Sex hormones and risk of breast cancer in premenopausal women: a collaborative reanalysis of individual participant data from seven prospective studies.

BACKGROUND: Associations between circulating concentrations of oestrogens, progesterone, and androgens with breast cancer and related risk factors in premenopausal women are not well understood. We aimed to characterise these associations with a pooled analysis of data from seven studies. METHODS: Individual participant data for prediagnostic sex hormone and sex hormone-binding globulin (SHBG) concentrations were contributed from seven prospective studies. We restricted analyses to women who were premenopausal and younger than 50 years at blood collection, and to women with breast cancer diagnosed before age 50 years. We estimated odds ratios (ORs) with 95% CIs for breast cancer associated with hormone concentrations by conditional logistic regression in cases and controls matched for age, date of blood collection, and day of cycle, with stratification by study and further adjustment for cycle phase. We examined associations of hormones with risk factors for breast cancer in control women by comparing geometric mean hormone concentrations in categories of these risk factors, adjusted for study, age, phase of menstrual cycle, and body-mass index (BMI). All statistical tests were two-sided. FINDINGS: We included data for up to 767 women with breast cancer and 1699 controls in the risk analyses. Breast cancer risk was associated with a doubling in concentrations of oestradiol (OR 1·19, 95% CI 1·06-1·35), calculated free oestradiol (1·17, 1·03-1·33), oestrone (1·27, 1·05-1·54), androstenedione (1·30, 1·10-1·55), dehydroepiandrosterone sulphate (1·17, 1·04-1·32), testosterone (1·18, 1·03-1·35), and calculated free testosterone (1·08, 0·97-1·21). Breast cancer risk was not associated with luteal phase progesterone (doubling in concentration OR 1·00, 95% CI 0·92-1·09), and adjustment for other factors had little effect on any of these ORs. Cross-sectional analyses in control women showed several associations of sex hormones with breast cancer risk factors. INTERPRETATION: Circulating oestrogens and androgens are positively associated with the risk for breast cancer in premenopausal women.

Dietary n-3 polyunsaturated acids and smoking-related chronic obstructive pulmonary disease.

BACKGROUND: Fish contain n-3 polyunsaturated fatty acids, principally eicosapentaenoic acid and docosahexaenoic acid, which are known to interfere with the body's inflammatory response and may be of benefit in chronic inflammatory conditions. METHODS: We studied the relation between the dietary intake of n-3 fatty acids and chronic obstructive pulmonary disease (COPD) in 8960 current or former smokers participating in a population-based study of artheroscierosis. Intake of fatty acids was estimated with a dietary questionnaire. The presence of COPD was assessed by a questionnaire on respiratory symptoms and by spirometry. Three case definitions of COPD were used: symptoms of chronic bronchitis (667 subjects), physician-diagnosed emphysema reported by the subject (185 subjects), and spirometrically detected COPD (197 subjects). RESULTS: After control for pack-years of smoking, age, sex, race, height, weight, energy intake, and educational level docosahexaenoic acid was inversely related to the ris of COPD in a quantity-dependent fashion. The adjusted odds ratio for the highest quartile was 0.66 for chronic bronchitis (95 percent confidence interval, 0.52 to 0.85; P<0.001 for linear trend across the range of intake value), 0.31 for physician-diagnosed emphysema (95 percent confidence interval, 0.18 to 0.52; P for liner trend, 0.003), and 0.50 for spirometrically detected COPD (95 percent confidence interval, 0.32 to 0.79; P for linear trend, 0.007). CONCLUSION: A high dietary intake of n-3 fatty acids may protect cigarette smokers against COPD.

Cigarette smoking and changes in respiratory findings.

Standardized surveys of cardiorespiratory findings were conducted among male telephone company employees 40 to 59 years of age, and repeated five to six years later. Cigarette smokers had considerably more cough, phlegm, and chronic wheeze and slightly more nasal catarrh and breathlessness on exertion than nonsmokers. Pipe and cigar smokers had intermediate levels of these symptoms. Men who quit cigarette smoking between two surveys showed considerable improvement in cough and phlegm. Respiratory symptoms and among smokers of nonfilter cigarettes. Forced expiratory volume decreased and sputum volume increased among all groups over the observation period. Both changes were least marked among men who quit smoking cigarettes and were most marked among those who continued to smoke cigarettes.

Respiratory effects of household exposures to tobacco smoke and gas cooking.

The records of 1,724 residents of Washington County, Maryland, who had participated in 2 studies of respiratory symptoms and ventilatory function were analyzed to evaluate the effects of exposures at home to tobacco smoke generated by other members of their households and to fumes from the use of gas as a cooking fuel. Currently smoking subjects showed the highest frequency of respiratory symptoms and impaired ventilatory function; former smokers showed a lower frequency of these findings; and persons who had never smoked had the lowest prevalence of abnormal respiratory findings. The presence of a smoker in the household other than the subject was not associated with the frequency of respiratory symptoms, and only suggestively associated with evidence of impaired ventilatory function. The use of gas for cooking was related to an increased frequency of respiratory symptoms and impaired ventilatory function among men, being most marked among men who had never smoked. There was no evidence that cooking with gas was harmful to women.

The risk of developing lung cancer associated with antioxidants in the blood: ascorbic acids, carotenoids, alpha-tocopherol, selenium, and total peroxyl radical absorbing capacity.

Lung cancer cases diagnosed during the period 1975 through 1993 and matched controls were identified in the rosters of Washington County, Maryland residents who had donated blood for a serum bank in 1974 or 1989. Plasma from participants in the 1989 project was assayed for ascorbic acid; serum or plasma was assayed for participants in either project for alpha- and beta-carotene, cryptoxanthin, lutein/zeaxanthin, lycopene, alpha-tocopherol, selenium, and peroxyl radical absorption capacity. Among the total group of 258 cases and 515 controls, serum/plasma concentrations were significantly lower among cases than controls for cryptoxanthin, beta-carotene, and lutein/zeaxanthin with case-control differences of -25.5, -17.1, and -10.1%, respectively. Modest nonsignificant case-control differences in a protective direction were noted for alpha-carotene and ascorbic acid. There were only trivial differences for lycopene, alpha-tocopherol, selenium, and peroxyl radical absorption capacity. Findings are reported for males and females and for persons who had never smoked cigarettes, former smokers, and current smokers at baseline. These results and those from previous studies suggest that beta-carotene is a marker for some protective factor(s) against lung cancer; that cryptoxanthin, alpha-carotene, and ascorbic acid need to be investigated further as potentially protective factors or associates of a protective factor; and that lycopene, alpha-tocopherol, selenium, and peroxyl radical absorption capacity are unlikely to be associated with lung cancer risk. Until specific preventive factors are identified, the best protection against lung cancer is still the avoidance of airborne carcinogens, especially tobacco smoke; second best is the consumption of a diet rich in fruits and vegetables.

Prostate-specific antigen levels and subsequent prostate cancer: potential for screening.

Prostate-specific antigen levels are increased in men with prostatic disease, including prostate cancer, and have been used clinically to monitor the response of prostate cancer to therapy. More recently, prostate-specific antigen levels, usually in combination with digital rectal examination or transrectal prostatic ultrasonography, have been suggested to be useful for the detection of prostate cancer. To evaluate the association between a single serum prostate-specific antigen level and the subsequent development of prostate cancer, we measured serum levels in 35 men who donated blood to a community-based serum bank in 1974 and who subsequently developed prostate cancer and in 35 matched controls from the same group of volunteers. Levels of prostate-specific antigen were significantly higher in men who went on to develop prostate cancer, up to 6 years prior to the time of diagnosis in the cases. The level of prostate-specific antigen decreased with increasing time to diagnosis. The mean level for prostate cancer cases diagnosed within the first 3 years of follow-up was 16.2 mug/liter compared to 2.4 mug/liter for controls (P = 0.002). The mean level for cancer cases diagnosed in years 4 through 6 following blood sampling was 9.6 mug/liter compared to 1.3 mug/liter for controls (p = 0.0002). The sensitivity and specificity of a prostate-specific antigen level >/= 4mug/liter up to 3 years prior to the time of clinical diagnosis were both 75% and up to 6 years were 67% and 85%, respectively. Because prostate-specific antigen levels are reasonably sensitive and specific in detecting prostate cancer up to 6 years prior to the time of usual diagnosis, their use in screening for the prevention of prostate cancer mortality should be evaluated in a controlled clinical trial.

A prospective cohort study of rectal cancer risk in relation to active cigarette smoking and passive smoke exposure.

PURPOSE: The present investigation prospectively examined active cigarette smoking and household passive smoke exposure and the risk of developing rectal cancer. METHODS: Cigarette smoking data were collected on all household members during two private censuses in Washington County, Maryland. These two cohorts were followed up, one cohort from 1963-1978 and the other from 1975-1994 for first-time diagnoses of rectal cancer. We identified 148 and 169 rectal cancer cases in the 1963 and 1975 cohorts, respectively. Relative risks were estimated by means of Poisson regression models. RESULTS: In men, the adjusted relative risks (aRR) and 95% confidence intervals (CI) for the association between current smoking and rectal cancer were 3.1 (1.2-7.8) in the 1963 cohort and 1.8 (0.9-3.7) in the 1975 cohort; the corresponding aRRs in women were 0.9 (0.5-1.8) and 1.6 (0.9-3.8) in the 1963 and 1975 cohorts, respectively. In nonsmokers, household passive smoke exposure was strongly associated with rectal cancer among men in the 1963 cohort (aRR = 5.8; 1.8-18.4) but not the 1975 cohort (aRR = 1.1; 0.2-5.0). In women, household passive exposure was not strongly associated with rectal cancer in either cohort. CONCLUSIONS: The results of our study suggest that active cigarette smoking may contribute to rectal cancer risk, but inconsistencies in the findings preclude drawing strong, clear-cut inferences.

Polychlorinated biphenyl levels in peripheral blood and non-Hodgkin's lymphoma: a report from three cohorts.

The incidence of non-Hodgkin's lymphoma (NHL) unrelated to HIV infection has steadily increased over the past several decades and remains substantially unexplained. Limited evidence suggests that increased concentrations of polychlorinated biphenyls (PCB) measured in blood or fat tissue are associated with increased risk of NHL. Although PCB congeners vary in their biological activity, the relation between individual congeners and NHL risk has not been examined previously using prospectively collected biospecimens. We examined congener-specific associations in three prospective cohorts. Prediagnostic serum or plasma concentrations of selected PCB congeners were measured among NHL cases and controls from these cohorts: Janus (190 cases and 190 controls) in Norway and CLUE I (74 cases and 147 controls) and the Nurses' Health Study (30 cases and 78 controls) in the United States. All blood samples were collected in the 1970s or 1980s. We used logistic regression to calculate odds ratios (OR) and 95% confidence intervals (95% CI) for the relations between risk of NHL and lipid-corrected plasma or serum concentrations. Several congeners (i.e., 118, 138, and 153) that were present at higher levels and were moderately to highly correlated with each other showed exposure-response trends with risk of NHL in all three cohorts. These associations were observed primarily among subjects diagnosed closer to the date of blood collection in the two cohorts with sufficient cases to permit stratification by time. Among cases diagnosed within the median years of follow-up (16 years in Janus and 12 years in CLUE I), ORs and 95% CIs for increasing fourths of concentration of congener 118 relative to the lowest fourth were as follows: 2.4 (0.9-6.5), 4.9 (1.6-15.3), and 5.3 (1.5-18.8; P(trend) < 0.005) in Janus and 8.1 (1.0-68.9), 6.6 (0.7-59.0), and 13.0 (1.6-106.8; P(trend) < 0.05) in CLUE I. Similar patterns were seen for congeners 138 and 153 and for total PCBs. Limited evidence of exposure-response trends was also observed for several other congeners. The primary 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane metabolite, p,p'-DDE, was not significantly associated with NHL in most analyses but slightly to moderately confounded the PCB associations. The results from these three cohorts suggest that concentrations of certain PCBs in blood are associated with increased risk of NHL.

Smoking and risk of fatal prostate cancer in a prospective U.S. study.

OBJECTIVES: To examine the association of cigarette smoking with subsequent fatal prostate cancer. METHODS: Two private censuses were conducted in Washington County, Maryland, in which 26,810 adult men in 1963 and 28,292 in 1975 provided smoking information. Prostate cancer deaths through 2000 (1963 cohort, 240 deaths; and 1975 cohort, 184 deaths) were ascertained by review of the death certificates. Poisson regression analysis was used to estimate the rate ratio of prostate cancer death adjusted for age. RESULTS: Overall, cigarette smokers in the 1963 census cohort were not more likely to die of prostate cancer than those who had never smoked cigarettes, pipes, or cigars when considering the total follow-up period. However, current smokers of 20 or more cigarettes per day (rate ratio 2.38; 95% confidence interval 0.94 to 5.99) and former smokers (rate ratio 2.75; 95% confidence interval 1.13 to 6.74) had a greater risk of death from prostate cancer during the first 10 years of follow-up. Weaker positive associations of prostate cancer death with current and former cigarette smoking were seen during the first 10 years of follow-up in the 1975 census cohort. Current cigarette smoking at baseline was not associated with the prostate cancer incidence. CONCLUSIONS: The lack of an association between cigarette smoking and prostate cancer incidence, but the tendency of greater prostate cancer mortality in former and current cigarette smokers earlier in the follow-up period is consistent with other studies in which smoking was assessed once at baseline.

Frequencies of single nucleotide polymorphisms in genes regulating inflammatory responses in a community-based population.

BACKGROUND: Allele frequencies reported from public databases or articles are mostly based on small sample sizes. Differences in genotype frequencies by age, race and sex have implications for studies designed to examine genetic susceptibility to disease. In a community-based cohort of 9,960 individuals, we compared the allele frequencies of 49 single nucleotide polymorphisms (SNPs) of genes involved in inflammatory pathways to the frequencies reported on public databases, and examined the genotypes frequencies by age and sex. The genes in which SNPs were analyzed include CCR2, CCR5, COX1, COX2, CRP, CSF1, CSF2, IFNG, IL1A, IL1B, IL2, IL4, IL6, IL8, IL10, IL13, IL18, LTA, MPO, NOS2A, NOS3, PPARD, PPARG, PPARGC1 and TNF. RESULTS: Mean(SD) age was 53.2(15.5); 98% were Caucasians and 62% were women. Only 1 out of 33 SNPs differed from the SNP500Cancer database in allele frequency by >10% in Caucasians (n = 9,831), whereas 12 SNPs differed by >10% (up to 50%) in African Americans (n = 105). Two out of 15 SNPs differed from the dbSNP database in allele frequencies by >10% in Caucasians, and 5 out of 15 SNPs differed by >10% in African Americans. Age was similar across most genotype groups. Genotype frequencies did not differ by sex except for TNF(rs1799724), IL2(rs2069762), IL10(rs1800890), PPARG(rs1801282), and CRP(rs1800947) with differences of less than 4%. CONCLUSION: When estimating the size of samples needed for a study, particularly if a reference sample is used, one should take into consideration the size and ethnicity of the reference sample. Larger sample size is needed for public databases that report allele frequencies in non-Caucasian populations.

Alcohol dehydrogenase genetic polymorphisms, low-to-moderate alcohol consumption, and risk of breast cancer.

BACKGROUND: In vitro, human isoenzymes encoded by genes homozygous for the ADH1C*1 or ADH1B*2 alleles metabolize ethanol to acetaldehyde at a faster rate than those homozygous for the ADH1C*2 or ADH1B*1 allele. Because alcohol is a known risk factor for breast cancer, we evaluated the joint association of genetic variants in ADH and alcohol consumption in relation to breast cancer. METHODS: A nested case-control study of 321 cases and matched controls was conducted. Five single nucleotide polymorphisms (SNPs) in the ADH1C and ADH1B genes were genotyped. Logistic regression was used to assess odds ratios (ORs) and 95% confidence limits (CIs) for each SNP. Haplotype analysis of all 5 SNPs was also undertaken. RESULTS: Among drinkers, the median intake of total alcohol was 13 g/wk (10th-90th percentiles; 4.5-135.9) in cases and 18 g/wk (10th-90th percentiles; 4.5-104.1) in controls. Women who drank alcohol tended to be at an increased risk of developing breast cancer compared with those who did not drink (OR=1.40%, 95% CI 0.97-2.03), particularly those who were premenopausal at the time of breast cancer diagnosis (OR=2.69%, 95% CI: 1.00-7.26). Of the known functional alleles, breast cancer risk was not significantly increased among carriers of at least 1 ADH1C*1 or ADH1B*2 allele, when compared with those homozygous for the genotype at each locus. However, breast cancer risk tended to be lower among women who inherited the G allele at ADH1B IVS1+896A>G (OR=0.62, 95% CI 0.37-1.04). Overall haplotype frequencies were not significantly different between cases and controls. CONCLUSIONS: In this study low levels of alcohol are associated with a modest increase in breast cancer risk that is not altered by known functional allelic variants of the ADH1B and 1C gene. The protective association conferred by the G allele at ADH1B IVS1+896A>G needs further evaluation.

A prospective cohort study of bladder cancer risk in relation to active cigarette smoking and household exposure to secondhand cigarette smoke.

Active cigarette smoking is a major risk factor for bladder cancer. Secondhand exposure to cigarette smoke may also contribute to bladder carcinogenesis. The authors conducted a prospective cohort study to examine the influence of both active smoking and household exposure to secondhand smoke (SHS) on subsequent bladder cancer risk. The study population included persons from two cohorts established from private censuses conducted in Washington County, Maryland, in 1963 (n = 45,749; 93 cases) and 1975 (n = 48,172; 172 cases). Poisson regression models were fitted to estimate the relative risk of bladder cancer associated with active and passive smoke exposure in the two cohorts (referent category: never smokers who did not live with any smokers). Current smokers had an elevated risk of bladder cancer in both the 1963 cohort (relative risk (RR) = 2.7, 95% confidence limits (CL): 1.6, 4.7) and the 1975 cohort (RR = 2.6, 95% CL: 1.7, 3.9) after adjustment for age, education, and marital status. Among nonsmoking women, current household SHS exposure was associated with bladder cancer risk in the 1963 cohort (RR = 2.3, 95% CL: 1.0, 5.4) but not in the 1975 cohort (RR = 0.9, 95% CL: 0.4, 2.3). This study further solidifies the evidence that active smoking is causally associated with bladder cancer. Additional studies are needed to determine whether passive smoking is a risk factor for bladder cancer.