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Objective: Epidemiologic evidence suggests a positive association between body mass, adult height, and postmenopausal breast cancer. However, most studies have not been large enough to examine the association across a very wide range of body mass or height, and few studies have assessed the relationship between body mass or height and postmenopausal breast cancer mortality. Methods: The relation between body mass index (BMI) and height and postmenopausal breast cancer mortality was examined in the American Cancer Society's Cancer Prevention Study II (CPS-II), a large prospective mortality study of US adults enrolled in 1982. After 14 years of follow-up, 2852 breast cancer deaths were observed among 424,168 postmenopausal women who were cancer-free at interview. Cox proportional hazards modeling was used to estimate relative risks and to control for potential confounding. Results: Breast cancer mortality rates increased continually and substantially with increasing BMI (rate ratio (RR) = 3.08, 95% confidence interval (CI) = 2.09-4.51 for BMI > 40.0 compared to BMI 18.5-20.49). If causal, the multivariate-adjusted RR estimates in this study correspond to approximately 30-50% of breast cancer deaths among postmenopausal women in the US population being attributable to overweight. Breast cancer mortality also increased with increasing height up to 66 inches with RR = 1.64, (95% CI = 1.23-2.18) in women 66 inches tall compared to those

Every year the American Cancer Society estimates the number of new cancer cases and deaths expected in the United States in the current year and compiles the most recent data on cancer incidence, mortality, and survival, using National Cancer Institute (NCI) incidence and National Center for Health Statistics (NCHS) mortality data. Incidence and death rates are age adjusted to the 1970 US standard population. It is estimated that 1,284,900 new cases of cancer will be diagnosed and 555,500 people will die from cancer in the United States in the year 2002. From 1992 to 1998, cancer death rates declined in males and females, while cancer incidence rates decreased among males and increased slightly among females. Most notably, African-American men showed the largest decline for both incidence and mortality. Nevertheless, African Americans still carry the highest burden of cancer with later-stage cancer diagnosis and poorer survival compared with whites. Despite the continued decline in cancer death rates, the total number of recorded cancer deaths in the United States continues to increase slightly due to the aging and expanding population.

Objective: To investigate prospectively the relationship between Jewish ethnicity and prostate cancer mortality. Methods: Men were selected from white male participants in two large American Cancer Society cohorts: Cancer Prevention Studies I (CPS-I) (enrolled in 1959 and followed through 1972) and II (CPS-II) (enrolled in 1982 and followed through 1996). During the follow-up periods there were 1751 prostate cancer deaths among 417,018 men in CPS-I and 3594 deaths among 447,780 men in CPS-II. Cox proportional hazards modeling was used to compute rate ratios (RR) and to adjust for known and suspected risk factors for prostate cancer. Results: Prostate cancer death rates were substantially lower among Jewish men than other white men in both cohorts (multivariate adjusted rate ratios (RR) = 0.54, 95% CI = 0.38–0.77 in CPS-I; RR = 0.72, 95% CI = 0.61–0.86 in CPS-II). Factors such as tobacco avoidance and measured dietary patterns did not account for this difference. Lower prostate cancer death rates were observed among Jewish men regardless of place of birth of the participants or their parents. Conclusions: Prostate cancer death rates are lower among Jewish men in the US and in Israel than among non-Jewish US white men. This may reflect persistent differences in unknown environmental risk factors or possible genetic susceptibility.

BACKGROUND: Genome-wide association studies have identified hundreds of genetic variants associated with specific cancers. A few of these risk regions have been associated with more than one cancer site; however, a systematic evaluation of the associations between risk variants for other cancers and lung cancer risk has yet to be performed. METHODS: We included 18023 patients with lung cancer and 60543 control subjects from two consortia, Population Architecture using Genomics and Epidemiology (PAGE) and Transdisciplinary Research in Cancer of the Lung (TRICL). We examined 165 single-nucleotide polymorphisms (SNPs) that were previously associated with at least one of 16 non-lung cancer sites. Study-specific logistic regression results underwent meta-analysis, and associations were also examined by race/ethnicity, histological cell type, sex, and smoking status. A Bonferroni-corrected P value of 2.5×10(-5) was used to assign statistical significance. RESULTS: The breast cancer SNP LSP1 rs3817198 was associated with an increased risk of lung cancer (odds ratio [OR] = 1.10; 95% confidence interval [CI] = 1.05 to 1.14; P = 2.8×10(-6)). This association was strongest for women with adenocarcinoma (P = 1.2×10(-4)) and not statistically significant in men (P = .14) with this cell type (P het by sex = .10). Two glioma risk variants, TERT rs2853676 and CDKN2BAS1 rs4977756, which are located in regions previously associated with lung cancer, were associated with increased risk of adenocarcinoma (OR = 1.16; 95% CI = 1.10 to 1.22; P = 1.1×10(-8)) and squamous cell carcinoma (OR = 1.13; CI = 1.07 to 1.19; P = 2.5×10(-5)), respectively. CONCLUSIONS: Our findings demonstrate a novel pleiotropic association between the breast cancer LSP1 risk region marked by variant rs3817198 and lung cancer risk.

Objectives. We investigated the association between body mass index (BMI) and mortality among Asian Americans. Methods. We pooled data from prospective cohort studies with 20 672 Asian American adults with no baseline cancer or heart disease history. We estimated hazard ratios and 95% confidence intervals (CIs) with Cox proportional hazards models. Results. A high, but not low, BMI was associated with increased risk of total mortality among individuals aged 35 to 69 years. The BMI was not related to total mortality among individuals aged 70 years and older. With a BMI 22.5 to Conclusions. High BMI is associated with increased mortality risk among Asian Americans.

Background. Adolescence is a high-risk period for the development of melanoma and nonmelanocytic skin cancers later in life. This study examines the prevalence and correlates of sun-protection practices among U.S. youth. Methods. During July–October, 1998, a national, population-based telephone survey was conducted (N = 1,192 paired interviews of youth and their parents). Weighted prevalence and adjusted prevalence odds ratios and 95% confidence intervals were estimated. Multiple logistic regression analyses examined associations between sociodemographics, attitudes, and other modifiable correlates to specific behaviors. Results. Routinely practiced sun-protection behaviors among youth on sunny days were wearing sunglasses (32%) or long pants (21%), staying in the shade (22%), and applying sunscreen (31%). Fifty-eight percent used a sunscreen with SPF ≥15 when at the beach or pool. Age, sex, and sun sensitivity were associated with substantial variation in some sun-protection behaviors. Factors associated with specific sun-protection behaviors included a lower appeal to tanning, a higher perceived benefit of sun protection, and information from family and friends about sun protection. Conclusion. Effective sun protection is practiced by less than one-third of U.S. youth. This baseline survey will help to monitor progress in skin cancer prevention in this critical age group in the future.

Background The American Cancer Society, the National Cancer Institute (NCI), the North American Association of Central Cancer Registries, and the Centers for Disease Control and Prevention, including the National Center for Health Statistics (NCHS), collaborate to provide an annual update on cancer occurrence and trends in the United States. This year's report contains a special feature that focuses on cancers with recent increasing trends. Methods From 1992 through 1998, age-adjusted rates and annual percent changes are calculated for cancer incidence and underlying cause of death with the use of NCI incidence and NCHS mortality data. Joinpoint analysis, a model of joined line segments, is used to examine long-term trends for the four most common cancers and for those cancers with recent increasing trends in incidence or mortality. Statistically significant findings are based on a P value of.05 by use of a two-sided test. State-specific incidence and death rates for 1994 through 1998 are reported for major cancers. Results From 1992 through 1998, total cancer death rates declined in males and females, while cancer incidence rates declined only in males. Incidence rates in females increased slightly, largely because of breast cancer increases that occurred in some older age groups, possibly as a result of increased early detection. Female lung cancer mortality, a major cause of death in women, continued to increase but more slowly than in earlier years. In addition, the incidence or mortality rate increased in 10 other sites, accounting for about 13% of total cancer incidence and mortality in the United States. Conclusions Overall cancer incidence and death rates continued to decline in the United States. Future progress will require sustained improvements in cancer prevention, screening, and treatment.

In observational studies, estrogen replacement therapy is associated with decreased cardiovascular disease rates and increased breast cancer rates. Recent evidence suggests that the impact of estrogen use on disease outcomes may vary by body mass. In a prospective study of 290,827 postmenopausal US women with no history of cancer or cardiovascular disease at enrollment in 1982, the authors examined the association between postmenopausal estrogen use and all-cause, coronary heart disease, stroke, all-cancer, and breast cancer death rates and whether these associations differed by body mass. After 12 years of follow-up, results from Cox proportional hazards models showed that all-cause death rates were lower among baseline estrogen users than never users (rate ratio (RR) = 0.82, 95% confidence interval (Cl): 0.78, 0.87). The lowest relative risk was found for coronary heart disease (RR = 0.66, 95% Cl: 0.58, 0.77). The inverse association between estrogen use and coronary heart disease mortality was strongest for thin women (body mass index

Objective: Multivitamins contain several nutrients, including folic acid, which are hypothesized to reduce colon cancer risk. Previous epidemiologic studies have suggested that effects of multivitamins containing substantial amounts of folic acid (introduced in 1973) may not be evident until 15 or more years since first use. Methods: We examined the association between daily multivitamin use and colon cancer mortality among 806,397 US men and women in the Cancer Prevention Study II cohort who completed a questionnaire at enrollment in 1982 and were followed for mortality through 1998. Results: After multivariate adjustment, multivitamin use at enrollment showed little association with colon cancer mortality. After 15 years since first use of a multivitamin potentially containing folic acid, we observed slightly decreased risk of colon cancer mortality (rate ratio (RR) = 0.89, 95% confidence interval (CI) 0.80–0.99). Consistent with previous reports, this association was stronger among participants consuming two or more alcoholic drinks per day (RR = 0.71, 95% CI 0.56–0.91). Conclusion: Our results are consistent with a modest reduction in colon cancer mortality associated with use of folic acid-containing multivitamins among moderate to heavy alcohol users.

Each year the American Cancer Society compiles estimates of the number of new cancer cases and deaths expected in the US in the current year and the most recent data on cancer incidence, mortality, and survival. An estimated 1,268,000 new cases of cancer will be diagnosed in the year 2001 and an estimated 553,400 Americans will die from cancer. Overall cancer incidence and death rates have continued to decrease in men and women since the early 1990s, and the decline in overall cancer mortality has been greater in recent years. Despite reductions in age-adjusted rates of cancer death, the total number of recorded cancer deaths in the US continues to increase, due to an aging and expanding population. Large disparities in cancer incidence and mortality across racial/ethnic groups continue. Black men and women experience higher incidence of cancer and poorer survival than white men and women. The disparity in survival reflects both diagnosis of cancer at later disease stages, and poorer survival within each stage of diagnosis.

Objective: To investigate the hypothesis that alcohol consumption increases the risk of breast cancer mortality. Methods: We examined breast cancer mortality in relation to self-reported alcohol consumption in women from the American Cancer Society Cancer Prevention Study (CPS)-II. After 14 years of follow-up, 1,442 eligible breast cancer deaths were observed among 242,010 women. Cox proportional hazards models were constructed for total alcohol consumption and for beer, wine, and liquor separately. Results: Total alcohol consumption was associated with increased risk of fatal breast cancer among post- but not pre- or perimenopausal women. Even less than one drink/day was associated with up to a 30% increase in breast cancer mortality among postmenopausal women compared to non-drinkers (RR = 1.3, 95% CI: 1.1-1.6 for women drinking 0.26

Objective: To investigate the hypothesis that tubal sterilization is associated with a reduced risk of breast cancer. Methods: We examined this hypothesis in a large prospective study of US adults. After 14 years of mortality follow-up, 3837 deaths from breast cancer were observed in a cohort of 619,199 women who were cancer-free at study entry in 1982. Results: Cox proportional hazards models (adjusted for multiple breast cancer risk factors) showed a significant inverse association between tubal sterilization and breast cancer mortality (adjusted rate ratio (RR) = 0.82, 95% confidence interval (CI) 0.70–0.96). Women who were sterilized before age 35 had a lower risk (adjusted RR = 0.69, 95% CI 0.53–0.88) than women who were sterilized at 35 years of age or older (adjusted RR = 0.92, 95% CI 0.75–1.13). Also, sterilizations performed before 1975 resulted in a lower risk (RR = 0.75, 95% CI 0.62–0.91) than those performed during or after 1975 (RR = 0.98, 95% CI 0.74–1.29), possibly reflecting the likelihood of greater tissue damage with earlier procedures. Conclusions: These results suggest that tubal sterilization may lower subsequent risk of breast cancer, especially among women who are sterilized at a relatively young age. Additional studies are needed to confirm or refute these findings.

We read with great interest the genome-wide association study (GWAS) of Li et al.1 in the April, 2010 issue of The Lancet Oncology, reporting an association (OR=1·46, 95%CI=1·26–1·70) between the single nucleotide polymorphism rs2352028 mapping to chromosome 13q31·3 and lung cancer risk in never smokers. We sought to replicate this finding using data from seven GWAS of lung cancer in Caucasian populations,2–5 with rs2352028 genotype data on 754 never smoker lung cancer cases and 10,580 controls. None of the seven studies provided statistically significant evidence for an association between rs2352028 and lung cancer risk in never smokers, even when combined (P=0·57, under both fixed and random effects models; Cochran’s Q Pheterogeneity=0·62, Figure 1), although we had >90% statistical power to detect an association with rs2352028 of 1·26 (the lower limit of the 95% CI reported by Li et al.) at the 5% significance level. Moreover, the association was not significant in the overall meta-analysis pooling results from our seven studies and from Li et al. (OR=1·10, P=0·25, under random effects model; Pheterogeneity=0·003). Analyses using other genetic models (Supplemental Figure 1); adjusting for additional potential confounders, including history of COPD, exposure to second-hand smoke and family history of lung cancer (EAGLE2 only, OR=0·86; 96% CI = 0·63–1·19, p=0·37); or restricted to adenocarcinomas (Figure 1) also provided no evidence for a significant relationship. Of note, all controls in our analyses were never smokers, with the exception of the UK sample for which we had no smoking information. However, the frequency of the rs2352028 T allele was not significantly different between ever smokers (19,656) and never smokers (7,453) (OR=1·04, p-value=0·30) from other groups, thus the results are not likely to be affected by smoking status in controls. Figure 1 Association between rs2352028 and lung cancer risk overall and in adenocarcinoma only in never smokers (additive genetic model). Results from seven independent studies and overall meta-analysis including results from the new seven independent studies ... The Li et al. GWAS was based on 888 cases and 1,384 controls and the association between rs2352028 and lung cancer was at P-value=5·94×10−6. While nominally significant, it is well recognized that as GWAS involve many markers, numerous false positive associations will inevitably be generated, with only a small number being truly associated with disease susceptibility. Hence, associations require a high level of statistical significance (5·0×10−7–5·0×10−8) to be established beyond reasonable doubt, and the reported association does not attain genome-wide significance. Moreover, under a random effects model the association between rs2352028 and lung cancer reported by Li et al. is weak (P=0·0027 overall and P=0·034 for adenocarcinomas). The significant heterogeneity between our studies and those from Li et al. could be due to genuine differences in underlying population characteristics and/or due to “winner’s curse” associated with a chance finding. Li et al. reported a relationship between GPC5 expression in 70 non-tumor lung tissue samples and rs2352028 genotype. We examined this correlation in fresh frozen lung tissue samples from 45 adenocarcinomas and 37 non-tumor samples6 and in blood samples from 62 adenocarcinoma cases and 77 controls. Although we found lower expression levels in tumor tissue vs. noninvolved tissue as previously reported1, we found no significant correlation of rs2352028 genotypes with GPC5 expression in the lung tumor and non-involved tissue samples from cases and in blood samples from controls (p-values=0·07, 0·32 and 0·41, respectively). We observed an association (p=0·03) between genotype and GPC5 expression in blood samples from adenocarcinoma cases, although no trend was apparent and no difference in GPC5 expression between cases and controls was observed (Supplemental Figure 2). This work highlights the importance of large sample sizes and the need for replication in multiple independent groups to identify true positive associations.

Background: Recent studies suggest that long-term cigarette smoking is associated with an increased risk of colorectal cancer. Whether the association is causal or due to confounding remains unclear. Methods: We examined cigarette smoking in relation to colorectal cancer mortality, evaluating smoking duration and recency and controlling for potential confounders in the Cancer Prevention Study II. This prospective nationwide mortality study of 1 184 657 adults (age ≥30 years) was begun by the American Cancer Society in 1982. After exclusions, our analytic cohort included 312 332 men and 469 019 women, among whom 4432 colon or rectal cancer deaths occurred between 1982 and 1996 among individuals who were cancer free in 1982. Rate ratios (RRs) and 95% confidence intervals (CIs) were estimated by fitting Cox proportional hazards models. All statistical tests were two-sided. Results: Multivariate-adjusted colorectal cancer mortality rates were highest among current smokers, were intermediate among former smokers, and were lowest in lifelong nonsmokers. The multivariate-adjusted RR (95% CI) for current compared with never smokers was 1.32 (1.16– 1.49) among men and 1.41 (1.26–1.58) among women. Increased risk was evident after 20 or more years of smoking for men and women combined as compared with never smokers. Risk among current and former smokers increased with duration of smoking and average number of cigarettes smoked per day; risk in former smokers decreased significantly with years since quitting. If the multivariate-adjusted RR estimates in this study do, in fact, reflect causality, then approximately 12% of colorectal cancer deaths among both men and women in the general U.S. population in 1997 were attributable to smoking. Conclusions: Long-term cigarette smoking is associated with increased risk of colorectal cancer mortality in both men and women. Clear reduction in risk is observed with early smoking cessation. [J Natl Cancer Inst 2000;92:1888–96]

The authors explored two methodological issues in the estimation of smoking-attributable mortality for the United States. First, age-specific and age-adjusted relative risk, attributable fraction, and smoking-attributable mortality estimates obtained using data from the American Cancer Society's second Cancer Prevention Study (CPS II), a cohort study of 1.2 million participants (1982-1988), were compared with those obtained using a combination of data from the National Mortality Follow-back Survey (NMFS), a representative sample of US decedents in which information was collected from informants (1986), and the National Health Interview Survey (NHIS), a nationally representative household survey (1987). Second, the potential for residual confounding of the disease-specific age-adjusted smoking-attributable mortality estimates was addressed with a model-based approach. The estimated smoking-attributable mortality based on the CPS II for the four most common smoking-related diseases-lung cancer, chronic obstructive pulmonary disease, coronary heart disease, and cerebrovascular disease-was 19% larger than the estimated smoking-attributable mortality based on the NMFS/NHIS, yet the two data sources yielded essentially the same smoking-attributable mortality estimate for lung cancer alone. Further adjustment of smoking-attributable mortality for disease-appropriate confounding factors (education, alcohol intake, hypertension status, and diabetes status) indicated little residual confounding once age was taken into account.

Purpose: To investigate the influence of smoking and pre-existing illness on the relationship between body-mass index (BMI) and mortality from all causes, cardiovascular disease (CVD) and cancer. Methods: Study subjects were 168,828 men and 290,149 women, 45–64 years of age who participated in the Cancer Prevention Study I with 12 years of follow-up. We examined participants in four strata: (1) healthy never smokers, (2) healthy current smokers, (3) unhealthy never smokers and (4) unhealthy current smokers. Cox proportional hazard models with a piece-wise quadratic spline with 8 knots for BMI were used to plot the BMI-mortality relationship. Interactions of smoking and pre-existing illness with BMI were tested. Results: Three-way interactions between BMI, smoking and pre-existing illness were statistically significant for all 3 mortality outcomes for both men and women. Healthy never-smoking participants tended to have the lowest hazard ratios at low BMI levels and the highest hazard ratios at high levels of BMI. Pre-existing illness tended to modify this effect more than smoking status. Conclusion: Pre-existing illness and smoking modify associations between BMI and mortality and should be carefully considered in an analysis of the BMI-mortality association.

Objectives: Cigarette smoking is considered an important risk factor for pancreatic cancer, but other purported risk factors are less well established. To learn more about the epidemiology of this important cause of mortality we examined associations with a variety of possible risk factors for death from pancreatic cancer in a large, prospective study of United States adults.

Background: At a time when the population is aging and medical practices are rapidly changing, ongoing surveillance of surgical treatments for cancer is valuable for health services planning.

This article reviews the epidemiologic studies of the association of ischemic heart disease risk and environmental tobacco smoke (ETS) exposure from a spouse who smokes. Seventeen studies (nine cohort, eight case-control) comprising more than 485,000 lifelong nonsmokers and 7,345 coronary heart disease (CHD) events were included in a meta-analysis. Together, these studies include 36% more CHD events and 58% more study subjects than were available for review by the U. S. Occupational Safety and Health Administration (OSHA) in 1994. The relative risk (RR) for fatal or nonfatal coronary events among never smokers married to smokers, compared to those whose spouses did not smoke, was RR = 1.25 (95% confidence interval [95% CI], 1.17-1.33) across the combined studies. This association was statistically similar in men (RR = 1.24; 95% CI, 1.15-1.32) and women (RR = 1.23; 95% CI, 1.15-1.32); in studies of cohort (RR = 1.23; 95% CI, 1.15-1. 31) and case-control (RR = 1.47; 95% CI, 1.19-1.81) design; in the United States (RR =1.22; 95% CI, 1.13-1.30) and other countries (RR = 1.41; 95% CI, 1.21-1.65); and in studies of fatal (RR = 1.22; 95% CI, 1.14-1.30) and nonfatal (RR = 1.32; 95% CI, 1.04-1.67) heart disease. In three studies that presented data separately for nonsmokers married to current or former smokers, the association was stronger when the spouses continued to smoke (RR = 1.16, 1.06-1.28) than with former smokers (RR = 0.98; 95% CI, 0.89-1.08). The aggregate data are unlikely to be attributable to chance, publication bias, confounding, or misclassification of exposure. The evidence linking heart disease and ETS exposure from a spouse has become substantially stronger since OSHA first proposed including heart disease in its risk assessment of ETS in 1994.

Background Body-mass index (the weight in kilograms divided by the square of the height in meters) is known to be associated with overall mortality. We investigated the effects of age, race, sex, smoking status, and history of disease on the relation between body-mass index and mortality. Methods In a prospective study of more than 1 million adults in the United States (457,785 men and 588,369 women), 201,622 deaths occurred during 14 years of follow-up. We examined the relation between body-mass index and the risk of death from all causes in four subgroups categorized according to smoking status and history of disease. In healthy people who had never smoked, we further examined whether the relation varied according to race, cause of death, or age. The relative risk was used to assess the relation between mortality and body-mass index. Results The association between body-mass index and the risk of death was substantially modified by smoking status and the presence of disease. In healthy people who had ne...

The impact of using different measures of the effect of obesity on mortality across age groups has not been explored. The authors examined this issue by using mortality data from 62,116 men and 262,965 women in the Cancer Prevention Study-I (1960-1972). Measures of effect were calculated separately, by decade of age, for five groups of participants aged 30-79 years. The rate ratio associated with obesity declined with age, from 2.60 (men) and 1.99 (women) for participants aged 30-39 years to 1.24 (men) and 1.15 (women) for those aged 70-79 years. In contrast, the rate differences between obese and reference-weight participants increased with age, from 201 (men) and 112 (women) deaths per 100,000 person-years for those in the youngest decade to 1,379 (men) and 626 (women) deaths per 100,000 person-years for those in the oldest decade. The years of life lost attributable to obesity tended to increase with age but declined for those in the oldest decade. The rate advancement period declined with decade of age. Standardization of estimates to a population changed some age-associated trends. The direction of trends varied regarding the effect of obesity on mortality across age groups, depending on the measure of effect used.

Background The American Cancer Society, the National Cancer Institute (NCI), and the Centers for Disease Control and Prevention (CDC), including the National Center for Health Statistics (NCHS), provide the second annual report to the nation on progress in cancer prevention and control, with a special section on lung cancer and tobacco smoking. Methods Age-adjusted rates (using the 1970 U.S. standard population) were based on cancer incidence data from NCI and underlying cause of death data compiled by NCHS. The prevalence of tobacco use was derived from CDC surveys. Reported P values are two-sided. Results From 1990 through 1996, cancer incidence (-0.9% per year; P = .16) and cancer death (-0.6% per year; P = .001) rates for all sites combined decreased. Among the 10 leading cancer incidence sites, statistically significant decreases in incidence rates were seen in males for leukemia and cancers of the lung, colon/rectum, urinary bladder, and oral cavity and pharynx. Except for lung cancer, incidence rates for these cancers also declined in females. Among the 10 leading cancer mortality sites, statistically significant decreases in cancer death rates were seen for cancers of the male lung, female breast, the prostate, male pancreas, and male brain and, for both sexes, cancers of the colon/rectum and stomach. Age-specific analyses of lung cancer revealed that rates in males first declined at younger ages and then for each older age group successively over time; rates in females appeared to be in the early stages of following the same pattern, with rates decreasing for women aged 40-59 years. Conclusions The declines in cancer incidence and death rates, particularly for lung cancer, are encouraging. However, unless recent upward trends in smoking among adolescents can be reversed, the lung cancer rates that are currently declining in the United States may rise again.

Although 25% of US men indicate that they are trying to lose weight, the association between intentional weight loss and longevity in men is unknown. The authors analyzed prospective data from 49,337 overweight (initial body mass indexor =27) white men aged 40-64 years who, in 1959-1960, answered questions on weight change direction, amount, time interval, and intent. Vital status was determined in 1972. Proportional hazards regression estimated mortality rate ratios for men who intentionally lost weight compared with men with no weight change. Analyses were stratified by health status and adjusted for age, initial body mass index, smoking status, alcohol intake, education, physical activity, health history, and physical symptoms. Among men with no reported health conditions (n = 36,280), intentional weight loss was not associated with total, cardiovascular (CVD), or cancer mortality, but diabetes-associated mortality was increased 48% (95% confidence interval (CI) -7% to +133%) among those who lost 20 pounds (9.1 kg) or more; this increase was largely related to non-CVD mortality. Among men with reported health conditions (n = 13,057), intentional weight loss had no association with total or CVD mortality, but cancer mortality increased 25% (95% confidence interval -4% to +63%) among those who lost 20 pounds or more. Diabetes-associated mortality was reduced 32% (95% confidence interval -52% to -5%) among those who lost less than 20 pounds and 36% (95% confidence interval -49% to -20%) among those who lost more than 20 pounds. These results and those from our earlier study in women (Williamson et al., Am J Epidemiol 1995;141:1128-41) suggest that intentional weight loss may reduce the risk of dying from diabetes, but not from CVD. In observational studies, however, it is difficult to separate intentional weight loss from unintentional weight loss due to undiagnosed, underlying disease. Well-designed observational studies, as well as randomized controlled trials, are needed to determine whether intentional weight loss reduces CVD mortality.The association between intentional weight loss and mortality is examined using data on 49,337 overweight white men aged 40-64 from the American Cancer Society's Cancer Prevention Study I. These data were originally collected in 1959-1960, and vital status reassessed in 1972. The results, along with an earlier study on women, suggest that intentional weight loss may reduce the risk of dying from diabetes, but not from cardiovascular effects. The difficulty of distinguishing between intentional and unintentional weight loss in such studies is stressed. Comments on the paper by Lewis H. Kuller are included (pp. 515-6) as well as a response from the principal author (pp. 517-8).

One-carbon metabolism mediates the interconversion of folates for the synthesis of precursors used in DNA synthesis, repair, and methylation. Inadequate folate nutrition or compromised metabolism can disrupt these processes and facilitate carcinogenesis. In this study, we investigated associations of 39 candidate single nucleotide polymorphisms (SNP) in 9 one-carbon metabolism genes with risk of prostate cancer using 1,144 cases and 1,144 controls from the Cancer Prevention Study-II Nutrition Cohort. None of these SNPs were significantly associated with prostate cancer risk, either overall or in cases with advanced prostate cancer. Thus, our findings do not support the hypothesis that common genetic variation in one-carbon metabolism genes influences prostate cancer risk. (Cancer Epidemiol Biomarkers Prev 2008;17(12):3612–4)

Lung cancer is the most preventable of all of the major forms of cancer because 85% to 90% of deaths from lung cancer are a result of active cigarette smoking. However, even in people who have never smoked, lung cancer accounts for approximately 15,000 deaths annually, similar to the number of deaths projected for ovarian cancer in 2006 and more than the number of deaths projected for brain cancer, bladder cancer, or multiple myeloma. Two important articles in this issue provide insights about sex differences in the epidemiology and molecular characteristics of lung cancer in lifelong nonsmokers. Nearly a decade ago, one of us (A.F.G.) postulated that differences in the histologic distribution of lung cancer between men and women signaled important differences in disease pathogenesis in response to tobacco smoke. Today, the evidence is substantially stronger, yet the issue seems more complex than ever. The report by Wakelee et al provides the first direct evidence that lung cancer incidence is higher among women than men who have never smoked based on five prospective cohort studies in the United States and one in Sweden. These data are particularly interesting because previous studies of lung cancer in lifelong nonsmokers have examined death rates but not incidence. Two massive American Cancer Society cohorts, together with other studies that are smaller or have shorter follow-up, collectively demonstrate that the death rate from lung cancer is approximately 25% higher in men than in women who have never smoked. It is important that other large cohorts attempt to replicate the observation by Wakelee et al that the opposite seems to be true for lung cancer incidence in never smokers age 40 to 79 years. Furthermore, replication would support the hypothesis by Henschke et al that women may be more susceptible to develop lung cancer than men but are less likely to die from the disease. Studies are also needed to determine whether the survival difference between male and female never smokers is large enough to account for the lower lung cancer death rates in women despite their higher incidence. Wakelee et al also note that the proportion of lung cancers that are adenocarcinoma is highest among male and female lifelong nonsmokers, intermediate in former smokers, and lowest in current smokers. It is well known that adenocarcinoma is the predominant cell type of lung cancer in women and in lifelong nonsmokers. What is less well known is that comparisons of proportions do not provide a direct comparison of risk. For example, although adenocarcinoma makes up a larger proportion of lung cancers in women than in men age 50 years and older, the incidence rate of adenocarcinoma is actually higher in men than women in the same age groups based on population-based cancer incidence registries in the United States. The reason why adenocarcinoma predominates in women is not that the risk of developing adenocarcinoma is higher in women than in men, but rather that the risk of developing other cell types of lung cancer, particularly squamous cell and small-cell cancers, is much lower. As Wakelee et al indicate, their study has certain limitations; it cannot assess whether the incidence of lung cancer among lifelong nonsmokers has changed over time or whether the pattern differs in geographic regions other than North America and northern Europe. Several prior studies have indicated that the proportion of never smokers in females with lung cancers is much higher than their male counterparts in certain parts of China and other Asian countries where women are exposed to indoor air pollution from unventilated fumes from cooking and heating at much higher concentrations than in the West. Here, too, comparisons of proportions are less informative than are comparisons based on incidence rates. In Asia, even more than in the United States, women comprise the majority of lifelong nonsmokers over age 60 years. The larger denominator, rather than any inherent sex difference in susceptibility, may explain why women outnumber men among never smokers with lung cancer. Subramanian and Govindan provide a comprehensive review of the current state of our knowledge about lung cancers in never smokers. Although they do not specifically point out the relationship between tobacco exposure and sex, many of the features of this disease, as discussed in their review, indicate a close interaction (Table 1). The higher incidence rate in women who have never smoked has already been discussed. Peripherally arising adenocarcinomas account for the majority of lung cancers occurring both in never smokers and in women. For practical purposes, centrally located small-cell carcinomas virtually never occur in never smokers, and squamous cell carcinomas are relatively rare. The role of estrogens and their receptors is complex and multifaceted, as summarized by Subramanian and Govindan and in other studies, and estrogens and their receptors may play a role in the pathogenesis of cancers occurring in smokers and never smokers. By influencing expression of polymorphic genes that regulate tobacco carcinogen metabolism, estrogens may play a role in carcinogenesis both by sex bias and at an individual level. Of interest, lung cancers may, on occasion, express relatively high levels of estrogen receptors alpha and beta, but their expression does not seem to show a sex bias (J. Minna and Y. Jeong, personal communication, October 2006). Studies from Taiwan suggest that JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 25 NUMBER 5 FEBRUARY 1

Although tobacco smoking causes many diseases and affects most of the organ systems in the body, lung cancer is typically the first condition that comes to mind when one considers the health impact of smoking. Lung cancer is also one of the most important and devastating illnesses caused by smoking, given its high incidence in populations where smoking is common, its high fatality rate, and the difficulty in detecting the disease when it is still localised. Therefore we commissioned an update on lung cancer and smoking from Dr Michael Thun of the American Cancer Society, which appears below. Shown on the cover of this issue of “Tobacco Control” are four false-colour scanning electron micrographs of lung cancer, obtained from the Science Photo Library in London ( http://www.sciencephoto.com ). The upper left image shows cancer of the human bronchus, the most common form of lung cancer. Until the 1970s, such cancers usually occurred near the division of the trachea or large bronchi into smaller bronchi, because this area suffers from heavy deposition of the carcinogenic tars from high tar cigarettes. However, squamous carcinomas in large airways have now become less common than adenocarcinomas in small, peripheral airways, paralleling the shift from “high” to “medium” and “lower” yield cigarettes, the smoke from which is inhaled more deeply. The disorganised region of malignant tumour cells at the bottom right of this image is seen invading the normal, ciliated epithelium (or lining) of the bronchus at the left and top. Cancers consist of primitive cells which have not developed any function, such as the cilia of normal, bronchial epithelial cells. (The cilia are small, hair-like projections used to sweep mucus, debris, and microorganisms out of the lung.) The upper right image shows a tiny lung cancer (orange) filling an alveolus (one of the blind-ended air sacs …

OBJECTIVE: Investigate risk factors for colon polyp using multivariate analyses. DESIGN: In a group responding to a 1992 mail survey, we assessed the association between physician-diagnosed colon polyp and possible risk factors reported primarily 10 years earlier. SETTING: Survey respondents within the Cancer Prevention Study II. PARTICIPANTS: Respondents, 72,868 men and 81,356 women, who reported no polyp diagnosis when questioned in 1982 at ages 40 to 64 years. MEASUREMENTS AND MAIN RESULTS: The characteristics of 7,504 men (10.3%) and 5,111 women (6.3%) reporting a first colon polyp were compared with those of participants who did not report a polyp. After adjustments for age, family history of colorectal cancer, and other potential risk factors, polyp occurrence was associated with 1982 histories of smoking, former smoking, alcohol use of at least two drinks per day (odds ratios [ORs] from 1.5 to 1.1; all p

Objectives: Diabetes mellitus and pancreatic cancer are known to be associated, but it is not known whether diabetes is a true risk factor, preceding development of the cancer, or if it is an early manifestation of the cancer. To address this uncertainty, we examined the association of pancreatic cancer mortality and reported diabetes of at least one year's duration in a large, prospective study of United States adults. The vast majority of diabetes in this cohort is likely to be non-insulin-dependent diabetes. Methods: After 12 years of follow-up, 2,953 deaths from pancreatic cancer were observed in a cohort of 1,089,586 men and women who were cancer-free at study entry in 1982. Cox proportional hazards models, adjusted for age, race, smoking, family history of pancreatic cancer, body mass index (wt/ht2), and education, were used to assess associations. Results: A history of diabetes was significantly related to pancreatic cancer mortality in both men (rate ratio [RR]=1.49, 95 percent confidence interval [CI]=1.25-1.77) and women (RR=1.51, CI=1.24-1.85). However, the strength of the association varied over the follow-up period. The death rate from pancreatic cancer was twice as high in diabetics as in non-diabetics during the second and third years of follow-up (adjusted RR=2.05, CI=1.56-2.69) but only about 40 percent higher in years nine to 12 (adjusted RR=1.38, CI=1.08-1.77). Conclusions: The small but persistent increased risk of death from pancreatic cancer, seen even when the diagnosis of diabetes preceded death by many years, supports the hypothesis that diabetes may be a true, albeit modest, risk factor for pancreatic cancer.

Objectives: It is difficult to separate the possible role of fertility drugs from underlying infertility as risk factors for ovarian cancer. The present study examined the relationship between self-reported infertility and death from ovarian cancer among married women unlikely to have been exposured to fertility drugs. Methods: Women were selected for study from the 676,526 female participants in Cancer Prevention Study II (CPS-II). After twelve years of follow-up, 797 deaths from ovarian cancer were observed among women with no prior history of cancer or hysterectomy and 40 years of age or older in 1967 when ovulatory stimulants were approved in the United States. Cox proportional hazards modeling was used to compute rate ratios (RRs) and to adjust for other potential risk factors. Results: Overall, self-reported infertility was not significantly associated with ovarian cancer mortality (adjusted rate ratio (RR) = 1.1, 95 percent confidence interval (CI) = 0.9-1.3). Ovarian cancer death rates among nulligravid women with self-reported infertility, however, were 40 percent higher than for nulligravid women who never tried to become pregnant (RR = 1.4, 95 percent CI = 0.9-2.4). Multigravid women who reported infertility problems were not at increased risk. Conclusions: These results suggest that infertility itself, without concomitant exposure to fertility drugs, may increase risk of fatal ovarian cancer among nulligravid women.

BACKGROUND: The effect of age on optimal body weight is controversial, and few studies have had adequate numbers of subjects to analyze mortality as a function of body-mass index across age groups. METHODS: We studied mortality over 12 years among white men and women who participated in the American Cancer Society's Cancer Prevention Study I (from 1960 through 1972). The 62,116 men and 262,019 women included in this analysis had never smoked cigarettes, had no history of heart disease, stroke, or cancer (other than skin cancer) at base line in 1959-1960, and had no history of recent unintentional weight loss. The date and cause of death for subjects who died were determined from death certificates. The associations between body-mass index (defined as the weight in kilograms divided by the square of the height in meters) and mortality were examined for six age groups in analyses in which we adjusted for age, educational level, physical activity, and alcohol consumption. RESULTS: Greater body-mass index was associated with higher mortality from all causes and from cardiovascular disease in men and women up to 75 years of age. However, the relative risk associated with greater body-mass index declined with age. For example, for mortality from cardiovascular disease, the relative risk associated with an increment of 1 in the body-mass index was 1.10 (95 percent confidence interval, 1.04 to 1.16) for 30-to-44-year-old men and 1.03 (95 percent confidence interval, 1.02 to 1.05) for 65-to-74-year-old men. For women, the corresponding relative risk estimates were 1.08 (95 percent confidence interval, 1.05 to 1.11) and 1.02 (95 percent confidence interval, 1.02 to 1.03). CONCLUSIONS: Excess body weight increases the risk of death from any cause and from cardiovascular disease in adults between 30 and 74 years of age. The relative risk associated with greater body weight is higher among younger subjects.

Background: Adenocarcinoma of the lung, once considered minimally related to cigarette smoking, has become the most common type of lung cancer in the United States. The increased incidence of this cancer might be explained by advances in diagnostic technology (i.e., increased ability to perform biopsies on tumors in smaller, more distal airways), changes in cigarette design (e.g., the adoption of filtertips), or changes in smoking practices. We examined data from the Connecticut Tumor Registry and two American Cancer Society studies to explore these possibilities. Methods: Connecticut Tumor Registry data from 1959 through 1991 were analyzed to determine whether the increase in lung adenocarcinoma observed during that period could be best described by birth cohort effects (i.e., generational changes in cigarette smoking) or calendar period effects (i.e., diagnostic advances). Associations between cigarette smoking and death from specific types of lung cancer during the first 2 years of follow-up in Cancer Prevention Study I (CPS-I), initiated in 1959) and Cancer Prevention Study II (CPS-II, initiated in 1982) were also examined. Results: Adenocarcinoma incidence in Connecticut increased nearly 17-fold in women and nearly 10-fold in men from 1959 through 1991. The increases followed a clear birth cohort pattern, paralleling gender and generational changes in smoking more than diagnostic advances. Cigarette smoking became more strongly associated with death from lung adenocarcinoma in CPS-II compared with CPS-I, with relative risks of 19.0 (95% confidence interval [CI] = 8.3‐47.7) for men and 8.1 (95% CI = 4.5‐14.6) for women in CPS-II and 4.6 (95% CI = 1.7‐12.6) for men and 1.5 (0.3‐7.7) for women in CPS-I. Conclusions: The increase in lung adenocarcinoma since the 1950s is more consistent with changes in smoking behavior and cigarette design than with diagnostic advances. [J Natl Cancer Inst 1997;89:1580‐6]

The authors examined the relation between smoking and the risk of fatal prostate cancer in a large prospective mortality study of 450,279 men who were cancer free at enrollment in 1982. During 9 years of follow-up, 1,748 deaths occurred from prostate cancer. Cox proportional hazards modeling was used to adjust for other risk factors. Current cigarette smoking was associated with fatal prostate cancer (rate ratio = 1.34, 95% confidence interval (CI) 1.16-1.56). The rate ratio was greater at younger ages, decreasing from 1.83 (95% CI 1.04-3.24) among men below the age of 60 years to 1.11 (95% CI 0.79-1.58) among men aged 80 years and above (p for trend = 0.16). No trend in risk was observed with the number of cigarettes per day or with the duration of smoking among current smokers at baseline, and no increased risk was found among former smokers. Race did not significantly modify the association between cigarette smoking and fatal prostate cancer. These data, together with those of three other large prospective studies that find higher death rates from prostate cancer in current cigarette smokers, and inconsistent findings in incidence studies suggest that smoking may adversely affect survival in prostate cancer patients.

Several studies suggest that tubal sterilization may decrease the risk of ovarian cancer. Data from the Cancer Prevention Study II were analyzed to examine the relation between tubal ligation and ovarian cancer mortality in a large prospective study. A total of 396,114 women who had not had hysterectomies and who had no prior history of cancer (except nonmelanoma skin cancer) were followed prospectively for approximately 9 years from 1982 to 1991. During this time, 799 ovarian cancer deaths were observed. Tubal ligation was significantly associated with a decreased risk of ovarian cancer mortality in an age- and race-adjusted Cox proportional hazards model (hazard ratio (HR) = 0.64, 95% confidence interval (CI) 0.42-0.96), and the results were essentially unchanged when controlling for potential ovarian cancer risk factors (HR = 0.68, 95% CI 0.45-1.03). The protective effect appeared to be greater in the first 20 years after the procedure (HR = 0.49, 95% CI 0.24-0.99) than later (HR = 0.80, 95% CI 0.48-1.34). No interactions between ever having had a tubal ligation and other covariates were observed. These data suggest that tubal ligation reduces the risk of fatal ovarian cancer.

Environmental tobacco smoke (ETS) has been classified as a human lung carcinogen by the United States Environmental Protection Agency (EPA), based both on the chemical similarity of sidestream and mainstream smoke and on slightly higher lung cancer risk in never-smokers whose spouses smoke compared with those married to nonsmokers. We evaluated the relation between ETS and lung cancer prospectively in the US, among 114,286 female and 19,549 male never-smokers, married to smokers, compared with about 77,000 female and 77,000 male never-smokers whose spouses did not smoke. Multivariate analyses, based on 247 lung cancer deaths, controlled for age, race, diet, and occupation. Dose-response analyses were restricted to 92,222 women whose husbands provided complete information on cigarette smoking and date of marriage. Lung cancer death rates, adjusted for other factors, were 20 percent higher among women whose husbands ever smoked during the current marriage than among those married to never-smokers (relative risk [RR]=1.2, 95 percent confidence interval [CI]=0.8-1.6). For never-smoking men whose wives smoked, the RR was 1.1 (CI=0.6-1.8). Risk among women was similar or higher when the husband continued to smoke (RR=1.2, CI=0.8-1.8), or smoked 40 or more cigarettes per day (RR=1.9, CI=1.0-3.6), but did not increase with years of marriage to a smoker. Most CIs included the null. Although generally not statistically significant, these results agree with the EPA summary estimate that spousal smoking increases lung cancer risk by about 20 percent in never-smoking women. Even large prospective studies have limited statistical power to measure precisely the risk from ETS.

Our objective was to determine if amyotrophic lateral sclerosis (ALS) risk varies according to body mass index (BMI) captured up to three decades earlier. At baseline 537,968 females and 562,942 males in five ongoing cohorts reported height, current weight and weight at age 18/21 years. During 14-28 years of follow-up, 1153 participants developed ALS. Cohort-specific Cox proportional hazards models were used to estimate rates that were then pooled with random-effects models. Results showed that lower BMI at baseline was associated with ALS; for each 5-unit increase in BMI, ALS rates were 21% lower (95% CI 14%-27%). Compared to individuals with healthy BMI, ALS rates were significantly lower among the overweight (RR = 0.76 (95% CI 0.62-0.93)) and obese (RR = 0.73 (95% CI 0.55-0.96)). Among never smokers the association persisted: RR = 0.75 (95% CI 0.65-0.85) for each 5-unit increase. Excluding the first seven years of follow-up, the associations were materially unchanged suggesting that weight loss from undiagnosed disease does not fully explain the findings. Overall, 75% of males and females had a healthy BMI at age 18/21 years, 15% of males and 8% of females were overweight or obese; there was no association with ALS although numbers with an unhealthy weight were small. In conclusion, these findings support an association between lower premorbid BMI and ALS.

Bladder cancer results from the combined effects of environmental and genetic factors, smoking being the strongest risk factor. Evaluating absolute risks resulting from the joint effects of smoking and genetic factors is critical to assess the public health relevance of genetic information. Analyses included up to 3,942 cases and 5,680 controls of European background in seven studies. We tested for multiplicative and additive interactions between smoking and 12 susceptibility loci, individually and combined as a polygenic risk score (PRS). Thirty-year absolute risks and risk differences by levels of the PRS were estimated for U.S. males aged 50 years. Six of 12 variants showed significant additive gene–environment interactions, most notably NAT2 (P = 7 × 10−4) and UGT1A6 (P = 8 × 10−4). The 30-year absolute risk of bladder cancer in U.S. males was 6.2% for all current smokers. This risk ranged from 2.9% for current smokers in the lowest quartile of the PRS to 9.9% for current smokers in the upper quartile. Risk difference estimates indicated that 8,200 cases would be prevented if elimination of smoking occurred in 100,000 men in the upper PRS quartile compared with 2,000 cases prevented by a similar effort in the lowest PRS quartile (Padditive = 1 × 10−4). Thus, the potential impact of eliminating smoking on the number of bladder cancer cases prevented is larger for individuals at higher than lower genetic risk. Our findings could have implications for targeted prevention strategies. However, other smoking-related diseases, as well as practical and ethical considerations, need to be considered before any recommendations could be made. Cancer Res; 73(7); 2211–20. ©2012 AACR.

Few large prospective studies have examined associations between nonsteroidal anti-inflammatory drug (NSAID) use and non-Hodgkin lymphoma (NHL). We examined the association between NSAID use and NHL incidence among 149,570 participants in the Cancer Prevention Study-II Nutrition cohort. Aspirin and nonaspirin NSAID use were reported at enrollment in 1992 and updated on periodic follow-up questionnaires. During follow-up through 2007, 1,709 incident NHLs were identified. Time-dependent hazard ratios were calculated using extended Cox regression. Compared to no use, current use of 60+ NSAID pills/month (aspirin and nonaspirin NSAIDs combined) was associated with slightly higher NHL incidence (hazard ratio [HR] = 1.26, 95% confidence interval [CI], 1.04–1.53), but no association with frequency of use was observed when NSAID exposure was lagged by approximately 2 years (HR = 1.08, 95% CI, 0.88–1.32). Long duration regular use (current use of 30+ pills/month for ≥5 years) was not associated with NHL incidence (HR = 1.09, 95% CI, 0.91–1.33). In subtype analyses, current use of 60+ NSAID pills/month was associated with follicular lymphoma incidence (HR = 1.87, 95% CI, 1.08–3.24). This association persisted when NSAID exposure was lagged (HR = 1.76, 95% CI, 1.04–2.98) and was similar for aspirin and nonaspirin NSAIDs. The association of current, but not lagged, NSAID use with risk of all NHL could be attributable to use of NSAIDs to relieve symptoms of undiagnosed NHL. However, the association with follicular lymphoma persisted in analyses where NSAID use was lagged and should be investigated further. These findings are particularly important for aspirin as the risks and benefits of prophylactic daily use are weighed. Cancer Epidemiol Biomarkers Prev; 22(3); 422–8. ©2013 AACR.

We thank Lippi and Mattiuzzi for their letter regarding the continuing increase in mortality from lung cancer and COPD that we observed among contemporary cigarette smokers in the United States...

Genome-wide association studies (GWAS) have identified multiple common genetic variants associated with an increased risk of prostate cancer (PrCa), but these explain less than one-third of the heritability. To identify further susceptibility alleles, we conducted a meta-analysis of four GWAS including 5953 cases of aggressive PrCa and 11 463 controls (men without PrCa). We computed association tests for approximately 2.6 million SNPs and followed up the most significant SNPs by genotyping 49 121 samples in 29 studies through the international PRACTICAL and BPC3 consortia. We not only confirmed the association of a PrCa susceptibility locus, rs11672691 on chromosome 19, but also showed an association with aggressive PrCa [odds ratio = 1.12 (95% confidence interval 1.03-1.21), P = 1.4 × 10(-8)]. This report describes a genetic variant which is associated with aggressive PrCa, which is a type of PrCa associated with a poorer prognosis.

The authors examined the association between the use of diethylstilbestrol during pregnancy and the risk of subsequent fatal breast cancer in a large prospective study of US adults. After 9 years of follow-up, 1,574 cases of fatal breast cancer were observed among 501,536 gravid women who reported no prior history of cancer in 1982. Results from Cox proportional hazards models showed a positive association between a history of diethylstilbestrol exposure (reported by 3.9% of all women) and fatal breast cancer (adjusted rate ratio = 1.34, 95% confidence interval 1.06-1.69). This excess risk did not increase over time; women who were exposed more than 35 years ago (rate ratio = 1.35, 95% confidence interval 0.97-1.87) were not at greater risk than women who were exposed within the past 35 years (rate ratio = 1.39, 95% confidence interval 1.01-1.93). The positive association was not observed in women who used diethylstilbestrol before age 25 years but was seen at all other ages. The age of study participants did not modify the association between exposure and breast cancer, and there were no significant interactions between ever use of diethylstilbestrol and any of the other potential risk factors included in the analysis. These findings are consistent with those of several other studies of diethylstilbestrol exposure and breast cancer.

The accumulating evidence suggests that aspirin or other NSAIDs may prevent or inhibit the development of colon and perhaps other digestive tract cancers. Although the clinical, experimental, and epidemiologic evidence is promising, the hypothesis remains unproven except in the models of chemically induced colon cancer in rodents and adenomatous polyps in patients with FAP. Clinicians should await the results of randomized trials before using NSAIDs for cancer prevention or treatment. Recommendations are as follows: 1. Experimental studies should define the mechanism or mechanisms by which NSAIDs inhibit tumorigenesis in the rodent model. 2. Experimental and clinical studies should define the optimal drug, dosage, and treatment regimen. The new, selective COX-2 inhibitors should be studied for efficacy and toxicity. 3. Epidemiologic studies should continue to explore the issues of dosage, duration, drug, and toxicity. Because full-scale, randomized trials are feasible only for studying intermediate end points such as polyp recurrence or proliferative indices in high-risk populations, epidemiologic studies have an ongoing role. 4. Carefully designed randomized, clinical trials, now underway, are needed to test the efficacy of NSAIDs in inhibiting colorectal polyps or cancer in humans. 5. Better criteria are needed as to who should take aspirin and who should not.

This is a pre-copyedited, author-produced version of an article accepted for publication in International Journal of Epidemiology following peer review. The version of record Gaudet, M.M., Carter, B.D., Brinton, L.A., Falk, R.T., Gram, I.T., Luo, J. ... Gapstur, S.M. (2017). Pooled analysis of active cigarette smoking and invasive breast cancer risk in 14 cohort studies. International Journal of Epidemiology, 46(3), 881-893. https://doi.org/10.1093/ije/dyw288 is available online at: https://doi.org/10.1093/ije/dyw288. Background: The 2014 US Surgeon General’s report noted research gaps necessary to determine a causal relationship between active cigarette smoking and invasive breast cancer risk, including the role of alcohol consumption, timing of exposure, modification by menopausal status and heterogeneity by oestrogen receptor (ER) status. Methods: To address these issues, we pooled data from 14 cohort studies contributing 934 681 participants (36 060 invasive breast cancer cases). Cox proportional hazard regression models were used to calculate multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs). Results: Smoking duration before first birth was positively associated with risk (P-value for trend = 2 × 10–7) with the highest HR for initiation >10 years before first birth (HR = 1.18, CI 1.12–1.24). Effect modification by current alcohol consumption was evident for the association with smoking duration before first birth (P-value=2×10–4); compared with never-smoking non-drinkers, initiation >10 years before first birth was associated with risk in every category of alcohol intake, including non-drinkers (HR = 1.15, CI 1.04–1.28) and those who consumed at least three drinks per day (1.85, 1.55–2.21). Associations with smoking before first birth were limited to risk of ER+ breast cancer (P-value for homogeneity=3×10–3). Other smoking timing and duration characteristics were associated with risk even after controlling for alcohol, but were not associated with risk in non-drinkers. Effect modification by menopause was not evident. Conclusions: Smoking, particularly if initiated before first birth, was modestly associated with ER+ breast cancer risk that was not confounded by amount of adult alcohol intake. Possible links with breast cancer provide additional motivation for young women to not initiate smoking.

OBJECTIVES: This study was undertaken to examine changes in smoking-specific death rates from the 1960s to the 1980s. METHODS: In two prospective studies, one from 1959 to 1965 and the other from 1982 to 1988, death rates from lung cancer, coronary heart disease, and other major smoking-related diseases were measured among more than 200,000 current smokers and 480,000 lifelong non-smokers in each study. RESULTS: From the first to the second study, lung cancer death rates (per 100,000) among current cigarette smokers increased from 26 to 155 in women and from 187 to 341 in men; the increase persisted after current daily cigarette consumption and years of smoking were controlled for. Rates among nonsmokers were stable. In contrast, coronary heart disease and stroke death rates decreased by more than 50% in both smokers and nonsmokers. The all-cause rate difference between smokers and nonsmokers doubled for women but was stable for men. CONCLUSIONS: Premature mortality (the difference in all-cause death rates between smokers and nonsmokers) doubled in women and continued unabated in men from the 1960s to the 1980s. Lung cancer surpassed coronary heart disease as the largest single contributor to smoking-attributable death among White middle-class smokers.

The authors examined the relation between use of estrogen replacement therapy and ovarian cancer mortality in a large prospective mortality study of 240,073 peri- and postmenopausal women, none of whom had a prior history of cancer, hysterectomy, or ovarian surgery at enrollment in 1982. During 7 years of follow-up, 436 deaths from ovarian cancer occurred. Cox proportional hazard regression was used to adjust for other risk factors. Ever use of estrogen replacement therapy was associated with a rate ratio for fatal ovarian cancer of 1.15 (95% confidence interval (CI) 0.94-1.42). The mortality rate ratio increased with duration of use prior to entry to this study to 1.40 (95 CI% 0.92-2.11) with 6-10 years of use and 1.71 (95% CI 1.06-2.77) with > or = 11 years of use. The increase in mortality associated with > or = 6 years of use was observed in both current users (rate ratio (RR) = 1.72, 95% CI 1.01-2.90) and former users at study entry (RR = 1.48, 95% CI 0.99-2.22), relative to never users. Risk associated with use was not modified by any of the other risk factors. These data suggest that long-term use of estrogen replacement therapy may increase the risk of fatal ovarian cancer.

BACKGROUND The results of several recent epidemiologic studies suggest that estrogen replacement therapy (ERT) in postmenopausal women may decrease their risk of subsequently developing colon or colorectal cancer. However, the association is not clear, as other similar studies have failed to show this inverse relationship. PURPOSE The present study attempts a more definitive analysis of the relationship between fatal colon cancer and use of ERT among women in a large prospective study of adults in the United States. METHODS Women were selected for study from the 676,526 female participants in Cancer Prevention Study II (CPS-II), a prospective mortality study of about 1.2 million American men and women (from all 50 states, the District of Columbia, and Puerto Rico), begun by the American Cancer Society in 1982. The median age of the female CPS-II participants was 56 years in 1982. Vital status was determined through December 31, 1989; 630,585 participants (93.2%) were still alive and 43,862 (6.5%) had died after 7 years of follow-up. Death certificates were obtained for 96.2% of participants known to have died. At the end of follow-up, 897 colon cancer deaths were observed in a cohort of 422,373 postmenopausal women who were cancer free at study entry. Cox proportional hazards modeling was used to compute rate ratios (RRs) and to adjust for other potential risk factors. The likelihood ratio test (two-sided) was used to determine the statistical significance of the interaction terms. RESULTS Ever use of ERT was associated with significantly decreased risk of fatal colon cancer (RR = 0.71; 95% confidence interval [CI] = 0.61-0.83). The reduction in risk was strongest among current users (RR = 0.55; 95% CI = 0.40-0.76), and there was a significant (P = .0001) trend of decreasing risk with increasing years of use among all users: Users of 1 year or less had an RR of 0.81 (95% CI = 0.63-1.03), while users of 11 years or more had an RR of 0.54 (95% CI = 0.39-0.76). These associations were not altered in multivariate analyses controlling for other risk factors. CONCLUSIONS In our data, estrogen therapy, particularly recent and long-term use, was associated with a substantial decrease in risk of fatal colon cancer. These results were consistent with several published studies suggesting a protective role of exogenous estrogens in the development of colorectal cancer and merit further investigation.

Time-series, cross-sectional, and prospective cohort studies have observed associations between mortality and particulate air pollution but have been limited by ecologic design or small number of subjects or study areas. The present study evaluates effects of particulate air pollution on mortality using data from a large cohort drawn from many study areas. We linked ambient air pollution data from 151 U.S. metropolitan areas in 1980 with individual risk factor on 552,138 adults who resided in these areas when enrolled in a prospective study in 1982. Deaths were ascertained through December, 1989. Exposure to sulfate and fine particulate air pollution, which is primarily from fossil fuel combustion, was estimated from national data bases. The relationships of air pollution to all-cause, lung cancer, and cardiopulmonary mortality was examined using multivariate analysis which controlled for smoking, education, and other risk factors. Although small compared with cigarette smoking, an association between mortality and particulate air pollution was observed. Adjusted relative risk ratios (and 95% confidence intervals) of all-cause mortality for the most polluted areas compared with the least polluted equaled 1.15 (1.09 to 1.22) and 1.17 (1.09 to 1.26) when using sulfate and fine particulate measures respectively. Particulate air pollution was associated with cardiopulmonary and lung cancer mortality but not with mortality due to other causes. Increased mortality is associated with sulfate and fine particulate air pollution at levels commonly found in U.S. cities. The increase in risk is not attributable to tobacco smoking, although other unmeasured correlates of pollution cannot be excluded with certainty.

Radon is a known cause of human lung cancer. Previously, the authors observed a significant positive association between mean county-level residential radon concentrations and lung cancer mortality in the Cancer Prevention Study II (CPS-II), a large prospective study of nearly 1.2 million participants recruited in 1982 by the American Cancer Society. There was also a significant positive association with mortality from chronic obstructive pulmonary disease. Because it is unclear whether radon is associated with mortality from other malignant or nonmalignant disease, the authors examined the association between radon and nonrespiratory mortality in the CPS-II. Mean county-level residential radon concentrations (mean = 53.5 (standard deviation: 38.0) Bq/m(3)) were linked to participants by their zip code at enrollment. Cox proportional hazards regression models were used to estimate adjusted hazard ratios and 95% confidence intervals for all-cause (excluding lung cancer and respiratory mortality) and cause-specific mortality associated with radon concentrations. A total of 811,961 participants in 2,754 counties were analyzed, including 265,477 deaths through 2006. There were no clear associations between radon and nonrespiratory mortality in the CPS-II. These findings suggest that residential radon is not associated with any other mortality beyond lung cancer or chronic obstructive pulmonary disease.