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Pharmacogenetic Profiling and Clinical Outcome of Patients With Advanced Gastric Cancer Treated With Palliative Chemotherapy

Annamaria Ruzzo, Francesco Graziano, Kazuyuki Kawakami, Go Watanabe, Daniele Santini, Vincenzo Catalano, Renato Bisonni, Emanuele Canestrari, Rita Ficarelli, Ettore Tito Menichetti, Davide Mari, Enrica Testa, Rosarita Silva, Bruno Vincenzi, Paolo Giordani, Stefano Cascinu, Lucio Giustini, Giuseppe Tonini, Mauro Magnani

From the Medical Oncology Unit, Hospital of Urbino; Institute of Biochemistry "G Fornaini," University of Urbino, Urbino; Medical Oncology Unit, University Campus Biomedico, Rome; Medical Oncology Unit, Hospital of Pesaro, Pesaro; Medical Oncology Unit, Hospital of Fermo, Fermo; Medical Oncology Unit, Hospital of Senigallia, Senigallia; Medical Oncology Unit, Hospital of Fabriano, Fabriano; Medical Oncology Unit, University of Ancona, Ancona, Italy; Department of Surgery, Kanazawa University School of Medicine, Kanazawa, Japan

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

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
PURPOSE: To investigate whether polymorphisms with putative influence on fluorouracil/cisplatin activity are associated with clinical outcomes of patients with advanced gastric cancer (AGC).

PATIENTS AND METHODS: Peripheral blood samples from 175 prospectively enrolled AGC patients treated with fluorouracil/cisplatin palliative chemotherapy were used for genotyping 13 polymorphisms in nine genes (TS, MTHFR, XPD, ERCC1, XRCC1, XRCC3, GSTPI, GSTTI, GSTMI). Genotypes were correlated to response and survival.

RESULTS: The overall response rate was 41%, the median progression-free survival (PFS) was 24 weeks (range, 4 to 50 weeks), and the median overall survival (OS) was 39 weeks (range, 8 to 72+ weeks). Chemoresistance and poor survival were significantly associated with TS 5'-UTR 3G-genotype (2R/3G, 3C/3G, 3G/3G) and GSTP1 105 A/A homozygous genotype. Sixty-one patients (35%) did not show any of these risk genotypes (group 0), 57 patients (32.5%) showed one of the two risk genotypes (group 1), and 57 patients (32.5%) showed both risk genotypes (group 2). Median PFS and OS in group 0 patients were 32 weeks (range, 8 to 50 weeks) and 49 weeks (range, 18 to 72+ weeks), respectively. Group 1 and group 2 patients showed significantly worse PFS (median, 26 weeks [range, 6 to 44 weeks] and 14 weeks [range, 4 to 38 weeks], respectively) and worse OS (median, 39 weeks [range, 10 to 58 weeks] and 28 weeks [range, 8 to 56 weeks]), respectively, than group 0 patients. This adverse effect was retained in multivariate analysis.

CONCLUSION: Specific polymorphisms may influence clinical outcomes of AGC patients. Selecting palliative chemotherapy on the basis of pretreatment genotyping may represent an innovative strategy that warrants prospective studies.

	INTRODUCTION

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Fluorouracil coupled with cisplatin has been a common combination regimen used in patients with advanced gastric cancer.¹ Genomic polymorphisms in drug target genes, genes encoding DNA-repair enzymes, and detoxification pathways may influence the activity of the two compounds.^2,3 Therefore, associations between polymorphisms and clinical end points may improve the prediction of treatment success and thereby the tailoring of chemotherapy. This would be especially useful now that novel compounds are available for the treatment of advanced gastric cancer.^4,5 Current evidence indicates that elevated thymidylate synthase (TS) protein levels may interfere with the mechanisms of action of fluorouracil.^2,3 The majority of studies have been performed in colorectal cancer patients, and a recent meta-analysis confirmed poorer overall survival of patients with enhanced TS activity compared with cases with low TS activity.⁶ Polymorphisms in the thymidylate synthase gene (TS) 5'-untranslated region (5'-UTR) have been shown to enhance mRNA translational efficiency and stability,^7-9 with upregulation of TS protein levels.^10-12 The polymorphic tandem repeat (VNTR) in TS 5'UTR consists of either two or three 28-bp repeated sequences (2R or 3R alleles).⁷ A G/C polymorphism within the 3R VNTR allele was found to determine two additional alleles (3G or 3C) at this locus.^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, 3G/3G) showed correlation with high TS mRNA expression.^11,12 Another 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+ genotype carriers than in 6–/6– genotype carriers¹² may influence chemosensitivity to fluorouracil and clinical outcomes.¹⁴

It is under investigation whether the presence of a C/T nucleotide change at the 677 position in the methylenetetrahydrofolate reductase (MTHFR) gene is correlated with better outcomes of gastrointestinal cancer patients treated with fluorouracil. MTHFR 677C/T results in an alanine-to-valine substitution in the MTHFR protein that induces a thermolabile variant of the enzyme with reduced activity. In experimental models, the MTHFR 677T allele was found to enhance fluorouracil chemosensitivity.¹⁵

Resistance to platinum agents has been attributed to enhanced tolerance and repair of DNA damage.^16,17 The excision repair cross complementing 1 (ERCC1) gene, the x-ray cross complementing group 1 (XRCC1) gene, the Xeroderma Pigmentosum Group D (XPD) gene and the x-ray Cross Complementing group 3 (XRCC3) gene participate in several distinct DNA-repair pathways. ERCC1, XRCC1, XPD, ERCC3 products showed potential influence on cisplatin sensitivity of tumor cells.^18-22 A number of putative functional polymorphisms in these genes^23-31 are under investigation for predictive role in patients with solid tumors treated with platinum compounds (Table 1). Resistance to platinum agents may also depend on altered detoxification pathways.^16,17 Cisplatin activity seems related to genetic variations in the glutathione S-transferase (GST) family of isoenzymes.^32-35 A single nucleotide substitution in GSTP1, which results in replacing isoleucine with valine, diminishes GSTP1 enzyme activity.³² Inherited homozygous deletions in GSTT1 or GSTM1 lead to an absence of enzymatic activity.^33,34

	PATIENTS AND METHODS

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Study Population
Two hundred seventy-two gastric cancer patients were prospectively accrued in two case-control studies for disease susceptibility.^36,37 Patients undergoing palliative chemotherapy were also evaluated for inclusion in a protocol of pharmacogenetic analysis. Eligibility criteria were: presence of metastatic disease (at diagnosis or during follow-up), presence of measurable disease, Karnofski performance status (KPS) 70, and indication for fluorouracil/cisplatin palliative chemotherapy. Blood samples for genotyping were taken before starting chemotherapy. Data management was centralized (University of Urbino, Urbino, Italy). 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
Genomic DNA was extracted from 200 mL whole blood using the QiaAmp kit (Qiagen, Valencia, CA). All polymorphisms were investigated using a polymerase chain reaction (PCR) –restriction fragment length polymorphism (RFLP) technique, except variants in GSTM1 and GSSTT1. GSTT1 null and GSTM1 null were determined simultaneously using a multiplex PCR protocol. The assays for studying polymorphisms were performed as described previously; primer sequences, restriction enzymes, and references are presented in Table 1.

Statistical Analyses
The Response Evaluation Criteria in Solid Tumors criteria were adopted for evaluation of response.³⁸ The overall survival (OS) time was calculated from the start of chemotherapy to death from any cause; patients who were alive at the last follow-up were censored at that time. The progression-free survival (PFS) time was calculated from the start of chemotherapy to first evidence of disease progression. Each genotype was independently analyzed for correlation with response to chemotherapy and survival times. A combined analysis was planned if multiple genotypes showed a significant association. The ² test was used to compare proportions of patients for demographic and genotype factors. The Kaplan-Meier method was adopted to estimate survival curves, and the log-rank test was used to compare patients' survival time between genotype groups. Univariate and multivariate analyses using Cox regression were used to assess the importance of genotypes with adjustment for clinical and histopathologic features. All P values were two-sided. Statistical significance was defined as P < .05 with subsequent Bonferroni correction for multiple comparisons where applicable.

	RESULTS

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Study Population
The study was performed in 175 of 185 eligible patients. Five patients were excluded since they had received chemotherapy with single-agent fluorouracil, and genotyping was unsuccessful in another five patients. The characteristics of the 175 studied patients are presented in Table 2. As expected, there was a prevalence of male patients and patients with intestinal-type gastric carcinoma. The majority of patients showed KPS ranging from 90 to 100, and metastatic disease to the liver and lymph nodes. Overall frequencies of the studied polymorphisms are presented in Table 3. No significant associations between polymorphisms and demographic, clinical, or pathological characteristics were observed (data not shown).

Survival and Genotypes
At the time of the final analysis (June 2005), all patients showed disease progression, and four patients were alive. In the whole group, the median PFS time was 24 weeks (range, 4 to 50 weeks) and the median OS time was 39 weeks (range, 8 to 72+). Among the 13 studied polymorphisms, significantly inferior OS and PFS times were found in TS 5'-UTR 3G carriers (2R/3G, 3C/3G, 3G/3G; Fig. 1A and B) and GSTP1 105A/A homozygous genotype carriers (Fig. 1C and D).

View larger version (18K): [in this window] [in a new window]   Fig 1. Kaplan-Meier estimates of progression-free (PFS) and overall survival (OS) by thymidylate synthase gene (TS) 5'-untranslated region (5'-UTR) and GSTP1 105 genotypes. (A) Patients with 3G/3G genotype and 2R/3G, 3C/3G genotypes had significantly worse PFS compared to patients with 2R/2R, 2R/3C, 3C/3C genotypes (P < .0001 and P = .0002, respectively). (B) Patients with 3G/3G genotype and 2R/3G, 3C/3G genotypes had significantly worse OS than patients with 2R/2R, 2R/3C, 3C/3C genotypes (P < .0001 and P = .0002, respectively). (C) Patients with GSTP1 105 A/A genotype had significantly worse PFS compared with those in either the GSTP1 105 G/A (P < .0001) or GSTP1 105 G/G (P < .0001) genotype groups. (D) Patients with GSTP1 105 A/A genotype had significantly worse OS compared with those in either the GSTP1 105 G/A (P < .0001) or GSTP1 105 G/G (P < .0001) genotype groups.

View larger version (9K): [in this window] [in a new window]   Fig 2. Progression-free (PFS) and overall survival (OS) curves in carriers of 0 risk genotypes (61 patients), one risk genotype (57 patients) and two risk genotypes (57 patients). (A) Number or risk genotypes and PFS; the results of log-rank comparisons are: P = .001 in 0 v 1; P < .0001 in 0 v 2; P = .0004 in 1 v 2. (B) Number or risk genotypes and OS. The results of log-rank comparisons are: P = .001 in 0 v 1; P < .0001 in 0 v 2; P < .0008 in 1 v 2.

	DISCUSSION

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In advanced colorectal cancer patients treated with fluorouracil chemotherapy, Pullarkat et al³⁹ found lower response rates in carriers of TS 5'-UTR 3R/3R and TS 5'-UTR 2R/3R genotypes compared with patients with homozygous TS 5'-UTR 2R/2R genotype. In colorectal cancer patients treated with a palliative fluorouracil/oxaliplatin regimen, Stoehlmacher et al⁴⁰ did not observe any significant difference in the outcome of patients according to TS 5'-UTR genotypes. In a recent study by Jakobsen et al,⁴¹ TS 5'-UTR 3R genotypes carriers showed even better outcomes than patients with TS 5'-UTR 2R/2R genotypes. These divergent findings suggest that the simple analysis of the TS 5'-UTR VNTR polymorphism and the distinction between 2R and 3R allele carriers may not be sufficient for studying clinical outcomes. The discovery of a single nucleotide C/G change within the 3R allele and the functional differentiation between 3G and 3C allele carriers has opened new perspectives for studying TS 5'-UTR genotypes.⁴² Recently, Marcuello et al⁴³ showed that colorectal cancer patients with 2R/3G, 3C/3G, 3G/3G genotypes had worse survival than patients with 2R/2R, 2R/3C, 3C/3C genotypes. Our findings corroborate the results of experimental and in vivo studies that indicate the TS 5'-UTR VNTR C/G double assessment more relevant than the simple TS 5'-UTR VNTR analysis and the TS 5'-UTR 3G genotype (2R/3G, 3C/3G, 3G/3G) as a marker of adverse clinical outcomes.

In the present study, the TS 3'-UTR 6+/6– polymorphism did correlate with clinical outcomes. Stoehlmacher et al⁴⁰ and McLeod et al⁴⁴ found adverse outcomes in TS 3'-UTR 6–carriers. In vitro, the TS 3'-UTR 6+ allele showed higher TS mRNA stability than the TS 3'-UTR 6–allele¹⁴ and therefore, TS 3'-UTR 6+ carriers should represent the category of patients with potential fluorouracil chemoresistance. One possible explanation for divergent findings between experimental and in vivo studies is that the TS 3'-UTR 6+/6–polymorphism does not play relevant functional roles per se, and the TS 3'-UTR 6–allele may emerge as a predictive/prognostic marker because of some linkage disequilibrium with TS 5'-UTR,³⁷ or a yet unidentified locus. Notably, in two subsequent experimental studies TS 3'-UTR 6+/6– variants did not show any significant correlation with TS mRNA efficiency/stability and protein levels.^45,46

The third polymorphism with putative influence on fluorouracil chemotherapy-sensitivity is MTHFR 677C/T. The reduced activity of the thermolabile variant of the MTHFR enzyme in allele T carriers increases availability of 5,10-methylenetetrahydrofolate, which is a necessary cofactor for fluorouracil inhibition of TS. In an experimental model, fluorouracil showed increased activity in the presence of the MTHFR 677T allele.¹⁵ However, other investigators did not confirm this finding.⁴⁶ Similarly, in vivo studies showed diverging results, with favorable^41,47 or no clear prognostic effect^48,49 of the MTHFR 677T allele in colorectal cancer patients treated with fluoropyrimidine-based palliative chemotherapy. In the present study, the MTHFR 677T allele was not associated with improved outcomes of advanced gastric cancer patients. Assuming the functional effect of the MTHFR 677T allele, there is another possible explanation for inconclusive observations in vivo. Cellular availability of cofactor 5,10-methylenetetrahydrofolate for fluorouracil TS inhibition may not only depend on the presence of the MTHFR 677C/T variant, but it is linked to other factors, like folate in the diet. It is possible that patients with low folate intake are more susceptible to the effects of MTHFR 677C/T than patients with optimal folate intake.⁵⁰ In the latter, cofactor 5,10-methylenetetrahydrofolate availability may be adequate for fluorouracil TS inhibition even if they are carriers of the MTHFR 677C allele. In this perspective, MTHFR 677C/T polymorphism may show variable pharmacogenetic effects according to the features of studied populations.

Among the three polymorphisms with potential influence on cisplatin activity because of altered drug detoxification (GSTP1, GSTM1, GSTT1), carriers of GSTP1 105A/A homozygous genotype showed unfavorable clinical outcomes. This finding parallels the results observed in colorectal cancer patients by other groups,^40,51 but for example, they are divergent with respect to studies in breast cancer patients,^52,53 where GSTM1 null and GSTT1 null variants showed prognostic influence. Assuming GSTM1 null and GSTT1 null as functional variants, it is likely that tissue specificity and drug specificity of GSTP, GSTM, and GSTT may explain the observed differences in the clinical impact of each isoemzyme. GSTP is the predominant GST in the majority of tumors, but its concentration was found to be significantly increased in lung, colon, and stomach cancer tissues⁵⁴ and lower in lymphoma and breast cancer.⁵⁵ In in vitro analyses of cancer cell lines,⁵⁶ the GSTM1 null genotype was dominant in small-cell lung, kidney, breast, and ovarian carcinoma cells, whereas the GSTT1 null genotype was dominant in cervical and endometrial carcinoma cells. Moreover, GSTP seems to be predominantly correlated with platinum compounds detoxification with respect to GSTT and GSTM variants.^57,58

In the present study, none of the polymorphisms with putative influence on DNA-repair functions from cisplatin damages showed correlation with clinical outcomes. In experimental models, the ERCC1 118T allele variant showed potential functional consequences, with a trend toward higher ERCC1 mRNA levels than those observed in the presence of the ERCC1 118C allele.⁵³ Stoehlmacher et al⁴⁰ found adverse prognostic effect of the ERCC1 118T allele, but it was limited to carriers of the ERCC1 118C/T heterozygous genotype. Notably, Viguier et al⁵⁹ found that colorectal cancer patients who were carriers of the ERCC1 118T allele were more likely to respond to oxaliplatin/fluorouracil chemotherapy than carriers of the ERCC1 118C allele. The ERCC1 118C/T polymorphism predicted adverse survival in two of three studies in non–small-cell lung cancer patients treated with cisplatin-based chemotherapy.^60-62 In vivo, XRCC1 399Arg/Gln and XPD 751Lys/Gln variants showed conflicting findings. These two polymorphisms were found to be predictive of clinical outcomes in colorectal cancer patients treated with oxaliplatin/fluorouracil.^63,64 Subsequently, Stoehlmacher et al⁴⁰ failed to confirm XRCC1 399Arg/Gln as a prognosticator, and McLeod et al⁴⁴ did not find a significant predictive role for XPD 751Lys/Gln. In non–small-cell lung cancer patients treated with cisplatin-based chemotherapy, both XRCC1 399Arg/Gln and XPD 312Aps/Asn⁶⁵ variants showed adverse prognostic effect, but these findings have not been confirmed by other groups.^61,62 To the best of our knowledge, the clinical impact of the XRCC3 241 polymorphism has only been investigated in soft tissue sarcoma patients and without showing any prognostic role.⁶⁶ Possible explanations for inconclusive data on the clinical impact of these polymorphisms are the small sample size of the studies, their retrospective nature and the heterogeneity of clinical settings. Also, some differences seem to exist between cisplatin and oxaliplatin detoxification/DNA repair pathways¹⁶; therefore, these polymorphisms may play variable roles according to the platinum compound that is used in the clinical practice. It must be also considered that these in vivo investigations have been performed on the basis of experimental data that have not always unequivocally indicated the functional effect of the studied polymorphisms. For example, it is still unclear how the ERCC1 118 C/T single nucleotide change may determine major functional consequences ever since the ERCC1 118T allele variant results in the same amino acid asparagines.²³ Lunn et al²⁸ showed that the possession of a XPD Lys/Lys751 genotype increased the risk of suboptimal DNA repair. On the opposite, Seker et al³¹ did not find functional effect of XPD Lys751Gln and Asp312Asn variants.

An additional potential confounder in cancer pharmacogenetic analyses is the presence of loss of heterozygosity (LOH) in the tumor. LOH has been described at TS 5'-UTR locus in colorectal carcinomas,⁶⁷ where the heterozygous TS 5'-UTR 2R/3G risk genotype could acquire either the 2R/loss or the 3G/loss genotype. Consequently, a proportion of patients with expected chemoresistance on the basis of the genomic TS 5'-UTR 2R/3G status may harbor the favorable 2R/loss genotype in cancer cells. We cannot exclude that LOH occurred in a proportion of our gastric cancer cases; however, the genomic TS 5'-UTR VNTR C/G double assessment demonstrated its predictive value.

In conclusion, TS 5'-UTR 3G allele genotypes and the GSTP1 105A/A genotype have been found to be predictive of suboptimal response to fluorouracil/cisplatin chemotherapy and poor survival of patients with advanced gastric cancer. When the two independent genotypes are both present, it seems possible to identify about one third of patients gaining the least benefit from palliative chemotherapy. The study plan did not include a formal assessment of the relationship between genotypes and toxicity. However, dose reduction, delay, and discontinuation of treatment did not differ significantly between genotype groups (data not shown). In our opinion, this analysis should rule out the association between genotypes and major adverse effects of chemotherapy. Selecting palliative chemotherapy on the basis of predictive genotypes may represent an innovative strategy that warrants prospective studies.

	Authors' Disclosures of Potential Conflicts of Interest

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
The authors indicated no potential conflicts of interest.

	Author Contributions

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 

Conception and design: Annamaria Ruzzo, Francesco Graziano, Kazuyuki Kawakami, Go Watanabe, Mauro Magnani Financial support: Mauro Magnani Administrative support: Francesco Graziano, Emanuele Canestrari, Enrica Testa, Mauro Magnani Provision of study materials or patients: Annamaria Ruzzo, Francesco Graziano, Kazuyuki Kawakami, Daniele Santini, Vincenzo Catalano, Renato Bisonni, Rita Ficarelli, Ettore Tito Menichetti, Davide Mari, Enrica Testa, Rosarita Silva, Bruno Vincenzi, Paolo Giordani, Stefano Cascinu, Lucio Giustini, Giuseppe Tonini, Mauro Magnani Collection and assembly of data: Annamaria Ruzzo, Francesco Graziano, Daniele Santini, Vincenzo Catalano, Renato Bisonni, Emanuele Canestrari, Rita Ficarelli, Ettore Tito Menichetti, Davide Mari, Rosarita Silva Data analysis and interpretation: Annamaria Ruzzo, Francesco Graziano, Kazuyuki Kawakami, Go Watanabe, Emanuele Canestrari, Mauro Magnani Manuscript writing: Annamaria Ruzzo, Francesco Graziano, Kazuyuki Kawakami, Mauro Magnani Final approval of manuscript: Annamaria Ruzzo, Francesco Graziano, Kazuyuki Kawakami, Go Watanabe, Daniele Santini, Vincenzo Catalano, Renato Bisonni, Emanuele Canestrari, Rita Ficarelli, Ettore Tito Menichetti, Davide Mari, Enrica Testa, Rosarita Silva, Bruno Vincenzi, Paolo Giordani, Stefano Cascinu, Lucio Giustini, Giuseppe Tonini, Mauro Magnani

 

	ACKNOWLEDGMENTS

 
We thank Cathie Spino, ScD, PhD, for fruitful comments and help in the editing of the manuscript.

	NOTES

 
Supported by Consorzio Interuniversitario per le Biotecnologie (CIB) and Fanoateneo.

A.R. and F.G. contributed equally to this study.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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Submitted November 9, 2005; accepted February 14, 2006.

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