|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
Journal of Clinical Oncology, Vol 25, No 10 (April 1), 2007: pp. 1247-1254 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.08.1844 Pharmacogenetic Profiling in Patients With Advanced Colorectal Cancer Treated With First-Line FOLFOX-4 Chemotherapy
From the Institute of Biochemistry G Fornaini, University of Urbino; Medical Oncology, Hospital of Urbino, Urbino; Medical Oncology, Hospital of Livorno, Livorno; Oncology Department, Istituto di Ricerche Farmacologiche Mario Negri, Milan; Medical Oncology, University Campus Biomedico, Rome; Medical Oncology, Hospital of Pesaro, Pesaro; Medical Oncology, Hospital of Senigallia, Senigallia; Medical Oncology, Hospital of Fermo, Fermo; Medical Oncology, University of Pisa, Pisa; Medical Oncology, Hospital of Fabriano, Fabriano; and Medical Oncology, Hospital of Fano, Fano, Italy Address reprint requests to Francesco Graziano, MD, Medical Oncology Unit, Hospital of Urbino, via Bonconte da Montefeltro, 61029, Urbino, Italy; e-mail: frada{at}tin.it
Purpose The objective is to investigate whether polymorphisms with putative influence on fluorouracil/oxaliplatin activity are associated with clinical outcomes of patients with advanced colorectal cancer treated with first-line oxaliplatin, folinic acid, and fluorouracil palliative chemotherapy. Materials and Methods Consecutive patients were prospectively enrolled onto medical oncology units in Central Italy. Patients were required to have cytologically/histologically confirmed metastatic disease with at least one measurable lesion. Peripheral blood samples were used for genotyping 12 polymorphisms in thymidylate synthase, methylenetetrahydrofolate reductase, xeroderma pigmentosum group D (XPD), excision repair cross complementing group 1 (ERCC1), x-ray cross complementing group 1, x-ray cross complementing protein 3, glutathione S-transferases (GSTs) genes. The primary end point of the study was to investigate the association between genotypes and progression-free survival (PFS). Results In 166 patients, ERCC1-118 T/T, XPD-751 A/C, and XPD-751 C/C genotypes were independently associated with adverse PFS. The presence of two risk genotypes (ERCC1-118 T/T combined with either XPD-751 A/C or XPD-751 C/C) occurred in 50 patients (31%). This profiling showed an independent role for unfavorable PFS with a hazard ratio of 2.84% and 95% CI of 1.47 to 5.45 (P = .002). Neurotoxicity was significantly associated with GSTP1-105 A/G. Carriers of the GSTP1-105 G/G genotype were more prone to suffer from grade 3 neurotoxicity than carriers of GSTP1-105 A/G and GSTP1-105 A/A genotypes. Conclusion A pharmacogenetic approach may be an innovative strategy for optimizing palliative chemotherapy in patients with advanced colorectal cancer. These findings deserve confirmation in additional prospective studies.
Since the first reports in the late 1990s, the FOLFOX regimen,1 which includes bolus/infusional fluorouracil (FU) with folinic acid modulation and oxaliplatin, has become one of the most common first-line treatments for patients with metastatic colorectal cancer (CRC).2 Recently, further attempts have been made to improve the efficacy of this regimen, and the addition of irinotecan (FOLFOXIRI) has shown promising results.3 Such a three-drug combination is associated with an increase in adverse effects, and its superiority over the FOLFOX regimen is yet to be established.2 It would be useful to identify patients who could benefit most from such an intensive multidrug regimen, as well as those who could be adequately treated using a two-drug oxaliplatin, folinic acid, and fluorouracil (FOLFOX-4) chemotherapy. Genomic polymorphisms in drug target genes, genes encoding DNA-repair enzymes, and detoxification pathways may influence the activity of FU and oxaliplatin.4 Therefore, associations between polymorphisms and clinical end points may help to tailor chemotherapy and find an optimal drug strategy.5 Elevated thymidylate synthase (TS) protein levels may interfere in the mechanisms of action of FU.4,5 A recent meta-analysis confirmed poorer overall survival (OS) of CRC patients with enhanced TS activity compared to cases with low TS activity.6 The variable number of tandem repeat (VNTR) polymorphism in TS 5'-untranslated region (5'-UTR), which consists of two (2R) or three (3R) 28-bp repeated sequences,7 showed enhanced mRNA translational efficiency/stability,7-9 with upregulation of TS levels.10-12 A G/C polymorphism in the 3R allele was found to determine two additional alleles at this locus (3G or 3C).8,9 In vitro, the 3G allele has been associated with higher reporter gene activity at both DNA transcriptional and mRNA translational levels than the 3C allele.8,9 In vivo, 3G-containing genotypes (2R/3G, 3C/3G, and 3G/3G) showed correlation with high TS mRNA expression.11,12 An additional TS polymorphism is a 6-bp insertion/deletion (6+/6-) in the 3'-untranslated region (3'UTR).13 Mandola et al14 found higher stability of chimeric mRNA composed of a luciferase reporter and the 3'-UTR 6+ variant compared with a corresponding 6- construct. Higher TS mRNA levels in 6+/6+ carriers than in 6-/6- carriers12 may influence chemosensitivity to FU.14 Functional polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene15,16 have been associated with alterations in the intracellular folate pool and methylation reactions.17,18 Increased availability of 5,10-methylenetetrahydrofolate, which is a necessary cofactor for FU inhibition of TS and silencing by hypermethylation of genes required for cell survival in the presence of cytotoxic agents19 may cause variable FU activity in vivo. Resistance to oxaliplatin has been attributed to enhanced tolerance and repair of DNA damage through the nucleotide excision repair (NER) pathway,20 which includes the excision repair cross complementing group 1 (ERCC1) and the xeroderma pigmentosum group D (XPD) products.21,22 A number of putative functional polymorphisms in NER genes and genes involved in additional DNA-repair pathways23-25 may influence the activity of platinum compounds.26-34 Variable chemosensitivity to oxaliplatin may also depend on detoxification pathways, including the glutathione S-transferase (GST) family of isoenzymes.4,5 A single nucleotide polymorphism in GSTP1 causing isoleucine/valine substitution diminishes GSTP1 activity.35,36 Inherited homozygous deletions in GSTT1 or GSTM1 lead to an absence of enzymatic activity.37 In the present study, we examined a panel of 12 polymorphisms within eight genes (Table 1). We investigated possible associations between these polymorphisms and progression-free survival (PFS) of patients with metastatic CRC treated with first-line FOLFOX-4 chemotherapy. PFS was preferred since OS might be influenced by selective use of second-line treatments with or without new target therapies, locoregional treatments and deaths attributed to causes unrelated to colorectal cancer.38 Additional associations between genotypes and response/toxicity to chemotherapy were explored.
Study Population This prospective study involved eight medical oncology units in Central Italy. Eligibility criteria were cytologically or histologically confirmed metastatic CRC, presence of at least one bidimensionally measurable lesion, Karnofski performance status (KPS) of 70 or greater, and indication to first-line FOLFOX-4 palliative chemotherapy.1 Previous adjuvant chemotherapy was allowed, but it had to be completed more than 6 months before study inclusion and with a regimen not including oxaliplatin. Pretreatment evaluation included a complete medical and clinical-physical examination, KPS evaluation, baseline measurement of tumor size based on computed tomography (CT) scans, x-ray or other radiographic means (comprising full assessment of all known metastatic disease), serum chemistries, and carcinoembryonic antigen. Objective response was evaluated after four cycles of treatment and then every 2 months, adopting the Response Evaluation Criteria in Solid Tumors Group (RECIST) criteria.39 All toxicities, except peripheral neuropathy, were graded according to the National Cancer Institute Common Toxicity Criteria. A specific neurotoxicity scale was used for oxaliplatin-related neurotoxicity.40 Patients' characteristics and their outcomes were unknown to investigators performing genetic analyses. The results of genotyping were disclosed to clinical investigators after data analysis. The study was approved by local ethical committees, and patients provided signed informed consent.
Analysis of Polymorphisms
Statistical Analyses Before assessing clinical associations, genotype frequencies were checked for agreement with those expected under Hardy-Weinberg equilibrium. Linkage disequilibrium (LD) between loci was assessed via the Genetic Linkage User Environment (GLUE) interface (www.hgmp.mrc.ac.uk) using the Unphased software package (MRC Biostatistics Unit, Cambridge, England). LD provides information about nonrandom association between two or more alleles. LD was estimated by r2, which can range from 0 (random coinheritance of alleles) to 1 (complete LD). In the presence of strong LD, a pharmacogenetic effect may not reflect a direct association, but it may result from LD of the tested genetic marker with a known causal, or another unknown or unprobed marker that is the one truly responsible for the association or effect modification. PFS was defined as the time from the start of chemotherapy to the first occurrence of disease progression or death. Patients without progression at the time of analysis were censored at their last available follow-up assessment. Each genotype was independently analyzed, and a combined analysis was planned if multiple genotypes showed a significant association. The association between genotypes and PFS was estimated by computing hazard ratios and their 95% CI from both univariate and multivariate Cox proportional hazards regression models. For the multivariate analysis, we considered predictors of survival that have been studied in patients with advanced CRC.1,42-44 Among them, KPS score (continuous variable), carcinoembryonic antigen levels (continuous variable), mucinous histology (dichotomous variable: adenocarcinoma versus mixed with mucinous component), number of metastatic sites (dichotomous variable: 1-2 versus > 2) were included in the multivariate model together with genotypes (dummy variables).
The
Study Population The analysis was performed in 166 of 175 enrolled patients (genotyping was not possible in nine patients whose blood samples were damaged during shipment), and their characteristics are shown in Table 2. At the time of the final analysis (May 2006), PFS time was calculated on the basis of disease progression in 138 patients. Twenty-eight patients (17%) who were maintaining stable disease were censored observations. Median PFS was 9.3 months (ranging from 1.5 to more than 23 months) in this study.
Clinical Outcomes and Genotypes Overall frequencies of the studied polymorphisms (Table 3) are consistent with those observed in previously reported investigations. No significant associations between polymorphisms and demographic, clinical, or pathological characteristics were observed (data not shown).
At univariate analysis (Table 3), a significantly higher risk of progression was associated with ERCC1-118 and XPD-751 variants. In the multivariate model (Table 3), ERCC1-118 T/T genotype, XPD-751 A/C genotype, and XPD-751 C/C genotype were genetic factors significantly associated with an increased risk of progression. Combinations of the ERCC1-118 T/T genotype with either XPD-751 A/C or XPD-751 C/C genotypes were analyzed in 165 patients (one patient not assessable for XPD-751 was excluded). In 26% of patients there were no risk genotypes (group 0), 44% of patients had one risk genotype (group 1), and 30% of patients had two risk genotypes (group 2). Median PFS times in group 0 patients, group 1 patients, and group 2 patients were 11.2 months, 9.8 months, and 8 months, respectively. Kaplan-Meier curves of the three groups are shown in Figure 1. The adverse effect with shorter PFS in group 2 was also observed in the multivariate analysis (HR = 2.84; 95% CI, 1.47 to 5.45, P = .002).
No significant association was detected (data not shown) between genotype frequencies and patients subdivided into responders (patients with complete or partial response) and nonresponders (patients with stable disease or disease progression;  2 test for categoric variables). An additional evaluation of the disease-control rate (patients with complete response, partial response, and stable disease versus patients with progressing disease) in group 0, group 1, and group 2 patients suggested that PFS differences between the three groups may be attributed to the distribution of stable disease and progression outcomes (Table 4).
Toxicity was recorded in each patient (Table 5). No significant association between toxicity and genotype was found except for oxaliplatin-related neurotoxicity and GSTP1-105 genotypes. The frequencies of GSTP1-105 A/A, A/G, and G/G genotypes were 63%, 34%, and 2%, respectively, in 78 patients with grade 1 to 2 neurotoxicity and 23%, 30%, and 47%, respectively, in 17 patients with grade 3 neurotoxicity (P < .001 of the 2 test was for categoric variables). Treatment discontinuation for reasons other than progression occurred in 16 patients (9.5%). Two patients stopped chemotherapy after serious hypersensitivity reaction to oxaliplatin during the infusion (sixth and eighth cycle, respectively). One patient refused chemotherapy due to grade 4 asthenia after the ninth cycle. In the remaining 13 patients, oxaliplatin was withdrawn for persistent grade 3 neurotoxicity (all of them completed six FOLFOX-4 cycles). In this group, frequencies of GSTP1-105 A/A, A/G, and G/G genotypes were 15%, 23%, and 61%, respectively.
Our findings support the hypothesis that pharmacogenetic profiling may be useful for improving the chemotherapeutic strategy in patients with metastatic CRC. In patients treated with first-line FOLFOX-4 regimen, the presence of unfavorable genotypes in ERCC1-118 and XPD-751 was associated with reduced PFS. The other studied polymorphisms and polymorphisms involved in the FU pathway in particular failed to demonstrate such a clinical association. In advanced CRC patients treated with FU chemotherapy, Pullarkat et al45 found lower response rates in carriers of TS 5'-UTR 3R genotypes compared to patients with homozygous TS 5'-UTR 2R/2R genotype. Stoehlmacher et al46 did not observe any significant difference in the outcome of patients according to TS 5'-UTR genotypes, while Jakobsen et al47 and Dotor et al48 found better survival outcomes in carriers of TS 5'-UTR 3R genotypes than in carriers of the TS 5'-UTR 2R/2R genotypes. Marcuello et al49 also studied the single nucleotide C/G change in TS 5'-UTR 3R allele, and they showed that CRC patients with 2R/3G, 3C/3G, and 3G/3G genotypes had worse survival than patients with 2R/2R, 2R/3C, and 3C/3C genotypes. However, Dotor et al48 found that the analysis of the double polymorphism in TS 5'-UTR did not add prognostic information. Uncertainty about the effect of the TS 3'-UTR 6-/6+ variant in FU-treated patients also exists. Dotor et al48 found a favorable effect on survival of the TS 3'-UTR 6- allele in adjuvantly treated patients, but a marginal association was found by Stoehlmacher et al46 in patients with metastatic disease treated with second-line chemotherapy. Possible explanations for divergent findings in in vivo studies should consider that predictions based on in vitro tests may not accurately reflect the situation in vivo, and information on functional effects of polymorphisms from experimental investigations is not always conclusive. Also, additional factors such as genetic and epigenetic interactions may not allow the observation of straight genotype/phenotype effects.50 Loss of heterozygosity (LOH) in the tumor at the TS locus47,51 may cause the heterozygous TS 5'-UTR 2R/3R risk genotype to acquire either the 2R/loss or the 3R/loss genotype. Consequently, a proportion of patients with expected chemoresistance on the basis of the genomic TS 5'-UTR 2R/3R status may harbor the favorable 2R/loss genotype in cancer cells. Finally, inhibition of TS by 5-fluoro-2'-deoxyuridine-5'-monophosphate does not seem to be the only mechanism of action of FU. Other mechanisms, including incorporation of 5-fluorouridine-5'-triphosphate into RNA and incorporation of 5-fluoro-2'-deoxyuridine-5'-triphosphate into DNA, have been reported.52,53 These findings may represent additional confounders in pharmacogenetic studies that investigate the predictive role of polymorphisms in TS as the sole target of activity of FU. In previous studies, MTHFR polymorphisms showed favorable46,54 or no clear prognostic effect55,56 in patients treated with fluoropyrimidine-based palliative chemotherapy. Again, inconsistency of data from experimental models, the possible presence of LOH, multiple mechanisms of FU cytotoxicity may be major limitations for detecting associations between MTHFR polymorphisms and clinical outcomes of patients with advanced CRC. ERCC1-118 and XPD-751 products are two major components of the NER pathway, which seems mainly to be involved in the repair of oxaliplatin-induced DNA damage.57 This feature may explain the lack of association between polymorphisms in genes involved in other DNA repair pathways and clinical outcomes of these patients. In experimental models, the ERCC1-118 T allele variant showed potential functional consequences with trend to higher ERCC1 mRNA levels than those observed in the presence of the ERCC1-118 C allele.26 So far, two studies have addressed the analysis of the ERCC1-118 C/T polymorphism in patients with advanced CRC treated with oxaliplatin-based chemotherapy and both showed an adverse effect of the ERCC1-118 T allele.46,58 As far as the predictive role of XPD variants is concerned, polymorphism in XPD-751 rather than in XPD-312 showed association with clinical outcomes of these patients.46,59 Carriers of the XPD-751 Gln allele faired the worst, having a significantly shorter PFS and OS when compared with Lys/Lys carriers.46,59 The tendency toward adverse PFS in XPD-312 G/A carriers could be explained on the basis of a weaker effect of this variant with respect to XPD-751, but also for the existing LD, however incomplete (r2 = 0.51) between the two XPD loci.46,59 Among polymorphisms with putative influence on oxaliplatin detoxification (GSTP1, GSTM1, and GSTT1), Stoehlmacher et al46,60 found an association between GSTP-105 variants and survival of patients with metastatic CRC treated with second- and third-line FU/oxaliplatin chemotherapy. The lack of a predictive role for GSTM1 and GSTT1 variants was explained on the basis of differences in tissue-specificity and drug-specificity of GSTP, GSTM, and GSTT isoenzymes.61-64 In the present study, none of the GSTP1, GSTM1, and GSTT1 variants showed an association with PFS, but the GSTP1-105 G allele was an unfavorable genetic factor for developing oxaliplatin-induced neurotoxicity. This finding parallels previous observations by Grothey et al,65 but conversely, Lecomte et al40 found an association between oxaliplatin-induced neurotoxicity and the GSTP1-105 A allele. As discussed above, there are biologic aspects that may explain often conflicting clinical findings in pharmacogenomics studies in CRC, and in FU-treated patients in particular. Additional factors include deficiencies in the study design as well as heterogeneity in clinical settings. Most pharmacogenetic studies have used the candidate gene approach, investigating the effects of only one or a few single polymorphisms in a specific gene at a time. In this case, since chemotherapy drugs exert their effects through a multistep, multigenic cascade, it may be difficult to identify possible pharmacogenetic associations. This aspect is even more relevant if the pharmacogenetic analysis is performed in patients receiving combination chemotherapy with two or more drugs exploiting independent biologic pathways (ie, the FOLFOX association). In some cases, results should be interpreted with caution because of methodological pitfalls such as studies with a limited number of events coupled with missing analysis of influent managements for patients with metastatic disease,48 or the lack of multivariate analysis for modeling marginally significant survival associations.47 Finally, it is plausible that pharmacogenetic associations may not always be reproducible when they are explored in different clinical settings. Findings in patients with early disease treated with adjuvant chemotherapy may not be confirmed in patients treated with first- or second-line chemotherapy for metastatic disease. Tumor progression is a dynamic process, while the germline status is a static portrait whose clinical impact may be more or less influenced by the accumulating genetic changes (ie, LOH, mutations, chromosomal aberrations) in the tumor cell. To the best of our knowledge, this is the first prospective study that has explored the association between polymorphisms with putative influence on FU/oxaliplatin and clinical outcomes of metastatic CRC patients treated with first-line chemotherapy. To this purpose, we accrued a homogeneous population of patients treated with FOLFOX-4 regimen. We found biologically plausible associations by applying a multiple polymorphisms approach to examine a comprehensive panel of variants in major genes involved in TS regulation, folate metabolism, nucleotide excision repair, base excision repair, double-strand break repair, and drug detoxification. Reduced PFS was observed in carriers of ERCC1-118 T/T and XPD-751 C genotypes (XPD-751 A/C or XPD-751 C/C). When two unfavorable genotypes are present, it seems possible to identify patients who gain the least benefit from this regimen. Likely, these patients could represent a subgroup deserving an intensive three-drug combination (ie, including irinotecan). Selecting palliative chemotherapy on the basis of pharmacogenetic information may represent an innovative strategy, which warrants prospective studies.
The authors indicated no potential conflicts of interest.
Conception and design: Annamaria Ruzzo, Francesco Graziano, Mauro Magnani Financial support: Mauro Magnani Provision of study materials or patients: Annamaria Ruzzo, Francesco Graziano, Fotios Loupakis, Daniele Santini, Vincenzo Catalano, Rita Ficarelli, Renato Bisonni, Gianluca Masi, Gaia Schiavon, Paolo Giordani, Lucio Giustini, Alfredo Falcone, Giuseppe Tonini, Rosarita Silva, Rodolfo Mattioli Collection and assembly of data: Annamaria Ruzzo, Francesco Graziano, Eliana Rulli, Emanuele Canestrari, Paolo Maltese Data analysis and interpretation: Francesco Graziano, Eliana Rulli, Irene Floriani, Mauro Magnani Manuscript writing: Annamaria Ruzzo, Francesco Graziano, Mauro Magnani Final approval of manuscript: Annamaria Ruzzo, Francesco Graziano, Fotios Loupakis, Eliana Rulli, Emanuele Canestrari, Daniele Santini, Vincenzo Catalano, Rita Ficarelli, Paolo Maltese, Renato Bisonni, Gianluca Masi, Gaia Schiavon, Paolo Giordani, Lucio Giustini, Alfredo Falcone, Giuseppe Tonini, Rosarita Silva, Rodolfo Mattioli, Irene Floriani, Mauro Magnani Other (genotyping): Emanuele Canestrari, Paolo Maltese
We thank Cathie Spino, DSc, for her help editing the manuscript.
Supported by Consorzio Interuniversitario per le Biotecnologie and Fanoateneo. A.R. and F.G. contributed equally to the study. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. de Gramont A, Figer A, Seymour M, et al: Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 18:2938-2947, 2000 2. Kelly H, Goldberg RM: Systemic therapy for metastatic colorectal cancer: Current options, current evidence. J Clin Oncol 23:4553-4560, 2005 3. Falcone A, Masi G, Allegrini G, et al: Biweekly chemotherapy with oxaliplatin, irinotecan, infusional Fluorouracil, and leucovorin: A pilot study in patients with metastatic colorectal cancer. J Clin Oncol 20:4006-4014, 2002 4. Marsh S, McLeod HL: Cancer pharmacogenetics. Br J Cancer 90:8-11, 2004[CrossRef][Medline] 5. Nagasubramanian R, Innocenti F, Ratain MJ: Pharmacogenetics in cancer treatment. Annu Rev Med 54:437-452, 2003[CrossRef][Medline] 6. Popat S, Matakidou A, Houlston RS: Thymidylate synthase expression and prognosis in colorectal cancer: A systematic review and meta-analysis. J Clin Oncol 22:529-536, 2004 7. Horie N, Aiba H, Oguro K, et al: Functional analysis and DNA polymorphism of the tandemly repeated sequences in the 5'-terminal regulatory region of the human gene for thymidylate synthase. Cell Struct Funct 20:191-197, 1995[Medline] 8. Kawakami K, Watanabe G: Identification and functional analysis of single nucleotide polymorphism in the tandem repeat sequence of the thymidylate synthase gene. Cancer Res 63:6004-6007, 2003 9. Mandola MV, Stoehlmacher J, Muller-Weeks S, et al: A novel single nucleotide polymorphism within the 5' tandem repeat polymorphism of the thymidylate synthase gene abolishes USF-1 binding and alters transcriptional activity. Cancer Res 63:2898-2904, 2003 10. Kawakami K, Omura K, Kanehira E, et al: Polymorphic tandem repeats in the thymidylate synthase gene is associated with its protein expression in human gastrointestinal cancers. Anticancer Res 19:3249-3252, 1999[Medline] 11. Morganti M, Ciantelli M, Giglioni B, et al: Relationships between promoter polymorphisms in the thymidylate synthase gene and mRNA levels in colorectal cancers. Eur J Cancer 41:2176-2183, 2005[CrossRef][Medline] 12. Kawakami K, Watanabe G: The association of thymidylate synthase mRNA expression with its three gene polymorphisms in colorectal cancer. Proc Am Assoc Cancer Res 45:484, 2004 (abstr 2104) 13. Ulrich CM, Bigler J, Velicer CM, et al: Searching expressed sequence Tag databases: Discovery and confirmation of a common polymorphism in the thymidylate synthase gene. Cancer Epidemiol Biomarkers Prev 9:1381-1385, 2000 14. Mandola MV, Stoehlmacher J, Zhang W, et al: A 6 bp polymorphism in the thymidylate synthase gene causes message instability and is associated with decreased intratumoral TS mRNA levels. Pharmacogenetics 14:319-327, 2004[CrossRef][Medline] 15. Sohn KJ, Croxford R, Yates Z, et al: Effect of the methylenetetrahydrofolate reductase C677T polymorphism on chemosensitivity of colon and breast cancer cells to 5-fluorouracil and methotrexate. J Natl Cancer Inst 96:134-144, 2004 16. Etienne MC, Ilc K, Formento JL, et al: Thymidylate synthase and methylenetetrahydrofolate reductase gene polymorphisms: Relationships with 5-fluorouracil sensitivity. Br J Cancer 90:526-534, 2004[CrossRef][Medline] 17. Kawakami K, Ruszkiewicz A, Bennett G, et al: The folate pool in colorectal cancers is associated with DNA hypermethylation and with a polymorphism in methylenetetrahydrofolate reductase. Clin Cancer Res 9:5860-5865, 2003 18. Paz MF, Avila S, Fraga MF, et al: Germ-line variants in methyl-group metabolism genes and susceptibility to DNA methylation in normal tissues and human primary tumors. Cancer Res 62:4519-4524, 2002 19. Iacopetta B: Methyl-group metabolism and the response of colorectal cancer to 5-Fluorouracil. Crit Rev Oncogenesis 12:1-12, 2006 20. Wang D, Lippard SJ: Cellular processing of platinum anticancer drugs. Nat Rev Drug Discov 4:307-320, 2005[CrossRef][Medline] 21. Altaha R, Liang X, Yu JJ, et al: Excision repair cross complementing-group 1: Gene expression and platinum resistance. Int J Mol Med 14:959-970, 2004[Medline] 22. Weaver DA, Crawford EL, Warner KA, et al: ABCC5, ERCC2, XPA, and XRCC1 transcript abundance levels correlate with cisplatin chemoresistance in non-small cell lung cancer cell lines. Mol Cancer 4:18, 2005[CrossRef][Medline] 23. Furuta T, Ueda T, Aune G, et al: Transcription-coupled nucleotide excision repair as a determinant of cisplatin sensitivity of human cells. Cancer Res 62:4899-4902, 2002 24. Xu ZY, Loignon M, Han FY, et al: Xrcc3 induces cisplatin resistance by stimulation of rad51-related recombinational repair, s-phase checkpoint activation, and reduced apoptosis. J Pharmacol Exp Ther 314:495-505, 2005 25. Raaphorst GP, Li LF, Yang DP: Evaluation of adaptive responses to cisplatin in normal and mutant cell lines with mutations in recombination repair pathways. Anticancer Res 26:1183-1187, 2006 26. Park DJ, Stoehlmacher J, Zhang W, et al: ERCC1 polymorphism is associated with differential ERCC1 mRNA levels. Proc Am Ass Cancer Res 43:321, 2002 (abstr. 1591) 27. Savas S, Kim DY, Ahmad MF, et al: Identifying functional genetic variants in DNA repair pathway using protein conservation analysis. Cancer Epidemiol Biomarkers Prev 13:801-807, 2004 28. Lunn RM, Langlois RG, Hsieh LL, et al: XRCC1 polymorphisms: Effects on aflatoxin B1-DNA adducts and glycophorin A variant frequency. Cancer Res 59:2557-2561, 1999 29. Au WW, Salama SA, Sierra-Torres CH: Functional characterization of polymorphisms in DNA repair genes using cytogenetic challenge assays. Environ Health Perspect 111:1843-1850, 2003[Medline] 30. Affatato AA, Wolfe KJ, Lopez MS, et al: Effect of XPD/ERCC2 polymorphisms on chromosome aberration frequencies in smokers and on sensitivity to the mutagenic tobacco-specific nitrosamine NNK. Environ Mol Mutagen 44:65-73, 2004[CrossRef][Medline] 31. Lunn RM, Helzlsouer KJ, Parshad R, et al: XPD polymorphisms: Effects on DNA repair proficiency. Carcinogenesis 21:551-555, 2000 32. Spitz MR, Wu X, Wang Y, et al: Modulation of nucleotide excision repair capacity by XPD polymorphisms in lung cancer patients. Cancer Res 61:1354-1357, 2001 33. Araujo FD, Pierce AJ, Stark JM, et al: Variant XRCC3 implicated in cancer is functional in homology-directed repair of double-strand breaks. Oncogene 21:4176-4180, 2002[CrossRef][Medline] 34. Seker H, Butkiewicz D, Bowman ED, et al: Functional significance of XPD polymorphic variants: Attenuated apoptosis in human lymphoblastoid cells with the XPD 312 Asp/Asp genotype. Cancer Res 61:7430-7434, 2001 35. Watson MA, Stewart RK, Smith GB, et al: Human glutathione S-transferase P1 polymorphisms: Relationship to lung tissue enzyme activity and population frequency distribution. Carcinogenesis 19:275-280, 1998 36. Goto S, Iida T, Cho S, et al: Overexpression of glutathione S-transferase pi enhances the adduct formation of Cisplatin with glutathione in human cancer cells. Free Radic Res 31:549-558, 1999[Medline] 37. Abdel-Rahman SZ, el-Zein RA, Anwar WA, et al: A multiplex PCR procedure for polymorphic analysis of GSTM1 and GSTT1 genes in population studies. Cancer Lett 107:229-233, 1996[CrossRef][Medline] 38. Louvet C, de Gramont A, Tournigand C, et al: Correlation between progression free survival and response rate in patients with metastatic colorectal carcinoma. Cancer 91:2033-2038, 2001[CrossRef][Medline] 39. Therasse P, Arbuck SG, Eisenhauer EA, et al: New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92:205-216, 2000 40. Lecomte T, Landi B, Beaune P, et al: Glutathione S-transferase P1 polymorphism (Ile105Val) predicts cumulative neuropathy in patients receiving oxaliplatin-based chemotherapy. Clin Cancer Res 12:3050-3056, 2006 41. Dupont WD, Plummer WD: Power and sample size calculations: A review and computer program. Controlled Clinical Trials 11:116-128, 1990[CrossRef][Medline] 42. Massacesi C, Pistilli B, Valeri M, et al: A. Predictors of short-term survival and progression to chemotherapy in patients with advanced colorectal cancer treated with 5-fluorouracil-based regimens. Am J Clin Oncol 25:140-148, 2002[CrossRef][Medline] 43. Massacesi C, Norman A, Price T, et al: Clinical nomogram for predicting long-term survival in advanced colorectal cancer. Eur J Cancer 36:2044-2052, 2000[CrossRef][Medline] 44. Cunningham D, Norman AR, Chong G, et al: Mucinous histology predicts for reduced fluorouracil responsiveness and survival in advanced colorectal cancer. Ann Oncol 16:1305-1310, 2005 45. Pullarkat ST, Stoehlmacher J, Ghaderi V, et al: Thymidylate synthase gene polymorphism determines response and toxicity of 5-FU chemotherapy. Pharmacogenom J 1:65-70, 2001 46. Stoehlmacher J, Park DJ, Zhang W, et al: A multivariate analysis of genomic polymorphisms: Prediction of clinical outcome to 5-FU/oxaliplatin combination chemotherapy in refractory colorectal cancer. Br J Cancer 91:344-354, 2004[Medline] 47. Jakobsen A, Nielsen JN, Gyldenkerne N, et al: Thymidylate synthase and methylenetetrahydrofolate reductase gene polymorphism in normal tissue as predictors of fluorouracil sensitivity. J Clin Oncol 23:1365-1369, 2005 48. Dotor E, Cuatrecases M, Martinez-Iniesta M, et al: Tumor thymidylate synthase 1494del6 genotype as a prognostic factor in colorectal cancer patients receiving fluorouracil-based adjuvant treatment. J Clin Oncol 24:1603-1611, 2006 49. Marcuello E, Altes A, del Rio E, et al: Single nucleotide polymorphism in the 5' tandem repeat sequences of thymidylate synthase gene predicts for response to fluorouracil-based chemotherapy in advanced colorectal cancer patients. Int J Cancer 112:733-737, 2004[CrossRef][Medline] 50. Pullmann R Jr, Abdelmohsen K, Lal A, et al: Differential stability of thymidylate synthase 3'UTR polymorphic variants regulated by AUF1. J Biol Chem 281:23456-23463, 2006 51. Uchida K, Hayashi K, Kawakami K, et al: Loss of heterozygosity at the thymidylate synthase (TS) locus on chromosome 18 affects tumor response and survival in individuals heterozygous for a 28-bp polymorphism in the TS gene. Clin Cancer Res 10:433-439, 2004 52. Hoshino S, Yamashita Y, Maekawa T, et al: Effects on DNA and RNA after the administration of two different schedules of 5-fluorouracil in colorectal cancer patients. Cancer Chemother Pharmacol 56:648-652, 2005[CrossRef][Medline] 53. Sobrero AF, Aschele C, Bertino JR: Fluorouracil in colorectal cancer—a tale of two drugs: Implications for biochemical modulation. J Clin Oncol 15:368-381, 1997 54. Cohen V, Panet-Raymond V, Sabbaghian N, et al: Methylenetetrahydrofolate reductase polymorphism in advanced colorectal cancer: A novel genomic predictor of clinical response to fluoropyrimidine-based chemotherapy. Clin Cancer Res 9:1611-1615, 2003 55. Etienne MC, Formento JL, Chazal M, et al: Methylenetetrahydrofolate reductase gene polymorphisms and response to fluorouracil-based treatment in advanced colorectal cancer patients. Pharmacogenetics 14:785-792, 2004[CrossRef][Medline] 56. Marcuello E, Altes A, Menoyo A, et al: Methylenetetrahydrofolate reductase gene polymorphisms: Genomic predictors of clinical response to fluoropyrimidine-based chemotherapy? Cancer Chemother Pharmacol 5:1-6, 2005[Medline] 57. Kweekel DM, Gelderblom H, Guchelaar HJ: Pharmacology of oxaliplatin and the use of pharmacogenomics to individualize therapy. Cancer Treat Rev 31:90-105, 2005[CrossRef][Medline] 58. Park DJ, Zhang W, Stoehlmacher J, et al: ERCC1 gene polymorphism as a predictor for clinical outcome in advanced colorectal cancer patients treated with platinum-based chemotherapy. Clin Adv Hematol Oncol 1:162-166, 2003[Medline] 59. Park DJ, Stoehlmacher J, Zhang W, et al: A Xeroderma pigmentosum group D gene polymorphism predicts clinical outcome to platinum-based chemotherapy in patients with advanced colorectal cancer. Cancer Res 61:8654-8658, 2001 60. Stoehlmacher J, Park DJ, Zhang W, et al: Association between glutathione S-transferase P1, T1, and M1 genetic polymorphism and survival of patients with metastatic colorectal cancer. J Natl Cancer Inst 94:936-942, 2002 61. Howie AF, Forrester LM, Glancey MJ, et al: Glutathione S-transferase and glutathione peroxidase expression in normal and tumour human tissues. Carcinogenesis 11:451-458, 1990 62. Moscow JA, Fairchild CR, Madden MJ, et al: Expression of anionic glutathione-S-transferase and P-glycoprotein genes in human tissues and tumors. Cancer Res 49:1422-1428, 1989 63. Ueda M, Hung YC, Terai Y, et al: Glutathione S-transferase GSTM1, GSTT1 and p53 codon 72 polymorphisms in human tumor cells. Hum Cell 16:241-251, 2003[Medline] 64. Hayes JD, Wolf CR: Townsend DM, et al: The role of glutathione-S-transferase in anti-cancer drug resistance. Oncogene 22:7369-7377, 2003[CrossRef][Medline] 65. Grothey A, McLeod HL, Green EM, et al: Glutathione S-transferase P1 I105V (GSTP1 I105V) polymorphism is associated with early onset of oxaliplatin-induced neurotoxicity. J Clin Oncol 23:3509, 2005 (abstr 3509) Submitted July 6, 2006; accepted December 20, 2006.
This article has been cited by other articles:
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
TOP
ABSTRACT
INTRODUCTION
