Elsevier

Clinical Lung Cancer

Volume 14, Issue 6, November 2013, Pages 680-687
Clinical Lung Cancer

Original study
Response to First-Line Chemotherapy in Patients With Non–Small-Cell Lung Cancer According to Epidermal Growth Factor Receptor and K-RAS Mutation Status

https://doi.org/10.1016/j.cllc.2013.05.004Get rights and content

Abstract

Background

Epidermal growth factor receptor (EGFR)–targeted therapy has shown a favorable efficacy in patients with non–small-cell lung cancer (NSCLC). Conversely, K-RAS mutations were reported to have an adverse effect on the survival of patients with NSCLC. These studies suggest that the tumor biology of patients with EGFR or K-RAS mutations is different from that of patients with wild-type mutations. Therefore, we hypothesized that the response to cytotoxic chemotherapy may differ among patients with and without EGFR or K-RAS mutations.

Methods

A total of 229 patients with advanced NSCLC who received platinum doublet chemotherapy were included in this retrospective study, and their clinical outcomes were analyzed according to EGFR and K-RAS mutation status.

Results

EGFR and K-RAS mutations were found in 52.4% and 27.9% of patients, respectively. Progression-free survival (PFS) was significantly higher in patients with EGFR mutations than in patients with wild-type EGFR (P = .008), and multivariate analysis showed that EGFR mutation was an independent factor to chemotherapy (P = .01). Among the patients with EGFR mutations, the disease control rate for docetaxel was higher than for gemcitabine-based therapy (P = .031). In addition, docetaxel or vinorelbine showed a longer PFS than gemcitabine-based chemotherapy in patients with EGFR mutations (P = .033 and P = .028). However, no similar differences were found according to the K-RAS mutations.

Conclusions

EGFR, but not K-RAS mutation, is associated with improved survival time to platinum-based chemotherapy. In patients with EGFR mutations, PFS for docetaxel and gemcitabine was higher than for vinorelbine-based chemotherapies. The predictive meaning of EGFR mutation for chemotherapy should be further investigated.

Introduction

Platinum-based doublet chemotherapy has been the standard first-line treatment for advanced non–small-cell lung cancer (NSCLC).1, 2 Despite the progress in the newly developed chemotherapy regimens, chemotherapy for NSCLC is still insufficient.3, 4 Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) recently have shown a favorable efficacy in patients with NSCLC.5, 6 Several phase III trials indicated that NSCLCs harboring EGFR mutations derive greater benefit from erlotinib or gefitinib than from chemotherapy and suggest that all patients with an EGFR mutation must be offered the opportunity to be treated with an EGFR TKI.7, 8, 9 Conversely, other studies have suggested that mutations in the K-RAS gene were associated with resistance to EGFR TKIs and have an adverse effect on the survival of patients with NSCLC.10, 11, 12 These findings indicate that the tumor biology of patients with EGFR or K-RAS mutations is different from that of patients with wild-type mutations and that EGFR or K-RAS may be a predictive factor for NSCLC.13, 14

On the basis of these studies, we hypothesized that the response to cytotoxic chemotherapy also may differ between tumors with and without EGFR or K-RAS mutations. Hotta et al15 demonstrated that EGFR mutations significantly affected progression-free survival (PFS) of front-line chemotherapy. The study by Cappuzzo et al16 indicated that among patients with EGFR mutations, only those who carried deletions in exon 19 have a favorable response to chemotherapy. However, other studies17, 18 suggested that the overall response rate (RR) and the PFS in patients with NSCLC after treatment of conventional chemotherapy were not influenced by EGFR or K-RAS mutation status. In contrast, a recent study of a chemosensitivity test reported that lung cancers with EGFR mutations were less sensitive to docetaxel than wild-type EGFR tumors.19 Therefore, the association of EGFR and K-RAS mutation status with the responsiveness to chemotherapy is still not clear.

In the present study, we reviewed 229 patients with advanced NSCLC who had received platinum-based doublet chemotherapy as a first-line therapy and evaluated the clinical outcome in terms of RR, overall survival, and time to tumor progression according to the EGFR and K-RAS mutation status.

Section snippets

Patients

We screened a total of 680 patients with advanced NSCLC between 2007 and 2010 in this retrospective analysis and reviewed 325 patients who had received carboplatin-based doublet chemotherapy as a first-line treatment. A cohort of 229 patients was selected, for whom the clinical records and computed tomography (CT) scans were complete and EGFR and K-RAS mutation status were available to detect. Histologic type was determined according to the World Health Organization criteria, and the stage of

Patient Characteristics

Patient characteristics are listed in Table 1. A total of 229 patients with NSCLC were included in the study. The ages ranged from 39 to 75 years (median age, 61 years), and 127 patients (55.5%) were male. The majority of the tumors were adenocarcinoma (112 patients, 48.9%), and 123 patients had stage IV disease (53.7%). Lung, bone, brain, and lymph nodes were the most frequently metastatic sites. All patients received carboplatin-based doublet chemotherapy as a first-line treatment.

Discussion

Preclinical studies have suggested a relationship between EGFR function and sensitivity to cytotoxic agents.20 However, few clinical studies have evaluated the response to first-line chemotherapy according to EGFR or K-RAS mutations. In the present study, we analyzed 229 patients with NSCLC who had received carboplatin-based doublet chemotherapy as a first-line treatment. The data demonstrated that the RR and DCR in patients with EGFR mutations were higher than in those with a wild-type EGFR,

Conclusion

The results of our study suggest that EGFR, but not K-RAS mutation, is associated with improved survival time to platinum-based chemotherapy. Moreover, EGFR mutations may be used as a predictive marker for the response to conventional chemotherapies involving gemcitabine, docetaxel, and vinorelbine. More prospective studies are needed to performed to evaluate the predictive meaning of EGFR mutation for chemotherapeutic regimens in patients with NSCLC.

Acknowledgments

This work was supported by the fund of Ministry of Health of China. The authors thank Yazhou Cui, Shandong Academy of Medical Sciences, Jinan, China, for valuable scientific suggestions.

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