Elsevier

Lung Cancer

Volume 53, Issue 3, September 2006, Pages 311-322
Lung Cancer

Complex mutation patterns of epidermal growth factor receptor gene associated with variable responses to gefitinib treatment in patients with non-small cell lung cancer

https://doi.org/10.1016/j.lungcan.2006.06.005Get rights and content

Summary

Mutational analysis was performed in the kinase domain (exons 18–21) of the EGFR gene on tumor tissues of 65 non-small cell lung cancer (NSCLC) patients who had received gefitinib monotherapy. The association between EGFR gene mutation, gefitinib treatment response, and the overall survival were evaluated. In total, EGFR mutations with complex patterns were identified in 32 tumors. The overall mutation rate was 49.2% (32/65). Twenty of the 32 patients were responders, 10 non-responders, and 2 not assessable. The most common mutation in non-responders was L858R. Gefitinib responsiveness was only significantly associated with EGFR mutation and adenocarcinoma. The median survival for responder (15.5 months) was much longer than non-responder (9.23 months), though the difference only had marginal significance (p = 0.056). The difference of overall survival between patients with and without EGFR mutation was non-significant (p = 0.7819), mainly due to the short survival of the non-responders with EGFR mutations (median survival = 6.2 months). Our study revealed that the response to gefitinib treatment in NSCLC patients with EGFR mutations could be quite variable even for the same EGFR mutation type. An analysis of the various EGFR mutations and the response patterns was also performed and compared with recently published reports on EGFR mutation and gefitinib responsiveness.

Introduction

Lung cancer, especially non-small cell lung cancer (NSCLC), has become the leading cause of cancer deaths in most countries in the world [1]. Although the efficacy of new chemotherapeutic regimens for NSCLC has been improved, the median survival for advanced-staged NSCLC by conventional chemotherapy is still around 7–8 months by randomized clinical trials [2], [3]. Of the newly developed approaches to treating cancers, targeted therapy that inhibits activated protein kinases with small-molecule drugs has been considered promising [4], [5], [6]. Of them, epidermal growth factor receptor (EGFR) inhibitors, gefitinib (Iressa, AstraZeneca Inc., UK) has been approved in Japan and the United States for NSCLC treatment and it is the most widely used EGFR inhibitor worldwide [7], [8], [9], [10]. One interesting observation with respect to this new drug is that only a subgroup of NSCLC patients responds to gefitinib, which acts faster than conventional chemotherapy but has relatively mild side effect [11], [12]. Lynch et al. and Paez et al. have discovered that somatic-activating mutations in the tyrosine kinase domain of EGFR are associated with gefitinib responsiveness [13], [14], and the finding is supportive of treatment selection based on molecular classification. Since then, there have been several large EGFR mutation studies of gefitinib-naïve or gefitinib-treated NSCLC patients [13], [14], [15], [16], [17], [18]. Nevertheless, the wide spectrum and complexity of EGFR mutations would suggest that not all patients with EGFR mutation will respond to gefitinib. Currently, the published EGFR mutations studies for gefitinib-treated patients have much smaller populations than those using gefitinib-naïve and chemo-naïve patients [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26]. Although most studies have shown that the EGFR mutations are well associated with gefitinib responsiveness, it remains uncertain whether all bearers of EGFR mutations are more sensitive to gefitinib treatment. Further, the association between EGFR mutation and prolonged overall survival was still inconsistent between the various studies [19], [20], [21], [22], [23], [24], [25], [26].

In this study, we performed EGFR mutation analysis on 65 gefitinib-treated NSCLC patients to determine the relationship with responsiveness and survival. Complex mutation patterns were identified in the responders, together with various mutations in patients unresponsive to gefitinib treatment. While EGFR mutations were still well associated with gefitinib responsiveness, the relationship with overall survival was not significant due to the short survivals of the non-responders with EGFR mutations. A review of all published reports on EGFR mutation and gefitinib responsiveness is also provided.

Section snippets

Patients and treatment

From September 2003 to November 2004, 96 patients with advanced NSCLC received gefitinib monotherapy at Chang-Gung Memorial Hospital. The sample included six patients who had been enrolled in the Expanded Access Program. In 65 of these patients, adequate tumor tissue was obtained for mutational analysis, and clinical follow-up data were available for evaluation of treatment response. In addition to the positive image findings of lung cancers, all patients had pathologically confirmed NSCLC and

EGFR mutations and patients’ characteristics

Of the 65 patients (28 males and 37 females) with adequate paraffin-embedded tissue for mutational analysis, 52 were adenocarcinomas (including 2 pure bronchioloalveolar carcinomas), 12 squamous cell carcinomas, and 1 was large cell carcinoma. Mutation(s) in the kinase domain (exons 18–21) of the EGFR gene were identified in 32 tumor specimens (Table 2). The mutation patterns of the 32 patients were rather complex and multiple mutations (2–4 in 1 patient) were found in 7 patients. The overall

Discussion

In this study, the EGFR mutation patterns were analyzed and the relationships with gefitinib responsiveness determined in a sample of 65 patients with advanced-staged NSCLC. A total of 32 patients carried the EGFR mutations. When the relationships between EGFR mutations and various clinical characteristics were tested by univariate analysis, statistical significance was only determined for adenocarcinoma histology and non-smoking history (Table 3). Further, EGFR mutation and adenocarcinoma were

Acknowledgements

We would like to express our gratitude to Dr. Yi-Rong Chen and Dr. Lin-Hui Li for their valuable suggestions, and to Dr. Mitsudomi and Dr. Takano for providing more detailed EGFR mutation data for their case series.

This work was supported by grants from the National Health Research Institutes (MG-093-PP-08), Taiwan.

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    • Rare epidermal growth factor receptor gene alterations in non-small cell lung cancer patients, tyrosine kinase inhibitor response and outcome analysis

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      The shorter median PFS of 6 months and median OS of 20 months for the uncommon mutation group in our study is comparable to studies by Wu et al. and Kate et al. [10 19]. The rate of complex mutations in the present study is 16%, and it conforms to the earlier studies [12 20-23], which report the rate between 7% - 26%. A higher rate of complex mutations is expected with massively parallel sequencing approaches [12 23].

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    Sixteen of the 65 patients in this series have been reported in our previous article: high frequency of EGFR mutations with complex patterns in non-small cell lung cancers related to gefitinib responsiveness in Taiwan. Clinical Cancer Research 2004;10:8195–8203.

    1

    These two authors contributed equally to the article.

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