Search

We prospectively evaluated fat intake as predictor of developing breast cancer (BC) subtypes defined by estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor 2 receptor (HER2), in a large (n = 337327) heterogeneous cohort of women, with 10062 BC case patients after 11.5 years, estimating BC hazard ratios (HRs) by Cox proportional hazard modeling. High total and saturated fat were associated with greater risk of ER(+)PR(+) disease (HR = 1.20, 95% confidence interval [CI] = 1.00 to 1.45; HR = 1.28, 95% CI = 1.09 to 1.52; highest vs lowest quintiles) but not ER(-)PR(-) disease. High saturated fat was statistically significantly associated with greater risk of HER2(-) disease. High saturated fat intake particularly increases risk of receptor-positive disease, suggesting saturated fat involvement in the etiology of this BC subtype., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

The authors investigated the role of known risk factors in educational differences in breast cancer incidence. Analyses were based on the European Prospective Investigation Into Cancer and Nutrition and included 242,095 women, 433 cases of in situ breast cancer, and 4,469 cases of invasive breast cancer. Reproductive history (age at first full-term pregnancy and parity), exposure to endogenous and exogenous hormones, height, and health behaviors were accounted for in the analyses. Relative indices of inequality (RII) for education were estimated using Cox regression models. A higher risk of invasive breast cancer was found among women with higher levels of education (RII = 1.22, 95% confidence interval (CI): 1.09, 1.37). This association was not observed among nulliparous women (RII = 1.13, 95% CI: 0.84, 1.52). Inequalities in breast cancer incidence decreased substantially after adjusting for reproductive history (RII = 1.11, 95% CI: 0.98, 1.25), with most of the association being explained by age at first full-term pregnancy. Each other risk factor explained a small additional part of the inequalities in breast cancer incidence. Height accounted for most of the remaining differences in incidence. After adjusting for all known risk factors, the authors found no association between education level and risk of invasive breast cancer. Inequalities in incidence were more pronounced for in situ breast cancer, and those inequalities remained after adjustment for all known risk factors (RII = 1.61, 95% CI: 1.07, 2.41), especially among nulliparous women.

Background: The contribution of genetic variation in DNA repair genes to gastric cancer (GC) risk remains essentially unknown. The aim of this study was to explore the relative contribution of DNA repair gene polymorphisms to GC risk and severe chronic atrophic gastritis (SCAG). Method A nested case control study within the EPIC cohort was performed including 246 gastric adenocarcinomas and 1175 matched controls. Controls with SCAG (n = 91), as defined by low pepsinogen A (PGA) levels, and controls with no SCAG (n = 1061) were also compared. Twelve polymorphisms at DNA repair genes (MSH2, MLH1, XRCC1, OGG1 and ERCC2) and TP53 gene were analysed. Antibodies against Helicobacter pylori were measured., Results: No association was observed for any of these polymorphisms with stomach cancer risk. However, ERCC2 K751Q polymorphism was associated with an increased risk for non-cardial neoplasm [odds ratio (OR) = 1.78; 95% confidence interval (CI) 1.02-3.12], being ERCC2 K751Q and D312N polymorphisms associated with the diffuse type. ERCC2 D312N (OR = 2.0; 95% CI 1.09-3.65) and K751Q alleles (OR = 1.82; 95% CI 1.01-3.30) and XRCC1 R399Q (OR = 1.69; 95% CI 1.02-2.79) allele were associated with an increased risk for SCAG., Conclusion: Our study supports a role of ERCC2 in non-cardial GC but not in cardial cancer. A concordant result was observed for subjects with low PGA levels. XRCC1 allele was associated also with SCAG. This is the first prospective study suggesting that individual variation in DNA repair may be relevant for gastric carcinogenesis, a finding that will require further confirmation validation in larger independent studies.

Background: EUROCARE found marked differences in cancer survival across European populations, provoking extensive discussion as to the cause. We investigated the influence of socioeconomic indicators on survival, making use of the indicator population-based age-standardized and cancer site-standardized relative survival for all cancers combined (all cancer survival)., Methods: Bivariate correlation and multivariate regression analyses investigated relations between 1995 socioeconomic variables and all cancer survival in EUROCARE-3 patients from 19 European countries diagnosed 1990-94 and followed to 1999., Results: Gross domestic product (GDP) and total national expenditure on health (TNEH) correlated highly with all cancer survival. Wealthy northern and western European countries had high survival; eastern European countries had low all cancer survival. GDP, TNEH, and number of computed tomography scanners per million--proxy of technological investment in cancer care--explained most survival differences. Low all cancer survival in the UK and Denmark compared to countries of similar wealth was closely related to fewer computed tomography scanners. Low all cancer survival in Poland compared to countries of similar wealth was also related to low TNEH., Conclusions: All cancer survival appears a useful and important indicator for monitoring countries' performance in cancer control. The most direct way for poorer European countries to improve all cancer survival would be to get richer; for richer countries more investment in health technology is important. However the sharply increasing costs of cancer care may render this impossible suggesting the need to radically rethink cancer control strategies.

Background: Low urinary melatonin levels have been associated with an increased risk of breast cancer in premenopausal women. However, the association between melatonin levels and breast cancer risk in postmenopausal women remains unclear., Methods: We investigated the association between melatonin levels and breast cancer risk in postmenopausal women in a prospective case-control study nested in the Hormones and Diet in the Etiology of Breast Cancer Risk cohort, which included 3966 eligible postmenopausal women. The concentration of melatonin's major metabolite, 6-sulfatoxymelatonin, was measured in a baseline 12-hour overnight urine sample from 178 women who later developed incident breast cancer and from 710 matched control subjects. We used multivariable-adjusted conditional logistic regression models to investigate associations. Relative risks are reported as odds ratios (ORs). All statistical tests were two-sided., Results: Increased melatonin levels were associated with a statistically significantly lower risk of invasive breast cancer in postmenopausal women (for women in the highest quartile of total overnight 6-sulfatoxymelatonin output vs the lowest quartile, multivariable OR also adjusted for testosterone = 0.56, 95% confidence interval [CI] = 0.33 to 0.97; P(trend) = .02). This association was strongest among never and past smokers (OR = 0.38, 95% CI = 0.20 to 0.74; P(trend) = .001) and after excluding women who were diagnosed with invasive breast cancer within 4 years after urine collection (OR = 0.34, 95% CI = 0.15 to 0.75; P(trend) = .002). We did not observe substantial variation in relative risks by hormone receptor status of breast tumors. Among the 3966 women in the cohort, 40 of the 992 women in the highest quartile of 6-sulfatoxymelatonin developed breast cancer during follow-up, compared with 56 of the 992 women in the lowest quartile of 6-sulfatoxymelatonin., Conclusion: Results from this prospective study provide evidence for a statistically significant inverse association between melatonin levels, as measured in overnight morning urine, and invasive breast cancer risk in postmenopausal women.

Background: Adiponectin, an adipocytokine secreted by adipose tissue, is decreased in obesity, insulin resistance, type 2 diabetes, and polycystic ovary syndrome, all of which are well-established risk factors for endometrial cancer., Methods: We conducted a case-control study nested within the European Prospective Investigation into Cancer and Nutrition to examine the relation between prediagnostic plasma adiponectin levels and endometrial cancer risk. Among pre- and postmenopausal women who were not currently using exogenous hormones, 284 women developed incident endometrial cancer during an average of 5.1 yr of follow-up. Using risk set sampling, 548 control subjects were selected, matched on center, age, menopausal status, phase of menstrual cycle, time of blood draw, and fasting status. Conditional logistic regression models were used to estimate relative risks and 95% confidence intervals., Results: Adiponectin levels were inversely associated with endometrial cancer risk [body mass index-adjusted relative risk for the top vs. bottom quartile = 0.56 (95% confidence interval 0.36-0.86), P(trend) = 0.006]. There was evidence of a stronger inverse association among obese women than among nonobese women (P(heterogeneity) = 0.03). The inverse association also appeared stronger for women who were postmenopausal or perimenopausal than premenopausal at baseline, but this was not statistically significantly heterogeneous (P(heterogeneity) = 0.51). The association remained statistically significant after separate adjustment for other obesity-related physiological risk factors such as C-peptide, IGF binding protein-1, IGF binding protein-2, SHBG, estrone, or free testosterone but only marginally statistically significant after simultaneous adjustment for these factors., Conclusions: High circulating adiponectin levels are associated with reduced endometrial cancer risk, largely independent of other obesity-related risk factors.

With the growing number of epidemiologic publications on the relation between dietary factors and cancer risk, pooled analyses that summarize results from multiple studies are becoming more common. Here, the authors describe the methods being used to summarize data on diet-cancer associations within the ongoing Pooling Project of Prospective Studies of Diet and Cancer, begun in 1991. In the Pooling Project, the primary data from prospective cohort studies meeting prespecified inclusion criteria are analyzed using standardized criteria for modeling of exposure, confounding, and outcome variables. In addition to evaluating main exposure-disease associations, analyses are also conducted to evaluate whether exposure-disease associations are modified by other dietary and nondietary factors or vary among population subgroups or particular cancer subtypes. Study-specific relative risks are calculated using the Cox proportional hazards model and then pooled using a random- or mixed-effects model. The study-specific estimates are weighted by the inverse of their variances in forming summary estimates. Most of the methods used in the Pooling Project may be adapted for examining associations with dietary and nondietary factors in pooled analyses of case-control studies or case-control and cohort studies combined.

Background: Dietary factors are thought to have an important role in gastric and esophageal carcinogenesis, but evidence from cohort studies for such a role is lacking. We examined the risks of gastric cancer and esophageal adenocarcinoma associated with meat consumption within the European Prospective Investigation Into Cancer and Nutrition (EPIC) cohort., Methods: A total of 521,457 men and women aged 35-70 years in 10 European countries participated in the EPIC cohort. Dietary and lifestyle information was collected at recruitment. Cox proportional hazard models were used to examine associations between meat intake and risks of cardia and gastric non-cardia cancers and esophageal adenocarcinoma. Data from a calibration substudy were used to correct hazard ratios (HRs) and 95% confidence intervals (CIs) for diet measurement errors. In a nested case-control study, we examined interactions between Helicobacter pylori infection status (i.e., plasma H. pylori antibodies) and meat intakes. All statistical tests were two-sided., Results: During a mean follow-up of 6.5 years, 330 gastric adenocarcinoma and 65 esophageal adenocarcinomas were diagnosed. Gastric non-cardia cancer risk was statistically significantly associated with intakes of total meat (calibrated HR per 100-g/day increase = 3.52; 95% CI = 1.96 to 6.34), red meat (calibrated HR per 50-g/day increase = 1.73; 95% CI = 1.03 to 2.88), and processed meat (calibrated HR per 50-g/day increase = 2.45; 95% CI = 1.43 to 4.21). The association between the risk of gastric non-cardia cancer and total meat intake was especially large in H. pylori-infected subjects (odds ratio per 100-g/day increase = 5.32; 95% CI = 2.10 to 13.4). Intakes of total, red, or processed meat were not associated with the risk of gastric cardia cancer. A positive but non-statistically significant association was observed between esophageal adenocarcinoma cancer risk and total and processed meat intake in the calibrated model. In this study population, the absolute risk of development of gastric adenocarcinoma within 10 years for a study subject aged 60 years was 0.26% for the lowest quartile of total meat intake and 0.33% for the highest quartile of total meat intake., Conclusion: Total, red, and processed meat intakes were associated with an increased risk of gastric non-cardia cancer, especially in H. pylori antibody-positive subjects, but not with cardia gastric cancer.

Background: Current evidence suggests that high red meat intake is associated with increased colorectal cancer risk. High fish intake may be associated with a decreased risk, but the existing evidence is less convincing., Methods: We prospectively followed 478 040 men and women from 10 European countries who were free of cancer at enrollment between 1992 and 1998. Information on diet and lifestyle was collected at baseline. After a mean follow-up of 4.8 years, 1329 incident colorectal cancers were documented. We examined the relationship between intakes of red and processed meat, poultry, and fish and colorectal cancer risk using a proportional hazards model adjusted for age, sex, energy (nonfat and fat sources), height, weight, work-related physical activity, smoking status, dietary fiber and folate, and alcohol consumption, stratified by center. A calibration substudy based on 36 994 subjects was used to correct hazard ratios (HRs) and 95% confidence intervals (CIs) for diet measurement errors. All statistical tests were two-sided., Results: Colorectal cancer risk was positively associated with intake of red and processed meat (highest [>160 g/day] versus lowest [<20 g/day] intake, HR = 1.35, 95% CI = 0.96 to 1.88; Ptrend = .03) and inversely associated with intake of fish (>80 g/day versus <10 g/day, HR = 0.69, 95 % CI = 0.54 to 0.88; Ptrend<.001), but was not related to poultry intake. Correcting for measurement error strengthened the associations between colorectal cancer and red and processed meat intake (per 100-g increase HR = 1.25, 95% CI =1.09 to 1.41, Ptrend = .001 and HR = 1.55, 95% CI = 1.19 to 2.02, Ptrend = .001 before and after calibration, respectively) and for fish (per 100 g increase HR = 0.70, 95% CI = 0.57 to 0.87, Ptrend<.001 and HR = 0.46, 95% CI = 0.27 to 0.77, Ptrend = .003; before and after correction, respectively). In this study population, the absolute risk of development of colorectal cancer within 10 years for a study subject aged 50 years was 1.71% for the highest category of red and processed meat intake and 1.28% for the lowest category of intake and was 1.86% for subjects in the lowest category of fish intake and 1.28% for subjects in the highest category of fish intake., Conclusions: Our data confirm that colorectal cancer risk is positively associated with high consumption of red and processed meat and support an inverse association with fish intake.

Background: Contrasting etiologic hypotheses about the role of endogenous sex steroids in breast cancer development among premenopausal women implicate ovarian androgen excess and progesterone deficiency, estrogen excess, estrogen and progesterone excess, and both an excess or lack of adrenal androgens (dehydroepiandrosterone [DHEA] or its sulfate [DHEAS]) as risk factors. We conducted a case-control study nested within the European Prospective Investigation into Cancer and Nutrition cohort to examine associations among premenopausal serum concentrations of sex steroids and subsequent breast cancer risk., Methods: Levels of DHEAS, (Delta4-)androstenedione, testosterone, and sex hormone binding globulin (SHBG) were measured in single prediagnostic serum samples from 370 premenopausal women who subsequently developed breast cancer (case patients) and from 726 matched cancer-free control subjects. Levels of progesterone, estrone, and estradiol were also measured for the 285 case patients and 555 matched control subjects who had provided information about the day of menstrual cycle at blood donation. Conditional logistic regression models were used to estimate relative risks of breast cancer by quartiles of hormone concentrations. All statistical tests were two-sided., Results: Increased risks of breast cancer were associated with elevated serum concentrations of testosterone (odds ratio [OR] for highest versus lowest quartile = 1.73, 95% confidence interval [CI] = 1.16 to 2.57; P(trend) = .01), androstenedione (OR for highest versus lowest quartile = 1.56, 95% CI = 1.05 to 2.32; P(trend) = .01), and DHEAS (OR for highest versus lowest quartile = 1.48, 95% CI = 1.02 to 2.14; P(trend) = .10) but not SHBG. Elevated serum progesterone concentrations were associated with a statistically significant reduction in breast cancer risk (OR for highest versus lowest quartile = 0.61, 95% CI = 0.38 to 0.98; P(trend) = .06). The absolute risk of breast cancer for women younger than 40 followed up for 10 years was estimated at 2.6% for those in the highest quartile of serum testosterone versus 1.5% for those in the lowest quartile; for the highest and lowest quartiles of progesterone, these estimates were 1.7% and 2.6%, respectively. Breast cancer risk was not statistically significantly associated with serum levels of the other hormones., Conclusions: Our results support the hypothesis that elevated blood concentrations of androgens are associated with an increased risk of breast cancer in premenopausal women.

Objective: Excess weight has been associated with increased risk of cancer at several organ sites. In part, this effect may be modulated through alterations in the metabolism of sex steroids and IGF-I related peptides. The objectives of the study were to examine the association of body mass index (BMI) with circulating androgens (testosterone, androstenedione and dehydroepiandrosterone sulfate (DHEAS)), estrogens (estrone and estradiol), sex hormone-binding globulin (SHBG), IGF-I and IGF-binding protein (IGFBP)-3, and the relationship between sex steroids, IGF-I and IGFBP-3., Design and Methods: A cross-sectional analysis was performed using hormonal and questionnaire data of 620 healthy women (177 pre- and 443 post-menopausal). The laboratory measurements of the hormones of interest were available from two previous case-control studies on endogenous hormones and cancer risk., Results: In the pre-menopausal group, BMI was not related to androgens and IGF-I. In the post-menopausal group, estrogens, testosterone and androstenedione increased with increasing BMI. The association with IGF-I was non-linear, with the highest mean concentrations observed in women with BMI between 24 and 25. In both pre- and post-menopausal subjects, IGFBP-3 did not vary across BMI categories and SHBG decreased with increasing BMI. As for the correlations between peptide and steroid hormones, in the post-menopausal group, IGF-I was positively related to androgens, inversely correlated with SHBG, and not correlated with estrogens. In the pre-menopausal group, similar but weaker correlations between IGF-I and androgens were observed., Conclusions: These observations offer evidence that obesity may influence the levels of endogenous sex-steroid and IGF-related hormones in the circulation, especially after menopause. Circulating IGF-I, androgens and SHBG appear to be related to each other in post-menopausal women.

Background: Screening programmes are often actively promoted to achieve high coverage, which may result in unrealistic expectations. We examined women's understanding of the likely benefits of mammography screening., Methods: Telephone survey of random samples of the female population aged > or =15 years in the US, UK, Italy, and Switzerland using three closed questions on the expected benefits of mammography screening., Results: A total of 5964 women were contacted and 4140 women (69%) participated. Misconceptions were widespread: a majority of women believed that screening prevents or reduces the risk of contracting breast cancer (68%), that screening at least halves breast cancer mortality (62%), and that 10 years of regular screening will prevent 10 or more breast cancer deaths per 1000 women (75%). In multivariate analysis higher number of correct answers was positively associated with higher educational status (odds ratio [OR] = 1.44, 95% CI: 1.25, 1.66) and negatively with having had a mammography in the last 2 years (OR = 0.86, 95% CI: 0.73, 1.01). Compared with US women (reference group) and Swiss women (OR = 0.98, 95% CI: 0.82, 1.18) respondents in Italy (OR = 0.61, 95% CI: 0.50, 0.74) and the UK (OR = 0.73, 95% CI: 0.60, 0.88) gave fewer correct answers., Conclusion: In the US and three European countries a high proportion of women overestimated the benefits that can be expected from screening mammography. This finding raises doubts on informed consent procedures within breast cancer screening programmes.

Background: Obesity is associated with increased breast cancer risk among postmenopausal women. We examined whether this association could be explained by the relationship of body mass index (BMI) with serum sex hormone concentrations., Methods: We analyzed individual data from eight prospective studies of postmenopausal women. Data on BMI and prediagnostic estradiol levels were available for 624 case subjects and 1669 control subjects; data on the other sex hormones were available for fewer subjects. The relative risks (RRs) with 95% confidence intervals (CIs) of breast cancer associated with increasing BMI were estimated by conditional logistic regression on case-control sets, matched within each study for age and recruitment date, and adjusted for parity. All statistical tests were two-sided., Results: Breast cancer risk increased with increasing BMI (P(trend) =.002), and this increase in RR was substantially reduced by adjustment for serum estrogen concentrations. Adjusting for free estradiol reduced the RR for breast cancer associated with a 5 kg/m2 increase in BMI from 1.19 (95% CI = 1.05 to 1.34) to 1.02 (95% CI = 0.89 to 1.17). The increased risk was also substantially reduced after adjusting for other estrogens (total estradiol, non-sex hormone-binding globulin-bound estradiol, estrone, and estrone sulfate), and moderately reduced after adjusting for sex hormone-binding globulin, whereas adjustment for the androgens (androstenedione, dehydroepiandrosterone, dehydroepiandrosterone sulfate, and testosterone) had little effect on the excess risk., Conclusion: The results are compatible with the hypothesis that the increase in breast cancer risk with increasing BMI among postmenopausal women is largely the result of the associated increase in estrogens, particularly bioavailable estradiol.

Background: The relationship between erythrocyte membrane fatty acids and postmenopausal breast cancer risk was analyzed previously only by retrospective studies, which suggested a protective effect of increased saturation index (SI), i.e., the ratio of membrane stearic to oleic acid. We investigated the relationships in a prospective study of hormones, diet, and prediagnostic breast cancer (the ORDET study) conducted in northern Italy., Methods: A total of 4052 postmenopausal women were followed for an average of 5.5 years; 71 cases of invasive breast cancer were identified. For each case subject, two matched control subjects were chosen randomly from among cohort members. The various fatty acids in erythrocyte membranes were measured as a percentage of total fatty acids. Conditional logistic regression analysis evaluated the association between membrane fatty acid composition and breast cancer risk. The SI, which is influenced by the activity of the enzyme delta 9 desaturase (Delta 9-d), was also investigated. All statistical tests were two-sided., Results: Oleic (highest versus lowest tertile of percentage of total fatty acids, odds ratio [OR] = 2.79; 95% confidence interval [CI] = 1.24 to 6.28) and monounsaturated fatty acids (highest to lowest tertile, OR = 5.21; 95% CI = 1.95 to 13.91) were positively associated with breast cancer risk. The SI (highest to lowest tertile, OR = 0.29; 95% CI = 0.13 to 0.64) was inversely associated with breast cancer risk. The analysis suggested an inverse association between total polyunsaturated fatty acids and breast cancer risk, but individual polyunsaturated fatty acids behaved differently. There was no association between saturated fatty acids and breast cancer risk., Conclusions: We have found that monounsaturated fats and SI in erythrocyte membranes are predictors of postmenopausal breast cancer. Both of these variables depend on the activity of the enzyme Delta 9-d. The dietary, metabolic, and hormonal factors acting on Delta 9-d expression and activity and, therefore, on patterns of fatty acid metabolism, should be further investigated as possible determinants of breast cancer.

Background: Occurrence of and prognosis for tumours of the colon and rectum are thought to be changing rapidly due to simultaneous changes in risk factor prevalence, early diagnosis and treatment. In this paper time trends of morbidity, survival and mortality for colorectal cancer during the period 1970-1990 are estimated and analysed., Methods: Mortality trends were obtained from official death certificates. Relative survival rates were computed from population-based cancer registries. Incidence and prevalence rates were estimated from mortality and survival data., Results: Incidence rates were increasing during the period considered, with a lower rate of increase for the youngest birth cohorts. Relative survival rates of both colon and rectum cancers were higher for women, and for younger age groups, and were positively associated with period of diagnosis. No significant survival difference among the cancer registries used was found. A total of about 155,000 prevalent cases, 40% of which had been diagnosed > or = 7 years before, were estimated in the Italian population for the year 1990. Mortality rates were slightly increasing for men and stable for women. Projections of colorectal cancer trends to the year 2000 indicate major expected rises in both incidence and prevalence., Conclusion: Colorectal cancer represents a problem of growing impact for health services in Italy. This conclusion can probably be extended to many developed countries.

A pilot questionnaire was developed for the EPIC centres of northern Italy, and validated in the feasibility part of the cohort project. The questionnaire was self-administered and of the food frequency type with portion size estimated by means of pictures. It was structured by courses within a meal characteristic of Italian dietary habits. Dietary intake estimated by the questionnaire was compared to the corresponding estimates obtained from 8-14 24-hour recall interviews administered over a 1-year period. The reference method was validated by means of urinary nitrogen in 4-6 repeated 24-hour urine collections. One hundred and ninety-seven volunteers (47 men and 150 women) were enrolled and completed the study lasting 1 year. They filled out two questionnaires at the beginning and at the end of the study, and had a 24-hour recall interview once a month. Twenty-four-hour urine samples were collected at regular intervals. Usual intake of energy, the major nutrients and some vitamins were estimated for the questionnaires and the reference method by means of food composition tables compiled for this study. The agreement between the questionnaire and the 24-hour recalls was only good for alcohol consumption: Pearson's correlation was 0.73 and 0.77 in men and women respectively. Otherwise the relative validity of the questionnaire ranged between 0.28 for fat to 0.52 for carbohydrates in men and 0.25 and 0.50 in women for the same nutrients. The validity of the two interview methods in estimating protein intake, compared to mean urinary nitrogen was 0.24 (M) and 0.18 (W) for the questionnaire and 0.63 (M) and 0.48 (W) for 24-hour recalls. The main causes of low performance of the questionnaire were identified to be the estimated intake of dressing and cooking fats, vegetables and meat. Remedies were devised and introduced in the final version of the questionnaire currently in use in the EPIC project.

Background: High levels of androgens and estrogens have been reported to be associated with breast cancer. However, the multiplicity of factors that influence hormone levels and methodologic issues complicate the study of the relationship between steroid sex hormones and breast cancer., Purpose: Using an improved study design, we assessed prospectively the relationship between the principal steroid sex hormones in serum and the subsequent occurrence of invasive breast cancer in postmenopausal women., Methods: Four thousand fifty-three healthy postmenopausal women aged 40-69 years, were enrolled from June 1987 through June 1992 in a prospective investigation of hormones and diet in the etiology of breast tumors (ORDET study) as part of a larger volunteer cohort of 10 788 premenopausal and postmenopausal women from Varese Province, northern Italy. At recruitment, blood samples were taken between 8:00 AM and 9:30 AM (after overnight fasting), and sera were preserved in -80 degree Celsius freezers. Women who had received hormone treatment in the 3 months prior to enrollment, who had bilateral ovariectomy, or who had a history of cancer or liver disease were not recruited. Twenty-five women in the final eligible cohort of postmenopausal women developed histologically confirmed, invasive breast cancer during the first 3.5 years of follow-up for the cohort (13 537 women-years). For each case subject, four control subjects were randomly chosen after matching for factors possibly affecting hormone preservation in serum. One case subject and eight control subjects were excluded because premenopausal hormonal patterns were found; thus, after also excluding the four control subjects matched to the ineligible case subject, we included 24 case and 88 control subjects. In the spring of 1994, stored sera of case and control subjects were assayed in a blinded manner for dehydroepiandrosterone sulfate and estradiol (E2) by in-house radioimmunoassay and for total and free testosterone and sex hormone-binding globulin by commercially available nonextraction iodination kits. Mean differences in risk factors were tested by analysis of variance for paired data. Relative risks (RRs) were estimated by conditional logistic regression analysis. All P values resulted from two-sided tests., Results: Age-adjusted mean values of total testosterone, free testosterone, and E2 were significantly higher in case subjects than in control subjects: total testosterone, 0.34 ng/mL versus 0.25 ng/mL (P<.001); free testosterone, 1.07 pg/ml versus 0.77 pg/mL (P= .006); and E2, 25 pg/mL versus 22 pg/mL (P= .027). Age-adjusted RRs for breast cancer in increasing tertiles were as follows: for total testosterone, 1.0, 4.8, and 7.0 (P for trend =.026); for free testosterone, 1.0, 1.8, and 5.7 (P for trend=.005); and for total E2, 1.0, 7.1, and 5.5 (P for trend= .128)., Conclusions and Implications: This prospective study provides further evidence in support of the already established association between elevated estrogen levels and breast cancer. Even more importantly, it provides new evidence that high serum testosterone levels precede breast cancer occurrence.

Retrospective assessment of asbestos exposure--II. At the job level: Complementarity of job-specific questionnaire and job exposure matrices. International Journal of Epidemiology 1993; 22 (Suppl. 2): S96-S105. The assessments of asbestos exposure by two a priori job exposure matrices (JEM) and by a job-specific questionnaire (SQ) are compared at job level. The data used for the comparison were generated by an ongoing case-control study on lung cancer in a region of northern Germany with a relatively high past prevalence of asbestos exposure. Among job periods assessed as unexposed by either JEM, 96% are recognized as such by the SQ. Discrepancies between the SQ and JEM were observed in jobs rated potentially exposed by the JEM. Despite varying estimates, the JEM and SQ were consistent as regards the relative classification of job periods by probability of exposure. The concordance of the methods, estimated by Kappa statistics, was stronger for the two JEM than for either of the JEM and the SQ. The identification of specific occupation/industry combinations in which discrepancies were most frequent and the comparison with expert ratings in some jobs yield insights into the sources of the disagreement between the methods. The misclassification of exposure by the JEM usually results in an overestimation of exposure. This is essentially related to loss of information due to the use of job codes as surrogates for job task descriptions and to the insufficiency of published data on asbestos exposure in different industries. As regards the SQ, two main sources of potential loss of sensitivity were identified: 1) possible omission of indirect sources of exposure by this method, 2) possible incompleteness of the SQ. The present comparison of methods of asbestos exposure assessment does not allow any one approach to be considered superior to another. Indeed, as proposed by Ahrens et al. in Part I of the study, both should be used to ensure optimal epidemiological performance.

The validity of retrospective assessment of occupational exposure greatly depends on the amount of detail in the available information, on the knowledge of the specific industrial process by the experts, and on the criteria adopted to define relevant exposure. These criteria are difficult to standardize and are rarely made explicit in published reports, which makes it difficult to interpret inconsistencies among different studies. In two ongoing case-control studies on kidney cancer and, respectively, malignant lymphomas, a detailed occupational history was obtained and supplemented by 19 additional questionnaires, specifically addressing industrial activities where the knowledge of job title alone would have been insufficient for reliable exposure assessment. One further questionnaire was used to collect details of task and environment for all the other activities. These data are used to establish probability, intensity and frequency of exposure to 30 substances known or suspected to be carcinogenic from previous studies. There are two basic steps in the exposure assessment procedure: firstly, general rules are defined for each job within each activity covered by specific questionnaires; secondly the judgement is modulated according to the detailed tasks, working conditions and environment. To illustrate the process and to facilitate comparison with other studies, examples are given for a few common exposures in the textile and metal industries--the two most frequent economic activities in the study area--namely exposure to mineral oils, formaldehyde, aromatic solvents, chlorinated solvents and other organic solvents.

Two methods used for retrospective evaluation of occupational exposures, a case by case assessment by expert and the application of a job exposure matrix (JEM), are compared using occupational histories collected for a case-control study on sinonasal cancer. The objective was to identify the main sources of discrepancies and to contribute to an optimal use of a JEM for population-based case-control studies. Comparisons were based on job periods, and were performed separately for two substances: formaldehyde and wood-dust. Job periods were classified according to the category of exposure assigned by the matrix, and to the probability and level of exposure assessed by the study expert. The sources of discrepancies were examined for job periods probably or definitely exposed according to the JEM and unexposed for the expert, or unexposed in the JEM and probably or definitely exposed to medium or high level for the expert. Such discrepancies were observed for 8% of the job periods for formaldehyde and 3% of the job periods for wood-dust. The agreement between the two approaches was better for wood-dust than for formaldehyde. The relative importance of different sources of discrepancies was not the same for formaldehyde and wood-dust. For formaldehyde a substantial part of the discrepancies was due to disagreements between the study expert and the matrix experts, which were mostly differences in threshold limits between 'not exposed' and 'definitely exposed at a low level'. Differences between experts' opinions did not explain the discordances observed for wood-dust. The presence of additional information in the questionnaire was an important source of discrepancy for the two substances.(ABSTRACT TRUNCATED AT 250 WORDS)

Correct retrospective assignment of subjects to an exposure category is affected by a variety of problems: 1) lack of an objective lifetime measurement; 2) dependence upon the accuracy and thoroughness of the job description; 3) heavy reliance upon the knowledge of experts. The aim of the study was the quantification of the performance of a job exposure matrix (JEM) in evaluating solvent exposure, using expert judgements as the reference method. The sources of discrepancies between the two methods were analysed within the framework of two community-based case-control surveys. One included 765 cases of bladder cancer (BC) and 765 controls, the other 298 cases of glomerulonephritis (GN) and 298 controls. The JEM had been set up previously for a case-control study on laryngeal cancer and is based on 4000 discrete job titles. Comparison between the JEM and expert exposure evaluation was carried out for 2736 job periods in the BC study and 929 in the GN study. Categories of exposure for both experts and JEM were dichotomized, using different cutoff points for exposure and non-exposure. Prevalence of exposure as assessed by the experts was twice as high in the GN study (19%) as in the BC study (10%), showing the importance of the questionnaire design and of the inclusiveness of the definition of exposure. Sensitivity of the JEM vis-a-vis the experts was low (23-63%), whereas specificity was rather high (87-98%). The best concordance between the two methods was obtained with a specific dichotomy from the JEM and a narrow definition of exposure by the experts. Bias and loss of power resulting from JEM misclassifications were calculated with a theoretical population odds ratio of 3 and an exposure prevalence of 10%. If the experts' classification of the subjects according to exposure is assumed to be 100% correct, using the JEM led to a bias in estimating the odds ratio, ranging from 1.5 to 2.1, and to a loss of power equivalent to a reduction in the number of subjects by a factor of 5 to 10. Analysis of systematic discrepancies between exposure assessments of the experts and the JEM showed that they were clustered with some job categories and arose from different sources: 1) inadequate job descriptions, related to the codification system adopted and necessitating the gathering of information at the individual level; 2) true disagreements between JEM and experts regarding the definition of solvent exposure.(ABSTRACT TRUNCATED AT 400 WORDS)

Retrospective assessment of asbestos exposure--I. Case-control analysis in a study of lung cancer: efficiency of job-specific questionnaires and job exposure matrices. International Journal of Epidemiology 1993; 22 (Suppl. 2): S83-S95. In a lung cancer study in Northern Germany the asbestos exposure assessment obtained from detailed supplementary questionnaires (SQ) was compared to the assessment obtained by the application of two job exposure matrices (JEM) to the job history. The study includes 391 incident male cases and the same number of controls from the general population, matched by sex, age, and region. Almost 16% of the subjects are considered as never having been exposed to asbestos and 24% are classified as certainly exposed according to both of the JEM, the corresponding percentages of the SQ-method being 68% and 32%. Sixty percent are considered by the JEM as having an intermediate probability of exposure. In general, the agreement between the different methods is better when the exposure definition is restricted to definite exposures, the corresponding Kappa statistic being 0.67 for the comparison between both JEM and 0.44/0.39 between the JEM and the SQ. The positive agreement between SQ and JEM (reference) increases from 12% and 17% for subjects with low probability of exposure to 61% and 69% for those with definite exposures. A ranking according to cumulative exposure shows some dose-response relationship for each of the three methods with a smoking-adjusted OR in the highest category of 1.85 (95% CI: 1.01-3.38) for the SQ method and 2.47 (95% CI: 1.40-4.37) and 2.94 (95% CI: 1.73-4.99) for the two JEM. The results are discussed with reference to the conceptual differences between the methods and their potential scope in future studies.

During 1983 and 1984, 240 newly diagnosed cases of brain glioma and 742 controls (465 non-glioma nervous system tumors and 277 patients with other neurologic diseases) were recruited and interviewed in the neurologic and neurosurgical departments of two hospitals in Milan, Italy. The occupational histories of cases and controls were compared, and relative risk estimates, adjusted for sex, age, residence, and socioeconomic status, were computed using the Mantel-Haenszel method. A statistically significant risk increase was found for farmers (relative risk (RR) = 1.6, p = 0.0025). This risk increase was attributable to those farmers who reported the use of chemicals (insecticides or fungicides, herbicides, and fertilizers). Among the three groups of investigated agrochemicals, only the use of insecticides or fungicides was associated with a significant increase in relative risk (RR = 2.0, p = 0.006). Many farmers exposed to fungicides reported the use of commercial compounds of copper sulfate. Some of these compounds contain methyl urea, which has a specific carcinogenic effect on the nervous system in animals. These data suggest that the occupational exposure of farmers to agrochemicals might be responsible for the observed excess risk of brain glioma in farmers.

Patients with gliomas of the central nervous system hospitalized during the period January 1979--March 1980 at the Neurological Institute C. Besta of Milan were compared with controls admitted to the Institute in the same period for nonneoplastic neurologic diseases or benign tumors. The comparison was based on occupational history, smoking habits, and alcohol consumption. Two analyses were carried out: the first by case-control pairs matched for age, sex, and residence; the second by age, sex, and residence stratification. Patients with glioma were more likely than controls to have worked in agricultural activities and showed a relative risk of 5.0 (p = 0.043) in the matched analysis and 1.9 (p = 0.113) in the analysis by stratification. This high risk was confined to those who performed agricultural work after 1960, suggesting a possible etiologic role of exposure to organic pesticides, fertilizers, and herbicides, which have only recently been commonly used in Italy. No significant difference was observed between cases and controls in regard to other analyzed occupations and habits.

A total of 417 lung cancer cases and 849 controls were interviewed on their life-long tobacco usage and their current intake of four food items rich in retinol or carotene. The study was a hospital-based case control where 'cases' were lung cancer patients diagnosed during the period 1979/80 at seven hospitals in the Lombardy region (90% pathologically confirmed) and controls were patients admitted to the same hospitals for causes unrelated to tobacco smoking (epithelial cancers being excluded from present analysis). Odds ratios (OR) have been computed for increasing frequencies of consumption of liver, cheese, carrots and leafy green vegetables, having controlled for the confounding effects of tobacco usage, residence and birthplace. Current smokers who did not consume carrots showed a three-fold risk of developing lung cancer compared with those who ate them more than once a week (OR = 2.9 less than p less than 0.01); the ORs for consumers in the categories of 1-2 and 3-4 times per month were 1.8 and 2.0 respectively, with a significant test for linear trend (p less than 0.01). Among ex-smokers or non-smokers, no decrease of lung cancer risk is evident associated with carrot consumption. An excess risk was also associated with low intake of green vegetables although it was not significant, while no excess risk was evident for non-consumers of liver and cheese. The effect of carrots is independent of histological type of lung cancer while the effect of green vegetables was confined to epidermoid carcinomas: low versus high intake group OR = 1.3.