Lung Cancer in Never Smokers: Molecular Profiles and Therapeutic Implications

Abstract

The majority of lung cancers are caused by long term exposure to the several classes of carcinogens present in tobacco smoke. Although a significant fraction of lung cancers in never smokers may also be attributable to tobacco, many such cancers arise in the absence of detectable tobacco exposure, and may follow a very different cellular and molecular pathway of malignant transformation. Recent studies summarized here suggest that lung cancers arising in never smokers have a distinct natural history, profile of oncogenic mutations, and response to targeted therapy. The majority of molecular analyses of lung cancer have focused on genetic profiling of pathways responsible for metabolism of primary tobacco carcinogens. Limited research has been conducted evaluating familial aggregation and genetic linkage of lung cancer, particularly among never smokers in whom such associations might be expected to be strongest. Data emerging over the past several years show that lung cancers in never smokers are much more likely to carry activating mutations of the epidermal growth factor receptor (EGFR), a key oncogenic factor and direct therapeutic target of several newer anticancer drugs. EGFR mutant lung cancers may represent a distinct class of lung cancers, enriched in the never-smoking population, and less clearly linked to direct tobacco carcinogenesis. These insights followed initial testing and demonstration of efficacy of EGFR-targeted drugs. Focused analysis of molecular carcinogenesis in lung cancers in never smokers is needed, and may provide additional biologic insight with therapeutic implications for lung cancers in both ever smokers and never smokers. Natural History and PrognosisThe preceding articles in this issue of CCR Focus present an overview, and a description of clinical epidemiology and risk factors associated with lung cancer in never smokers (1, 2). This article is intended to summarize the current status of molecular profiling of lung cancer in never smokers, to indicate how profiles differ between lung cancer in ever smokers and never smokers, and to review the therapeutic implications of these molecular characteristics. To place the therapeutic implications in context, this section will first summarize recent studies of differential clinical outcomes in lung cancer patients by ever smoker versus never smoker status, irrespective of therapies targeting particular molecular determinants.Four recent retrospective analyses have compared the characteristics and treatment outcomes of never smokers and smokers with lung cancer across stages of disease and regardless of modality of treatment (3-6). All of these series report on data obtained prior to widespread use of epidermal growth factor receptor (EGFR) inhibitors or other targeted therapies. Together these studies suggest that lung cancer in never smokers has peak incidence at a younger age than in smokers, is more likely to arise in women, and is more likely to be of adenocarcinoma histology. Furthermore, these studies show a survival adva...

Identification of a Novel Biomarker, SEMA5A, for Non–Small Cell Lung Carcinoma in Nonsmoking Women

“…Recent studies suggest that lung cancers arising in nonsmokers are more often adenocarcinoma, are more likely to have epidermal growth factor receptor mutations, and have a better natural history and prognosis with therapy (37). However, the majority of molecular analyses of lung cancer have focused on genetic profiling of pathways responsible for metabolism of tobacco carcinogens.…”

Lung cancer in never-smokers: a case–control study in a radon-prone area (Galicia, Spain)

“…Tobacco consumption is the most important risk factor for lung cancer; however, between 15-25% of all lung cancer cases occur in neversmokers [1]. Recent research suggests that lung cancer in never-smokers could be a different disease than lung cancer in smokers, since different molecular pathways are present in never-smokers' lung cancer [2,3]. These patients also have higher survival, a different age of onset and have mainly adenocarcinomas [4,5].…”

cIAP2 Upregulated by E6 Oncoprotein via Epidermal Growth Factor Receptor/Phosphatidylinositol 3-Kinase/AKT Pathway Confers Resistance to Cisplatin in Human Papillomavirus 16/18–Infected Lung Cancer

“…However, information on the chemotherapeutic efficacy in lung cancer of never smokers is needed, as there is no available information in this area (6)(7)(8). Therefore, optimal treatment approaches for never smokers with lung cancer should be established.…”