© 2006 European Society for Medical Oncology
gastrointestinal tumors |
Prognostic value of expression of ERCC1, thymidylate synthase, and glutathione S-transferase P1 for 5-fluorouracil/oxaliplatin chemotherapy in advanced gastric cancer
1 Department of Internal Medicine
2 Department of Pathology
3 Department of Surgery, Dong-A University College of Medicine, Busan, Korea
* Correspondence to: Prof H.-J. Kim, Department of Internal Medicine, Dong-A University College of Medicine, 3-1 Dongdaeshin-dong, Seo-gu, Busan 602-715, Korea. Tel: +82-51-240-2951; Fax: +82-51-240-2951; E-mail: kimhj{at}dau.ac.kr
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Abstract |
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 Top Abstract introductionpatients and methodsresultsdiscussionReferences |
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Background: The aim of this study was to determine whether expressions of the excision repair cross-complementing (ERCC1), thymidylate synthase (TS), and glutathione S-transferase P1 (GSTP1) predict clinical outcome in patients with advanced gastric cancer treated with fluorouracil (5-fluorouracil)/oxaliplatin chemotherapy.
Patients and methods: The study population consisted of 64 advanced gastric cancer patients (median age 51 years). Patients were treated with oxaliplatin 85 mg/m2 as a 2-h infusion at day 1 plus leucovorin 20 mg/m2 over 10 min, followed by 5-FU bolus 400 mg/m2 and 22-h continuous infusion of 600 mg/m2 at days 1–2. Treatment was repeated in 2-week intervals. The expressions of ERCC1, TS, and GSTP1 of primary tumors were examined by immunohistochemistry.
Results: The positive rates of ERCC1, TS, and GSTP1 were 70.3%, 29.7%, and 50.0%, respectively. The patients without ERCC1 expression were more likely to respond to chemotherapy (P = 0.045). There were no significant differences between response and TS or GSTP1 expression pattern (P = 0.813, P = 0.305, respectively). Median overall survival (OS) was significantly longer in patients without ERCC1 expression (P = 0.0396). TS or GSTP1 expression were not related to survival (P = 0.4578, P = 0.8121, respectively). Multivariate analysis revealed that ERCC1 expression significantly impacted on OS (hazard ratio 1.92, P = 0.037).
Conclusion: Immunohistochemical studies for ERCC1 may be useful in prediction of the clinical outcome in advanced gastric cancer patients treated with 5-FU and oxaliplatin.
Key words: ERCC1, Gastric Cancer, Oxaliplatin
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introduction |
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TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
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In Korea, gastric cancer is the most common carcinoma and the second leading cause of death [1]. Despite substantial developments in early gastric cancer detection, only about 30% of patients are eligible for resection at presentation. Moreover, its high incidence of relapse is invariably associated with incurability. In general prognosis is poor; 5-year overall survival (OS) of patients with advanced gastric cancer is 5%–15% [2]. In the past three decades, a variety of chemotherapy regimens have been developed to treat advanced gastric cancer [3]. Systemic chemotherapy is widely accepted as palliative treatment, and leads to objective response, an improved quality of life, and prolonged survival, and a 5-fluorouracil (5-FU) and platinum-based regimens have been indicated as effective first-line treatments for advanced gastric cancer [4, 5]. Response to this combination chemotherapy in advanced or metastatic gastric cancer is usually about 30%–55%. There is, however, an urgent need for new treatments with better therapeutic indices and novel agents with lower levels of cross-resistance.
Oxaliplatin is an innovative third-generation platinum compound with powerful antineoplastic competence, a lack of cross drug resistance with cisplatin, a synergistic effect with 5-FU, and a satisfactory safety profile [6, 7]. Oxaliplatin is an alkylating agent that inhibits DNA replication by forming adducts between adjacent guanines or guanine and adenine. Moreover, these oxaliplatin adducts appear to be more effective than those of cisplatin with regard to inhibiting DNA synthesis [8]. In addition, oxaliplatin has a more favorable toxicity profile than cisplatin [9]. The oxaliplatin/5-FU combination has proven to be an effective first- or second-line treatment of advanced colorectal cancer [10, 11], and the preliminary results of several recent studies indicate that various combinations of oxaliplatin and 5-FU may be as effective in gastric cancer [12–14].
Although the synergistic effects of 5-FU and oxaliplatin have increased response rates to 25%, even in heavily pretreated relapsing patients, the mechanisms of resistance remain unknown. Resistance to platinum agents has been attributed to enhanced tolerance to platinum DNA adducts, decreased drug accumulation, and enhanced DNA repair [15]. Proteins of the nucleotide excision repair (NER) pathway are believed to repair DNA damage caused by platinum agents. Moreover, the excision repair cross-complementing (ERCC) gene family prevents damage to DNA caused by nucleotide excision and repair. The interactions between the product of the ERCC1 gene and XPA (Xeroderma pigmentosum group A) and XPF are critical in this repair process [16]. Moreover, correlations between increased ERCC1 expression and response and survival have been reported for colon cancer [17].
Fluoropyrimidines are widely used to treat gastric cancer, and high levels of their target, enzyme thymidylate synthase (TS), have been correlated with drug resistance and a poorer outcome [18]. TS is the rate-limiting enzyme in the synthesis of pyrimidine nucleotides required for DNA synthesis and is also a critical target for fluoropyrimidines. Increased expression of TS protein may be an important mechanistic component of resistance to fluoropyrimidines. Moreover, intrinsic cell TS content may be a predictor of response to 5-FU chemotherapy. Conflicting results, however, have been reported concerning TS expression in gastric cancer [19, 20].
Glutathione and other components of the glutathione metabolic pathway may also have critical roles in determining cellular sensitivity to platinum-based chemotherapy. Glutathione is a ubiquitous tripeptide, which has been hypothesized to protect against the DNA damaging effects of agents by conjugating toxic moieties, including metal compounds, in the cytoplasm and preventing their interaction with DNA [21]. Glutathione S-transferase 
(GST) is a member of a family of isozymes that play an important role in the detoxification of many xenobiotic substances through conjugation to glutathione [22], and the subclass GSTP1 (Glutathione S-transferase pi 1) is widely expressed in normal human epithelial tissues and has been shown to be highly overexpressed in colon cancer [23]. GSTP1 participates directly in the detoxification of platinum compounds and is an important mediator of both intrinsic and acquired resistance to platinum [24]. In fact, immunohistochemical studies have shown that GSTP1 expression may predict response to cisplatin-based chemotherapy [25].
The aim of this study was to determine whether expressions of ERCC1, TS, and GSTP1 predict clinical outcome in patients with advanced gastric cancer treated with 5-FU/oxaliplatin.
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patients and methods |
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TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
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eligibility criteria
All patients in this study had histologically confirmed adenocarcinoma of the stomach. They had unresectable metastases with bidimensionally measurable lesions
2 cm. These patients were treated by 5-FU/oxaliplatin chemotherapy. Patients were selected for this analysis primarily on the basis of availability of adequate tissue for study. Clinical data were obtained by retrospective chart review. All patients had a performance status less than or equal to two according to the Eastern Cooperative Oncology Group scale, and adequate bone marrow and renal function, and age between 18 and 79 years. Previous adjuvant chemotherapy must be completed at least 6 months before inclusion. Exclusion criteria included the presence of central nervous system metastases, serious or uncontrolled concurrent medical illness, and a history of other malignancies. Written informed consent was obtained from each patient before study entry. The use of all patient material was approved by our institutional review board.
treatment protocols and dose modification
On day 1, oxaliplatin (85 mg/m2) was administered by intravenous (i.v.) infusion in 500 ml of normal saline or dextrose over 2 h. On day 1 and 2, leucovorin (20 mg/m2) was administered as an i.v. bolus, immediately followed by 5-FU (400 mg/m2) given as a 10-min i.v. bolus, followed by 5-FU (600 mg/m2) as a continuous 22-h infusion, with a light shield. Dose modifications of oxaliplatin or 5-FU were made for hematologic, gastrointestinal, or neurologic toxic effects on the basis of the most severe grade of toxicity that had occurred during the previous cycle. Treatment could be delayed for up to 2 weeks if symptomatic toxicity persisted, or if the absolute number of neutrophils was <1500/µl or platelets count was <100 000/µl. The 5-FU dose was reduced by 25% for subsequent courses after National Cancer Institute Common Toxicity Criteria (NCI-CTC) grade 3 diarrhea, stomatitis, or dermatitis had occurred. The dose of oxaliplatin was reduced by 25% in subsequent cycles if there were persistent paresthesias between cycles or paresthesias with functional impairment lasting >7 days. Treatment was continued until there were signs of disease progression, unacceptable toxic effects developed, or the patient refused further treatment.
follow-up evaluation and assessment of response
Before each treatment courses, a physical examination, routine hematology, biochemistry, and chest X-ray were carried out. The serum CEA (carcinoembryonic antigen) levels were determined after each cycle. Computed tomography scans to define the extent of the disease, and the responses were carried out after four cycles of chemotherapy, or sooner if there was evidence of any clinical deterioration. Patients were assessed before starting each 2-week cycle using the NCI-CTC, except in the case of neurotoxicity. For the neurotoxicity, an oxaliplatin-specific scale was used: grade 1, paresthesias or dysesthesias of short duration, but resolving before the next dosing; grade 2, paresthesias persisting between doses (2 weeks); and grade 3, paresthesias interfering with function. Complete response was defined as the complete disappearance of all assessable disease for at least 4 weeks; partial response indicated a decrease of at least 50% in the sum of the products of the diameters of measurable lesions for at least 4 weeks. Stable disease was defined as a decrease of <50% or an increase of <25% in tumor size, and progressive disease was an increase of at least 25% or the appearance of new neoplastic lesions.
immunohistochemical analysis for ERCC1, TS, and GSTP1
The tumor samples were taken from primary stomach by endoscopic biopsy or curative surgery. Immunohistochemical studies for ERCC1, TS, and GSTP1 were carried out on formalin-fixed, paraffin-embedded, 4 µm-thick tissue sections, using the avidin–biotin-peroxidase complex method. The primary antibodies used were mouse monoclonal antibodies directed against ERCC1 (1 : 100, Neomarker, Fremont, CA), TS (1 : 50, Zymed, South San Francisco, Carpinteria, CA), and GSTP1 (1 : 50, Dako, CA). Deparaffinization of all sections was carried out through a series of xylene baths, with rehydration through a series of graded alcohol solutions. To enhance the immunoreactivity, microwave antigen retrieval was carried out at 750 W for 10 min in Tris–EDTA buffer (pH 9.0) for ERCC1 and in citrate buffer (pH 6.0) for TS and GSTP1. After blocking the endogenous peroxidase activity with 3% hydrogen peroxidase for 30 min, the primary antibody incubation for ERCC1 was carried out for 1 h at room temperature and those for TS and GSTP1 were carried out for 1.5 h at room temperature. A Cap-PlusTM Detection Kit (Zymed) was used for the secondary antibody for 30 min at room temperature. After washing the tissue samples in Tris buffered saline for 10 min, 3, 3'-diaminobenzidine was used as a chromogen, and then Gill's hematoxylin V counterstain was applied. Staining was graded for intensity of staining (1, weak; 2, moderate; 3, strong) and percentage of cells stained (1, 0% to <10%; 2, 10% to <50%; 3, 50%–100%). Staining for ERCC1 was considered to be positive when tumor cells showed nuclei reactivity and both scores were two or above. Stainings for TS and GST were considered to be positive when tumor cells showed nuclei or cytoplasmic reactivity and both scores were two or above; negative otherwise.
statistical analysis
The variables of inclusion in the model were sex, age, the baseline CEA level, sites of metastases, number of metastasis, previous operation, and expression of biological markers include ERCC1, TS, and GSTP1. Contingency tables and Fisher's exact test were used for the categorical variables to evaluate the association of the expression of markers and the response to chemotherapy. The time to progression (TtP) and OS were calculated from the date therapy started to the date of disease progression and death, respectively. Patients who were alive at the last follow-up were censored at that time. Patients who were taken off study or who died before progression were censored at the time that they were taken off study. The association of each marker with survival was analyzed using Kaplan–Meier plots, the log-rank test, and its associated 95% confidence interval (CI) was calculated. Multivariate analyses were carried out using the Cox proportional hazards model. All tests were two-sided, and P < 0.05 was considered statistically significant. Analyses were done using SPSS version 11.0 (SPSS Inc, Chicago, IL).
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results |
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patient characteristics
Sixty-four patients registered from January 2004 to August 2005 were enrolled into this study. Demographic details on the patients included in the study are shown in Table 1. Median age of the patients was 51 years (range 31–74). Forty patients underwent curative operation (stage I, 8; stage II, 12; stage IIIA, 10; stage IIIB, 10), and a palliative resection was done in 19 out of 24 stage IV patients. Twenty-one patients received 5-FU-based adjuvant chemotherapy, and 11 patients received postoperative chemoradiotherapy.
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biological marker expression
Positive staining for ERCC1 was observed in the nuclei in 45 of the 64 cases (70.3%, Figure 1A). TS expression was observed in 19 cases (29.7%, Figure 1B). GSTP1 was detected in 50% (32 of 64, Figure 1C). For all biological markers, the staining pattern was heterogeneous, and not all cancer cells were stained. Expression of biological markers was not associated with age, sex, CEA level, and sites of metastasis (data not shown).
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association of biological marker expression with chemotherapy response
The overall chemotherapy response rate for treatment was 39.1% (25 of 64 cases). Table 2 shows the relationship between biological markers and clinical response to chemotherapy. Although there was a trend between expression of ERCC1 markers and clinical resistance to chemotherapy (P = 0.045), none of the biological markers measured were significantly correlated with response. Other parameters, such as age, sex, performance status, previous operation, CEA level, and number of organ involvement were not significantly correlated with clinical response to chemotherapy.
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association of biological marker expression with TtP and OS
The median OS was 8.9 months (95% CI 7.6–10.2 months), and the median TtP was 4.2 months (95% CI 2.8–5.6 months). Table 3 shows the association of patients' characteristics and clinicopathologic features with TtP in the 64 patients analyzed. For biological markers analyzed, TtP was approximately twice as long for patients who were ERCC1-negative compared with patients who were ERCC1-positive and the difference achieved statistical significance (P = 0.0211). Expression of TS and GSTP1 were not significantly correlated with TtP in patients treated with palliative chemotherapy. Clinical parameters including age, sex, performance status, CEA level, and previous operation were not correlated with TtP. Patients with more than two sites of metastasis were related to worse TtP (P = 0.0016).
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Those patients with significant ERCC1 expression had an overall poorer survival compared with patients whose tumors did not express ERCC1 (P = 0.0396, Figure 2). Expression of TS and GSTP1 were not correlated to OS for the patients evaluated. Among clinical parameters evaluated, good performance status and lower number of metastasis were associated with an improved OS (P = 0.0223, P = 0.0042, respectively), but other clinicopathological factors were not statistically associated with OS (Table 3). Therefore, three variables were significant predictors of OS: performance status, number of metastasis, and ERCC1 expression. The final multivariable analysis is shown in Table 4. ERCC1 was the only significant independent prognostic factor impacted on OS (hazard ratio 1.91, P = 0.037).
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discussion |
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The 5-FU/oxaliplatin regimen is used as effective palliative treatment of gastric cancer [15–18]. We previously reported on the effectiveness of oxaliplatin with biweekly low-dose leucovorin and bolus/continuous infusion of 5-FU (modified FOLFOX 4) as a salvage therapy in advanced gastric cancer patients [13], and found a response rate of 26.7%, a median TtP of 3.5 months, and a median OS time of 7.9 months [13]. Recently, an Italian study revealed that the FOLFOX 4 regimen is also effective as a first-line chemotherapy in advanced gastric cancer [14]. Therefore, prognostic markers are required to identify those patients likely to benefit from treatment.
Oxaliplatin is a new platinum analogue that differs chemically from cisplatin by the presence of a diaminocyclohexane ligand. Oxaliplatin/DNA adducts are repaired by the NER system, and two enzymes, XPA and ERCC1, have been found to be essential for this repair process [26]. Moreover, low ERCC1 expression is known to be correlated with prolonged survival after cisplatin-based chemotherapy in non-small-cell lung cancer and colorectal cancer [27, 28]. In addition, ERCC1 and TS messenger RNA (mRNA) levels have been reported to predict the response rate and survival of gastric cancer patients on combination cisplatin and fluorouracil chemotherapy [29]. We also found that ERCC1 expression is related to response to chemotherapy (P = 0.045), and poorer OS (P = 0.0396). Irinotecan or taxane-based regimens can be used to treat ERCC1-positive advanced gastric cancer patients [3].
The inhibition of TS by fluorodeoxyuridine monophosphate is a principal mechanism of 5-FU. Overexpression of TS at the protein and mRNA levels has been found to be correlated with resistance to 5-FU chemotherapy in colorectal and gastric cancer patients [30]. In the present study, however, TS expression was not found to be related to chemotherapeutic response (P = 1.000) or OS (P = 0.4578), which concurs with a previous study [19]. In the present study, the lack of an association between TS expression in primary tumors and patient OS may be due to the fact that 50% (32 of 64) of our patients received 5-FU-based adjuvant chemotherapy or chemoradiation. There is also a possibility that the level and extent of TS protein expression in primary tumors does not correlate with OS in patients with metastatic or recurrent colorectal cancer [31]. Variable molecular phenotypes and clinical behaviors of diseases at metastatic sites may be related to the lack of an association between TS expression in primary tumors and OS.
The GST superfamily participates in the detoxification of platinum compounds. Oxaliplatin, like cisplatin, is inactivated by being reacted with glutathione, a reaction catalyzed by GST. Few biochemical studies and clinical reports provide strong evidence of the direct involvement of GSTP1 in resistance to platinum compounds. GSTP1, however, is directly involved in the detoxification of cisplatin via the formation of cisplatin–glutathione adducts, which indicates that GSTP1 plays a role in the acquisition of resistance to this platinum compound [24]. Clinical reports on head and neck cancers also reflect the important role of GST enzymes in the metabolism of platinum drugs [32, 33]. The majority of patients who showed low GST protein expression levels in tumor tissues responded to a platinum-based treatment and showed better survival than patients with high GST expression levels. Moreover, the GSTP1 Ile105Val polymorphism has been reported to be associated in a dose-dependent fashion with the increased survival of advanced colorectal cancer patients receiving 5-FU/oxaliplatin chemotherapy [34]. In the present study, however, GSTP1 was not associated with chemotherapeutic response (P = 0.305) or OS (P = 0.8121).
Limitations of immunohistochemical staining are attributable to its semiquantitative nature, tissue aging effects, the staining technique and the enzyme antibody used, and interobserver variation. These points may explain the lack of association between enzyme expression and chemotherapeutic response and survival in the present study. Nevertheless, multivariate analysis revealed that ERCC1 expression is significantly related to OS (hazard ratio 1.91, P = 0.037), which indicates that immunohistochemical staining for ERCC1 may be useful for predicting the clinical outcomes of advanced gastric cancer patients treated with 5-FU and oxaliplatin.
Recently, it was reported that distinct patterns of functional genomic polymorphisms in genes involved in drug metabolic pathways and DNA repair may predict clinical outcome to 5-FU/oxaliplatin chemotherapy in patients with advanced gastric cancer [35]. Germline genetic polymorphisms in TS and XPD may effectively predict response to FOLFOX chemotherapy in advanced gastric cancer, but no marker was found to be significantly associated with OS. Moreover, the technique required to determine the presence of genomic polymorphisms is difficult to setup, expensive, and time consuming, and these genetic variations may be dependent on ancestry [36]. Thus, genomic polymorphism analyses are limited in terms of their usefulnesses in the clinical setting.
The results of the present study warrant further large-scale clinical studies to determine the ability of ERCC1 expression to predict the efficacy using 5-FU/oxaliplatin chemotherapy and prognosis in advanced gastric cancer.
conclusions
We were able to find a correlation between clinical outcome and the expression of ERCC1. We suggest that immunohistochemical studies for ERCC1 may be useful in prediction of the clinical outcome of advanced gastric cancer patients treated with 5-FU and oxaliplatin.
Received for publication September 3, 2006. Revision received October 18, 2006. Accepted for publication October 18, 2006.
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