Lung Cancer in Never-Smokers: A Different Disease

Summary of Key Points

The known or suspected etiologic factors for lung cancer arising in never-smokers are weak carcinogens or rare factors, which cannot explain the relatively high frequency of cancer in never-smokers. This also applies to environmental tobacco smoke.
Genetic factors play an increasing role in the etiology of lung cancer in never-smokers. These include rare high penetrance mutations in crucial genes such as the T790M mutation in the EGFR gene. However, high-frequency, low-penetrance variations in susceptibility genes are playing an increasingly prominent role. These include loci that predispose to smoking as well as those that may contribute directly to cancers arising in smokers and never-smokers.
The molecular alterations in lung cancers arising in smokers and never-smokers are very different. Smoke related tumors are associated with high numbers of mutations, especially C:G>A:T transversions, while never-smoker tumors are associated with low numbers of mutations targeting C:G>T:A transitions.
The specific mutational targets are also different in smoker and never-smoker tumors. Thus KRAS mutations are more frequent in ever-smoker tumors, while EGFR mutations and ALK translocations are more frequent in never-smokers. Paradoxically, the number of therapeutic actionable mutations is more frequent in never-smoker tumors.
Lung cancers arising in never-smokers show major differences based on ethnicity, gender, and histology. The ethnic differences point out the importance of genetic susceptibility loci in the development of lung cancers.
The major clinical, ethnic, gender, and histology differences between lung cancers arising from smokers and never-smokers, coupled with their different etiologic factors and major molecular differences, indicate that they represent very different tumor types, confirming that lung cancers in never-smokers represent a different form of cancer.

Key Terms

Ever-smoker

An individual who has smoked 100 or more cigarettes during his or her lifetime.

Never-smoker

An individual who has smoked fewer than 100 cigarettes during his or her lifetime.

Current smoker

An individual who is currently smoking or who has quit smoking during the past 12 months.

Former smoker

An ever-smoker who quit more than 12 months earlier.

Lung cancer is the leading cause of cancer-related mortality worldwide, with about 1.4 million deaths each year. In 2008, lung cancer was the most commonly diagnosed cancer globally, the leading cause of cancer-related death in men, and the fourth most commonly diagnosed cancer and second leading cause of cancer-related death in women. The lung cancer incidence rate for men in East Asia ranks as the fifth highest in the world, after Eastern and Southern Europe, North America, Micronesia, and Polynesia, with an age-standardized incidence rate by gender and area of the world of 45.0 per 100,000 cases. For women, the third highest lung cancer incidence rate is found in East Asia, Australia, and New Zealand, with 19.9 per 100,000 cases. Interestingly, the lung cancer incidence rate for women is higher in China (21.3 cases per 100,000 women) than in Germany (16.4) and Italy (11.4), although adult smoking prevalence is substantially lower in China (4% vs. 20%).

The World Health Organization estimates that lung cancer is the cause of 1.37 million deaths globally per year, or 18% of all cancer deaths. An estimated 71% of lung cancers are caused by smoking, indicating that about 400,000 deaths each year are caused by lung cancer in lifetime never-smokers. It has been estimated that 15% of men and 53% of women with lung cancer worldwide are never-smokers. Thus, lung cancer in never-smokers is among the seven or eight most common causes of cancer death. However, lung cancer in never-smokers is often grouped together with lung cancer in ever-smokers. In this chapter, we describe the clinical-pathologic and molecular differences between these two types of lung cancer. Although several review articles have addressed this topic, this chapter focuses on lung cancer in never-smokers in East Asian countries, where the incidence rate is higher than in other geographic regions. In addition, we discuss molecular differences between lung cancer in never-smokers and ever-smokers. For these purposes, we use standard definitions as follows:

Epidemiology of Nonsmoking-Related Lung Cancer

Although numerous articles on lung cancer in never-smokers in Asia have been published, some data are inconsistent and other data are suspect, as the definitions of never-smokers are not uniform, and the quality of some of the data is questionable. Also, smoking incidence rates differ among women even within a single country. For example, the smoking incidence rates among women in northeastern China are considerably higher than the rates among women in southern China. For these reasons, we extensively cite reviews or meta-analyses that combine data from multiple published reports and from cancer registries. By doing so, we can avoid some of the biases from small, individual studies, and we can place ethnic, gender, and geographic differences in their proper context. Findings from a case–control study on epidemiologic risk factors for lung cancer in never-smokers are described in a 2010 article by Brenner et al.

A review of published studies on the epidemiology of lung cancer (18 studies, comprising 82,037 people) showed a marked gender bias that lung cancer among never-smokers appears to affect women more frequently than men, irrespective of geography ( p < 0.0001). The proportion of women with lung cancer who reported never having smoked regularly is particularly high in East Asia (61%) and South Asia (83%), whereas only 15% of women with lung cancer in the United States are never-smokers. In contrast, only 11% of men with lung cancer in East Asia are never-smokers.

Thun et al. published an analysis of 13 cohorts and 22 cancer registry studies with data from nearly 2.5 million never-smokers and from cancer registries in 10 countries covering several decades. Some of the key findings from this comprehensive analysis regarding lung cancer in never-smokers include the following:

death rates from lung cancer were higher among men than women across all age and racial groups
incidence rates among men and women were similar, with some variation by age
death rates were higher among East Asian individuals (but not among those living in the United States) and black Americans than among white Americans
no temporal trends were seen for American women
lung cancer incidence rates were higher and more variable among East Asian women.

Known or Suspected Etiologic Factors for Lung Cancer in Never-Smokers

Because tobacco use is a powerful carcinogen and the major cause of lung cancer, most attention has focused on environmental tobacco exposure as the major cause of lung cancer in lifetime never-smokers. Although environmental tobacco exposure has been identified as a contributing factor for lung cancer in never-smokers since 1986, the Surgeon General of the United States 2006 report confirmed that environmental tobacco exposure modestly increased the risk of lung cancer. However, the odds ratios for the development of lung cancer in the United States indicated that such exposure is a very weak carcinogen compared with active smoking, as cited in the Surgeon General’s report. According to that report, the odds ratio is 1.0 for never-smokers who do not have environmental tobacco exposure and 1.2 for never-smokers who do have such exposure; in contrast, the odds ratio is 40.4 for ever-smokers. Thus, if environmental tobacco exposure is a weak carcinogen and cannot be the major cause of lung cancer in never-smokers, other known or suspected factors should be considered, such as indoor air pollution, environmental and occupational toxins (e.g., arsenic, radon, asbestos), and human papillomavirus (HPV) infection (and possibly other infections). Genetic factors should also be considered, and these are discussed later.

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