Clinical Investigation
Epidermal Growth Factor Receptor Mutation Is Associated With Longer Local Control After Definitive Chemoradiotherapy in Patients With Stage III Nonsquamous Non–Small-Cell Lung Cancer

https://doi.org/10.1016/j.ijrobp.2014.08.344Get rights and content

Purpose

To determine the frequency and clinical significance of epidermal growth factor receptor (EGFR) mutations in patients with potentially curable stage III non–small-cell lung cancer (NSCLC) who are eligible for definitive chemoradiotherapy (CRT).

Patients and Methods

Between January 2001 and December 2010, we analyzed the EGFR mutational status in consecutive NSCLC patients who were treated by CRT. The response rate, relapse-free survival, 2-year relapse-free rate, initial relapse sites, and overall survival of the patients were investigated.

Results

A total of 528 patients received CRT at our hospital during the study period. Of these, 274 were diagnosed as having nonsquamous NSCLC. Sufficient specimens for mutational analyses could be obtained from 198 of these patients. The proportion of patients with EGFR activating mutations was 17%. In addition to the well-known characteristics of patients carrying EGFR mutations (female, adenocarcinoma, and never/light smoker), the proportion of cases with smaller primary lesions (T1/2) was found to be higher in patients with EGFR mutations than in those with wild-type EGFR. Patients with EGFR mutations showed similar response rate, relapse-free survival, and 2-year relapse-free rates as compared to patients with wild-type EGFR. Local relapses as the site of initial relapse occurred significantly less frequently in patients with EGFR mutation (4% vs 21%; P=.045). Patients with EGFR mutations showed longer local control (adjusted hazard ratio 0.49; P=.043). After disease progression, a majority of the patients with EGFR mutations received EGFR tyrosine kinase inhibitors (62%), and these patients showed longer postprogression survival than those with wild-type EGFR.

Conclusions

Our study is the first to show radiosensitive biology of EGFR-mutated tumors in definitive CRT with curative intent. This finding could serve as a credible baseline estimate of EGFR-mutated population in stage III nonsquamous NSCLC.

Introduction

Lung cancer remains the leading cause of cancer-related deaths worldwide (1). Non–small-cell lung cancer (NSCLC) accounts for 80% of all cases of lung cancer, and approximately 30% of patients with NSCLC present with stage III disease 2, 3. For patients with good performance status and adequate organ function, combined chemotherapy plus radiation therapy (RT) is the standard of care 4, 5. Combined platinum-containing chemotherapy with concurrent RT has been reported to offer a median survival time of approximately 20 months 6, 7, 8, 9, 10.

The findings of driver mutations, such as mutations of epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) translocation, brought paradigm shifts in the therapeutic strategy for advanced NSCLC 11, 12. The frontline treatment for mutated patients changed from platinum-based chemotherapy to the respective specific tyrosine kinase inhibitors (TKIs). The overall survival of NSCLC patients with EGFR mutations increased from 10 months to approximately 20 months with the introduction of TKIs 13, 14, 15.

A preclinical study indicated the radiosensitizing effect of gefitinib in various solid tumors 16, 17, and another study demonstrated the radiosensitive phenotype of EGFR-mutated cell lines (18). It has been retrospectively reported that the clinical response to whole-brain RT of brain metastases in patients with EGFR mutation was superior to that of wild-type EGFR (19).

In this context, it is essential to understand the baseline estimate of the EGFR-mutated population in stage III NSCLC and the biological behavior of these tumors. However, the frequency of EGFR mutations in stage III nonsquamous NSCLC patients is still unclear, because it has no clinical consequences to analyze EGFR mutational status at the time of diagnosis, considering the unsatisfactory results of previous trials that incorporated EGFR-TKI into chemoradiotherapy (CRT) 20, 21. Moreover, the impact of driver mutational status on the relapse and survival in this population is yet to be clarified.

The aim of this study was to clarify the proportion of stage III nonsquamous NSCLC patients eligible for definitive CRT who harbor EGFR mutations, and to explore the radiosensitive biology according to EGFR mutational status.

Section snippets

Patients

Between January 2001 and December 2010, a total of 528 NSCLC patients received CRT at our hospital. Under an institutional review board–approved protocol, we reviewed the medical records of all of these patients. Of these, we identified 274 patients with unresectable stage III nonsquamous NSCLC. Patients who were enrolled in clinical trials that include EGFR-TKI as study therapy (Japanese Clinical Oncology Group 0402 [21]), were enrolled in ongoing clinical trials whose results had yet to be

EGFR mutational status

Of the 274 patients intended for EGFR mutation analysis, the analysis could not be conducted in 76 because of lack of availability of specimens at our hospital (47 cases) and insufficient specimens available for analysis (29 cases) (Supplementary Fig. E1; available online at www.redjournal.org). Among the 198 patients analyzed consequently, 34 (17%) had EGFR activating mutation, and 164 (83%) had wild-type EGFR. The proportion of cases with each mutational status was as follows; exon 19

Discussion

We demostrate that the proportion of patients harboring EGFR activating mutation was 17% in stage III NSCLC patients receiving CRT. Patients with EGFR mutations showed significantly longer local control (adjusted hazard ratio 0.49; P=.043), suggesting the radiosensitive characteristic of the EGFR mutated tumors. The SPP was significantly longer in patients harboring EGFR mutations treated with EGFR-TKIs after relapse.

We found that the frequency of local relapse as the initial relapse site was

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    This work was supported in part by the National Cancer Center Research and Development Fund (23-A-30, 24-A-1) and by Grants-in-Aid from the Ministry of Education, Culture, Sports, Science, and Technology of Japan for Scientific Research on Innovative Areas (22131006).

    Conflict of interest: T.K. reports grants from the National Cancer Center Research and Development Fund and the Ministry of Education, Culture, Sports, Science, and Technology of Japan, during the conduct of the study. T.T. reports grants from the National Cancer Center Research and Development Fund, during the conduct of the study.

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