin, 5-fluorouracil and folinic acid (FOLFOX) is known to be effective in the treatment of metastatic colon cancer. Genes regulating the actions of 5-fluorouracil and oxaliplatin have been identified, but precisely which gene is dominant has not yet been determined. The aim of the investigation reported here was to identify which gene polymorphism is a dominant factor in FOLFOX chemotherapy–the methylenetetrahydrofolate reductase (MTHFR) gene for 5-fluorouracil or the X-ray cross-complementing1 (XRCC1) gene for oxaliplatin.

Methods: Paraffin-embedded tissues from 54 patients with unresectable metastases from colorectal cancer who had undergone chemotherapy with the FOLFOX regimen were analyzed for MTHFR polymorphisms in the MTHFR gene (677C->T, Ala->Val mutation) and XRCC1 gene (Arg->Gln substitution in exon 10). Response rates and survivals were compared by types of polymorphism.

Results: Analyses of the patterns of MTHFR polymorphism revealed that 29.6% of the patients showed no mutation, 51.6% showed heterozygous mutations, and 11.8% showed homozygous mutations. Analyses of the XRCC1 polymorphism revealed that 60.8% of the patients showed no mutation, 31.4% showed heterozygous mutations, and 7.8% showed homozygous mutations. After four cycles of chemotherapy, 3.7% showed a complete response, 57.4% showed a partial response (PD) or stable disease, and 38.9% showed PD. The MTHFR polymorphism was not significant in predicting response and 30-month-survival (P > 0.1), whereas the XRCC1 polymorphism was a significant prognostic factor for both response (P = 0.038) and survival (P = 0.011).

Conclusions: We found a higher rate of mutations in the MTHFR gene than in the XRCC1 gene in Korean colorectal cancer patients. Response to FOLFOX was better in the patient group with mutations for MTHFR and worse in the patient group with mutations for XRCC1. However, only the XRCC1 polymorphism was a significant prognostic factor for the response to FOLFOX chemotherapy and short-term survival.

Key Words: Metastatic colon cancer • FOLFOX • XRCC1 • MTHFR • Gene polymorphism


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
In the not-too-distant future, tailored chemotherapy based on drug sensitivity and pharmacogenomics will be the major determining factor in the treatment of cancer.1,2 An accumulating body of evidence suggests that functional genomic polymorphisms in drug target genes, metabolizing enzymes, and DNA-repair enzymes may be involved in drug efficacy.3–6 Many studies on pharmacogenomic variations in predicting drug response, toxicity, and survival to specific chemotherapy regimens have been published,7,8 and despite the presence of contradictory results, significant associations between genomic polymorphisms and defined clinical end points, such as survival, response, and toxicity have been established.9 These results will definitely improve the prediction of treatment success and thereby facilitate the tailoring of chemotherapy.

Combination chemotherapy using oxaliplatin, 5-fluorouracil (5-FU), and leukovorin (FOLFOX) has proven to be effective in the treatment of unresectable metastatic colon cancer, which is otherwise hopeless to treat.10,11 Doublets incorporating oxaliplatin into a backbone of 5-FU/leukovorin (FL) generate responses twice that of both bolus and infusional FL regimens.12 In 2004, the North Central Cancer Treatment Group (NCCTG) reported the results of GI Intergroup trial N9741, a randomized phase III trial comparing IFL (irinotecan and oxaliplatin) with FOLFOX and IROX (every-3-weeks a treatment with irinotecan and oxaliplatin).13 The FOLFOX arm in N9741 showed a significant prolongation of median survival–from 15 to 19.5 months–over an irinotecan and bolus FL-based comparator (IFL). Combination therapy, however, is associated with a greater toxicity than is observed with a single agent administered alone.14 For example, oxaliplatin increases the incidence of diarrhea and neutropenia in patients in comparison to a regimen of FL alone. Moreover, 50% of the patients with metastatic colorectal cancer are still resistant to FOLFOX treatment, and many responders suffer from increased toxicity. The mechanism for drug resistance and toxicity has been explored in part, but most mechanisms remain as yet unknown.15 This lack of knowledge provided our group with the incentive to identify the mechanism governing drug efficacy by means of a pharmacogenetic study.

Genes regulating the actions of 5-FU and oxaliplatin have been reported, but to date just which gene is the dominant factor has yet to be clarified. The aim of our investigation was to determine which gene polymorphism plays a dominant role in the response to FOLFOX chemotherapy and short-term survival of the patients. To this end, we chose two representative genes and examined their polymorphisms: the methylenetetrahydrofolate reductase (MTHFR) gene for 5-FU and the x-ray cross-complementing-1 (XRCC1) gene for oxaliplatin.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Study Population and Chemotherapy
We retrospectively analyzed tissue samples from a group of 54 patients diagnosed with advanced colorectal cancer (30 men, 24 women; mean age: 57.8 years, range: 35–79 years; Eastern Cooperative Oncology Group performance status ≤ 2) that were treated in Ajou University Hospital, Suwon (Korea). The analytical protocol was approved by the Ajou University Hospital Institutional Review Board. All patients exhibited Duke’s D colorectal cancer (20 colon, 34 rectum) with unresectable metastases (28 synchronous, 26 metachronous). Only those patients whose primary tumors had been resected and who had at least one measurable indicator lesion, such as liver or lung metastases, were included in the study. Ascites and pleural effusions were not considered to be measurable.

All patients were administered a modified FOL-FOX4 regimen which consisted of a 2-week cycle of oxaliplatin (85 mg/m2) combined with bolus 5-FU (400 mg/m2), leukovorin (20 mg/m2), and continuous infusion of 5-FU (600 mg/m2). Patients with synchronous metastases had not experienced any chemotherapy previously, and FOLFOX chemotherapy was started within 4 weeks after the resection of the primary cancer. However, patients with metastases occurring remotely after the primary cancer treatment had experienced each of two types of chemotherapy. Those whose initial stages were Dukes’ C (n = 22) were treated by six cycles of infusional 5-FU treatment (500 mg/m2 5-FU and 20 mg/m2 folinic acid for five consecutive days, repeated every 4 weeks), and those whose initial stages were Dukes’ B (n = 4) were treated by oral fluoropyrimidines (900 mg Furtulone/day) for 12 months.

Clinical response was assessed (computed tomography) 8 weeks (four cycles) after the start of chemotherapy according to WHO criteria. After four cycles of initial chemotherapy, responders underwent four more cycles of FOLFOX. Nonresponders underwent palliative chemotherapy using various regimens. In either case, metastasectomy was never performed.

Amplification of the MTHFR and XRCC1 Genes by PCR
The MTHFR polymorphism (677C->T, Ala->Val mutation) and XRCC1 polymorphism (Arg->Gln substitution in exon 10) were analyzed simultaneously on DNA extracted from five 10-um-thick paraffin sections containing a representative portion of each tumor block by means of the QIAamp DNA Mini kit (Qiagen, Hilden, Germany).

Briefly, 100 ng of DNA was amplified in a 2–0 µl reaction solution containing 2 µl of 10x buffer (Roche, Mannheim, Germany), 1.75–3 mM MgCl2, 0.4 µM primer pairs, 250 µM deoxynucleoside tri-phosphate, and 2.5 U DNA polymerase (Roche). The amplifications profile consisted of: a 5-min initial denaturation at 94°C, followed by 30 cycles of 30 s at 94°C, 30 s at 60°C, and 30 s at 72°C, with a final 5-min extension at 72°C. The PCR products were gel-purified with the QIAgen Gel Extraction kit (Qiagen).

The primer sequences for the MTHFR analysis were: MTHFR-F: 5'-TGAAGGAGAAGGTGT CTGCGGGA-3' MTHFR-R: 5'-AGGACGGTG CGGTGAGAGTG-3' The primer sequences for the XRCC1 analysis (Arg->Gln substitution at codon 399) were XRCC1-F: 5'-CCCCAAGTACAGCCA GGTC-3' XRCC1-R: 5'-TGTCCCGCTCCTCTCAGTAG-3'.

Fluorescence-based Direct Sequencing
DNA templates were processed for the DNA sequencing reaction using the ABI-PRISM BigDye Terminator version 3.1 (Applied Biosystems, Foster City, Calif.) with both forward and reverse sequence-specific primers. A 20-ng aliquot of purified PCR products was used in a 20-uL sequencing reaction solution containing 8 uL of BigDye Terminator v3.1 and 0.1 uM of the same PCR primer. The sequencing reactions consisted of 25 cycles of 10 s at 96°C, 5 s at 50°C, and 4 min at 60°C. Sequence data were generated with the ABI PRISM 3100 DNA Analyzer (Applied Biosystems), and the sequences were analyzed by means of Sequencer 3.1.1. software (Applied Biosystems) to compare variations.

Patient Follow-up
Patients were followed up after completion of their chemotherapy every 3 months until death. During their follow-up visits, the patients underwent physical examination. Blood work was obtained to evaluate their complete blood cell count as well as to perform liver function tests and the carcinoembryonic antigen test. Computed tomography (CT) imaging was performed every 6 months. The mean follow-up time was 23.6 months (range: 6–35 months).

Statistical Analysis
Statistical analysis was performed using SPSS (ver. 11.0; SPSS, Chicago, Ill.). Chi-square and Student t tests were used for comparing the variables between groups. Survival curves were generated using the Kaplan-Meier method. Survival was calculated from the date of surgical treatment to the date of death (any cause) or date last seen. The log rank statistic was used to compare survival distributions.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Clinical Response to FOLFOX Chemotherapy
The response of the patients to the FOLFOX chemotherapy was as follows: 33 responded to the chemotherapy [61.1%; two complete response (CR), eight partial response (PR), 23 stable disease (SD)], and 21 showed disease progression (nonresponders, 38.9%).

Patient Characteristics According to Chemoresponse
The demographic and pathologic characteristics were not different between responders and nonresponders (Table 1Go).


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  		TABLE 1. Characteristics of patients compared by response to FOLFOX chemotherapy
 
MTHFR and XRCC1 Genotypes
Yield rates of genotyping were varied with paraffin-embedded tissue condition. Genotypic analysis of MTHFR was possible in 50 specimens and XRCC1 analysis was possible in 51 specimens. The distribution of the 677C->T (Ala->Val) genotype in the primary tumor tissues was 16 specimens with the wt/wt (32.0%) genotype, 28 (56.0%) heterozygous, and six (12.0%) mut/mut; that with the Arg->Gln genotype was 31 wt/wt (60.8%), 16 (31.4%) heterozygous, and four (7.8%) mut/mut (Fig. 1Go). The distribution of the 677C->T variation was in agreement with Hardy-Weinberg equilibrium, but that of Arg->Gln was not.


Figure 1
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  		FIG. 1. Fluorescence-based direct sequencing revealed three patterns of gene polymorphism: 677 C->T in MTHFR gene (above), Arg->Gln substitution at codon 399 in XRCC1 (below).

 
Association Between Genotypes and Clinical Outcomes
When the responders (n = 33) were divided according to MTHFR genotypes, 37.5% were wt/wt, 53.1% were heterogenous, and 9.4% were mut/mut. The relative risk of response according to MTHFR genotypes is highest for the wt/wt and mut/mut patients–1.50 (95% CI: 0.64–3.50). However, the relationship between response to chemotherapy and MTHFR genotypes did not reach statistical significance (P = 0.234). When the responders were separated according to XRCC1 genotypes, 69.7% were wt/wt, 27.3% were heterogenous, and 3.0% were mut/mut. The relative risk of response according to XRCC1 genotypes was the highest between wt/wt/and mut/mut–2.97 (95% CI : 0.53–16.4). The relationship between chemoresponse and XRCC1 genotypes reached statistical significance (P = 0.038) (Tables 2Go, 3Go).


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  		TABLE 2. The association between MTHFR genotypes and response to FOLFOX chemotherapy
 

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  		TABLE 3. The association between XRCC1 genotypes and response to FOLFOX chemotherapy
 
When survival rates were compared, median survivals according to MTHFR genotypes were 30.0 months in the wt/wt group, 28.4 months in the heterogenous group, and 12.8 months in the mut/mut group. The association between survival and MTHFR genotypes did not reach a statistical significance (P = 0.418). However, median survivals according to XRCC1 genotypes showed a statistically significant difference between groups: 30.0 months in the wt/wt group, 16.5 months in the heterogenous group, and 12.8 months in the mut/mut group (P = 0.022). When the XRCC1 genotypes were classified as two groups–the normal group (wt/wt) and the mutation group (heterogenous and mut/mut)–the difference between the two groups by median survival reached a higher statistical significance (30.0 vs. 16.4, P = 0.011) (Figs. 2Go, 3Go).


Figure 2
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  		FIG. 2. Kaplan-Meier survival curves; outcome after FOLFOX chemotherapy according to MTHFR genotypes (P = 0.418).

 

Figure 3
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  		FIG. 3. Kaplan-Meier survival curves; outcome after FOLFOX chemotherapy according to XRCC1 genotypes (P = 0.022).

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Despite aggressive surgical resections and combination chemotherapy, the prognosis for patients with metastatic colorectal carcinoma (CRC) is still dismal.18 Metastasectomy under curative intention provides some 30% of these patients with a 3-year-survival rate.19 However, the metastasectomy is still a controversial procedure which can only be performed on a highly selected patient. Therefore, the treatment option for most patients with metastatic CRC is limited to chemotherapy, and long-term survivals cannot be expected in most cases. Recently, two agents have been added to the battery of classical agents active against CRC. When incorporated into a 5-FU with leukovorin regimen (FL), both irinotecan and oxaliplatin improve the response rate and survival over FL alone. These combinations have set the new benchmark of survival for metatstatic CRC at about 20 months.20

In the prediction of response to certain chemotherapeutic agent, variations in host genes involving drug metabolism are important. Variation in genes or genetic polymorphisms are different from mutations. Polymorphisms and mutations have shared morphological characteristics, such as nucleotide substitutions and deletions, but the difference is in the incidence. When the variation is observed in less than 1% of the general population, it is called a mutation. When the variation is observed in more than 1% of general population, it is polymorphsim.21 Polymorphism in one nucleotide (SNP) can arise in 16 million genomes so that the ranges of genetic polymorphism are truly expansive.22 In cancer treatment, the outcome of surgery depends largely upon the pathological status (cancer factor). Conversely, the outcome of chemotheapy may vary with the polymorphism in host genes involved in the drug metabolism (host factor).

In CRC, in which 5-FU is the mainstay of chemotherapy, enzymes such as thymidylate synthase,23 dihydropyrimidine dehydrogenase,24 and MTHFR16 play important roles. Among these, MTHFR, which reduces 5,10-MTHF to 5-methyltetrahydrofolate, is the enzyme which has been extensively researched for its clinical usefulness. Genes encoding MTHFR are located in the short arm of chromosome 1 (36.3 locus). During the reduction of MTHFR, CH3 is produced and delivered to homocysteine to produce methionine. A cytosine-to-thymine substitution(C->T) in the 677 locus is the most frequent polymorphism in the MTHFR gene and results in the production of valine instead of alanine.7 A mutation in the 677 locus (C->T) can reduce MTHFR activity by 40–80% of its normal value by which two theoretic results can be assumed.25 Firstly, the active form of 5-FU increases with reduced MTHFR activity and this enhances the anticancer activity. Secondly, accumulated homocysteine together with reduced methionine can cause carcinogenesis.26 The incidence of the 677(C->T) mutation has been reported to be 10–15% in Europe and the United States.7 The 11.1% incidence in the Korean population examined in the present study is comparable to these values.

Oxaliplatin, the third generation platinum compound, contains diaminohexane. Its action mechanism includes DNA binding, adduct formation, strand breaks, and subsequent apoptosis.15 Therefore, it can be hypothesized that cancer cells impairing DNA repair mechanism are more susceptible to platinum-based chemotherapy. The XRCC1 gene was the first mammalian gene isolated that affects cellular sensitivity to ionizing radiation.17 The 633 amino acid protein encoded by the human XRCC1 gene is required for the maintenance of genome stability and the efficient repair of oxidative DNA base damage and DNA single-strand breaks by the base excision repair (BER) and single-strand break repair (SSBR) pathways, respectively. Both pathways are essential for the repair of DNA damage inflicted by ionizing radiation and alkylating agents, including many chemotherapeutic drugs currently in use.17 Several types of polymorphism have been reported for the XRCC1 gene and a SNP at codon 399–a switch from arginine to glutamine (399A->G SNP)–is known to have therapeutic significance.8 Cells having a 399 A->G SNP impair DNA repair by failing to recognize single-strand breaks. Theoretically, cells with a 399 A->G SNP, such as Arg/Glu and Glu/Glu, show larger amounts of damaged DNA and the therapeutic effect of oxaliplatin is augmented.8 However, in the present study the prognosis of the Arg/Arg group (normal) was better. This result is in agreement with the result of the previous study in which CRC cells with the Gln/Gln genotype were observed to have a 5.2-fold greater risk of treatment failure when oxaliplatin was administered. The incidence of the 399A->G SNP has been reported to be about 8–9% in Asian and Caucasians and 20% in Black populations, thereby demonstrating an ethnic discrepancy.8,17 We found a relatively low incidence (7.8%) of this SNP in our Korean population.

The discrepancy between the theoretical results and experimental results can be explained by two facts. Firstly, glutamine substitution may induce chemoresistance to oxaliplatin. Previous studies revealed that cells with an impaired repair system of DNA replication errors are more resistant to alkylating agents, cisplatin, and doxorubicin. Secondly, XRCC1 protein repairs DNA replication errors specifically by the base excision repair (BER) mechanism which incorporates two enzymes, such as DNA ligase III and polymerase beta.27–29 Unexpectedly, the large product of DNA adduct, which is the main action of oxaliplatin, cannot be repaired by BER but by nucleotide excision repair (NER). A newly found protein, XGP, is known to have dual actions for both BER and NER. It is hypothesized that XGP is closely related with the XRCC1 protein and that it can work normally with normal XRCC1 protein.8,27–29

In combination chemotherapy, overall drug response is a net effect of individual drug responses. Although oxaliplatin is known to have more a potent cytotoxic effect than 5-FU in the treatment of CRC, it would appear to be important to determine which gene polymorphism is dominant when administering FOLFOX combination chemotherapy. We found a significant correlation between the XRCC1 polymorphism and the prognosis. It is not yet clear why the MTHFR polymorphism had no significant effect on the chemotherapy. Two possible factors are the small number of patients and the refractoriness of the metastatic lesion to 5-FU. A large patient cohort within the framework of a prospective study will help clarify the role of the MTHRF polymorphism. Based on our limited number of patients, we suggest that that an assay for the XRCC1 polymorphism is necessary before deciding on a oxaliplatin-based chemotherapy. If the patient has mutations in the gene, other drugs, such as irinotecan, instead of oxaliplatin may be justified.

In conclusion, we found homozygous mutations in the MTHFR and XRCC1 genes of CRC specimens at an incidence of 12.0 and 7.8%, respectively. These figures are similar to those from the Western population. Drug response and ultimate prognosis of metastatic CRC patients treated with FOLFOX4 were exclusively related with the XRCC1 gene polymorphism and not with the MTHFR gene. With thousands of SNPs and thousands of potential outcomes to analyze, P < 0.05 simply means that for every 20 potential analysis, five will have an association by chance. While this observation is true for all studies, it is particularly relevant since the present study has not demonstrated any direct molecular pathways between the polymorphism and response to oxaliplatin. Future prospective studies incorporating larger numbers of patients will enable us to determine which gene is dominant in multi-drug treatments such as FOLFOX and facilitate the choice of a tailored chemotherapy for a patient.

Received for publication May 24, 2006. Accepted for publication May 24, 2006.


   REFERENCES
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 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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