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تعداد آیتم قابل مشاهده باقیمانده : 2 مورد

Lung cancer in never smokers

Lung cancer in never smokers
Author:
Elaine Shum, MD
Section Editor:
Rogerio C Lilenbaum, MD, FACP
Deputy Editor:
Sadhna R Vora, MD
Literature review current through: Apr 2025. | This topic last updated: May 28, 2024.

INTRODUCTION — 

Lung cancer is the leading cause of cancer death worldwide, causing about 1.8 million deaths per year [1,2]. Exposure to tobacco smoke is the primary etiologic factor responsible for lung cancer, and its importance is illustrated by the decline in lung cancer incidence and mortality in the United States that has accompanied the decline in smoking [3-5]. (See "Cigarette smoking and other possible risk factors for lung cancer".)

Despite the predominance of tobacco smoking as its presumed etiology, lung cancer is also a significant health problem in those with no history of smoking [6-8]. Lung cancer in people who have never smoked (LCINS) is distinct enough from an epidemiologic and biologic standpoint to be considered a separate entity [9-12]. Furthermore, as the number of people who have never smoked in the United States and other countries rise, the issue of lung cancer in this group is a growing public health concern. Currently, LCINS is projected to be the fifth most common cause of cancer-related deaths worldwide [1,13].

The epidemiology, risk factors, biologic differences, and potential implications for treatment of lung cancer in people who have never smoked are reviewed here. General aspects of lung cancer biology and management are discussed elsewhere. (See "Clinical manifestations of lung cancer" and "Overview of the initial treatment and prognosis of lung cancer" and "Overview of the initial treatment of advanced non-small cell lung cancer".)

EPIDEMIOLOGY — 

In general, the term "never smoker" refers to individuals who have smoked fewer than 100 cigarettes in their lifetime. The incidence of small cell lung cancer in never smokers is exceedingly small [14], and this discussion will therefore focus on non-small cell lung cancer (NSCLC), predominantly adenocarcinoma (while 50 to 60 percent of cancers in never smokers are adenocarcinomas, only approximately 10 to 20 percent are squamous cell carcinomas [15]).

Firm data on the incidence of lung cancer in never smokers is difficult to ascertain because most population-based cancer registries, including the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) database, do not collect patient smoking information. SEER data have been linked with population-based tobacco use information [16], but this only allows for estimates of lung cancer in never smokers within broad geographic areas.

Cancer registry data will need to collect information on the smoking status of patients in order to carefully examine trends in the incidence rate of lung cancer among never smokers. Self-reported smoking status can be challenging to obtain, but the validity of this method has been verified in several studies that have shown only small smoker misclassification rates [17,18].

Incidence — Worldwide, smoking accounts for approximately two-thirds of lung cancer cases, with the remaining occurring due to other causes [1]. There are major geographic and sex differences, particularly in Asia, where 60 to 80 percent of females with the disease have never smoked [6]. Females in East Asia specifically have a higher incidence of LCINS compared with other regions suggesting contributions from genetic or environmental factors [19].

In one analysis in the United States, an estimated 19 percent of females with lung cancer had never smoked, compared with approximately 9 percent of males with the disease [20]. These results are based upon an analysis of data from patients in five large United States cohort studies [21-26]. The age-adjusted incidence rate for lung cancer in never smokers aged 40 to 79 years ranged from 11.2 to 13.7 per 100,000 person-years for males and from 15.2 to 20.8 per 100,000 person-years for females. These incidence rates are similar to those for myeloma in males or cervical cancer in females in this country [27]. By contrast, the age-adjusted rates of lung cancer in current smokers in the same cohorts were approximately 12 to 30 times higher.

An analysis of lung cancer patients diagnosed between 1991 and 2005 in Southern California utilized a novel text-mining programming algorithm to evaluate smoking status based on information from electronic medical record abstracts in the regional cancer registry. This study determined that 8.9 percent of over 25,000 patients with known smoking status were never smokers, including 6 percent of males and 14 percent of females [19,28].

Another analysis of 13 cohorts and 22 cancer registries, however, did not find any apparent difference in the incidence rate of lung cancer in people who had never smoked by sex overall, although females had a higher incidence rate than males among never smokers aged 40 to 59 years [29]. In this multinational analysis, the age-standardized incidence rates for lung cancer (per 100,000 using the 2000 world population age standard) for females were 12.4 for females of European descent, 15 for Asian females, and 19.4 for African American females. This compared with rates of 11.2, 12.9, and 12.3, respectively, for males of European, Asian, and African American background.

Another study using cancer registry data from seven states in the United States showed that 12.5 percent of lung cancer patients were never smokers. The proportion of LCINS was higher in females than males both overall (15.7 versus 9.6 percent; prevalence ratio 1.63, 95% CI 1.58-1.68) and across all age groups, race/ethnicities, and histologies. For White female patients, the proportion with lung cancer was 13.4 percent, 19 percent in Black female patients, 57.4 percent in Asian/Pacific Islander patients, and 32.6 percent in Hispanic patients [13].

Whether the incidence of lung cancer in never smokers has been changing over time had been debated, with older studies yielding conflicting results:

●A study from the Swedish construction worker's health care program, which is linked to the national cancer registry, showed a substantial increase in the age-adjusted incidence rate of nonsmoking lung cancer comparing the period 1976 to 1980 with 1991 to 1995 (1.5 versus 5.4 per 100,000) [30].

●Two American Cancer Society prevention study cohorts found a statistically significant but smaller increase in the mortality rate in females due to nonsmoking-associated lung cancer comparing the period 1959 to 1972 with 1982 to 2000 (12.3 to 14.7 per 100,000) in 1982 to 2000 [31]. The rates did not change over time for males.

●Indirect evidence comes from a series of nearly 12,000 patients with lung cancer in Southern California [32]. Comparing the interval 1995 to 1999 with 1999 to 2003, the percentage of never smokers with the subtype formerly known as bronchioloalveolar carcinoma increased from 19 to 26 percent, while the percentage with other forms of lung cancer went from 8.6 to 9.4 percent.

●Data collected from cancer registries in Japan and Southern California with smoking information focused on lung cancer in never smokers over two time periods, 1991 to 1996 and 1997 to 2001, and did not show a substantial numerical change in the percent of lung cancer patients who were never smokers during the two time periods (28 and 31 percent versus 7.2 and 7.4 percent for the Japanese and Southern Californian registries at earlier and later time periods, respectively) [33].

●In a previous comparison of two case-control studies from the United Kingdom done at the same hospitals and community settings in 1950 and in 1990, the percentage of never smokers among male lung cancer cases did not change, although the percentage of never smokers among the controls increased from 4.5 to 19 percent [34]. The percentage of lung cancer in never smokers who were females dropped dramatically during this time period, while the rate of smoking in the controls dropped less dramatically. A subsequent analysis of early-stage lung cancer cases from a single institution in the United Kingdom, though, demonstrated an increase in the annual frequency of lung cancer in never smokers from 13 to 28 percent looking from 2008 to 2014 [35].

●A single institution evaluation from Japan found that over the 30-year period 1974 to 2004, the proportion of never smoking, early-stage NSCLC patients increased from approximately 16 to 33 percent [9]. The large pooled analysis of 13 cohorts compared contemporary rates with those in Connecticut in the 1930s when smoking was very rare in females and found no substantial change over time [29].

A pooled analysis of over 10,000 patients treated from 1990 to 2013 at three large academic hospitals in the southern United States identified an increase in the proportion of people who had never smoked with lung cancer from 8 percent in 1990 to 1995 to 14.9 percent in 2011 to 2013 (p <0.001) in a multivariable logistic regression analysis that accounted for sex, stage, and ethnicity [36].

A similar analysis looking at the proportion of newly diagnosed patients who were never smokers at a large institution in Singapore in 1999 to 2002 versus 2008 to 2011 found the proportion of lung cancer patients who were never smokers increased from 31 to 48 percent (p <0.001) [37].

Though the data are unclear, the increasing prevalence of lung cancer in patients without a smoking history is widely accepted.

Sex — Despite the fact that a higher percentage of females with lung cancer have never smoked compared with males as reported in several analyses [6,20,38,39], the age-adjusted mortality rate from lung cancer among never smokers was higher in males than females in two American Cancer Society cancer prevention study cohorts [31]. These two cohorts formed the bulk of patients of European ancestry in a larger pooled analysis of 13 cohort studies and multiple cancer registries that showed age-standardized lung cancer mortality rates of 12 per 100,000 for never smoking males and 9.5 per 100,000 for never smoking females of European ancestry. In Asian populations, the rates were 26 and 16.1 per 100,000 for males and females, respectively [29]. Females with lung cancer live longer than males, but how much this explains the differences seen between incidence and mortality is not known [40]. (See "Females and lung cancer", section on 'Outcome'.)

By contrast, in a Japanese study, 33 percent of lung cancer deaths in males and 85 percent of lung cancer deaths in females were not due to cigarette smoking. In Japan, the percentage of females with lung cancer who are never smokers is much higher [41,42].

Ethnicity — The risk of smoking-associated lung cancer differs by race/ethnicity. Accurate data on differences in rates of lung cancer among never smokers based upon race or ethnicity are extremely limited.

●A Southern California analysis of over 20,000 patients found that for females, 46 percent of all lung cancer in Asian/Pacific Islanders occurred in never smokers compared with 25 percent in Hispanic individuals, 11 percent in African Americans, and 10 percent in non-Hispanic White individuals [28].

●A Northern California analysis of lung cancer cases diagnosed from 1998 to 2008 found that for females, of all lung cancer cases identified, 71 percent of lung cancer in Asian/Pacific Islanders occurred in never smokers compared with 35 percent of cases in Hispanic females and 40 percent in non-Hispanic White individuals [43]. This study also looked at survival differences in these groups.

●Further data on this topic come from a large pooled analysis of cohort and registry data that show wide variability in incidence and mortality from lung cancer in never smokers, even within certain Asian countries including China and Thailand, but overall increased rates in African Americans compared with other ethnic groups [29].

Age — Although it has been postulated that lung cancer occurs at a younger age in never smokers [44], this has only been validated in some [39], but not all, cohort analyses in Western populations [20]. In studies from Asia, however, a younger age at diagnosis is characteristic of lung cancer people who have never smoked [45].

RISK FACTORS — 

The known and potential causes of lung cancer are discussed in detail separately. (See "Cigarette smoking and other possible risk factors for lung cancer".)

The causative factors for lung cancer in never smokers are not well understood. The risk factors that are considered to be most important among never smokers are discussed here.

Secondhand smoke — Secondhand smoke is an important risk factor for lung cancer among never smokers [17,46-48]. However, the extent of this problem is not clear. (See "Secondhand smoke exposure: Effects in adults", section on 'Lung cancer'.)

Several studies suggest that approximately 15 to 35 percent of lung cancer among never smokers is due to secondhand smoke [49-53] and that risk may be increased in those with exposure prior to age 25 [54].

●A study from France of 1493 lung cancer patients found that 79 percent of females and 21 percent of males who were never smokers had secondhand smoke exposure [53].

●A population-based case-control study in Canada of 445 cases and 948 controls found no association between exposure to secondhand smoke at home or the workplace and development of lung cancer [39].

●A population-based prospective study in Japan reported a hazard ratio (HR) of 2.03 (95% CI 1.07-3.86) for development of adenocarcinoma for never smoking females who lived with a smoking spouse as compared with never smoking females with a nonsmoking spouse [55].

●A United States case-control study reported an increase in lung cancer risk in never smokers with secondhand smoke exposure during childhood (odds ratio [OR] 2.5; 95% CI 1.04-4.90) [56].

●In a report based upon the largest sample, analysis from a case-control study in Europe of 520,000 people estimated that the proportion of lung cancer related to secondhand smoke was 16 to 24 percent in nonsmokers [52]. An additional 5 to 7 percent of lung cancer among never smokers was thought to be due to air pollution.

●Spousal smoking increased the risk of lung cancer in a never smoking spouse (relative risk [RR] 1.27, 95% CI 1.17-1.37) in a meta-analysis that included 55 international studies [57].

●In the European Prospective Investigation into Cancer and Nutrition study evaluating the risk of cancer in nearly 500,000 people, the risk of lung cancer in never smokers was significantly elevated in those with secondhand smoke exposure (HR 1.65, 95% CI 1.04-2.63) [58].

Subsequent data demonstrate the challenges in proving secondhand smoke as a truly causative factor in the development of lung cancer in never smokers.

●The Women's Health Initiative (WHI) observational study included over 76,000 females with a complete smoking history [59]. With a mean follow-up of 10.5 years, 901 cases of lung cancer were identified. Among the never smokers, there was no overall association with passive smoking exposure (HR 0.88, 95% CI 0.52-1.49), although there was a trend toward an increase in female never smokers with adult-home passive smoking exposure (HR 1.61, 95% CI 1.00-2.58).

The hypothesis that secondhand smoke may be responsible for higher rates of lung cancer in never smokers in Asia was questioned by whole-genome sequencing of lung cancer from Asian patients with and without a smoking history. The mutational signatures of the Asian never-smoker lung cancers were very similar to those of European never-smoker lung cancers but different from the patterns of smokers in either group [60]. In addition, data on smoking-related somatic mutational signatures from LCINS with reported secondhand smoke exposure have not shown a correlation [61,62].

Radon — Radon is a gaseous decay product of uranium-238 and radium-226, which is capable of damaging respiratory epithelium via the emission of alpha particles. Radon is present in soil, rock, and groundwater, and it can accumulate in homes. The increased risk of lung cancer among uranium miners has been more clearly established and is thought to be due to radiation from radon [63]. (See "Cigarette smoking and other possible risk factors for lung cancer", section on 'Radon'.)

It is considered the second-leading environmental cause of lung cancer after tobacco smoke in those who have smoked and is largely considered the leading cause in those who have never smoked [64]. Several studies have demonstrated that exposure to radon within the home may play a role in the development of lung cancer in never smokers [65-68].

Air pollution — Outdoor air pollution is also associated with lung cancer risk [69]. Using mean long-term ambient fine particulate matter (PM2.5) as a measure of air pollution, there was a 15 to 27 percent increase in lung cancer mortality in never smokers for each 10 mcg/m3 increase in PM2.5 concentrations in the Cancer Prevention Study-II [70]. A meta-analysis including this and 17 other studies concluded that the meta-RR for lung cancer associated with PM2.5 was 1.09 (95% CI 1.04-1.14); this was particularly evident in never smokers (meta-analysis RR 1.18, 95% CI 1.00-1.39) [71].

A link between air pollution and lung cancer has been described. Increasing PM2.5 levels have been associated with increased rates of epidermal growth factor receptor (EGFR)-mutated lung cancer in England [72]. EGFR-mutated non-small cell lung cancer (NSCLC) is exceedingly common in never smokers who develop lung cancer and less frequent in those who develop lung cancer with a smoking history. PM2.5 has been shown to promote inflammation (partly through the IL1B pathway) that allows lung cells with driver mutations to fully develop into malignancy.

Environmental exposures — Other occupational exposures are known to increase lung cancer risk in smokers, and to a lesser extent, in never smokers as well.

●Commonly associated toxins include asbestos, chromium, and arsenic [73-76]. Occupational exposure to organic dust has been linked as a risk factor for lung cancer [77]. A Dutch analysis of occupational asbestos exposure found an RR of lung cancer of 3.5 after controlling for age, smoking, and other factors [76]. In a French study of 1493 cases, some occupational exposure was identified in 9.4 percent of females and 48.6 percent of males who developed lung cancer as never smokers [53]. In a Canadian case-control study, the OR for lung cancer risk from occupational exposures in never smokers was 2.1 (95% CI 1.3-3.3) but was higher for exposure to solvents, paints, or thinners (OR 2.8, 95% CI 1.6-5.0) [39]. A meta-analysis focused on lung cancer risk in painters reported an RR for lung cancer in all painters of 1.35 (95% CI 1.29-1.41) but 2.0 (95% CI 1.09-3.67) in the never smokers [78]. (See "Asbestos-related pleuropulmonary disease".)

●Arsenic has implicated as a cause of lung cancer where it contaminates drinking water, such as in some areas of Taiwan and Chile [79,80].

●Various dietary factors have been studied as possible causes of lung cancer but none are clearly implicated. Higher intake of fruits and vegetables may be protective against lung cancer [41,81,82]. A case-control study from Italy found an RR for lung cancer of 2.4 (95% CI 1.4-4.0) for the highest versus lowest quartiles of red meat consumption in never smokers [83], and another report indicated that higher consumption of fish may protect against lung cancer in never smokers [84]. A separate United States study focused exclusively on never smokers reported a reduced risk of lung cancer in those with the "healthiest" dietary patterns (ie, high consumption of fruits and vegetables and of low-fat foods) [85]. In one pooled analysis of 22 case-control and cohort studies including over 2500 never smoking lung cancer patients and over 9000 never smoking controls, the consumption of low-moderate amounts of alcohol was potentially protective against lung cancer [86].

●Indoor air pollutants such as vapors from cooking oil and the smoke from burning coal have been linked to lung cancer, particularly in Asia [87-91], although older studies have questioned the role of cooking oil fumes and lung cancer risk [92-94].

Lung disease — The risk of lung cancer among never smokers is increased in those with prior damage to the lungs from underlying pulmonary disease or exposure to radiation or chemotherapy [39,95-98]. The magnitude of this risk is unclear because the vast majority of pulmonary disease is related to smoking. When one looks at idiopathic pulmonary fibrosis, the literature is conflicting regarding the association with lung cancer, though an association does seem to be supported by the majority of studies [99,100]. (See "Cigarette smoking and other possible risk factors for lung cancer", section on 'Inflammation and benign lung disease'.)

Genetic factors — Multiple studies have shown an association between lung cancer in never smokers and a family history of lung cancer, suggesting a role for genetic factors [39,47,101-106].

As an example, in a case-control study of 257 cases of lung cancer among never smokers and an equivalent number of control never smokers, lung cancer was significantly more common among those with a positive family history (OR 7.2) [104]. In another case-control study that included over 2400 relatives of 316 never smoker lung cancer cases, there was a 25 percent excess risk of any type of cancer among first-degree relatives of cases, particularly of early-onset lung cancer (<50 years) among those relatives who smoked [105]. In an analysis from the Environment And Genetics in Lung cancer Etiology study, the RR of lung cancer associated with a positive family history, adjusted for age, sex, residence, education, and smoking, was 1.57 (95% CI 1.25-1.98) [107]. Efforts to decipher the interactions between family history and environment exposure in the development of lung cancer in never smokers will be aided by an environmental exposure index developed to look at these questions in Chinese never smokers. There was an OR of 30.6 (95% CI 9.4-99.9) for males with both positive family history and high environmental exposure compared with those with neither, but the associations in females were not as strong with this model [108]. Suboptimal DNA repair capacity as measured by the host-cell reactivation assay nearly doubled the risk of lung cancer in a case-control study of never smokers (RR 1.92, 95% CI 1.3-2.9) [109].

Studies have suggested susceptibility loci for lung cancer in never smokers at various locations including chromosomes 6q [110], 5p15.33 (TERT) [111-113], 13q31.3 (GPC5) [114], 15q25, and 6p21 [115], and in a Korean population at 18p11.22 [116]. However, the results of genome-wide association studies (GWAS) have not been consistent [117]. Pooled data from 14 studies of ethnic Chinese patients (n = 5510 never smoking females with lung cancer and 4544 controls) reported three new susceptibility loci (10q25.2, 6q22.2, and 6p21.32) and confirmed the 5p15.33, 3q28, and 17q24.3 loci [118]. However, the studies in this analysis included some of the trials used initially to identify certain loci.

A large GWAS in never smokers from two large United States academic centers and a confirmation cohort from Taiwan identified two potential loci associated with decreased survival in never smokers, but these were different from loci identified by other groups, which might be related to lung cancer susceptibility [119]. In Korea, an analysis of 181 never smoking females with lung cancer and 179 controls identified colony-stimulating factor 1 receptor (CSF1R) as a candidate gene of interest for lung cancer susceptibility in this group [120].

Another large GWAS of lung adenocarcinoma of East Asian ancestry identified 12 novel susceptibility variants including FADS1 and ELF5. Four loci were noted in both East Asian and European populations. A polygenic risk score based on the top 25 susceptibility variant loci demonstrated a strong association in never smokers compared to those with a smoking history (Pinteraction = 0.0058) [121].

Specific germline mutations have been identified in limited numbers of families with high rates of NSCLC in never smokers. The best understood are germline mutations in the EGFR [122-125]. Few other germline mutations have been reported in association with increased lung cancer risk in never smokers, but a novel germline mutation in human epidermal growth factor 2 (HER2) was identified in a Japanese family with nine affected family members [126]. Another study identified an association between a germline ATM L2307F mutation and lung adenocarcinoma, with never-smoking females with the variant to be approximately four to seven times more likely to develop lung adenocarcinoma than noncarriers [127]. In addition, R331W, a germline variant in YAP1 identified in a nonsmoking Taiwanese family with high frequency of lung adenocarcinoma was noted to have an allele frequency of 1.1 percent in lung adenocarcinoma compared with 0.18 percent in those without cancer [128].

Estrogens — The role of estrogens and other female hormones in lung cancer risk in females is uncertain, regardless of smoking status. Multiple studies have shown that the majority of NSCLCs express the estrogen receptor beta [129-131] and that the expression of this receptor is more common in never smokers compared with smokers [132].

The clinical implications of these laboratory studies are unclear. Multiple studies have looked at the relationship of lung cancer incidence to early menopause [133,134], use of hormone therapy [135,136], age at first birth [137], number of children [138], and use of tamoxifen [139]. However, the results have been inconsistent in establishing a relationship. Data from the randomized WHI trial indicated that females assigned to postmenopausal estrogen and progesterone had a higher risk of death from lung cancer without a higher incidence of the disease compared with females assigned to placebo [140]. However, females randomized to estrogen alone had no such increase in lung cancer mortality, nor in lung cancer incidence, compared with those on placebo [141]. Further analyses of the WHI trial indicated that the incidence and mortality of lung cancer did not differ by hormone use in never smoking females, but mortality from lung cancer was significantly higher in smoking females who used estrogen plus progesterone hormone therapy compared with smoking females who did not [142].

BIOLOGIC DIFFERENCES COMPARED WITH LUNG CANCER IN PEOPLE WHO HAVE SMOKED

Histology — Adenocarcinoma is more common in never smokers, light smokers, and former smokers while squamous cell carcinoma and small cell lung cancer are seen with a higher incidence in heavy smokers [6,7]. In a review of published reports on the histology of lung cancer that included smoking data, adenocarcinoma was more common than squamous cell carcinoma among nonsmokers (62 versus 18 percent, based upon 5144 cases). By contrast, adenocarcinoma was less frequent among smokers (19 versus 53 percent in 21,853 cases) [6]. Subsequent series of lung cancer in never smokers continue to report adenocarcinoma as the most common histology [20,42,45].

Molecular biology — Contemporary advances in the understanding of the molecular biology of lung cancer have led to the identification of substantial differences between never smokers compared with smokers with lung cancer, most significantly the identification of oncogenic driver alterations. These factors are arguably more important than any clinical differences. (See "Personalized, genotype-directed therapy for advanced non-small cell lung cancer".)

In one study performing whole-exome and RNA sequencing in patients with lung adenocarcinoma, there was a higher prevalence of clinically actionable driver alterations in never smokers compared with smokers (78 to 92 percent versus 50 percent) [61]. Whole genome sequencing of 232 patients with LCINS reported 60 percent of samples with alterations in EGFR, KRAS, ALK, MET, HER2, RET or ROS1 [62].

Several efforts to determine frequencies of the known "driver" mutations in NSCLC have been reported [143-145]. The National Cancer Institute's Lung Cancer Mutation Consortium initially presented data at the American Society of Clinical Oncology 2011 annual meeting and for the first approximately 800 patients tested, reported mutation frequencies of 25 percent KRAS; 23 percent EGFR; 6 percent ALK rearrangements; and 3 percent or less each of BRAF, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), mesenchymal-epithelial transition factor (MET) amplification, human epidermal growth factor receptor 2 (HER2), MAP/ERK kinase 1 (MEK1), and neuroblastoma RAS viral oncogene homolog (NRAS) [146]. Though those results are for adenocarcinomas in general, the identification of such mutations in over 60 percent of patients sampled and the mutually exclusive nature of the majority of those mutations indicate how far we have come in our biologic understanding of adenocarcinoma, the most frequent histology in never smokers.

Further updates have confirmed these relative percentages of mutations, which have also been looked at by The Cancer Genome Atlas effort [147].

EGFR mutations — One of the most frequent driver mutations noted in never smokers versus current and former smokers is in the expression and mutations of the epidermal growth factor receptor (EGFR). Mutations in the EGFR gene are more common in lung tumors from people who have never smoked compared with those with a smoking history [148-153]. Several analyses of patients with the most common activating mutations in the EGFR gene (predominantly deletions in exon 19 and the L858R mutation on exon 21) report that the frequency of the mutations, especially exon 19 and 21 mutations, is much higher in never smokers than ever smokers (p <0.001) in both males and females [154,155]. Uncommon EGFR mutations such as EGFR exon 20 insertions also are more common in female nonsmokers [156,157]. (See "Systemic therapy for advanced non-small cell lung cancer with an activating mutation in the epidermal growth factor receptor".)

The contribution of secondhand exposure to tobacco smoke to the incidence of EGFR mutations in never smokers is unclear. In a Korean study of 179 never smokers with non-small cell lung cancer (NSCLC), EGFR mutations were significantly less frequent in those with a positive history of secondhand tobacco smoke (39 versus 61 percent), and there was a progressive decrease in the incidence with increasing secondhand tobacco smoke exposure [158]. This is in contrast to a Japanese publication focused on 126 never smokers with NSCLC, which reported an increase in EGFR-activating mutations with increasing secondhand smoke exposure [159] (see 'Secondhand smoke' above). The potential correlation of air pollution and EGFR-mutated lung cancers is discussed earlier. (See 'Air pollution' above.)

ALK rearrangements — A fusion gene comprising portions of the echinoderm microtubule-associated protein-like 4 (EML4) gene and the anaplastic lymphoma kinase (ALK) gene in NSCLC is found in 3 to 7 percent of NSCLC and appears to be nearly mutually exclusive with EGFR and KRAS mutations [160]. This frequency is higher in those who develop lung cancer as never smokers [160-162]. The rate of ALK fusion oncogene positivity was nearly 20 percent of NSCLC in one study from China and 42 percent in those patients in that analysis who were known to have wildtype EGFR and KRAS [163]. (See "Anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer".)

Other oncogenic fusions — ROS1, RET, NTRK1-3, FRGFR1, FGFR3, and NRG1 fusions are also noted with increased prevalence in LCINS [164-166]. (See "Personalized, genotype-directed therapy for advanced non-small cell lung cancer".)

HER2 — The majority of HER2 mutations noted in NSCLC occur as small in-frame insertions in exon 20. These account for approximately 1.5 percent of NSCLC and are more common in nonsmokers and females [156]. (See "Personalized, genotype-directed therapy for advanced non-small cell lung cancer".)

KRAS mutations — Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations have been thought to be more common in lung cancer patients who are ever smokers [153,167]. An analysis of 482 lung adenocarcinomas, however, found that the rate of KRAS mutations in codons 12 and 13 was not significantly different in never smokers (15 percent) compared with former smokers (22 percent) and current smokers (25 percent) [168]. The nature of the mutations was significantly different though, with more transition mutations (G to A) compared with transversion mutations (G to T or G to C) in tumors from patients with a smoking history.

PROGNOSIS AND TREATMENT IMPLICATIONS — 

Whether or not patients with non-small cell lung cancer (NSCLC) who are never smokers have a better response to standard treatment and/or a better prognosis than those with a positive smoking history is uncertain. Recognition of the increased likelihood of targetable alterations in LCINS drives the majority of treatment options for this population and underlines the importance of comprehensive next generation sequencing, both DNA and RNA-based, at diagnosis. Some earlier observational studies have demonstrated a better survival outcome [32,169-172], although this has not been true in all studies [173-175].

As an example, in an analysis of 12,000 patients from California, smokers had a shorter survival compared with never smokers (hazard ratio [HR] for death 1.09, 95% CI 1.00-1.18) [32]. Similarly, in another study of patients with lung adenocarcinoma comparing 132 never smokers with 522 current smokers, it was found that the five-year survival was significantly better among never smokers (23 versus 16 percent), a difference that was significant on multivariate analysis [169]. By contrast, in another study of 254 patients with lung cancer, the five-year survival was not significantly different in never smokers compared with smokers (27 versus 31 percent, respectively) [173]. Subsequently, a much larger lung cancer registry trial, which included over 15,000 Japanese and over 13,000 White American patients from Southern California, demonstrated a statistically significant improvement in survival for the patients with no smoking history [33]. In an expanded analysis of 26,957 NSCLC patients from Japan, the median overall survival was significantly longer for never smokers compared with ever smokers (30 versus 19 months) [176].

Targeted therapies — Identification of oncogenic driver mutations with targeted therapies has changed the paradigm of treatment approach in LCINS. The differences in LCINS and lung cancer in smoking populations was first observed with the initial differences in treatment response with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (erlotinib, gefitinib, afatinib, osimertinib). Higher response rates and better survival were reported in never smokers with these drugs compared with current or former smokers, though the true factor is presence or absence of an EGFR-activating mutation [150,177,178].

The iPASS and First-Signal trials comparing first-line gefitinib versus chemotherapy for never smoking Asian patients with advanced-stage NSCLC emphasize this point [179,180]. In both studies, high frequencies of EGFR mutations were found among never smokers, and gefitinib conferred an overall progression-free survival benefit only in those with activating EGFR mutations, while those without the EGFR-activating mutations did better with first-line chemotherapy. Thus, smoking status should not be used as a determining factor in selection of therapy, though the pretest probability of an actionable driver mutation is higher in those who develop lung cancer as a never smoker, and testing for these mutations is critical in that patient population. (See "Systemic therapy for advanced non-small cell lung cancer with an activating mutation in the epidermal growth factor receptor".)

Newer strategies of treatment combinations of targeted therapy with chemotherapy are emerging, as well as the incorporation of targeted therapies in the adjuvant setting [181-184]. Additional information on specific treatment options for specific targetable driver mutations are discussed elsewhere. (See "Personalized, genotype-directed therapy for advanced non-small cell lung cancer".)

Checkpoint inhibitors — Many developments in lung cancer have been in the use of immune checkpoint inhibitors. The activity of the checkpoint inhibitors can be predicted to some extent by programmed death-ligand 1 (PD-L1) expression levels, but other factors play a key role as well. One of the earliest clinical observations was that responses were more likely in patients who developed lung cancer who had a smoking history compared with never smokers. In a specific analysis of patients with KRAS-mutated NSCLC, investigators found that patients with a smoking history were more likely to express PD-L1 (44 percent) versus former (20 percent) or never smokers (13 percent) [185].

Overall PD-L1 expression has been observed to be low or zero in LCINS [61,139]. Patients with ALK rearranged or ROS1 rearranged tumors are more frequently noted to have PD-L1 positivity compared with EGFR-mutated tumors [186-189]; however, PD-L1 positivity is not thought to reflect a true T cell-mediated immunogenicity that would correlate with a response to immune checkpoint inhibitors, and rather an intrinsic oncogene-driven activation of downstream signaling effectors that upregulate PD-L1 [8,190,191].

EARLY DETECTION — 

Current lung cancer screening guidelines exist only for those with current or prior smoking history based on several studies demonstrating reduction in lung cancer mortality [192,193]. (See "Screening for lung cancer".)

As more treatment options emerge for early-stage lung cancer, increased efforts to potentially expand lung cancer screening to nonsmoking populations are being explored. In Taiwan for example, 55 percent of the lung cancers develop in people who have never smoked, with 90 percent of females who develop lung cancer having no history of smoking. These observations have led to lung cancer screening programs in patients without a smoking history (TALENT trial) [194].

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Diagnosis and management of lung cancer".)

SUMMARY

●Incidence – Although most cases of lung cancer are due to tobacco smoking, lung cancer among never smokers is an important problem, with the age-adjusted incidence rate for lung cancer in never smokers aged 40 to 79 years ranging from 11.2 to 13.7 per 100,000 person-years for males and from 15.2 to 20.8 per 100,000 person-years for females. (See 'Incidence' above.)

●Risk factors – Although the etiology for lung cancer among never smokers is not always clear, risk factors include air pollution, secondhand tobacco smoke, radon, and other environmental exposures. More comprehensive whole genome sequencing, whole exome sequencing, and genome-wide association studies are being conducted to further elucidate the etiology of lung cancer in never smokers (LCINS). (See 'Risk factors' above and "Cigarette smoking and other possible risk factors for lung cancer".)

●Pathology – Adenocarcinoma is the most common histology among never smokers and is more common than among ever smokers. (See 'Histology' above.)

●Molecular biology – There are important differences at the molecular level between lung cancers arising in people who have never smoked and those who currently smoke or previously smoked such as increased incidences of targetable oncogenic alterations. The best understood of these are the abnormalities in the epidermal growth factor receptor (EGFR) pathway. These EGFR pathway abnormalities seen in never smokers have been associated with a particular responsiveness to erlotinib, gefitinib, afatinib, and osimertinib and other agents that inhibit EGFR tyrosine kinase. The anaplastic lymphoma kinase (ALK) fusion oncogene is another molecular variant in non-small cell lung cancer that is seen more frequently in never smokers and for which targeted therapy is available. Similar increases in frequency of other driver mutations are reported in lung cancer in never smokers. (See 'Molecular biology' above.)

●Treatment – Optimal treatment choices for the majority of LCINS are dependent on the presence of driver oncogenic alterations for possible targeted therapies. (See 'Prognosis and treatment implications' above and "Personalized, genotype-directed therapy for advanced non-small cell lung cancer".)

ACKNOWLEDGMENT — 

The UpToDate editorial staff acknowledges Heather Wakelee, MD, who contributed to earlier versions of this topic review.

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  152. Pham D, Kris MG, Riely GJ, et al. Use of cigarette-smoking history to estimate the likelihood of mutations in epidermal growth factor receptor gene exons 19 and 21 in lung adenocarcinomas. J Clin Oncol 2006; 24:1700.
  153. Tam IY, Chung LP, Suen WS, et al. Distinct epidermal growth factor receptor and KRAS mutation patterns in non-small cell lung cancer patients with different tobacco exposure and clinicopathologic features. Clin Cancer Res 2006; 12:1647.
  154. Toyooka S, Matsuo K, Shigematsu H, et al. The impact of sex and smoking status on the mutational spectrum of epidermal growth factor receptor gene in non small cell lung cancer. Clin Cancer Res 2007; 13:5763.
  155. Lee YJ, Shim HS, Kang YA, et al. Dose effect of cigarette smoking on frequency and spectrum of epidermal growth factor receptor gene mutations in Korean patients with non-small cell lung cancer. J Cancer Res Clin Oncol 2010; 136:1937.
  156. Friedlaender A, Subbiah V, Russo A, et al. EGFR and HER2 exon 20 insertions in solid tumours: from biology to treatment. Nat Rev Clin Oncol 2022; 19:51.
  157. Arcila ME, Nafa K, Chaft JE, et al. EGFR exon 20 insertion mutations in lung adenocarcinomas: prevalence, molecular heterogeneity, and clinicopathologic characteristics. Mol Cancer Ther 2013; 12:220.
  158. Lee YJ, Cho BC, Jee SH, et al. Impact of environmental tobacco smoke on the incidence of mutations in epidermal growth factor receptor gene in never-smoker patients with non-small-cell lung cancer. J Clin Oncol 2010; 28:487.
  159. Kawaguchi T, Ando M, Kubo A, et al. Long exposure of environmental tobacco smoke associated with activating EGFR mutations in never-smokers with non-small cell lung cancer. Clin Cancer Res 2011; 17:39.
  160. Shaw AT, Yeap BY, Mino-Kenudson M, et al. Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK. J Clin Oncol 2009; 27:4247.
  161. Rodig SJ, Mino-Kenudson M, Dacic S, et al. Unique clinicopathologic features characterize ALK-rearranged lung adenocarcinoma in the western population. Clin Cancer Res 2009; 15:5216.
  162. Kwak EL, Bang YJ, Camidge DR, et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med 2010; 363:1693.
  163. Zhang X, Zhang S, Yang X, et al. Fusion of EML4 and ALK is associated with development of lung adenocarcinomas lacking EGFR and KRAS mutations and is correlated with ALK expression. Mol Cancer 2010; 9:188.
  164. Pao W, Hutchinson KE. Chipping away at the lung cancer genome. Nat Med 2012; 18:349.
  165. Takeuchi K, Soda M, Togashi Y, et al. RET, ROS1 and ALK fusions in lung cancer. Nat Med 2012; 18:378.
  166. Harada G, Yang SR, Cocco E, Drilon A. Rare molecular subtypes of lung cancer. Nat Rev Clin Oncol 2023; 20:229.
  167. Le Calvez F, Mukeria A, Hunt JD, et al. TP53 and KRAS mutation load and types in lung cancers in relation to tobacco smoke: distinct patterns in never, former, and current smokers. Cancer Res 2005; 65:5076.
  168. Riely GJ, Kris MG, Rosenbaum D, et al. Frequency and distinctive spectrum of KRAS mutations in never smokers with lung adenocarcinoma. Clin Cancer Res 2008; 14:5731.
  169. Nordquist LT, Simon GR, Cantor A, et al. Improved survival in never-smokers vs current smokers with primary adenocarcinoma of the lung. Chest 2004; 126:347.
  170. Sardari Nia P, Weyler J, Colpaert C, et al. Prognostic value of smoking status in operated non-small cell lung cancer. Lung Cancer 2005; 47:351.
  171. Bryant A, Cerfolio RJ. Differences in epidemiology, histology, and survival between cigarette smokers and never-smokers who develop non-small cell lung cancer. Chest 2007; 132:185.
  172. Tsao AS, Liu D, Lee JJ, et al. Smoking affects treatment outcome in patients with advanced nonsmall cell lung cancer. Cancer 2006; 106:2428.
  173. Subramanian J, Velcheti V, Gao F, Govindan R. Presentation and stage-specific outcomes of lifelong never-smokers with non-small cell lung cancer (NSCLC). J Thorac Oncol 2007; 2:827.
  174. Herbst RS, Prager D, Hermann R, et al. TRIBUTE: a phase III trial of erlotinib hydrochloride (OSI-774) combined with carboplatin and paclitaxel chemotherapy in advanced non-small-cell lung cancer. J Clin Oncol 2005; 23:5892.
  175. Meguid RA, Hooker CM, Harris J, et al. Long-term survival outcomes by smoking status in surgical and nonsurgical patients with non-small cell lung cancer: comparing never smokers and current smokers. Chest 2010; 138:500.
  176. Kawaguchi T, Takada M, Kubo A, et al. Performance status and smoking status are independent favorable prognostic factors for survival in non-small cell lung cancer: a comprehensive analysis of 26,957 patients with NSCLC. J Thorac Oncol 2010; 5:620.
  177. Thatcher N, Chang A, Parikh P, et al. Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer). Lancet 2005; 366:1527.
  178. Shepherd FA, Rodrigues Pereira J, Ciuleanu T, et al. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 2005; 353:123.
  179. Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 2009; 361:947.
  180. Han JY, Park K, Kim SW, et al. First-SIGNAL: first-line single-agent iressa versus gemcitabine and cisplatin trial in never-smokers with adenocarcinoma of the lung. J Clin Oncol 2012; 30:1122.
  181. Planchard D, Jänne PA, Cheng Y, et al. Osimertinib with or without Chemotherapy in EGFR-Mutated Advanced NSCLC. N Engl J Med 2023; 389:1935.
  182. Wu YL, Tsuboi M, He J, et al. Osimertinib in Resected EGFR-Mutated Non-Small-Cell Lung Cancer. N Engl J Med 2020; 383:1711.
  183. Tsuboi M, Herbst RS, John T, et al. Overall Survival with Osimertinib in Resected EGFR-Mutated NSCLC. N Engl J Med 2023; 389:137.
  184. Solomon BJ, Ahn JS, Dziadziuszko R, et al. LBA2 ALINA: Efficacy and safety of adjuvant alectinib versus chemotherapy in patients with early-stage ALK+ non-small cell lung cancer (NSCLC). Ann Oncol 2023; 34S:ESMO #S1295.
  185. Calles A, Liao X, Sholl LM, et al. Expression of PD-1 and Its Ligands, PD-L1 and PD-L2, in Smokers and Never Smokers with KRAS-Mutant Lung Cancer. J Thorac Oncol 2015; 10:1726.
  186. Chang GC, Yang TY, Chen KC, et al. ALK variants, PD-L1 expression, and their association with outcomes in ALK-positive NSCLC patients. Sci Rep 2020; 10:21063.
  187. Tseng JS, Yang TY, Wu CY, et al. Characteristics and Predictive Value of PD-L1 Status in Real-World Non-Small Cell Lung Cancer Patients. J Immunother 2018; 41:292.
  188. Evans M, O'Sullivan B, Hughes F, et al. The Clinicopathological and Molecular Associations of PD-L1 Expression in Non-small Cell Lung Cancer: Analysis of a Series of 10,005 Cases Tested with the 22C3 Assay. Pathol Oncol Res 2020; 26:79.
  189. Lee J, Park CK, Yoon HK, et al. PD-L1 expression in ROS1-rearranged non-small cell lung cancer: A study using simultaneous genotypic screening of EGFR, ALK, and ROS1. Thorac Cancer 2019; 10:103.
  190. Koh J, Jang JY, Keam B, et al. EML4-ALK enhances programmed cell death-ligand 1 expression in pulmonary adenocarcinoma via hypoxia-inducible factor (HIF)-1α and STAT3. Oncoimmunology 2016; 5:e1108514.
  191. Shen J, Li S, Medeiros LJ, et al. PD-L1 expression is associated with ALK positivity and STAT3 activation, but not outcome in patients with systemic anaplastic large cell lymphoma. Mod Pathol 2020; 33:324.
  192. National Lung Screening Trial Research Team, Aberle DR, Adams AM, et al. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med 2011; 365:395.
  193. de Koning HJ, van der Aalst CM, de Jong PA, et al. Reduced Lung-Cancer Mortality with Volume CT Screening in a Randomized Trial. N Engl J Med 2020; 382:503.
  194. Chang GC, Chiu CH, Yu CJ, et al. Low-dose CT screening among never-smokers with or without a family history of lung cancer in Taiwan: a prospective cohort study. Lancet Respir Med 2024; 12:141.
Topic 4600 Version 33.0

References

1 : Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries.

2 : Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries.

3 : Annual Report to the Nation on the Status of Cancer, Part 1: National Cancer Statistics.

4 : Epidemiology of tobacco use in the United States.

5 : Cancer Statistics, 2021.

6 : Lung cancer in never smokers--a different disease.

7 : Lung cancer in never smokers: a review.

8 : Lung cancer in patients who have never smoked - an emerging disease.

9 : Never-smoking nonsmall cell lung cancer as a separate entity: clinicopathologic features and survival.

10 : Molecular genetics of lung cancer in people who have never smoked.

11 : Lung cancer in 'Never-smokers': a unique entity.

12 : Lung cancer in never smokers: molecular profiles and therapeutic implications.

13 : Proportion of Never Smokers Among Men and Women With Lung Cancer in 7 US States.

14 : Small-cell lung cancer in never-smokers: a case series with information on family history of cancer and environmental tobacco smoke.

15 : Small-cell lung cancer in never-smokers: a case series with information on family history of cancer and environmental tobacco smoke.

16 : Annual report to the nation on the status of cancer, 1975-2005, featuring trends in lung cancer, tobacco use, and tobacco control.

17 : A European validation study of smoking and environmental tobacco smoke exposure in nonsmoking lung cancer cases and controls.

18 : Misclassification rates for current smokers misclassified as nonsmokers.

19 : Epidemiology study of never-smokers with non-small cell lung cancer (NSCLC): High percentages of Asian and Hispanic female never-smokers and the significance of Asian ethnicity

20 : Lung cancer incidence in never smokers.

21 : Lung cancer rates in men and women with comparable histories of smoking.

22 : The Nurses' Health Study: 20-year contribution to the understanding of health among women.

23 : High breast cancer incidence rates among California teachers: results from the California Teachers Study (United States).

24 : A multiethnic cohort in Hawaii and Los Angeles: baseline characteristics.

25 : Ethnic and racial differences in the smoking-related risk of lung cancer.

26 : Intake of vitamins E, C, and A and risk of lung cancer. The NHANES I epidemiologic followup study. First National Health and Nutrition Examination Survey.

27 : Intake of vitamins E, C, and A and risk of lung cancer. The NHANES I epidemiologic followup study. First National Health and Nutrition Examination Survey.

28 : Asian ethnicity is a favorable prognostic factor for overall survival in non-small cell lung cancer (NSCLC) and is independent of smoking status.

29 : Lung cancer occurrence in never-smokers: an analysis of 13 cohorts and 22 cancer registry studies.

30 : Incidence of lung cancer in a large cohort of non-smoking men from Sweden.

31 : Lung cancer death rates in lifelong nonsmokers.

32 : Epidemiology of bronchioloalveolar carcinoma: improvement in survival after release of the 1999 WHO classification of lung tumors.

33 : Japanese ethnicity compared with Caucasian ethnicity and never-smoking status are independent favorable prognostic factors for overall survival in non-small cell lung cancer: a collaborative epidemiologic study of the National Hospital Organization Study Group for Lung Cancer (NHSGLC) in Japan and a Southern California Regional Cancer Registry databases.

34 : Smoking, smoking cessation, and lung cancer in the UK since 1950: combination of national statistics with two case-control studies.

35 : Increasing frequency of non-smoking lung cancer: Presentation of patients with early disease to a tertiary institution in the UK.

36 : Proportion of Never-Smoker Non-Small Cell Lung Cancer Patients at Three Diverse Institutions.

37 : A Decade of Never-smokers Among Lung Cancer Patients-Increasing Trend and Improved Survival.

38 : Global cancer statistics, 2002.

39 : Lung cancer risk in never-smokers: a population-based case-control study of epidemiologic risk factors.

40 : Lung cancer in women: exploring sex differences in susceptibility, biology, and therapeutic response.

41 : Updated information on risk factors for lung cancer: findings from the JACC Study.

42 : Gender, histology, and time of diagnosis are important factors for prognosis: analysis of 1499 never-smokers with advanced non-small cell lung cancer in Japan.

43 : Survival following non-small cell lung cancer among Asian/Pacific Islander, Latina, and Non-Hispanic white women who have never smoked.

44 : Adenocarcinoma of the lung in young patients: the M. D. Anderson experience.

45 : Never-smokers with lung cancer: epidemiologic evidence of a distinct disease entity.

46 : Secondhand smoke exposure in adulthood and risk of lung cancer among never smokers: a pooled analysis of two large studies.

47 : Never smokers and lung cancer risk: a case-control study of epidemiological factors.

48 : Environmental tobacco smoke and risk of respiratory cancer and chronic obstructive pulmonary disease in former smokers and never smokers in the EPIC prospective study.

49 : Environmental tobacco smoke and risk of respiratory cancer and chronic obstructive pulmonary disease in former smokers and never smokers in the EPIC prospective study.

50 : Tobacco and cancer: recent epidemiological evidence.

51 : Tobacco smoke and involuntary smoking.

52 : Lung cancers attributable to environmental tobacco smoke and air pollution in non-smokers in different European countries: a prospective study.

53 : Characteristics of never smoker lung cancer including environmental and occupational risk factors.

54 : Second hand smoke, age of exposure and lung cancer risk.

55 : Passive smoking and lung cancer in Japanese non-smoking women: a prospective study.

56 : Childhood exposure to secondhand smoke and functional mannose binding lectin polymorphisms are associated with increased lung cancer risk.

57 : Meta-analysis of studies of passive smoking and lung cancer: effects of study type and continent.

58 : Occupational exposures, environmental tobacco smoke, and lung cancer.

59 : Active and passive smoking in relation to lung cancer incidence in the Women's Health Initiative Observational Study prospective cohort.

60 : Whole-genome sequencing of asian lung cancers: second-hand smoke unlikely to be responsible for higher incidence of lung cancer among Asian never-smokers.

61 : Genomic Profiling of Lung Adenocarcinoma in Never-Smokers.

62 : Genomic and evolutionary classification of lung cancer in never smokers.

63 : Radon, smoking and lung cancer risk: results of a joint analysis of three European case-control studies among uranium miners.

64 : Radon, smoking and lung cancer risk: results of a joint analysis of three European case-control studies among uranium miners.

65 : Radon and lung cancer.

66 : A combined analysis of North American case-control studies of residential radon and lung cancer.

67 : Radon in homes and risk of lung cancer: collaborative analysis of individual data from 13 European case-control studies.

68 : Systematic review and meta-analysis of residential radon and lung cancer in never-smokers.

69 : Air pollution and lung cancer incidence in 17 European cohorts: prospective analyses from the European Study of Cohorts for Air Pollution Effects (ESCAPE).

70 : Long-term ambient fine particulate matter air pollution and lung cancer in a large cohort of never-smokers.

71 : Outdoor particulate matter exposure and lung cancer: a systematic review and meta-analysis.

72 : Lung adenocarcinoma promotion by air pollutants.

73 : Epidemiology of lung cancer: looking to the future.

74 : Occupational and environmental thoracic malignancies.

75 : Occupation and lung cancer in nonsmokers.

76 : Occupational exposure to carcinogens and risk of lung cancer: results from The Netherlands cohort study.

77 : Occupational exposure to organic dust increases lung cancer risk in the general population.

78 : Lung cancer risk in painters: a meta-analysis.

79 : Ingested arsenic, cigarette smoking, and lung cancer risk: a follow-up study in arseniasis-endemic areas in Taiwan.

80 : Lung cancer and arsenic concentrations in drinking water in Chile.

81 : Prospective study of fruit and vegetable consumption and risk of lung cancer among men and women.

82 : Dietary intake of fruit and vegetable and lung cancer risk: a case-control study in Harbin, northeast China.

83 : Intakes of red meat, processed meat, and meat mutagens increase lung cancer risk.

84 : Meat consumption and risk of lung cancer among never-smoking women.

85 : Dietary patterns affect lung cancer risk in never smokers.

86 : Alcohol and lung cancer risk among never smokers: A pooled analysis from the international lung cancer consortium and the SYNERGY study.

87 : Contribution of environmental factors to cancer risk.

88 : Dose-response relationship between cooking fumes exposures and lung cancer among Chinese nonsmoking women.

89 : Chinese food cooking and lung cancer in women nonsmokers.

90 : Lung cancer and indoor exposure to coal and biomass in rural China.

91 : The risk of lung cancer among cooking adults: a meta-analysis of 23 observational studies.

92 : Lung cancer among Chinese women.

93 : Lung cancer in nonsmoking Chinese women: a case-control study.

94 : Analysis and estimates of attributable risk factors for lung cancer in Nanjing, China.

95 : Lung cancer following chemotherapy and radiotherapy for Hodgkin's disease.

96 : Prior lung disease and risk of lung cancer in a large prospective study.

97 : Previous lung disease and risk of lung cancer among men and women nonsmokers.

98 : Previous lung disease and risk of lung cancer among lifetime nonsmoking women in the United States.

99 : Lung cancer and cryptogenic fibrosing alveolitis. A population-based cohort study.

100 : Pulmonary fibrosis and lung cancer in the United States: analysis of the multiple cause of death mortality data, 1979 through 1991.

101 : Family history of cancer and risk of lung cancer among lifetime nonsmoking women in the United States.

102 : Family history of cancer and risk of lung cancer in lifetime non-smokers and long-term ex-smokers.

103 : Cancer aggregation and complex segregation analysis of families with female non-smoking lung cancer probands in Taiwan.

104 : Familial risk of lung cancer among nonsmokers and their relatives.

105 : Aggregation of cancer among relatives of never-smoking lung cancer patients.

106 : Systematic review of the relationship between family history and lung cancer risk.

107 : Family history of cancer and nonmalignant lung diseases as risk factors for lung cancer.

108 : Joint effects of environmental exposures and familial susceptibility to lung cancer in Chinese never smoking men and women.

109 : DNA repair capacity and lung cancer risk in never smokers.

110 : A susceptibility locus on chromosome 6q greatly increases lung cancer risk among light and never smokers.

111 : Common 5p15.33 and 6p21.33 variants influence lung cancer risk.

112 : Role of 5p15.33 (TERT-CLPTM1L), 6p21.33 and 15q25.1 (CHRNA5-CHRNA3) variation and lung cancer risk in never-smokers.

113 : The 5p15.33 locus is associated with risk of lung adenocarcinoma in never-smoking females in Asia.

114 : Genetic variants and risk of lung cancer in never smokers: a genome-wide association study.

115 : Replication of lung cancer susceptibility loci at chromosomes 15q25, 5p15, and 6p21: a pooled analysis from the International Lung Cancer Consortium.

116 : The 18p11.22 locus is associated with never smoker non-small cell lung cancer susceptibility in Korean populations.

117 : A rigorous and comprehensive validation: common genetic variations and lung cancer.

118 : Genome-wide association analysis identifies new lung cancer susceptibility loci in never-smoking women in Asia.

119 : Genome-wide association study of genetic predictors of overall survival for non-small cell lung cancer in never smokers.

120 : A functional polymorphism in CSF1R gene is a novel susceptibility marker for lung cancer among never-smoking females.

121 : Genome-wide association study of lung adenocarcinoma in East Asia and comparison with a European population.

122 : Inherited susceptibility to lung cancer may be associated with the T790M drug resistance mutation in EGFR.

123 : Novel germline mutation: EGFR V843I in patient with multiple lung adenocarcinomas and family members with lung cancer.

124 : Familial lung adenocarcinoma caused by the EGFR V843I germ-line mutation.

125 : Activating germline R776H mutation in the epidermal growth factor receptor associated with lung cancer with squamous differentiation.

126 : Novel germline mutation in the transmembrane domain of HER2 in familial lung adenocarcinomas.

127 : Protein-altering germline mutations implicate novel genes related to lung cancer development.

128 : R331W Missense Mutation of Oncogene YAP1 Is a Germline Risk Allele for Lung Adenocarcinoma With Medical Actionability.

129 : ER beta: identification and characterization of a novel human estrogen receptor.

130 : Human non-small cell lung tumors and cells derived from normal lung express both estrogen receptor alpha and beta and show biological responses to estrogen.

131 : Expression of estrogen receptors alpha and beta in human lung tissue and cell lines.

132 : The significance of estrogen receptor beta in 301 surgically treated non-small cell lung cancers.

133 : Re: Endocrine factors and adenocarcinoma of the lung in women.

134 : Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial.

135 : Reproductive factors, hormone use, estrogen receptor expression and risk of non small-cell lung cancer in women.

136 : Hormone therapy and risk of lung cancer: a meta-analysis.

137 : Reproductive and hormonal factors and risk of lung cancer in women: a prospective cohort study.

138 : Parity and risk of lung cancer in women.

139 : Tamoxifen does not reduce the risk of lung cancer in women

140 : Oestrogen plus progestin and lung cancer in postmenopausal women (Women's Health Initiative trial): a post-hoc analysis of a randomised controlled trial.

141 : Lung cancer among postmenopausal women treated with estrogen alone in the women's health initiative randomized trial.

142 : Smoking and estrogen plus progestin (E+P) and lung cancer incidence and mortality

143 : Prospective Analysis of Oncogenic Driver Mutations and Environmental Factors: Japan Molecular Epidemiology for Lung Cancer Study.

144 : Lung cancer mutation profile of EGFR, ALK, and KRAS: Meta-analysis and comparison of never and ever smokers.

145 : Multi-institutional Oncogenic Driver Mutation Analysis in Lung Adenocarcinoma: The Lung Cancer Mutation Consortium Experience.

146 : A multicenter effort to identify driver mutations and employ targeted therapy in patients with lung adenocarcinomas: The Lung Cancer Mutation Consortium (LCMC)

147 : Comprehensive molecular profiling of lung adenocarcinoma.

148 : Mutations in the epidermal growth factor receptor gene are linked to smoking-independent, lung adenocarcinoma.

149 : Mutations of the epidermal growth factor receptor gene in lung cancer: biological and clinical implications.

150 : Erlotinib in lung cancer - molecular and clinical predictors of outcome.

151 : EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib.

152 : Use of cigarette-smoking history to estimate the likelihood of mutations in epidermal growth factor receptor gene exons 19 and 21 in lung adenocarcinomas.

153 : Distinct epidermal growth factor receptor and KRAS mutation patterns in non-small cell lung cancer patients with different tobacco exposure and clinicopathologic features.

154 : The impact of sex and smoking status on the mutational spectrum of epidermal growth factor receptor gene in non small cell lung cancer.

155 : Dose effect of cigarette smoking on frequency and spectrum of epidermal growth factor receptor gene mutations in Korean patients with non-small cell lung cancer.

156 : EGFR and HER2 exon 20 insertions in solid tumours: from biology to treatment.

157 : EGFR exon 20 insertion mutations in lung adenocarcinomas: prevalence, molecular heterogeneity, and clinicopathologic characteristics.

158 : Impact of environmental tobacco smoke on the incidence of mutations in epidermal growth factor receptor gene in never-smoker patients with non-small-cell lung cancer.

159 : Long exposure of environmental tobacco smoke associated with activating EGFR mutations in never-smokers with non-small cell lung cancer.

160 : Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK.

161 : Unique clinicopathologic features characterize ALK-rearranged lung adenocarcinoma in the western population.

162 : Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer.

163 : Fusion of EML4 and ALK is associated with development of lung adenocarcinomas lacking EGFR and KRAS mutations and is correlated with ALK expression.

164 : Chipping away at the lung cancer genome.

165 : RET, ROS1 and ALK fusions in lung cancer.

166 : Rare molecular subtypes of lung cancer.

167 : TP53 and KRAS mutation load and types in lung cancers in relation to tobacco smoke: distinct patterns in never, former, and current smokers.

168 : Frequency and distinctive spectrum of KRAS mutations in never smokers with lung adenocarcinoma.

169 : Improved survival in never-smokers vs current smokers with primary adenocarcinoma of the lung.

170 : Prognostic value of smoking status in operated non-small cell lung cancer.

171 : Differences in epidemiology, histology, and survival between cigarette smokers and never-smokers who develop non-small cell lung cancer.

172 : Smoking affects treatment outcome in patients with advanced nonsmall cell lung cancer.

173 : Presentation and stage-specific outcomes of lifelong never-smokers with non-small cell lung cancer (NSCLC).

174 : TRIBUTE: a phase III trial of erlotinib hydrochloride (OSI-774) combined with carboplatin and paclitaxel chemotherapy in advanced non-small-cell lung cancer.

175 : Long-term survival outcomes by smoking status in surgical and nonsurgical patients with non-small cell lung cancer: comparing never smokers and current smokers.

176 : Performance status and smoking status are independent favorable prognostic factors for survival in non-small cell lung cancer: a comprehensive analysis of 26,957 patients with NSCLC.

177 : Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer).

178 : Erlotinib in previously treated non-small-cell lung cancer.

179 : Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma.

180 : First-SIGNAL: first-line single-agent iressa versus gemcitabine and cisplatin trial in never-smokers with adenocarcinoma of the lung.

181 : Osimertinib with or without Chemotherapy in EGFR-Mutated Advanced NSCLC.

182 : Osimertinib in Resected EGFR-Mutated Non-Small-Cell Lung Cancer.

183 : Overall Survival with Osimertinib in Resected EGFR-Mutated NSCLC.

184 : LBA2 ALINA: Efficacy and safety of adjuvant alectinib versus chemotherapy in patients with early-stage ALK+ non-small cell lung cancer (NSCLC)

185 : Expression of PD-1 and Its Ligands, PD-L1 and PD-L2, in Smokers and Never Smokers with KRAS-Mutant Lung Cancer.

186 : ALK variants, PD-L1 expression, and their association with outcomes in ALK-positive NSCLC patients.

187 : Characteristics and Predictive Value of PD-L1 Status in Real-World Non-Small Cell Lung Cancer Patients.

188 : The Clinicopathological and Molecular Associations of PD-L1 Expression in Non-small Cell Lung Cancer: Analysis of a Series of 10,005 Cases Tested with the 22C3 Assay.

189 : PD-L1 expression in ROS1-rearranged non-small cell lung cancer: A study using simultaneous genotypic screening of EGFR, ALK, and ROS1.

190 : EML4-ALK enhances programmed cell death-ligand 1 expression in pulmonary adenocarcinoma via hypoxia-inducible factor (HIF)-1αand STAT3.

191 : PD-L1 expression is associated with ALK positivity and STAT3 activation, but not outcome in patients with systemic anaplastic large cell lymphoma.

192 : Reduced lung-cancer mortality with low-dose computed tomographic screening.

193 : Reduced Lung-Cancer Mortality with Volume CT Screening in a Randomized Trial.

194 : Low-dose CT screening among never-smokers with or without a family history of lung cancer in Taiwan: a prospective cohort study.