Lung cancer incidence in never-smokers

doi:10.1200/JCO.2006.07.2983

J Clin Oncol. Author manuscript; available in PMC 2009 October 20.

Published in final edited form as:

J Clin Oncol. 2007 February 10; 25(5): 472–478.

doi: 10.1200/JCO.2006.07.2983

PMCID: PMC2764546

NIHMSID: NIHMS150119

Lung cancer incidence in never-smokers

Heather A. Wakelee,¹ Ellen T. Chang,² Scarlett L. Gomez,² Theresa H. M. Keegan,² Diane Feskanich,³ Christina A. Clarke,^2,⁴ Lars Holmberg,⁵ Lee C. Yong,⁶ Laurence N. Kolonel,⁷ Michael K. Gould,⁸ and Dee W. West^2,⁴

¹ Stanford University School of Medicine, Stanford, CA, USA

² Northern California Cancer Center, Fremont, CA, USA and Department of Health Research and Policy, Stanford University School of Medicine, Stanford, CA, USA

³ Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA; on behalf of the Nurses’ Health Study Investigators and Health Professionals Follow-Up Study Investigators

⁴ On behalf of the California Teachers Study Investigators

⁵ Regional Oncologic Center, Uppsala University Hospital, Uppsala, Sweden; on behalf of the Uppsala/Örebro Regional Lung Cancer Register

⁶ Division of Surveillance, Hazard Evaluations and Field Studies, National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention, Cincinnati, OH, USA

⁷ Cancer Epidemiology Program, Cancer Research Center of Hawaii, University of Hawaii, Honolulu, HI, USA; on behalf of the Multiethnic Cohort Study

⁸ Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA and Stanford University School of Medicine, Stanford, CA, USA

Correspondence to: Heather Wakelee, MD, Assistant Professor of Medicine, Division of Medical Oncology, Stanford Clinical Cancer Center, 875 Blake Wilbur Drive, Stanford, CA 94305-5826, 650 736-7221, Fax 650 724-3697, Email: hwakelee/at/stanford.edu

The publisher's final edited version of this article is available at J Clin Oncol

See other articles in PMC that cite the published article.

Abstract

Purpose

Lung cancer is a leading cause of cancer death worldwide. While smoking remains the predominant cause of lung cancer, lung cancer in never-smokers is an increasingly prominent public health issue. Data on this topic, particularly lung cancer incidence rates in never-smokers, however, are limited.

Methods

We review the existing literature on lung cancer incidence and mortality rates among never-smokers and present new data regarding rates in never-smokers from large, population-based cohorts: 1) Nurses’ Health Study, 2) Health Professionals Follow-up Study, 3) California Teachers Study, 4) Multiethnic Cohort Study, 5) Swedish Lung Cancer Register in the Uppsala/Örebro region, and the 6) First National Health and Nutrition Examination Survey Epidemiologic Follow-up Study.

Results

Truncated age-adjusted incidence rates of lung cancer among never-smokers aged 40 to 79 years in these six cohorts ranged from 14.4 to 20.8 per 100,000 person-years in women and 4.8 to 13.7 per 100,000 person-years in men, supporting earlier observations that women are more likely than men to have non-smoking-associated lung cancer. The distinct biology of lung cancer in never-smokers is apparent in differential responses to epidermal growth factor receptor inhibitors and an increased prevalence of adenocarcinoma histology in never-smokers.

Conclusion

Lung cancer in never-smokers is an important public health issue needing further exploration of its incidence patterns, etiology, and biology.

Introduction

In the United States, lung cancer incidence and mortality rates have been steadily declining over the past decade, following the well-documented decline in the prevalence of tobacco smoking.¹^–³ However, in the US, lung cancer remains the leading cause of cancer death, killing more patients than breast, colon, and prostate cancers combined.⁴ While tobacco smoke is the predominant risk factor for development of lung cancer, there is a distinct group of patients who develop the disease without a history of tobacco smoking. Clinical observations suggest that the percentage of never-smokers among lung cancer patients may be increasing; however, it is unclear whether this apparent trend represents an increase in lung cancer incidence among never-smokers or the increasing prevalence of never-smokers in the general population. The growing number of never-smokers in the US and other countries underscores the importance of understanding the epidemiology and biology underlying lung cancer in this population.

Are lung cancer rates among never-smokers on the rise? While we can take only the first step towards answering this question, in this article we review the current knowledge regarding the incidence patterns and biology of non-smoking-associated lung cancer, and suggest future research directions to improve understanding of this disease in the growing at-risk population. To this end, we summarize the existing literature on lung cancer incidence rates among never-smokers and present new data on rates from selected large, population-based cohorts. Finally, we present evidence suggesting biologic and genetic differences between smoking-related and non-smoking-related lung cancers, and posit important new research questions.

In the US, the most widely used resource for documenting cancer trends in population groups is the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) cancer registries.⁵ However, SEER and most other cancer registries do not collect information on patient smoking history, which precludes the examination of cancer incidence patterns by smoking status. Furthermore, information on the prevalence of current and former smokers within subgroups of age, sex, and race/ethnicity in the general population, data necessary for detailed incidence calculations, are difficult to obtain for many populations. SEER data have been linked with population-based tobacco use information,⁶ but this approach only allows for ecologic correlations between the population-level prevalence of smoking and incidence of lung cancer in broad demographic subgroups; individual patient-level data on smoking status are still needed for more specific inference on patterns of smoking-related cancer.⁷

Previous studies reporting incidence rates of lung cancer in never-smokers cannot easily be compared because of dissimilar population standards for age-adjustment of incidence rates. We present updated and previously unpublished incidence data, age-adjusted to a common population, for lung cancer in never-smokers from six cohorts. We also provide distributions of lung cancer histology and age at diagnosis to illustrate differences in the characteristics of lung cancer according to smoking status. It is important to emphasize that while these data add to the sparse body of knowledge on incidence rates of lung cancer in never-smokers, they cannot contribute to an understanding of whether rates have changed over time, primarily because cohort recruitment in all of these studies took place over a circumscribed period of time.

Methods

Using data from six large cohort populations (Table 1), truncated (that is, limited to ages 40 to 79 years, rather than all ages),⁸ age-adjusted incidence rates were calculated based on the 2000 US standard population, with the proportions of 5-year age groups between 40 and 79 years recalculated to summate to 1.0. The age-adjusted incidence rates, with exact Poisson 95% confidence intervals (CIs),⁹ were limited to adults aged 40 to 79 years to facilitate comparison among the cohorts. We also examined the percentage, with exact binomial 95% (CIs),⁹ of lung cancer cases aged 40 to 79 years at diagnosis with adenocarcinoma histology, and the median age at diagnosis among current, former, and never-smokers in each cohort (Table 2). Histology was ascertained through medical records or linkage to cancer registries for all cohorts for which such information was available, as detailed in Table 1.

Table 1

Characteristics of the NHS, HPFS, CTS, MEC, U/OLCR, and NHEFS cohort members included in this analysis

Table 2

Lung cancer age-adjusted incidence rate (AAIR) per 100,000 person-years among adults aged 40–79 years; and number of lung cancer cases aged 40 to 79 years at diagnosis, proportion of cases with adenocarcinoma histology, and median age at diagnosis (more ...)

Details about the methodology of the Nurses’ Health Study (NHS),¹⁰^,¹¹ Health Professionals Follow-up Study (HPFS),¹⁰^,¹² California Teachers Study (CTS),¹³ Multiethnic Cohort (MEC) Study,¹⁴^,¹⁵ Swedish Uppsala/Örebro Lung Cancer Register (U/OLCR),¹⁶ and the First National Health and Nutrition Examination Survey Epidemiologic Follow-up Study (NHEFS)¹⁷ have been previously reported, and are summarized in Table 1. These 6 cohorts were selected because they were prospective, provided pre-diagnosis data on smoking status, followed cohort members for validated diagnoses of incident cases of lung cancer, enrolled adults aged 40–79 years and provided diversity both geographically and demographically.

Results

Table 2 shows the age-adjusted incidence rates of lung cancer in never, former and current smokers in all 6 cohorts. These rates per 100,000 person-years for never-smokers aged 40 to 79 were 15.2 (female) in the NHS, 11.2 (male) in the HPFS, 20.8 (female) in the CTS, 13.7 (male) and 20.7 (female) in the MEC, 4.8 (male) and 14.4 (female) in the U/OLCR, and 12.7 (male) and 19.3 (female) in the NHEFS. By comparison, age-adjusted rates in current smokers are roughly 12 to 30 times higher. Overall rates were comparable between the population-based cohorts, including the MEC and NHEFS, and the cohorts of highly selected populations, including the NHS, HPFS, and CTS, although rates in the U/OLCR were consistently lower than in the US cohorts. In 2002, the age-adjusted (standardized to the 2000 US standard population) incidence rates of lung cancer in all males and females in Sweden overall were 29.9 and 20.0 per 100,000 person-years, respectively,¹⁸ whereas those among white males and females in the entire US were 72.5 and 49.9 per 100,000 person-years, respectively.¹⁹

As expected, lung cancer age-adjusted incidence rates in all 6 cohorts were significantly lower in never-smokers than former or current smokers. Adenocarcinoma was more common in never-smokers than in former or current smokers in all cohorts for which information about histology was available, although the small number of never-smoking cases resulted in wide confidence intervals (Table 2). While never-smokers were slightly older at lung cancer diagnosis than current smokers in two population-based cohorts (MEC and NHEFS), this difference was not observed in the majority of cohorts evaluated (NHS, HPFS, CTS, U/OLCR) (Table 2).

Among never-smoking females, the incidence rates in the CTS and MEC were slightly, albeit non-significantly, higher than the rate in the NHS, which was established nearly two decades earlier than the other two cohorts. Likewise, the incidence rate of non-smoking-associated lung cancer was slightly but non-significantly higher among males in the MEC than males in the earlier-established HPFS, although the discrepancy could also be due to racial/ethnic differences in risk of lung cancer in never-smokers. Though a higher relative risk of lung cancer associated with smoking has been demonstrated in racial/ethnic groups that are more prevalent in the MEC than in the HPFS,¹⁵ data on rates of non-smoking-associated lung cancer by racial/ethnic group are limited.

Evaluating comparable groups of males and females, rates of non-smoking-associated lung cancer were consistently higher among females in the NHS, MEC, U/OLCR, and NHEFS, compared to males in the HPFS, MEC, U/OLCR, and NHEFS, respectively. The higher rate among females suggests sex-based differences in either susceptibility or exposure to risk factors (such as secondhand smoke) for non-smoking-associated lung cancer.

Discussion

Our analysis of recent cohort data finds truncated age-adjusted incidence rates of lung cancer in never-smokers ranging from 4.8 to 20.8 per 100,000 in 40- to 79-year old men and women. Because the effects of time cannot be separated from those of aging in these cohorts, we cannot assess secular trends in the incidence rate of non-smoking-associated lung cancer in these cohorts, nor can we compare these rates to historical data to evaluate incidence changes over time. Establishing the current incidence rates, as we have done, however, is an important step in better understanding this distinct disease subset. To put the problem of lung cancer in never-smokers in perspective, the rates we report are similar to age-adjusted rates for myeloma (13.2 per 100,000) in men, or cervical (15.4 per 100,000) or thyroid cancer (17.3 per100,000) in women aged 40–79 years old, diagnosed in the US between 1998 and 2002.¹⁹

Better understanding of the incidence rate and etiology of lung cancer in never-smokers is important because of the implications for therapeutic trials and epidemiologic studies of lung cancer. Differences in lung cancer biology between never-smokers and smokers are illustrated by findings from several studies. One of the most striking distinctions is the observed differential response to drugs that target the epidermal growth factor receptor (EGFR). Compared to current or former smokers diagnosed with lung cancer, never-smoking patients treated with these agents have higher response rates to treatment and better survival.²⁰^,²¹ In a randomized phase III trial with the EGFR kinase inhibitor gefitinib in refractory, advanced lung cancer patients, never-smokers treated with gefitinib, compared to placebo, had a reduced risk of death from lung cancer (relative risk for survival analysis [hazard ratio (HR)]=0.67, p=0.012), whereas the HR of lung cancer death in ever-smokers did not differ between the gefitinib and placebo arms (HR=0.92, p=0.242).²⁰ In the registration trial (BR.21) for the EGFR kinase inhibitor erlotinib, the overall response rate to erlotinib was 24.7% for never-smokers and 3.9% (p <.001) for former/current smokers.²¹ Of all the variables tested, only a history of never smoking was a significant independent predictor of improved survival with erlotinib therapy.²¹

The biology underlying the differential response to treatment with EGFR inhibitors is an area of active investigation, and helps to illustrate why lung cancer in never-smokers may behave differently. Mutations in the EGFR are seen more often in tumors from never-smokers.²²^–²⁵ Differences in EGFR expression may also contribute to differences in treatment response,²² with a distinct EGFR pathway immunohistochemical profile seen in never versus current smokers.²⁶ Other analyses have also demonstrated distinct mutational or expression patterns in KRAS, p53 and nitrotyrosine (a marker of nitric oxide protein damage) in tumors of never-smokers compared to smokers.²⁵^,²⁷

A majority of reports show a modest survival benefit for non-small cell lung cancer (NSCLC) patients who are never-smokers, compared to smokers, regardless of therapy. This was seen for never-smokers in the BR.21 trial with erlotinib (HR=0.8, p=0.048 compared to ever-smokers regardless of therapy),²¹ and in a review of 12,000 Southern California NSCLC patients (comparing ever- to never-smokers, HR=1.09, p=0.045).²⁸ Additionally, a single-institution review of 650 patients with NSCLC found the 5-year overall survival to be 16% for current smokers versus 23% for never-smokers, p=0.004.²⁹ Another review of 311 patients with early-stage lung cancer found that the relative risk of death was 0.45 (p=0.042) comparing never- to current smokers.³⁰ Finally, among 61 patients with screen-detected lung cancer in Japan, the mean tumor volume doubling time was twice as long in 31 never-smokers (607 ± 392 days) as it was in 30 current smokers (292 ± 297 days, P=0.001).³¹ The implications of these results for epidemiologic studies are clear: improvements in lung cancer survival over time might be due to an increasing proportion of never-smokers among lung cancer patients rather than improved therapies.

Other evidence for a biologic difference in lung cancer between smokers and never-smokers comes from differences in histology. Adenocarcinomas appear to be more common in never-smokers, light smokers, or former smokers, whereas squamous cell or other histologic types are more common in heavy smokers and current smokers.³²^,³³^,²⁶ Furthermore, the prevalence of adenocarcinoma among lung cancer cases increases with years since quitting smoking.³⁴ Likewise, our data show a higher proportion of adenocarcinoma among never-smokers than among former or current smokers (Table 2).

As our data show, lung cancer rates in never-smokers are comparable to the incidence rates of cervical cancer or myeloma in the US, yet the etiology of this disease is not known. Identifying risk factors for lung cancer among never-smokers has been an area of active inquiry. Secondhand smoke has been established as a major risk factor among never-smokers.³⁵^–³⁷ Occupational exposures such as asbestos, chromium, arsenic and others also play a role, though more so in smokers.³⁸^–⁴⁰ Domestic radon exposure may also contribute to the risk of lung cancer in never-smokers,⁴¹^,⁴² though some controversy remains,⁴³ and arsenic in drinking water has also been implicated.⁴⁴^,⁴⁵ Other factors including indoor pollutants (cooking oil vapors, coal burning),⁴⁶ previous lung disease,⁴⁷^–⁴⁹ dietary factors,⁵⁰^,⁵¹ family history,³⁶^,⁵²^,⁵³ and genetic factors may also affect lung cancer development.⁵⁴^–⁵⁶^,⁵⁷^,⁵⁸^,⁵⁹

Overall lung cancer incidence rates in the U/OLCR were consistently lower than in the US cohorts. Although the lower prevalence of smoking in Sweden than in the US likely contributes to the lower overall incidence rate of lung cancer in Sweden,¹⁸^,¹⁹ perhaps in part due to lower exposure to secondhand smoke among never-smokers, it does not entirely explain our finding of lower rates of lung cancer among never-smokers only or among smokers only. Instead the discrepancies between the countries even within strata of smoking status suggest differences in smoking patterns among smokers, and in the prevalence of environmental or genetic co-factors for lung cancer among both smokers and never-smokers. The cumulative risk of lung cancer among Swedish male smokers is also considerably lower than that among men from other European countries.⁶⁰

The biologic differences in lung cancer in never-smokers versus ever-smokers are apparent primarily in differential response to specific therapies (most notably EGFR inhibitors), and in distribution of histology (increased adenocarcinoma in never-smokers), as supported by our data. Our data also support the observation that women are more likely than men to have non-smoking-associated lung cancer, in contrast to the finding that men had a higher mortality rate from non-smoking-associated lung cancer than women in the American Cancer Society Cancer Prevention Study cohorts.⁶¹ This discrepancy could be due in part to better survival among women than men with non-smoking-associated lung cancer, although data on this subject are lacking. The literature does support a survival benefit for women versus men with lung cancer overall.⁶² Clearly, more research is needed regarding the intriguing etiology, prognosis, treatment, and outcomes of non-smoking-associated lung cancer.

Future directions

Despite the emergence of clinical and epidemiological studies focused on identifying biological and genetic differences between smoking- and non-smoking-associated lung cancers, and risk factors for non-smoking-associated lung cancer, it remains uncertain whether the incidence of lung cancer in never-smokers is increasing.

Evaluation of secular trends is possible in longitudinal studies with open enrollment over a long span of time, such that incidence changes due to aging are distinguishable from secular changes. To our knowledge, there have been only two published examples of data of this type. The first is a linkage of the nationwide Swedish construction workers’ health care program to the national cancer registry, which documented an increase in the age-adjusted (standardized to the 2000 World Standard Population) incidence rate of non-smoking-related lung cancer between 1976–80 (1.5 per 100,000) and 1991–95 (5.4 per 100,000).⁶³ The second is a comparison of two American Cancer Society Cancer Prevention Study cohorts, in which the age-adjusted (standardized to the combined age distribution of the two cohorts, and therefore not directly comparable to the Swedish construction worker’s study) mortality rate of non-smoking-associated lung cancer in women increased slightly, but statistically significantly, from 12.3 per 100,000 in 1959–1972 to 14.7 per 100,000 in 1982–2000, with most of the increase occurring among women aged 70–84 years.⁶¹ The mortality rate among men, however, did not change over time.

In a comparison of two large, hospital- and community-based case-control studies conducted in the United Kingdom in 1950 and 1990, the percentage of never-smokers among the male lung cancer cases was 0.5% in both studies, whereas the percentage of never-smokers among male controls increased from 4.5% to 19.0%.⁶⁴ Among women, the percentage of never-smoker lung cancer cases was 37.0% in 1950 and 7.6% in 1990, whereas the percentage of never-smoking controls decreased less dramatically, from 54.6% to 50.3%. These results suggest that the proportion of never-smoking cases does not necessarily reflect population-level changes in smoking prevalence.

In the US, a study of 100 NSCLC patients seen at a single institution in the late 1980s determined smoking status through questionnaires and medical record review, and found that 11% of patients were never-smokers.³² In a large case series of 11,969 NSCLC patients from three Southern California counties (1995–2003), investigators estimated that 9.7% of patients were never-smokers.²⁸ A non-significant increase in the prevalence of never-smokers with NSCLC was noted in 1999–2003 versus 1995–1999 in this study.

To examine trends in the incidence of lung cancer among never-smokers, cancer registry data would need to add information on patients’ smoking status, obtained from medical records or patient interviews. Smoker misclassification rates have generally been small when the validity of self-reported smoking status has been investigated,⁶⁵^–⁶⁸ though one study found a false reporting rate of 8% for those claiming to be never-smokers.⁶⁹ Smoking is the critical variable in this proposed research and investigators will need to carefully verify smoking status. In addition to smoking data, the numbers of never-smokers in age-, sex-, and race/ethnicity-specific population groups, needed for denominators to calculate rates, would have to be estimated from large population surveys, because the proportion of never-smokers and rate of lung cancer vary by these characteristics.⁷⁰

If an increase in non-smoking-associated lung cancer incidence is indeed taking place, the next step will be determination of the underlying cause. The role of secondhand smoke has received considerable exploration,⁶⁵ as have other environmental toxins and some genetic polymorphisms. A viral etiology has even been proposed, with some literature supporting a potential role of human papillomavirus in lung cancer development,⁷¹^,⁷² as well as pathological similarities between BAC and the retrovirus-induced ovine pulmonary adenocarcinoma.⁷³ With lung cancer persisting as the leading cause of cancer mortality in the US, research into the epidemiology of lung cancer in never-smokers should be an important public health priority.

Acknowledgments

This research was supported in part by grant R01 CA77398 from the National Cancer Institute and contract 97-10500 from the California Cancer Research Fund.

The authors thank Alison Canchola and Sarah Marshall for their assistance with the California Teachers Study data; Lynne Wilkens (Cancer Epidemiology Program, Cancer Research Center of Hawaii, University of Hawaii) for her assistance with the Multiethnic Cohort Study data; Inna Feldman (Uppsala/Örebro Regional Oncology Center) for her assistance with the Swedish regional questionnaire data; and Lisa Kahle (Information Management Systems, Inc.) and Philip Taylor (Division of Cancer Epidemiology and Genetics, National Cancer Institute) for their assistance with the First National Health and Nutrition Examination Survey Epidemiologic Follow-up Study data.

Footnotes

This article contains original information that has not previously been published or presented.

References

1. Giovino GA, Schooley MW, Zhu BP, et al. Surveillance for selected tobacco-use behaviors--United States, 1900–1994. MMWR CDC Surveill Summ. 1994;43:1–43. [PubMed]

2. Jemal A, Chu KC, Tarone RE. Recent trends in lung cancer mortality in the United States. J Natl Cancer Inst. 2001;93:277–83. [PubMed]

3. Jemal A, Ward E, Thun MJ. Contemporary lung cancer trends among U.S. women. Cancer Epidemiol Biomarkers Prev. 2005;14:582–5. [PubMed]

4. Jemal A, Siegel R, Ward E, et al. Cancer statistics. CA Cancer J Clin. 2006;56:106–30. [PubMed]

5. Glaser SL, Clarke CA, Gomez SL, et al. Cancer surveillance research: a vital subdiscipline of cancer epidemiology. Cancer Causes Control. 2005;16:1009–19. [PubMed]

6. Wingo PA, Ries LA, Giovino GA, et al. Annual report to the nation on the status of cancer, 1973–1996, with a special section on lung cancer and tobacco smoking. J Natl Cancer Inst. 1999;91:675–90. [PubMed]

7. Morgenstern H. Ecologic studies in epidemiology: concepts, principles, and methods. Annu Rev Public Health. 1995;16:61–81. [PubMed]

8. Gondos A, Parkin DM, Chokunonga E, et al. Calculating age-adjusted cancer survival estimates when age-specific data are sparse: an empirical evaluation of various methods. Br J Cancer. 2006;94:450–4. [PMC free article] [PubMed]

9. Daly L. Simple SAS macros for the calculation of exact binomial and Poisson confidence limits. Comput Biol Med. 1992;22:351–61. [PubMed]

10. Bain C, Feskanich D, Speizer FE, et al. Lung cancer rates in men and women with comparable histories of smoking. J Natl Cancer Inst. 2004;96:826–34. [PubMed]

11. Colditz GA, Manson JE, Hankinson SE. The Nurses’ Health Study: 20-year contribution to the understanding of health among women. J Womens Health. 1997;6:49–62. [PubMed]

12. Rimm EB, Stampfer MJ, Colditz GA, et al. Effectiveness of various mailing strategies among nonrespondents in a prospective cohort study. Am J Epidemiol. 1990;131:1068–71. [PubMed]

13. Bernstein L, Allen M, Anton-Culver H, et al. High breast cancer incidence rates among California teachers: results from the California Teachers Study (United States) Cancer Causes Control. 2002;13:625–35. [PubMed]

14. Kolonel LN, Henderson BE, Hankin JH, et al. A multiethnic cohort in Hawaii and Los Angeles: baseline characteristics. Am J Epidemiol. 2000;151:346–57. [PubMed]

15. Haiman CA, Stram DO, Wilkens LR, et al. Ethnic and racial differences in the smoking-related risk of lung cancer. N Engl J Med. 2006;354:333–42. [PubMed]

16. Lamberg K, Wagenius G, Garmo H, et al. Account of materials for 1995–2003. Uppsala: Regional Oncological Center; 2004. Lung cancer in the Uppsala/Orebro region. Register for lung cancer.

17. Yong LC, Brown CC, Schatzkin A, et al. Intake of vitamins E, C, and A and risk of lung cancer. The NHANES I epidemiologic followup study. Am J Epidemiol. 1997;146:231–43. [PubMed]

18. Swedish Cancer Registry. Cancer Incidence in Sweden 2002. Stockholm: National of Health and Welfare, Centre for Epidemiology; 2003.

19. Surveillance, Epidemiology, and End Results (SEER) Program. National Cancer Institute, DCCPS, Surveillance Research Program, Cancer Statistics Branch; 2005. Seer*Stat Database: Incidence - SEER 13 Regs Public-Use, Nov 2004 Sub for Expanded Races (1992–2002) www.seer.cancer.gov. Released April 2005, based on the November 2004 submission.

20. 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;366:1527–37. [PubMed]

21. Shepherd FA, Rodrigues Pereira J, Ciuleanu T, et al. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med. 2005;353:123–32. [PubMed]

22. Tsao MS, Sakurada A, Cutz JC, et al. Erlotinib in lung cancer - molecular and clinical predictors of outcome. N Engl J Med. 2005;353:133–44. [PubMed]

23. Pao W, Miller V, Zakowski M, et al. EGF receptor gene mutations are common in lung cancers from “never smokers” and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci U S A. 2004;101:13306–11. [PubMed]

24. 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;24:1700–4. [PubMed]

25. 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;12:1647–53. [PubMed]

26. Dutu T, Michiels S, Fouret P, et al. Differential expression of biomarkers in lung adenocarcinoma: a comparative study between smokers and never-smokers. Ann Oncol. 2005 [PubMed]

27. 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;65:5076–83. [PubMed]

28. Zell JA, Ou SH, Ziogas A, et al. Epidemiology of bronchioloalveolar carcinoma: improvement in survival after release of the 1999 WHO classification of lung tumors. J Clin Oncol. 2005;23:8396–405. [PubMed]

29. Nordquist LT, Simon GR, Cantor A, et al. Improved survival in never-smokers vs current smokers with primary adenocarcinoma of the lung. Chest. 2004;126:347–51. [PubMed]

30. Sardari Nia P, Weyler J, Colpaert C, et al. Prognostic value of smoking status in operated non-small cell lung cancer. Lung Cancer. 2005;47:351–9. [PubMed]

31. Hasegawa M, Sone S, Takashima S, et al. Growth rate of small lung cancers detected on mass CT screening. Br J Radiol. 2000;73:1252–9. [PubMed]

32. Sridhar KS, Raub WA., Jr Present and past smoking history and other predisposing factors in 100 lung cancer patients. Chest. 1992;101:19–25. [PubMed]

33. Brownson RC, Loy TS, Ingram E, et al. Lung cancer in nonsmoking women. Histology and survival patterns. Cancer. 1995;75:29–33. [PubMed]

34. Muscat JE, Wynder EL. Lung cancer pathology in smokers, ex-smokers and never smokers. Cancer Lett. 1995;88:1–5. [PubMed]

35. Brennan P, Buffler PA, Reynolds P, et al. Secondhand smoke exposure in adulthood and risk of lung cancer among never smokers: a pooled analysis of two large studies. Int J Cancer. 2004;109:125–31. [PubMed]

36. Gorlova OY, Zhang Y, Schabath MB, et al. Never smokers and lung cancer risk: a case-control study of epidemiological factors. Int J Cancer. 2006;118:1798–804. [PubMed]

37. Vineis P, Airoldi L, Veglia P, et al. Environmental tobacco smoke and risk of respiratory cancer and chronic obstructive pulmonary disease in former smokers and never smokers in the EPIC prospective study. Bmj. 2005;330:277. [PMC free article] [PubMed]

38. Alberg AJ, Brock MV, Samet JM. Epidemiology of lung cancer: looking to the future. J Clin Oncol. 2005;23:3175–85. [PubMed]

39. Gottschall EB. Occupational and environmental thoracic malignancies. J Thorac Imaging. 2002;17:189–97. [PubMed]

40. Neuberger JS, Field RW. Occupation and lung cancer in nonsmokers. Rev Environ Health. 2003;18:251–67. [PubMed]

41. Krewski D, Lubin JH, Zielinski JM, et al. A combined analysis of North American case-control studies of residential radon and lung cancer. J Toxicol Environ Health A. 2006;69:533–97. [PubMed]

42. Darby S, Hill D, Auvinen A, et al. Radon in homes and risk of lung cancer: collaborative analysis of individual data from 13 European case-control studies. Bmj. 2005;330:223. [PMC free article] [PubMed]

43. Sandler DP, Weinberg CR, Shore DL, et al. Indoor radon and lung cancer risk in connecticut and utah. J Toxicol Environ Health A. 2006;69:633–54. [PubMed]

44. Chen CL, Hsu LI, Chiou HY, et al. Ingested arsenic, cigarette smoking, and lung cancer risk: a follow-up study in arseniasis-endemic areas in Taiwan. Jama. 2004;292:2984–90. [PubMed]

45. Ferreccio C, Gonzalez C, Milosavjlevic V, et al. Lung cancer and arsenic concentrations in drinking water in Chile. Epidemiology. 2000;11:673–9. [PubMed]

46. Boffetta P, Nyberg F. Contribution of environmental factors to cancer risk. Br Med Bull. 2003;68:71–94. [PubMed]

47. Littman AJ, Thornquist MD, White E, et al. Prior lung disease and risk of lung cancer in a large prospective study. Cancer Causes Control. 2004;15:819–27. [PubMed]

48. Mayne ST, Buenconsejo J, Janerich DT. Previous lung disease and risk of lung cancer among men and women nonsmokers. Am J Epidemiol. 1999;149:13–20. [PubMed]

49. Wu AH, Fontham ET, Reynolds P, et al. Previous lung disease and risk of lung cancer among lifetime nonsmoking women in the United States. Am J Epidemiol. 1995;141:1023–32. [PubMed]

50. Wakai K, Ando M, Ozasa K, et al. Updated information on risk factors for lung cancer: findings from the JACC Study. J Epidemiol. 2005;15 (Suppl 2):S134–9. [PubMed]

51. Feskanich D, Ziegler RG, Michaud DS, et al. Prospective study of fruit and vegetable consumption and risk of lung cancer among men and women. J Natl Cancer Inst. 2000;92:1812–23. [PubMed]

52. Wu AH, Fontham ET, Reynolds P, et al. Family history of cancer and risk of lung cancer among lifetime nonsmoking women in the United States. Am J Epidemiol. 1996;143:535–42. [PubMed]

53. Brownson RC, Alavanja MC, Caporaso N, et al. Family history of cancer and risk of lung cancer in lifetime non-smokers and long-term ex-smokers. Int J Epidemiol. 1997;26:256–63. [PubMed]

54. Raimondi S, Boffetta P, Anttila S, et al. Metabolic gene polymorphisms and lung cancer risk in non-smokers An update of the GSEC study. Mutat Res. 2005 [PubMed]

55. Wenzlaff AS, Cote ML, Bock CH, et al. CYP1A1 and CYP1B1 polymorphisms and risk of lung cancer among never smokers: a population-based study. Carcinogenesis. 2005;26:2207–2212. [PubMed]

56. Taioli E, Gaspari L, Benhamou S, et al. Polymorphisms in CYP1A1, GSTM1, GSTT1 and lung cancer below the age of 45 years. Int J Epidemiol. 2003;32:60–3. [PubMed]

57. Bonner MR, Bennett WP, Xiong W, et al. Radon, secondhand smoke, glutathione-S-transferase M1 and lung cancer among women. Int J Cancer. 2006 [PubMed]

58. Wenzlaff AS, Cote ML, Bock CH, et al. GSTM1, GSTT1 and GSTP1 polymorphisms, environmental tobacco smoke exposure and risk of lung cancer among never smokers: a population-based study. Carcinogenesis. 2005;26:395–401. [PubMed]

59. Jung CY, Choi JE, Park JM, et al. Polymorphisms in the hMSH2 gene and the risk of primary lung cancer. Cancer Epidemiol Biomarkers Prev. 2006;15:762–8. [PubMed]

60. Crispo A, Brennan P, Jockel KH, et al. The cumulative risk of lung cancer among current, ex- and never-smokers in European men. Br J Cancer. 2004;91:1280–6. [PMC free article] [PubMed]

61. Thun MJ, Henley SJ, Burns D, et al. Lung cancer death rates in lifelong nonsmokers. J Natl Cancer Inst. 2006;98:691–9. [PubMed]

62. Donington JS, Le QT, Wakelee HA. Lung cancer in women: exploring sex differences in susceptibility, biology, and therapeutic response. Clin Lung Cancer. 2006;8:22–9. [PubMed]

63. Boffetta P, Jarvholm B, Brennan P, et al. Incidence of lung cancer in a large cohort of non-smoking men from Sweden. Int J Cancer. 2001;94:591–3. [PubMed]

64. Peto R, Darby S, Deo H, et al. Smoking, smoking cessation, and lung cancer in the UK since 1950: combination of national statistics with two case-control studies. BMJ. 2000;321:323–9. [PMC free article] [PubMed]

65. Nyberg F, Agudo A, Boffetta P, et al. A European validation study of smoking and environmental tobacco smoke exposure in nonsmoking lung cancer cases and controls. Cancer Causes Control. 1998;9:173–82. [PubMed]

66. Wells AJ, English PB, Posner SF, et al. Misclassification rates for current smokers misclassified as nonsmokers. Am J Public Health. 1998;88:1503–9. [PubMed]

67. Caraballo RS, Giovino GA, Pechacek TF, et al. Factors associated with discrepancies between self-reports on cigarette smoking and measured serum cotinine levels among persons aged 17 years or older: Third National Health and Nutrition Examination Survey, 1988–1994. Am J Epidemiol. 2001;153:807–14. [PubMed]

68. Klebanoff MA, Levine RJ, Clemens JD, et al. Serum cotinine concentration and self-reported smoking during pregnancy. Am J Epidemiol. 1998;148:259–62. [PubMed]

69. Cope GF, Battersby N. Smoking verification and the risk of myocardial infarction. J Epidemiol Community Health. 2004;58:156. author reply 156–7. [PMC free article] [PubMed]

70. UCLA Center for Health Policy Research CDoHS. Public Health Institute: California Health Interview Survey (CHIS) 2005. www.chis.ucla.edu.

71. Ciotti M, Giuliani L, Ambrogi V, et al. Detection and expression of human papillomavirus oncogenes in non-small cell lung cancer. Oncol Rep. 2006;16:183–9. [PubMed]

72. Chen YC, Chen JH, Richard K, et al. Lung adenocarcinoma and human papillomavirus infection. Cancer. 2004;101:1428–36. [PubMed]

73. Mornex JF, Thivolet F, De las Heras M, et al. Pathology of human bronchioloalveolar carcinoma and its relationship to the ovine disease. Curr Top Microbiol Immunol. 2003;275:225–48. [PubMed]

74. Statistics Sweden. Statistical database: Population. 2006. http://www.scb.se. Last updated 2006-04-11.