This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Wakelee, H. A. Articles by West, D. W. Search for Related Content PubMed PubMed Citation Articles by Wakelee, H. A. Articles by West, D. W.

Lung Cancer Incidence in Never Smokers

Heather A. Wakelee, Ellen T. Chang, Scarlett L. Gomez, Theresa H. Keegan, Diane Feskanich, Christina A. Clarke, Lars Holmberg, Lee C. Yong, Laurence N. Kolonel, Michael K. Gould, Dee W. West

From the Division of Oncology, Department of Medicine and the Department of Health Research and Policy, Stanford University School of Medicine, Stanford; Northern California Cancer Center, Fremont; Veterans Affairs Palo Alto Health Care System, Palo Alto, CA; Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital; Harvard Medical School, Boston, MA; Division of Surveillance, Hazard Evaluations and Field Studies, National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention, Cincinnati, OH; Cancer Epidemiology Program, Cancer Research Center of Hawaii, University of Hawaii, Honolulu, HI; and Regional Oncologic Center, Uppsala University Hospital, Uppsala, Sweden

Address reprint requests to Heather Wakelee, MD, Division of Medical Oncology, Stanford Clinical Cancer Center, 875 Blake Wilbur Dr, Stanford, CA 94305-5826; e-mail: hwakelee{at}stanford.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
Purpose: Lung cancer is a leading cause of cancer death worldwide. Although smoking remains the predominant cause of lung cancer, lung cancer in never smokers is an increasingly prominent public health issue. However, data on this topic, particularly lung cancer incidence rates in never smokers, are limited.

Methods: We reviewed the existing literature on lung cancer incidence and mortality rates among never smokers and present new data regarding rates in never smokers from the following large, prospective cohorts: Nurses’ Health Study; Health Professionals Follow-Up Study; California Teachers Study; Multiethnic Cohort Study; Swedish Lung Cancer Register in the Uppsala/Örebro region; and First National Health and Nutrition Examination Survey Epidemiologic Follow-Up Study.

Results: Truncated age-adjusted incidence rates of lung cancer among never smokers age 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, and further exploration of its incidence patterns, etiology, and biology is needed.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
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 United States, lung cancer remains the leading cause of cancer death, killing more patients than breast, colon, and prostate cancers combined.⁴ Although 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 United States 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 increasing? Although 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, prospective 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 United States, 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) is difficult to obtain for many populations. SEER data have been linked with population-based tobacco use information,⁶ but this approach allows only 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, although 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

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
Using data from six large cohort populations (Table 1), truncated (ie, limited to age 40 to 79 years, rather than all ages),⁸ age-adjusted incidence rates were calculated based on the 2000 United States 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% CIs,¹⁸ were limited to adults age 40 to 79 years to facilitate comparison among the cohorts. We also examined the percentage, with exact binomial 95% CI,¹⁸ of lung cancer patients age 40 to 79 years at diagnosis with adenocarcinoma histology and the median age at diagnosis of 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.

	RESULTS

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
Table 2 presents the age-adjusted incidence rates of lung cancer in never, former, and current smokers in all six cohorts. These rates per 100,000 person-years for never smokers age 40 to 79 years 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 US population-based cohorts, including MEC and NHEFS, and the cohorts of highly selected populations, including 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,¹⁹ whereas the rates among white males and females in the entire United States were 72.5 and 49.9 per 100,000 person-years, respectively.²⁰

As expected, lung cancer age-adjusted incidence rates in all six 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 patients who never smoked resulted in wide CIs (Table 2). Although 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, and U/OLCR; Table 2).

Among female never smokers, the incidence rates in CTS and MEC were slightly, albeit nonsignificantly, higher than the rate in 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 nonsignificantly higher among males in MEC than males in the earlier established HPFS, although the discrepancy could be a result of racial/ethnic differences in risk of lung cancer in never smokers. Although a higher relative risk of lung cancer associated with smoking has been demonstrated in racial/ethnic groups that are more prevalent in MEC than in HPFS,¹⁴ 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 cohorts compared with males in the HPFS, MEC, U/OLCR, and NHEFS cohorts. 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

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
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 person-years in men and women 40 to 79 years old. 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, and we also cannot compare these rates to historical data to evaluate incidence changes over time. However, establishing the current incidence rates, as we have done, 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 per 100,000) in women age 40 to 79 years old diagnosed in the United States between 1998 and 2002.²⁰

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 with current or former smokers diagnosed with lung cancer, never smoker patients treated with these agents have higher response rates to treatment and better survival.^21,22 In a randomized phase III trial with the EGFR kinase inhibitor gefitinib in refractory, advanced lung cancer patients, never smokers treated with gefitinib compared with placebo had a reduced risk of death from lung cancer (relative risk for survival analysis, hazard ratio [HR] = 0.67, P = .012), whereas the HR of lung cancer death in former/current smokers did not differ between the gefitinib and placebo arms (HR = 0.92, P = .242).²¹ 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.²² Of all the variables tested, only a history of never smoking was a significant independent predictor of improved survival with erlotinib therapy.²²

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.^23-26 Differences in EGFR protein expression may also contribute to differences in treatment response,²³ with a distinct EGFR pathway immunohistochemical profile seen in never versus current smokers.²⁷ Other analyses have also demonstrated distinct mutational or expression patterns in KRAS TP53, p53, and nitrotyrosine (a marker of nitric oxide protein damage) in tumors of never smokers compared with smokers.^26,28

Most reports show a modest survival benefit for non–small-cell lung cancer (NSCLC) patients who are never smokers compared with smokers, regardless of therapy. This was seen for never smokers in the BR.21 trial with erlotinib (HR = 0.8, P = .048 compared with current/former smokers regardless of therapy)²² and in a review of 12,000 Southern California NSCLC patients (comparing current/former with never smokers, HR = 1.09, P = .045).²⁹ Additionally, a single-institution review of 650 patients with NSCLC found the 5-year overall survival rate to be 16% for current smokers versus 23% for never smokers (P = .004).³⁰ Another review of 311 patients with early-stage lung cancer found that the relative risk of death was 0.45 (P = .042) comparing never smokers with current smokers.³¹ 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 = .001).³² The implications of these results for epidemiologic studies are clear; improvements in lung cancer survival over time might be a result of 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 seem to be more common in never smokers, light smokers, and former smokers, whereas squamous cell or other histologic types are more common in heavy smokers and current smokers.^27,33,34 Furthermore, the prevalence of adenocarcinoma among lung cancer patients increases with years since quitting smoking.³⁵ 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 United States, yet the etiology of this disease is not well understood. 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.^36-38 Occupational exposures, such as asbestos, chromium, arsenic, and others, also play a role, although more so in smokers.^39-41 Domestic radon exposure may also contribute to the risk of lung cancer in never smokers,^42,43 although some controversy remains,⁴⁴ and arsenic in drinking water has also been implicated.^45,46 Other factors including indoor pollutants (cooking oil vapors and coal burning),⁴⁷ previous lung disease,^48-50 dietary factors,^51,52 family history,^37,53,54 and genetic factors may also affect lung cancer development.^55-60

Overall, lung cancer incidence rates in the U/OLCR cohort were consistently lower than in the US cohorts. Although the lower prevalence of smoking in Sweden compared with the United States likely contributes to the lower overall incidence rate of lung cancer in Sweden,^19,20 perhaps in part as a result of 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 cofactors 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.⁶¹

The biologic differences in lung cancer in never smokers versus current/former 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, which is 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.⁶² This discrepancy could be, in part, a result of 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.⁶³ Clearly, more research is needed regarding the intriguing etiology, prognosis, treatment, and outcomes of non–smoking-associated lung cancer.

Despite the emergence of clinical and epidemiologic studies focused on identifying biologic 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 caused by 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 to 1980 (1.5 per 100,000) and 1991 to 1995 (5.4 per 100,000).⁶⁴ 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 workers’ study) mortality rate of non–smoking-associated lung cancer in women increased slightly, but statistically significantly, from 12.3 per 100,000 in 1959 to 1972 to 14.7 per 100,000 in 1982 to 2000, with most of the increase occurring among women age 70 to 84 years.⁶² 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 patients was 0.5% in both studies, whereas the percentage of never smokers among male controls increased from 4.5% to 19.0%.⁶⁵ Among women, the percentage of lung cancer patients who never smoked was 37.0% in 1950 and 7.6% in 1990, whereas the percentage of never-smokers among female controls decreased less dramatically from 54.6% to 50.3%. These results suggest that the proportion of lung cancer patients who never smoked does not necessarily reflect population-level changes in smoking prevalence.

In the United States, 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.³³ In a large case series of 11,969 NSCLC patients from three Southern California counties (1995 to 2003), investigators estimated that 9.7% of patients were never smokers.²⁹ In this study, a nonsignificant increase in the prevalence of never smokers with NSCLC was noted in 1999 to 2003 versus 1995 to 1999.

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,^66-69 although one study found a false reporting rate of 8% for those claiming to be never smokers.⁷⁰ 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.⁷¹

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,⁶⁶ 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,^72,73 as well as pathologic similarities between bronchioloalveolar carcinoma and the retrovirus-induced ovine pulmonary adenocarcinoma.⁷⁴ With lung cancer persisting as the leading cause of cancer mortality in the United States, research into the epidemiology of lung cancer in never smokers should be an important public health priority.

	Authors’ Disclosures of Potential Conflicts of Interest

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
The authors indicated no potential conflicts of interest.

	Author Contributions

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
Conception and design: Heather A. Wakelee, Ellen T. Chang, Scarlett L. Gomez, Theresa H.M. Keegan, Christina A. Clarke, Michael K. Gould, Dee W. West

Provision of study materials or patients: Ellen T. Chang, Diane Feskanich, Christina A. Clarke, Lars Holmberg, Lee C. Yong, Laurence N. Kolonel, Dee W. West

Collection and assembly of data: Heather A. Wakelee, Ellen T. Chang, Diane Feskanich, Christina A. Clarke, Lars Holmberg, Lee C. Yong, Laurence N. Kolonel

Data analysis and interpretation: Heather A. Wakelee, Ellen T. Chang, Scarlett L. Gomez, Theresa H.M. Keegan, Diane Feskanich, Christina A. Clarke, Lars Holmberg, Lee C. Yong, Laurence N. Kolonel, Michael K. Gould, Dee W. West

Manuscript writing: Heather A. Wakelee, Ellen T. Chang, Scarlett L. Gomez, Theresa H.M. Keegan

Final approval of manuscript: Heather A. Wakelee, Ellen T. Chang, Scarlett L. Gomez, Theresa H.M. Keegan, Diane Feskanich, Christina A. Clarke, Lars Holmberg, Lee C. Yong, Laurence N. Kolonel, Michael K. Gould, Dee W. West

	ACKNOWLEDGMENTS

 
We thank Alison Canchola, Inna Feldman, Lisa Kahle, Sarah Marshall, Philip Taylor, and Lynne Wilkens for their assistance with data from the various cohorts.

	NOTES

 
Supported in part by Grant No. R01 CA77398 from the National Cancer Institute and Contract No. 97-10500 from the California Cancer Research Fund.

The findings and conclusions in this article are those of the authors and do not necessarily represent the views of the National Institute for Occupational Safety and Health.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 

1. Giovino GA, Schooley MW, Zhu BP, et al: Surveillance for selected tobacco-use behaviors–United States, 1900-1994. MMWR CDC Surveill Summ 43:1-43, 1994[Medline]
2. Jemal A, Chu KC, Tarone RE: Recent trends in lung cancer mortality in the United States. J Natl Cancer Inst 93:277-283, 2001[Abstract/Free Full Text]
3. Jemal A, Ward E, Thun MJ: Contemporary lung cancer trends among U.S. women. Cancer Epidemiol Biomarkers Prev 14:582-585, 2005[Abstract/Free Full Text]
4. Jemal A, Siegel R, Ward E, et al: Cancer statistics, 2006. CA Cancer J Clin 56:106-130, 2006[Abstract/Free Full Text]
5. Glaser SL, Clarke CA, Gomez SL, et al: Cancer surveillance research: A vital subdiscipline of cancer epidemiology. Cancer Causes Control 16:1009-1019, 2005[CrossRef][Medline]
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 91:675-690, 1999[Abstract/Free Full Text]
7. Morgenstern H: Ecologic studies in epidemiology: Concepts, principles, and methods. Annu Rev Public Health 16:61-81, 1995[CrossRef][Medline]
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 94:450-454, 2006[CrossRef][Medline]
9. Bain C, Feskanich D, Speizer FE, et al: Lung cancer rates in men and women with comparable histories of smoking. J Natl Cancer Inst 96:826-834, 2004[Abstract/Free Full Text]
10. Colditz GA, Manson JE, Hankinson SE: The Nurses’ Health Study: 20-year contribution to the understanding of health among women. J Womens Health 6:49-62, 1997[Medline]
11. Rimm EB, Stampfer MJ, Colditz GA, et al: Effectiveness of various mailing strategies among nonrespondents in a prospective cohort study. Am J Epidemiol 131:1068-1071, 1990[Abstract/Free Full Text]
12. 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 13:625-635, 2002[CrossRef][Medline]
13. Kolonel LN, Henderson BE, Hankin JH, et al: A multiethnic cohort in Hawaii and Los Angeles: Baseline characteristics. Am J Epidemiol 151:346-357, 2000[Abstract/Free Full Text]
14. Haiman CA, Stram DO, Wilkens LR, et al: Ethnic and racial differences in the smoking-related risk of lung cancer. N Engl J Med 354:333-342, 2006[Abstract/Free Full Text]
15. Lamberg K, Wagenius G, Garmo H, et al: Lung cancer in the Uppsala/Orebro region: Register for lung cancer: Account of materials for 1995-2003. Uppsala, Sweden, Regional Oncological Center, 2004
16. 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 146:231-243, 1997[Abstract/Free Full Text]
17. Statistics Sweden: Statistical database: Population. http://www.scb.se
18. Daly L: Simple SAS macros for the calculation of exact binomial and Poisson confidence limits. Comput Biol Med 22:351-361, 1992[CrossRef][Medline]
19. Swedish Cancer Registry: Cancer Incidence in Sweden 2002. Stockholm, Sweden, National of Health and Welfare, Centre for Epidemiology, 2003
20. Surveillance, Epidemiology, and End Results (SEER) Program Seer*Stat Database: Incidence - SEER 13 Regs Public-Use, Nov 2004 Sub for Expanded Races (1992-2002). Bethesda, MD, National Cancer Institute, Division of Cancer Control and Population Sciences, Surveillance Research Program, Cancer Statistics Branch, released April 2005, based on the November 2004 submission
21. 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 366:1527-1537, 2005[CrossRef][Medline]
22. Shepherd FA, Rodrigues Pereira J, Ciuleanu T, et al: Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 353:123-132, 2005[Abstract/Free Full Text]
23. Tsao MS, Sakurada A, Cutz JC, et al: Erlotinib in lung cancer: Molecular and clinical predictors of outcome. N Engl J Med 353:133-144, 2005[Abstract/Free Full Text]
24. 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 101:13306-13311, 2004[Abstract/Free Full Text]
25. 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 24:1700-1704, 2006[Abstract/Free Full Text]
26. 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 12:1647-1653, 2006[Abstract/Free Full Text]
27. 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 16:1906-1914, 2005[Abstract/Free Full Text]
28. 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 65:5076-5083, 2005[Abstract/Free Full Text]
29. 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 23:8396-8405, 2005[Abstract/Free Full Text]
30. Nordquist LT, Simon GR, Cantor A, et al: Improved survival in never-smokers vs current smokers with primary adenocarcinoma of the lung. Chest 126:347-351, 2004[CrossRef][Medline]
31. Sardari Nia P, Weyler J, Colpaert C, et al: Prognostic value of smoking status in operated non-small cell lung cancer. Lung Cancer 47:351-359, 2005[CrossRef][Medline]
32. Hasegawa M, Sone S, Takashima S, et al: Growth rate of small lung cancers detected on mass CT screening. Br J Radiol 73:1252-1259, 2000[Abstract]
33. Sridhar KS, Raub WA Jr: Present and past smoking history and other predisposing factors in 100 lung cancer patients. Chest 101:19-25, 1992[Medline]
34. Brownson RC, Loy TS, Ingram E, et al: Lung cancer in nonsmoking women: Histology and survival patterns. Cancer 75:29-33, 1995[CrossRef][Medline]
35. Muscat JE, Wynder EL: Lung cancer pathology in smokers, ex-smokers and never smokers. Cancer Lett 88:1-5, 1995[CrossRef][Medline]
36. 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 109:125-131, 2004[CrossRef][Medline]
37. Gorlova OY, Zhang Y, Schabath MB, et al: Never smokers and lung cancer risk: A case-control study of epidemiological factors. Int J Cancer 118:1798-1804, 2006[CrossRef][Medline]
38. 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 330:277, 2005[Abstract/Free Full Text]
39. Alberg AJ, Brock MV, Samet JM: Epidemiology of lung cancer: Looking to the future. J Clin Oncol 23:3175-3185, 2005[Abstract/Free Full Text]
40. Gottschall EB: Occupational and environmental thoracic malignancies. J Thorac Imaging 17:189-197, 2002[CrossRef][Medline]
41. Neuberger JS, Field RW: Occupation and lung cancer in nonsmokers. Rev Environ Health 18:251-267, 2003[Medline]
42. 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 69:533-597, 2006[CrossRef][Medline]
43. 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 330:223, 2005[Abstract/Free Full Text]
44. Sandler DP, Weinberg CR, Shore DL, et al: Indoor radon and lung cancer risk in Connecticut and Utah. J Toxicol Environ Health A 69:633-654, 2006[CrossRef][Medline]
45. 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 292:2984-2990, 2004[Abstract/Free Full Text]
46. Ferreccio C, Gonzalez C, Milosavjlevic V, et al: Lung cancer and arsenic concentrations in drinking water in Chile. Epidemiology 11:673-679, 2000[CrossRef][Medline]
47. Boffetta P, Nyberg F: Contribution of environmental factors to cancer risk. Br Med Bull 68:71-94, 2003[Abstract/Free Full Text]
48. Littman AJ, Thornquist MD, White E, et al: Prior lung disease and risk of lung cancer in a large prospective study. Cancer Causes Control 15:819-827, 2004[CrossRef][Medline]
49. Mayne ST, Buenconsejo J, Janerich DT: Previous lung disease and risk of lung cancer among men and women nonsmokers. Am J Epidemiol 149:13-20, 1999[Abstract/Free Full Text]
50. 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 141:1023-1032, 1995[Abstract/Free Full Text]
51. Wakai K, Ando M, Ozasa K, et al: Updated information on risk factors for lung cancer: Findings from the JACC Study. J Epidemiol 15:S134-S139, 2005 (suppl 2)[CrossRef][Medline]
52. 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 92:1812-1823, 2000[Abstract/Free Full Text]
53. 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 143:535-542, 1996[Abstract/Free Full Text]
54. 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 26:256-263, 1997[Abstract/Free Full Text]
55. 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 592:45-57, 2005[Medline]
56. 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 26:2207-2212, 2005[Abstract/Free Full Text]
57. 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 32:60-63, 2003[Abstract/Free Full Text]
58. Bonner MR, Bennett WP, Xiong W, et al: Radon, secondhand smoke, glutathione-S-transferase M1 and lung cancer among women. Int J Cancer 119:1462-1467, 2006[CrossRef][Medline]
59. 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 26:395-401, 2005[Abstract/Free Full Text]
60. Jung CY, Choi JE, Park JM, et al: Polymorphisms in the hMSH2 gene and the risk of primary lung cancer. Cancer Epidemiol Biomarkers Prev 15:762-768, 2006[Abstract/Free Full Text]
61. 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 91:1280-1286, 2004[CrossRef][Medline]
62. Thun MJ, Henley SJ, Burns D, et al: Lung cancer death rates in lifelong nonsmokers. J Natl Cancer Inst 98:691-699, 2006[Abstract/Free Full Text]
63. Donington JS, Le QT, Wakelee HA: Lung cancer in women: Exploring sex differences in susceptibility, biology, and therapeutic response. Clin Lung Cancer 8:22-29, 2006[Medline]
64. 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 94:591-593, 2001[CrossRef][Medline]
65. 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 321:323-329, 2000[Abstract/Free Full Text]
66. 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 9:173-182, 1998[CrossRef][Medline]
67. Wells AJ, English PB, Posner SF, et al: Misclassification rates for current smokers misclassified as nonsmokers. Am J Public Health 88:1503-1509, 1998[Abstract/Free Full Text]
68. 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 153:807-814, 2001[Abstract/Free Full Text]
69. Klebanoff MA, Levine RJ, Clemens JD, et al: Serum cotinine concentration and self-reported smoking during pregnancy. Am J Epidemiol 148:259-262, 1998[Abstract/Free Full Text]
70. Cope GF, Battersby N: Smoking verification and the risk of myocardial infarction. J Epidemiol Community Health 58:156, 2004[Free Full Text]
71. University of California, Los Angeles Center for Health Policy Research CDoHS, Public Health Institute: California Health Interview Survey (CHIS). www.chis.ucla.edu
72. Ciotti M, Giuliani L, Ambrogi V, et al: Detection and expression of human papillomavirus oncogenes in non-small cell lung cancer. Oncol Rep 16:183-189, 2006[Medline]
73. Chen YC, Chen JH, Richard K, et al: Lung adenocarcinoma and human papillomavirus infection. Cancer 101:1428-1436, 2004[CrossRef][Medline]
74. 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 275:225-248, 2003[Medline]

This article has been cited by other articles:

				S. Dubey and C. A. Powell Update in Lung Cancer 2007 Am. J. Respir. Crit. Care Med., May 1, 2008; 177(9): 941 - 946. [Full Text] [PDF]

				S. Mahabir, M. R. Spitz, S. L. Barrera, Y. Q. Dong, C. Eastham, and M. R. Forman Dietary Boron and Hormone Replacement Therapy as Risk Factors for Lung Cancer in Women Am. J. Epidemiol., May 1, 2008; 167(9): 1070 - 1080. [Abstract] [Full Text] [PDF]

				C. M. Tammemagi, M. T. Freedman, T. R. Church, M. M. Oken, W. G. Hocking, P. A. Kvale, P. Hu, T. L. Riley, L. R. Ragard, P. C. Prorok, et al. Factors Associated with Human Small Aggressive Non Small Cell Lung Cancer Cancer Epidemiol. Biomarkers Prev., October 1, 2007; 16(10): 2082 - 2089. [Abstract] [Full Text] [PDF]

				A. F. Gazdar and M. J. Thun Lung Cancer, Smoke Exposure, and Sex J. Clin. Oncol., February 10, 2007; 25(5): 469 - 471. [Full Text] [PDF]

This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Wakelee, H. A. Articles by West, D. W. Search for Related Content PubMed PubMed Citation Articles by Wakelee, H. A. Articles by West, D. W.