Expression of excision repair cross-complementation group 1 and class III β-tubulin predict survival after chemotherapy for completely resected non-small cell lung cancer
Introduction
Lung cancer is the leading cause of cancer death worldwide. The most promising therapy for cure is complete resection. However, 20–30% of patients with pathological I die within 5 years after complete resection, and the percentage is worse in more advanced cases [1], [2]. For the advanced NSCLC patients, chemotherapy is more important to treat the disseminated disease. Several papers reported the ability of adjuvant chemotherapy to improve survival after complete resection of non-small cell lung cancer (NSCLC) [3], [4], [5], [6]. Randomized studies have confirmed the benefit of postoperative platinum-based therapy in NSCLC. Platinum-based therapy has only a modest effect in survival, with an absolute improvement in 5-year overall survival ranging from 4 to 15% [3], [4], [5], [6]. On the other hand, platinum-based therapy is associated with serious adverse effects. If we can predict the effects of chemotherapy before the treatment, we can avoid adverse effects and spending unnecessary time.
Excision repair cross-complementation group 1 (ERCC1) is a DNA repair gene in the nucleotide excision repair (NER) pathway that is activated when platinum-based chemotherapeutic agents, such as cisplatin and carboplatin, form DNA adducts [7]. High ERCC1 expression in several cancers has been associated with resistance to platinum-based treatment [8], [9], [10]. Class III β-tubulin is one of the major components of microtubules that is one of the targets of taxanes, which exert their growth-inhibitory effects through the inhibition of microtubule dynamics, resulting in the growth arrest of tumor cells at the G2-M phase [11]. Class III β-tubulin differs from other tubulin isotypes and several investigators have shown that the overexpression of class III β-tubulin was associated with taxane resistance in human cancer [12], [13], [14].
Recently, the mutation of epidermal growth factor receptor (EGFR) has been shown to be related to the effect of tyrosine kinase inhibitor (TKI), such as gefitinib and erlotinib [15], [16], [17]. These studies were the first to show that a mutation in the target gene affect the effectiveness of the molecular targeted therapy. However, the effect of EGFR mutation on conventional chemotherapy has not been fully investigated.
In this study, we investigated the ERCC1 and class III β-tubulin protein expression in completely resected lung cancer patients who have been treated with platinum doublet. The results suggest that the expression of these proteins may predict the effectiveness of the chemotherapy and the survival of the patients.
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Patients and treatment
This study analyzed completely resected tumor samples from 90 patients who underwent surgery for primary NSCLC between February 1997 and August 2006 at Nagoya City University Hospital. All patients consented to the use of their tissues for the present analysis. Fifty-one patients received preoperative neo-adjuvant chemotherapy, and 39 patients received postoperative adjuvant chemotherapy. Among these patients, 17 had stage I (18.9%), 28 had stage II (31.1%), 42 had stage III (46.7%), and 4 had
ERCC1 expression in 90 NSCLC patients who received platinum-based chemotherapy
ERCC1 protein expression was evaluated using IHC in 90 patients who received platinum-based chemotherapy and the result is summarized in Table 1. Fig. 1 shows that ERCC1 is localized to the nucleus of cancer cells. A semiquantitative approach was used to calculate a score for each tissue section. 51/90 cases which had a score <1.0 were considered as IHC negative, and 39/90 cases which had a score ≥1.0 were considered as IHC positive. No statistical association was found between the ERCC1
Discussion
In this study, we retrospectively investigated the effect of the ERCC1 and class III β-tubulin protein expression in the Japanese NSCLC patients treated with platinum-based and paclitaxel chemotherapy. ERCC1 positive cases had a shorter overall survival than the negative cases. This effect of ERCC1 expression was lost when we studied the 59 patients who were treated with surgery alone in the same period. These results might suggest that the ERCC1 positive cases were more resistance to the
Conflict of interest
None declared.
Acknowledgements
The authors would like to thank Mrs. Emi Sugiyama and Mariko Nishio for their excellent technical assistances.
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Predictors of chemotherapy efficacy in non-small-cell lung cancer: A challenging landscape
2016, Annals of OncologyCan the response to a platinum-based therapy be predicted by the DNA repair status in non-small cell lung cancer?
2016, Cancer Treatment ReviewsCitation Excerpt :A similar prospective Asiatic study analyzed stage IB-IIIA NSCLC patients undergoing radical surgery receiving adjuvant chemotherapy according to ERCC1, RRM1, and TS expression without significant differences in disease-free survival [36]. When the prognostic role of ERCC1 was investigated [37–40], ERCC1-positivity seemed to be a favorable factor for survival, except for a single analysis showing an inverse correlation. [41]. Two additional studies underpinned a better prognostic role of ERCC1 expression in squamous cell carcinoma rather than in adenocarcinoma subtype [42,43].
Role of hormone receptor expression in patients with advanced-stage lung cancer treated with chemotherapy
2012, Clinical Lung CancerCitation Excerpt :This lack of correlation may be explained in several ways. First, in NSCLC, ERCC1 protein expression has not always been invariably associated with a survival benefit in early and advanced stage,57-61 and, in some studies, a sex difference in the level of protein and/or messenger RNA expression was not observed; second, the limited number and the heterogeneity of patients considered in our series; and third, the possibility that ERCC1 is not entirely reflecting the NER activity of the tumor and other DNA repair pathways are more relevant in conferring resistance to chemotherapy.62 Combined assessment of ERCC1 and ER-β showed a significantly better survival in men with NSCLC and with NSCLC having both low ERCC1 and ER-β expression, compared with those with high/high or high/low (low/high) IHC profile.