Elsevier

Clinical Lung Cancer

Volume 14, Issue 5, September 2013, Pages 521-526
Clinical Lung Cancer

Original study
Analysis of Intratumor Heterogeneity of EGFR Mutations in Mixed Type Lung Adenocarcinoma

https://doi.org/10.1016/j.cllc.2013.04.005Get rights and content

Abstract

Background

Epidermal growth factor receptor mutations are predictive of the success of EGFR tyrosine kinase inhibitor treatment in patients with advanced non–small-cell lung cancer. As with other solid tumors, lung cancer is thought to be the result of an accumulation of genetic alterations after exposure to carcinogens. The aim of the present study was to clarify the relationship between multistep carcinogenesis and the accumulation of EGFR mutations.

Patients and Methods

The intratumor heterogeneity of EGFR mutations was analyzed in 38 patients with resected mixed-type lung adenocarcinoma according to histological patterns, and the clinical features of the patients harboring intratumor heterogeneity of EGFR mutations were evaluated.

Results

Intratumor heterogeneity of EGFR mutations was detected in 9 of 38 tumors. EGFR mutations were more common in the bronchioloalveolar (lepidic) carcinoma pattern than in the papillary and acinar patterns, although this difference was not significant. However, there was a significant correlation between intratumor heterogeneity of EGFR mutations and smoking history (P < .043).

Conclusion

Intratumor heterogeneity of EGFR mutations correlates with the distribution of histological subtype in mixed type adenocarcinoma and is associated with smoking history.

Introduction

Lung cancer is the most common cause of cancer-related deaths worldwide. Despite recent advances in the management of advanced non–small-cell lung cancer (NSCLC), the cure rate remains low.1, 2 Further molecular investigation of lung cancer is required to develop new treatment strategies and improve patients' prognoses.

Activation or proliferation of NSCLC is regulated by growth factors and receptors of the epidermal growth factor receptor (EGFR) subfamily.3, 4 Considering this phenomenon, the first growth factor receptor to be proposed as a target in NSCLC treatment was EGFR and its signal transduction pathway. Gefitinib and erlotinib are EGFR tyrosine kinase inhibitors (TKIs) that are used in patients with advanced NSCLC. Recently, several studies have shown that EGFR mutations are factors predictive of response to EGFR-TKI treatment.5, 6, 7 The most common mutations are a deletion in exon 19 and L858R point mutation.8 Recently, 2 randomized, phase III trials were conducted in Japan to evaluate the efficacy of gefitinib in chemotherapy-naive patients with advanced NSCLC harboring EGFR mutations. In both trials, the patients treated with gefitinib had better progression-free survival than those treated with platinum-doublet chemotherapy.9, 10 Gefitinib was subsequently approved in Japan as a first-line treatment option for patients with advanced NSCLC harboring EGFR mutations.

We previously reported a case of a patient with mixed-type lung adenocarcinoma (corresponding to “invasive adenocarcinoma” in the International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society [IASLC/ATS/ERS] classification of lung adenocarcinoma in resection specimens11) comprising papillary, acinar, and bronchioloalveolar carcinoma (BAC) (corresponding to “lepidic” in the IASLC/ATS/ERS Classification of Lung Adenocarcinoma in Resection Speimens11) patterns that responded partially to gefitinib after developing multiple metastases. In this patient, each pathological subtype contained a different type of EGFR mutation.12

As with other solid tumors, lung cancer is thought to be the result of the accumulation of genetic alterations over a long course of exposure to a carcinogen.13 However, the genetic mechanism of this development is unclear in NSCLC, because there is no adequate means of monitoring 1 or a few genes; furthermore, the complexity of lung cancer cells limits pangenomic decipherment. In this study, intratumor heterogeneity of EGFR mutations was analyzed in patients with resected mixed-type lung adenocarcinoma according to the histological patterns. Then, to clarify the relationship between multistep carcinogenesis and the accumulation of EGFR mutations, the clinical features of patients harboring intratumor heterogeneity of EGFR mutations were evaluated.

Section snippets

Patients and Samples

Patients were recruited according to the following criteria: stage IA and IB mixed type lung adenocarcinoma without poorly differentiated lesions (mixed type lung adenocarcinoma and its histological pattern were defined in accordance with the 2004 World Health Organization (WHO) pathologic criteria14); underwent lobectomy or bilobectomy; aged 85 years or younger; and without interstitial pulmonary fibrosis or occupational lung disease, such as asbestosis or silicosis. Cases with a poorly

Patient Characteristics and Survival

The patient characteristics are listed in Table 1. The median age was 68 years. Of these 38 patients, 22 (56%) were women, 30 (79%) had stage IA cancer, and 24 (63%) were light (fewer than 10 packs per year) and never-smokers. The median DFS was 65.4 months. Four patients had recurrent disease. One had bronchial stump recurrence that was treated with stereotactic irradiation (STI). Two patients had new pulmonary nodules and were diagnosed with lung cancer recurrence; they were also treated with

Discussion

The results of the present study show that intratumor heterogeneity of a deletion of exon 19 and an L858R point mutation exists in accordance with the histological pattern in mixed type adenocarcinoma. EGFR mutations were more common in the BAC (lepidic) pattern than in the papillary and acinar patterns, though the difference was not significant. A significant association was seen between intratumor heterogeneity of EGFR mutations and smoking history. These findings suggest that EGFR mutations

Conclusion

Intratumor heterogeneity of a deletion of exon 19 and an L858R point mutation correlates with the histological patterns in mixed adenocarcinoma. This heterogeneity was significantly associated with smoking history. With heterogeneity in advanced lung adenocarcinoma, the response to EGFR-TKIs would be partial and insufficient. New treatment strategies, such as the combination of EGFR-TKIs and cytotoxic agents in chemotherapy, are needed to improve the prognosis of patients with lung

Disclosure

The authors have stated that they have no conflicts of interest.

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