Jo L. Freudenheim

Estrogen metabolism and risk of breast cancer: A prospective study of the 2:16α-hydroxyestrone ratio in premenopausal and postmenopausal women

Experimental and clinical evidence suggests that 16&agr;-hydroxylated estrogen metabolites, biologically strong estrogens, are associated with breast cancer risk, while 2-hydroxylated metabolites, with lower estrogenic activity, are weakly related to this disease. This study analyzes the association of breast cancer risk with estrogen metabolism, expressed as the ratio of 2-hydroxyestrone to 16&agr;-hydroxyestrone, in a prospective nested case-control study. Between 1987 and 1992, 10,786 women (ages 35–69 years) were recruited to a prospective study on breast cancer in Italy, the “Hormones and Diet in the Etiology of Breast Cancer” (ORDET) study. Women with a history of cancer and women on hormone therapy were excluded at baseline. At recruitment, overnight urine was collected from all participants and stored at −80°C. After an average of 5.5 years of follow-up, 144 breast cancer cases and four matched controls for each case were identified among the participants of the cohort. Among premenopausal women, a higher ratio of 2-hydroxyestrone to 16&agr;-hydroxyestrone at baseline was associated with a reduced risk of breast cancer: women in the highest quintile of the ratio had an adjusted odds ratio (OR) for breast cancer of 0.58 [95% confidence interval (CI) = 0.25−1.34]. The corresponding adjusted OR in postmenopausal women was 1.29 (95% CI = 0.53–3.10). Results of this prospective study support the hypothesis that the estrogen metabolism pathway favoring 2-hydroxylation over 16&agr;-hydroxylation is associated with a reduced risk of invasive breast cancer risk in premenopausal women.

Type I and II Endometrial Cancers: Have They Different Risk Factors?

PURPOSE Endometrial cancers have long been divided into estrogen-dependent type I and the less common clinically aggressive estrogen-independent type II. Little is known about risk factors for type II tumors because most studies lack sufficient cases to study these much less common tumors separately. We examined whether so-called classical endometrial cancer risk factors also influence the risk of type II tumors. PATIENTS AND METHODS Individual-level data from 10 cohort and 14 case-control studies from the Epidemiology of Endometrial Cancer Consortium were pooled. A total of 14,069 endometrial cancer cases and 35,312 controls were included. We classified endometrioid (n = 7,246), adenocarcinoma not otherwise specified (n = 4,830), and adenocarcinoma with squamous differentiation (n = 777) as type I tumors and serous (n = 508) and mixed cell (n = 346) as type II tumors. RESULTS Parity, oral contraceptive use, cigarette smoking, age at menarche, and diabetes were associated with type I and type II tumors to similar extents. Body mass index, however, had a greater effect on type I tumors than on type II tumors: odds ratio (OR) per 2 kg/m(2) increase was 1.20 (95% CI, 1.19 to 1.21) for type I and 1.12 (95% CI, 1.09 to 1.14) for type II tumors (P heterogeneity < .0001). Risk factor patterns for high-grade endometrioid tumors and type II tumors were similar. CONCLUSION The results of this pooled analysis suggest that the two endometrial cancer types share many common etiologic factors. The etiology of type II tumors may, therefore, not be completely estrogen independent, as previously believed.

Positional Accuracy of Geocoded Addresses in Epidemiologic Research

Background Geographic information systems (GIS) offer powerful techniques for epidemiologists. Geocoding is an important step in the use of GIS in epidemiologic research, and the validity of epidemiologic studies using this methodology depends, in part, on the positional accuracy of the geocoding process. Methods We conducted a study comparing the validity of positions geocoded with a commercially available program to positions determined by Global Positioning System (GPS) satellite receivers. Addresses (N = 200) were randomly selected from a recently completed case–control study in Western New York State. We geocoded addresses using ArcView 3.2 on the GDT Dynamap/2000 U.S. Street database. In addition, we measured the longitude and latitude of these addresses with a GPS receiver. The distance between the locations obtained by these two methods was calculated for all addresses. Results The distance between the geocoded point and the GPS point was within 100 m for the majority of subject addresses (79%), with only a small proportion (3%) having a distance greater than 800 m. The overall median distance between GPS points and geocoded points was 38 m (90% confidence interval [CI] = 34–46). Distances were not different for cases and controls. Urban addresses (median = 32 m; CI = 28–37) were slightly more accurate than nonurban addresses (median = 52 m; CI = 44–61). Conclusions. This study indicates that the suitability of geocoding for epidemiologic research depends on the level of spatial resolution required to assess exposure. Although sources of error in positional accuracy for geocoded addresses exist, geocoding of addresses is, for the most part, very accurate.

Cruciferous Vegetables, Genetic Polymorphisms in Glutathione S-Transferases M1 and T1, and Prostate Cancer Risk

Abstract: Cruciferous vegetables contain anticarcinogenic isothiocyanates (ITCs), particularly the potent sulforaphane, which may decrease risk of prostate cancer through induction of phase II enzymes, including glutathione S-transferases (GSTs). We evaluated this hypothesis in a population-based, case-control study of prostate cancer, including 428 men with incident prostate cancer and 537 community controls. An in-person interview included an extensive food-frequency questionnaire. Genotyping for deletions in GSTM1 and GSTT1 was performed in a subset of men who provided blood. Intakes of cruciferous vegetables and of broccoli, the greatest source of sulforaphane, were associated with decreased prostate cancer risk at all levels above the lowest consumers [adjusted 4th quartile odds ratio (OR) = 0.58; 95% confidence interval (CI) = 0.38, 0.89, and 0.72 (95% CI = 0.49, 1.06)], respectively. In relation to genotypes, there was a nonsignificant increase in risk with the GSTT1 null genotype (OR = 1.51; 95% CI = 0.98, 2.31) but no effects of GSTM1 genotype. However, men with GSTM1-present genotype and high broccoli intake had the greatest reduction in risk (OR = 0.49; 95% CI = 0.27, 0.89). Our findings provide evidence that two or more servings per month of cruciferous vegetables may reduce risk of prostate cancer, especially among men with GSTM1-present alleles, and are consistent with a role of dietary ITCs as chemopreventive agents against prostate cancer.

Body fat distribution, relative weight, and liver enzyme levels: A population‐based study

Regional body fat distribution may represent an independent risk factor for several conditions, especially metabolic and cardiovascular diseases; recent findings have shown that abdominal fat accumulation can be an independent predictor of hepatic steatosis. Very few studies, mostly using selected clinical samples, have focused on the relationship between indices of abdominal visceral fat accumulation and the most commonly used biochemical liver tests, such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma‐glutamyltransferase (GGT). The aim of the present study was to evaluate the relation between central fat accumulation, as assessed by abdominal height, relative weight, as determined by body mass index (BMI), and liver function tests (ALT, AST, and GGT) in a random sample of 2,704 residents of Erie and Niagara Counties in New York State, 35–80 years of age and free from known hepatic disease. Multiple linear regression models were used, with liver enzymes as dependent variables with abdominal height and BMI as independent variables, and the inclusion of several covariates (age, race, education, smoking status, pack‐years of smoking, drinking status, and total ounces of ethanol in the past 30 days). Abdominal height was consistently a better correlate of ALT and GGT levels than BMI in both sexes. In addition, abdominal height was the most powerful independent predictor of ALT in both sexes as well as of GGT among women. In conclusion, these findings support a role for central adiposity independent from BMI in predicting increased levels of hepatic enzymes, likely as a result of unrecognized fatty liver. (HEPATOLOGY 2004;39:754–763.)

Dietary Carotenoids and Risk of Lung Cancer in a Pooled Analysis of Seven Cohort Studies

Intervention trials with supplemental β-carotene have observed either no effect or a harmful effect on lung cancer risk. Because food composition databases for specific carotenoids have only become available recently, epidemiological evidence relating usual dietary levels of these carotenoids with lung cancer risk is limited. We analyzed the association between lung cancer risk and intakes of specific carotenoids using the primary data from seven cohort studies in North America and Europe. Carotenoid intakes were estimated from dietary questionnaires administered at baseline in each study. We calculated study-specific multivariate relative risks (RRs) and combined these using a random-effects model. The multivariate models included smoking history and other potential risk factors. During follow-up of up to 7–16 years across studies, 3,155 incident lung cancer cases were diagnosed among 399,765 participants. β-Carotene intake was not associated with lung cancer risk (pooled multivariate RR = 0.98; 95% confidence interval, 0.87–1.11; highest versus lowest quintile). The RRs for α-carotene, lutein/zeaxanthin, and lycopene were also close to unity. β-Cryptoxanthin intake was inversely associated with lung cancer risk (RR = 0.76; 95% confidence interval, 0.67–0.86; highest versus lowest quintile). These results did not change after adjustment for intakes of vitamin C (with or without supplements), folate (with or without supplements), and other carotenoids and multivitamin use. The associations generally were similar among never, past, or current smokers and by histological type. Although smoking is the strongest risk factor for lung cancer, greater intake of foods high in β-cryptoxanthin, such as citrus fruit, may modestly lower the risk.

Diet and alcohol consumption and lung cancer risk in the New York State Cohort (United States)

The relationship between diet and alcohol and lung cancer was evaluated among participants of the New York State Cohort (United States),comprising 27,544 men (395 cases) and 20,456 women (130 cases) who completed a brief mailed questionnaire in 1980. Participants were followed up through1987 with the assistance of the New York State Department of Healths Vital Statistics Section and Cancer Registry. Among men, inverse relationships with vitamin C, folate, and carotenoids, and positive associations with total fat, monounsaturated and saturated fat were observed after adjusting for age, education, cigarettes/day, years smoking, and total energy intake. The relationships observed with folate and saturated fat were stronger for heavy smokers. Also, the effect of folate, total fat, and monounsaturated fat seemed to be limited to squamous cell carcinomas. We found no indication that cholesterol or polyunsaturated fat was associated with lung cancer. Diet did not appear to exert a major role on lung cancer risk among women. Although diet modification should never be considered a substitute for smoking cessation, its role as an additional strategy in lung cancer prevention deserves attention.

Relationship of Alcohol Drinking Pattern to Risk of Hypertension: A Population-Based Study

Epidemiological studies have demonstrated a positive relationship between heavy alcohol use and hypertension, but few studies have directly addressed the role of drinking pattern. This study was designed to investigate the association of current alcohol consumption and aspects of drinking pattern with hypertension risk in a sample of 2609 white men and women from western New York, aged 35 to 80 years, and free from other cardiovascular diseases. Hypertension was defined by systolic blood pressure ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg or use of antihypertensive medication. Odds ratios (95% confidence intervals) were computed after adjustment for several covariates. Compared with lifetime abstainers, participants reporting drinking on a daily basis (1.75 [1.13 to 2.72]) or mostly without food (1.64 [1.08 to 2.51]) exhibited significantly higher risk of hypertension. When analyses were restricted to current drinkers, daily drinkers and participants consuming alcohol without food exhibited a significantly higher risk of hypertension compared with those drinking less than weekly (1.65 [1.18 to 2.30]) and those drinking mostly with food (1.49 [1.10 to 2.00]), respectively. After additional adjustment for the amount of alcohol consumed in the past 30 days, the results were follows: 0.90 (0.58 to 1.41) for daily drinkers and 1.41 (1.04 to 1.91) for drinkers without food. For predominant beverage preference, no consistent association with hypertension risk was found across the various types of beverages considered (beer, wine, and liquor). In conclusion, drinking outside meals appears to have a significant effect on hypertension risk independent of the amount of alcohol consumed.

Fruits, vegetables and lung cancer: A pooled analysis of cohort studies

Inverse associations between fruit and vegetable consumption and lung cancer risk have been consistently reported. However, identifying the specific fruits and vegetables associated with lung cancer is difficult because the food groups and foods evaluated have varied across studies. We analyzed fruit and vegetable groups using standardized exposure and covariate definitions in 8 prospective studies. We combined study‐specific relative risks (RRs) using a random effects model. In the pooled database, 3,206 incident lung cancer cases occurred among 430,281 women and men followed for up to 6–16 years across studies. Controlling for smoking habits and other lung cancer risk factors, a 16–23% reduction in lung cancer risk was observed for quintiles 2 through 5 vs. the lowest quintile of consumption for total fruits (RR = 0.77; 95% CI = 0.67–0.87 for quintile 5; p‐value, test for trend < 0.001) and for total fruits and vegetables (RR = 0.79; 95% CI = 0.69–0.90; p‐value, test for trend = 0.001). For the same comparison, the association was weaker for total vegetable consumption (RR = 0.88; 95% CI = 0.78–1.00; p‐value, test for trend = 0.12). Associations were similar between never, past, and current smokers. These results suggest that elevated fruit and vegetable consumption is associated with a modest reduction in lung cancer risk, which is mostly attributable to fruit, not vegetable, intake. However, we cannot rule out the possibility that our results are due to residual confounding by smoking. The primary focus for reducing lung cancer incidence should continue to be smoking prevention and cessation.

Serum iron, copper and zinc concentrations and risk of cancer mortality in US adults.

PURPOSE To examine the prospective association of serum iron, copper, and zinc with cancer mortality. METHODS The study sample included 3000 men and 3244 women free from cancer at baseline who participated in the Second National Health and Nutrition Examination Survey. Vital status at follow-up was identified by the Social Security Administrations death file and the National Death Index. Iron, transferrin saturation (TS), copper, and zinc were categorized into 4 levels using the 10th, 50th, and 90th percentiles for cutoffs. Relative risks (RRs) were derived from the proportional hazard models after adjustment for a number of potential confounders. RESULTS Three hundred seven cancer deaths (ICD-9 140-195, 199-208) were identified during 83,664.4 person-years of follow-up. Cancer mortality per 1000 person-years was 3.7 (4.7 for men and 2.8 for women). For men and women combined, the adjusted RRs (95% confidence intervals, CI) for the four levels were 0.96 (0.57-1.61), 1.00 (reference), 1.12 (0.80-1.58), 1.86 (1.07-3.22) for iron; 0.97 (0.56-1.70), 1.00 (reference), 1.36 (0.99-1.87), 1.82 (1.10-3.02) for TS; 0.76 (0.44-1.31), 1.00 (reference), 1.10 (0.77-1.58), 1.89 (1.07-3.32) for copper; and 0.75 (0.50-1.13), 1.00 (reference), 0.64 (0.47-0.88), 0.84 (0.53-1.33) for zinc. When the exposures were analyzed as continuous variables, the adjusted RRs (CI) were 1.66 (1.03-2.68) for 100 microg/dl iron increase, 1.17 (1.01-1.36) for 10% TS increase, 1.98 (1.12-3.50) for 100 microg/dl copper increase, and 0.57 (0.16-1.96) for 100 microg/dl zinc increase. Sex differences in the adjusted RRs for iron, TS, and copper were suggestive. CONCLUSION People with higher serum iron, TS, or copper concentrations had an increased risk of dying from cancer.