Disorn Sookthai

Premenopausal serum sex hormone levels in relation to breast cancer risk, overall and by hormone receptor status - results from the EPIC cohort.

Results from prospective studies on premenopausal serum hormone levels in relation to breast cancer risk have been inconclusive, especially with regard to tumor subtypes. Using a case–control study nested within the prospective European Prospective Investigation into Cancer and Nutrition (EPIC) cohort (801 breast cancer cases and 1,132 matched control subjects), we analyzed the relationships of prediagnostic serum estradiol, free estradiol, progesterone, testosterone, free testosterone and sex hormone‐binding globulin (SHBG) levels with the risk of breast cancer by estrogen and progesterone receptor‐positive and ‐negative breast tumors and by age at diagnoses. Higher prediagnostic serum levels of testosterone and free testosterone were associated with an increased overall risk of breast cancer [ORQ4‐Q1 = 1.56 (95% CI 1.15–2.13), ptrend = 0.02 for testosterone and ORQ4‐Q1 = 1.33 (95% CI 0.99–1.79), ptrend = 0.04 for free testosterone], but no significant risk association was observed for estradiol, free estradiol, progesterone and SHBG. Tests for heterogeneity between receptor‐positive and ‐negative tumors were not significant. When analysis were stratified by age at tumor diagnosis, the odds ratios observed for estradiol were stronger and borderline significant for breast cancer diagnosed at age less than 50 [ORQ4‐Q1 = 1.32 (95% CI 0.87–2.01), ptrend = 0.05] compared to breast cancer diagnosed at age 50 or above [ORQ4‐Q1 = 0.94 (95% CI 0.60–1.47), ptrend = 0.34, phet = 0.04]. In conclusion, our data indicate that higher premenopausal circulating testosterone levels are associated with an increased risk of developing breast cancer, but do not show a significant association of estradiol or progesterone with breast cancer risk, overall, by menstrual cycle phase or by tumor receptor status, although a possible risk increase with higher estradiol levels for tumors diagnosed before age 50 was seen.

Circulating prolactin and breast cancer risk among pre- and postmenopausal women in the EPIC cohort

BACKGROUND Experimental and epidemiological evidence suggests that prolactin might play a role in the etiology of breast cancer. We analyzed the relationship of prediagnostic circulating prolactin levels with the risk of breast cancer by menopausal status, use of postmenopausal hormone replacement therapy (HRT) at blood donation, and by estrogen and progesterone receptor status of the breast tumors. PATIENTS AND METHODS Conditional logistic regression was used to analyze the data from a case-control study nested within the prospective European EPIC cohort, including 2250 invasive breast cancer and their matched control subjects. RESULTS Statistically significant heterogeneity in the association of prolactin levels with breast cancer risk between women who were either pre- or postmenopausal at the time of blood donation was observed (Phet = 0.04). Higher serum levels of prolactin were associated with significant increase in the risk of breast cancer among postmenopausal women [odds ratio (OR)Q4-Q1 = 1.29 (95% confidence interval, CI, 1.05-1.58), Ptrend = 0.09]; however, this increase in risk seemed to be confined to women who used postmenopausal HRT at blood donation [ORQ4-Q1 = 1.45 (95% CI 1.08-1.95), Ptrend = 0.01], whereas no statistically significant association was found for the non-users of HRT [ORQ4-Q1 = 1.11 (95%CI 0.83-1.49), Ptrend = 0.80] (Phet = 0.08). Among premenopausal women, a statistically non-significant inverse association was observed [ORQ4-Q1 = 0.70 (95% CI 0.48-1.03), Ptrend = 0.16]. There was no heterogeneity in the prolactin-breast cancer association by hormone receptor status of the tumor. CONCLUSION Our study indicates that higher circulating levels of prolactin among the postmenopausal HRT users at baseline may be associated with increased breast cancer risk.BACKGROUND Experimental and epidemiological evidence suggests that prolactin might play a role in the etiology of breast cancer. We analyzed the relationship of prediagnostic circulating prolactin levels with the risk of breast cancer by menopausal status, use of postmenopausal hormone replacement therapy (HRT) at blood donation, and by estrogen and progesterone receptor status of the breast tumors. PATIENTS AND METHODS Conditional logistic regression was used to analyze the data from a case-control study nested within the prospective European EPIC cohort, including 2250 invasive breast cancer and their matched control subjects. RESULTS Statistically significant heterogeneity in the association of prolactin levels with breast cancer risk between women who were either pre- or postmenopausal at the time of blood donation was observed (Phet = 0.04). Higher serum levels of prolactin were associated with significant increase in the risk of breast cancer among postmenopausal women [odds ratio (OR)Q4-Q1 = 1.29 (95% confidence interval, CI, 1.05-1.58), Ptrend = 0.09]; however, this increase in risk seemed to be confined to women who used postmenopausal HRT at blood donation [ORQ4-Q1 = 1.45 (95% CI 1.08-1.95), Ptrend = 0.01], whereas no statistically significant association was found for the non-users of HRT [ORQ4-Q1 = 1.11 (95%CI 0.83-1.49), Ptrend = 0.80] (Phet = 0.08). Among premenopausal women, a statistically non-significant inverse association was observed [ORQ4-Q1 = 0.70 (95% CI 0.48-1.03), Ptrend = 0.16]. There was no heterogeneity in the prolactin-breast cancer association by hormone receptor status of the tumor. CONCLUSION Our study indicates that higher circulating levels of prolactin among the postmenopausal HRT users at baseline may be associated with increased breast cancer risk.

Insulin-like growth factor I and risk of breast cancer by age and hormone receptor status-A prospective study within the EPIC cohort.

Experimental evidence shows cross‐talk in mammary cells between estrogen, insulin‐like growth factor I (IGF‐I) and their respective receptors and possible synergistic effects of estrogen receptor (ER) activation and increased IGF‐I signaling with regard to breast tumor development, and epidemiological evidence suggests that circulating IGF‐I levels may be related more to the risk of ER‐positive than ER‐negative breast cancer. Using a case–control study nested within the prospective European EPIC cohort (938 breast cancer cases and 1,394 matched control subjects), we analyzed the relationships of prediagnostic serum IGF‐I levels with the risk of estrogen and progesterone receptor‐positive and ‐negative breast tumors. IGF‐I levels were positively associated with the risk of ER+ breast tumors overall (pre‐ and postmenopausal women combined, odds ratio (OR)Q4‐Q1 = 1.41 [95% confidence interval (CI) 1.01–1.98] for the highest vs. lowest quartile; OR = 1.17 [95% CI 1.04–1.33] per 1‐standard deviation (SD) increase in IGF‐I, ptrend = 0.01) and among women who were diagnosed with breast cancer at 50 years or older (ORQ3‐Q1 = 1.38 [95% CI 1.01–1.89]; OR = 1.19 [95% CI 1.04–1.36] per 1‐SD increase in IGF‐I, ptrend = 0.01) but not with receptor‐positive disease diagnosed at an earlier age. No statistically significant associations were observed for ER− breast tumors overall and by age at diagnosis. Tests for heterogeneity by receptor status of the tumor were not statistically significant, except for women diagnosed with breast cancer at 50 years or older (phet = 0.03 for ER+/PR+ vs. ER−/PR− disease). Our data add to a global body of evidence indicating that higher circulating IGF‐I levels may increase risk specifically of receptor‐positive, but not receptor‐negative, breast cancer diagnosed at 50 years or older.

Selecting High-Risk Individuals for Lung Cancer Screening: A Prospective Evaluation of Existing Risk Models and Eligibility Criteria in the German EPIC Cohort

Lung cancer risk prediction models are considered more accurate than the eligibility criteria based on age and smoking in identification of high-risk individuals for screening. We externally validated four lung cancer risk prediction models (Bach, Spitz, LLP, and PLCOM2012) among 20,700 ever smokers in the EPIC-Germany cohort. High-risk subjects were identified using the eligibility criteria applied in clinical trials (NELSON/LUSI, DLCST, ITALUNG, DANTE, and NLST) and the four risk prediction models. Sensitivity, specificity, and positive predictive value (PPV) were calculated based on the lung cancers diagnosed in the first 5 years of follow-up. Decision curve analysis was performed to compare net benefits. The number of high-risk subjects identified by the eligibility criteria ranged from 3,409 (NELSON/LUSI) to 1,458 (NLST). Among the eligibility criteria, the DLCST produced the highest sensitivity (64.13%), whereas the NLST produced the highest specificity (93.13%) and PPV (2.88%). The PLCOM2012 model showed the best performance in external validation (C-index: 0.81; 95% CI, 0.76–0.86; E/O: 1.03; 95% CI, 0.87–1.23) and the highest sensitivity, specificity, and PPV, but the superiority over the Bach model and the LLP model was modest. All the models but the Spitz model showed greater net benefit over the full range of risk estimates than the eligibility criteria. We concluded that all of the lung cancer risk prediction models apart from the Spitz model have a similar accuracy to identify high-risk individuals for screening, but in general outperform the eligibility criteria used in the screening trials. Cancer Prev Res; 8(9); 777–85. ©2015 AACR.

Primary Preventive Potential for Stroke by Avoidance of Major Lifestyle Risk Factors The European Prospective Investigation Into Cancer and Nutrition-Heidelberg Cohort

Background and Purpose— Because primary prevention of stroke is a priority, our aim was to assess the primary preventive potential of major lifestyle risk factors for stroke in middle-aged women and men. Methods— Among 23 927 persons, 551 (195 women and 356 men) had a first diagnosis of stroke during an average follow-up of 12.7 years. Using Cox proportional hazards models, we estimated the associations of adiposity, smoking, physical activity, alcohol consumption, and diet with risk of developing stroke. A competing risk model built from cause-specific proportional hazards models accounting for concurrent risk of death was used to calculate relative and absolute reductions in stroke occurrences that could have been achieved by maintaining a healthy lifestyle pattern. Results— Obesity, smoking, alcohol consumption, diet, and physical inactivity were each identified as modifiable lifestyle risk factors for stroke. About 38% of stroke cases were estimated as preventable through adherence to a healthy lifestyle profile (never smoking, maintaining optimal body mass index and waist circumference, performing physical exercise, consuming a moderate quantity of alcohol, and following a healthy dietary pattern). Age-specific estimates of 5-year incidence rates for stroke in the actual cohort and in a hypothetical, comparable cohort of individuals following a healthy lifestyle would be reduced from 153 to 94 per 100 000 women and from 261 to 161 per 100 000 men for the age group 60 to 65 years. Conclusions— Our analysis confirms the strong primary prevention potential for stroke based on avoidance of excess body weight, smoking, heavy alcohol consumption, unhealthy diet, and physical inactivity.

Intra-individual variation of plasma trimethylamine-N-oxide (TMAO), betaine and choline over 1 year

Abstract Background: Circulating trimethylamine-N-oxide (TMAO) has been implicated in the development of cardiovascular and chronic kidney diseases (CKD). However, while higher TMAO levels have been associated with increased risks of cardiovascular or renal events in first prospective studies, it remained unclear how much plasma TMAO concentrations vary over time. Methods: We measured fasting plasma levels of TMAO and two of its precursors, betaine and choline by LC-MS, in two samples of 100 participants of the European Investigation into Cancer and Nutrition (EPIC)-Heidelberg study (age range: 47–80 years, 50% female) that were collected 1 year apart, and assessed their intra-individual variation by Spearman’s correlation coefficients (ρ). Results: Correlations of metabolite concentrations over 1 year were at ρ=0.29 (p=0.003) for TMAO, ρ=0.81 (p<0.001) for betaine, and ρ=0.61 (p<0.001) for choline. Plasma levels of TMAO were not significantly associated with food intake, lifestyle factors, or routine biochemistry parameters such as C-reactive protein (CRP), low-density lipoprotein (LDL)-cholesterol, or creatinine. Conclusions: In contrast to fasting plasma concentrations of betaine and choline, concentrations of TMAO were more strongly affected by intra-individual variation over 1 year in adults from the general population. The modest correlation of TMAO levels over time should be considered when interpreting associations between TMAO levels and disease endpoints.

Risk factors for cancers of unknown primary site: Results from the prospective EPIC cohort

Cancer of unknown primary site (CUP) may be called an “orphan” disease, as it is diagnosed when metastases are detected while the primary tumor typically remains undetected, and because little research has been done on its primary causes. So far, few epidemiological studies, if any, have addressed possible risk factors for CUP. We analyzed data from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort (N = 476,940). During prospective follow‐up, a total of 651 cases of incident cases of CUP were detected (ICD‐O‐2 code C809). Proportional hazards models were conducted to examine the associations of lifetime history of smoking habits, alcohol consumption, levels of education and anthropometric indices of adiposity with risk of being diagnosed with CUP. Risk of being diagnosed with CUP was strongly related to smoking, with a relative risk of 3.66 [95% C.I., 2.24–5.97] for current, heavy smokers (26+ cigarettes/day) compared to never smokers (adjusted for alcohol consumption, body mass index, waist circumference and level of education) and a relative risk of 5.12 [3.09–8.47] for cases with CUP who died within 12 months. For alcohol consumption and level of education, weaker associations were observed but attenuated and no longer statistically significant after adjusting for smoking and indices of obesity. Finally, risk of CUP was increased by approximately 30 per cent for subjects in the highest versus lowest quartiles of waist circumference. Our analyses provide further documentation, in addition to autopsy studies, that a substantial proportion of cancers of unknown primary site may have their origin in smoking‐related tumors, in particular.

Circulating prolactin and in situ breast cancer risk in the European EPIC cohort: a case-control study.

IntroductionThe relationship between circulating prolactin and invasive breast cancer has been investigated previously, but the association between prolactin levels and in situ breast cancer risk has received less attention.MethodsWe analysed the relationship between pre-diagnostic prolactin levels and the risk of in situ breast cancer overall, and by menopausal status and use of postmenopausal hormone therapy (HT) at blood donation. Conditional logistic regression was used to assess this association in a case-control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, including 307 in situ breast cancer cases and their matched control subjects.ResultsWe found a significant positive association between higher circulating prolactin levels and risk of in situ breast cancer among all women [pre-and postmenopausal combined, ORlog2 = 1.35 (95% CI 1.04-1.76), Ptrend = 0.03]. No statistically significant heterogeneity was found between prolactin levels and in situ cancer risk by menopausal status (Phet = 0.98) or baseline HT use (Phet = 0.20), although the observed association was more pronounced among postmenopausal women using HT compared to non-users (Ptrend = 0.06 vs Ptrend = 0.35). In subgroup analyses, the observed positive association was strongest in women diagnosed with in situ breast tumors <4 years compared to ≥4 years after blood donation (Ptrend = 0.01 vs Ptrend = 0.63; Phet = 0.04) and among nulliparous women compared to parous women (Ptrend = 0.03 vs Ptrend = 0.15; Phet = 0.07).ConclusionsOur data extends prior research linking prolactin and invasive breast cancer to the outcome of in situ breast tumours and shows that higher circulating prolactin is associated with increased risk of in situ breast cancer.

The effects of intermittent calorie restriction on metabolic health: Rationale and study design of the HELENA Trial

Mechanistic studies suggest benefits of intermittent calorie restriction (ICR) in chronic disease prevention that may exceed those of continuous calorie restriction (CCR), even at equal net calorie intake. Despite promising results from first trials, it remains largely unknown whether ICR-induced metabolic alterations reported from experimental studies can also be observed in humans, and whether ICR diets are practicable and effective in real life situations. Thus, we initiated the HELENA Trial to test the effects of ICR (eu-caloric diet on five days and very low energy intake on two days per week) on metabolic parameters and body composition over one year. We will assess the effectiveness of ICR compared to CCR and a control diet over a 12-week intervention, 12-week maintenance phase and 24-week follow-up in 150 overweight or obese non-smoking adults (50 per group, 50% women). Our primary endpoint is the difference between ICR and CCR with respect to fold-changes in expression levels of 82 candidate genes in abdominal subcutaneous adipose tissue biopsies (SATb) during the intervention phase. The candidate genes represent pathways, which may link obesity-related metabolic alterations with the risk for major chronic diseases. In secondary and exploratory analyses, changes in metabolic, hormonal, inflammatory and metagenomic parameters measured in different biospecimens (SATb, blood, urine, stool) are investigated and effects of ICR/CCR/control on imaging-based measures of subcutaneous, visceral and hepatic fat are evaluated. Our study is the first randomized trial over one year testing the effects of ICR on metabolism, body composition and psychosocial factors in humans.

Prolactin Determinants in Healthy Women: A Large Cross-Sectional Study within the EPIC Cohort

Background: Experimental and epidemiologic data suggest that higher circulating prolactin is associated with breast cancer risk; however, how various risk factors for breast cancer influence prolactin levels in healthy women is not clear. Methods: We analyzed cross-sectional associations between several suggested reproductive and lifestyle risk factors for breast cancer and circulating prolactin among pre- and postmenopausal women, taking into account the use of current postmenopausal hormone therapy, among 2,560 controls from a breast cancer nested case–control study within the EPIC cohort. Results: Adjusted geometric mean prolactin levels were significantly higher among premenopausal women, and among postmenopausal women using hormone therapy compared with nonusers (8.2, 7.0, and 6.3 ng/mL, respectively; Pcat = <0.0001). Furthermore, prolactin levels were significantly higher among users of combined estrogen–progestin hormone therapy compared with users of estrogen-alone hormone therapy (6.66 vs. 5.90 ng/mL; Pcat = 0.001). Prolactin levels were lower among parous women compared with nulliparous women (8.61 vs. 10.95 ng/mL; Pcat = 0.0002, premenopausal women); the magnitude of this difference depended on the number of full-term pregnancies (22.1% lower, ≥3 vs. 1 pregnancy, Ptrend = 0.01). Results for parity were similar but lower in magnitude among postmenopausal women. Prolactin did not vary by other studied factors, with the exception of lower levels among postmenopausal smokers compared with never smokers. Conclusions: Our study shows that current hormone therapy use, especially the use of combined hormone therapy, is associated with higher circulating prolactin levels in postmenopausal women, and confirms prior findings of lower circulating prolactin in parous women. Impact: Our study extends the knowledge linking various breast cancer risk factors with circulating prolactin. Cancer Epidemiol Biomarkers Prev; 23(11); 2532–42. ©2014 AACR.