Background
Adenocarcinoma is commonest non-small cell lung carcinoma (NSCLC), generally diagnosed in the advanced stage of the disease when it is not operable [
1]. If we exclude adenocarcinomas with PD-L1 expression ≥50%, and those with
ALK, EGFR and
ROS mutations, the basic current care of advanced disease is chemotherapy based on platinum [
2]. Drugs based on platinum form platinum-DNA adducts that obstruct cell replication and cause apoptosis. DNA damage could be repaired trough many biological processes and cause resistance to the platinum [
3]. On the contrary to the immune and the molecular targeted therapies, no specific predictive marker is so fare available for platinum-based chemotherapy in lung adenocarcinoma. The best validated marker is the endonuclease excision repair cross-complementation group 1 (ERCC1), one of thirty enzymes of the nucleotide excision repair pathway. ERCC1 is the major enzyme that repairs DNA damage caused by the action of platinum, and is one of the possible factors that reduces the platinum effect [
4]. The results of many studies on the significance of ERCC1 in lung adenocarcinoma are inconsistent. Previous retrospective studies and meta-analyses have correlated high ERCC1 expression with poor prognosis and platinum resistance [
3,
5,
6], in a contrast to study of Booton et al. who did not find any correlation between the ERCC1 status and survival [
7]. Sad et al. reported that longer survival was associated with low ERCC1 expression in lung adenocarcinoma patients who received chemotherapy based on platinum compared with those with high ERCC1 expression [
8]. The same observation was presented in the study of Zhao et al. who found out that in advanced NSCLC, low ERCC1 expression indicates better prognosis and improved effectiveness for platinum-based chemotherapy [
9]. In a contrary, Lee et al. concluded in a prospective ERCC1 trial (ET) that selecting chemotherapy by using a commercially available ERCC1 antibody did not prolong survival [
10].
Therefore, the aim of the study was to present our single-institution experience on the importance of ERCC1 analysis in lung adenocarcinoma patients.
Discussion
Previous retrospective studies and meta-analyses revealed that high ERCC1 expression is a negative predictor in patients who received chemotherapy based on platinum and good prognostic marker in patients who did not [
2,
3,
6,
13‐
15]. The same observations were found in ovarian epithelial carcinoma, squamous carcinoma of the head and neck, and gastroenteric carcinomas [
16,
17]. So far, conflicting results were found in few studies according to correlation of ERCC1with prediction or prognosis in NSCLC. Findings in the meta-analysis of Roth et al. supported the hypothesis that ERCC1 is associated with response to chemotherapy based on platinum and OS in advanced NSCLC, but the study of Booton et al. did not confirmed that hypothesis [
7,
14]. Several prospective studies have suggested that ERCC1 is predictive in NSCLC. The study by Cobo et al. prospectively evaluated expression of ERCC1 mRNA in advanced stage of NSCLC in order to predict response to cisplatin-free or cisplatin-based therapy. Patients in control group received docetaxel/cisplatin combination. The other group of patients received docetaxel/cisplatin or docetaxel/gemcitabine regimens respectively, according to low or high ERCC1 mRNA levels and their response rates were significantly higher (50.3%) compared with the control group (39.3%) [
18]. Takemoto et al. prospectively evaluated the benefit of therapy without platinum for patients in TNM stages IIIB/IV who expressed high level of ERCC1 mRNA, and concluded that therapy without platinum might be effective for those patients [
19]. In a contrast to these findings, Lee et al. concluded in a prospective ERCC1 trial (ET) that in patients with advanced disease, choosing the best suitable chemotherapy by using a commercially available ERCC1 antibody, did not prolong survival [
10]. Our study was retrospective, and chemotherapy based on platinum was applied to all of our patients. In a few patients, chemotherapy was combined with surgery or radiotherapy depended on the TNM stage of the disease and the clinical condition of the patient. A correlation between low ERCC1 expression and longer OS was found in patients in all TMN stages. Knowing that ERCC1 is the major enzyme involved in platinum damage repair, this result was hypothetically expected, as a consequence of the ineffectiveness of the ERCC1 enzyme to repair the damage caused by platinum [
20]. Awareness of the fact that a lot of other factors, in addition to ERCC1 contribute to chemotherapy response, more analysis are required for verification of this hypothesis.
ERCC1 status could be evaluated trough the immunohistochemical (IHC) staining or by real-time polymerase chain reaction (RT-PCR) method. Carter et al. emphasized the importance of selected therapy trough molecular analysis of cancer cells using IHC, with the intention to increase patients’ benefits, and ERCC1 was evaluated as a predictor of better outcome in lung adenocarcinoma patients [
21]. In our study, the expression of ERCC1 was assessed trough IHC staining and graded using the same scoring system as Olaussen. The median H score of 0.1 (0–3) was used to define low versus high ERCC1 expression [
5], and it was lower than in Olaussens study (0.1 vs 1), but when we correlated our results to patients’ outcome, the results between these two studies were in agreement. Although, IHC is useful method for evaluation the protein expression in tumor tissue, we have to be careful with the interpretation of IHC staining. There are several limitations such as different antibodies, variations among observers and the different values for separating low from high ERCC1 expression. This suggests that inconsistent prognostic interpretations of ERCC1 might have been influenced by the scoring system which emphasis the need for consensus about methodology [
22]. Furthermore, the ERCC1 evaluation by IHC is questionable, because ERCC1 is present as four isoforms in the nucleus, but only one of them (isoform 202) was involved in the repair of platinum adducts. [
23]. These observations could have been one of the possible explanation for discrepancy among the studies. Currently, none of the available antibody, allows for differentiating between four ERCC1 isoforms, leading to possibility of wrong evaluation and classification of ERCC1 expression. More valid method for ERCC1 analysis is RT-PCR for detection of the mRNA from tumor tissue. Prospective studies, mentioned above were conducted using paraffin blocks of tumor biopsies, previously fixed in formalin for mRNA extraction. Formalin destroys the mRNA, so tumor samples should be taken for ERCC1 analysis before fixation to avoid wrong evaluation of ERCC1 expression [
19].
We assumed that the small sample tissue, as a commonest, and derived from bronchial biopsies, would be sufficient for IHC analysis of ERCC1 expression and representative for the total tumor despite of tumor heterogeneity, according to Taillade et al. who reported a high correlation for ERCC1 expression comparing bronchial biopsies and resected surgical specimens in the same patient [
24].
In our research, beside ERCC1, a smaller tumor size was found out to be a factor of better prognosis which correlates with the findings of Rami-Porta et al. [
25]. They emphasized the importance of the new 8thTNM staging system where T1 lesions were subdivided into T1a, T1b, and T1c lesions corresponding to lung cancers up to 10 mm, between 11 and 20 mm, and between 21 and 30 mm, respectively [
10]. Prognosis was significantly better for the smallest lesions, as 5-year survival rates for clinical staging were 92, 83, and 76% for T1a, T1b, and T1c cancers, respectively [
25]. It is obvious that tumour size is an important prognostic factor.
The prognosis of NSCLC has been changed with immunotherapy but without the long-term benefit for many patients. The association of ERCC1 with immunotherapy response was analysed, assuming that ineffective ERCC1 increases defects in the DNA of tumor cells and causes stronger immune response to the tumor. Chabanon et al. revealed correlation between low expression of ERCC1 and better response to immunotherapy due to increased neo-antigens in tumor cells [
26]. It seems that ERCC1 has remained not only an important predictive marker of chemotherapy based on platinum, but it could also be a predictor of immunotherapy response.
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