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Nutrition influences health throughout the life course. Good nutrition increases the probability of good pregnancy outcomes, proper childhood development, and healthy aging, and it lowers the probability of developing common diet-related chronic diseases, including obesity, cardiovascular disease, cancer, and type 2 diabetes. Despite the importance of diet and health, studying these exposures is among the most challenging in population sciences research. US and global food supplies are complex; eating patterns have shifted such that half of meals are eaten away from home, and there are thousands of food ingredients with myriad combinations. These complexities make dietary assessment and links to health challenging for both population sciences research and for public health policy and practice. Furthermore, most studies evaluating nutrition and health usually rely on self-report instruments prone to random and systematic measurement error. Scientific advances involve developing nutritional biomarkers and then applying these biomarkers as stand-alone nutritional exposures or for calibrating self-reports using specialized statistics. Expected final online publication date for the

Background: Despite evidence of substantial breast cancer risk reduction, few high-risk women adopt chemopreventive medications such as selective estrogen receptor modulators (SERMs) or aromatase inhibitors (AIs). Women with benign breast disease, such as atypical hyperplasia (AH) or lobular carcinoma in situ (LCIS), have an increased risk of developing breast cancer and derive a greater benefit from antiestrogens compared to other high-risk women. Reasons for low uptake of chemoprevention include insufficient patient and clinician knowledge about antiestrogens, time constraints during the clinical encounter, and concerns about side effects. To address these barriers, we have developed patient and provider web-based decision support tools to improve informed choice about breast cancer chemoprevention among women with AH or LCIS. Study design: We are conducting a cluster-randomized controlled trial of clinical decision support to improve chemoprevention informed choice among women with AH or LCIS and their treating providers. Twenty-six U.S. sites through the SWOG Cancer Research Network were randomly assigned 1:1 to standard educational materials alone or in combination with the patient-centered decision aid (RealRisks) and provider decision support tool (BNAV). A total of 415 patients and 200 healthcare providers will be recruited from these sites. RealRisks consists of interactive modules to calculate personalized breast cancer risk and elicit preferences on chemoprevention. The modules are available in English and Spanish. BNAV is comprised of self-directed case-based learning modules on breast cancer risk assessment and chemoprevention. Patients complete questionnaires at baseline, 6 and 12 months. Providers complete surveys at baseline and after their enrolled patient’s 6-month clinical encounter. The primary endpoint is chemoprevention informed choice at 6 months, using a measure combining knowledge, attitude, and intention scales. Secondary endpoints include perceived breast cancer risk/worry, chemoprevention knowledge/intention, decision conflict/regret, shared decision-making, and chemoprevention uptake. For patients who begin chemoprevention, adherence and reasons for discontinuation are assessed annually for up to 5 years. Barriers and facilitators to implementing RealRisks and BNAV into clinic workflow will be assessed by conducting patient and provider interviews at baseline and mid-implementation. Eligibility criteria: Eligible patients include women, age 35-74 years, with AH or LCIS, no history of breast cancer, no prior use of SERMs or AIs, no bilateral mastectomies, English or Spanish-speaking, and access to the internet. Eligible providers include breast surgeons, medical oncologists, primary care providers, and physician extenders who see patients with AH or LCIS. Statistical methods: We have 90% power to detect a 15% increase in the frequency of chemoprevention informed choice with a 1-sided 0.025 level test, assuming an intraclass correlation (ICC) of 0.02 to account for clustering, roughly equal accrual at each site, 10% loss to follow-up, and ≤10% event rate in the control arm. Current/target accrual: The trial was activated on 9/1/2020. As of 7/7/2022, all 26 sites have been randomized, 157/200 providers and 184/415 patients have been enrolled. Discussion: Our hybrid effectiveness/implementation study seeks to evaluate the effectiveness of a multi-level intervention in promoting informed decision-making about breast cancer chemoprevention. Study results will provide valuable insights on how the decision support tools are integrated in diverse clinical settings. Citation Format: Katherine D. Crew, Garnet Anderson, Kathryn Arnold, Andrew Stieb, Jacquelyn N. Amenta, Cynthia Law, Ana Sandoval-Leon, Sarah Colonna, Tari King, Debra Mangino, Sandhya Pruthi, Maria Grosse Perdekamp, Christa Braun-Inglis, Stacy Krisher, Lisa Yee, Danielle Bertoni, Samantha Seaward, Kari B. Wisinski, Justin Floyd, Corrine Zarwan, Tarah J. Ballinger, Lindi VanderWalde, Masey M. Ross, Preston Steen, Shelly Lo, Alison Conlin, Kathleen Yost, John Ellerton, Erin Lin, Holly J. Pederson, Sagar Sardesai, Cheryl Jernigan, Dawn Hershman, Marian L. Neuhouser, Banu K. Arun, Rita Kukafka. SWOG 1904: Cluster-randomized controlled trial of patient and provider decision support to increase chemoprevention informed choice among women with atypical hyperplasia or lobular carcinoma in situ (MiCHOICE) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT1-15-01.

Background: Neoadjuvant chemotherapy is available to women with locally advanced breast cancer where chemotherapy is given prior to surgery. By examining resected tissue following neoadjuvant chemotherapy pathological complete response (pCR) can be determined. pCR is a favorable prognostic factor associated with longer survival compared to residual disease after neoadjuvant chemotherapy. Physical activity and diet may improve some side effects during treatment, but less is known about their effect on chemotherapy completion and more specifically on pCR in the neoadjuvant setting. Utilizing data from a randomized trial of diet and physical activity with a primary endpoint of chemotherapy completion in women with newly diagnosed breast cancer initiating chemotherapy, we evaluated the effect of a lifestyle intervention on pCR among the subset of women in the trial who received neoadjuvant chemotherapy. Methods: The Lifestyle, Exercise and Nutrition Early after Diagnosis (LEANer) Study enrolled 173 women with Stage I-III breast cancer who were randomized to usual care (n = 86) or a yearlong, 16-session, in-person or telephone-administered diet and physical activity intervention (n = 87) delivered by registered dietitians. Among study participants, 73 women received neoadjuvant chemotherapy and of these, 72 (98.6%) had complete follow-up pCR data (intervention = 40; usual care = 32). pCR, dates, doses and reason for dose-adjustments/delays of chemotherapy were abstracted from electronic medical records and confirmed with treating oncologists. A Chi-square test was used to examine the effect of the intervention versus usual care on pCR. Results: The 72 women receiving neoadjuvant chemotherapy with complete follow-up pCR data in LEANer were 49.4±11.6 years old, had a body mass index of 30.0+6.7 kg/m2, and 37.0% and 49.3% had stage I or II breast cancer, respectively. Just over half (52.1%) of women had ER/PR positive cancers and 32.9% of tumors were HER2 positive, with no statistically significant differences in tumor type by study arm. 92.7% of the women randomized to intervention adhered to all of the counseling sessions during their neoadjuvant chemotherapy and had statistically significant improvements in mean physical activity (161 minute increase versus 40 minute increase, p-value = < 0.001) and fiber intake (0.21 gram/day increase versus -5.17 g/day decrease, p-value = 0.020), as well as median fruit and vegetable intake (0.6 serving/day increase versus -0.5 serving/day decrease, p-value = 0.041) compared to usual care. There was a benefit of the intervention on pCR compared to usual care (52.5% with pCR in the intervention arm versus 28.1% with pCR in the usual care arm, p-value = 0.037). The intervention effect on pCR did not appear to be impacted by chemotherapy completion (relative dose intensity of 92% in intervention versus 90% in usual care) or chemotherapy dose delays as these were similar in the two study arms. In mediation analyses, results suggested that the changes in physical activity mediated, at least partially, the intervention effect on pCR. Conclusions: A primarily telephone-based diet and physical activity intervention led to improved pCR compared to usual care among the subset of women with breast cancer in the LEANer Study who received neoadjuvant chemotherapy. As pCR is an important prognostic factor for breast cancer, additional lifestyle interventions focusing on the neoadjuvant treatment setting with pCR as the primary outcome are necessary to confirm the potential benefits of lifestyle changes on pCR. Citation Format: Leah Ferrucci, Tara B. Sanft, Maura Harrigan, Brenda Cartmel, Fangyong Li, Michelle Zupa, Courtney McGowan, Leah Puklin, Thai Hien Nguyen, Anna M. Tanasijevic, Marian L. Neuhouser, Dawn Hershman, Karen Basen-Engquist, Beth Jones, Tish Knobf, Anees B. Chagpar, Andrea L.M. Silber, Jennifer A. Ligibel, Melinda L. Irwin. PD12-08 Randomized trial of exercise and nutrition on pathological complete response among women with breast cancer receiving neoadjuvant chemotherapy: the Lifestyle, Exercise and Nutrition Early after Diagnosis (LEANer) Study [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD12-08.

BACKGROUND: Studies of diet and chronic disease include a recent important focus on dietary patterns. Patterns are typically defined by listing dietary variables and by totaling scores that reflect whether consumption is encouraged or discouraged for listed variables. However, precision may be improved by including total energy consumption among the dietary variables and by scoring dietary variables empirically. OBJECTIVES: To relate Healthy Eating Index (HEI)–2010 components and total energy intake to all-cause and cause-specific mortality in Women's Health Initiative (WHI) cohorts and to define and evaluate an associated Empirical-Scores Healthy Eating Index (E-HEI). METHODS: Analyses are conducted in WHI cohorts (n = 67,247) of healthy postmenopausal women, aged 50–79 y, when enrolled during 1993–1998 at 40 US clinical centers, with embedded nutrition biomarker studies. Replicate food-frequency assessments for HEI-2010 ratio variables and doubly labeled water total energy assessments, separated by ∼6 mo, are used as response variables to jointly calibrate baseline dietary data to reduce measurement error influences, using 2 nutrition biomarker studies (n = 199). Calibrated dietary variables are associated with mortality risk, and an E-HEI is defined, using cross-validated HR regression estimation. RESULTS: Of 15 dietary variables considered, all but empty calories calibrated well. Ten variables related significantly (P

Background: Multivitamin (MVI) use is a common health behavior but there is conflicting evidence from prospective studies about whether this behavior increases or decreases prostate cancer risk. Methods: Associations of MVI use and prostate cancer risk were evaluated using data from the Selenium and Vitamin E Cancer Prevention Trial (SELECT). Cox proportional hazards models estimated associations of MVI use with risk of total, low-, and high-grade prostate cancer. Longitudinal data were used to evaluate screening and biopsy patterns. To account for differential biopsy patterns, the probability of prostate cancer was estimated for men with a positive screening value but no biopsy. Incidence density ratios were used to approximate HRs, and associations of MVI use with predicted prostate cancer risk were compared with observed. Results: Analyses of data from observed biopsies suggest a respective 19% (95% confidence interval, 10%–28%) and 21% (12%–31%) higher risk of high-grade prostate cancer for current and long-term MVI use, compared with no use. Current and long-term MVI use was associated with a shorter time to first on-study biopsy, indicating the potential for detection bias. After accounting for differential acceptance of biopsy, associations of MVI use with prostate cancer were attenuated and not statistically significant. Conclusions: In SELECT, biopsy acceptance patterns differed by MVI use. Estimates of associations of MVI use with prostate cancer risk based on observed biopsy data may be biased by differential acceptance of biopsy. Impact: Differential biopsy ascertainment may impact associations of risk factors and prostate cancer. Detailed screening and biopsy data can be used to analytically minimize such bias.

BACKGROUND: The associations of red and processed meat with chronic disease risk remain to be clarified, in part because of measurement error in self-reported diet. OBJECTIVES: We sought to develop metabolomics-based biomarkers for red and processed meat, and to evaluate associations of biomarker-calibrated meat intake with chronic disease risk among postmenopausal women. METHODS: Study participants were women who were members of the Women's Health Initiative (WHI) study cohorts. These participants were postmenopausal women aged 50–79 y when enrolled during 1993–1998 at 40 US clinical centers with embedded human feeding and nutrition biomarker studies. Literature reports of metabolomics correlates of meat consumption were used to develop meat intake biomarkers from serum and 24-h urine metabolites in a 153-participant feeding study (2010–2014). Resulting biomarkers were used in a 450-participant biomarker study (2007–2009) to develop linear regression calibration equations that adjust FFQ intakes for random and systematic measurement error. Biomarker-calibrated meat intakes were associated with cardiovascular disease, cancer, and diabetes incidence among 81,954 WHI participants (1993–2020). RESULTS: Biomarkers and calibration equations meeting prespecified criteria were developed for consumption of red meat and red plus processed meat combined, but not for processed meat consumption. Following control for nondietary confounding factors, hazard ratios were calculated for a 40% increment above the red meat median intake for coronary artery disease (HR: 1.10; 95% CI: 1.07, 1.14), heart failure (HR: 1.26; 95% CI: 1.20, 1.33), breast cancer (HR: 1.10; 95% CI: 1.07, 1.13) for, total invasive cancer (HR: 1.07; 95% CI: 1.05, 1.09), and diabetes (HR: 1.37; 95% CI: 1.34, 1.39). HRs for red plus processed meat intake were similar. HRs were close to the null, and mostly nonsignificant following additional control for dietary potential confounding factors, including calibrated total energy consumption. CONCLUSIONS: A relatively high-meat dietary pattern is associated with somewhat higher chronic disease risks. These elevations appear to be largely attributable to the dietary pattern, rather than to consumption of red or processed meat per se.

Supplementary Table

Supplementary Data from The Association of Predicted Resting Energy Expenditure with Risk of Breast Cancer among Postmenopausal Women in the Women's Health Initiative Cohort

Perspective on this Article from Finasteride Modifies the Relation between Serum C-Peptide and Prostate Cancer Risk: Results from the Prostate Cancer Prevention Trial

Increased adiposity and diets high in glycemic load (GL) are associated with increased risk of many chronic diseases including cancer. Using plasma from 80 healthy individuals [40 men/40 women, 29 with DXA-derived low fat mass (FM) and 51 with high FM] in a randomized cross-over–controlled feeding trial and arrays populated with 3,504 antibodies, we measured plasma proteins collected at baseline and end of each of two 28-day controlled diets: a low GL diet high in whole grains, legumes, fruits, and vegetables (WG) and a high GL diet high in refined grains and added sugars (RG). Following univariate testing for proteins differing by diet, we evaluated pathway-level involvement. Among all 80 participants, 172 proteins were identified as differing between diets. Stratifying participants by high and low FM identified 221 and 266 proteins, respectively, as differing between diets (unadjusted P < 0.05). These candidate proteins were tested for overrepresentation in Reactome pathways, corresponding to 142 (of 291) pathways in the high-FM group and 72 (of 274) pathways in the low-FM group. We observed that the cancer-related pathways, DNA Repair, DNA Replication, and Cell Cycle, were overrepresented in the high-FM participants while pathways involved in post-translational protein modification were overrepresented in participants with either FM. Although high-GL diets are associated with increased risk of some cancers, our study further suggests that biology associated with consumption of GL diets is variable depending on an individual's adiposity and dietary recommendations related to cancer prevention be made with the additional consideration of an individual's FM.

Vitamin D may influence prostate cancer risk, but evidence is inconsistent. We conducted a nested case–control study in the Prostate Cancer Prevention Trial (PCPT). Cases (n = 1,128) and controls (n = 1,205) were frequency matched on age, first-degree relative with prostate cancer, and PCPT treatment arm (finasteride/placebo); African-Americans were oversampled and case/control status was biopsy confirmed. We selected 21 SNPs in vitamin D–related genes (VDR, GC, C10orf88, CYP2R1, CYP24A1, CYP27B1, DHCR7, and NADSYN1) to test genotype and genotype–treatment interactions in relation to prostate cancer. We also tested mean serum 25(OH)D differences by minor allele distributions and tested for serum 25(OH)D–genotype interactions in relation to prostate cancer risk. Log-additive genetic models (Bonferroni-corrected within genes) adjusted for age, body mass index, PSA, and family history of prostate cancer revealed a significant interaction between treatment arm and GC/rs222016 (finasteride OR = 1.37, placebo OR = 0.85; Pinteraction < 0.05), GC/rs222014 (finasteride OR = 1.36, placebo OR = 0.85; Pinteraction < 0.05), and CYP27B1/rs703842 (finasteride OR = 0.76, placebo OR = 1.10; Pinteraction < 0.05) among Caucasians, and C10orf88/rs6599638 (finasteride OR = 4.68, placebo OR = 1.39; Pinteraction < 0.05) among African-Americans. VDR/rs1544410 and CYP27B1/rs703842 had significant treatment interactions for high-grade disease among Caucasians (finasteride OR = 0.81, placebo OR = 1.40; Pinteraction < 0.05 and finasteride OR = 0.70, placebo OR = 1.28; Pinteraction < 0.05, respectively). Vitamin D–related SNPs influenced serum 25(OH)D, but gene-serum 25(OH)D effect modification for prostate cancer was marginally observed only for CYP24A1/rs2248359. In conclusion, evidence that vitamin D–related genes or gene-serum 25(OH)D associations influence prostate cancer risk is modest. We found some evidence for gene–finasteride interaction effects for prostate cancer in Caucasians and African-Americans. Results suggest only minimal associations of vitamin D with total or high-grade prostate cancer.

Background: The respiratory quotient (RQ), defined as the ratio of carbon dioxide exhaled to oxygen uptake, reflects substrate utilization when energy is expended. Fat and alcohol have RQ values of approximately 0.7, compared with 1.0 for carbohydrate, and approximately 0.8 for protein. Here, the association between RQ and postmenopausal breast cancer risk is studied.Methods: Paired RQ measurements were obtained, separated by approximately 6 months, for women in the reliability subset of a Women's Health Initiative (WHI) Nutrition and Physical Activity Assessment Study. Linear regression of the average of the paired log RQ assessments on a corresponding log food quotient (FQ) average and other study subject characteristics, including age, body mass index, race, and education, yielded calibration equations for predicting RQ.Results: Calibration equations, using any of food frequency, food record, or dietary recall data, explained an appreciable fraction of measured log RQ variation, and these were used to compute calibrated RQ estimates throughout WHI cohorts. Calibrated RQ estimates using 4-day food record (4DFR) data related inversely (P = 0.004) to (invasive) breast cancer risk in the WHI Dietary Modification trial comparison group, and corresponding RQ estimates using food-frequency data related inversely (P = 0.002) to breast cancer incidence in this cohort combined with the larger WHI observational study.Conclusion: Although preliminary, these analyses suggest a substantially higher postmenopausal breast cancer risk among women having relatively low RQ.Impact: RQ elevation could provide a novel target for breast cancer risk reduction. Cancer Epidemiol Biomarkers Prev; 22(12); 2374–83. ©2013 AACR.

Supplementary material and methods: supplementary information on data collection, statistical analyses, and presentation of results in the figures.

Editorial from Specialty Supplement Use and Biologic Measures of Oxidative Stress and DNA Damage

This file contains Supplementary Figure 1, parts A - D, and the figure description.

This file contains Supplementary tables 1 - 7 and the text for Supplementary Figure 1A-D.

Supplementary Material. Section A: Excluding incomplete 24-hour urine samples based on PABA Section B: Calibrating the urinary sugars biomarker using a measurement error model that does not include age

Background: Measurement error in self-reported sugars intake may be obscuring the association between sugars and cancer risk in nutritional epidemiologic studies.Methods: We used 24-hour urinary sucrose and fructose as a predictive biomarker for total sugars, to assess measurement error in self-reported sugars intake. The Nutrition and Physical Activity Assessment Study (NPAAS) is a biomarker study within the Women's Health Initiative (WHI) Observational Study that includes 450 postmenopausal women ages 60 to 91 years. Food Frequency Questionnaires (FFQ), four-day food records (4DFR), and three 24-hour dietary recalls (24HRs) were collected along with sugars and energy dietary biomarkers.Results: Using the biomarker, we found self-reported sugars to be substantially and roughly equally misreported across the FFQ, 4DFR, and 24HR. All instruments were associated with considerable intake- and person-specific bias. Three 24HRs would provide the least attenuated risk estimate for sugars (attenuation factor, AF = 0.57), followed by FFQ (AF = 0.48) and 4DFR (AF = 0.32), in studies of energy-adjusted sugars and disease risk. In calibration models, self-reports explained little variation in true intake (5%–6% for absolute sugars and 7%–18% for sugars density). Adding participants' characteristics somewhat improved the percentage variation explained (16%–18% for absolute sugars and 29%–40% for sugars density).Conclusions: None of the self-report instruments provided a good estimate of sugars intake, although overall 24HRs seemed to perform the best.Impact: Assuming the calibrated sugars biomarker is unbiased, this analysis suggests that measuring the biomarker in a subsample of the study population for calibration purposes may be necessary for obtaining unbiased risk estimates in cancer association studies. Cancer Epidemiol Biomarkers Prev; 23(12); 2874–83. ©2014 AACR.

Background: Oxidative stress and resulting cellular damage have been suggested to play a role in the etiology of several chronic diseases, including cancer and cardiovascular disease. Identifying factors associated with reduced oxidative stress and resulting damage may guide future disease-prevention strategies.Methods: In the VITamins And Lifestyle (VITAL) biomarker study of 209 persons living in the Seattle area, we examined the association between current use of several specialty supplements and oxidative stress, DNA damage, and DNA repair capacity. Use of glucosamine, chondroitin, fish oil, methylsulfonylmethane (MSM), coenzyme Q10 (CoQ10), ginseng, ginkgo, and saw palmetto was ascertained by a supplement inventory/interview, whereas the use of fiber supplements was ascertained by questionnaire. Supplements used by more than 30 persons (glucosamine and chondroitin) were evaluated as the trend across number of pills/week (non-use, Results: Use of glucosamine (Ptrend: 0.01), chondroitin (Ptrend: 0.003), and fiber supplements (P: 0.01) was associated with reduced PGF2α concentrations, whereas CoQ10 supplementation was associated with reduced baseline DNA damage (P: 0.003).Conclusions: Use of certain specialty supplements may be associated with reduced oxidative stress and DNA damage.Impact: Further research is needed to evaluate the association between specialty supplement use and markers of oxidative stress and DNA damage. Cancer Epidemiol Biomarkers Prev; 22(12); 2312–22. ©2013 AACR.

Supplementary Figure Legends for Figures S1-S15.

Background: Several prospective studies suggest that use of cholesterol-lowering statin drugs is inversely associated with advanced stage and possibly high-grade prostate cancer. One study reported that men with low cholesterol had a lower risk of high-grade prostate cancer. Given these findings, we investigated the association between low serum cholesterol and prostate cancer risk in the Prostate Cancer Prevention Trial.Methods: We conducted a cohort study of 5,586 men ages ≥55 years who were randomized to the placebo arm of the Prostate Cancer Prevention Trial between 1993 and 1996. Serum cholesterol was measured enzymatically at entry. By the end of follow-up, 1,251 prostate cancer cases were confirmed. We used logistic regression to calculate the multivariable odds ratio (OR) of total, and Gleason 2 to 6 (n = 993), 7 (n = 199), and 8 to 10 (n = 59) prostate cancer comparing low serum (normal, Results: Men with low cholesterol had a lower risk of Gleason 8 to 10 prostate cancer [OR, 0.41; 95% confidence interval (CI), 0.22-0.77] than men with high cholesterol. No association was present for prostate cancer overall (OR, 0.97; 95% CI, 0.85-1.11), Gleason 2 to 6 disease (OR, 1.03; 95% CI, 0.89-1.18), or Gleason 7 disease (OR, 0.93; 95% CI, 0.69-1.24).Conclusion: These prospective results support that men with low cholesterol have a reduced risk of high-grade prostate cancer. These and other contemporary data that suggest that cholesterol metabolism should be investigated further in the etiology of prostate cancer. (Cancer Epidemiol Biomarkers Prev 2009;18(11):2807–13)

Biliary tract cancers are rare but highly fatal with poorly understood etiology. Identifying potentially modifiable risk factors for these cancers is essential for prevention. Here we estimated the relationship between adiposity and cancer across the biliary tract, including cancers of the gallbladder (GBC), intrahepatic bile ducts (IHBDC), extrahepatic bile ducts (EHBDC), and the ampulla of Vater (AVC). We pooled data from 27 prospective cohorts with over 2.7 million adults. Adiposity was measured using baseline body mass index (BMI), waist circumference, hip circumference, waist-to-hip, and waist-to-height ratios. HRs and 95% confidence intervals (95% CI) were estimated using Cox proportional hazards models adjusted for sex, education, race, smoking, and alcohol consumption with age as the time metric and the baseline hazard stratified by study. During 37,883,648 person-years of follow-up, 1,343 GBC cases, 1,194 EHBDC cases, 784 IHBDC cases, and 623 AVC cases occurred. For each 5 kg/m2 increase in BMI, there were risk increases for GBC (HR = 1.27; 95% CI, 1.19–1.36), IHBDC (HR = 1.32; 95% CI, 1.21–1.45), and EHBDC (HR = 1.13; 95% CI, 1.03–1.23), but not AVC (HR = 0.99; 95% CI, 0.88–1.11). Increasing waist circumference, hip circumference, waist-to-hip ratio, and waist-to-height ratio were associated with GBC and IHBDC but not EHBDC or AVC. These results indicate that adult adiposity is associated with an increased risk of biliary tract cancer, particularly GBC and IHBDC. Moreover, they provide evidence for recommending weight maintenance programs to reduce the risk of developing these cancers.Significance:These findings identify a correlation between adiposity and biliary tract cancers, indicating that weight management programs may help minimize the risk of these diseases.

This file contains Supplementary Tables 1-3. Supplementary Table 1 gives the distribution of prostate cancer cases by subtype included in the pooled Analyses of fruit, vegetable, and mature bean consumption and prostate cancer risk. Supplementary Table 2 gives the results of analyses using all main exposures modeled continuously. Supplementary Table 3 provides information on funding information for all cohort studies included in the pooled analysis.

PDF file - 66K, Total Energy Calibration Equation Coefficients from Linear Regression of Log DLW Energy on Log Self-Reported Energy and Personal Characteristics, Using Data from 450 NPAAS Women.

Editorial for this Article from Men with Low Serum Cholesterol Have a Lower Risk of High-Grade Prostate Cancer in the Placebo Arm of the Prostate Cancer Prevention Trial

The role of insulin-like growth factors (IGF) in prostate cancer development is not fully understood. To investigate the association between circulating concentrations of IGFs (IGF-I, IGF-II, IGFBP-1, IGFBP-2, and IGFBP-3) and prostate cancer risk, we pooled individual participant data from 17 prospective and two cross-sectional studies, including up to 10,554 prostate cancer cases and 13,618 control participants. Conditional logistic regression was used to estimate the ORs for prostate cancer based on the study-specific fifth of each analyte. Overall, IGF-I, IGF-II, IGFBP-2, and IGFBP-3 concentrations were positively associated with prostate cancer risk (Ptrend all ≤ 0.005), and IGFBP-1 was inversely associated weakly with risk (Ptrend = 0.05). However, heterogeneity between the prospective and cross-sectional studies was evident (Pheterogeneity = 0.03), unless the analyses were restricted to prospective studies (with the exception of IGF-II, Pheterogeneity = 0.02). For prospective studies, the OR for men in the highest versus the lowest fifth of each analyte was 1.29 (95% confidence interval, 1.16–1.43) for IGF-I, 0.81 (0.68–0.96) for IGFBP-1, and 1.25 (1.12–1.40) for IGFBP-3. These associations did not differ significantly by time-to-diagnosis or tumor stage or grade. After mutual adjustment for each of the other analytes, only IGF-I remained associated with risk. Our collaborative study represents the largest pooled analysis of the relationship between prostate cancer risk and circulating concentrations of IGF-I, providing strong evidence that IGF-I is highly likely to be involved in prostate cancer development. Cancer Res; 76(8); 2288–300. ©2016 AACR.

Supplementary tables and figures showing study and assay characteristics, correlations between analytes, and the relationships of the analytes with prostate cancer risk overall, by study and study design, and subdivided by clinical and other characteristics.

PDF file - 68K, Characteristics of Breast Cancer Cases and Controls in Four-day Food Record (4DFR)-Based Case-Control Analyses, and Food Frequency Questionnaire (FFQ)-Based Cohort Analyses from the Women's Health Initiative.

Background: Relationships between fruit, vegetable, and mature bean consumption and prostate cancer risk are unclear.Methods: We examined associations between fruit and vegetable groups, specific fruits and vegetables, and mature bean consumption and prostate cancer risk overall, by stage and grade, and for prostate cancer mortality in a pooled analysis of 15 prospective cohorts, including 52,680 total cases and 3,205 prostate cancer–related deaths among 842,149 men. Diet was measured by a food frequency questionnaire or similar instrument at baseline. We calculated study-specific relative risks using Cox proportional hazards regression, and then pooled these estimates using a random effects model.Results: We did not observe any statistically significant associations for advanced prostate cancer or prostate cancer mortality with any food group (including total fruits and vegetables, total fruits, total vegetables, fruit and vegetable juice, cruciferous vegetables, and tomato products), nor specific fruit and vegetables. In addition, we observed few statistically significant results for other prostate cancer outcomes. Pooled multivariable relative risks comparing the highest versus lowest quantiles across all fruit and vegetable exposures and prostate cancer outcomes ranged from 0.89 to 1.09. There was no evidence of effect modification for any association by age or body mass index.Conclusions: Results from this large, international, pooled analysis do not support a strong role of collective groupings of fruits, vegetables, or mature beans in prostate cancer.Impact: Further investigation of other dietary exposures, especially indicators of bioavailable nutrient intake or specific phytochemicals, should be considered for prostate cancer risk. Cancer Epidemiol Biomarkers Prev; 26(8); 1276–87. ©2017 AACR.

Determinants of circulating levels of total adiponectin (µg/mL) among pooled controls.

Risk of MM in relation to circulating total adiponectin levels estimated using a restricted cubic spline regression model with 4 knots.

ORs (95% CIs) of CRC by quartile of plasma DMG:choline ratio.

Circulating levels of high-molecular-weight adiponectin and risk of multiple myeloma.

Description of additional methods and procedures used in the study. Also includes Supplementary References.

Few studies have examined associations between plasma choline metabolites and risk of colorectal cancer. Therefore, we investigated associations between plasma biomarkers of choline metabolism [choline, betaine, dimethylglycine, and trimethylamine N-oxide (TMAO)] and colorectal cancer risk among postmenopausal women in a case–control study nested within the Women's Health Initiative Observational Study. We selected 835 matched case–control pairs, and cases were further stratified by tumor site (proximal, distal, or rectal) and stage (local/regional or metastatic). Colorectal cancer was assessed by self-report and confirmed by medical records over the mean of 5.2 years of follow-up. Baseline plasma choline metabolites were measured by LC/MS-MS. In multivariable-adjusted conditional logistic regression models, plasma choline tended to be positively associated with rectal cancer risk [OR (95% confidence interval, CI)highest vs. lowest quartile = 2.44 (0.93–6.40); P trend = 0.08], whereas plasma betaine was inversely associated with colorectal cancer overall [0.68 (0.47–0.99); P trend = 0.01] and with local/regional tumors [0.64 (0.42–0.99); P trend = 0.009]. Notably, the plasma betaine:choline ratio was inversely associated with colorectal cancer overall [0.56 (0.39–0.82); P trend = 0.004] as well as with proximal [0.66 (0.41–1.06); P trend = 0.049], rectal [0.27 (0.10–0.78); P trend = 0.02], and local/regional [0.50 (0.33–0.76); P trend = 0.001] tumors. Finally, plasma TMAO, an oxidative derivative of choline produced by intestinal bacteria, was positively associated with rectal cancer [3.38 (1.25–9.16); P trend = 0.02] and with overall colorectal cancer risk among women with lower (vs. higher) plasma vitamin B12 levels (P interaction = 0.003). Collectively, these data suggest that alterations in choline metabolism, which may arise early in disease development, may be associated with higher risk of colorectal cancer. The positive association between plasma TMAO and colorectal cancer risk is consistent with an involvement of the gut microbiome in colorectal cancer pathogenesis. Cancer Res; 74(24); 7442–52. ©2014 AACR.

The association between obesity and multiple myeloma risk may be partly attributed to reduced circulating levels of adiponectin in obese individuals. To prospectively evaluate multiple myeloma risk in relation to adiponectin levels overall and stratified by body mass index and other characteristics, we conducted a pooled investigation of pre-diagnosed peripheral blood samples from 624 multiple myeloma cases and 1,246 individually matched controls from seven cohorts participating in the Multiple Myeloma Cohort Consortium. Analysis of circulating analyte levels measured by ELISA revealed that higher total adiponectin levels were associated with reduced multiple myeloma risk overall [highest quartile vs. lowest: OR, 0.64; 95% confidence interval (CI) 0.47–0.85; Ptrend = 0.001]. This association was apparent among cases diagnosed six or more years after blood collection (OR, 0.60; 95% CI, 0.40–0.90; Ptrend = 0.004) and was similar in magnitude for men and women (OR, 0.59 and 0.66, respectively). Interestingly, we observed strong associations among subjects who were overweight (OR, 0.41; 95% CI, 0.26–0.65) or obese (OR, 0.41; 95% CI, 0.17–0.98) but not among those with normal weight (OR, 1.20; 95% CI, 0.73–2.00; overweight/obese vs. normal weight, Pinteraction = 0.04). Our findings provide the strongest epidemiologic evidence to date that adiponectin protects against multiple myeloma development, particularly among overweight and obese individuals, and offer a method for risk assessment in this susceptible population of heavier patients. Cancer Res; 76(7); 1935–41. ©2016 AACR.

ORs (95% CIs) of CRC by quartile of plasma DMG:betaine ratio.

ORs (95% CIs) of CRC by quartile of plasma DMG.

We investigated the association of coffee and caffeine with breast cancer (BCa) risk, overall and by ER/PR status. We also examined potential interactions of coffee and caffeine with postmenopausal hormone use.Our study included 77,688 postmenopausal participants from the Women's Health Initiative observational study cohort without a history of any cancer at baseline (except non-melanoma skin) and with valid Food Frequency Questionnaire data and complete data on dietary caffeine. Regular coffee (none, 1, 2-3, 4-5, and ≥ 6 cups/day) and caffeine (tertiles) were assessed at baseline. Information on BCa risk factors was collected at baseline. The associations were examined using survival analysis, accounting for death as a competing risk.The median follow-up time for our cohort was 18.3 years. During the follow-up, 5005 women developed invasive breast cancer. In multivariable analysis, coffee was not associated with the overall invasive BCa risk. Higher caffeine intake was mildly associated with increased BCa risk (2nd vs. 1st tertile SHR = 1.10, 95% CI 1.03-1.18, 3rd vs. 1st tertile SHR-1.05, 95% CI 0.98-1.13, overall p = 0.03). We found no interaction of coffee/caffeine with postmenopausal hormone use (p interaction = 0.44 and 0.42, respectively). In the exploratory analysis by ER/PR status, we found a positive association of caffeine with ER+ /PR+ BCa (2nd vs. 1st tertile SHR = 1.17, 95% CI 1.07-1.28, 3rd vs. 1st tertile SHR = 1.13, 95% CI 1.03-1.24, overall p = 0.002); no associations were observed for ER-/PR- tumors. Coffee was not associated with the risk of ER+ /PR+ or ER-/PR- tumors.We found no associations of coffee with BCa risk, overall and for ER/PR-defined tumor subtypes. The higher caffeine consumption was mildly and positively associated with the overall BCa risk and with ER+ /PR+ tumors.

BACKGROUND: Genetic variation in one-carbon metabolism may affect nutrient concentrations and biological functions. However, data on genetic variants associated with blood biomarkers of one-carbon metabolism in US postmenopausal women are limited, and whether these associations were affected by the nationwide folic acid (FA) fortification program is unclear. OBJECTIVES: We investigated associations between genetic variants and biomarkers of one-carbon metabolism using data from the Women's Health Initiative Observational Study. METHODS: In 1573 non-Hispanic White (NHW) and 282 Black/African American, American Indian/Alaska Native, Asian/Pacific Islander, and Hispanic/Latino women aged 50–79 y, 288 nonsynonymous and tagging single-nucleotide variants (SNVs) were genotyped. RBC folate, plasma folate, pyridoxal-5′-phosphate (PLP), vitamin B-12, homocysteine, and cysteine concentrations were determined in 12-h fasting blood. Multivariable linear regression tested associations per variant allele and for an aggregated genetic risk score. Effect modifications before, during, and after nationwide FA fortification were examined. RESULTS: After correction for multiple comparisons, among NHW women, 5,10-methylenetetrahydrofolate reductase (MTHFR) rs1801133 (677C→T) variant T was associated with lower plasma folate (−13.0%; 95% CI: −17.3%, −8.6%) and higher plasma homocysteine (3.5%; 95% CI: 1.7%, 5.3%) concentrations. Other associations for nonsynonymous SNVs included DNMT3A rs11695471 (T→A) with plasma PLP; EHMT2 rs535586 (G→A), TCN2 rs1131603 (L349S A→G), and TCN2 rs35838082 (R188W G→A) with plasma vitamin B-12; CBS rs2851391 (G→A) with plasma homocysteine; and MTHFD1 rs2236224 (G→A) and rs2236225 (R653Q G→A) with plasma cysteine. The influence of FA fortification on the associations was limited. Highest compared with lowest quartiles of aggregated genetic risk scores from SNVs in MTHFR and MTRR were associated with 14.8% to 18.9% lower RBC folate concentrations. Gene–biomarker associations were similar in women of other races/ethnicities. CONCLUSIONS: Our findings on genetic variants associated with several one-carbon metabolism biomarkers may help elucidate mechanisms of maintaining B vitamin status in postmenopausal women.

BACKGROUND: It is currently unknown if within high-quality dietary intake there exist distinct dietary patterns associated with health benefits that are identifiable with multidimensional dietary pattern analyses. The purpose of this study was to identify specific dietary patterns and groups therein and their associations with all-cause, CVD, and cancer mortality. METHODS: We conducted sex-specific k-means cluster analyses within Healthy Eating Index 2015 (HEI-2015) quintile 5 in 3 US cohorts [NIH-American Association of Retired Persons Diet and Health Study (AARP), the Multiethnic Cohort (MEC), Women's Health Initiative Observational Study (WHI OS)], clusters ranging from n = 1190 to n = 12,007. Characterizations incorporated HEI-2015 overall and component-specific percentage adherence goals, using untruncated and truncated radar graphs and shape analyses. Using cohort- and sex-specific Cox proportional hazards models, associations of quintile 5 clusters with all-cause, cardiovascular disease (CVD), and cancer mortality were evaluated relative to quintile 1. RESULTS: In each cohort sex-specific sample, 3 identified clusters included 16%–62% of participants, providing evidence for variation within high-quality dietary intake. Clusters revealed commonalities in total fruits and whole fruits intakes that exceeded goals and high sodium intake. Dairy and whole grain intakes oftentimes fell below goal. Some clusters were in addition characterized by total vegetables, greens & beans, and seafood & plant protein intakes exceeding goals. All high-quality dietary patterns were associated with a multivariable-adjusted significant 15%–26% lower risk of all-cause death than diet intake in quintile 1 (except for cluster 2 in WHI OS), and with a 16%–25% lower risk of CVD mortality in the AARP and MEC cohorts. Cancer mortality results were inconsistent. CONCLUSIONS: Multiple ways to achieve a high-quality diet were identified and significant associations with lower all-cause and CVD mortality were seen in some cohorts.

Molecular mechanisms linking obesity to prostate cancer involve steroid hormone and insulin/insulin-like growth factor-1 (IGF-1) pathways. We investigated the association of circulating serum markers (e.g., androgens & IGFs/IGFBPs) with BMI and in modifying the association of obesity with prostate cancer risk. Data and specimens for this nested case-control study are from the Prostate Cancer Prevention Trial, a randomized, placebo-controlled trial of finasteride for prostate cancer prevention. Presence or absence of cancer was determined by prostate biopsy. Serum samples were assayed for sex steroid hormone concentrations and IGF-1 axis analytes. Logistic regression estimated odds ratio and 95% confidence intervals (CIs) for risk of overall, low-grade (Gleason 2–6), and high-grade (Gleason 7–10) cancers. We found significant associations between BMI with serum steroids and IGFs/IGFBPs; the IGF-1 axis significantly associated with several serum steroids. Serum steroid levels did not affect the association of BMI with prostate cancer risk; however, IGFBP2 and IGFs modified the association of obesity with low- and high-grade disease. While serum steroids and IGFs/IGFBPs are associated with BMI, only the IGF-1 axis contributed to obesity-related prostate cancer risk. Understanding the biological mechanisms linking obesity to prostate cancer risk as it relates to circulating serum markers will aid in developing effective prostate cancer prevention strategies and treatments.