Review
Lung cancer in never smokers – A review

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Abstract

An estimated 10–25% of lung cancers worldwide occur in never smokers, i.e. individuals having smoked less than 100 cigarettes in their lifetime. Lung cancer in never smokers (LCINS) is more frequent in women, although large geographic variations are found. Histologically, adenocarcinomas predominate.

The mere existence of LCINS suggests that risk factors other than smoking must be present. Exposure to environmental tobacco smoke (particularly in women) and exposure to workplace carcinogens (particularly in men) are the two most important alternative risk factors. However, a history of either is absent in more than a third of LCINS. The large proportion of women in LCINS suggest a hormonal element that may interact with other identified factors such as hereditary risks, a history of respiratory infections or disease, exposure to air pollution, cooking and heating fumes, or exposure to ionising radiation.

The study of genomic polymorphisms finds constitutive DNA variations across subjects according to their smoking status, particularly in genes coding for enzymes that participate in the metabolism of certain carcinogens, in those coding for DNA repair enzymes, or in genes associated with tobacco addiction, or inflammatory processes. The type of molecular mutation in p53 or KRAS varies with smoking status. EGFR mutations are more frequent in never smokers, as are EML4-ALK fusions. The mutually exclusive nature of certain mutations is a strong argument in favour of separate genetic paths to cancer for ever smokers and never smokers.

In the present paper we review current clinical and molecular aspects of LCINS.

Introduction

Tobacco use is the oldest1 and most well-established2 risk factor for lung cancer. However, this malignancy occurs in a very small number of patients who have no history of smoking. Lung cancer in never smokers (LCINS) has only been described in detail in the past 5 years3, 4, 5 and its frequency is increasing according to some authors. LCINS has been found to be accessible via targeted treatments, and thus has become the subject of major research.6, 7 The present article focused on providing an in-depth literature review of LCINS.

A ‘never smoker’ is commonly defined as an individual who has smoked less than 100 cigarettes over his or her lifetime. Never smokers are thus differentiated from ‘ever smokers’ (more than 100 cigarettes over their lifetime), who are normally sub-categorised as either ‘ex-smokers’, i.e. those who have currently and completely stopped smoking for more than 1 year, and ‘current smokers’, i.e. those who currently smoke or have quit for less than 1 year.3, 8 The concept of ‘light smoker’ lacks clarity and is debatable, as there is no tobacco threshold effect for the risk of lung cancer. In IPASS study, authors have defined light smokers as people who have smoked less than 10PY in their lifetime and quit smoking since at least 15 years.9 This cut-off value seems henceforth too high. Although no official definition has been established, a history of less than 5 pack-years is now commonly thought of as light smoking. Debate continues on where the reported incidence of LCINS in recent years represents a true increase. In 2001, Bofetta et al. observed a significant increase in the incidence of LCINS in a Swedish cohort: from 1.5/100 000 in 1976–1980 to as much as 5.4/100,000 in 1991–1995.10 Their results seemed to confirm earlier observations suggesting a progressive increase in LCINS since the 1930s11, 12 and the emergence of non-tobacco related lung cancer risks. However, in a large analysis of cohorts and registries, Thun et al. observes no significant temporal trend in LCINS incidence and mortality among United States of America (US) never smokers from 1959 to 2004.13, 14 The authors of a recent work found a decrease incidence in men but increase in women when compared to the preceding generation.15 Leaving methodology debates aside, an increase in LCINS incidence could be real, or the result of the decrease in the proportion of ever smokers in some strata of the general population, and/or ageing within these categories.16

The World Health Organisation estimates that 25% of lung cancer worldwide occurs in never smokers.17 This percentage is probably closer to 10–15% in Western countries. However, LCINS proportions vary widely, from more than 50% in women in Southeast Asia, to approximately 2–6% in men in Western series.3, 8, 18 If considered as an independent entity, LCINS is the 7th largest cause of cancer-related mortality in the world19 and a top-ten cause of death in the United States.14, 20 In France a study of the Bas Rhin registry found LCINS proportions of 1.4% and 28.9% respectively in men and women21; within the KBP-2000 study, these proportions were 2.5% and 32.3%.22 Comparing these results to cancer mortality estimations for France in 2011,23 LCINS represents the 3rd-leading cause of death by cancer in women. At the European level, data from the European Cancer Observatory24 show that LCINS is the 17th cause of cancer mortality (9th for women, see Supplementary Fig.1). There is thus a considerable geographical effect, particularly in women, for LCINS. Indeed, the malignancy is more frequently diagnosed in Asia than it is in the United States, and more frequently in the United States than in Europe. However its ethnic/genetic attributes and/or environmental factures remain unknown.3

Section snippets

Clinical and pathological presentation

In all LCINS series, women are systematically over-represented.3, 5, 6, 8, 25 Mortality rates in female patients are of the same as for male patients.14

Contradictory data exist concerning age and diagnoses of LCINS, with some authors reporting the cancer’s penchant for older patients, while others find it in significantly younger patients. The data from several French studies tend to illustrate a predominance of LCINS in advanced-age patients. In the KBP-2000 study, the proportion of never

Lung cancer risk factors other than smoking (Table 1)

Lung cancer in individuals who do not smoke obviously suggests the existence of risk factors other than tobacco (Table 1).3, 8, 18, 29 These other risk factors are in no way found exclusively in never smokers; indeed, different risk factors, related or not to smoking, are frequently associated and sometimes cumulative or synergic. Several epidemiological studies have identified several factors associated with risk of lung cancer. From those, most are linked to pollution: occupational,

Genomic polymorphisms(Table 2)

Polymorphisms of genes involved in carcinogen metabolism are very relevant and productive for smokers with lung cancer.

Two polymorphisms in exon 7 of CYP1A1, the substitutions T3801C (MspI) and A2455G (Ile462Val), are linked to an increased risk of lung cancer.94 Specifically in Caucasian never smokers (in data pooled from 14 studies) there was a significant effect for the Ile462Val mutation (OR = 2.21 [95% CI = 1.12–4.37]) but a non-significant effect for the MspI mutation. 95 The Leu432Val

P53 mutations

There is a linear relation between p53 mutation risk and tobacco consumption123; mutations are thus rarer in never smokers (10–47%) than in ever smokers (26–71%).124 Additionally, the spectrum and type of mutation differ according to smoking status: G to T transversions are more frequently found in ever smokers, whereas G to A transitions and G to C transversions are more common in never smokers.123, 124 Finally, it is interesting to note that p53 mutations are more frequent in never-smoker

Conclusion

Lung cancer in never smokers is a distinct medical entity that is more frequent in women than in men and in certain geographical regions than in others (Asia > North America > Europe). Pollution (including environmental tobacco smoke and occupational exposure) is an important factor in this population. Close to 50% of never-smoker patients present molecular mutations that may be treatable currently or in the near future via targeted therapies compared to potentially 10% of ever smokers.

The genomic

Conflict of interest statement

SC declares having received grants, paid to his institution from: Roche SA France, Pfizer, Boeringher Ingelheim, Pierre Fabre, Astra Zeneca and Lilly. GZ declares having received grants, paid to his institution from Lilly and supports for travel to meeting from Lilly. FM: None declared. BM: None declared. PJS: None declared.

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