Kathy J. Helzlsouer

Circulating 25-Hydroxyvitamin D and Risk of Pancreatic Cancer Cohort Consortium Vitamin D Pooling Project of Rarer Cancers

Results from epidemiologic studies examining pancreatic cancer risk and vitamin D intake or 25-hydroxyvitamin D (25(OH)D) concentrations (the best indicator of vitamin D derived from diet and sun) have been inconsistent. Therefore, the authors conducted a pooled nested case-control study of participants from 8 cohorts within the Cohort Consortium Vitamin D Pooling Project of Rarer Cancers (VDPP) (1974–2006) to evaluate whether prediagnostic circulating 25(OH)D concentrations were associated with the development of pancreatic cancer. In total, 952 incident pancreatic adenocarcinoma cases occurred among participants (median follow-up, 6.5 years). Controls (n = 1,333) were matched to each case by cohort, age, sex, race/ethnicity, date of blood draw, and follow-up time. Conditional logistic regression analysis was used to calculate smoking-, body mass index-, and diabetes-adjusted odds ratios and 95% confidence intervals for pancreatic cancer. Clinically relevant 25(OH)D cutpoints were compared with a referent category of 50–<75 nmol/L. No significant associations were observed for participants with lower 25(OH)D status. However, a high 25(OH)D concentration (≥100 nmol/L) was associated with a statistically significant 2-fold increase in pancreatic cancer risk overall (odds ratio = 2.12, 95% confidence interval: 1.23, 3.64). Given this result, recommendations to increase vitamin D concentrations in healthy persons for the prevention of cancer should be carefully considered.

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

BACKGROUNDnAssociations 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.nnnMETHODSnIndividual 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.nnnFINDINGSnWe 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.nnnINTERPRETATIONnCirculating oestrogens and androgens are positively associated with the risk for breast cancer in premenopausal women.

Prospective observational study to assess value of prostate specific antigen as screening test for prostate cancer

Abstract Objective: To evaluate measurement of serum prostate specific antigen as a potential screening test for future clinical prostate cancer among healthy men. Design: Nested case-control study with stored serum samples collected from 49261 men with follow up using national death and cancer registration systems. Subjects: 265 asymptomatic men who subsequently developed clinical prostate cancer and 1055 controls matched for age, study centre, and duration of storage of samples. Main outcome measures: Distribution of concentrations of the antigen in men who developed prostate cancer and in controls. Results: Prostate specific antigen concentrations were significantly higher in men who subsequently developed prostate cancer than in controls. In the first three years after blood collection the median concentration was 23 times greater in cases than in controls of the same age at the same centre (that is, 23 multiples of the median). A smaller difference persisted thereafter; 4.0 multiples of the median 3-6 years after blood collection, 3.6 6-10 years, and 1.8 after 10 years. In the first three years the proportion of men who developed prostate cancer and had raised levels of the antigen (>/=12 multiples of the median) (detection rate or sensitivity) was 81% (95% confidence interval 54% to 96%). The proportion of men who did not develop prostate cancer but had levels this high (false positive rate) was only 0.5%. Conclusion: Prostate specific antigen measurement is a highly discriminatory screening test for prostate cancer among healthy men. In the general population, 60-74 year old men who had >/=12 times the normal median level would have about a 50% chance of developing clinical prostate cancer in the next three years. Measurement of this antigen is a good enough screening test to justify a randomised controlled trial to determine any reduction in mortality from prostate cancer.

Steroid hormone measurements from different types of assays in relation to body mass index and breast cancer risk in postmenopausal women: Reanalysis of eighteen prospective studies.

Epidemiological studies have examined breast cancer risk in relation to sex hormone concentrations measured by different methods: “extraction” immunoassays (with prior purification by organic solvent extraction, with or without column chromatography), “direct” immunoassays (no prior extraction or column chromatography), and more recently with mass spectrometry-based assays. We describe the associations of estradiol, estrone and testosterone with both body mass index and breast cancer risk in postmenopausal women according to assay method, using data from a collaborative pooled analysis of 18 prospective studies. In general, hormone concentrations were highest in studies that used direct assays and lowest in studies that used mass spectrometry-based assays. Estradiol and estrone were strongly positively associated with body mass index, regardless of the assay method; testosterone was positively associated with body mass index for direct assays, but less clearly for extraction assays, and there were few data for mass spectrometry assays. The correlations of estradiol with body mass index, estrone and testosterone were lower for direct assays than for extraction and mass spectrometry assays, suggesting that the estimates from the direct assays were less precise. For breast cancer risk, all three hormones were strongly positively associated with risk regardless of assay method (except for testosterone by mass spectrometry where there were few data), with no statistically significant differences in the trends, but differences may emerge as new data accumulate. Future epidemiological and clinical research studies should continue to use the most accurate assays that are feasible within the design characteristics of each study.

Selenium and Prostate Cancer: Analysis of Individual Participant Data From Fifteen Prospective Studies

Background: Some observational studies suggest that a higher selenium status is associated with a lower risk of prostate cancer but have been generally too small to provide precise estimates of associations, particularly by disease stage and grade. Methods: Collaborating investigators from 15 prospective studies provided individual-participant records (from predominantly men of white European ancestry) on blood or toenail selenium concentrations and prostate cancer risk. Odds ratios of prostate cancer by selenium concentration were estimated using multivariable-adjusted conditional logistic regression. All statistical tests were two-sided. Results: Blood selenium was not associated with the risk of total prostate cancer (multivariable-adjusted odds ratio [OR] per 80 percentile increase = 1.01, 95% confidence interval [CI] = 0.83 to 1.23, based on 4527 case patients and 6021 control subjects). However, there was heterogeneity by disease aggressiveness (ie, advanced stage and/or prostate cancer death, Pheterogeneity = .01), with high blood selenium associated with a lower risk of aggressive disease (ORu2009=u20090.43, 95% CIu2009=u20090.21 to 0.87) but not with nonaggressive disease. Nail selenium was inversely associated with total prostate cancer (ORu2009=u20090.29, 95% CIu2009=u20090.22 to 0.40, Ptrend < .001, based on 1970 case patients and 2086 control subjects), including both nonaggressive (ORu2009=u20090.33, 95% CIu2009=u20090.22 to 0.50) and aggressive disease (ORu2009=u20090.18, 95% CIu2009=u20090.11 to 0.31, Pheterogeneity = .08). Conclusions: Nail, but not blood, selenium concentration is inversely associated with risk of total prostate cancer, possibly because nails are a more reliable marker of long-term selenium exposure. Both blood and nail selenium concentrations are associated with a reduced risk of aggressive disease, which warrants further investigation.

Anti-Mullerian hormone and endometrial cancer: a multi-cohort study.

Background:The Mullerian ducts are the embryological precursors of the female reproductive tract, including the uterus; anti-Mullerian hormone (AMH) has a key role in the regulation of foetal sexual differentiation. Anti-Mullerian hormone inhibits endometrial tumour growth in experimental models by stimulating apoptosis and cell cycle arrest. To date, there are no prospective epidemiologic data on circulating AMH and endometrial cancer risk.Methods:We investigated this association among women premenopausal at blood collection in a multicohort study including participants from eight studies located in the United States, Europe, and China. We identified 329 endometrial cancer cases and 339 matched controls. Anti-Mullerian hormone concentrations in blood were quantified using an enzyme-linked immunosorbent assay. Conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CI) across tertiles and for a doubling of AMH concentrations (ORlog2). Subgroup analyses were performed by ages at blood donation and diagnosis, oral contraceptive use, and tumour characteristics.Results:Anti-Mullerian hormone was not associated with the risk of endometrial cancer overall (ORlog2: 1.07 (0.99–1.17)), or with any of the examined subgroups.Conclusions:Although experimental models implicate AMH in endometrial cancer growth inhibition, our findings do not support a role for circulating AMH in the aetiology of endometrial cancer.

Strengthening Global Partnership in Breast Cancer Research

The global diaspora of peoples has major implications for health and disease and can provide critical insights for understanding etiology and improving treatment. Historically, for example, women in East Asia have experienced lower risks of breast cancer than women of European descent living in Europe and North America. Studies on women of East Asian descent who migrated to North America, however, have demonstrated rates of breast cancer comparable to those of women of European descent among second-generation immigrants, with intermediate rates among first-generation women. The Michigan-Ghana study team report a higher proportion of triple-negative breast cancer (TNBC) among women in West Africa compared with women of European descent living in North America, with North American women of mixed African and European descent falling in between the two proportions. Because TNBC is most common among women with premenopausal onset of breast cancer, the age distribution of the reported patients with breast cancer is important to consider. Theauthors state that the rankingspersisted among women younger than age 50 years. More recently, the Michigan-Ghana group has expanded their work to include breast cancers among Ethiopian women. Rates of TNBC are much lower among these women compared with those in West Africa, consistent with genetic admixture with peoples of Arab descent. Their preliminary work suggests potential biologic underpinnings, which hopefully will be followed by more expansive investigations of multiple factors. A key remaining question is to what extent these observed differences in the proportion of specific subtypesofbreast cancerarea result of underlying genetic factors, constitutional or environmental factors, or, most likely, a combination of these risk factors. Studying differences in exposures across varied populations may help in detecting clues for prevention.