Elsevier

Lung Cancer

Volume 62, Issue 1, October 2008, Pages 105-112
Lung Cancer

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

https://doi.org/10.1016/j.lungcan.2008.02.021Get rights and content

Summary

In this study, we examined the expression of excision repair cross-complementation group 1 (ERCC1) protein in 90 completely resected lung cancer samples from patients who received adjuvant or neo-adjuvant platinum-based chemotherapy. Epidermal growth factor receptor (EGFR) was also studied in these samples. We also examined class III β-tubulin protein expression in 50 patients treated with a platinum-based drug plus paclitaxel. Among 90 patients treated with platinum-based chemotherapy, the loss of ERCC1 protein expression was associated with a better prognosis (p = 0.0068). The effect of ERCC1 expression on survival was not seen in a separate set of 59 patients who underwent curative resection but did not receive adjuvant chemotherapy. Among 50 patients treated with a platinum-based drug plus paclitaxel, loss of class III β-tubulin protein expression was also associated with a better prognosis (p = 0.0303). When combined, patients with a tumor that was negative for both ERCC1 and class III β-tubulin had a significantly longer overall survival than those with a tumor that expressed either ERCC1 or class III β-tubulin (p = 0.0230). There was no relationship between the presence of an EGFR mutation and the patients’ survival after the platinum-based chemotherapy. In conclusion, we found that the loss of ERCC1 and class III β-tubulin protein expression were predictors of better survival in patients who received a platinum-based plus taxane chemotherapy.

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.

Section snippets

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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