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Purpose: Circulating hormone concentrations are associated with breast cancer risk, with well-established associations for postmenopausal women. Biomarkers may represent minimally invasive measures to improve risk prediction models.Experimental Design: We evaluated improvements in discrimination gained by adding serum biomarker concentrations to risk estimates derived from risk prediction models developed by Gail and colleagues and Pfeiffer and colleagues using a nested case–control study within the EPIC cohort, including 1,217 breast cancer cases and 1,976 matched controls. Participants were pre- or postmenopausal at blood collection. Circulating sex steroids, prolactin, insulin-like growth factor (IGF) I, IGF-binding protein 3, and sex hormone–binding globulin (SHBG) were evaluated using backward elimination separately in women pre- and postmenopausal at blood collection. Improvement in discrimination was evaluated as the change in concordance statistic (C-statistic) from a modified Gail or Pfeiffer risk score alone versus models, including the biomarkers and risk score. Internal validation with bootstrapping (1,000-fold) was used to adjust for overfitting.Results: Among women postmenopausal at blood collection, estradiol, testosterone, and SHBG were selected into the prediction models. For breast cancer overall, model discrimination after including biomarkers was 5.3 percentage points higher than the modified Gail model alone, and 3.4 percentage points higher than the Pfeiffer model alone, after accounting for overfitting. Discrimination was more markedly improved for estrogen receptor–positive disease (percentage point change in C-statistic: 7.2, Gail; 4.8, Pfeiffer). We observed no improvement in discrimination among women premenopausal at blood collection.Conclusions: Integration of hormone measurements in clinical risk prediction models may represent a strategy to improve breast cancer risk stratification. Clin Cancer Res; 23(15); 4181–9. ©2017 AACR.

Supplemental Table 1 shows associations between candidate biomarkers and breast cancer risk in women postmenopausal at blood collection using 5-year risk from Pfeiffer's model as a regression offset. ORs are estimated per doubling of concentration (from log2-transformed measurements) Supplemental Table 2 shows the estimated biomarker effects on risk of breast cancer, per doubling of concentration, in women postmenopausal at blood collection. The estimates provided are adjusted for Pfeiffer's risk score from the common model (i.e. mutually adjusted) and in the selected model. Supplemental Table 3 shows the performance of the full and selected models in women postmenopausal at blood collection in terms of concordance-statistic ("C"), integrated discrimination improvement index (IDI), and net-reclassification improvement (NRI continuous), each with 95%-Confidence interval and optimism-correction from 1000 bootstrap-samples.

Previous prospective studies assessing the relationship between circulating concentrations of vitamin D and prostate cancer risk have shown inconclusive results, particularly for risk of aggressive disease. In this study, we examine the association between prediagnostic concentrations of 25-hydroxyvitamin D [25(OH)D] and 1,25-dihydroxyvitamin D [1,25(OH)2D] and the risk of prostate cancer overall and by tumor characteristics. Principal investigators of 19 prospective studies provided individual participant data on circulating 25(OH)D and 1,25(OH)2D for up to 13,462 men with incident prostate cancer and 20,261 control participants. ORs for prostate cancer by study-specific fifths of season-standardized vitamin D concentration were estimated using multivariable-adjusted conditional logistic regression. 25(OH)D concentration was positively associated with risk for total prostate cancer (multivariable-adjusted OR comparing highest vs. lowest study-specific fifth was 1.22; 95% confidence interval, 1.13–1.31; P trend < 0.001). However, this association varied by disease aggressiveness (Pheterogeneity = 0.014); higher circulating 25(OH)D was associated with a higher risk of nonaggressive disease (OR per 80 percentile increase = 1.24, 1.13–1.36) but not with aggressive disease (defined as stage 4, metastases, or prostate cancer death, 0.95, 0.78–1.15). 1,25(OH)2D concentration was not associated with risk for prostate cancer overall or by tumor characteristics. The absence of an association of vitamin D with aggressive disease does not support the hypothesis that vitamin D deficiency increases prostate cancer risk. Rather, the association of high circulating 25(OH)D concentration with a higher risk of nonaggressive prostate cancer may be influenced by detection bias.Significance:This international collaboration comprises the largest prospective study on blood vitamin D and prostate cancer risk and shows no association with aggressive disease but some evidence of a higher risk of nonaggressive disease.

Background: Alcohol is an established risk factor for several cancers, but modest alcohol-cancer associations may be missed due to measurement error in self-reported assessments. The identification of biomarkers of habitual alcohol intake may enhance evidence on the role of alcohol in cancer onset. Methods: Untargeted metabolomics was used to identify metabolites correlated with habitual alcohol intake in a discovery dataset from the European Prospective Investigation into Cancer and Nutrition (EPIC; n=454). Significant correlations were replicated in independent datasets of controls from case-control studies nested within EPIC (n=281) and the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC; n=438) study. Conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) for associations of alcohol-associated metabolites and self-reported alcohol intake with risk of pancreatic cancer, hepatocellular carcinoma (HCC), liver cancer, and liver disease mortality in the contributing studies. Results: Two metabolites displayed a dose-response association with alcohol intake: 2-hydroxy-3-methylbutyric acid and an unidentified compound (m/z(+):231.0839). A 1-SD increase in log2-transformed levels of 2-hydroxy-3-methylbutyric acid was associated with risk of HCC (OR=2.14; 95% CI=1.39-3.31) and pancreatic cancer (OR=1.65; 95% CI=1.17-2.32) in EPIC and liver cancer (OR=2.00; 95% CI=1.44-2.77) and liver disease mortality (OR=2.16; 95% CI=1.63-2.86) in ATBC. Conversely, a 1-SD increase in log2-transformed questionnaire-derived alcohol intake was not associated with risk of HCC or pancreatic cancer in EPIC or liver cancer in ATBC but was associated with risk of liver disease mortality (OR=2.19; 95% CI=1.60-2.98) in ATBC. Conclusions: 2-Hydroxy-3-methylbutyric acid is a candidate biomarker of habitual alcohol intake that may advance the study of alcohol and cancer risk in population-based studies. Citation Format: Erikka Loftfield, Magdalena Stepien, Vivian Viallon, Laura Trijsburg, Joseph Rothwell, Nivonirina Robinot, Carine Biessy, Ingvar A. Bergdahl, Stina Bodén, Matthias B. Schulze, Manuela Bergmann, Elisabete Weiderpass, Julie A. Schmidt, Rual Zamora-Ros, Therese H. Nøst, Torkjel M. Sandanger, Emily Sonestedt, Bodil Ohlsson, Verena Katzke, Rudolf Kaaks, Fulvio Ricceri, Anne Tjønneland, Christina C. Dahm, Maria-Jose Sánchez, Antonia Trichopoulou, Rosario Tumino, María-Dolores Chirlaque, Giovanna Masala, Eva Ardanaz, Roel Vermeulen, Paul Brennan, Demetrius Albanes, Stephanie J. Weinstein, Augustin Scalbert, Augustin Scalbert, Neal D. Freedman, Marc J. Gunter, Mazda Jenab, Rashmi Sinha, Pekka Keski-Rahkonen, Pietro Ferrari. Novel biomarkers of habitual alcohol intake and associations with risk of pancreatic and liver cancers and liver disease mortality [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 747.