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Background: Cigarette smoking is associated with earlier menopause, but the impact of being a former smoker and any dose-response relationships on the degree of smoking and age at menopause have been less clear. If the toxic impact of cigarette smoking on ovarian function is irreversible, we hypothesized that even former smokers might experience earlier menopause, and variations in intensity, duration, cumulative dose, and age at start/quit of smoking might have varying impacts on the risk of experiencing earlier menopause., Methods and Findings: A total of 207,231 and 27,580 postmenopausal women were included in the cross-sectional and prospective analyses, respectively. They were from 17 studies in 7 countries (Australia, Denmark, France, Japan, Sweden, United Kingdom, United States) that contributed data to the International collaboration for a Life course Approach to reproductive health and Chronic disease Events (InterLACE). Information on smoking status, cigarettes smoked per day (intensity), smoking duration, pack-years (cumulative dose), age started, and years since quitting smoking was collected at baseline. We used multinomial logistic regression models to estimate multivariable relative risk ratios (RRRs) and 95% confidence intervals (CIs) for the associations between each smoking measure and categorised age at menopause (<40 (premature), 40-44 (early), 45-49, 50-51 (reference), and ≥52 years). The association with current and former smokers was analysed separately. Sensitivity analyses and two-step meta-analyses were also conducted to test the results. The Bayesian information criterion (BIC) was used to compare the fit of the models of smoking measures. Overall, 1.9% and 7.3% of women experienced premature and early menopause, respectively. Compared with never smokers, current smokers had around twice the risk of experiencing premature (RRR 2.05; 95% CI 1.73-2.44) (p < 0.001) and early menopause (1.80; 1.66-1.95) (p < 0.001). The corresponding RRRs in former smokers were attenuated to 1.13 (1.04-1.23; p = 0.006) and 1.15 (1.05-1.27; p = 0.005). In both current and former smokers, dose-response relationships were observed, i.e., higher intensity, longer duration, higher cumulative dose, earlier age at start smoking, and shorter time since quitting smoking were significantly associated with higher risk of premature and early menopause, as well as earlier menopause at 45-49 years. Duration of smoking was a strong predictor of age at natural menopause. Among current smokers with duration of 15-20 years, the risk was markedly higher for premature (15.58; 11.29-19.86; p < 0.001) and early (6.55; 5.04-8.52; p < 0.001) menopause. Also, current smokers with 11-15 pack-years had over 4-fold (4.35; 2.78-5.92; p < 0.001) and 3-fold (3.01; 2.15-4.21; p < 0.001) risk of premature and early menopause, respectively. Smokers who had quit smoking for more than 10 years had similar risk as never smokers (1.04; 0.98-1.10; p = 0.176). A limitation of the study is the measurement errors that may have arisen due to recall bias., Conclusions: The probability of earlier menopause is positively associated with intensity, duration, cumulative dose, and earlier initiation of smoking. Smoking duration is a much stronger predictor of premature and early menopause than others. Our findings highlight the clear benefits for women of early smoking cessation to lower their excess risk of earlier menopause., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: JEC is a director of Dietary Assessment Ltd, a University of Leeds spin out company to support measurement of dietary intake. All other authors have declared that no competing interests exist.

Background: Previous studies suggest that smokers have lower risks of cutaneous melanoma than nonsmokers, but data from population-based prospective studies are scarce. We investigated associations between smoking and melanoma in a cohort study purpose-designed to investigate skin cancer outcomes. Methods: Participants with no prior history of melanoma ( n = 38,697) completed a risk factor survey at baseline (2011). Patients were followed through linkage to the cancer registry. We estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for associations between smoking (including intensity, duration, time since quitting) and melanoma using multivariate Cox proportional hazards regression, accounting for death as a competing event. Results: During a mean follow-up of 3.5 years, invasive melanomas developed in 247 participants. Compared with never smokers, former smokers (but not current smokers) had lower risks of invasive melanoma (HR 0.76; 95% CI, 0.57-1.01). Among former smokers, risks were lower with greater quantity of cigarettes smoked (HR 0.75; 95% CI, 0.56-0.98 per 10 cigarettes/day). No association was observed with duration of smoking while longer time since quitting was associated with a relative risk of melanoma that was not significantly different from the null (HR 1.18; 95% CI, 0.91-1.51, for every 10 years since quitting). Conclusions: We observed complex associations between smoking and melanoma, with some suggestion that former smokers had lower risks than never or current smokers. The apparent inverse association among former smokers may be due to residual confounding, although surveillance bias or biological effects cannot be excluded entirely. Impact: Smoking does not increase the risk of cutaneous melanoma. Cancer Epidemiol Biomarkers Prev; 27(8); 874-81. ©2018 AACR ., (©2018 American Association for Cancer Research.)

Objectives: To estimate the population attributable fraction (PAF) and numbers of cancers occurring in Australia in 2010 attributable to tobacco smoking, both personal and by a partner., Methods: We used a modified Peto-Lopez approach to calculate the difference between the number of lung cancer cases observed and the number expected assuming the entire population developed lung cancer at the same rate as never smokers. For cancers other than lung, we applied the standard PAF formula using relative risks from a large cohort and derived notional smoking prevalence. To estimate the PAF for partners' smoking, we used the standard formula incorporating the proportion of non-smoking Australians living with an ever-smoking partner and relative risks associated with partner smoking., Results: An estimated 15,525 (13%) cancers in Australia in 2010 were attributable to tobacco smoke, including 8,324 (81%) lung, 1,973 (59%) oral cavity and pharynx, 855 (60%) oesophagus and 951 (6%) colorectal cancers. Of these, 136 lung cancers in non-smokers were attributable to partner tobacco smoke., Conclusions: More than one in eight cancers in Australia is attributable to tobacco smoking and would be avoided if nobody smoked., Implications: Strategies to reduce the prevalence of smoking remain a high priority for cancer control., (© 2015 The Authors.)

Purpose: Cigarette smoking is an established risk factor for pancreatic adenocarcinoma. However, few studies have thoroughly investigated the effects of independent smoking dimensions (duration, intensity, cumulative dose and time since quitting) on risk estimates. We analysed data from the Queensland Pancreatic Cancer Study (QPCS), an Australian population-based case-control study, with the aim of determining which smoking component is primarily important to pancreatic cancer risk., Methods: Our study included 705 pancreatic cancer patients and 711 controls. Logistic regression and generalised additive logistic regression (for non-linear dose effects) were used to determine odds ratios (ORs) and 95% confidence intervals (CIs)., Results: Compared to never-smokers, current smokers had an increased risk of pancreatic cancer (OR=3.4; 95% CI 2.4-5.0) after adjustment for age, sex, education, alcohol intake and birth country. Of the various smoking dimensions, smoking duration and time since quitting had a greater effect on OR estimates (OR 1.3; 95% CI 1.1-1.4 and OR 0.8; 95% CI 0.7-0.8) than smoking intensity (OR 1.1; 95% CI 0.9-1.2), once ever-smoking was accounted for., Conclusions: This study confirms the association between cigarette smoking and pancreatic adenocarcinoma, and provides evidence to suggest that smoking pattern, in addition to dose effect, may affect disease risk., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Objective: Alcohol and tobacco are the two major established environmental factors associated with squamous cell carcinoma of the esophagus (ESCC). However, the prevalence of these exposures differs substantially between men and women. Moreover, the prevalence of smoking has declined in recent years, whereas per capita consumption of alcohol has remained steady in both sexes. Quantifying the burden of ESCC attributable to these causal factors is necessary to inform potential preventive strategies., Methods: We estimated the population attributable fraction (PAF) of ESCC due to smoking and alcohol, using data from an Australian population based case-control study (305 ESCC cases, 1554 controls)., Results: Estimated PAF for ESCC were 49% (95% CI: 38-60) and 32% (95% CI: 25-40) due to smoking and heavy alcohol consumption respectively. More than 75% of the ESCC burden in men could be attributed to smokers with heavy alcohol consumption. The highest burden was among ≥30 pack years smokers who also consumed alcohol heavily (>17 drinks/week); this differed significantly between men (PAF 36%, 95% CI 29-44) and women (PAF 5%, 95% CI 2-10). Among women only, low intakes of fruit and vegetables accounted for about 9% of the ESCC burden., Conclusion: The burden of ESCC attributable to smoking combined with heavy alcohol consumption is remarkably high in men. In women, the burden of ESCC due to these factors is lower, and poor nutrition may also play a role., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: Cigarette smoking is associated with esophageal adenocarcinoma (EAC), esophagogastric junctional adenocarcinoma (EGJA) and esophageal squamous cell carcinoma (ESCC), and alcohol consumption with ESCC. However, no analyses have examined how delivery rate modifies the strength of odds ratio (OR) trends with total exposure, i.e., the impact on the OR for a fixed total exposure of high exposure rate for short duration compared with low exposure rate for long duration., Methods: The authors pooled data from 12 case-control studies from the Barrett's Esophagus and Esophageal Adenocarcinoma Consortium (BEACON), including 1242 (EAC), 1263 (EGJA) and 954 (ESCC) cases and 7053 controls, modeled joint ORs for cumulative exposure and exposure rate for cigarette smoking and alcohol consumption, and evaluated effect modification by sex, body mass index (BMI), age and self-reported acid reflux., Results: For smoking, all sites exhibited inverse delivery rate effects, whereby ORs with pack-years increased, but trends weakened with increasing cigarettes/day. None of the examined factors modified associations, except for ESCC where younger ages at diagnosis enhanced smoking effects (P<0.01). For EAC and EGJA, ORs with drink-years exhibited inverse associations in <5 drinks/day consumers and no association in heavier consumers. For ESCC, ORs with drink-years increased, with trends strengthening with greater drinks/day. There was no significant effect modification, except for EAC and EGJA where acid reflux mitigated the inverse associations (P=0.02). For ESCC, younger ages at diagnosis enhanced drinking-related ORs (P<0.01)., Conclusions: Patterns of ORs by pack-years and drink-years, delivery rate effects and effect modifiers revealed common as well as distinct etiologic elements for these diseases., (Published by Elsevier Ltd.)

Background: Observational studies suggest that body mass index (BMI) is inversely associated with esophageal squamous cell carcinoma (ESCC). However, questions remain regarding reverse causation and confounding, especially by smoking, as alternative explanations., Methods: The authors examined the association between BMI and measures of weight history and risk of ESCC in a population-based Australian case-control study (from 2002 to 2005) comprising 287 patients with ESCC (cases) and a control group of 1544 individuals who were sampled from a population registry. Stratified analyses were performed specifically to explore whether this association was influenced by smoking. Multivariable logistic regression models were used to derive odds ratios (ORs)., Results: After adjusting for smoking, significant inverse associations with ESCC for BMI and weight 1 year before diagnosis, maximum adult BMI, and weight gain since age 20 years were observed (all P(trend) < .001). The risk of ESCC was reduced by 35% (range, 23%-44%) per 5-unit increase in recent BMI. Participants who gained weight after age 20 years had a lower risk than those who maintained their weight during adult life (OR for gain of >20 kg, 0.51; 95% confidence interval [CI], 0.33-0.77). In stratified analyses, higher BMI was associated with a decreasing risk of ESCC both in never-smokers (OR, 0.32; 95% CI 0.13-0.76) and smokers (OR 0.22, 95%CI 0.07-0.67) comparing the highest versus the lowest BMI quintile., Conclusions: In this study, the inverse associations between BMI, long-term weight gain, and other body measures and ESCC appeared to be robust and could not be explained by smoking status or potential confounding factors., (Copyright © 2011 American Cancer Society.)

Obesity, gastroesophageal reflux, and smoking have repeatedly been shown to be important and independent risk factors for adenocarcinoma of the esophagus (EAC) and of the gastroesophageal junction (GEJAC). There have been few attempts, however, to quantify the proportion of disease associated with these potentially modifiable factors. The authors have estimated the population attributable fraction of EAC and GEJAC attributable to obesity, symptoms of gastroesophageal reflux, and smoking using data from a population-based case-control study conducted in Australia between 2002 and 2005. Cases were patients with EAC (n = 364) or GEJAC (n = 425). Controls (n = 1,580) were randomly sampled from a population register. Combinations of smoking, body mass index (weight in kilograms divided by height in meters squared), and gastroesophageal reflux together accounted for 76% (95% confidence interval: 66, 84) of EAC cases and 69% (95% confidence interval: 58, 78) of GEJAC cases. Individually, high body mass index (≥30) and frequent acid reflux (≥1 time/week) accounted for the greatest proportions of EAC (23% and 36%, respectively), and smoking and frequent symptoms of acid reflux accounted for the greatest proportions of GEJAC (43% and 28%, respectively). The present study suggests that these cancers may be largely prevented by maintaining healthy body mass index, avoiding smoking, and controlling symptomatic gastroesophageal reflux.

Background: Previous studies that showed an association between smoking and adenocarcinomas of the esophagus and esophagogastric junction were limited in their ability to assess differences by tumor site, sex, dose-response, and duration of cigarette smoking cessation., Methods: We used primary data from 10 population-based case-control studies and two cohort studies from the Barrett's Esophagus and Esophageal Adenocarcinoma Consortium. Analyses were restricted to white non-Hispanic men and women. Patients were classified as having esophageal adenocarcinoma (n = 1540), esophagogastric junctional adenocarcinoma (n = 1450), or a combination of both (all adenocarcinoma; n = 2990). Control subjects (n = 9453) were population based. Associations between pack-years of cigarette smoking and risks of adenocarcinomas were assessed, as well as their potential modification by sex and duration of smoking cessation. Study-specific odds ratios (ORs) estimated using multivariable logistic regression models, adjusted for age, sex, body mass index, education, and gastroesophageal reflux, were pooled using a meta-analytic methodology to generate summary odds ratios. All statistical tests were two-sided., Results: The summary odds ratios demonstrated strong associations between cigarette smoking and esophageal adenocarcinoma (OR = 1.96, 95% confidence interval [CI] = 1.64 to 2.34), esophagogastric junctional adenocarcinoma (OR = 2.18, 95% CI = 1.84 to 2.58), and all adenocarcinoma (OR = 2.08, 95% CI = 1.83 to 2.37). In addition, there was a strong dose-response association between pack-years of cigarette smoking and each outcome (P < .001). Compared with current smokers, longer smoking cessation was associated with a decreased risk of all adenocarcinoma after adjusting for pack-years (<10 years of smoking cessation: OR = 0.82, 95% CI = 0.60 to 1.13; and > or =10 years of smoking cessation: OR = 0.71, 95% CI = 0.56 to 0.89). Sex-specific summary odds ratios were similar., Conclusions: Cigarette smoking is associated with increased risks of adenocarcinomas of the esophagus and esophagogastric junction in white men and women; compared with current smoking, smoking cessation was associated with reduced risks.

Objective: To measure the extent to which risks of oesophageal cancers associated with gastro-oesophageal reflux (GOR) are modified by common factors including smoking, non-steroidal anti-inflammatory drugs (NSAIDs) and acid suppressant medications., Design and Setting: Population-based case-control study., Participants: Cases were patients with oesophageal (OAC; n = 365) or gastro-oesophageal junction (GOJAC; n = 426) adenocarcinomas, or squamous cell carcinomas (OSCC; n = 303). Controls were sampled from a population register (n = 1580)., Main Outcome Measure: Odds ratio and 95% confidence interval., Results: Frequent (at least weekly) symptoms of GOR were associated with significant 6.4-fold, 4.6-fold and 2.2-fold increased risks of OAC, GOJAC and OSCC, respectively. Under models examining effects of combined exposure, patients with frequent GOR symptoms who were also heavy smokers had markedly higher OAC risks (OR = 12.3, 95% CI 6.3 to 24.0) than those with frequent GOR who did not smoke (OR = 6.8, 95% CI 3.6 to 12.9). Similar patterns were observed for GOJAC and OSCC. Among people with frequent GOR symptoms, regular use of aspirin/NSAIDs was associated with almost two-thirds lower OAC risks (OR = 4.8, 95% CI 2.5 to 9.2) than non-users (13.9, 95% CI 6.5 to 30.0). In contrast, among those with frequent GOR symptoms, users of acid suppressants had similar OAC risks (OR 7.8, 95% CI 5.2 to 11.8) to non-users (OR 5.3, 95% CI 3.2 to 9.0)., Conclusions: People experiencing frequent GOR symptoms have markedly increased risks of OAC and GOJAC, and this effect may be greater amongst smokers. Use of aspirin and NSAIDs, but not acid suppressants, significantly reduced the risks of oesophageal cancers associated with GOR.

Objective: Participation rates have been declining in case-control studies, particularly among controls, raising concerns about possible bias. Formal assessments of the effect of low participation on odds ratios (OR) are seldom presented however. We sought to quantify possible bias using multiple imputation techniques., Methods: Using data from two Australian case-control studies, we estimated the relative risks of oesophageal squamous cell carcinoma (OSCC) and adenocarcinoma (OAC), and serous ovarian cancer (SOC) associated with smoking and body mass index (BMI). We compared ORs observed using self-reported data from participating controls with ORs derived using imputed exposures for non-participating controls., Results: Participating controls were less likely than non-participants to smoke currently. Smoking remained significantly associated with oesophageal cancer even under the most extreme assumption of smoking prevalence among non-participants (OSCC: observed OR 6.54, 4.62-9.28, imputed OR 3.94, 2.83-5.49; OAC: observed OR 2.69, 1.87-3.85 imputed OR 1.58, 1.13-2.22). For SOC however, risks associated with smoking were attenuated to null under plausible smoking assumptions among non-participants. BMI distributions were similar among participating and non-participating controls, and risk estimates were essentially unchanged., Conclusion and Implications: Bias is not an inevitable consequence of low control participation and depends on the association examined. Sensitivity analyses can assist in interpretation of results.

Smoking has been identified as a risk factor for esophageal cancer; however, there is evidence that magnitudes and patterns of association differ by histologic type. The authors aimed to measure and compare the independent effects of various dimensions of smoking (duration, intensity, total dose, and time since quitting) on risks of esophageal adenocarcinoma (EAC), gastroesophageal junction adenocarcinoma (GEJAC), and esophageal squamous cell carcinoma (ESCC). They used data from a population-based Australian case-control study (2002-2005) comprising 367 EAC cases, 426 GEJAC cases, and 309 ESCC cases and 1,580 controls. Multivariate logistic and generalized additive logistic regression (for nonlinear dose effects) were used. Ever smokers had significantly higher risks of EAC (odds ratio (OR) = 1.7, 95% confidence interval (CI): 1.3, 2.3), GEJAC (OR = 2.4, 95% CI: 1.8, 3.2), and ESCC (OR = 2.8, 95% CI: 2.0, 4.0) than did never smokers; however, there were significant differences in magnitude and patterns of association between subtypes. When multiple dimensions of smoking were assessed concurrently, duration was significantly associated with all three subtypes but intensity was associated only with GEJAC and ESCC, and the associations were nonlinear. For all types of esophageal cancer, time since quitting was independently associated with approximately 15-19% risk reductions per decade.

Objective: To measure the relative risks of adenocarcinomas of the oesophagus and gastro-oesophageal junction associated with measures of obesity, and their interactions with age, sex, gastro-oesophageal reflux symptoms and smoking., Design and Setting: Population-based case-control study in Australia., Patients: Patients with adenocarcinomas of the oesophagus (n = 367) or gastro-oesophageal junction (n = 426) were compared with control participants (n = 1580) sampled from a population register., Main Outcome Measure: Relative risk of adenocarcinoma of the oesophagus or gastro-oesophageal junction., Results: Risks of oesophageal adenocarcinoma increased monotonically with body mass index (BMI) (p(trend) <0.001). Highest risks were seen for BMI >or=40 kg/m2 (odds ratio (OR) = 6.1, 95% CI 2.7 to 13.6) compared with "healthy" BMI (18.5-24.9 kg/m2). Adjustment for gastro-oesophageal reflux and other factors modestly attenuated risks. Risks associated with obesity were substantially higher among men (OR = 2.6, 95% CI 1.8 to 3.9) than women (OR = 1.4, 95% CI 0.5 to 3.5), and among those aged <50 years (OR = 7.5, 95% CI 1.7 to 33.0) than those aged >or=50 years (OR = 2.2, 95% CI 1.5 to 3.1). Obese people with frequent symptoms of gastro-oesophageal reflux had significantly higher risks (OR = 16.5, 95% CI 8.9 to 30.6) than people with obesity but no reflux (OR = 2.2, 95% CI 1.1 to 4.3) or reflux but no obesity (OR = 5.6, 95% 2.8 to 11.3), consistent with a synergistic interaction between these factors. Similar associations, but of smaller magnitude, were seen for gastro-oesophageal junction adenocarcinomas., Conclusions: Obesity increases the risk of oesophageal adenocarcinoma independently of other factors, particularly among men. From a clinical perspective, these data suggest that patients with obesity and frequent symptoms of gastro-oesophageal reflux are at especially increased risk of adenocarcinoma.

Aspirin may reduce the risk of cancer at some sites but its effect at the lung is unclear. We prospectively examined associations between aspirin use and risk of lung cancer in 109,348 women in the Nurses' Health study from 1980 to 2004. During this time, 1,360 lung cancers were documented in participants 36-82 years of age. Aspirin use and smoking were assessed every 2 years. Risk of lung cancer was a non-significant 16% lower for regular aspirin users of one or two tablets per week and a significant 55% higher for users of 15 or more tablets per week compared with women who never regularly used aspirin. Results were similar when limited to never smokers. For both the low and high quantity aspirin users, risk of lung cancer did not decline or increase with longer durations of use, and associations attenuated as the latency period between aspirin assessment and lung cancer diagnosis was lengthened. Our findings, together with those from previous clinical trials and prospective studies, do not provide consistent evidence that aspirin influences the development of lung cancer and further investigation is required with adjustment for smoking. [ABSTRACT FROM AUTHOR]