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 neversmokers is apparent in differential responses to epidermal growth factor receptor inhibitors and an increased prevalence of adenocarcinoma histology in never-smokers.

Abstract*Correspondence, page proofs, and reprint requests to: James D. Tucker, Ph.D., Department of Biological Sciences, 1370 Biological Sciences Building, 5047 Gullen Mall, Wayne State University, Detroit, TEL: (313) 577-2783, FAX: (313) 577-3602, EMAIL: E-mail: jtucker@biology.biosci.wayne.edu. z Retired Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Chromosome translocations in peripheral blood lymphocytes of normal, healthy humans increase with age, but the effects of gender, race, and cigarette smoking on background translocation yields have not been examined systematically. Further, the shape of the relationship between age and translocation frequency (TF) has not been definitively determined. We collected existing data from sixteen laboratories in North America, Europe, and Asia on TFs measured in peripheral blood lymphocytes by fluorescence in situ hybridization whole chromosome painting among 1933 individuals. In Poisson regression models, age, ranging from newborns (cord blood) to 85 years, was strongly associated with TF and this relationship showed significant upward curvature at older ages vs. a linear relationship (p <0.001). Ever smokers had significantly higher TFs than non-smokers (rate ratio (RR) = 1.19, 95% confidence interval (CI), 1.09-1.30) and smoking modified the effect of age on TFs with a steeper age-related increase among ever smokers compared to non-smokers (p<0.001). TFs did not differ by gender. Interpreting an independent effect of race was difficult owing to laboratory variation. Our study is three times larger than any pooled effort to date, confirming a suspected curvilinear relationship of TF with age. The significant effect of cigarette smoking has not been observed with previous pooled studies of TF in humans. Our data provide stable estimates of background TF by age, gender, race, and smoking status and suggest an acceleration of chromosome damage above age 60 and among those with a history of smoking cigarettes. NIH Public Access

The relation between the dietary intake of vitamins E, C, and A (estimated by a 24-hour recall) and lung cancer incidence was examined in the First National Health and Nutrition Examination Survey Epidemiologic Followup Study cohort of 3,968 men and 6,100 women, aged 25-74 years. During a median follow-up period of 19 years (from 1971-1975 to 1992), 248 persons developed lung cancer. Adjusted for potential confounders using Cox proportional hazards regression methods with age as the underlying time variable, the relative risk of lung cancer for subjects in the highest quartile of vitamin C intake compared with those in the lowest quartile was 0.66 (95% confidence interval (CI) 0.45-0.96). For vitamin A intake, a protective effect was observed only for its fruit and vegetable component (carotenoids) among current smokers (relative risk = 0.49, 95% CI 0.29-0.84), but this was modified by the intensity of smoking (a statistically significant effect (relative risk = 0.33, 95% CI 0.13-0.84) was observed only for those in the lowest tertile of pack-years of smoking). The vitamin E intake-lung cancer relation was modified by the intensity of smoking with a significant protective effect confined to current smokers in the lowest tertile of pack-years of smoking (relative risk = 0.36, 95% CI 0.16-0.83). Overall, there was no additional protective effect of supplements of vitamins E, C, and A beyond that provided through dietary intake. When vitamin E, vitamin C, and carotenoid intakes were examined in combination, a strong protective effect was observed for those in the highest compared with those in the lowest quartile of all three intakes (relative risk = 0.32, 95% CI 0.14-0.74). These data provide support for a protective role of dietary vitamins E and C and of carotenoids against lung cancer risk but with a modification in effects by the intensity of cigarette exposure. While smoking avoidance is the most important behavior to reduce lung cancer risk, the daily consumption of a variety of fruits and vegetables that provides a combination of these nutrients and other potential protective factors may offer the best dietary protection against lung cancer.

The diet-plasma relationships for carotenoids were examined in a group of 98 nonsmoking premenopausal women who participated in the cross-sectional phase of the National Cancer Institute (NCI)-US Department of Agriculture (USDA) diet study on alcohol-hormone metabolism, 1988-90. With use of the newly developed USDA-NCI carotenoid food-composition database, the mean daily intakes of carotenoids were significantly higher when estimated from the food-frequency questionnaire (FFQ) than from the 7-d diet records. Lycopene (mean = 0.58 mmol/L), lutein plus zeaxanthin (mean = 0.46 mmol/L), and beta-carotene (mean = 0.34 mmol/L) were the major plasma carotenoids. After adjustment for body mass index, energy and alcohol intakes, and total plasma cholesterol concentration, the following significant correlation (P < 0.05) were observed between the diet record and the FFQ-estimated carotenoid intakes and their respective plasma concentrations: alpha-carotene (r = 0.58 vs 0.49), beta-carotene (r = 0.51 vs 0.49), beta-cryptoxanthin (r = 0.49 vs 0.36), lutein plus zeaxanthin (r = 0.31 vs 0.37), lycopene (r = 0.50 vs 0.26), and total carotenoids (r = 0.57 vs 0.49). These data indicate that plasma carotenoid concentrations are reflective of dietary intake, but the magnitude of the correlation varies depending on the specific carotenoid and on the dietary assessment tool.