The aim of this study was to determine whether the ERCC1 expression is effective to predict the clinical outcomes of patients with advanced gastric cancer (AGC) and who were treated with cisplatin-based first-line chemotherapy.
A total of 89 measurable AGC patients received cisplatin and capecitabine, with or without epirubicin, as a part of a randomized phase II study. Patients were included for the current molecular analysis if they had received two or more cycles of chemotherapy, their objective tumor responses were measured and if their paraffin-embedded tumor samples were available. The ERCC1 expression was examined by performing immunohistochemical (IHC) staining, and the patients were divided into two groups (positive or negative) according to the presence of IHC staining of the tumor cell nuclei.
Of the 32 eligible patients, 21 patients (66%) had tumor with a positive expression of ERCC1 and the remaining 11 patients had tumor with a negative ERCC1-expression. The ERCC1-negative patients achieved a higher response rate than that of the ERCC1-positive patients (44% vs. 28%, respectively), although the difference was not statistically significant (p=0.42). The median survival time for the all patients was 14.6 months (95% CI: 13.6 to 15.6 months). The one-year survival rate was similar for the ERCC1-negative patients (61%) and the ERCC1-positive patients (70%).
In the current study, the tumor ERCC1 expression by IHC staining could not predict the clinical response or survival of AGC patients who were treated with cisplatin-based first-line chemotherapy. The ERCC1 protein expression does not appear to be a useful tool for the selection of tailored chemotherapy for these patients.
Gastric cancer is the most frequently occurring malignancy in Korea, and it is one of the main causes of cancer death (
Platinum asserts its cytotoxicity through disrupting double stranded DNA in cells by forming intra-strand adducts that inhibit DNA replication. Nucleotide excision repair (NER) is one of several DNA repair pathways for correcting the abnormal DNA structures that arise from DNA damage, replication errors or recombination processes (
Olaussen et al. (
Recent studies have been done on tailored therapy by selecting the patients who are likely to respond to a particular chemotherapeutic regimen, and this may allow improved treatment efficacy while avoiding unnecessary treatment side effects. In an effort to investigate the role of the ERCC1 protein expression as a predictive marker with respect to cisplatin-based chemotherapy for AGC, we conducted an exploratory analysis of the archived tumor tissues that were obtained within a prospective phase II study. The study population of that prospective phase II study consisted of chemotherapy-naïve AGC patients who were treated with cisplatin plus capecitabine combination regimens (
This is a retrospective, exploratory analysis of the patients who were drawn from a prospective phase II study (
The response was evaluated after every two cycles of therapy according to the Response Evaluation Criteria in Solid Tumors (RECIST), and the response was assessed by abdominopelvic CT or by the same tests that were initially used to stage the tumor. PFS was calculated from the day of registration to the date of progression, death or the last contact. OS was measured from the day of registration to death or the last contact date. The results of the 89 patients from the previous clinical study have been reported elsewhere (
Paraffin-embedded tumor material from the biopsy was cut into 2 µm-thick sections and placed onto glass slides. For immunohistochemical (IHC) staining, the slides were depafaffinized in xylene. Staining for ERCC1 was performed automatically using the Leica Bond Max immunostainer with Bond Polymer Refine Detection Kits and heat-induced epitope retrieval pH 8.0 (Bond max ER2 (EDTA) solution, Australia) for 15 min. The ERCC1 expression was analyzed using a mouse monoclonal antibody specific for the full-length human ERCC1-protein (Clone 8F1, 1 : 150, GeneTex, CA).
Protein staining was assessed semiquantitatively by a pathologist (KMK) who was kept "blind" to the clinical data. The ERCC1 nuclear and cytoplasmic immunoreactivity were evaluated semiquantitatively, and the percentage of positive tumor nuclei was calculated for each specimen at 400×. A biopsy with the cells showing positive nuclear staining was defined as positive.
The correlations between the IHC expression and the response to chemotherapy were examined using the Chi-square test or Fisher's exact test, as appropriate. Logistic regression analysis was used to calculate the odds ratios and their confidence intervals (CI). Additionally, the other known clinical factors (gender, the performance status, the chemotherapy regimens, the metastatic sites and the previous therapy) were included in the multivariate analysis. The Cox proportional hazards model (as stratified by the chemotherapy regimens: CX vs. ECX) was used to compare the PFS and OS between the patients with ERCC1-negative and positive tumor. The association between the ERCC1 status and the other clinical characteristics was tested for by chi-square tests.
Of the 89 patients who were treated with either CX or ECX, 81 patients received at least two cycles of chemotherapy. Of these 81 patients, 32 patients provided tumor samples for ERCC1 analysis. The clinical characteristics of the eligible patients are listed in
Eleven of the 32 patients (34%) achieved an objective response. Although it was statistically insignificant, a higher RR to chemotherapy was noted for the patients with ERCC1-negative tumors as compared to those patients with ERCC1-positive tumors (44% vs. 28%, respectively; p=0.42). Besides ERCC1 positivity, another possible factor associated with the lack of optimal response was the ECOG performance status (36% for ECOG 0-1 vs. 0% for ECOG 2; p=0.01). The RR was not influenced by gender, age, the chemotherapy regimens, the histology or tumor differentiation, or a prior history of adjuvant treatment. Using a multiple logistic regression model for which we entered all the predictive factors as covariates, the ERCC1 status (odds ratio: 2.08) was not associated with the RR to chemotherapy (
The median PFS and OS were 6.9 months (95% CI: 5.4 to 8.4 months) and 14.6 months (95% CI: 13.6 to 15.6 months), respectively. There was no statistically significant difference between the ERCC1 expression statuses and OS (p=0.57). The Kaplan-Meier OS curves are presented in
We also analyzed the association between the ERCC1 expression status and PFS. The respective PFS curves are presented in
Although the multi-drug combination chemotherapy regimens have failed to provide significantly better OS than fluoropyrimidine monotherapy (
Several previous studies have suggested that the ERCC1 status is associated with RR, and the ERCC1 status is prognostic for cisplatinbased chemotherapy. Metzger et al. (
There may be several reasons that could explain the discrepancies in the studies. The incidence of an ERCC1 protein expression was not consistent in the previous studies. The reason for the difference in the incidence of an ERCC1 expression can be explained, to some extent, by the different patient populations. Our result should be interpreted with caution because it represents only a small group of patients with AGC in this study and the majority of patients had unfavorable clinical characteristics: poorly-differentiated carcinoma in 41% of the patients and 75% had more than one metastatic site. Our study is limited due to a small sample size, but it only indicated that ERCC1-positive AGC could respond to cisplatin-based chemotherapy.
Moreover, the lack of a uniformly approved method for detecting the ERCC1 expression suggests that any conclusions must still be regarded as preliminary at best. There are different sensitivities and specificities between reverse transcriptase-polymerase chain reaction (RT-PCR) and the IHC staining for detecting the ERCC1 expression. The ERCC1 levels can be measured by performing RT-PCR on the intratumoral ERCC1 mRNA derived from paraffin-embedded or fresh-frozen tumor specimens. Most of the previous studies used the RT-PCR method, which is currently known to be the gold standard rather than IHC (
Another explanation for the current study's negative results is that the ERCC1 expression might not have a defined role as a predictive marker because cisplatin is not likely to play a major role in treating gastric cancer. Unlike lung cancer or ovarian cancer in which platinum is the standard of care, AGC patients are usually treated with fluoropyrimidine-based chemotherapy. Although combination chemotherapy regimens involving fluoropyrimidines and cisplatin are most commonly used for AGC patients, the role of cisplatin in the treatment of AGC is currently limited. In this study, we could not find a correlation between the clinical outcome and the expression of ERCC1. Furthermore, there might have been an unbalanced distribution of other genetic variants that may potentially interfere with the efficacy of chemotherapy, such as those genetic variants in the thymidylate synthase gene (
ERCC1 may be prognostic for the survival of cancer patients who are treated with platinum-based chemotherapy. However, it is currently unclear if a high ERCC1 expression is the direct cause of a poor prognosis or if it is just a marker for chemotherapy resistance. Interestingly, an ERCC1 expression has been shown to have paradoxical prognostic significance in a previous study. For the lung cancer patients who did not receive platinum-based chemotherapy, the patients with ERCC1-positive tumors had a better survival when compared with those with ERCC1-negative tumors (
Our analyses suggested that an ERCC1 expression is not perfect for determining the responsiveness of patients to cisplatin-based chemotherapy, although may be important. The ERCC1 expression did not appear to be a useful tool for the selection of tailored chemotherapy to treat patients with AGC. Given our findings, we question the validity of selecting patients who would benefit from cisplatin-based chemotherapy based on only the ERCC1 expression. Selecting patient in such a manner would lead to inappropriately turning away patients who would otherwise possibly benefit from platinum-based therapy, be it monotherapy or part of combination chemotherapy.
Overall survival.
Progression-free survival.
The patients' characteristics
*ECOG denotes the Eastern Cooperative Oncology Group, †because the patients could have metastases at multiple sites, the total number of metastases is greater than the number of patients.
The clinical response to platinum-based chemotherapy according to the expression of ERCC1