ABSTRACT: Lung cancer in “never-smokers” constitutes only a small proportion of patients with lung cancer. Nevertheless, the topic has recently attracted a good deal of attention. Initially this was due to the fact that never-smokers with lung cancer had better outcomes with epidermal growth factor receptor–tyrosine kinase (EGFR-TK) inhibitors, compared to tobacco smokers with lung cancer. More recently the identification of molecular changes unique to lung cancer in never-smokers has generated further interest in this disease. These findings have the potential to enhance our knowledge of lung cancer biology and lead to the development of new, more effective treatments for lung cancer. In this review, we summarize the existing body of knowledge on lung cancer in never-smokers.
Lung cancer continues to be a leading cause of cancer-related mortality in the United States and globally. In 2009, it is estimated that more than 200,000 patients were diagnosed with lung cancer.[1] Non–small-cell lung cancer (NSCLC) comprises more than 85% of all lung cancers,[2] and tobacco smoking is the leading cause of NSCLC. Recently it was reported that patients with lung cancer who are lifelong “never-smokers” have better response rates with epidermal growth factor receptor–tyrosine kinase (EGFR-TK) inhibitors than smokers with lung cancer. This has led to an increased research focus on never-smokers with lung cancer, resulting in rapid growth of our knowledge on the outcomes and tumor biology of this disease. In the United States, the age-adjusted incidence rate for lung cancer in never-smokers aged 40 to 79 years ranges from 4.8 to 13.7 per 100,000 person-years for men and 14.4 to 20.8 per 100,000 person-years for women.[3] This review summarizes some of the recent and relevant findings on lung cancer in never-smokers.
Risk Factors
No single major risk factor for the development of lung cancer in never-smokers has been identified. Several potential risk factors have been studied including environmental exposures such as environmental tobacco smoke (ETS), radon, asbestos, cooking fumes, genetic susceptibility, hormonal factors, and oncogenic viruses.
Environmental Exposures
• Environmental Tobacco Smoke—Environmental tobacco smoke (ETS) is a combination of sidestream tobacco smoke (smoke from the end of a smoldering cigarette) and the mainstream tobacco smoke exhaled by the smoker. The US Surgeon General’s report published in 2006 stated that ETS increased the risk of lung cancer in never-smokers by 20% to 30%, based on a pooled analysis of more than 100 previously published studies. ETS as a risk factor for lung cancer in never-smokers possibly accounts for only a small proportion of patients.
• Radon—Radon is a uranium degeneration product that is known to cause lung cancer in uranium miners.[4] The risk for lung cancer from nonoccupational radon exposure has been evaluated by several large cohort and case-control studies in the United States. A pooled analysis of all the major North American case-control studies, with a total of 4,081 cases and 5,281 controls, revealed that the odds for developing lung cancer increased with residential radon concentration (excess odds ratio = 0.10 per 100 Bq/m3; 95% confidence interval [CI] = –0.01 to 0.26).[5] When the data analysis was restricted to never-smokers, the risk for lung cancer increased with radon concentration (excess odds ratio = 0.09 per 100 Bq/m3; 95% CI = –0.01 to 0.26).
• Asbestos—Nonoccupational asbestos exposure as a risk factor for lung cancer was studied in women from mining communities in Quebec. There was no increased mortality in this population (standardized proportionate mortality ratio = 1.1; 95% CI = 0.88–1.38).[6] In a more recent study from Australia, nonoccupational exposure to asbestos in women identified increased risk of death from lung cancer with a standardized mortality ratio of 2.15 (95% CI = 1.45–3.07).[7] Variations in geography as well as in type and amount of asbestos exposure could account for some of the conflicting data.
• Cooking Fumes—Exposure to cooking oil fumes and coal burning has been studied extensively in Chinese women with lung cancer. In a case-control study of 672 women with lung cancer and 735 healthy controls, exposure to rapeseed oil fumes was associated with increased risk for lung cancer (relative risk [RR] = 2.6; 95% CI = 1.3–5.1).[8] Coal fumes from cooking and indoor heating have been reported to be associated with increased risk of lung cancer in the Chinese population. In a case-control study of 846 lung cancer patients and 1,740 population controls from rural China, exposure to indoor coal fumes over a period of 30 years was associated with an increased risk for lung cancer (odds ratio = 1.29; 95% CI = 1.03–1.61).[9] Several other case-control studies have confirmed the increased risk for lung cancer in never-smokers exposed to cooking oil fumes and coal fumes (reviewed in reference 10).
Well known environmental risk factors such as ETS account for a small proportion of lung cancer cases in never-smokers. The risk of lung cancer in never-smokers from nonoccupational radon and asbestos exposure appears to be minimal. Exposure to cooking oil and coal fumes has been studied predominantly in the Chinese population and other Pacific Rim countries. It may have a wider role in other developing nations, although data are lacking. This factor is unlikely to be an issue in developed countries.
Genetic Susceptibility
The role of family history as a risk factor for lung cancer in never-smokers has been the focus of several studies. Analysis of 11 studies identified family history of lung cancer to be associated with an increased risk of developing lung cancer in never-smokers, with a pooled RR estimate of 1.51 (95% CI = 1.11–2.06).[11] Two genome-wide association studies of more than 3,000 cases and controls identified two single-nucleotide polymorphisms (SNPs) on chromosome 15q25 (rs1051730 and rs8034191) to be associated with an increased risk of developing lung cancer.[12,13] Both studies concluded that in never-smokers, these SNPs were not associated with an increased risk of lung cancer. However, these findings are limited by the small number of never-smokers compared to the entire study population (352 and 125 patients in the two studies, respectively).
Polycyclic amino hydrocarbons (PAH) in tobacco smoke are metabolized in a two-phase process, initially activated by the cytochrome P450 enzymes (CYPs) and then detoxified by glutathione-S-transferases (GSTs). In a pooled analysis of 14 case-control studies consisting of 302 never-smokers with lung cancer and 1,631 never-smoking controls without lung cancer, the risk of lung cancer was significantly increased if the CYP1A1 Ile(462)Val polymorphism was present (odds ratio = 2.99; 95% CI = 1.51–5.91).[14]
The association between lung cancer risk and alterations in DNA repair pathways has received wide attention. X-ray cross-complementing group 1 (XRCC1) is a DNA repair protein involved in base excision repair of DNA base damage and single-strand breaks. Evidence suggests that XRCC1 Arg399Gln polymorphism is associated with deficient DNA repair.[15] In a case-control study of 1,091 Caucasians with lung cancer and 1,240 healthy controls, the risk of lung cancer was increased in never-smokers with the XRCC1 Arg399Gln polymorphism (odds ratio = 2.4; 95% CI = 1.2–5.0).[16] In a larger study, the risk for lung cancer in never-smokers with XRCC1 Arg399Gln polymorphism was not significant (odds ratio = 0.83; 95% CI = 0.46–1.48).[17]
The increased risk for lung cancer in never-smokers with a family history of lung cancer indicates the existence of an inherited risk factor. Progress has been made in identifying genetic variants associated with increased risk for lung cancer. The identification of the SNPs rs1051730 and rs8034191 on 15q25 as a risk factor for lung cancer is an important advance in this field. At present it is not clear whether these SNPs are associated with lung cancer because they affect tobacco-smoking behavior or they directly increase the risk of lung cancer by another mechanism.[18] Polymorphisms of genes involved in xenobiotic metabolism and DNA repair have been extensively investigated. CYP1A1 Ile(462)Val polymorphism has now been shown in several studies to be associated with increased risk for lung cancer in never-smokers.[10] Polymorphisms of DNA repair genes require further investigation to identify their role in the development of lung cancer in never-smokers.
Oncogenic Virus
Human papillomavirus (HPV) is well known to be associated with cervical and tonsillar cancer. In a recent review of 53 studies from all over the world, the mean incidence of HPV in lung cancer tumor tissue was reported to be 24.5%.[19] Asians with lung cancer have a higher mean incidence of HPV in tumor tissue (36%) than patients with lung cancer from Europe (17%) and United States (15%). HPV 16/18 expression was detected by nested polymerase chain reaction (PCR) in 77 of 141 lung cancer tumor samples from Taiwan.[20] The detection rate was significantly higher in never-smokers with lung cancer than in tobacco smokers with lung cancer; for HPV 16 it was 48.7% vs 29% and for HPV 18 it was 57.3% vs 20.6%, respectively (P < .001). Subsequent studies from China fail to confirm the higher prevalence of HPV in never-smokers.[21,22] At the present time, an association between HPV and never-smokers with lung cancer remains unproven.
Hormonal Factors
Never-smokers with lung cancer are more likely to be women than men. Estrogen receptors ER-alpha and ER-beta are expressed in both normal and cancerous lung tissue.[23,24] Activation of these receptors by estrogen has been shown to promote proliferation of both normal and tumor cells.[24] Metabolic products of estrogen may cause DNA damage by forming DNA adducts, thereby promoting carcinogenesis.[25]
Epidemiologic studies have examined the role of estrogen as a risk factor for lung cancer. In a case-control study with 180 women with lung cancer and 303 controls from the United States, estrogen replacement therapy (ERT) was associated with increased risk for lung adenocarcinoma in smokers (odds ratio = 32.4; 95% CI = 15.9–665.3) but not in never-smokers (odds ratio = 1.0; 95% CI = 0.3–3.8).[26] However, other studies have reported no association between ERT and lung cancer (reviewed in reference 10). At present, there is no definitive evidence linking estrogen with increased risk for lung cancer. However, the role of sex hormones requires further investigation since never-smokers with lung cancer are more likely to be women than men.
