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1.  Radiation and smoking effects on lung cancer incidence among atomic-bomb survivors 
Radiation research  2010;174(1):10.1667/RR2083.1.
While radiation increases the risk of lung cancer among members of the Life Span Study (LSS) cohort of atomic-bomb survivors, there are still important questions about the nature of its interaction with smoking, the predominant cause of lung cancer. Among 105,404 LSS subjects, 1,803 primary lung cancer incident cases were identified for the period 1958–1999. Individual smoking history information and the latest radiation dose estimates were utilized to investigate the joint effects of radiation and smoking on lung cancer rates using Poisson grouped survival regression methods. Relative to never-smokers lung cancer risks increased with the amount and duration of smoking, and decreased with time since quitting smoking at any level of radiation exposure. Models assuming generalized interactions of smoking and radiation fit markedly better than simple additive or multiplicative interaction models. The joint effect appeared to be super-multiplicative for light/moderate-smokers, with a rapid increase in excess risk with smoking intensity up to about 10 cigarettes per day, but additive or sub-additive for heavy-smokers smoking a pack or more per day, with little indication of any radiation-associated excess risk. The gender-averaged excess relative risk per Gy of lung cancer (at age 70 after radiation exposure at 30) was estimated as 0.59 (95% confidence interval: 0.31–1.00) for non-smokers with a female:male ratio of 3.1. About one-third of the lung cancer cases in this cohort were estimated to be attributable to smoking while about 7% were associated with radiation. The joint effect of smoking and radiation on lung cancer in the LSS is dependent on smoking intensity, and best described by the generalized interaction model rather than a simple additive or multiplicative model.
doi:10.1667/RR2083.1
PMCID: PMC3857029  PMID: 20681801
radiation health effects; lung cancer; dose response; joint effect; smoking
2.  Invited Commentary: The Etiology of Lung Cancer in Men Compared With Women 
American Journal of Epidemiology  2013;177(7):613-616.
Lung cancer is the leading cause of cancer death among women in the United States and other Western nations. The predominant cause of lung cancer in women is active cigarette smoking. Secondhand exposure to tobacco smoke is another important cause. The hypothesis that women are more susceptible than men to smoking-induced lung cancer has not been supported by the preponderance of current data, as noted by De Matteis et al. (Am J Epidemiol. 2013;177(7):601–612) in the accompanying article. However, aspects of lung cancer in men and women continue to indicate potential male-female differences in the etiology of lung cancer, based on several observations: 1) among never smokers, women have higher lung cancer incidence rates than men; 2) there is evidence that estrogen may contribute to lung cancer risk and progression; and 3) there are different clinical characteristics of lung cancer in women compared with men, such as the higher percentage of adenocarcinomas in never smokers, the greater prevalence of epidermal growth factor receptor gene (EGFR) mutations in adenocarcinomas among never smokers, and better prognosis. Considered in total, observations such as these offer enticing clues that, even amid cigarette smoking and other commonalities in the etiology of lung cancer in men and women, distinct differences may remain to be delineated that could potentially be of scientific and clinical relevance.
doi:10.1093/aje/kws444
PMCID: PMC3657534  PMID: 23425628
cigarettes; estrogen; lung cancer; men; secondhand smoke exposure; sex; smoking; women
3.  LUNG CANCER IN NEVER SMOKERS: MOLECULAR PROFILES AND THERAPEUTIC IMPLICATIONS 
The majority of lung cancers are caused by long term exposure to the several classes of carcinogens present in tobacco smoke. While a significant fraction of lung cancers in never smokers may also be attributable to tobacco, many such cancers arise in the absence of detectable tobacco exposure, and may follow a very different cellular and molecular pathway of malignant transformation. Recent studies summarized here suggest that lung cancers arising in never smokers have a distinct natural history, profile of oncogenic mutations, and response to targeted therapy. The majority of molecular analyses of lung cancer have focused on genetic profiling of pathways responsible for metabolism of primary tobacco carcinogens. Limited research has been conducted evaluating familial aggregation and genetic linkage of lung cancer, particularly among never smokers in whom such associations might be expected to be strongest. Data emerging over the past several years demonstrates that lung cancers in never smokers are much more likely to carry activating mutations of the Epidermal Growth Factor Receptor (EGFR), a key oncogenic factor and direct therapeutic target of several newer anti-cancer drugs. EGFR mutant lung cancers may represent a distinct class of lung cancers, enriched in the never smoking population, and less clearly linked to direct tobacco carcinogenesis. These insights followed initial testing and demonstration of efficacy of EGFR-targeted drugs. Focused analysis of molecular carcinogenesis in lung cancers in never smokers is needed, and may provide additional biologic insight with therapeutic implications for lung cancers in both ever smokers and never smokers.
doi:10.1158/1078-0432.CCR-09-0377
PMCID: PMC2950319  PMID: 19755392
4.  Anthropometric Measures and Physical Activity and the Risk of Lung Cancer in Never-Smokers: A Prospective Cohort Study 
PLoS ONE  2013;8(8):e70672.
Worldwide, lung cancer in never-smokers is ranked the seventh most common cause of cancer death; however, the etiology of lung cancer in never-smokers is unclear. We investigated associations for body mass index (BMI) at various ages, waist circumference, hip circumference, and physical activity with lung cancer in 158,415 never-smokers of the NIH-AARP Diet and Health Study. Multivariable hazard ratios (HR) and 95% confidence intervals (CI) were estimated from Cox proportional hazards models. Over 11 years of follow-up, 532 lung cancer cases occurred. The risk estimate for obese (BMI≥30 kg/m2) participants at baseline was 1.21 (95%CI = 0.95–1.53) relative to those with a normal BMI between 18.5≤BMI<25.0. Overweight (25.0≤BMI<30.0) at age 18 (HRoverweight-vs-normal = 1.51;95%CI = 1.01–2.26) and time spent sitting (HR≥3 hrs-vs-<3 hrs = 1.32;95%CI = 1.00–1.73) was each associated with lung cancer after adjustment for baseline BMI, as was waist (HRQ4-vs-Q1 = 1.75;95%CI = 1.09–2.79) and hip circumference (HRQ4-vs-Q1 = 0.62;95%CI = 0.39–0.99), after mutual adjustment for each other and baseline BMI. No associations were observed for vigorous activity or television watching. In summary, using a large prospective cohort study, we found no evidence that BMI at baseline or middle age was associated with decreased lung cancer risk in never smokers. If anything, we observed some evidence for positive associations with a larger BMI or waist circumference.
doi:10.1371/journal.pone.0070672
PMCID: PMC3734257  PMID: 23940620
5.  Morbidity and mortality in relation to smoking among women and men of Chinese ethnicity: The Singapore Chinese Health Study 
Objectives
We examined the association among cigarette smoking, smoking cessation and a broad range of cancer incidence and all cause and cause-specific mortality in a population-based cohort of adults of Chinese ethnicity in Singapore.
Methods
Subjects were 61,320 participants of the Singapore Chinese Health Study (44.5% men, aged 45–74 years, recruitment from 1993–1998) who were free of cancer at the baseline examination. Main outcomes-of-interest included cancer incidence, all cause and cause-specific mortality as of December 31, 2005.
Results
Cigarette smoking was positively associated with overall cancer incidence, including cancers at the following specific sites: head and neck region, upper gastrointestinal tract, hepatobiliary and pancreas cancer, lung, and bladder/renal pelvis cancer. Compared to never smokers, the relative risk (RR) (95% confidence interval [CI]) of cancer incidence (all cancer sites) among current smokers smoking >22 cigarettes/day was 1.9 (1.7–2.1), p-trend<0.0001. Similarly, cigarette smoking was associated with all cause and cause-specific mortality, including deaths due to cancer, ischemic heart disease, other heart diseases, and chronic obstructive pulmonary disease. Compared to never smokers, RR (95%CI) of all cause mortality among current smokers smoking >22 cigarettes/day was 1.8 (1.6–2.0), p-trend<0.0001. Also, relative to current smokers, ex-smokers experienced reduced cancer incidence and total mortality. The population attributable risk of smoking in men for cancer incidence as well as all-cause mortality was 23%, whereas in women it ranged from 4–5%.
Conclusions
Cigarette smoking is an important risk factor for cancer incidence and major causes of mortality in Chinese men and women of Singapore.
doi:10.1016/j.ejca.2007.10.015
PMCID: PMC2259462  PMID: 18006298
Smoking; Smoking cessation; Cancer; Mortality; Population attributable risk; Chinese; Singapore
6.  Progesterone and estrogen receptor expression and activity in human non-small cell lung cancer 
Steroids  2011;76(9):910-920.
Lung cancer is the most common cause of cancer mortality in male and female patients in the US. Although it is clear that tobacco smoking is a major cause of lung cancer, about half of all women with lung cancer worldwide are never-smokers. Despite a declining smoking population, the incidence of non-small cell lung cancer (NSCLC), the predominant form of lung cancer, has reached epidemic proportions particularly in women. Emerging data suggest that factors other than tobacco, namely endogenous and exogenous female sex hormones, have a role in stimulating NSCLC progression. Aromatase, a key enzyme for estrogen biosynthesis, is expressed in NSCLC. Clinical data show that women with high levels of tumor aromatase (and high intratumoral estrogen) have worse survival than those with low aromatase. The present and previous studies also reveal significant expression and activity of estrogen receptors (ERα, ERβ) in both extranuclear and nuclear sites in most NSCLC. We now report further on the expression of progesterone receptor (PR) transcripts and protein in NSCLC. PR transcripts were significantly lower in cancerous as compared to non-malignant tissue. Using immunohistochemistry, expression of PR was observed in the nucleus and/or extranuclear compartments in the majority of human tumor specimens examined. Combinations of estrogen and progestins administered in vitro cooperate in promoting tumor secretion of vascular endothelial growth factor and, consequently, support tumor-associated angiogenesis. Further, dual treatment with estradiol and progestin increased the numbers of putative tumor stem/progenitor cells. Thus, ER- and/or PR-targeted therapies may offer new approaches to manage NSCLC.
doi:10.1016/j.steroids.2011.04.015
PMCID: PMC3129425  PMID: 21600232
Progesterone; Estrogen; Steroid hormone receptor; Non-small cell lung cancer; VEGF; Progenitor cells; Cancer stem cells; Angiogenesis
7.  Cohort Life Tables By Smoking Status Removing Lung Cancer as a Cause of Death 
The purpose of this study was to develop life tables by smoking status removing lung cancer as a cause of death. These life tables are inputs to studies that compare the effectiveness of lung cancer treatments or interventions, and provide a way to quantify time until death from causes other than lung cancer. The study combined actuarial and statistical smoothing methods, as well as data from multiple sources, to develop separate life tables by smoking status, birth cohort, by single year of age, and by sex. For current smokers, separate life tables by smoking quintiles were developed based on the average number of cigarettes smoked per day by birth cohort. The end product is the creation of six non-lung cancer life tables for males and six tables for females: five current smoker quintiles and one for never smokers. Tables for former smokers are linear combinations of the appropriate table based on the current smoker quintile prior to quitting smoking and the never smoker probabilities, plus added covariates for the smoking quit age and time since quitting.
doi:10.1111/j.1539-6924.2011.01662.x
PMCID: PMC3594098  PMID: 22882890
Life Tables; Competing Risks; Lung Cancer and Smoking
8.  Increased Risk of Lung Cancer in Men with Tuberculosis in the Alpha- Tocopherol, Beta-Carotene Cancer Prevention Study 
Background
Lung cancer and tuberculosis cause significant morbidity and mortality worldwide. Tuberculosis may increase lung cancer risk through substantial and prolonged pulmonary inflammation. However, prospective data on tuberculosis and lung cancer risk are limited.
Methods
Our study included 29,133 Finnish male smokers followed prospectively in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (1985–2005). Lung cancers were identified through linkage with the Finish Cancer Registry, and hospital-treated tuberculosis cases were ascertained from the National Hospital Discharge Register. We assessed the association between tuberculosis and lung cancer risk with proportional hazards regression models, adjusting for age and cigarette smoking.
Results
Forty-four lung cancer cases occurred among 273 men with tuberculosis (incidence rate=1,786 per 100,000 person-years). Tuberculosis was associated with a two-fold elevation in lung cancer risk (hazard ratio [HR]=1.97; 95% confidence interval [CI] 1.46–2.65) with significant associations observed for both incident (HR=2.05; 95% CI 1.42–2.96) and prevalent tuberculosis (HR=1.82; 95% CI 1.09–3.02). Lung cancer risk was greatest in the two-year window after tuberculosis diagnosis (HR=5.01; 95% CI 2.96–8.48), but remained elevated at longer latencies (HR=1.53; 95% CI 1.07–2.20). Though tuberculosis was associated with an increased risk of squamous cell carcinoma (HR=3.71), adenocarcinoma (HR=1.71), small cell carcinoma (HR=1.72), and lung cancer of other (HR=1.23) and unknown histologies (HR=1.35), only the association for squamous cell carcinoma was statistically significant.
Conclusions
Tuberculosis is associated with increased lung cancer risk in male smokers.
Impact statement
Our results add to the growing body of evidence implicating chronic inflammation and pulmonary scarring in the etiology of lung cancer.
doi:10.1158/1055-9965.EPI-10-1166
PMCID: PMC3076700  PMID: 21335509
9.  Genome-Wide Association Study of Lung Cancer in Korean Non-Smoking Women 
Journal of Korean Medical Science  2013;28(6):840-847.
Lung cancer in never-smokers ranks as the seventh most common cause of cancer death worldwide, and the incidence of lung cancer in non-smoking Korean women appears to be steadily increasing. To identify the effect of genetic polymorphisms on lung cancer risk in non-smoking Korean women, we conducted a genome-wide association study of Korean female non-smokers with lung cancer. We analyzed 440,794 genotype data of 285 cases and 1,455 controls, and nineteen SNPs were associated with lung cancer development (P < 0.001). For external validation, nineteen SNPs were replicated in another sample set composed of 293 cases and 495 controls, and only rs10187911 on 2p16.3 was significantly associated with lung cancer development (dominant model, OR of TG or GG, 1.58, P = 0.025). We confirmed this SNP again in another replication set composed of 546 cases and 744 controls (recessive model, OR of GG, 1.32, P = 0.027). OR and P value in combined set were 1.37 and < 0.001 in additive model, 1.51 and < 0.001 in dominant model, and 1.54 and < 0.001 in recessive model. The effect of this SNP was found to be consistent only in adenocarcinoma patients (1.36 and < 0.001 in additive model, 1.49 and < 0.001 in dominant model, and 1.54 and < 0.001 in recessive model). Furthermore, after imputation with HapMap data, we found regional significance near rs10187911, and five SNPs showed P value less than that of rs10187911 (rs12478012, rs4377361, rs13005521, rs12475464, and rs7564130). Therefore, we concluded that a region on chromosome 2 is significantly associated with lung cancer risk in Korean non-smoking women.
doi:10.3346/jkms.2013.28.6.840
PMCID: PMC3677999  PMID: 23772147
Lung Neoplasms; Genome-Wide Association Study; Non-Smoking Women
10.  Estrogen Signaling in Lung Cancer: An Opportunity for Novel Therapy 
Cancers  2012;4(4):969-988.
Lung cancer is the leading cause of cancer death in U.S. and represents a major public health burden. Epidemiologic data have suggested that lung cancer in women may possess different biological characteristics compared to men, as evidenced by a higher proportion of never-smokers among women with lung cancer. Emerging data indicate that female hormones such as estrogen and progesterone play a significant role in lung carcinogenesis. It has been reported that estrogen and progesterone receptors are expressed in lung cancer cell lines as well as in patient-derived tumors. Hormone related risk factors such as hormone replacement therapy have been implicated in lung carcinogenesis and several preclinical studies show activity of anti-estrogen therapy in lung cancer. In this review, we summarize the emerging evidence for the role of reproductive hormones in lung cancer and implications for lung cancer therapy.
doi:10.3390/cancers4040969
PMCID: PMC3712734  PMID: 24213497
lung cancer; estrogen; progesterone; aromatase; hormone receptors
11.  Lung Cancer Occurrence in Never-Smokers: An Analysis of 13 Cohorts and 22 Cancer Registry Studies  
PLoS Medicine  2008;5(9):e185.
Background
Better information on lung cancer occurrence in lifelong nonsmokers is needed to understand gender and racial disparities and to examine how factors other than active smoking influence risk in different time periods and geographic regions.
Methods and Findings
We pooled information on lung cancer incidence and/or death rates among self-reported never-smokers from 13 large cohort studies, representing over 630,000 and 1.8 million persons for incidence and mortality, respectively. We also abstracted population-based data for women from 22 cancer registries and ten countries in time periods and geographic regions where few women smoked. Our main findings were: (1) Men had higher death rates from lung cancer than women in all age and racial groups studied; (2) male and female incidence rates were similar when standardized across all ages 40+ y, albeit with some variation by age; (3) African Americans and Asians living in Korea and Japan (but not in the US) had higher death rates from lung cancer than individuals of European descent; (4) no temporal trends were seen when comparing incidence and death rates among US women age 40–69 y during the 1930s to contemporary populations where few women smoke, or in temporal comparisons of never-smokers in two large American Cancer Society cohorts from 1959 to 2004; and (5) lung cancer incidence rates were higher and more variable among women in East Asia than in other geographic areas with low female smoking.
Conclusions
These comprehensive analyses support claims that the death rate from lung cancer among never-smokers is higher in men than in women, and in African Americans and Asians residing in Asia than in individuals of European descent, but contradict assertions that risk is increasing or that women have a higher incidence rate than men. Further research is needed on the high and variable lung cancer rates among women in Pacific Rim countries.
Michael Thun and colleagues pooled and analyzed comprehensive data on lung cancer incidence and death rates among never-smokers to examine what factors other than active smoking affect lung cancer risk.
Editors' Summary
Background.
Every year, more than 1.4 million people die from lung cancer, a leading cause of cancer deaths worldwide. In the US alone, more than 161,000 people will die from lung cancer this year. Like all cancers, lung cancer occurs when cells begin to divide uncontrollably because of changes in their genes. The main trigger for these changes in lung cancer is exposure to the chemicals in cigarette smoke—either directly through smoking cigarettes or indirectly through exposure to secondhand smoke. Eighty-five to 90% of lung cancer deaths are caused by exposure to cigarette smoke and, on average, current smokers are 15 times more likely to die from lung cancer than lifelong nonsmokers (never smokers). Furthermore, a person's cumulative lifetime risk of developing lung cancer is related to how much they smoke, to how many years they are a smoker, and—if they give up smoking—to the age at which they stop smoking.
Why Was This Study Done?
Because lung cancer is so common, even the small fraction of lung cancer that occurs in lifelong nonsmokers represents a large number of people. For example, about 20,000 of this year's US lung cancer deaths will be in never-smokers. However, very little is known about how age, sex, or race affects the incidence (the annual number of new cases of diseases in a population) or death rates from lung cancer among never-smokers. A better understanding of the patterns of lung cancer incidence and death rates among never-smokers could provide useful information about the factors other than cigarette smoke that increase the likelihood of not only never-smokers, but also former smokers and current smokers developing lung cancer. In this study, therefore, the researchers pooled and analyzed a large amount of information about lung cancer incidence and death rates among never smokers to examine what factors other than active smoking affect lung cancer risk.
What Did the Researchers Do and Find?
The researchers analyzed information on lung cancer incidence and/or death rates among nearly 2.5 million self-reported never smokers (men and women) from 13 large studies investigating the health of people in North America, Europe, and Asia. They also analyzed similar information for women taken from cancer registries in ten countries at times when very few women were smokers (for example, the US in the late 1930s). The researchers' detailed statistical analyses reveal, for example, that lung cancer death rates in African Americans and in Asians living in Korea and Japan (but not among Asians living in the US) are higher than those in people of the European continental ancestry group. They also show that men have higher death rates from lung cancer than women irrespective of racial group, but that women aged 40–59 years have a slightly higher incidence of lung cancer than men of a similar age. This difference disappears at older ages. Finally, an analysis of lung cancer incidence and death rates at different times during the past 70 years shows no evidence of an increase in the lung cancer burden among never smokers over time.
What Do These Findings Mean?
Although some of the findings described above have been hinted at in previous, smaller studies, these and other findings provide a much more accurate picture of lung cancer incidence and death rates among never smokers. Most importantly the underlying data used in these analyses are now freely available and should provide an excellent resource for future studies of lung cancer in never smokers.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050185.
The US National Cancer Institute provides detailed information for patients and health professionals about all aspects of lung cancer and information on smoking and cancer (in English and Spanish)
Links to other US-based resources dealing with lung cancer are provided by MedlinePlus (in English and Spanish)
Cancer Research UK provides key facts about the link between lung cancer and smoking and information about all other aspects of lung cancer
doi:10.1371/journal.pmed.0050185
PMCID: PMC2531137  PMID: 18788891
12.  Smoking and Risk of Incident Psoriasis Among Women and Men in the United States: A Combined Analysis 
American Journal of Epidemiology  2012;175(5):402-413.
The authors evaluated the association between smoking and the incidence of psoriasis among 185,836 participants from a cohort of older women (the Nurses’ Health Study, 1996–2008), a cohort of younger women (the Nurses’ Health Study II, 1991–2005), and a cohort of men (Health Professionals’ Follow-up Study, 1986–2006). Information on smoking was collected biennially during follow-up. The authors identified a total of 2,410 participants with incident psoriasis. Compared with never smokers, past smokers had a relative risk of incident psoriasis of 1.39 (95% confidence interval (CI): 1.27, 1.52) and current smokers had a relative risk of 1.94 (95% CI: 1.64, 2.28). For current smokers who smoked 1–14 cigarettes/day, the relative risk was 1.81 (95% CI: 1.38, 2.36); for those who smoked 15–24 cigarettes/day, the relative risk was 2.04 (95% CI: 1.68, 2.47); and for those who smoked 25 or more cigarettes/day, the relative risk was 2.29 (95% CI: 1.74, 3.01). There was a trend toward an increased risk of psoriasis with increasing pack-years or duration of smoking (Ptrend < 0.0001). The risk was highest among smokers who had 65 or more pack-years of smoking (relative risk = 2.72, 95% CI: 2.05, 3.60) and among those with a smoking duration of 30 or more years (relative risk = 1.99, 95% CI: 1.75, 2.25). The authors observed a graded reduction of risk with an increase in time since smoking cessation (Ptrend <0.0001). In this study, smoking was found to be an independent risk factor for psoriasis in both women and men. Psoriasis risk was particularly augmented for heavy smokers and persons with longer durations of smoking.
doi:10.1093/aje/kwr325
PMCID: PMC3329197  PMID: 22247049
cohort studies; psoriasis; smoking
13.  Family history of lung cancer in never smokers with non-small-cell lung cancer and its association with tumors harboring EGFR mutations 
INTRODUCTION
Inherited susceptibility to lung cancer is understudied. Never smokers are an important subgroup of patients enriched for tumors harboring oncogene aberrations in the EGFR and ALK genes. We aimed to better characterize the incidence of family history of lung cancer among never smokers with NSCLC.
METHODS
Clinicopathologic data, tumor genotype, family history of cancer, and specifically family history of lung cancer from 230 consecutive never smokers was retrospectively compiled and analyzed.
RESULTS
In our cohort, the median age was 56 years, 67% were women, 75% were white, 59% had advanced NSCLC and 87% had adenocarcinoma histology. In these tumors, 98/230 (42%) had an EGFR mutation, 17/155 (11%) had KRAS mutations and 27/127 (21%) had an ALK translocation. Family history of any cancer was common (57%) and specific family history of lung cancer was present in 42/230 cases (18%). The percentage of cases with family history of lung cancer was higher in the EGFR mutated versus EGFR wild-type NSCLCs. Out of the cases with a family history of any cancer, 22/53 (41.5%) EGFR mutated, 1/5 (20%) KRAS mutated and 3/19 (15.5%) ALK translocated cohorts had a family history of lung cancer. The ratio of family history of lung cancer to family history of cancer was significantly higher in the EGFR mutated cohort when compared to the ALK translocated plus KRAS mutated cohorts (p=0.039).
CONCLUSIONS
Family history of lung cancer is common in never smokers with NSCLC, and there seems to be a particular link in families in which the proband has an EGFR mutated tumor when compared to ALK translocated or KRAS mutated tumors. Further study of families with EGFR-mutated NSCLC may yield insights into the pathogenesis of this tumor type.
doi:10.1016/j.lungcan.2012.12.002
PMCID: PMC3566317  PMID: 23273562
lung cancer; non-small-cell lung cancer; family history; never smokers; epidermal growth factor receptor; EGFR; anaplastic lymphoma kinase; ALK; KRAS
14.  Dietary B vitamin and methionine intakes and lung cancer risk among female never smokers in China 
Cancer causes & control : CCC  2012;23(12):1965-1975.
Purpose
B vitamins and methionine have been postulated to have potential effects on carcinogenesis; however, findings from previous epidemiologic studies on B vitamins, methionine, and lung cancer risk are inconsistent. We investigated associations of dietary intakes of B vitamins (i.e., riboflavin, niacin, vitamin B6, folate, and vitamin B12) and methionine with lung cancer risk among female never smokers.
Methods
The Shanghai Women’s Health Study, a population-based, prospective cohort study, included 74,941 women. During a median follow-up of 11.2 years, 428 incident lung cancer cases accrued among 71,267 women with no history of smoking or cancer at baseline. Baseline dietary intakes were derived from a validated, interviewer-administered food frequency questionnaire. Cancer incidence and vital status were ascertained through annual linkage to the Shanghai Cancer Registry and Shanghai Vital Statistics Registry databases and through biennial in-person follow-ups with participants. Adjusted hazard ratios (HR) and 95% confidence intervals (CI) were calculated using Cox regression.
Results
Dietary riboflavin intake was inversely associated with lung cancer risk (HR = 0.62; 95% CI = 0.43–0.89; P-trend = 0.03 for the highest quartile compared with the lowest). A higher than median intake of methionine was associated with lower risk of lung cancer (HR = 0.78; 95% CI = 0.60–0.99), however, there was no dose-response relation. Intakes of other B vitamins were not associated with lung cancer risk.
Conclusions
Our study suggests that dietary riboflavin intake may be inversely associated with lung cancer risk among female never smokers, which warrants further investigation.
doi:10.1007/s10552-012-0074-z
PMCID: PMC3518409  PMID: 23065072
B vitamins; methionine; lung cancer; never smokers; women
15.  Reproductive and Hormonal Factors and Lung Cancer Risk in the NIH-AARP Diet and Health Study Cohort 
Background
Lung cancer exhibits unique patterns among women, including high adenocarcinoma rates among non-smokers. Inconsistent findings regarding hormonal factors on risk may reflect incomplete control for confounding, misclassification of exposures, or insufficient attention to variation by histology.
Methods
Among 185,017 women, ages 50–71 years, recruited during 1995–1996 for the NIH-AARP Diet and Health Study, we identified 3,512 incident lung cancers (including 276 in never smokers) in follow-up through December 2006. Multivariable Cox proportional hazards models estimated relative risks (RRs) and 95% confidence intervals (CIs) for self-reported hormonally-related risk factors.
Results
After adjustment for smoking and other confounders, subjects with late menarche were at reduced risk, with the association specific for adenocarcinomas (RR=0.72 for menarche 15+ vs. <11, p for trend<0.01). Subjects with early ages at ovarian cessation (either from natural menopause or bilateral oophorectomy) were at an increased risk for adenocarcinomas and squamous cell tumors, but the associations were strongest for smokers, suggesting either residual confounding or an enhanced effect of menopausally-related factors among subjects with decreased endogenous estrogens. In contrast, we saw no relationships of risk with either parity, age at first birth, or exogenous hormone use.
Conclusions
Elevated levels of hormones may adversely affect lung function early in life, while assisting with cellular and immunologic responses later in life. Additional attention towards the role of hormonal factors may further our understanding of lung carcinogenesis.
Impact
Our findings provide some support for a role of hormonal factors in the etiology of lung cancer, although the mechanisms appear complicated.
doi:10.1158/1055-9965.EPI-10-1325
PMCID: PMC3507989  PMID: 21467241
lung cancer; hormonal factors; menopause; risk; histology
16.  Deaths in Canada from lung cancer due to involuntary smoking. 
Recently published evidence indicates that involuntary smoking causes an increased risk of lung cancer among nonsmokers. Information was compiled on the proportion of people who had never smoked among victims of lung cancer, the risk of lung cancer for nonsmokers married to smokers and the prevalence of such exposure. On the basis of these data we estimate that 50 to 60 of the deaths from lung cancer in Canada in 1985 among people who had never smoked were caused by spousal smoking; about 90% occurred in women. The total number of deaths from lung cancer attributable to exposure to tobacco smoke from spouses and other sources (mainly the workplace) was derived by applying estimated age- and sex-specific rates of death from lung cancer attributable to such exposure to the population of Canadians who have never smoked; about 330 deaths from lung cancer annually are attributable to such exposure.
PMCID: PMC1491963  PMID: 3567810
17.  Impact of smoking on the social gradient in health expectancy in Denmark 
Study objective: Health expectancy is arrived at by dividing life expectancy into average lifetime in different states of health. The purpose of the study was to estimate health expectancy among never smokers and smokers in groups at high, medium, and low educational levels in Denmark.
Design: Life tables for never smokers and smokers with a high, medium, and low educational level were constructed on the basis of Statistics Denmark registers and combined with data from the Danish Health Interview Survey 2000. Health expectancy was calculated by Sullivan's method.
Main results: Life expectancy at age 30 differs on average by 8.5 years between never smokers and heavy smokers. Expected lifetime in self rated good health was 39.4 years for a never smoking man corresponding to 82.0% of the rest of his life. For male lifelong heavy smokers these figures were reduced to 27.3 years and 69.2%. The proportion of expected lifetime in self rated good health was 89.5% and 71.3% among male never smokers and lifelong heavy smokers with a high educational level, respectively; and the proportion among male never smokers and heavy smokers with a low educational level was 73.4% and 63.6%, respectively. Similar results were seen as regards expected lifetime without longstanding illness. For women the social gradient in health expectancy was intensified among smokers.
Conclusions: Within each educational group smoking reduces expected lifetime in a healthy state. The social gradient in health expectancy cannot be explained by a reverse social gradient in smoking prevalence.
doi:10.1136/jech.2003.012955
PMCID: PMC1732832  PMID: 15194724
18.  Lung cancer in never smokers Epidemiology and risk prediction models 
In this chapter we review the epidemiology of lung cancer incidence and mortality among never smokers/ nonsmokers and describe the never smoker lung cancer risk models used by CISNET modelers. Our review focuses on those influences likely to have measurable population impact on never smoker risk, such as secondhand smoke, even though the individual-level impact may be small. Occupational exposures may also contribute importantly to the population attributable risk of lung cancer. We examine the following risk factors in this chapter: age, environmental tobacco smoke, cooking fumes, ionizing radiation including radon gas, inherited genetic susceptibility, selected occupational exposures, preexisting lung disease, and oncogenic viruses. We also compare the prevalence of never smokers between the three CISNET smoking scenarios and present the corresponding lung cancer mortality estimates among never smokers as predicted by a typical CISNET model.
doi:10.1111/j.1539-6924.2012.01768.x
PMCID: PMC3485693  PMID: 22882894
19.  Soy Food Intake and Risk of Lung Cancer: Evidence From the Shanghai Women's Health Study and a Meta-Analysis 
American Journal of Epidemiology  2012;176(10):846-855.
The authors prospectively evaluated the association of soy food intake with lung cancer risk, overall and by tumor aggressiveness, and performed a meta-analysis of published data. Included in the analysis were 71,550 women recruited into the Shanghai Women's Health Study (Shanghai, China) in 1997–2000. Usual soy food intake was assessed at baseline and reassessed during follow-up through in-person interviews. During a mean follow-up period of 9.1 years, 370 incident lung cancer cases were identified; 340 patients were lifetime never smokers. After adjustment for potential confounders, soy food intake was inversely associated with subsequent risk of lung cancer (Ptrend = 0.004); the hazard ratio for the highest quintile of intake compared with the lowest was 0.63 (95% confidence interval: 0.44, 0.90). This inverse association appeared predominately among women with later age at menopause (Pinteraction = 0.01) and for aggressive lung cancer as defined by length of survival (<12 months vs. ≥12 months; Pheterogeneity = 0.057). Meta-analysis of 7 studies conducted among nonsmokers found a summary relative risk of 0.59 (95% confidence interval: 0.49, 0.71) for the highest categories of soy or isoflavone intake versus the lowest. This study suggests that soy food consumption may reduce lung cancer risk in nonsmoking women, particularly for aggressive tumors, and its effect may be modified by endogenous estrogens.
doi:10.1093/aje/kws168
PMCID: PMC3626060  PMID: 23097255
cohort studies; lung neoplasms; meta-analysis; risk; soy foods; women
20.  Longer Telomere Length in Peripheral White Blood Cells Is Associated with Risk of Lung Cancer and the rs2736100 (CLPTM1L-TERT) Polymorphism in a Prospective Cohort Study among Women in China 
PLoS ONE  2013;8(3):e59230.
A recent genome-wide association study of lung cancer among never-smoking females in Asia demonstrated that the rs2736100 polymorphism in the TERT-CLPTM1L locus on chromosome 5p15.33 was strongly and significantly associated with risk of adenocarcinoma of the lung. The telomerase gene TERT is a reverse transcriptase that is critical for telomere replication and stabilization by controlling telomere length. We previously found that longer telomere length measured in peripheral white blood cell DNA was associated with increased risk of lung cancer in a prospective cohort study of smoking males in Finland. To follow up on this finding, we carried out a nested case-control study of 215 female lung cancer cases and 215 female controls, 94% of whom were never-smokers, in the prospective Shanghai Women’s Health Study cohort. There was a dose-response relationship between tertiles of telomere length and risk of lung cancer (odds ratio (OR), 95% confidence interval [CI]: 1.0, 1.4 [0.8–2.5], and 2.2 [1.2–4.0], respectively; P trend = 0.003). Further, the association was unchanged by the length of time from blood collection to case diagnosis. In addition, the rs2736100 G allele, which we previously have shown to be associated with risk of lung cancer in this cohort, was significantly associated with longer telomere length in these same study subjects (P trend = 0.030). Our findings suggest that individuals with longer telomere length in peripheral white blood cells may have an increased risk of lung cancer, but require replication in additional prospective cohorts and populations.
doi:10.1371/journal.pone.0059230
PMCID: PMC3608613  PMID: 23555636
21.  Obesity and Smoking: Comparing Cessation Treatment Seekers with the General Smoking Population 
Obesity (Silver Spring, Md.)  2009;17(6):1301-1305.
Obesity and smoking represent the leading preventable causes of morbidity and mortality in the United States. This study compared the prevalence of obesity among smokers seeking cessation treatment (n = 1428) versus a general population (n = 4081) of never smokers, former smoker, and current smokers. Data from treatment-seeking smokers in the Wisconsin Smokers’ Health Study (WSHS) and individuals who completed the National Health and Nutrition Examination Survey (NHANES) 2005-06 were pooled and obesity rates and other health characteristics were compared. The prevalence of obesity was significantly higher among WSHS treatment-seeking smokers (36.8%) versus NHANES current smokers (29.6%), but the obesity rates of WSHS treatment-seeking smokers did not differ from NHANES former smokers (36.5%) or never smokers (36.5%). Treatment-seeking smokers were more likely to be female and to have higher educational attainment compared to NHANES participants. Analysis of health characteristics revealed treatment-seeking smokers had higher levels of dietary fiber and vitamin C and lower blood levels of total cholesterol, triglycerides, and fasting glucose compared to NHANES current smokers. Results suggest that treatment-seeking smokers may have a different health profile than current smokers in the general population. Health care providers should be aware of underlying heath issues, particularly obesity, in patients seeking smoking cessation treatment.
doi:10.1038/oby.2009.36
PMCID: PMC2918403  PMID: 19247276
22.  Smoking and Smoking Cessation in Relation to Mortality 
Context
Smoking causes death in many ways, but the rate of risk reduction after quitting, compared to continuing to smoke, is uncertain. There is inadequate or insufficient evidence to infer the presence or absence of a causal relationship between smoking and ovarian cancer and colorectal cancer.
Objective
To assess the relation between cigarette smoking and smoking cessation on total and cause-specific mortality in women.
Design, Setting, and Participants
Prospective observational study of 104,519 female participants in the Nurses’ Health Study followed from 1980 to 2004.
Main Outcome Measure
Hazard ratios for total mortality, further categorized into vascular and respiratory diseases, cancers and other causes.
Results
A total of 12483 deaths occurred in this cohort, 4485 (35.9%) among never smokers, 3602 (28.9%) among current smokers, and 4396 (35.2%) among past smokers. Compared to never smokers, current smokers had an increased risk of total mortality (hazard ratio = 2.81, 95% confidence interval (CI) = 2.68–2.95) and all major cause-specific mortality evaluated. The hazard ratio for cancers classified by the 2004 Surgeon General’s report to be smoking-related was 7.25 (CI:6.43–8.18) and for other cancers, 1.58 (CI:1.45–1.73). The hazard ratio for colorectal cancer was 1.63 (CI:1.29–2.05) for current smokers and 1.23 (CI:1.02–1.49) for former smokers, compared to never smokers. A significant association was not observed for ovarian cancer. Significant trends were observed for earlier age at initiation for total mortality (P=0.003), respiratory disease mortality (P=0.001), and all smoking-caused cancer mortality (P=0.001). The excess risk for all-cause mortality decreases to the level of a never smoker 20 years after quitting, with different timeframes for risk reduction observed across outcomes. Approximately 64% of deaths among current smokers and 28% of deaths among former smokers were attributable to cigarette smoking.
Conclusions
Most of the excess risk of vascular mortality due to smoking can be eliminated rapidly upon cessation and within 20 years for lung diseases. Postponing the age of smoking initiation has a dramatic impact on risk of respiratory disease, lung cancer, and other smoking-caused cancer deaths and little effect on other cause-specific mortality. These data suggest that smoking increases the risk of colorectal cancer mortality but not ovarian cancer mortality.
doi:10.1001/jama.299.17.2037
PMCID: PMC2879642  PMID: 18460664
23.  Retrospective cohort study of smoking and lung cancer incidence in rural prefecture, Japan 
Objectives
We conducted an epidemiological study of the relationship between lung cancer incidence and smoking, with special reference to the benefits of smoking cessation for reducing lung cancer incidence, to promote a local smoking control program.
Methods
The study was a retrospective cohort study. The population studied was 16,383 male examinees of lung cancer health examinations in 1995 in Tottori Prefecture, Japan. Smoking status from the questionnaire during the health examination was used as the exposure variable. Endpoint (lung cancer incidence) was obtained from the Tottori population-based cancer registry. A multivariable analysis using the Cox proportional hazard model was adapted for statistical analysis. The average follow-up period was 4.3 years.
Results
The hazard ratio of current smokers for the incidence of lung cancer was 4.9, whereas that of ex-smokers was 2.2. The dose-response relationship between lung cancer incidence and lifetime cigarette consumption (pack year) was determined. The ratio increased among younger subjects (under 65 years old). The hazard ratio of ex-smokers decreased with years just after quitting smoking, and reached the level of never smokers after 10–19 years from smoking cessation.
Conclusions
We reconfirmed that the magnitude of risk estimates of smoking for lung cancer incidence was similar to those of previous studies, and smoking cessation was effective for reducing lung cancer risk.
doi:10.1007/BF02897988
PMCID: PMC2723299  PMID: 21432062
cigarette smoking; lung cancer; cohort study; smoking cessation; Japan
24.  Survival following non-small cell lung cancer among Asian/Pacific Islander, Latina, and non-Hispanic White women who have never smoked 
BACKGROUND
Lung cancer is the leading cause of cancer death among US Asian/Pacific Islander (API) and Latina women, despite low smoking prevalence. This study examined survival patterns following non-small cell lung cancer in a population-based sample of lung cancer cases from the San Francisco Bay Area Lung Cancer Study (SFBALCS).
METHODS
Women diagnosed with lung cancer from 1998–2003 and 2005–2008 and identified through the Greater Bay Area Cancer Registry were telephone-screened for eligibility for the SFBALCS. The screener data were linked to the cancer registry data to determine follow-up. This analysis included 187 non-Hispanic White, 23 US-born Latina, 32 foreign-born Latina, 30 US-born API, and 190 foreign-born API never smokers diagnosed with lung cancer and followed through 2008.
RESULTS
All-cause survival was poorer among APIs (hazard ratio (HR) and 95% confidence interval (CI) = 1.7 (1.0–2.8) among US-born APIs; 1.2 (0.9–1.5) among foreign-born APIs), and Latinas (HR (95% CI) = 2.1 (1.2–3.6) among US-born Latinas; 1.4 (0.9–2.3) among foreign-born Latinas), relative to non-Hispanic Whites. These survival differences were not explained by differences in selected sociodemographic or clinical factors.
CONCLUSIONS
Further research should focus on factors such as cultural behaviors, access to or attitudes toward health care, and genetic variations, as possible explanations for these striking racial/ethnic differences.
IMPACT
Latina and API female never smokers diagnosed with lung cancer were up to two-times more likely to die than non-Hispanic Whites, highlighting the need for additional research to identify the underlying reasons for the disparities, as well as heightened clinical awareness.
doi:10.1158/1055-9965.EPI-10-0965
PMCID: PMC3070404  PMID: 21239685
lung cancer survival; Asian; Latina; Hispanic; never smokers; nativity
25.  Body Mass Index and Risk of Lung Cancer Among Never, Former, and Current Smokers 
Background
Although obesity has been directly linked to the development of many cancers, many epidemiological studies have found that body mass index (BMI)—a surrogate marker of obesity—is inversely associated with the risk of lung cancer. These studies are difficult to interpret because of potential confounding by cigarette smoking, a major risk factor for lung cancer that is associated with lower BMI.
Methods
We prospectively examined the association between BMI and the risk of lung cancer among 448 732 men and women aged 50–71 years who were recruited during 1995–1996 for the National Institutes of Health–AARP Diet and Health Study. BMI was calculated based on the participant’s self-reported height and weight on the baseline questionnaire. We identified 9437 incident lung carcinomas (including 415 in never smokers) during a mean follow-up of 9.7 years through 2006. Multivariable Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) with adjustment for lung cancer risk factors, including smoking status. To address potential bias due to preexisting undiagnosed disease, we excluded potentially unhealthy participants in sensitivity analyses. All statistical tests were two-sided.
Results
The crude incidence rate of lung cancer over the study follow-up period was 233 per 100 000 person-years among men and 192 per 100 000 person-years among women. BMI was inversely associated with the risk of lung cancer among both men and women (BMI ≥35 vs 22.5–24.99 kg/m2: HR = 0.81, 95% CI = 0.70 to 0.94 and HR = 0.73, 95% CI = 0.61 to 0.87, respectively). The inverse association was restricted to current and former smokers and was stronger after adjustment for smoking. Among smokers, the inverse association persisted even after finely stratifying on smoking status, time since quitting smoking, and number of cigarettes smoked per day. Sensitivity analyses did not support the possibility that the inverse association was due to prevalent undiagnosed disease.
Conclusions
Our results suggest that a higher BMI is associated with a reduced risk of lung cancer in current and former smokers. Our inability to attribute the inverse association between BMI and the risk of lung cancer to residual confounding by smoking or to bias suggests the need for considering other explanations.
doi:10.1093/jnci/djs179
PMCID: PMC3352831  PMID: 22457475

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