Original studyAnalysis of Intratumor Heterogeneity of EGFR Mutations in Mixed Type Lung Adenocarcinoma
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.
References (31)
- et al.
Randomized phase III study of cisplatin plus irinotecan versus carboplatin plus paclitaxel, cisplatin plus gemcitabine, and cisplatin plus vinorelbine for advanced non-small-cell lung cancer: Four-Arm Cooperative Study in Japan
Ann Oncol
(2007) - et al.
The status and role of ErbB receptors in human cancer
Exp Mol Pathol
(2008) - et al.
Epidermal growth factor receptor: mechanisms of activation and signalling
Exp Cell Res
(2003) - et al.
Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial
Lancet Oncol
(2010) - et al.
International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society international multidiscliplinary classification of lung adenocarcinoma
J Thorac Oncol
(2011) - et al.
Heterogeneity of epidermal growth factor receptor mutations within a mixed adenocarcinoma lung nodule
Lung Cancer
(2008) - et al.
Chemoprevention of lung cancer
Lancet Oncol
(2003) - et al.
‘Targeting’ the epidermal growth factor receptor tyrosine kinase with gefitinib (Iressa) in non-small cell lung cancer (NSCLC)
Semin Cancer Biol
(2004) - et al.
Risk factors for interstitial lung disease and predictive factors for tumor response in patients with advanced non-small cell lung cancer treated with gefitinib
Lung Cancer
(2004) - et al.
Sequential molecular changes during multistage pathogenesis of small peripheral adenocarcinomas of the lung
J Thorac Oncol
(2008)
Direct comparison of 3 PCR methods in detecting EGFR mutations in patients with advanced non-small-cell lung cancer
Clin Lung Cancer
Disappearance of an activated EGFR mutation after treatment with EGFR tyrosine kinase inhibitors
Lung Cancer
Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer
N Engl J Med
Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib
N Engl J Med
EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy
Science
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Radiomic Features Are Associated With EGFR Mutation Status in Lung Adenocarcinomas
2016, Clinical Lung CancerRare discrepancies in a driver gene alteration within histologically heterogeneous primary lung cancers
2015, Lung CancerCitation Excerpt :The 2015 World Health Organization (WHO) classification of lung tumors [22] confirmed the rationality of lung adenocarcinomas and the necessity of known driver gene mutations (such as EGFR, KRAS). Recent studies examined EGFR mutational heterogeneity in primary tumors, metastases, multiple lung nodules, therapies tailored to gene status and the ITH within the primary tumor, but reached conflicting conclusions [8–15,23–25]. In previous work, we found that heterogeneity about EGFR mutations was relatively rare in primary tumors and in metastases, but much more in multiple pulmonary nodules [26].