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.

Figure 1

Differential frequencies of EGFR and KRAS mutations reported in lung adenocarcinomas in East Asia vs. United States, in never smokers and ever smokers. Activating mutations in both genes are found predominantly in adenocarcinomas, and occur in non-overlapping cohorts. US estimates of EGFR mutation frequencies are based on pooled data summarized in (41) and (22), and of KRAS mutation frequencies from (44). East Asian estimates for both genes are based on pooled data of (39) and (36).

Figure 2

TP53 mutation spectra in cancers in lung cancer by smoking status. Source: IARC Database version R13, November 2008 release.