Lung cancer in never smokers

Lung cancer in never smokers (LCINS) is the seventh leading cause of death among solid tumors. The main risk factor for lung cancer is smoking; however, approximately 15% of lung cancer patients have never smoked. LCINS is more frequent in women, irrespective of geographical location, nevertheless, the highest incidence has been found in South-East Asia. The histological incidence of adenocarcinoma is higher in the group of never smokers than squamous cell carcinoma. There is a familial clustering of lung cancer that is more pronounced in never smokers, where the family history was associated with an increased risk. Genome-wide association studies identified certain chromosomal aberrations in LCINS. Furthermore, the oncogenic mutation pattern is distinct in nonsmoking patients: activating mutations of EGFR or anaplastic lymphoma kinase are more frequent. The etiology of LCINS includes several environmental factors as well, such as environmental tobacco smoke, viral and hormonal factors, a variety of pulmonary diseases and certain occupational exposures. It is now established that EGFR-tyrosine kinase inhibitor treatment (erlotinib and geftinib) in lung cancer is more effective in LCINS, owing to the higher incidence of EGFR mutation in nonsmokers. Despite the growing body of information on LCINS in recent years there is a need to further investigate the pathogenesis of this particular lung cancer. Future studies on LCINS should try to tackle the issues of prevention, early diagnosis and the exploration of novel therapeutic targets to combat lung cancer disease.     

Rauchen, Passivrauchen und Krebserkrankungen

Tobacco smoking is the most important avoidable cause of cancer. About one third of all cancer deaths in many Western countries can be attributed to smoking. Lung cancer is the most prominent tobacco-induced cancer. In Europe, about 90% of all lung cancer deaths among men and 60% among women are caused by smoking. Duration of smoking is the strongest determinant of lung cancer. Risk also increases in proportion to the number of cigarettes smoked. Stopping smoking reduces the risk. The younger the age at cessation, the greater the benefit. An updated evaluation of epidemiological studies by the International Agency for Research on Cancer (IARC) concluded that, in addition to cancer of the lung, oral cavity, oro- and hypopharynx, larynx, pancreas, renal pelvis, urinary bladder and esophagus (squamous cell carcinoma), there is sufficient evidence for a causal association between smoking and cancers of the nasal and sinonasal cavities, nasopharynx, esophagus (adenocarcinoma), stomach, liver, uterine cervix, as well as myeloid leukemia, and renal cancer. Among never-smokers, exposure to environmental tobacco smoke is an established causal risk factor for lung cancer.     

Lung cancer in never smokers--a review

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.     

Lifetime residential and workplace exposure to environmental tobacco smoke and lung cancer in never-smoking women, Canada 1994-97

Although the risk of lung cancer among never-smokers living with a spouse who smokes has been extensively studied, the impact of lifetime residential and workplace environmental tobacco smoke has received less attention. As part of a large population-based case-control study of lung cancer, we collected lifetime residential and occupational passive smoking information from 71 women with lung cancer and 761 healthy control subjects, all of whom reported being lifetime nonsmokers. The adjusted odds ratio (OR) for lung cancer associated with residential passive exposure only was 1.21 (95% confidence interval [CI] 0.5-2.8). Although more years of and more intense residential passive smoke exposure tended to be associated with higher risk estimates, no clear dose-response relationship was evident. The OR for women with passive exposure as a child and as an adult was 1.63 (95% CI 0.8-3.5) and for those only exposed as an adult 1.20 (95%CI 0.5-3.0). Exposure to environmental tobacco smoke only in the workplace was associated with an adjusted OR of 1.27 (95% CI 0.4-4.0). Risks associated with increasing occupational exposure year tertiles were 1.24, 1.71 and 1.71. Total smoker-years of residential and occupational exposure combined resulted in a statistically significant trend (linear test for trend p = 0.05) with ORs for tertiles of exposure of 0.83, 1.54 and 1.82. Our results are consistent with the literature suggesting that long-term, regular exposure to either residential or occupational environmental tobacco smoke is associated with increased lung cancer risk in never-smoking women.     

Tobacco smoking and cancer: a brief review of recent epidemiological evidence

This report summarises the epidemiological evidence on the association between tobacco smoking and cancer, which was reviewed by an international group of scientists convened by IARC. Studies published since the 1986 IARC Monograph on "Tobacco smoking" provide sufficient evidence to establish a causal association between cigarette smoking and cancer of the nasal cavities and paranasal sinuses, nasopharynx, stomach, liver, kidney (renal cell carcinoma) and uterine cervix, and for adenocarcinoma of the oesophagus and myeloid leukaemia. These sites add to the previously established list of cancers causally associated with cigarette smoking, namely cancer of the lung, oral cavity, pharynx, larynx, oesophagus, pancreas, urinary bladder and renal pelvis. Other forms of tobacco smoking, such as cigars, pipes and bidis, also increase risk for cancer, including cancer of the lung and parts of the upper aerodigestive tract. A meta-analysis of over 50 studies on involuntary smoking among never smokers showed a consistent and statistically significant association between exposure to environmental tobacco smoke and lung cancer risk. Smoking is currently responsible for a third of all cancer deaths in many Western countries. It has been estimated that every other smoker will be killed by tobacco.     

Rationale and Design of the Japan Molecular Epidemiology for Lung Cancer Study

We present the rationale for the Japan Molecular Epidemiology for Lung Cancer study designed to elucidate molecular mechanisms of carcinogenesis in smokers and never-smokers with non–small-cell lung cancer. This prospective, ongoing, multicenter study is being conducted nationwide in Japan. Although there is no doubt that active smoking is the major cause of lung cancer, the contribution of other possible factors, including environmental tobacco or wood smoke, human papilloma virus, radon, occupational exposures, and genetic susceptibility, is highly likely, based on studies of never-smokers with non–small-cell lung cancer. Because of the predominance of women in the never-smoker subgroup, the role of female hormones in lung cancer development has also been considered. We hypothesize that driver mutations, which are critical for the development of lung cancer, are triggered by the environmental factors with or without the influence of the hormone. The SWOG-led intergroup molecular epidemiology study S0424 was conducted to focus on these issues by using a detailed questionnaire and specimen collection in statistically significant cohorts of smokers and never-smokers from both sexes. The Japan Molecular Epidemiology for Lung Cancer study follows and extends the S0424 molecular epidemiology concept in principle by using a similar approach that will facilitate future comparisons between the studies but with a greater focus on more recently defined driver mutations and broad genomic sequencing.     

What proportion of lung cancer in never-smokers can be attributed to known risk factors?

Though tobacco smoking is the primary risk factor for lung cancer, a significant fraction of lung cancer deaths occur in lifetime nonsmokers. In this article, we calculate the burden of lung cancer in never-smokers attributable to previously identified risk factors in North America, Europe and China, using population-based estimates of exposure prevalence and estimates of relative risk derived from recently published meta-analyses. Population attributable fractions (PAFs) for individual risk factors ranged from 0.40 to 19.93%. Because of differences in the prevalence of exposures, the PAFs associated with several of the risk factors varied greatly by geographical region. Exposure to the selected risk factors appeared to explain a much larger proportion of lung cancer cases in never-smokers in China than in Europe and North America. Our results demonstrate the geographic variability of the epidemiology of lung cancer in never-smokers and highlight the need for further research in this area, particularly in Europe and North America.     

Smoking and Passive Smoking in Relation to Lung Cancer in Women

in a population based case-control study the association between female lung cancer and some possible etiological agents was investigated; 210 incident cases in Stockholm county, Sweden, and 209 age-matched population controls were interviewed about their exposure experiences according to a structured questionnaire. A strong association between smoking habits and lung cancer risk was found for all histological subgroups. Relative risks for those who had smoked daily during at least one year ranged between 3.1 for adenocarcinoma to 33.7 for small cell carcinoma in a comparison with never-smokers. All histological types showed strong dose-response relationships for average daily cigarette consumption, duration of smoking, and cumulative smoking. there was no consistent effect of parental smoking on the lung cancer risk in smokers. Only 38 cases had never been regular smokers and the risk estimates for exposure to environmental tobacco smoke were inconclusive. the high relative risks of small cell and squamous cell carcinoma associated with smokmg may have implications for risk assessments regarding passive smoking.     

Gene-environment interaction in tobacco-related cancers

This review summarizes the carcinogenic effects of tobacco smoke and the basis for interaction between tobacco smoke and genetic factors. Examples of published papers on gene-tobacco interaction and cancer risk are presented. The assessment of gene-environment interaction in tobacco-related cancers has been more complex than originally expected for several reasons, including the multiplicity of genes involved in tobacco metabolism, the numerous substrates metabolized by the relevant genes and the interaction of smoking with other metabolic pathways. Future studies on gene-environment interaction and cancer risk should include biomarkers of smoking dose, along with markers of quantitative historical exposure to tobacco. Epigenetic studies should be added to classic genetic analyses, in order to better understand gene-environmental interaction and individual susceptibility. Other metabolic pathways in competition with tobacco genetic metabolism/repair should be incorporated in epidemiological studies to generate a more complete picture of individual cancer risk associated with environmental exposure to carcinogens.     

美国吸烟者与非吸烟者肺癌流行病学概况

人们已清楚知道，吸烟是肺癌的主要危险因素，也知道吸烟和职业暴露以外的因素在某些肺癌特别是腺癌中起作用。本文以医院病例为基础进行大样本的病冽对照研究来分析肺癌与吸烟因素（吸烟量，过滤咀烟，黑白人种的吸烟习惯）及非吸烟因素（ＥＴＳ暴露，原发性肿瘤和治疗，生殖和内分泌因素，躯体指数）的联系。虽然吸烟与所有主要细胞类型的肺癌都有剂量－效应关系，但与腺癌的联系强度较弱，提示吸烟以外的因素对腺癌的重要性。在白人和黑人中，无论男、女，肺癌的ＯＲ值均随香烟焦油摄入量的增加而增加，并随戒烟年限的延长而减少。是否吸含薄荷香烟，对肺癌的危险性影响不大。未见到ＥＴＳ与肺癌的联系，即使丈夫吸烟也未能使不吸烟妻子患肺癌的危险性增加。生殖系统原发性肿瘤和放射治疗，可使不吸烟女性患肺癌的危险性增加４倍。曾观察到身体瘦弱与现在吸烟、以前吸烟和从不吸烟的女性肺癌之间的联系。以上结果在本文中分别加以讨论。总的来说，人群中肺癌患病率的不同，可能由于：（１）香烟烟雾中的致癌物不同；（２）香烟烟雾的作用因素不同，包括受到机体敏感性及对致癌物的代谢的影响；（３）暴露于吸烟以外的其他各种危险因素     

Epidemiology of lung cancer: smoking, secondhand smoke, and genetics

The link between smoking and development of lung cancer has been demonstrated, not only for smokers but also for those exposed to secondhand smoke. Despite the obvious carcinogenic effects of tobacco smoking, not all smokers develop lung cancer, and conversely some nonsmokers can develop lung cancer in the absence of other environmental risk factors. A multitude of genetic factors are beginning to be explored that interact with environmental exposure to alter the risk of developing this deadly disease. By more fully appreciating the complex interrelationship between genetics and other risks the development of lung cancer can be more completely understood.     

Environmental tobacco smoke and lung cancer mortality in the American Cancer Society's Cancer Prevention Study II

Environmental tobacco smoke (ETS) has been classified as a human lung carcinogen by the United States Environmental Protection Agency (EPA), based both on the chemical similarity of sidestream and mainstream smoke and on slightly higher lung cancer risk in never-smokers whose spouses smoke compared with those married to nonsmokers. We evaluated the relation between ETS and lung cancer prospectively in the US, among 114,286 female and 19,549 male never-smokers, married to smokers, compared with about 77,000 female and 77,000 male never-smokers whose spouses did not smoke. Multivariate analyses, based on 247 lung cancer deaths, controlled for age, race, diet, and occupation. Dose-response analyses were restricted to 92,222 women whose husbands provided complete information on cigarette smoking and date of marriage. Lung cancer death rates, adjusted for other factors, were 20 percent higher among women whose husbands ever smoked during the current marriage than among those married to never-smokers (relative risk [RR]=1.2, 95 percent confidence interval [CI]=0.8-1.6). For never-smoking men whose wives smoked, the RR was 1.1 (CI=0.6-1.8). Risk among women was similar or higher when the husband continued to smoke (RR=1.2, CI=0.8-1.8), or smoked 40 or more cigarettes per day (RR=1.9, CI=1.0-3.6), but did not increase with years of marriage to a smoker. Most CIs included the null. Although generally not statistically significant, these results agree with the EPA summary estimate that spousal smoking increases lung cancer risk by about 20 percent in never-smoking women. Even large prospective studies have limited statistical power to measure precisely the risk from ETS.     

Proportion and number of cancer cases and deaths attributable to behavioral risk factors in Vietnam

Identifying modifiable risk factors that contribute to cancer is essential in setting up preventive strategies. Therefore, this study aimed to estimate the number and proportion of cancer cases and deaths attributable to five behavior-related risk factors—tobacco smoking, second-hand smoking, alcohol consumption, high body mass index and insufficient physical activity in Vietnam in 2020. Population attributable fractions were calculated for relationships of risk factors and cancer types based on sufficient evidence according to IARC or strong evidence according to WCRF/AICR. Relative risks were retrieved from meta-analyses where possible. Prevalence of risk factors was obtained from the most current available nationally representative population surveys in Vietnam. Cancer cases and deaths were obtained from GLOBOCAN 2020. An estimated 40.5% of all cancer cases in men (39 924 cases) and 7.8% in women (6542 cases) were attributable to these risk factors. The proportions of cancer deaths attributable to these risk factors were 44.0% in men (32 807 cases) and 8.9% in women (4235 cases). Tobacco smoking was the leading cause of cancer cases and deaths in men, followed by alcohol consumption and high BMI. In women, high BMI accounted for the highest proportion of cancer cases and second-hand smoking accounted for the highest proportion of cancer deaths. Lung and upper aerodigestive tract cancer cases and deaths could have been reduced at least by half if these risk factors had been eliminated. To reduce cancer incidence and mortality, preventive actions focusing on tobacco control are likely to have the most significant impact, especially in men.     

The XPD variant alleles are associated with increased aromatic DNA adduct level and lung cancer risk

The DNA repair protein xeroderma pigmentosum complementation group D (XPD) is involved in the nucleotide excision repair of DNA lesions induced by many tobacco and environmental carcinogens. In order to study the functional impact of the common polymorphisms in XPD exon 10 (G > A, Asp312Asn) and exon 23 (A > C, Lys751Gln), we have genotyped 185 Swedish lung cancer cases (97 smokers and 88 never-smokers) and 162 matched population controls (83 smokers and 79 never-smokers). Presence of one or two variant alleles was associated with increased risk for lung cancer among never-smokers only, in particular younger (<70 years) never-smokers [odds ratio (OR) = 2.6, 95% confidence interval (CI) = 1.1-6.5 for exon 10; OR = 3.2, 95% CI = 1.3-8.0 for exon 23, adjusted for age, gender and environmental tobacco smoke]. Aromatic DNA adduct level (AL) in peripheral lymphocytes was found to be similar between cases and controls, but significantly increased by current or recent smoking. Overall, there was a significant trend for increasing AL with increasing number of variant alleles in exon 10 (P = 0.02) or in exon 23 (P = 0.001). In addition, subjects with the combined exon 10 AA and exon 23 CC genotype showed a significantly higher AL compared with all those with any of the other genotypes (P = 0.02). We conclude that the XPD variant alleles may be associated with reduced repair of aromatic DNA adducts in general and increased lung cancer risk among never-smokers.     

The International Agency for Research on Cancer （IARC） evaluation of the carcinogenicity of outdoor air pollution： focus on China

The International Agency for Research on Cancer （IARC） has classified outdoor air pollution and the particulate matter （PM） in outdoor air pollution as carcinogenic to humans, as based on sufficient evidence of carcinogenicity in humans and experimental animals and strong support by mechanistic studies. The data with important contributions to the evaluation are reviewed, highlighting the data with particular relevance to China, and implications of the evaluation with respect to China are discussed. The air pollution levels in Chinese cities are among the highest observed in the world today and frequently exceed health based national and international guidelines. Data from high-quality epidemiologic studies in Asia, Europe, and North America consistently show positive associations between lung cancer and PM exposure and other indicators of air pollution, which persist after adjustment for important lung cancer risk factors, such as tobacco smoking. Epidemiologic data from China are limited but nevertheless indicate an increased risk of lung cancer associated with several air pollutants. Excess cancer risk is also observed in experimental animals exposed to polluted outdoor air or extracted PM. The exposure of several species to outdoor air pollution is associated with markers of genetic damage that have been linked to increased cancer risk in humans. Numerous studies from China, especially genetic biomarker studies in exposed populations, support that the polluted air in China is genotoxic and carcinogenic to humans. The evaluation by IARC indicates both the need for further research into the cancer risks associated with exposure to air pollution in China and the urgent need to act to reduce exposure to the population.     

Risk of lung cancer from environmental exposures to tobacco smoke

Epidemiologic evidence on the relation between environmental tobacco smoke and cancer is reviewed. The labeling of tobacco smoke as an environmental cause of lung cancer has been challenged based on allegations of bias in the epidemiologic data. However, tobacco smoke has been shown to increase the risk of lung cancer down to the lowest exposure levels. Environmental tobacco smoke contains the same carcinogenic compounds as those found in the tobacco smoke inhaled directly by the smoker. Nonsmokers environmentally exposed have elevated levels of tobacco smoke byproducts in biological samples. These observations alone are sufficient to identify tobacco smoke as an environmental carcinogen. The epidemiologic studies showing that environmental exposure to tobacco smoke is associated weakly but consistently with increased risk of lung cancer. While these epidemiologic studies have been challenged, it does not appear that the observed epidemiologic associations are due to misclassification or confounding. Indeed, the epidemiologic results, particularly among the studies with superior data collection methods and better control of bias and confounding, find consistent associations between environmental tobacco smoke and lung cancer. This paper summarizes the evidence that environmental exposure to tobacco smoke increases the risk of lung cancer, and considers the criticisms of the epidemiologic evidence which have been raised.     

Screening for Lung Cancer in Individuals Who Never Smoked: An International Association for the Study of Lung Cancer Early Detection and Screening Committee Report

Screening with low-dose computed tomography of high-risk individuals with a smoking history reduces lung cancer mortality. Current screening guidelines and eligibility criteria can miss more than 50% of lung cancers, and in some geographic areas, such as East Asia, a large proportion of the missed lung cancers are in never-smokers. Although randomized trials revealed the benefits of screening for people who smoke, these trials generally excluded never-smokers. Thus, the feasibility and effectiveness of lung cancer screening of individuals who never smoked are uncertain. Several known and suspected risk factors for lung cancers in never-smokers such as exposure to secondhand smoke, occupational carcinogens, radon, air pollution, and pulmonary diseases, such as chronic obstructive pulmonary disease and interstitial lung diseases, and intrinsic factors, such as age, are well noted. In this regard, knowledge of risk factors may make possible quantification and prediction of lung cancer risk in never smokers. It is worth considering if and how never smokers could be included in population-based screening programs. As the implementation of these programs is challenging in many countries owing to multiple factors and the epidemiologic differences by global regions, these issues will need to be evaluated in each country taking into account various factors, including accuracy of risk assessment and cost-effectiveness of screening in never smokers. This report aims to outline current knowledge on risk factors for lung cancer in never smokers to propose research strategies for this topic and initiate a broader discussion on lung cancer screening of never smokers. Similar considerations can be made in current and ex-smokers, which do not fulfill the current screening inclusion criteria, but otherwise are at increased risk. Although screening of never smokers may in the future be effectively conducted, current evidence to support widespread implementation of this practice is lacking.     

P53 protein overexpression in lung adenocarcinomas in non-smokers

Greater than 55% of all lung cancers contain mutations in the p53 tumor suppressor gene, and the frequency of p53 mutations has been directly correlated with the use of tobacco and the smoking of cigarettes. To determine if environmental tobacco smoke (ETS) is associated with changes in p53 expression in human lung cancer in never-smokers, we determined the degree of p53 protein expression in ten lung tumors from never-smokers exposed to ETS. We show that 5 of 8 (62.5%) adenocarcinomas contained significant levels of p53 protein overexpression as detected by immunohistochemical staining. While these findings suggest that ETS is a possible inducer of altered p53 expression in lung adenocarcinoma in non-smokers, larger studies are needed to confirm this relationship.     

Risk factors associated with lung cancer in Hong Kong

The purpose of this study was to investigate the risk factors associated with lung cancer in Hong Kong. Three hundred and thirty-one histologically or cytologically proven consecutive cases of lung cancer and the same number of in- and out-patients without cancer matched for age and sex were recruited for this study using a detailed questionnaire completed by a trained interviewer. Smoking was the most important risk factor associated with lung cancer but the attributable risk (AR) was estimated to be 45.8% in men and 6.2% in women, considerably lower compared with those estimated in early 1980s. In addition, among women, exposure to environmental tobacco smoke (ETS) at work+/-at home and lack of education, were independent risk factors for lung cancer with adjusted odds ratio (OR) 3.60, (95% confidence interval (CI) 1.52-8.51) and OR 2.41 (95% CI 1.27-4.55), respectively. Among men, exposure to insecticide/pesticide/herbicide, ETS exposure at work or at home, and a family history of lung cancer and were independent risk factors with adjusted OR 3.29 (95% CI 1.22-8.9, OR 2.43, 95% CI 1.24-4.76 and OR 2.37, 95% CI 1.43-3.94, respectively). Exposure to incense burning and frying pan fumes were not significant risk factors in both sexes. A moderate or high consumption of fat in the diet was associated with increased risk in men but decreased risk in women. The results of this study suggested that as the prevalence of smoking declined, the influence of smoking as a risk factor for lung cancer decreased even further. Moreover, the contribution of other environmental, occupational and socioeconomic factors may be more apparent as etiological factors for lung cancer in a population with relatively high lung cancer incidence but low AR from active smoking.     

Risk factors for primary lung cancer among never smokers by gender in a matched case–control study

Objective

Lung cancers that occur in never smokers differ from those that occur in smokers. We performed an analysis of potential epidemiological risk factors for lung cancer among never smokers.

Methods

In this hospital-based matched case–control study, all 1,540 matched case–control pairs were Han Chinese in Taiwan. The data on demographic characteristics, smoking habit, exposure to environmental tobacco smoke, medical history of lung diseases, family history of lung cancer, and female characteristics were collected from a structured questionnaire. A multiple conditional logistic regression was used to estimate odds ratios and 95 % confidence intervals after adjusting for possible confounders.

Results

Overall, several epidemiological factors of lung cancer in never smokers were different between males and females. For the female population, subjects who were exposed to environmental tobacco smoke (OR = 1.39, 95 % CI = 1.17–1.67) with a history of pulmonary tuberculosis and with family history of lung cancer in first-degree relatives (OR = 2.44, 95 % CI = 1.79–3.32) had higher risk of lung cancer, while subjects with a history of hormone replacement therapy and using fume extractors for those who cooked were protective. For the male population, only subjects with family history of lung cancer in first-degree relatives (OR = 2.77, 95 % CI = 1.53–5.01) were significantly associated with risk of lung cancer.

Conclusion

This study provides insights about the epidemiological factors of lung cancer in never smokers, adding to existing evidence that family history of lung cancer and environmental tobacco smoke may moderate lung cancer risk.