Lung Adenocarcinoma From East Asian Never-Smokers Is a Disease Largely Defined by Targetable Oncogenic Mutant Kinases

Every year, there are approximately 400,000 Chinese people died of lung cancer, within which the lung adenocarcinoma is the most common type. The study of genetic mutation in lung cancer is significant for clinical diagnosis and prognosis. Recently, the research group led by Prof. Hongbin Ji from SIBCB and Prof. Haiquan Chen from Fudan University discovered that lung adenocarcinoma from East Asian never-smokers is a disease largely defined by targetable oncogenic mutant kinases. Their finding was published on Journal of Clinical Oncology.

 

Approximately 10% to 15% of all lung cancers arise in never-smoker. The importance of never-smokers has emerged in lung cancer because of recent clinical observations. During the development of the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), gefitinib and erlotinib, retrospective studies showed that never-smoking status, along with adenocarcinoma histology and East Asian ethnicity, were associated with a higher likelihood of responding to treatment. Subsequently, EGFR kinase domain mutations (ie, deletions in exon 19 and L858R point mutations in exon 21) were found to be enriched in patients with these clinical features and to be highly associated with increased sensitivity to EGFR TKIs. Furthermore, lung cancers in patients with minimal and/or a remote history of direct tobacco exposure were found to share some molecular features with their never-smoking counterparts. For example, the likelihood of EGFR mutations decreases as the number of pack-years increases. Collectively, all of these observations led to a randomized phase III trial open-label study (Iressa Pan Asian Study [IPASS]), in which previously untreated patients in East Asia who had advanced pulmonary adenocarcinomas and who were neversmokers or former light-smokers (those who had stopped smoking at least 15 years previously and had a total of ≤10pack-years of smoking) were randomly assigned to receive gefitinib or conventional chemotherapy with carboplatin plus paclitaxel. Patients with EGFR mutant tumors experienced longer progression-free survival with gefitinib, and patients without mutations had longer progression-free survival with chemotherapy. Similar results have been observed with erlotinib in white never-smokers with lung adenocarcinoma. In IPASS, the objective radiographic response rate in all patients treated with gefitinib was 43%. In contrast, for patients with known EGFR mutations, the response rate was 71.2%. A similar high response rate (62.1%) to gefitinib was reported in another recent study, the WJTOG3405 trial, in which only patients with known EGFR tumor mutations were randomly assigned to EGFR TKI or chemotherapy.

 

To explore the discrepancy between these results and to better characterize lung adenocarcinomas in never-smokers, the researchers performed a comprehensive analysis of major known driver mutations in 52 East Asian patients from a single institution with resected pulmonary adenocarcinomas and who were never-smokers. Driver mutations occur in genes that encode signaling proteins critical for cellular proliferation and survival. In lung adenocarcinomas, such mutations include EGFR, HER2, KRAS, BRAF, PIK3CA, and EML4-ALK. The scientists also examined tumors for mutations in other genes (ie, the oncogenes, HRAS and NRAS and the tumor suppressor genes TP53 and LKB1). Their results have clear therapeutic implications for never-smokers with lung cancer.

 

This research was supported by the Ministry of Science and Technology, National Natural Science Foundation of China, Shanghai Municipal Commission for Science and Technology.