|Year : 2015 | Volume
| Issue : 3 | Page : 277-280
Is there relationship between excision repair cross-complementation 1 expression level and response to treatment and prognosis in an advanced stage lung cancer treated with cisplatin-based chemotherapy?
G Polat1, U Yilmaz1, C Anar1, B Kömürcüoglu1, Z Aydogdu2
1 Department of Chest Diseases, Dr. Suat Seren Chest Diseases and Surgery Research and Training Hospital, Turkey
2 Department of Pathology, Dr. Suat Seren Chest Diseases and Surgery Research and Training Hospital, Turkey
|Date of Web Publication||18-Feb-2016|
Department of Chest Diseases, Dr. Suat Seren Chest Diseases and Surgery Research and Training Hospital
Source of Support: None, Conflict of Interest: None
Aim: It is important to know the tumor resistance against cisplatin before the treatment of non-small cell lung cancer (NSCLC). The purpose of this study was to evaluate the response to treatment and survival in patients with NSCLC treated with cisplatin-based chemotherapy according to excision repair cross-complementation 1 (ERCC1) expression. Materials and Methods: Among 119 patients treated with cisplatin and vinorelbine or docetaxel, 39 (32%) patients enrolled who have enough tumor tissue to analyze ERCC1 expression. ERCC1 expression defined as negative in score 0-1, positive in score 2-3. Results: There was no difference between ERCC1 positive and negative groups (P = 0.63). Mean survival was 14.7 months (95% confidence interval [CI]; 10.0-19.3 month) in ERCC1 negative group, 10.9 months (95% CI; 7.4-14.3 month) in ERCC1 positive group (P = 0.23). Progression free survival was 7.9 months in ERCC1 negative group (95% CI; 5.8-9.9 months), 6.2 months in ERCC1 positive group (95% CI; 4.0-8.5 months) (P = 0.27). Conclusion: Identification of ERCC1expression level of tumor tissues in NSCLC patients before treatment was not useful in prediction of treatment response and prognosis.
Keywords: Cisplatin, excision repair cross-complementation 1, lung cancer, metastatic, treatment
|How to cite this article:|
Polat G, Yilmaz U, Anar C, Kömürcüoglu B, Aydogdu Z. Is there relationship between excision repair cross-complementation 1 expression level and response to treatment and prognosis in an advanced stage lung cancer treated with cisplatin-based chemotherapy?. Indian J Cancer 2015;52:277-80
|How to cite this URL:|
Polat G, Yilmaz U, Anar C, Kömürcüoglu B, Aydogdu Z. Is there relationship between excision repair cross-complementation 1 expression level and response to treatment and prognosis in an advanced stage lung cancer treated with cisplatin-based chemotherapy?. Indian J Cancer [serial online] 2015 [cited 2019 Aug 20];52:277-80. Available from: http://www.indianjcancer.com/text.asp?2015/52/3/277/176760
| » Introduction|| |
Lung cancer is still at the top in cancer related deaths. Non-small cell lung (NSCLC) is the most common type of cancer (about 80% of all cases). During diagnosis, more than half of these patients appear to be in an advanced stage. In this period, the standard treatment in a good performance patients is cisplatin-based chemotherapy. Chance of survival, which is obtained with cisplatin-based chemotherapy is far from being satisfactory. Better life duration is expected in cases where objective responses are taken. Therefore, cisplatin which is the primary choice that can cause problem due to toxicity in some patients must be identified for tumor resistance, which is important to predict. Cisplatin is a heavy metal. It incorporates into the cross-bonds in deoxyribonucleic acid (DNA) double helix. By this way, it prevents DNA replication and transcription. One of the important ways for removal and repair of damaged section of DNA is “excision repair cross-complementation 1 (ERCC1)” and related to platins with cellular resistance.
The tumor cells that express more ERCC1 show more resistance to platins. In NSCLC cases treated with cisplatin and gemcitabine it was shown that patients who expressed less ERCC1 messenger ribonucleic acid (mRNA) have longer survival.,
In another study in NSCLC cases, which were fully resected and tumor tissue was negative for ERCC1, it was reported that adjuvant cisplatin-based chemotherapy extended the survival. When ERCC1 expression evaluated immunohistochemically (IHC) in patients with recurrent NSCLC It was informed that there was an independent prognostic factor for progression free and overall survival. In that study in general, it can be said that in cases who had a platinum-based chemotherapy with low level ERCC1 had a longer survival time than the ones with a high level ERCC1. The similar findings were also reported in ovarian, gastric and colorectal cancers.,,
The purpose of this study was to investigate the relationship between IHC measured ERCC1 expression level in tumor samples of NSCLC patients before treatment with cisplatin-based chemotherapy and response to treatment and prognosis.
| » Materials and Methods|| |
A total of 119 patients were diagnosed as NSCLC between 2005 and 2009 who had a first line chemotherapy with cisplatin and vinorelbine or docetaxel, 39 have sufficient tumor tissue (32%). These tumor samples were IHC analyzed regarding ERCC1 expression.
By determining formalin tumor tissue samples which were buried into paraffin were examined by cutting via 4 µm thick through the coated glass slide. After deparaffinization with xylonite and dehydration with ethanol of tumor tissues, the endogenous peroxidase activity was blocked with hydrogen peroxide in methanol. The antigens for ERCC1 dying were obtained by heating in citric acid for 10 min. Sections were incubated in blocking solution (Thermo Scientific Fremont). Then the anti-ERCC1 (spring bioscience clone SPM243) monoclonal antibody was put into a reaction for 30 min. The reaction was visualized with 3.3 diaminobenzidine substrate system and was counter stained with hematoxylin. IHC staining of appropriate tissue samples were evaluated in terms of ERCC1 expression by a pathologist (Z.A.D) who did not know clinical data under light microscope. ERCC1 nucleate expression was classified into 4 categories. Score 0; no ERCC1 expression in tumor cells, score 1+; expression lesser than 10% in tumor cells, score 2+; weak-medium expression more than 10%, score 3+ strong expression more than 10%. The age, gender, performance status, tumor histology, stage, site of metastasis, response to the therapy of cases were evaluated. Response to the treatment was evaluated according to the response evaluation criteria in solid tumors 1.0 criteria after two cycles chemotherapy.
All patients had chest radiograph, thorax computed tomography (CT), upper abdomen and brain CT and whole-body bone scintigraphy before the start of chemotherapy. The response was evaluated after 2 cycles of chemotherapy and completion of chemotherapy.
ERCC1 expression defined as negative in score 0-1, positive in score 2-3. The difference of patients' properties and response ratios between groups were identified by using Fisher's exact test. The survival time of the patients in each group was identified with Kaplan Meier method and the difference between survival data were analyzed with log-rank test.
Progression-free survival time was defined as the time between initial of chemotherapy and first recurrence detection time and the overall survival time was defined as the time between initiation of chemotherapy and the last observation date or till to the death. The sum of complete or partial responses was defined as objective response. P <0.05 was considered to be statistically significant. All statistical analysis was performed by using the program Statistical Package for the Social Sciences 15.0 for windows.
| » Results|| |
Of 119 NSCLC patients who had therapy with cisplatin and vinorelbine or docetaxel, the tumor samples of 39 (36%) patients were found IHC appropriate for ERCC1 expression analysis. The properties of 39 patients were given in [Table 1]. The average age of the patients was 57 (31-72). 12 cases were squamous cell lung cancer, 13 were adenocarcinoma and 14 were NSCLC that could not give any type determination. Tumor samples were obtained by bronchoscopic biopsy in 30 patients, by lymph node excision in 5 cases and by wedge resection or lobectomy in four cases. Between ERCC1 positive and negative patients, no difference was identified in terms of age, gender, performance status, tumor histology, stage, site of metastasis (P > 0.05).
Average of CT cycles was 4 (1-6). The response ratio obtained with chemotherapy and the response ratio in accordance with the subgroup of ERCC1 expression was seen in [Table 2]. Objective response was observed as full response in 2 cases (5.1%) and partial response in 11 cases (28.2%). Median follow-up time was 12 months (range 1-53 months), Mean survival was 14.7 months (95% confidence interval [CI]; 10.0-19.3 months) in ERCC1 negative group, 10.9 months (95% CI; 7.4-14.3 months) in ERCC1 positive group (P: 0.23) [Figure 1].
|Figure 1: Overall survival in excision repair cross-complementation 1 negative and positive groups|
Click here to view
Progression free survival was 7.9 months in ERCC1 negative group (95% CI; 5.8-9.9 months), 6.2 months in ERCC1 positive group (95% CI; 4.0-8.5 months) (P = 0.27) [Figure 2].
|Figure 2: Progression free survival in excision repair cross-complementation 1 negative and positive groups|
Click here to view
| » Discussion|| |
IHC evaluation of ERCC1 was shown as a promising marker in NSCLC patients who were treated with cisplatin (as an adjuvant) based chemotherapy.
In patients receiving palliative chemotherapy, the situation is not so clear. The purpose of this study was to investigate the prognostic value of ERCC1 protein levels in prediction of survival time and predictive value in prediction of tumor response in advanced/metastatic NSCLC cases who received cisplatin-based chemotherapy.
In this study, it was observed that ERCC1 expression levels, which were detected by IHC method in pre-treatment tumor samples were not a prognostic factor for prediction of progression-free and overall survival time. In a study conducted by Lord et al., in 56 advanced stage NSCLC patients who were treated with cisplatin-gemcitabine, it was found that ERCC1 expression levels were related to the treatment response and survival time. In this study mRNA was isolated from formalin fixed pre-treatment tumor samples real time reverse transcription-polymerase chain reaction (RT-PCR) and ERCC1 expression levels were described. Median overall survival time in patients with low ERCC1 expression (61.6 week, 95% CI: 42.4-80.7 week), was found longer in patients with high ERCC1 expressions. Booton et al., informed that ERCC1 mRNA expression levels were not predictive or prognostic in terms of chemotherapy response and survival time in 66 patients with NSCLC. In a randomized study called as “International adjuvant lung cancer trial” (IALT), by application of adjuvant cisplatin-based chemotherapy to more than 1800 NSCLC patients 14% reduction in risk of death and 4.1% mutual benefit in 5 year chance of survival were achieved. In a study named as IALT-bio tumor samples taken from 761 of these patients, ERCC1 was evaluated as IHC. In cases with low ERCC1 expression patients receive adjuvant therapy lived longer than the observation group (for death adjusted hazard ratio, 0.65; %95 GA: 0.50-0.86; P = 0.002). In cases with high ERCC1 expression, this effect of adjuvant therapy was not seen (for death adjusted hazard ratio, 1.14; %95 GA: 0.84-1.55; P < 0.40).
In the study of Wachter et al., where ERCC1 nuclear staining as IHC in tumor samples of 33 NSCLC patients who received chemotherapy was evaluated. They informed that ERCC1 expression level was not predictive or prognostic for response to therapy.
On the other hand when Lee et al., evaluated ERCC1 expression as IHC in tumor samples of 50 NSCLC patients before cisplatin-based chemotherapy they identified high ERCC1 expression as a bad prognostic factor (P = 0.002). In a study where the tumor samples of 264 advanced stage NSCLC patients were evaluated it was indicated that ERCC1 positivity point to bad prognosis (P = 0.028) and a more powerful negative prognostic indicator in patients with adenocarcinoma (P = 0.007).
Our results are not compatible with the research results of Lee and Vilmar et al.,
The predictive and prognostic effect of ERCC1 expression level in different histological subgroups is out of our goal in the research. ERCC1 appears to be a double edged sword. The role of ERCC1 protein in DNA repairing has a two way effect. In theory, the low DNA repair capacity cause more genomic instability in tumor cells and as a result malign, metastatic capacity gain evolving faster in tumor cells. On the other hand in high DNA repair capacity, in theory, DNA damage quickly repaired in tumor cells created by chemotherapy and tumor response created by the drug is prevented. However, it is known that ERCC1 is not the only responsible in repair of DNA damage formed by platinum. One of the limitations of our study is 32% of our 119 patients that had cisplatin-based chemotherapy have suitable tumor samples for IHC analysis. In the cellular level samples obtained by fine needle aspiration difficulty or impossibility of analysis prevent us to add all patients to our study.
In some patients, not enough tumor samples were found in paraffin blocks for IHC study. As a result the number of patients that the analysis performed was dropped. Another is the ERCC1 prognostic value may have been affected by the performed chemotherapy to our patients. Evaluation method used in a research in order to find a biomarker that can be clinically applicable is important. Basically, two methods are used related to ERCC1namely IHC and real time RT-PCR.
Protein expression which is the functional product of IHC and ERCC1 can be determined. Cheap, fast, basic and easily accessible are the advantages. The assessment criteria must be well-identified. ERCC1 mRNA expression levels are identified by real time RT-PCR. Fresh frozen tumor samples or tumor tissue samples blocked in paraffin can be used. In a phase III randomized study conducted by Cobo et al., the response ratios and survival times were better in the group where treatment regimens were selected as with and without cisplatin-based according to ERCC1 mRNA expression levels than the control group where no genotype study was performed. While in genotypic group the objective response ratios was 50.7%, it was found that in the control group the ratio was 39.3%. However, no difference was generated between the survival times (P = 0.02).
As a result, IHC ERCC1 expression level identification in tumor samples in pre-treatment of NSCLC patients in our study group has not been useful in estimating the cisplatin-based chemotherapy response and prognosis.
| » References|| |
Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin 2005;55:74-108.
Azuma K, Sasada T, Kawahara A, Takamori S, Hattori S, Ikeda J, et al
. Expression of ERCC1 and class III beta-tubulin in non-small cell lung cancer patients treated with carboplatin and paclitaxel. Lung Cancer 2009;64:326-33.
Lord RV, Brabender J, Gandara D, Alberola V, Camps C, Domine M, et al
. Low ERCC1 expression correlates with prolonged survival after cisplatin plus gemcitabine chemotherapy in non-small cell lung cancer. Clin Cancer Res 2002;8:2286-91.
Ceppi P, Volante M, Novello S, Rapa I, Danenberg KD, Danenberg PV, et al
. ERCC1 and RRM1 gene expressions but not EGFR are predictive of shorter survival in advanced non-small-cell lung cancer treated with cisplatin and gemcitabine. Ann Oncol 2006;17:1818-25.
Olaussen KA, Dunant A, Fouret P, Brambilla E, André F, Haddad V, et al
. DNA repair by ERCC1 in non-small-cell lung cancer and cisplatin-based adjuvant chemotherapy. N Engl J Med 2006;355:983-91.
Azuma K, Komohara Y, Sasada T, Terazaki Y, Ikeda J, Hoshino T, et al
. Excision repair cross-complementation group 1 predicts progression-free and overall survival in non-small cell lung cancer patients treated with platinum-based chemotherapy. Cancer Sci 2007;98:1336-43.
Dabholkar M, Vionnet J, Bostick-Bruton F, Yu JJ, Reed E. Messenger RNA levels of XPAC and ERCC1 in ovarian cancer tissue correlate with response to platinum-based chemotherapy. J Clin Invest 1994;94:703-8.
Park DJ, Lenz HJ. Determinants of chemosensitivity in gastric cancer. Curr Opin Pharmacol 2006;6:337-44.
Shirota Y, Stoehlmacher J, Brabender J, Xiong YP, Uetake H, Danenberg KD, et al
. ERCC1 and thymidylate synthase mRNA levels predict survival for colorectal cancer patients receiving combination oxaliplatin and fluorouracil chemotherapy. J Clin Oncol 2001;19:4298-304.
Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, 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 2000;92:205-16.
Booton R, Ward T, Ashcroft L, Morris J, Heighway J, Thatcher N. ERCC1 mRNA expression is not associated with response and survival after platinum-based chemotherapy regimens in advanced non-small cell lung cancer. J Thorac Oncol 2007;2:902-6.
Wachters FM, Wong LS, Timens W, Kampinga HH, Groen HJ. ERCC1, hRad51, and BRCA1 protein expression in relation to tumour response and survival of stage III/IV NSCLC patients treated with chemotherapy. Lung Cancer 2005;50:211-9.
Lee HW, Choi YW, Han JH, Kim JH, Jung JH, Jeong SH, et al
. Expression of excision repair cross-complementation group 1 protein predicts poor outcome in advanced non-small cell lung cancer patients treated with platinum-based doublet chemotherapy. Lung Cancer 2009;65:377-82.
Vilmar AC, Santoni-Rugiu E, Sørensen JB. ERCC1 and histopathology in advanced NSCLC patients randomized in a large multicenter phase III trial. Ann Oncol 2010;21:1817-24.
Cobo M, Isla D, Massuti B, Montes A, Sanchez JM, Provencio M, et al
. Customizing cisplatin based on quantitative excision repair cross-complementing 1 mRNA expression: A phase III trial in non-small-cell lung cancer. J Clin Oncol 2007;25:2747-54.
[Figure 1], [Figure 2]
[Table 1], [Table 2]