Anthropometric measures of body fat and obesity-related cancer risk: sex-specific differences in Framingham Offspring Study adults.

BACKGROUND/OBJECTIVE: Obesity has been associated with the risk of developing certain cancers. A limited number of studies have examined effects of various anthropometric measures of body composition on cancer risk. The aim of this study was to estimate the sex-specific effects of various anthropometric measures on risk of obesity-related cancers (ObCa). SUBJECTS/METHODS: Data on body mass index (BMI), waist circumference (WC), waist-to-height ratio (WHtR), and hip circumference (HC) among 3818 45-69-year olds in the Framingham Offspring Study were included. Cox proportional hazards models were used to estimate adjusted risks of 16 obesity-related cancers, with the most common being postmenopausal breast, endometrial, and colon cancers. RESULTS: Obesity as measured by BMI in both men and women was a predictor of ObCa; those in the highest quintile (Q5) of BMI (>30.07 in women; >30.80 kg/m2 in men) had more than twice the risk of ObCa (HR = 2.07; 95% CI: 1.06-4.07 (women) and HR = 2.25; 95% CI: 1.08-4.69 (men)). Waist-related measures (WC, WHtR) were stronger predictors of ObCa in men than in women, and HC confounded the relations between waist size and cancer risk. After adjusting for HC, men in Q5 of WC had more than a threefold increased risk of ObCa (HR: = 3.22; 95% CI: 1.39-7.45). Comparable effects in women were weak and non-statistically significant. Results were similar for WHtR. Finally, an inverse J-shaped relation was found between HC and ObCa after adjusting for WC among men but not in women. CONCLUSIONS: These results suggest that obesity as measured by BMI is a predictor of obesity-related cancer risk in men and women. They also suggest that waist and hip circumference measures are interrelated and confound the independent effects of each measure. Among men, a large waist size and a small hip size are independent predictors of cancer risk.

Midlife weight gain is a risk factor for obesity-related cancer.

BACKGROUND: Overweight and diabetes are known cancer risk factors. This study examines independent and combined effects of weight gain and metabolic dysfunction during middle-adult years on obesity-related cancer risk. METHODS: Subjects (n = 3850) aged 45-69 years at exams 3-5 in the Framingham Offspring Study were classified according to current and prior (~14 years earlier) weight status, interim weight change and prevalent metabolic dysfunction. Cancer risk among subjects who were overweight at baseline and remained overweight, as well as those who became overweight during follow-up, was compared with risk among normal-weight individuals. RESULTS: Gaining ≥0.45 kg (≥1.0 pound)/year (vs. maintaining stable weight) over ~14 years increased cancer risk by 38% (95% confidence interval (CI), 1.09, 1.76); combined with metabolic dysfunction, weight gain increased cancer risk by 77% (95% CI, 1.21, 2.59). Compared with non-overweight adults, men and women who became overweight during midlife had 2.18-fold and 1.60-fold increased cancer risks; those who were overweight from baseline had non-statistically significant 28 and 33% increased cancer risks, respectively, despite having a midlife body mass index that was 3.4 kg/m2 higher than those who gained weight later. CONCLUSION: Midlife weight gain was a strong cancer risk factor. This excess risk was somewhat stronger among those with concurrent metabolic dysfunction.

Association of Initial and Longitudinal Changes in C-reactive Protein With the Risk of Cardiovascular Disease, Cancer, and Mortality.

OBJECTIVE: To evaluate the value of serial C-reactive protein (CRP) measurements in predicting the risk of cardiovascular disease (CVD), cancer, and mortality. METHODS: The analysis was performed using data from two prospective, population-based observational cohorts: the Prevention of Renal and Vascular End-Stage Disease (PREVEND) study and the Framingham Heart Study (FHS). A total of 9253 participants had CRP measurements available at two examinations (PREVEND: 1997-1998 and 2001-2002; FHS Offspring cohort: 1995-1998 and 1998-2001). All CRP measurements were natural log-transformed before analyses. Cardiovascular disease included fatal and nonfatal cardiovascular, cerebrovascular and peripheral vascular events, and heart failure. Cancer included all malignancies except nonmelanoma skin cancers. RESULTS: The mean age of the study population at baseline was 52.4±12.1 years and 51.2% (n=4733) were women. Advanced age, female sex, smoking, body mass index, and total cholesterol were associated with greater increases in CRP levels over time (Pall<.001 in the multivariable model). Baseline CRP, as well as increase in CRP over time (ΔCRP), were associated with incident CVD (hazard ratio [HR]: 1.29 per 1-SD increase; 95% confidence interval [CI]: 1.29 to 1.47, and HR per 1-SD increase: 1.19; 95% CI: 1.09 to 1.29 respectively). Similar findings were observed for incident cancer (baseline CRP, HR: 1.17; 95% CI: 1.09 to 1.26; ΔCRP, HR: 1.08; 95% CI: 1.01 to 1.15) and mortality (baseline CRP, HR: 1.29; 95% CI: 1.21 to 1.37; ΔCRP, HR: 1.10; 95% CI: 1.05 to 1.16). CONCLUSION: Initial as well as subsequent increases in CRP levels predict future CVD, cancer, and mortality in the general population.

Cardiovascular disease related circulating biomarkers and cancer incidence and mortality: is there an association?

AIMS: Recent studies suggest an association between cardiovascular disease (CVD) and cancer incidence/mortality, but the pathophysiological mechanisms underlying these associations are unclear. We aimed to examine biomarkers previously associated with CVD and study their association with incident cancer and cancer-related death in a prospective cohort study. METHODS AND RESULTS: We used a proteomic platform to measure 71 cardiovascular biomarkers among 5032 participants in the Framingham Heart Study who were free of cancer at baseline. We used multivariable-adjusted Cox models to examine the association of circulating protein biomarkers with risk of cancer incidence and mortality. To account for multiple testing, we set a 2-sided false discovery rate <0.05. Growth differentiation factor-15 (also known as macrophage inhibitory cytokine-1) was associated with increased risk of incident cancer [hazards ratio (HR) per 1 standard deviation increment 1.31, 95% CI 1.17-1.47], incident gastrointestinal cancer (HR 1.85, 95% CI 1.37-2.50), incident colorectal cancer (HR 1.94, 95% CI 1.29-2.91), and cancer-related death (HR 2.15, 95% CI 1.72-2.70). Stromal cell-derived factor-1 showed an inverse association with cancer-related death (HR 0.75, 95% CI 0.65-0.86). Fibroblast growth factor-23 showed an association with colorectal cancer (HR 1.55, 95% CI 1.20-2.00), and granulin was associated with haematologic cancer (HR 1.61, 95% CI 1.30-1.99). Other circulating biomarkers of inflammation, immune activation, metabolism, and fibrosis showed suggestive associations with future cancer diagnosis. CONCLUSION: We observed several significant associations between circulating CVD biomarkers and cancer, supporting the idea that shared biological pathways underlie both diseases. Further investigations of specific mechanisms that lead to both CVD and cancer are warranted.

Association of Cardiometabolic Disease With Cancer in the Community.

Background: Obesity and cardiometabolic dysfunction have been associated with cancer risk and severity. Underlying mechanisms remain unclear. Objectives: The aim of this study was to examine associations of obesity and related cardiometabolic traits with incident cancer. Methods: FHS (Framingham Heart Study) and PREVEND (Prevention of Renal and Vascular End-Stage Disease) study participants without prevalent cancer were studied, examining associations of obesity, body mass index (BMI), waist circumference, visceral adipose tissue (VAT) and subcutaneous adipose tissue depots, and C-reactive protein (CRP) with future cancer in Cox models. Results: Among 20,667 participants (mean age 50 years, 53% women), 2,619 cancer events were observed over a median follow-up duration of 15 years. Obesity was associated with increased risk for future gastrointestinal (HR: 1.30; 95% CI: 1.05-1.60), gynecologic (HR: 1.62; 95% CI: 1.08-2.45), and breast (HR: 1.32; 95% CI: 1.05-1.66) cancer and lower risk for lung cancer (HR: 0.62; 95% CI: 0.44-0.87). Similarly, waist circumference was associated with increased risk for overall, gastrointestinal, and gynecologic but not lung cancer. VAT but not subcutaneous adipose tissue was associated with risk for overall cancer (HR: 1.22; 95% CI: 1.05-1.43), lung cancer (HR: 1.92; 95% CI: 1.01-3.66), and melanoma (HR: 1.56; 95% CI: 1.02-2.38) independent of BMI. Last, higher CRP levels were associated with higher risk for overall, colorectal, and lung cancer (P < 0.05 for all). Conclusions: Obesity and abdominal adiposity are associated with future risk for specific cancers (eg, gastrointestinal, gynecologic). Although obesity was associated with lower risk for lung cancer, greater VAT and CRP were associated with higher lung cancer risk after adjusting for BMI.

A genome-wide association study of breast and prostate cancer in the NHLBI's Framingham Heart Study.

BACKGROUND: Breast and prostate cancer are two commonly diagnosed cancers in the United States. Prior work suggests that cancer causing genes and cancer susceptibility genes can be identified. METHODS: We conducted a genome-wide association study (Affymetrix 100K SNP GeneChip) of cancer in the community-based Framingham Heart Study. We report on 2 cancer traits--prostate cancer and breast cancer--in up to 1335 participants from 330 families (54% women, mean entry age 33 years). Multivariable-adjusted residuals, computed using Cox proportional hazards models, were tested for association with qualifying SNPs (70, 987 autosomal SNPs with genotypic call rate > or =80%, minor allele frequency > or =10%, Hardy-Weinberg test p > or = 0.001) using generalized estimating equations (GEE) models and family based association tests (FBAT). RESULTS: There were 58 women with breast cancer and 59 men with prostate cancer. No SNP associations attained genome-wide significance. The top SNP associations in GEE models for each trait were as follows: breast cancer, rs2075555, p = 8.0 x 10(-8) in COL1A1; and prostate cancer, rs9311171, p = 1.75 x 10(-6) in CTDSPL. In analysis of selected candidate cancer susceptibility genes, two MSR1 SNPs (rs9325782, GEE p = 0.008 and rs2410373, FBAT p = 0.021) were associated with prostate cancer and three ERBB4 SNPs (rs905883 GEE p = 0.0002, rs7564590 GEE p = 0.003, rs7558615 GEE p = 0.0078) were associated with breast cancer. The previously reported risk SNP for prostate cancer, rs1447295, was not included on the 100K chip. Results of cancer phenotype-genotype associations for all autosomal SNPs are web posted at http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?id=phs000007 webcite. CONCLUSION: Although no association attained genome-wide significance, several interesting associations emerged for breast and prostate cancer. These findings can serve as a resource for replication in other populations to identify novel biologic pathways contributing to cancer susceptibility.

Alcohol consumption and risk of lung cancer: the Framingham Study.

BACKGROUND: Reports on the association between alcohol consumption and the risk of lung cancer have been inconsistent. The purpose of this study was to assess this association in a cohort study. METHODS: This study included 4265 participants in the original population-based Framingham Study cohort and 4973 subjects in the offspring cohort. Alcohol consumption data were collected periodically for both cohorts. We used the risk sets method to match control subjects to each case patient based on age, sex, smoking variables, and year of birth. We used a conditional logistic regression model to estimate the relative risk of lung cancer according to alcohol consumption. RESULTS: Alcohol consumption was generally light to moderate (i.e., <12 g/day) in both cohorts. During mean follow-ups of 32.8 years in the original and 16.2 years in the offspring cohorts, 269 cases of lung cancer occurred. In categories of total alcohol consumption of 0, 0.1-12, 12.1-24, and greater than 24 g/day, the crude incidence rates of lung cancer were 7.4, 13.6, 16.4, and 25.2 cases per 10 000 person-years, respectively, in the original cohort and 6.6, 4.3, 7.9, and 12.3 cases per 10 000 person-years, respectively, in the offspring cohort. However, after adjustment for age, sex, pack-years of smoking, smoking status, and year of birth in a multivariable conditional logistic regression model, relative risks for lung cancer from the lowest to the highest category of alcohol consumption were 1.0 (referent), 1.0 (95% confidence interval [CI] = 0.5 to 2.1), 1.0 (95% CI = 0.5 to 2.3), and 1.1 (95% CI = 0.5 to 2.3), respectively, in the original cohort and 1.0, 1.4 (95% CI = 0.5 to 3.6), 1.1 (95% CI = 0.3 to 3.6), and 2.0 (95% CI = 0.7 to 5.7), respectively, in the offspring cohort. CONCLUSION: Alcohol consumption among subjects in the Framingham Study, most of whom were light to moderate drinkers, was not statistically significantly associated with the risk of lung cancer.

Fat quality and incident cardiovascular disease, all-cause mortality, and cancer mortality.

CONTEXT: Cellular characteristics of fat quality have been associated with cardiometabolic risk and can be estimated by computed tomography (CT) attenuation. OBJECTIVE: The aim was to determine the association between CT attenuation (measured in Hounsfield units [HU]) and clinical outcomes. METHODS: This was a prospective community-based cohort study using data from the Framingham Heart Study (n = 3324, 48% women, mean age 51 years) and Cox proportional hazard models. MAIN OUTCOMES: The primary outcomes of interest were incident cardiovascular disease (CVD) and all-cause mortality. The secondary outcomes of interest were incident cancer, non-CVD death, and cancer death. RESULTS: There were 111 incident CVD events, 137 incident cancers, 85 deaths including 69 non-CVD deaths, and 45 cancer deaths in up to 23 047 person-years of follow-up. A 1-SD increment in visceral adipose tissue (VAT) HU was inversely associated with incident CVD in the age- and sex-adjusted model (hazard ratio [HR] 0.78, P = .02) but not after multivariable adjustment (HR 0.83, P = .11). VAT HU was directly associated with all-cause mortality (multivariable HR 1.40, P = .003), which maintained significance after additional adjustment for body mass index (HR 1.53, P < .001) and VAT volume (HR 1.99, P < .001). Non-CVD death remained significant in all 3 models, including after adjustment for VAT volume (HR 1.97, P < .001). VAT HU was also associated with cancer mortality (HR 1.93, P = .002). Similar results were obtained for sc adipose tissue HU. CONCLUSIONS: Fat quality, as estimated by CT attenuation, is associated with all-cause mortality, non-CVD death, and cancer death. These associations highlight how indirect indices of fat quality can potentially add to a better understanding of obesity-related complications.

Bone mass and the risk of prostate cancer: the Framingham Study.

PURPOSE: To examine the relation of bone mass-a potential biologic marker for cumulative exposure to androgens, insulin-like growth factors, and calcium intake-to subsequent development of prostate cancer. METHODS: We used radiogrammetry to measure the second metacarpal cortical area of 1012 white men with no history of prostate cancer who had undergone posteroanterior hand radiography between 1967 and 1970. Participants were followed until the end of 1999. All incident cases of prostate cancer were confirmed histologically. We examined bone mass in relation to the risk of prostate cancer using a Cox proportional hazards model. RESULTS: During follow-up, 100 men developed prostate cancer. Incidence rates per 1000 person-years were 3.8 among men in the lowest quartile of bone mass, 4.8 in the second quartile, 7.4 in the third quartile, and 6.5 in the highest quartile. Compared with men in the lowest quartile of bone mass, the multivariate-adjusted rate ratio was 1.3 (95% confidence interval [CI]: 0.7 to 2.5) for those in the second quartile, 1.9 (95% CI: 1.0 to 3.4) in the third quartile, and 1.6 (95% CI: 0.9 to 3.0) in the highest quartile (P for trend = 0.06). CONCLUSION: Men with high bone mass may be at an increased risk of prostate cancer. Although the biological mechanisms underlying this relation are not understood, cumulative exposure to high levels of androgen, insulin-like growth factor 1, or calcium intake may be involved.

Metabolic health reduces risk of obesity-related cancer in framingham study adults.

BACKGROUND: It is unknown whether the risk for obesity-related cancers differs between metabolically unhealthy and healthy overweight/obese adults. METHODS: Data on body mass index (BMI), waist circumference (WC), waist-to-height ratio (WHtR), and random blood glucose in Framingham Heart Study adults (n = 3,763) ages 55 to 69 years were used to estimate risks of obesity-related cancers (n = 385), including postmenopausal breast, female reproductive, colon, liver, gallbladder, pancreas, and kidney cancers, as well as esophageal adenocarcinomas. Multivariable-adjusted Cox proportional hazards models were used to estimate risk for obesity-related cancers associated with body fat and metabolic health (as defined by glucose levels) among subjects in three risk groups (vs. referent group with normal weight/normal glucose): normal weight/elevated glucose, overweight/normal glucose, and overweight/elevated glucose. RESULTS: Overweight adults [BMI ≥ 25 or WHtR ≥ 0.51 (men) and ≥0.57 (women)] with elevated glucose (≥125 mg/dL) had a statistically significant 2-fold increased risk of developing obesity-related cancer, whereas overweight adults with normal glucose had a 50% increased risk. Normal-weight adults with elevated glucose had no excess cancer risk. The effects of BMI and WHtR were independent of one another. Finally, overweight women with elevated blood glucose had a 2.6-fold increased risk [95% confidence interval (CI), 1.4-4.9] of female reproductive (cervical, endometrial, uterine cancers) and postmenopausal breast cancers, whereas overweight women with normal glucose levels had only a 70% increased risk (95% CI, 1.1-2.5). CONCLUSION: These results suggest that cancer risk may be lower among metabolically healthy overweight/obese older adults than among overweight/obese adults with metabolic dysfunction. IMPACT: Metabolic dysfunction and obesity act synergistically to increase cancer risk.

Body fat distribution, incident cardiovascular disease, cancer, and all-cause mortality.

OBJECTIVES: The aim of this study was to determine whether ectopic fat depots are prospectively associated with cardiovascular disease, cancer, and all-cause mortality. BACKGROUND: The morbidity associated with excess body weight varies among individuals of similar body mass index. Ectopic fat depots may underlie this risk differential. However, prospective studies of directly measured fat are limited. METHODS: Participants from the Framingham Heart Study (n = 3,086; 49% women; mean age of 50.2 years) underwent assessment of fat depots (visceral adipose tissue, pericardial adipose tissue, and periaortic adipose tissue) using multidetector computed tomography and were followed up longitudinally for a median of 5.0 years. Cox proportional hazards regression models were used to examine the association of each fat depot (per 1 SD increment) with the risk of incident cardiovascular disease, cancer, and all-cause mortality after adjustment for standard risk factors, including body mass index. RESULTS: Overall, there were 90 cardiovascular events, 141 cancer events, and 71 deaths. After multivariable adjustment, visceral adipose tissue was associated with cardiovascular disease (hazard ratio: 1.44; 95% confidence interval: 1.08 to 1.92; p = 0.01) and cancer (hazard ratio: 1.43; 95% confidence interval: 1.12 to 1.84; p = 0.005). Addition of visceral adipose tissue to a multivariable model that included body mass index modestly improved cardiovascular risk prediction (net reclassification improvement of 16.3%). None of the fat depots were associated with all-cause mortality. CONCLUSIONS: Visceral adiposity is associated with incident cardiovascular disease and cancer after adjustment for clinical risk factors and generalized adiposity. These findings support the growing appreciation of a pathogenic role of ectopic fat.

Inverse association between cancer and Alzheimer's disease: results from the Framingham Heart Study.

OBJECTIVES: To relate cancer since entry into the Framingham Heart Study with the risk of incident Alzheimer's disease and to estimate the risk of incident cancer among participants with and without Alzheimer's disease. DESIGN: Community based prospective cohort study; nested age and sex matched case-control study. SETTING: Framingham Heart Study, USA. PARTICIPANTS: 1278 participants with and without a history of cancer who were aged 65 or more and free of dementia at baseline (1986-90). MAIN OUTCOME MEASURES: Hazard ratios and 95% confidence intervals for the risks of Alzheimer's disease and cancer. RESULTS: Over a mean follow-up of 10 years, 221 cases of probable Alzheimer's disease were diagnosed. Cancer survivors had a lower risk of probable Alzheimer's disease (hazard ratio 0.67, 95% confidence interval 0.47 to 0.97), adjusted for age, sex, and smoking. The risk was lower among survivors of smoking related cancers (0.26, 0.08 to 0.82) than among survivors of non-smoking related cancers (0.82, 0.57 to 1.19). In contrast with their decreased risk of Alzheimer's disease, survivors of smoking related cancer had a substantially increased risk of stroke (2.18, 1.29 to 3.68). In the nested case-control analysis, participants with probable Alzheimer's disease had a lower risk of subsequent cancer (0.39, 0.26 to 0.58) than reference participants, as did participants with any Alzheimer's disease (0.38) and any dementia (0.44). CONCLUSIONS: Cancer survivors had a lower risk of Alzheimer's disease than those without cancer, and patients with Alzheimer's disease had a lower risk of incident cancer. The risk of Alzheimer's disease was lowest in survivors of smoking related cancers, and was not primarily explained by survival bias. This pattern for cancer is similar to that seen in Parkinson's disease and suggests an inverse association between cancer and neurodegeneration.

Alcohol consumption and the risk of bladder cancer in the Framingham Heart Study.

The association between alcohol consumption and bladder cancer is controversial. We used data from 10,125 participants in the Framingham Heart Study to assess the association between total and beverage-specific alcohol consumption and the risk of bladder cancer. For each case of bladder cancer, up to five control subjects were selected and matched on major confounders using a risk set method. We used conditional logistic regression to assess the risk of bladder cancer according to categories of alcohol consumption. During a mean follow-up of 27.3 +/- 10.1 years, there were 126 incident cases of bladder cancer. There was no statistically significant association between alcohol consumption and risk of bladder cancer (P(trend) =.3). In beverage-specific analyses, beer consumption was associated with a reduced risk of bladder cancer (P(trend) =.03), whereas wine (P(trend) =.7) and spirit (P(trend) =.2) consumption were not. Our data suggest that total and beverage-specific alcohol consumption are not associated with an increased risk of bladder cancer.

Weight change and the risk of late-onset breast cancer in the original Framingham cohort.

OBJECTIVE: Adult weight gain has been associated with a twofold risk of postmenopausal breast cancer. Data are limited regarding whether weight gain at specific periods of marked changes in estrogen- and insulin-related hormones have different risk associations. This study assesses the relation of adult weight change overall and at specific, hormonally relevant times with diagnosis of a first breast cancer after age 55 (late onset). METHODS: Framingham study data were used to assess premenopausal (25-44 yr), perimenopausal (45-55 yr), postmenopausal (after 55 yr), and adult lifetime (from 25 yr) weight change in relation to late-onset breast cancer in 2,873 women followed for up to 48 yr, with 206 late-onset breast cancers. RESULTS: Adult lifetime weight gain was associated with an increased risk of late-onset breast cancer (P trend = 0.046). Weight gain during specific time periods was not associated with breast cancer. Data suggested a possible decreased risk of breast cancer with weight loss from ages 25 to 44 and 45 to 55 yr (relative risk = 0.4 [0.2-1.2] and 0.5 [0.3-0.9], respectively). CONCLUSION: These data confirm prior reports of an association between adult lifetime weight gain and increased risk of late-onset breast cancer and support current recommendations to avoid adult weight gain.

Does more "appropriateness" explain higher rates of cardiac procedures among patients hospitalized with coronary heart disease?

BACKGROUND: There have been few studies of the extent to which differences in the pool of patients being managed might account for geographic variations in treatment rates. OBJECTIVE: For two cardiac procedures, cardiac catheterization and revascularization, we evaluate the hypothesis that differences in "the percentage of patients for whom the procedure is appropriate" is a factor explaining variations in use rates among those hospitalized with coronary heart disease (CHD). RESEARCH DESIGN: Based on hospital utilization patterns in Massachusetts in 1990, we created 70 small geographic areas. Using 1992 Massachusetts Peer Review Organization data, areas were ranked from highest to lowest based on (empirical-Bayes-adjusted) hospitalization rates for each procedure. One thousand seven hundred four cases from 43 hospitals were sampled, roughly half each from high and low use areas. Half had a procedure and half were candidates for the same procedure but did not have it. For each procedure, medical records were reviewed to determine whether the procedure was (or, for those not having it, would have been) appropriate, based on criteria developed using a modified Delphi approach. RESULTS: Among those having either procedure, appropriateness rates were similar in high and low rate areas (P = 0.59 for catheterization and P = 0.30 for revascularization). However, among candidates for either procedure who did not have it, appropriateness for performing the procedure was greater in high-rate areas (41.4% vs. 32.1%, P = 0.05 for catheterization; 71.2% vs. 57.2%, P = 0.003, for revascularization). CONCLUSION: Among those hospitalized with CHD, appropriateness rates for two cardiac procedures are higher in areas with higher use rates.