Lung cancer in never smokers: Disease characteristics and risk factors

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Critical Reviews in Oncology/Hematology xxx (2013) xxx–xxx

Lung cancer in never smokers: Disease characteristics and risk factors Athanasios G. Pallis ∗ , Konstantinos N. Syrigos Oncology Unit GPP, Athens School of Medicine, Athens, Greece Accepted 28 June 2013

Contents 1. 2. 3. 4. 5.

6.

7.

8. 9.

Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Search strategy and selection criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pathology and clinical characteristics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Risk factors for lung cancer development in never-smokers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. Second hand smoking . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2. Hormonal factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3. Genetic factors and lung cancer susceptibility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Inherited susceptibility to lung cancer in never smokers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.1. Carcinogen metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2. DNA repair genes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.3. Inflammatory response genes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acquired somatic mutations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.1. EGFR . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.2. HER-2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.3. ALK rearrangements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.4. ROS1 rearrangements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Prognostic and predictive role. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Reviewers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Biographies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Abstract It is estimated that approximately 25% of all lung cancer cases are observed in never-smokers and its incidence is expected to increase due to smoking prevention programs. Risk factors for the development of lung cancer described include second-hand smoking, radon exposure, occupational exposure to carcinogens and to cooking oil fumes and indoor coal burning. Other factors reported are infections (HPV and Mycobacterium tuberculosis), hormonal and diatery factors and diabetes mellitus. Having an affected relative also increases the risk for lung cancer while recent studies have identified several single nucleotide polymorphisms associated with increased risk for lung cancer development in never smokers. Distinct clinical, pathology and molecular characteristics are observed in lung cancer in never smokers; more frequently is observed in females and adenocarcinoma is the predominant histology while it has a different pattern of molecular alterations. The purpose of this review is to summarize our current knowledge of this disease. © 2013 Elsevier Ireland Ltd. All rights reserved. Keywords: Lung cancer; Smoking; Never smokers; NSCLC; EGFR ∗ Corresponding author at: Oncology Unit GPP, Athens School of Medicine, Sotiria General Hospital, Mesogion 152, 115 26 Athens, Greece. Tel.: +30 2107475034. E-mail address: [email protected] (A.G. Pallis).

1040-8428/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.critrevonc.2013.06.011

Please cite this article in press as: Pallis AG, Syrigos KN. Lung cancer in never smokers: Disease characteristics and risk factors. Crit Rev Oncol/Hematol (2013), http://dx.doi.org/10.1016/j.critrevonc.2013.06.011

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1. Introduction Lung cancer is the leading cause of cancer related death in Western world, with approximately 1.6 million new cases and 1.4 million deaths globally in 2008 [1]. Cigarette smoking is considered the major and most well-established risk factor for human lung cancer and there is a huge bank of both prospective and retrospective epidemiologic research data supporting this association [2–4]. The relative risk of lung cancer development in a long-term smoker compared with a never-smoker is estimated to be 10- to 30-fold [5]. However, lung cancer occurs also in individuals with no history of smoking. After the observation that gefitinib is very active in never-smokers non-small-cell lung cancer (NSCLC) patients [6] attention was turned toward this population. Lung cancer in never-smokers has been described recently and major clinic-pathological differences and differences on the molecular level have been observed, implying that this might be a different disease compared with lung cancer in smokers [7–9]. Patients who have smoked less than 100 cigarettes during their lifetime are considered as “never-smokers”, while people who have smoked more are considered as “ever-smokers” [7]. The purpose of this review is to summarize our current knowledge of the epidemiological, clinical and molecular characteristics of lung cancer in never-smokers.

2. Search strategy and selection criteria A bibliographic search of the Medline database was conducted for papers published from 2000 to 2012, with the keywords “lung cancer”, “lung neoplasm”, “chemotherapy”, “NSCLC”, “risk factors”, “smoking”, and “smoker”. The search was limited to articles written in English. The Medline search was supplemented by a manual search of meeting abstracts (World Conference on Lung Cancer, European Society of Medical Oncology Annual Congress, American Society of Clinical Oncology Annual Meeting, and European Lung Cancer Conference) as well as reference lists of original and review articles.

3. Epidemiology According to the World Health Organization the incidence of lung cancer in never-smokers is approximately 25% of all cases [10]. However, there is considerable variance in the proportions of lung cancer in never smokers (LCNS) ranging from approximately 10% in males in Western world [11], up to almost 40% in females in Asia [12]. If LCNS is considered as a separate entity then it is the seventh cause of cancer-related death in the world [7]. Wakelee et al. using data from six big epidemiological studies found that in these six cohorts age-adjusted incidence rates of lung cancer among never smokers age 40 to 79 years ranged from 14.4 to 20.8 per

100,000 person-years in women and 4.8 to 13.7 per 100,000 person-years in men [13]. A large epidemiological study from US with approximately 12,000 patients found that approximately 10% of them were never-smokers [14], while a large population-based study of 20,500 cases by Radzikowska et al. found that only 4.3% of all these cases were never-smokers [15]. There are conflicting data regarding changes in the incidence of LCNS. A report by Bofetta et al. observed a significant increase in LCNS incidence (from 1.5 to 5.4/100,000 of population) in a Swedish cohort study [16], while another large epidemiological study from US observed a non-significant increase in the prevalence of LCNS (bronchoalveolar subtype) from 1995–1999 to 1999–2003 [14]. Finally, two large case control studies from UK (hospital and community based) found no difference in the percentage of never-smokers among male lung cancer patients between 1950 and 1990 (0.5% in both cases), while for women the percentage of never-smokers among lung cancer patients decreased from 37% in 1950 to 7.6% in 1990 [17].

4. Pathology and clinical characteristics Small-cell lung cancer is rarely observed in never-smokers [18], while in NSCLC the most common histological type in never-smokers is adenocarcinoma [8,9,12,13,19–22]. A case–control study by Sobue et al. [23] demonstrated that the relative risk for incident cases associated with current smokers versus never-smokers according to histologic type was 12.7 (95% Confidence Interval [CI]: 4.7–34.7) and 17.5 (95% CI: 4.9–62.1) for squamous cell carcinoma and small cell carcinoma, while for adenocarcinoma it was 2.8 (95% CI: 1.6–4.9) and 2.0 (95% CI: 0.8–5.0) for men and women, respectively. Similarly, in a report by Toh et al., adenocarcinomas involved 69.9% of cases in never-smokers, versus 39.9% in current and 47.3% in former smokers (p-value < 0.001) [8]. It is also noteworthy that adenocarcinoma was also the most common histology in young patients population (<40 years of age), in which population the proportion of neversmokers was high [24]. An analysis of 17 trials by Sun et al. demonstrated that adenocarcinoma was 3.4 times more frequent than squamous carcinoma in never smokers [7], and this higher incidence of adenocarcinoma was also confirmed by Radzikowska et al. [15]. Significant gender variations are also observed in LCNS. Lung cancer in never smokers is more common in women and this is confirmed in numerous series [7–9,12,13,15,19–22,25]. However, it is not clear whether this higher incidence in females is due to inherent susceptibility or to a greater contribution of risk factors other than smoking, or this simply represents the fact that twice as many women as men are never smokers and this difference increases with age [26]. Furthermore, significant geographical variation is observed in the proportion of never-smokers among female lung cancer cases, with that proportion being

Please cite this article in press as: Pallis AG, Syrigos KN. Lung cancer in never smokers: Disease characteristics and risk factors. Crit Rev Oncol/Hematol (2013), http://dx.doi.org/10.1016/j.critrevonc.2013.06.011

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approximately 10–15% in the Western world to 80% in south Asia [7]. On the contrary, an analysis of 13 cohorts by Thun et al., found no significant difference in the incidence rates between male (14.0 per 100,000) and female (13.8 per 100,000) never-smokers lung cancer patients of European descent, when the rates were standardized to all ages 40 years and above, although women had higher incidence rates in the age group of 40–59 years [27]. However, despite the higher incidence rates in females, prospective data have consistently reported higher death rates from lung cancer in male than female LCNS [26,27]. Thun et al. studied data from two large American Cancer Society Cancer Prevention Study cohorts (CPS I and II) and the age-standardized lung cancer death rates among never-smokers were 17.1 and 14.7 per 100,000, for men and women, respectively [26]. Several studies mostly from Asia support that LCNS is diagnosed in earlier age [8,12,21], although this was not confirmed in all cases [9,13,20]. An epidemiological study in a Caucasian population found a higher percentage of never smokers (23.9%) among a cohort of early onset (≤50 years) lung cancer patients than among patients diagnosed at ≥70 years of age (17.6%; p-value < 0.001) [28], although another study limited to patients with adenocarcinoma had the opposite result (median age of diagnosis 63.5 for LCNS patients versus 59.4 for smokers; p-value = 0.0005) [25]. Furthermore, retrospective reports found that LCNS is presented at a more advanced disease stage [8,21]. This is reasonable given that because lung cancer is a disease of smokers the clinical threshold for examining a symptomatic never-smoker potential lung cancer patient is higher, a fact that leads to delayed diagnosis and thus to a more advanced disease stage at presentation for never smokers. However, this observation has not been confirmed by other studies [12,19,20,22].

5. Risk factors for lung cancer development in never-smokers Although the most well established risk factor for lung cancer is smoking several other, unrelated to smoking, risk factors have been described however, the association is weak to moderate and the cause(s) of lung cancer in never-smokers remain to be found. 5.1. Second hand smoking Given the strong association between smoking and lung cancer the issue of second hand smoking has been widely studied. This assumption is supported also by a recent study supporting that tobacco metabolites can be found in 90% of urine samples of children whose parents smoke [29]. According to a retrospective analysis of data from 192 countries approximately 21,000 deaths of lung cancer could be attributed to second hand smoking [30]. Similarly a big European prospective study estimated the proportion of lung cancers in never- and ex-smokers attributable to

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environmental tobacco smoke as between 16 and 24%, mainly due to the contribution of work-related exposure [31]. A meta-analysis published in 1997 demonstrated a 25% excess risk for lung cancer development in non-smokers who lived with a smoker [32]. The International Agency for Research on Cancer (IARC) analysis estimated the risk to develop lung cancer to be increased by 35% in men and 25% in women who were exposed to second hand smoking, compared to men and women who were not exposed [33]. An updated meta-analysis of the IARC analysis including data from 19 studies of women who did not smoke (n = 3588 lung cancer patients) demonstrated an increased risk of approximately 20% due to second hand smoking [34]. The current evidence supports that second-hand smoking plays a modest role to lung-cancer development and larger samples may be required to detect a strong relationship. 5.2. Hormonal factors The predominance of females among LCNS patients also implies a potential role for hormones. Estrogen receptors (ER ␣ and ␤) are expressed in both normal lung tissue and lung tumors [35]. Other studies also found that ER-␤ is more frequently expressed in women and never smokers [36] and in certain types of adenocarcinomas [37]. Activation of ERs result in increased expression of genes involved in cellular proliferation and tumor growth [38,39]. Expression of estrogen receptors is also associated with prognosis. ER-␣ is a poor prognostic factor while the expression of ER-␤ is associated with better prognosis [35]. The fact that ERs may be involved in carcinogenesis mechanisms and may have an impact on lung cancer prognosis has raised the question about the role of hormone replacement therapy (HRT). Current data do not support an association between HRT and increased risk of lung cancer, although it should be noted that available data is limited [40]. Several other risk factors are presented in Table 1. However, it should be emphasized that the association is weak to moderate highlighting the need for further research in this area. 5.3. Genetic factors and lung cancer susceptibility Although as stated before the major risk factor for lung cancer is smoking, there is a growing bank of data supporting that genetic factors may play a role in lung cancer susceptibility and development. Tokuhata and Lilienfeld [41] initially reported a 2.5-fold higher lung cancer risk in smoking first-degree relatives of lung cancer cases compared with smoking relatives of controls. They also demonstrated that the familial aggregation occurred irrespective of tobacco use history [41]. This observation was confirmed by several epidemiological studies that consistently demonstrated an approximately 2.5-fold higher risk for lung cancer attributable to a family history of lung cancer after controlling for tobacco smoke [42].

Please cite this article in press as: Pallis AG, Syrigos KN. Lung cancer in never smokers: Disease characteristics and risk factors. Crit Rev Oncol/Hematol (2013), http://dx.doi.org/10.1016/j.critrevonc.2013.06.011

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Table 1 Smoking-unrelated risk factors for lung cancer development. Factor Second-hand smoking Radon exposure Occupational exposure to carcinogens Cooking oil vapors and indoor coal burning Hormonal factors Air pollution Infectious factors Diabetes mellitus Diatery factors

A meta-analysis on passive smoking found a higher cancer risk due to spousal exposure [32–34] Radon is an established risk factor for lung cancer [95] A list of potential lung carcinogens are recognized by the International Agency for Research on Cancer (asbestos, polycyclic aromatic hydrocarbons, silica, heavy metals) [96] Epidemiological studies in Asia have confirmed an association between exposure to cooking oil fumes and indoor coal burning and lung cancer development [97,98]. An IARC study in Caucasians found that solid fuel use for heating or cooking was associated with higher risk for lung cancer development (odds ratio 1.24 for heating and 1.37 for cooking) [99]. Epidemiological studies have suggested that exogenous and endogenous estrogen may be associated in lung carcinogenesis [40] An increase in lung cancer risk has been reported as a result of exposure to air pollution components [100] HPV infection might be associated with lung cancer development [101] M. tuberculosis is considered as a risk factor for lung cancer [102] It is considered as an independent risk factor for lung cancer [103] Healthy eating pattern (vegetables, fruits, and low-fat food items) is associated with significantly reduced risk of lung-cancer in never-smokers [104]

A recent review by Matakidou et al. using data from both case–control and cohort studies show a significantly increased lung cancer risk associated with having an affected relative [43]. Risk was greater in relatives of cases diagnosed at a young age and in those with multiple affected family members. A pooled analysis of all case–control studies (n = 28 with a total of 15,766 cases and 18,184 controls) demonstrated a significantly elevated relative risk (RR) of lung cancer associated with having an affected relative (RR: 1.82; 95% CI: 1.58–2.10). Pooled analysis of four cohort studies that have investigated the relationship between family history and lung cancer risk demonstrated a pooled RR of 2.01 (95% CI: 1.62–2.50).

6. Inherited susceptibility to lung cancer in never smokers Recent multistage genome-wide association (GWAS) studies identified a locus within chromosome region 15q24-15q25.1 that contributes to lung cancer risk [44,45]. This region contains several genes, including three that encode nicotinic acetylcholine receptor subunits (CHRNA5, CHRNA3 and CHRNB4). These subunits are expressed in alveolar epithelial cells, pulmonary neuroendocrine cells and lung cancer cell lines, and they bind to N -nitrosonornicotine and potential lung carcinogens. Two single-nucleotide polymorphisms (SNPs), (rs1051730 and rs8034191) were identified and associated with increased lung cancer risk [45]. For rs8034191 and rs1051730, the combined P values were 3.15 × 10−18 and 7.00 × 10−18 , respectively. Combined adjusted ORs for lung cancer associated with rs8034191 and rs1051730 were 1.32 (95% CI: 1.24–1.41) and 1.32 (95% CI: 1.23–1.39), respectively. Hung et al. [44] observed that these SNPs were associated with lung cancer risk and they were found to account for 14% (attributable risk) of lung cancer cases. Statistically similar risks were reported regardless of smoking status or propensity to smoke tobacco. A study by Amos et al. failed to confirm this

observation [45]. However, it should be noted that the latter study included only 125 never-smoking cases in their series. Genome-wide association studies have also identified chromosome 5p15.33 as one of the regions associated with lung cancer in non-smokers [46,47]. In these studies a highly significant association between the common SNP rs2736100 localized in the 5p15.33 chromosome and lung cancer was observed (p = 0.02 in the McKay study [46] and p = 2.6 × 10−20 in the Hsiung study [47]). The McKay study [46] included both smokers and never-smokers, while the Hsiung study [47] included only lung adenocarcinoma neversmoker females. This 5p15.33 region contains two candidate susceptibility genes, TERT and CLPTM1L. TERT encodes a catalytic subunit of telomerase that maintains telomere ends and its overexpression leads to prolongation of the life span of the cell. Although not detectable in most normal tissues, it is overexpressed in cancer cells. CLPTM1L is implicated in apoptosis and its upregulation results in cisplatin-resistant cell lines. The study by McKay et al. identified also a second SNP that was significantly associated with higher risk for lung cancer, the rs402710 (p = 4 × 10−6 ). Another region that has been implicated by GWAS in susceptibility to lung cancer is the HLA region at chromosome 6p21.33 [48]. The authors identified significant associations for two SNPs (rs3117582 and rs3131379) after adjustment for multiple testing. Two susceptibility genes have been identified; BAT3 and MSH5. BAT3 is implicated in apoptosis and the protein complexes with E1A-binding protein p300, required for acetylation of p53 in response to DNA damage [49]. MSH5 is involved in DNA mismatch repair (MMR) and meiotic recombination, and deficiency of MMR has been documented to have a role in lung cancer [50]. Li et al. also identified a SNP (rs2352028) within chromosome 13q31.3 that was significantly associated with risk for lung cancer in never smokers [51]. According to authors more than 10% of cases of lung cancer in never smokers could be attributed to genetic variation of the SNP rs2352028. This SNP was correlated with decreased GPC5 gene expression. GPC5 is a member of the glypican gene family, and glypicans (family of heparan sulphate proteoglycans (HSPGs) that

Please cite this article in press as: Pallis AG, Syrigos KN. Lung cancer in never smokers: Disease characteristics and risk factors. Crit Rev Oncol/Hematol (2013), http://dx.doi.org/10.1016/j.critrevonc.2013.06.011

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are linked to the exocytoplasmic surface of the plasma membrane) influence cell growth, differentiation, and the cellular response to the environment [52]. These studies imply that there may be some genetic predisposition for lung cancer development (even in the absence of smoking), however, the literature is still immature and further evidence is required. 6.1. Carcinogen metabolism Polymorphisms for genes encoding the metabolic enzymes that are implicated in carcinogen metabolism might contribute to the variability in individual susceptibility to cancer [53]. A pooled analysis of 14 case–control studies on lung cancer in Caucasian non-smokers (n = 302 cases and 1631 controls) was performed by Hung et al. to study CYP1A1 and GSTM1 genetic polymorphisms [54]. The odds ratio (OR) of lung cancer was 2.99 (95%CI: 1.51–5.91) for the variant CYP1A1 Ile(462)Val polymorphism and this effect was stronger on lung adenocarcinoma (OR 4.85: 95%CI 2.03–11.6). The authors also observed a combined effect of the CYP1A1 Ile(462)Val polymorphism and GSTM1 null genotype with an OR of 4.67 (95%CI: 2.00–10.9). Similarly, a meta-analysis by Chen et al. [55] studied the polymorphism of cytochrome P4501B1 (CYP1B1) codon 432 (rs1056836) (n = 6501 subjects) and found an association between the CYP1B1 codon 432 polymorphism and risk of lung cancer in Caucasians (Leu/Val variant vs. Leu/Leu variant, OR = 1.30; 95% CI = 1.03–1.64). This association was irrespective of smoking status. 6.2. DNA repair genes Polymorphisms of genes involved in DNA repair mechanisms have also been studied as risk factors for lung cancer in never-smokers. Zhou et al. [56] observed an increase in lung cancer risk in subjects with the Arg399Gln polymorphism of the XRCC1 gene (OR 2.4, 95% CI: 1.2–5.0). When this polymorphism was present in combination with two polymorphisms of the ERCC2 gene (Asp312Asn and Lys751Gln), the adjusted ORs versus wild genotype were 5.2 (95% CI, 1.7–16.6) for never-smokers. A higher lung cancer risk was also identified among non-smokers carrying the variant ERCC2 allele of Asp312Asn (OR = 2.10; 95% CI: 1.22–3.64) [57]. Finally, a study by Gorlova et al. demonstrated that suboptimal DNA repair capacity level (below the control median) was associated with a significantly increased lung cancer risk in never smokers (OR 1.92; 95% CI: 1.3–2.9) [58]. The risk was 3.38-fold higher for individuals with DNA repair capacity below the first quartile compared with individuals with DNA repair capacity above the third quartile. 6.3. Inflammatory response genes It is reported that chronic inflammation plays a role in tumor initiation and promotion most probably through

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altered cytokine levels [59]. Oh et al. using data form three case-control studies demonstrated that the IL10 gene SNP rs1800871 is associated with lung cancer among never smokers (OR: 2.5, 95% CI: 1.3–5.1) while the TNF gene rs1799964 SNP is inversely associated with smoking-related cancer (CC vs. CT + TT OR: 0.36, 95% CI: 0.17–0.77) [59]. So far numerous studies have been reported studying the role of candidate susceptibility SNPs in LCNS, and those involved in carcinogen metabolism, DNA repair or in inflammatory response. However, their role remains still to be fully clarified and further studies are needed to better understand the role for genetic factors in LCNS development.

7. Acquired somatic mutations Several acquired molecular abnormalities have been observed in lung cancer that contribute to tumorigenesis and might be necessary for tumor maintenance. Some of these are majorly observed in patients with a never-smoking history. 7.1. EGFR EGFR pathway is one of the most well documented and investigated pathways in NSCLC. EGFR is over-expressed in the majority of NSCLC and plays a strong stimulatory effect on cell proliferation, survival, migration and angiogenesis [60]. The discovery of EGFR mutations in 2004 [61,62] and their direct association with response to gefitinib and erlotinib has highlighted the importance of this signaling pathway for many NSCLCs. Most common of these are inframe deletions in exon 19 (codons 746–750) and a missense mutation leading to a substitution of arginine for leucine at codon 858 (L858R) [63]. The incidence of these mutations is significantly higher in females compared with males, in Asians versus Caucasians, in adenocarcinoma histology versus other histological types and in non-smokers [64]. Mutations are inversely associated with smoking history with a higher prevalence in never-smokers [65]. The incidence of these mutations is approximately 17% in the Western population [66] while in the Asian population it is approximately 60% [67]. As pack-years smoked increases, the probability of detecting an activating EGFR mutation falls. One large nonconsecutive series of both East Asian and Western patients reported no mutations in patients with more than a 75 packyear exposure, with a prevalence of 51% in never smokers, 19% in former smokers, and 4% in current smokers [68]. 7.2. HER-2 The HER2 gene, encodes a transmembrane receptor that is involved in the regulation of cell proliferation. The HER2 receptor is a member of the Epidermal Growth Factor receptor (EGFR) family, does not have a known ligand, and is activated by homodimerization with other HER2 receptors or by heterodimerization, preferentially with either EGFR

Please cite this article in press as: Pallis AG, Syrigos KN. Lung cancer in never smokers: Disease characteristics and risk factors. Crit Rev Oncol/Hematol (2013), http://dx.doi.org/10.1016/j.critrevonc.2013.06.011

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or HER3 [69]. The activation of HER2 triggers the initiation of the PI3K/AKT/mTOR and RAS/RAF/MEK cascades [69]. Heterodimers between EGFR and HER2 are more stable than complexes containing other Erb family members [70] and thus Her-2 plays a major role in the EGFR signaling network [71]. HER-2 is overexpressed in approximately 20% of non-small cell lung cancer (NSCLC) cases, while gene amplification and gene mutations are observed in approximately 2% of NSCLC patients [72]. These mutations usually involve in frame insertions in exon 20 and are more frequently observed in never-smokers, in women, and in Asian patients, and are more common in adenocarcinoma histology than in other histological types [73]. HER-2 mutations are mutually exclusive with EGFR or KRAS mutations and result in the constitutive activation of the receptor [74]. HER-2 mutations have been associated with response to treatment with tyrosine kinase inhibitors (TKIs) that target both EGFR and HER2 (e.g., lapatinib) but not to those that target EGFR alone [75]. 7.3. ALK rearrangements ALK gene encodes a transmembrane receptor tyrosine kinase that is part of the insulin receptor superfamily that is not expressed in normal lung tissue [76]. In lung cancer activating mutations of the ALK do not occur and the gene is activated by the formation of fusion genes [77]. Somatic rearrangement within the small arm of chromosome 2p leads to the formation of EML4-ALK fusion gene. This fusion gene results in constitutive activation of the kinase domain [77]. This rearrangement is relatively rare and observed in 3–7% of the original reporting series [77]. An increased incidence is observed in patients with adenocarcinoma histology, younger patients, and in people who are never-smokers or ex light-smokers (≤15 pack-years) [78]. EML4-ALK translocation is considered as mutually exclusive to other genotypes (EGFR mutation, and KRAS mutation) [78]. Presence of ALK rearrangement in lung tumors is related to significant response and clinical benefit with the use of ALK TKIs, such as crizotinib [79]. 7.4. ROS1 rearrangements ROS1 is a receptor tyrosine kinase of the insulin receptor family and several publications demonstrated that ROS1 gene is involved in chromosomal translocations in glioblastoma [80] and more recently lung cancer [81]. A study by Rikova et al. identified ROS1 fusions as potential driver mutations in NSCLC cell line and also in a NSCLC patient tumor sample (CD74-ROS1) [81]. These fusions lead to constitutive kinase activity and are associated with sensitivity in vitro to TKIs. A recent report by Bergethon et al. screened 1073 lung cancer patients and 18 (1.7%) were identified with ROS1 rearrangements by FISH, and 31 (2.9%) were ALK rearranged [82]. ROS1 rearrangements were more frequently observed in

younger and never-smokers patients (each p-value < 0.001). All of the ROS1-positive tumors were adenocarcinomas, with a tendency toward higher grade.

8. Prognostic and predictive role Several reports have demonstrated that LCNS patients have better survival compared with ever smoker patients [14,25,83]. Placebo controlled phase III trials of EGFR TKIs (erlotinib BR.21 study [84]; gefitinib ISEL study [85]) demonstrated that never-smoker patients in the placebo arm had a trend toward better outcome compared to ever smokers (median overall survival for never-smokers vs. ever smokers: BR.21 5.6 months vs. 4.6 months; ISEL 6.1 vs. 4.9), although this difference was not statistically significant. A retrospective analysis of 26,957 patients with NSCLC demonstrated a significant difference in median OS between never-smoker and ever smoker patients (median OS: never vs. ever-smokers: 30.0 months vs. 19.0 months, respectively; p-value < 0.0001). Multivariate analysis identified good PS, never smoker status, early stage, female gender, squamous cell carcinoma histology, and treatment as independent favorable prognostic factors [86]. Another retrospective review of 12,000 patients in USA demonstrated a worse prognosis for ever smokers vs. never smokers (HR: 1.09; p-value = 0.045) [14]. Other smaller series had similar results [9,20,21,87], although this observation was not confirmed in all studies [12,19,22]. However, it should be noted that although these differences in survival could represent differences in the biology of lung cancer between ever and never-smokers, they could also simply reflect the higher proportion of early stage disease in the never-smokers group which impacts prognosis [87]. On the other hand a prospective study in 2010 NSCLC patients with advanced disease (stage IIIB/IV) who completed a smoking questionnaire demonstrated that neversmokers had longer OS compared with ever-smokers (17.8 months vs. 11.3 months, respectively; p-value < 0.001) [88]. More cigarette smoking (as measured in pack-years) was associated with decreased survival. Similarly a retrospective analysis of a phase III trial by Scagliotti et al. observed that smoking was a negative prognostic factor for both OS (p-value < 0.05) and PFS (p-value < 0.05) [89]. The role of smoking as a predictive factor for treatment outcomes is not widely studied. Three chemotherapy trials in treatment naïve NSCLC patients reported subgroup results by smoking status [90–92]. All of these trials failed to demonstrate any difference in treatment effects between ever and never-smokers. A small retrospective report however, demonstrated a significantly higher response rate for neversmokers patients [93]. Response rates for never vs. former vs. current smokers were 19% vs. 8% vs. 12%, respectively (p-value = 0.004). Never-smoker patients had lower rates of progressive disease (p-value = 0.002) and higher OS rates (p-value < 0.0001).

Please cite this article in press as: Pallis AG, Syrigos KN. Lung cancer in never smokers: Disease characteristics and risk factors. Crit Rev Oncol/Hematol (2013), http://dx.doi.org/10.1016/j.critrevonc.2013.06.011

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For targeted treatments there is a striking difference in treatment outcome of never-smokers vs. ever-smokers NSCLC patients when treated with EGFR TKIs, but this should be attributed to the higher incidence of EGFR activating mutations in the never-smokers population [6].

9. Conclusions The incidence of LCNS is expected to increase due to extensive and successful smoking prevention and cessation programs that are implemented, especially in the developed countries. Strong epidemiological data support a causal association between second-hand smoking and lung cancer development. Similarly, radon exposure, indoor coal burning and oil vapors, hormonal factors, air pollution, viral factors and dietary factors are reported as causes of lung caner in never smokers. Although there are a few published reports in the field familial aggregation and genetic susceptibility studies did not focus on LCNS as a separate entity. Similarly although GWAS studies demonstrated some very important observations, they primarily focused on genes associated with tobacco carcinogen metabolism which may be less important in LCNS. GWAS studies in never-smokers specifically could be very important and reveal genetic loci that predispose to LCNS. A very important finding however, is that a big percentage of these patients present with driver aberrations (EGFR and HER2 mutations, ALK and ROS1 rearrangements). These alterations could potentially be treated with targeted agents already in clinical use or under development. Impressive results have already been observed with erlotinib and gefitinib in EGFR mutated patients [94] and with crizotinib in patients with ALK and ROS1 rearrangements [79,82]. Therefore understanding the biology of LCNS and the distinct clinical and pathology characteristics of this disease is crucial.

Conflict of interest Both authors have no conflict of interest.

Reviewers Filippo de Marinis, MD, Director, San Camillo Hospital, 1st Puòmonary Oncological Division, Via Goffredo Mameli 3/1, IT-16122 Genova, Italy. Robert Pirker, MD, Medical University Vienna, Department of Medicine I, Währinger Gürtel 18, Vienna, Austria.

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Please cite this article in press as: Pallis AG, Syrigos KN. Lung cancer in never smokers: Disease characteristics and risk factors. Crit Rev Oncol/Hematol (2013), http://dx.doi.org/10.1016/j.critrevonc.2013.06.011

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Biographies Athanasios Pallis, M.D., M.Sc., Ph.D. graduated from School of Medicine, University of Crete, in 1997. He was trained in Medical Oncology at the Medical Oncology Department of the University General Hospital of Heraklion, Crete (University of Crete). In 2003 he got his PhD degree from the School of Medicine, in University of Crete. He has served as an EORTC fellow in 2008–2009. Dr Pallis has served as a reviewer for several international journals. Ha has published more than 80 peer-reviewed, international articles with more than 1200 citations and contributed in 10 chapters in international books. Currently he serves on the editorial board of 3 scientific journals His main fields of interest are Lung Cancer, Targeted Therapies, and Geriatric Oncology. Konstantinos Syrigos, M.D., Ph.D. Assc. Professor and Head, Oncology Unit GPP, Athens School of Medicine. Visiting Professor of Thoracic Oncology, Yale School of Medicine, CT, USA. Assc. Professor Kostas Syrigos graduated from Athens School of Medicine in 1988. He was trained in Internal Medicine at the Laikon University

Hospital (Athens University) and in Medical Oncology at the Hammersmith Hospital (London University). He got his MD thesis with distinction from the Athens School of Medicine, in 1995 and his PhD thesis from the Imperial College of Science, Technology and Medicine, London University, in 2000. He worked as Medical Oncologist Senior Registrar at the Hammersmith and St Bartholomew’s Hospitals, in London and as consultant at the Sotiria General Hospital, in Athens. In 2002 he was appointed Assc. Professor of Oncology in Medicine and Head of the Sotiria Oncology Unit. From 2006 he is also Visiting Professor of Thoracic Oncology at Yale University, CT, USA. His main fields of interest are Targeted Therapies, drugs development as well as Thoracic and Head & Neck oncology. Dr Syrigos participated in several international clinical trials Phase I-IV in lung, colon, head & neck and pancreatic cancer. He is a member of numerous scientific societies, including the European Society of Medical Oncology (ESMO), the European Respiratory Society (ERS), the American Society of Clinical Oncology (ASCO), the American Association of Cancer Research (AACR) and the International Association for the Study of Lung Cancer (IASLC). He is a manuscript reviewer for 18 scientific journals and currently serves on the editorial board of 5 scientific journals. He is the editor of 8 International Scientific Volumes. He has contributed 80 chapters in international books and he is the author of 290 peer-reviewed, international articles, with more than 4900 citations. He is currently sitting as member of the ESMO Translational Research Group and of the MASCC Board of Directors.

Please cite this article in press as: Pallis AG, Syrigos KN. Lung cancer in never smokers: Disease characteristics and risk factors. Crit Rev Oncol/Hematol (2013), http://dx.doi.org/10.1016/j.critrevonc.2013.06.011