Expression of ERCC1 and class III β-tubulin in resected non-small cell lung cancer and its correlation with platinum-based adjuvant chemotherapy
To explore the relationship between the expression of excision repair cross-complementation group 1 (ERCC1) and class III ß-tubulin and the clinical characteristics and overall survival of patients with non-small cell lung cancer (NSCLC).
Immunohistochemical analysis was used to determine the protein expression of ERCC1 and class III ß-tubulin in 160 completely resected NSCLC primary tumor samples, 50 of which were paired with adjacent normal tissue samples and another 40 benign lung lesion tissue samples as controls. Clinical data at baseline, disease-free survival and overall survival were also collected. Univariate and multivariate Cox models were used to analyze the risk factors.
In 160 tumor samples, the ERCC1 and class III ß-tubulin positive rates obtained with immunohistochemistry were 46.9% and 49.4%, respectively. Both biomarkers had a higher positive rate in male patients. For patients who did not receive adjuvant chemotherapy, ERCC1 positivity was associated with longer survival (median survival time 73 vs 53 months, p=0.041), while in patients treated with platinum chemotherapy, ERCC1 positivity tended to be associated with poor survival (median survival time 41 vs 54 months, p=0.014). Class III ß-tubulin positivity was also associated with poor survival (median survival time 38 vs 58 months, p<0.001), but had no influence on the survival of patients who did not receive adjuvant chemotherapy.
ERCC1 and class III ß-tubulin could be important survival predictors for completely resected NSCLC patients treated with adjuvant chemotherapy. Further prospective studies need to be performed to test this hypothesis in Chinese patients.
Available from: Ming-Sound Tsao
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ABSTRACT: The excision repair cross-complementation group 1 (ERCC1) protein is a potential prognostic biomarker of the efficacy of cisplatin-based chemotherapy in non-small-cell lung cancer (NSCLC). Although several ongoing trials are evaluating the level of expression of ERCC1, no consensus has been reached regarding a method for evaluation.
We used the 8F1 antibody to measure the level of expression of ERCC1 protein by means of immunohistochemical analysis in a validation set of samples obtained from 494 patients in two independent phase 3 trials (the National Cancer Institute of Canada Clinical Trials Group JBR.10 and the Cancer and Leukemia Group B 9633 trial from the Lung Adjuvant Cisplatin Evaluation Biology project). We compared the results of repeated staining of the entire original set of samples obtained from 589 patients in the International Adjuvant Lung Cancer Trial Biology study, which had led to the initial correlation between the absence of ERCC1 expression and platinum response, with our previous results in the same tumors. We mapped the epitope recognized by 16 commercially available ERCC1 antibodies and investigated the capacity of the different ERCC1 isoforms to repair platinum-induced DNA damage.
We were unable to validate the predictive effect of immunostaining for ERCC1 protein. The discordance in the results of staining for ERCC1 suggested a change in the performance of the 8F1 antibody since 2006. We found that none of the 16 antibodies could distinguish among the four ERCC1 protein isoforms, whereas only one isoform produced a protein that had full capacities for nucleotide excision repair and cisplatin resistance.
Immunohistochemical analysis with the use of currently available ERCC1 antibodies did not specifically detect the unique functional ERCC1 isoform. As a result, its usefulness in guiding therapeutic decision making is limited. (Funded by Eli Lilly and others.).
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ABSTRACT: The study aims to investigate whether the glutathione S transferase P1 (GSTP1) and excision repair cross-complementing group 1 (ERCC1) polymorphism influence the response to treatment with platinum-based chemotherapy in Chinese patients with non-small cell lung cancer. Ninety-one patients with metastatic non-small lung cancer were evaluated. Blood samples were obtained from each patient before chemotherapy. They are all administered modified TP, GP, NP regimens. Curative effects in patients were evaluated after at least two cycles of treatment. TTP was calculated. The response rate of GSTP1 with G/G + G/A group and A/A group is 54.55 % (24/44) and 21.28 % (10/47) (P = 0.001), respectively. The response rate of ERCC1 with C/C group and C/T + T/T group is 51.11 % (23/45) and 23.91 % (11/46) (P = 0.007), respectively. Patients with both G/G + G/A and C/C has the response rate of 64.52 % (20/31) (P = 0.000). Logistic regression analysis shows a significant increased chance of treatment response in patients with G/G + G/A genotype versus A/A genotype (P = 0.008) and with T/T + C/T genotype versus C/C genotype (P = 0.001). The median TTP of all patients is 7.32 months. The TTP of individuals with G/G + G/A genotype is 9.56 months, and those with A/A genotype had an TTP of 5.23 months. The TTP of individuals with C/C genotype is 9.16 months, and those with T/T + C/T genotype is 5.53 months. Kaplan-Meier analysis shows that ERCC1 and GSTP1 polymorphisms are correlated with TTP. The log-rank test is was marginally significant (P < 0.01). GSTP1 and ERCC1 polymorphism are correlated with response to platinum-based chemotherapy and have prognostic value for TTP.
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ABSTRACT: The objective of this study was to analyze the expression of aminopeptidase N/CD13 (APN/CD13) in non-small cell lung cancer (NSCLC) and investigate its correlation with various clinical factors, including prognosis and efficacy of adjuvant chemotherapy.
Using immunohistochemistry analysis, we analyzed the expression of CD13 in clinicopathologically characterized 127 NSCLC cases. The relationship between the expression levels of CD13 and clinical features was analyzed and presented.
The data were analyzed using statistical package for the social sciences software (Ver 13.0, IBM, USA). Those conforming to Gauss distribution criteria was represented as Mean SD and those not conforming to Gauss distribution criteria was represented as median (M). The overall survival was recorded from the date of surgery to the date of cancer-specific death. APN/CD13 expression levels and clinicopathological factors were analyzed by Chi-square test or by Fisher's exact test. The Kaplan-Meier method was used to evaluate the probability of survival data and analyzed by Log rank test. Multivariate analysis was performed by Cox regression model. P < 0.05 was considered to be statistically significant.
APN/CD13 was mainly expressed in the cellular membrane of cancer cells in pulmonary adenocarcinoma and in the cellular membrane of interstitial cells in squamous carcinoma. Positive APN/CD13 was detected in 62.3% (43 of 69) squamous carcinoma patients and in 50% (29/58) adenocarcinoma patients. Expression of APN/CD13 was not correlated with age, gender, tumor, node, metastasis (TNM) stage, histological type and tumor size, but with TNM stage (P = 0.041) and lymph node metastasis status (P = 0.009). As indicated by Kaplan-Meier survival curve, over-expression of APN/CD13 was significantly correlated with the low survival rate. Cox regression analysis showed that APN/CD13 expression was an independent impact factor for the survival of lung adenocarcinoma patients receiving adjuvant chemotherapy (P = 0.006).
Expression of APN/CD13 is a potential unfavorable factor to predict the efficacy and prognosis of post-operative chemotherapy in NSCLC patients, especially in lung adenocarcinoma patients.
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