Proportion and clinical features of never-smokers with non-small cell lung cancer
© The Author(s) 2017
Received: 9 March 2016
Accepted: 23 August 2016
Published: 8 February 2017
The proportion of never-smokers with non-small cell lung cancer (NSCLC) is increasing, but that in Korea has not been well addressed in a large population. We aimed to evaluate the proportion and clinical features of never-smokers with NSCLC in a large single institution.
We analyzed clinical data of 1860 consecutive patients who were newly diagnosed with NSCLC between June 2011 and December 2014.
Of the 1860 NSCLC patients, 707 (38.0%) were never-smokers. The proportions of women (83.7% vs. 5.6%) and adenocarcinoma (89.8% vs. 44.9%) were higher among never-smokers than among ever-smokers. Significantly more never-smokers were diagnosed at a younger median age (65 vs. 68 years, P < 0.001) and earlier stage (stage I–II, 44.5% vs. 38.9%, P = 0.015) compared with ever-smokers. Epidermal growth factor receptor mutations (57.8% vs. 24.4%, P < 0.001) and anaplastic lymphoma kinase rearrangements (7.8% vs. 2.8%, P < 0.001) were more common in never-smokers, whereas Kirsten rat sarcoma viral oncogene homolog mutations (5.8% vs. 9.6%, P = 0.021) were less frequently encountered in never-smokers than in ever-smokers. Never-smokers showed longer survival after adjusting for the favorable effects of younger age, female sex, adenocarcinoma histology, better performance status, early stage disease, being asymptomatic at diagnosis, received antitumor treatment, and the presence of driver mutations (hazard ratio, 0.624; 95% confidence interval, 0.460–0.848; P = 0.003).
More than one-third of the Korean patients with NSCLC were never-smokers. NSCLC in never-smokers had different clinical characteristics and major driver mutations and resulted in longer overall survival compared with NSCLC in ever-smokers.
Lung cancer is the leading cause of cancer death, accounting for an estimated 1.6 million deaths in 2012 worldwide . In Korea, lung cancer has been the most common cause of cancer death since 1999 and was expected to account for 22.6% of all cancer deaths in 2012, although the age-standardized mortality due to lung cancer has decreased slightly in both men and women since 2002 . Lung cancer is considered a preventable cancer because tobacco smoking is the major cause of lung cancer . According to comprehensive tobacco control programs, the incidence of lung cancer has been decreasing, whereas the proportion of never-smoking patients with non-small cell lung cancer (NSCLC) has been increasing [4, 5]. Global statistics estimate that overall 25% of lung cancers worldwide occur in never-smokers, and this proportion is approximately 10%–15% in Western countries . The percentage is higher in Eastern Asia, as studies from Japan  and Singapore  have reported that never-smokers comprise approximately 32% of NSCLC patients.
It has been suggested that NSCLC in never-smokers should be regarded as a separate disease entity, as it bears striking differences from NSCLC in ever-smokers in terms of its epidemiologic and clinical characteristics; never-smokers with NSCLC are mostly women and have adenocarcinoma histology [5, 7, 8]. Recent molecular epidemiologic studies have supported that NSCLC in never-smokers has distinct underlying molecular mechanisms. Epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangements are more frequent in never-smokers with NSCLC, whereas Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations are associated with ever-smokers [9–11]. These genetic alterations occur in a mutually exclusive fashion, providing evidence that NSCLC in never-smokers arises through different genetic pathways [8, 12].
Although there have been several studies reporting the clinical characteristics and prognosis of never-smoking NSCLC patients in Eastern Asia [5, 7], large-scale studies in the Korean population are lacking. This study was aimed to evaluate the proportion and clinical features of never-smokers with NSCLC in a large single institution in Korea.
Patients and methods
This study included all consecutive patients who were newly diagnosed with NSCLC at the Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea between June 2011 and December 2014. Patients with recurred NSCLC were excluded. This study was approved by the institutional review board of the Seoul National University Hospital (H-1401-033-548). The requirement for informed consent was waived.
Clinical and pathologic variables
All data were collected from medical records. Subjects were categorized based on the smoking status as never- and ever-smokers. An individual who had a lifetime exposure of <100 cigarettes was defined as a never-smoker. An individual who smoked no <100 cigarettes during one’s lifetime was defined as an ever-smoker. The clinical and pathologic data reviewed for analysis included age, sex, symptoms at diagnosis, histologic subtype, Eastern Cooperative Oncology Group (ECOG) performance status, disease stage, treatment received. Disease stage was defined as pathologic tumor, node, metastasis (TNM) stage for surgical cases and clinical TNM stage for non-surgical cases at the time of initial diagnosis, according to the seventh edition of the American Joint Committee on Cancer Staging Manual .
DNA was extracted from formalin-fixed, paraffin-embedded tissue as per the standard protocol. Initially, the EGFR mutation status (exons 18–21) and the KRAS mutation status (exon 2) of the extracted DNA were determined with nested polymerase chain reaction (PCR) followed by bidirectional direct sequencing, as previously described . However, after peptide nucleic acid (PNA) clamping technology was recognized as a more sensitive method compared to direct sequencing for the detection of gene mutations in diagnostic specimens with a low proportion of tumor cells , PNA-mediated real-time PCR clamping replaced direct sequencing since February 1, 2013. The PNAClamp EGFR Mutation Detection Kit (Panagene Inc., Daejeon, Korea) was used as previously described . KRAS mutations in codons 12 and 13 were detected with PNA-mediated real-time PCR. To test for ALK rearrangements, immunohistochemistry (IHC) for ALK protein expression was used as a screening modality, and fluorescence in situ hybridization (FISH) was used for confirmation. Unstained slides of formalin-fixed, paraffin-embedded tumor tissues were analyzed with FISH using the Vysis ALK Dual Color, Break Apart Rearrangement probe (Abbott Molecular, Abbott Park, IL, USA) as previously described . ALK rearrangements were defined via split ALK 5′ and 3′ probe signals or isolated 3′ signals in more than 15% of scored tumor cells .
The schedules of follow-up were determined by clinicians. Overall survival (OS) was measured from the date of diagnosis to the date of death or the date of last follow-up. Death certificate data were obtained from the Korea National Statistical Office on 16 February 2015. The last follow-up was performed in February 2015.
Continuous data are presented as median (range), whereas categorical data are presented as numbers (percentages). Clinicopathologic variables between never-smokers and ever-smokers were compared using the independent samples t test or the Mann–Whitney U test for continuous variables and the χ2 test or Fisher’s exact test for categorical variables. The OS rates were calculated according to the Kaplan–Meier method, and the differences among the groups were tested using the log-rank test. Multivariate analysis was performed with the Cox proportional hazards model adjusting for variables with a P < 0.2 in the univariate analysis. All statistical analyses were performed using Stata statistical software (Version 12.0, StataCorp LP, College Station, TX, USA).
Characteristics of 1860 patients with NSCLC according to smoking status
Never-smokers [cases (%)]
Ever-smokers [cases (%)]
Squamous cell carcinoma
Symptoms at diagnosis
EGFR mutations (n = 1284)
KRAS mutations (n = 1089)
ALK rearrangements (n = 1288)
Frequencies of driver mutations according to smoking status
Of the 1860 patients, 1284 were tested for EGFR mutations, 1288 were tested for ALK rearrangements, and 1089 were tested for KRAS mutations. As expected, the frequencies of EGFR mutations (353/611 [57.8%] vs. 164/673 [24.4%]) and ALK rearrangements (47/605 [7.8%] vs. 19/683 [2.8%]) were significantly higher in never-smokers than in ever-smokers (both P < 0.001) (Table 1). Among the EGFR mutations, exon 19 deletions and exon 21 point mutations were significantly associated with never-smoking status (all P < 0.001), whereas mutations in exons 18 and 20 were not (P = 0.227, P = 0.167, respectively).
Type and frequency of KRAS mutations according to smoking status in 80 patients with NSCLC
Amino acid substitution
Never-smokers [cases (%)]
Ever-smokers [cases (%)]
Total [cases (%)]
Multivariate analysis of overall survival using the Cox regression in 1860 patients with NSCLC
Whole cohort (n = 1860)
Never-smokers (n = 707)
Ever-smokers (n = 1153)
Squamous cell carcinoma
Symptoms at diagnosis
Separate multivariate survival analyses were further conducted for 707 never-smokers and 1153 ever-smokers (Table 3). The histologic subtype, ECOG performance status, disease stage, treatment received, and status of EGFR mutations were common prognostic factors in both never- and ever-smokers. However, younger age and being asymptomatic at diagnosis were no longer associated with prolonged OS in never-smokers. In ever-smokers, KRAS mutations and ALK rearrangements were not independent prognostic factors for OS.
In the current study, we summarized the clinical characteristics and major driver mutations of NSCLC patients and compared survival outcomes between never- and ever-smokers in 1860 Korean NSCLC patients. We provided the profile of major genes (EGFR, KRAS, and ALK), and we adjusted for the presence of each driver mutation in the survival analysis. Never-smokers accounted for 38.0% of the NSCLC patients, and smoking status was an independent prognostic factor regardless of whether NSCLC patients had oncogenic driver mutations.
In our study, never-smokers were diagnosed at an earlier age than ever-smokers, which was consistent with a previous report from Singapore . However, several studies from Western countries reported the opposite observation: never-smokers were diagnosed at a similar or older age than ever-smokers [4, 18]. This might be explained by later ages of initiation of smoking in Asian smokers than in Western smokers; because the age at smoking onset in Asian countries is much older than that in Western countries, the age at cancer diagnosis for Asian smokers may be older. In addition, the great contribution of risk factors other than smoking might affect the development of lung cancer in Asian countries . Another interesting observation was that never-smokers tended to present disease at an early stage. This finding was consistent with the result of a study performed in Japan , whereas studies from Singapore  and the United States  reported that never-smokers were more likely to present with advanced disease and another study from the United States found no differences .
Although EGFR mutations have been well known as the most common genetic alteration in never-smoking NSCLC patients, EGFR mutations were detected in 24.4% of ever-smoking NSCLC patients in our study. The frequencies of EGFR mutations in ever-smokers vary widely, from 8.4% to 11.9% in Europe and North America to 26.0%–35.9% in Japan and China . Several potential risk factors other than EGFR mutations in never-smokers have been proposed, including environmental tobacco smoke, residential radon, asbestos exposure, cooking oil fumes, genetic susceptibility, hormone factors, and oncogenic viruses, which may contribute with varied degrees in line with sex and geographical areas .
In the present study, Gly12Cys, resulting from a codon 12 GGT>TGT substitution, was the most frequent subtype of KRAS mutations, which was consistent with the results of studies in Western countries [22, 23]. However, a recent study analyzing 82 KRAS mutations in 1420 Korean NSCLC patients reported that Gly12Asp, resulting from a codon 12 GGT>GAT substitution, was the most frequent KRAS substitution . In contrast to the previous studies showing that never-smokers were more likely to have a transition mutation rather than a transversion mutation [22, 24], the association between never-smoking status and transition mutations was not statistically significant in our cohort (P = 0.149). Because the frequency of KRAS mutations in the Asian population is relatively low, our study lacked the power to reach any firm conclusions about distinct characteristics of KRAS mutation in the Korean population even though the study included over one thousand NSCLC patients who were tested for KRAS mutations.
Our study has several limitations, such as its retrospective design, and the fact that it was conducted at a single institution. However, our institution is a 1750-bed tertiary teaching hospital and a large referral center in Korea. Moreover, we recruited all consecutive patients with newly diagnosed NSCLC during the study period to minimize the selection bias. The major limitation of this study was that the information regarding administration of specific targeted agents was not available. The use of targeted therapy may be a confounding factor of inherent mutation status in predicting survival. Another limitation was the relatively short follow-up period. In addition, information about exposure to risk factors other than smoking was unavailable. Further studies are needed to elucidate the potential risk factors for NSCLC in never-smokers.
In summary, more than one-third of Korean patients with NSCLC were never-smokers. We showed distinct features of NSCLC in Korean never-smokers compared with ever-smokers, including a better prognosis in never-smokers. After adjusting for the favorable effects of younger age, better performance status, earlier stage of disease, being asymptomatic at diagnosis, and the presence of driver mutations, the association between never-smoking status and prolonged survival became apparent.
JC and YSP had full access to data, writing, and responsibility for the manuscript. CHL, DWK and YWK contributed to data acquisition and analysis. SMC, JL, SML, JJY, CGY and SKH contributed to data acquisition and review of the manuscript. YTK performed surgical resection of lung cancer. All authors read and approved the final manuscript.
The authors thank the Medical Research Collaborating Center at Seoul National University Hospital for statistical analyses.
This work was not funded by any organizations or companies. The authors declare that they have no competing interests.
This study was approved by the institutional review board of the Seoul National University Hospital (H-1401-033-548). The requirement for informed consent was waived.
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
- Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65:87–108.View ArticlePubMedGoogle Scholar
- Jung KW, Won YJ, Kong HJ, Oh CM, Cho H, Lee DH, et al. Cancer statistics in Korea: incidence, mortality, survival, and prevalence in 2012. Cancer Res Treat. 2015;47:127–41.View ArticlePubMedPubMed CentralGoogle Scholar
- Fang B, Mehran RJ, Heymach JV, Swisher SG. Predictive biomarkers in precision medicine and drug development against lung cancer. Chin J Cancer. 2015;34:295–309.View ArticlePubMedGoogle Scholar
- Wakelee HA, Chang ET, Gomez SL, Keegan TH, Feskanich D, Clarke CA, et al. Lung cancer incidence in never smokers. J Clin Oncol. 2007;25:472–8.View ArticlePubMedPubMed CentralGoogle Scholar
- Yano T, Miura N, Takenaka T, Haro A, Okazaki H, Ohba T, et al. Never-smoking nonsmall cell lung cancer as a separate entity: clinicopathologic features and survival. Cancer. 2008;113:1012–8.View ArticlePubMedGoogle Scholar
- Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin. 2005;55:74–108.View ArticlePubMedGoogle Scholar
- Toh CK, Gao F, Lim WT, Leong SS, Fong KW, Yap SP, et al. Never-smokers with lung cancer: epidemiologic evidence of a distinct disease entity. J Clin Oncol. 2006;24:2245–51.View ArticlePubMedGoogle Scholar
- Sun S, Schiller JH, Gazdar AF. Lung cancer in never smokers—a different disease. Nat Rev Cancer. 2007;7:778–90.View ArticlePubMedGoogle Scholar
- Tam IY, Chung LP, Suen WS, Wang E, Wong MC, Ho KK, 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;12:1647–53.View ArticlePubMedGoogle Scholar
- Shaw AT, Yeap BY, Mino-Kenudson M, Digumarthy SR, Costa DB, Heist RS, et al. Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK. J Clin Oncol. 2009;27:4247–53.View ArticlePubMedPubMed CentralGoogle Scholar
- Fu S, Wang HY, Wang F, Huang MY, Deng L, Zhang X, et al. Clinicopathologic characteristics and therapeutic responses of Chinese patients with non-small cell lung cancer who harbor an anaplastic lymphoma kinase rearrangement. Chin J Cancer. 2015;34:404–12.View ArticlePubMedGoogle Scholar
- Gainor JF, Varghese AM, Ou SH, Kabraji S, Awad MM, Katayama R, et al. ALK rearrangements are mutually exclusive with mutations in EGFR or KRAS: an analysis of 1,683 patients with non-small cell lung cancer. Clin Cancer Res. 2013;19:4273–81.View ArticlePubMedGoogle Scholar
- Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A, et al. AJCC cancer staging manual. 7th ed. New York: Springer; 2010.Google Scholar
- Kim YT, Seong YW, Jung YJ, Jeon YK, Park IK, Kang CH, et al. The presence of mutations in epidermal growth factor receptor gene is not a prognostic factor for long-term outcome after surgical resection of non-small-cell lung cancer. J Thorac Oncol. 2013;8:171–8.View ArticlePubMedGoogle Scholar
- Han HS, Lim SN, An JY, Lee KM, Choe KH, Lee KH, et al. Detection of EGFR mutation status in lung adenocarcinoma specimens with different proportions of tumor cells using two methods of differential sensitivity. J Thorac Oncol. 2012;7:355–64.View ArticlePubMedGoogle Scholar
- Rodig SJ, Mino-Kenudson M, Dacic S, Yeap BY, Shaw A, Barletta JA, et al. Unique clinicopathologic features characterize ALK-rearranged lung adenocarcinoma in the western population. Clin Cancer Res. 2009;15:5216–23.View ArticlePubMedPubMed CentralGoogle Scholar
- Kwak EL, Bang YJ, Camidge DR, Shaw AT, Solomon B, Maki RG, et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med. 2010;363:1693–703.View ArticlePubMedPubMed CentralGoogle Scholar
- Nordquist LT, Simon GR, Cantor A, Alberts WM, Bepler G. Improved survival in never-smokers vs current smokers with primary adenocarcinoma of the lung. Chest. 2004;126:347–51.View ArticlePubMedGoogle Scholar
- Brownson RC, Alavanja MC, Caporaso N, Simoes EJ, Chang JC. Epidemiology and prevention of lung cancer in nonsmokers. Epidemiol Rev. 1998;20:218–36.View ArticlePubMedGoogle Scholar
- Dibble R, Langeburg W, Bair S, Ward J, Akerley W, editors. Natual history of non-small cell lung cancer in non-smokers. In: ASCO Annual Meeting Proceedings; 2005.Google Scholar
- Dearden S, Stevens J, Wu YL, Blowers D. Mutation incidence and coincidence in non small-cell lung cancer: meta-analyses by ethnicity and histology (mutMap). Ann Oncol. 2013;24:2371–6.View ArticlePubMedPubMed CentralGoogle Scholar
- Riely GJ, Kris MG, Rosenbaum D, Marks J, Li A, Chitale DA, et al. Frequency and distinctive spectrum of KRAS mutations in never smokers with lung adenocarcinoma. Clin Cancer Res. 2008;14:5731–4.View ArticlePubMedPubMed CentralGoogle Scholar
- Maus MKH, Grimminger PP, Mack PC, Astrow SH, Stephens C, Zeger G, et al. KRAS mutations in non-small-cell lung cancer and colorectal cancer: implications for EGFR-targeted therapies. Lung Cancer. 2014;83:163–7.View ArticlePubMedGoogle Scholar
- Kim EY, Kim A, Kim SK, Kim HJ, Chang J, Ahn CM, et al. KRAS oncogene substitutions in Korean NSCLC patients: clinical implication and relationship with pAKT and RalGTPases expression. Lung Cancer. 2014;85:299–305.View ArticlePubMedGoogle Scholar