epiH Search


Epidemiol Health > Volume 37; 2015 > Article
Bae: Modifiable risk factors of lung cancer in “never-smoker” women


Korean women with a history of never smoking and with adenocarcinoma showed an increasing trend in lung cancer occurrence during 2002 to 2012. The two modifiable factors of never-smoker lung cancer in women are hormone and oncogenic virus infection. Based on previous studies, hormone replacement therapy (HRT) and human papillomavirus (HPV) infection might afford protection or be a risk factor, respectively. It is necessary to perform a pooled analysis of cohort studies to evaluate HRT and never-smoker lung cancer in women and a systematic review of case-control studies to determine the association between HPV infection and never-smoker lung cancer.


Lung cancer is a primary site cancer that causes the highest number of cancer deaths in Koreans [1]. Smoking is considered the main cause of lung cancer [2,3]. According to cancer incidence and death statistics provided by the Korean Statistical Information Service (www.kosis.kr) and the Korea Central Cancer Registry (KCCR, www.ncc.re.kr), cancer incidence sex ratio decreased steadily for men in comparison to women from 2002 to 2012; there has been no change in mortality rate (Figure 1). In addition, according to the histological distribution of lung cancer patients provided by the KCCR (Figure 2), the incidence of squamous cell carcinoma, which was found primarily in men in 2002, continuously decreased, whereas the incidence of adenocarcinoma increased continuously, becoming the cancer with the highest incidence in 2012. In women, incidence of adenocarcinoma, which accounted for the highest cancer incidence in 2002, increased continuously and accounted for 81% of the lung cancer occurrences in women in 2012. It was consistently reported that 73.0% of women with lung cancer treated in a regional cancer center was never-smoker, and frequency of adenocarcinoma occurrence was higher in never-smokers [4].
Figures 1 and 2 and other articles indicate that occurrence of adenocarcinoma, which has a relatively favorable prognosis among lung cancers, increased in never-smoker women during the past 10 years. As such, since epidemiological characteristics of patients who had never smoked but who had lung cancer (never-smoker lung cancer; NSLCa) were female gender, Asian race, and adenocarcinoma [5,6], NSLCa is determined to be a new disease [7].


Known risk factors of NSLCa include environmental exposures such as second-hand smoke, radon, asbestos, and cooking fumes; genetic susceptibility; hormones; and oncogenic virus [5,6,8]. Of these, the factors closely related to women can be narrowed down to (1) second-hand smoke exposure, (2) cooking fumes, (3) hormones, and (4) infection by human papillomavirus (HPV).
Since cooking fumes or second-hand smoke exposure in childhood has already occurred, they are not modifiable; hence, the effect of a preventive project is limited. In addition, based on genomic analysis of NSLCa, Krishnan et al. [9] claimed that second-hand smoke exposure was unlikely to cause lung cancer in Asians without a smoking history. However, it is clearly necessary to take preventive measures against exposure to second-hand smoke in daily surroundings including the workplace [10]. However, it is not easy to conduct an epidemiological study to determine a cause and effect relationship due to methodological limitations in measuring levels of exposure to second-hand smoke [11,12].
As for female hormones, Siegfried [13] summarized experimental, epidemiological, and clinical evidences that suspected oral contraceptives (OC) and hormone replacement therapy (HRT), and some systematic reviews (SRs) have been performed on these factors. Wu et al. [14] performed SR on results of 9 case-control studies and 5 cohort studies in order to determine the relationship between OC and lung cancer; no significant association was found despite subgroup analysis by two study designs. Three SRs investigated the association between HRT and lung cancer [15-17]. All of them showed statistically significant protective effects of HRT based on meta-analysis of the results of case-control studies. In contrast, meta-analysis results on cohort study data showed no consistency or statistical significance. Thus, it is necessary to conduct an additional cohort study to reveal any relationship between the occurrence of female lung cancer and HRT [18] as well as pooled analysis with already-reported follow-up data of cohort studies.
After the claim by Syrjänen [19] in 1979 that infection by HPV among oncogenic viruses was related with lung cancer occurrence, the prevalence of HPV DNA in lung cancer tissues was studied. SR of the results of such studies [20-23] have reported that about 20% of lung cancer cases were HPV positive, of which the 16 and 18 types were found to be mostly involved. In addition, it has been reported that summary odds ratio by HPV infection was 5.67 times (95% CI, 3.09 to 10.40) more likely based on a SR of case-control studies examining a causal association [24]. As it was found to be associated with lung cancer in never-smoker women [25], HPV vaccination could prevent not only cervical and breast cancer [26], but also lung cancer. However, since it was reported that HPV 16/18 DNA was detected in the blood of lung cancer patients [27], it would be possible to use detection of HPV DNA as a method for early diagnosis of lung cancer in never-smoker women [28].


Of the risk factors for lung cancer in never-smoker women, the grounds of association between HRT history and HPV infection histories, which are modifiable factors, have been reviewed in this study. It is necessary to conduct pooled analysis on cohort studies for HRT history and a SR on case-control studies for HPV infection history. If the findings from these studies show that HRT history is a protective factor against lung cancer incidence and HPV infection history is a risk factor, it would be possible to prepare preventive measures that are more effective.


We thank the Korea Central Cancer Registry for providing information on histological classification of registered lung cancer patients in 2002-2012.





Figure 1.
Trends of sex ratios in incidence and mortality rates of lung cancers in Koreans during 2002 and 2012. Source from Korean Statistical Information Service (www.kosis.kr); Korea Central Cancer Registry (www.ncc.re.kr).
Figure 2.
Trands of the histological proportion (%) of lung cancers in Korean during 2002 and 2012. Source from Korea Central Cancer Registry (www.ncc.re.kr). M, men; W, women; Sq, squamous cell carcinoma; Ad, adenocarcinoma; Sm, small cell carcinoma; Lg, large cell carcinoma.


1. 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: 127-141. PMID: 25761484
crossref pmid pmc pdf
2. Bae JM, Li ZM, Shin MH, Kim DH, Lee MS, Ahn YO. Lung cancer incidence by smoking status in Korean men: 16-years of observations in the Seoul Male Cancer Cohort study. J Korean Med Sci 2013; 28: 636-637. PMID: 23580076
crossref pmid pmc
3. Dela Cruz CS, Tanoue LT, Matthay RA. Lung cancer: epidemiology, etiology, and prevention. Clin Chest Med 2011; 32: 605-644. PMID: 22054876
crossref pmid pmc
4. Kang H, Park CW, Kim W, Song SY, Na KJ, Jeong JU, et al. Never-smoker lung cancer is increasing. J Lung Cancer 2012; 11: 89-93 (Korean).
5. Subramanian J, Govindan R. Lung cancer in ‘never-smokers’: a unique entity. Oncology (Williston Park) 2010; 24: 29-35. PMID: 20187318
6. Alberg AJ, Wallace K, Silvestri GA, Brock MV. Invited commentary: the etiology of lung cancer in men compared with women. Am J Epidemiol 2013; 177: 613-616. PMID: 23425628
crossref pmid pmc
7. Sun S, Schiller JH, Gazdar AF. Lung cancer in never smokers--a different disease. Nat Rev Cancer 2007; 7: 778-790. PMID: 17882278
crossref pmid
8. Planchard D, Besse B. Lung cancer in never-smokers. Eur Respir J 2015; 45: 1214-1217. PMID: 25931484
crossref pmid
9. Krishnan VG, Ebert PJ, Ting JC, Lim E, Wong SS, Teo AS, et al. Whole-genome sequencing of asian lung cancers: second-hand smoke unlikely to be responsible for higher incidence of lung cancer among Asian never-smokers. Cancer Res 2014; 74: 6071-6081. PMID: 25189529
crossref pmid
10. Besaratinia A, Pfeifer GP. Second-hand smoke and human lung cancer. Lancet Oncol 2008; 9: 657-666. PMID: 18598930
crossref pmid pmc
11. Jaakkola MS, Jaakkola JJ. Assessment of exposure to environmental tobacco smoke. Eur Respir J 1997; 10: 2384-2397. PMID: 9387970
crossref pmid
12. Kawaguchi T, Ando M, Kubo A, Takada M, Atagi S, Okishio K, 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: 39-45. PMID: 21059816
crossref pmid
13. Siegfried JM. Smoking out reproductive hormone actions in lung cancer. Mol Cancer Res 2014; 12: 24-31. PMID: 24398390
crossref pmid pmc
14. Wu W, Yin ZH, Guan P, Ren YW, Zhou BS. Association of oral contraceptives use and lung cancer risk among women: an updated meta-analysis based on cohort and case-control studies. Asian Pac J Cancer Prev 2014; 15: 1205-1210. PMID: 24606442
crossref pmid
15. Oh SW, Myung SK, Park JY, Lym YL, Ju W. Hormone therapy and risk of lung cancer: a meta-analysis. J Womens Health (Larchmt) 2010; 19: 279-288. PMID: 20095904
crossref pmid
16. Chen X, Cai L. Meta-analysis of the effects on hormone replacement therapy and oral contraceptives associated with female lung cancer risk. Wei Sheng Yan Jiu 2009; 38: 672-676 (Chinese). PMID: 20047219
17. Yao Y, Gu X, Zhu J, Yuan D, Song Y. Hormone replacement therapy in females can decrease the risk of lung cancer: a meta-analysis. PLoS One 2013; 8: e71236. PMID: 23967172
crossref pmid pmc
18. Bae JM, Kim EH. Hormonal replacement therapy and risk of lung cancer in women: an adaptive meta-analysis of cohort studies. J Prev Med Public Health 2015; doi: http://dx.doi.org/10.3961/jpmph.15.054. PMID: 26639742
crossref pmid pmc pdf
19. Syrjänen KJ. Condylomatous changes in neoplastic bronchial epithelium. Report of a case. Respiration 1979; 38: 299-304. PMID: 538337
crossref pmid
20. Srinivasan M, Taioli E, Ragin CC. Human papillomavirus type 16 and 18 in primary lung cancers--a meta-analysis. Carcinogenesis 2009; 30: 1722-1728. PMID: 19620233
crossref pmid pmc
21. Hasegawa Y, Ando M, Kubo A, Isa S, Yamamoto S, Tsujino K, et al. Human papilloma virus in non-small cell lung cancer in never smokers: a systematic review of the literature. Lung Cancer 2014; 83: 8-13. PMID: 24252423
crossref pmid
22. Klein F, Amin Kotb WF, Petersen I. Incidence of human papilloma virus in lung cancer. Lung Cancer 2009; 65: 13-18. PMID: 19019488
crossref pmid
23. Syrjänen K. Detection of human papillomavirus in lung cancer: systematic review and meta-analysis. Anticancer Res 2012; 32: 3235-3250. PMID: 22843898
24. Zhai K, Ding J, Shi HZ. HPV and lung cancer risk: a meta-analysis. J Clin Virol 2015; 63: 84-90. PMID: 25315992
crossref pmid
25. Bae JM, Kim EH. Human papillomavirus infection and risk of lung cancer in never-smoking women: an adaptive meta-analysis for case-control studies. Epidemiol Health 2015; 37: e2015052.

26. Bae JM. Two hypotheses of dense breasts and viral infection for explaining incidence of breast cancer by age group in Korean women. Epidemiol Health 2014; 36: e2014020. PMID: 25266421
crossref pmid pmc
27. Chiou HL, Wu MF, Liaw YC, Cheng YW, Wong RH, Chen CY, et al. The presence of human papillomavirus type 16/18 DNA in blood circulation may act as a risk marker of lung cancer in Taiwan. Cancer 2003; 97: 1558-1563. PMID: 12627521
crossref pmid
28. Li YJ, Tsai YC, Chen YC, Christiani DC. Human papilloma virus and female lung adenocarcinoma. Semin Oncol 2009; 36: 542-552. PMID: 19995646
crossref pmid


Browse all articles >

Editorial Office
Graduate School of Cancer Science and Policy, National Cancer Center


Developed in M2community

Close layer
prev next