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Obesity is caused by a prolonged positive energy balance1,2. Whether reduced energy expenditure stemming from reduced activity levels contributes is debated3,4. Here we show that in both sexes, total energy expenditure (TEE) adjusted for body composition and age declined since the late 1980s, while adjusted activity energy expenditure increased over time. We use the International Atomic Energy Agency Doubly Labelled Water database on energy expenditure of adults in the United States and Europe (n = 4,799) to explore patterns in total (TEE: n = 4,799), basal (BEE: n = 1,432) and physical activity energy expenditure (n = 1,432) over time. In males, adjusted BEE decreased significantly, but in females this did not reach significance. A larger dataset of basal metabolic rate (equivalent to BEE) measurements of 9,912 adults across 163 studies spanning 100 years replicates the decline in BEE in both sexes. We conclude that increasing obesity in the United States/Europe has probably not been fuelled by reduced physical activity leading to lowered TEE. We identify here a decline in adjusted BEE as a previously unrecognized factor.

Background Many of the 3.8 million breast cancer survivors in the United States experience long‐term side effects of cancer therapy including peripheral neuropathy (PN). We assessed the prevalence and predictors of PN among women with breast cancer followed in the Women's Health Initiative's Life and Longevity After Cancer survivorship cohort. Methods The study population included 2420 women with local (79%) or regional (21%) stage disease. Presence of PN was based on the reports of “nerve problems and/or tingling sensations” after treatment and PN severity was assessed using the Functional Assessment of Cancer Therapy‐Gynecologic Oncology Group/Neurotoxicity instrument. Logistic regression analysis was used to evaluate the socio‐demographic and clinical factors associated with PN prevalence and severity. Results Initial breast cancer treatment included surgery‐only (21%), surgery and radiation (53%), or surgery and chemotherapy (±radiation) (26%). Overall, 17% of women reported PN occurring within days (30%), months (46%), or years (24%) after treatment and 74% reported ongoing symptoms at a median of 6.5 years since diagnosis. PN was reported by a larger proportion of chemotherapy recipients (33%) compared to those who had surgery alone (12%) or surgery+radiation (11%) (p

The potential role of nutritional factors in the development of peripheral arterial disease (PAD) remains poorly understood. We evaluated multiple recommended eating patterns as reflected by predefined diet quality indices in relation to long-term risk of PAD. We included 138 506 US postmenopausal women in the Women’s Health Initiative who had no known PAD at baseline (1993–1998). Four diet quality indices, including alternate Mediterranean diet index, alternate Healthy Eating Index-2010, Dietary Approaches to Stop Hypertension diet index, and Healthy Eating Index-2015, were derived using dietary information collected by a validated food frequency questionnaire at baseline. Incident cases of symptomatic PAD in the lower extremities were ascertained and adjudicated through March 2019 via medical record review. During a median 18.6 years of follow-up, 1036 incident PAD cases were identified. After multivariable adjustment, all diet quality scores were significantly and inversely associated with 21% (for alternate Healthy Eating Index 2010) to 34% (for Dietary Approaches to Stop Hypertension index) lower risk of PAD when comparing the highest with the lowest quartiles (all P -for-trend values ≤0.010). Among contributing food groups and nutrients, intakes of legumes, dietary fiber, and vegetable protein were associated lower risk of PAD, while intakes of unprocessed red meat, processed meat, and regular soft drinks were associated with higher risk. In a broad sample of US postmenopausal women, adhering to different recommended eating patterns is associated with lower risk of PAD. Our findings suggest that current clinical and public health strategies that recommend healthful eating patterns may also be applicable to PAD prevention.

BACKGROUND: Epidemiologic studies examining the relations between dairy product and calcium intakes and breast cancer have been inconclusive, especially for tumor subtypes. OBJECTIVE: To evaluate the associations between intakes of specific dairy products and calcium and risk of breast cancer overall and for subtypes defined by estrogen receptor (ER) status. METHOD: We pooled the individual-level data of over 1 million women who were followed for a maximum of 8–20 years across studies. Associations were evaluated for dairy product and calcium intakes and risk of incident invasive breast cancer overall (n = 37,861 cases) and by subtypes defined by ER status. Study-specific multivariable hazard ratios (HRs) were estimated and then combined using random-effects models. RESULTS: Overall, no clear association was observed between the consumption of specific dairy foods, dietary (from foods only) calcium, and total (from foods and supplements) calcium, and risk of overall breast cancer. Although each dairy product showed a null or very weak inverse association with risk of overall breast cancer (P, test for trend >0.05 for all), differences by ER status were suggested for yogurt and cottage/ricotta cheese with associations observed for ER-negative tumors only (pooled HR = 0.90, 95% CI: 0.83, 0.98 comparing ≥60 g/d with

Background Prospective evidence on associations between diet quality indices and lung cancer risk is limited, particularly among older women. Objectives We investigated associations between 4 diet quality indices [Healthy Eating Index-2015 (HEI-2015), Alternate Healthy Eating Index 2010 (AHEI-2010), alternate Mediterranean Diet (aMED), and Dietary Approaches to Stop Hypertension (DASH)] and lung cancer incidence and mortality in the Women's Health Initiative Observational Study. Methods Postmenopausal women aged 50-79 y at baseline (1993-1998) self reported their diet intake and information on relevant covariates. We used Cox proportional hazards regression models to estimate HRs and 95% CIs after controlling for age, smoking, and other relevant covariates. Results During ∼17 y of follow-up among 86,090 participants, 1491 lung cancer cases and 1393 lung cancer deaths were documented. Dietary indices were not associated with overall lung cancer incidence but were protective against squamous cell carcinoma (12.8% of total lung cancer) cases (HEI-2015: HR: 0.85; 95% CI: 0.76, 0.96; AHEI-2010: HR: 0.87; 95% CI: 0.78, 0.98; aMED: HR: 0.90; 95% CI: 0.81, 0.99; DASH: HR: 0.87; 95% CI: 0.77, 0.98). Among the indices, only HEI-2015 showed an inverse trend (P-trend = 0.02) with overall lung cancer mortality. Smoking status or participant age at baseline did not modify the association between dietary indices and lung cancer incidence or mortality. Conclusions After comprehensive control of smoking exposure, we found that diet quality was not associated with overall lung cancer among postmenopausal women. However, a high-quality diet was inversely related to incident lung cancer of the squamous cell subtype. Future studies in populations with diverse age, smoking history, and dietary intake may further elucidate the relation between diet quality indices and lung cancer, especially by histological subtype.

BackgroundThe potential cardiovascular impact of dietary cholesterol intake has been actively debated for decades.ObjectivesWe aimed to evaluate associations of dietary cholesterol and egg intakes with incident cardiovascular disease (CVD) and all-cause and cause-specific mortality.MethodsWe included 96,831 US postmenopausal women aged 50-79 y without known CVD or cancer during baseline enrollment (1993-1998) of the Women's Health Initiative. Dietary information was collected using a validated FFQ. Incident CVD [i.e., ischemic heart disease (IHD) and stroke] and all-cause and cause-specific mortality were ascertained and adjudicated through February 2018.ResultsA total of 9808 incident CVD cases and 19,508 all-cause deaths occurred during a median follow-up of 17.8 y and 18.9 y, respectively. After multivariable adjustment for traditional risk factors and key dietary nutrients including dietary saturated fat, there were modest associations of dietary cholesterol intake with incident CVD (HRQ5versusQ1: 1.12; 95% CI: 1.03, 1.21; P-trend0.05). Higher egg consumption was also associated with modestly higher risk of incident CVD (P-trend=0.004) and all-cause mortality (P-trend&nbsp

Non-supplemental carotenoids and retinol may potentiate antioxidant and anti-inflammatory mechanisms. Chronic intraprostatic inflammation is linked to prostate carcinogenesis. We investigated the association of circulating carotenoids and retinol with intraprostatic inflammation in benign tissue. We included 235 men from the Prostate Cancer Prevention Trial placebo arm who had a negative end-of-study biopsy, most (92.8%) done without clinical indication. α-carotene, β-carotene, β-cryptoxanthin, lycopene, and retinol were assessed by high-performance liquid chromatography using pooled year 1 and 4 serum. Presence and extent of intraprostatic inflammation in benign tissue was assessed in 3 (of 6-10) biopsy cores. Logistic (any core with inflammation vs none) and polytomous logistic (some or all cores with inflammation vs none) regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) of intraprostatic inflammation by concentration tertile adjusting for age, race, prostate cancer family history, and serum cholesterol. None of the carotenoids or retinol was associated with intraprostatic inflammation, except β-cryptoxanthin, which appeared to be positively associated with any core with inflammation [vs none, T2: OR (95% CI) = 2.67 (1.19, 5.99); T3: 1.80 (0.84, 3.82), P-trend = 0.12]. These findings suggest that common circulating carotenoids and retinol are not useful dietary intervention targets for preventing prostate cancer via modulating intraprostatic inflammation.

Background Cardiometabolic abnormalities are a leading cause of death among women, including women with cancer. Methods This study examined the association between prediagnosis cardiovascular health and total and cause-specific mortality among 12,076 postmenopausal women who developed local- or regional-stage invasive cancer in the Women's Health Initiative (WHI). Cardiovascular risk factors included waist circumference, hypertension, high cholesterol, and type 2 diabetes. Obesity-related cancers included breast cancer, colorectal cancer, endometrial cancer, kidney cancer, pancreatic cancer, ovarian cancer, stomach cancer, liver cancer, and non-Hodgkin lymphoma. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) adjusted for important predictors of survival. Results After a median follow-up of 10.0 years from the date of the cancer diagnosis, there were 3607 total deaths, with 1546 (43%) due to cancer. Most participants (62.9%) had 1 or 2 cardiometabolic risk factors, and 8.1% had 3 or 4. In adjusted models, women with 3 to 4 risk factors (vs none) had a higher risk of all-cause mortality (HR, 1.99; 95% CI, 1.73-2.30), death due to cardiovascular disease (CVD) (HR, 4.01; 95% CI, 2.88-5.57), cancer-specific mortality (HR, 1.37; 95% CI, 1.1-1.72), and other-cause mortality (HR, 2.14; 95% CI, 1.70-2.69). A higher waist circumference was associated with greater all-cause mortality (HR, 1.17; 95% CI, 1.06-1.30) and cancer-specific mortality (HR, 1.22; 95% CI, 1.04-1.42). Conclusions Among postmenopausal women diagnosed with cancer in the WHI, cardiometabolic risk factors before the cancer diagnosis were associated with greater all-cause, CVD, cancer-specific, and other-cause mortality. These results raise hypotheses regarding potential clinical intervention strategies targeting cardiometabolic abnormalities that require future prospective studies for confirmation. Lay summary This study uses information from the Women's Health Initiative (WHI) to find out whether cardiac risk factors are related to a greater risk of dying among older women with cancer. The WHI is the largest study of medical problems faced by older women in this country. The results show that women who have 3 or 4 risk factors are more likely to die of any cause, heart disease, or cancer in comparison with women with no risk factors. It is concluded that interventions to help to lower the burden of cardiac risk factors can have an important impact on survivorship among women with cancer.

Background Most studies demonstrating an association between excess adiposity and postmenopausal breast cancer have used anthropometric measures, particularly body mass index (BMI). However, more direct body fat measures may more accurately determine the relationship between body fat distribution and breast cancer risk. Methods Cox proportional hazards regression models were created to examine the associations of dual‐energy x‐ray absorptiometry (DXA) body fat measures (at baseline and during follow‐up) with breast cancer risk among 10 931 postmenopausal women from the Women's Health Initiative cohort. A total of 639 incident invasive breast cancer cases (including 484 estrogen receptor positive (ER+) cases) were ascertained after a median follow‐up of 15.0 years. Results Excess whole body fat mass and trunk fat mass were positively associated with risk invasive breast cancer risk. These associations persisted even after additional adjustment for standard anthropometric measures. In time‐dependent analyses, we observed that both whole body fat mass and trunk fat mass, in the highest versus lowest category, were associated with a doubling of risk of invasive breast cancer overall (HR: 2.17; 95% CI: 1.54‐3.05 and 2.20; 1.55‐3.14, respectively) and of ER+ breast cancer (2.05; 1.37‐3.05 and 2.03; 1.34‐3.07, respectively). The remaining DXA measures were also positively associated with breast cancer risk in baseline and time‐dependent analyses. Conclusion These findings suggest that DXA‐derived body fat measures are positively associated with breast cancer risk after adjustment for BMI and other conventional breast cancer risk factors., Our study demonstrated that DXA‐derived body fat measures were positively associated with breast cancer risk after adjustment for BMI and other conventional breast cancer risk factors. These findings suggest that DXA‐derived measures of overall and central adiposity may explain invasive breast cancer risk beyond that of BMI and other risk factors.

Background: Advanced prostate cancer etiology is poorly understood. Few studies have examined associations of anthropometric factors (e.g. early adulthood obesity) with advanced prostate cancer risk.Patients and methods: We carried out pooled analyses to examine associations between body fatness, height, and prostate cancer risk. Among 830 772 men, 51 734 incident prostate cancer cases were identified, including 4762 advanced (T4/N1/M1 or prostate cancer deaths) cases, 2915 advanced restricted (same as advanced, but excluding localized cancers that resulted in death) cases, 9489 high-grade cases, and 3027 prostate cancer deaths. Cox proportional hazards models were used to calculate study-specific hazard ratios (HR) and 95% confidence intervals (CI); results were pooled using random effects models.Results: No statistically significant associations were observed for body mass index (BMI) in early adulthood for advanced, advanced restricted, and high-grade prostate cancer, and prostate cancer mortality. Positive associations were shown for BMI at baseline with advanced prostate cancer (HR = 1.30, 95% CI = 0.95-1.78) and prostate cancer mortality (HR = 1.52, 95% CI = 1.12-2.07) comparing BMI >= 35.0 kg/m(2) with 21-22.9 kg/m(2). When considering early adulthood and baseline BMI together, a 27% higher prostate cancer mortality risk (95% CI = 9% to 49%) was observed for men with BMI = 30.0 kg/m(2) at baseline compared with BMI = 110 cm with = 1.00 with = 1.90 m withConclusion: Our findings suggest that height and total and central adiposity in mid-to-later adulthood, but not early adulthood adiposity, are associated with risk of advanced forms of prostate cancer. Thus, maintenance of healthy weight may help prevent advanced prostate cancer.

Cadmium is a widespread heavy metal pollutant that may act as an exogenous estrogenic hormone. Environmental cadmium exposure has been associated with risk of breast cancer in retrospective studies. We prospectively assessed the relationship between cadmium exposure, evaluated by creatinine-normalized urinary cadmium concentration, and invasive breast cancer among 12,701 postmenopausal women aged ≥50 years in a Women's Health Initiative study of bone mineral density. After a median of 13.2 years of follow-up (1993-2010), 508 cases of invasive breast cancer and 1,050 comparison women were identified for a case-cohort analysis. Multivariable Cox regression was used to calculate hazard ratios and 95% confidence intervals. Risk of breast cancer was not associated with urinary cadmium parameterized either in quartiles (comparing highest quartile with lowest, hazard ratio = 0.80, 95% confidence interval: 0.56, 1.14; P for trend = 0.20) or as a log-transformed continuous variable (per 2-fold higher urinary cadmium concentration, hazard ratio = 0.94, 95% confidence interval: 0.86, 1.03). We did not observe an association between urinary cadmium and breast cancer risk in any subgroup examined, including never smokers and women with body mass index (weight (kg)/height (m)(2)) less than 25. Results were consistent in both estrogen receptor-positive and estrogen receptor-negative tumors. Our results do not support the hypothesis that environmental cadmium exposure is associated with risk of postmenopausal breast cancer.

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.

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.

Active surveillance (AS) is increasingly used to monitor patients with low-risk prostate cancer; however, approximately 50% of AS patients experience disease reclassification requiring definitive treatment and little is known about patient characteristics that modify the risk of reclassification. Obesity may be one of the major contributing factors. The Prostate Cancer Active Lifestyle Study (PALS) is a clinical trial evaluating the impact of weight loss among overweight/obese (Body Mass Index (BMI) ≥ 25 kg/m2) men with clinically localized prostate cancer on AS. Two hundred participants will be randomized to either the PALS intervention, a 6-month structured diet and exercise program adapted from the Diabetes Prevention Program followed by 6 months of maintenance, or control (general diet and physical activity guidelines delivered in a single session). The PALS intervention involves one-on-one instruction with a registered dietitian and exercise physiologist to achieve the study goal of loss of 7% of baseline weight. Participation is coordinated so that the 6-month time point coincides with the participants' standard-of-care AS prostate biopsy. Primary outcomes will evaluate the intervention effects on circulating and tissue markers of glucose and insulin regulation, health-related quality of life and pathologic upgrading on follow-up prostate biopsies. Additional analyses will determine whether changes in weight and glucose regulation can be sustained for 6 months after the end of instruction. Findings from this trial may have wide reaching implications for men diagnosed with clinically-localized prostate cancer by providing an active lifestyle-based approach to improve prostate cancer patient outcomes.

Background:Advanced glycation end-products (AGE) are formed through nonenzymatic glycation of free amino groups in proteins or lipid. They are associated with inflammation and oxidative stress, and their accumulation in the body is implicated in chronic disease morbidity and mortality. We examined the association between postdiagnosis dietary Nϵ-carboxymethyl-lysine (CML)–AGE intake and mortality among women diagnosed with breast cancer.Methods:Postmenopausal women aged 50 to 79 years were enrolled in the Women's Health Initiative (WHI) between 1993 and 1998 and followed up until death or censoring through March 2018. We included 2,023 women diagnosed with first primary invasive breast cancer during follow-up who completed a food frequency questionnaire (FFQ) after diagnosis. Cox proportional hazards (PH) regression models estimated adjusted hazard ratios (HR) and 95% confidence intervals (CI) of association between tertiles of postdiagnosis CML-AGE intake and mortality risk from all causes, breast cancer, and cardiovascular disease.Results:After a median 15.1 years of follow-up, 630 deaths from all causes were reported (193 were breast cancer–related, and 129 were cardiovascular disease–related). Postdiagnosis CML-AGE intake was associated with all-cause (HRT3vsT1, 1.37; 95% CI, 1.09–1.74), breast cancer (HRT3vsT1, 1.49; 95% CI, 0.98–2.24), and cardiovascular disease (HRT3vsT1, 1.91; 95% CI, 1.09–3.32) mortality.Conclusions:Higher intake of AGEs was associated with higher risk of major causes of mortality among postmenopausal women diagnosed with breast cancer.Impact:Our findings suggest that dietary AGEs may contribute to the risk of mortality after breast cancer diagnosis. Further prospective studies examining dietary AGEs in breast cancer outcomes and intervention studies targeting dietary AGE reduction are needed to confirm our findings.

Background The World Cancer Research Fund and the American Cancer Society provide nutrition and physical activity guidelines for cancer survivors. Many women with breast cancer do not follow these guidelines and delay efforts toward following them until active treatment is complete. However, adoption of these recommended lifestyle behaviors soon after diagnosis may prevent adverse treatment-related side effects and may improve adherence to treatment, resulting in improved breast cancer prognosis. The L ifestyle, E xercise, and N utrition Ear ly after Diagnosis (LEANer) study is testing the effect of a nutrition and physical activity intervention on chemotherapy completion rates. Methods 172 women with stage I-III breast cancer undergoing chemotherapy will be randomized 1:1 to a yearlong, 16 session, nutrition and exercise intervention or usual care control group. The intervention is delivered by registered dietitians specializing in oncology nutrition and exercise training. The intervention includes goal setting to meet nutrition and physical activity guidelines for cancer survivors. After each chemotherapy session, date and dose of each drug administered, and reason for dose-adjustments and/or dose-delays are abstracted from the electronic medical record or obtained from the treating oncologist. Chemotherapy completion rate is assessed as the average relative dose-intensity (RDI) for the originally planned regimen based on standard formulas. Secondary endpoints of endocrine therapy adherence, treatment-related side effects, and changes in inflammatory and metabolic biomarkers, body composition, and patient reported outcomes are assessed at four timepoints. Discussion If successful, this study has the potential to make healthy lifestyle interventions a standard component of breast cancer treatment.

BackgroundPrior studies of dietary protein intake and breast cancer have been mixed and were limited by dietary self-report measurement error.MethodsBiomarker-calibrated total protein intake and estimated vegetable protein and animal protein intake were determined from baseline food frequency questionnaires in 100 024 Women’s Health Initiative participants. Associations between total, animal, and vegetable protein intake and breast cancer incidence, deaths from breast cancer, and deaths after breast cancer were estimated using Cox proportional hazards regression. Breast cancers were verified by medical record review and survival outcomes enhanced by National Death Index queries. All statistical tests were 2-sided.ResultsAfter 14 years of follow-up, there were 6340 incident breast cancers, 764 deaths from breast cancer, and 2059 deaths after breast cancer. In multivariable analyses, higher calibrated total protein intake was not associated with breast cancer incidence or deaths from or after breast cancer. Vegetable protein intake was associated with statistically significantly lower breast cancer incidence (hazard ratio [HR] = 0.98, 95% confidence interval [CI] = 0.96 to 0.99, Ptrend = .006) and statistically significantly lower risk of death after breast cancer (HR = 0.93, 95% CI = 0.91 to 0.97, Ptrend < .001) but not with deaths from breast cancer. In contrast, higher animal protein intake was associated with statistically significantly higher breast cancer incidence (HR = 1.03, 95% CI = 1.01 to 1.06, Ptrend = .02) but not with deaths from or after breast cancer.ConclusionsCalibrated total protein intake was not associated with breast cancer incidence or mortality. Higher vegetable protein intake was associated with lower breast cancer incidence and lower risk of death after breast cancer. Higher animal protein intake was associated with higher breast cancer incidence.

Background In the Women's Health Initiative (WHI) dietary modification (DM) randomised trial, the low-fat dietary intervention reduced deaths from breast cancer (P = 0.02). Extending these findings, secondary analysis examined dietary intervention influence on breast cancer mortality by metabolic syndrome (MS) components. Methods In total, 48,835 postmenopausal women with no prior breast cancer were randomised to a low-fat dietary intervention or comparison groups. Four MS components were determined at entry in 45,833 participants: (1) high waist circumference, (2) high blood pressure, (3) high cholesterol and (4) diabetes history. Forest plots of hazard ratios (HRs) were generated with P-values for interaction between randomisation groups and MS component score. Primary outcome was death from breast cancer by metabolic syndrome score. Results HRs and 95% confidence intervals (CI) for dietary intervention influence on death from breast cancer were with no MS components (n = 10,639), HR 1.09, 95% CI 0.63-1.87; with 1-2 MS components (n = 30,948), HR 0.80, 95% CI 0.62-1.02; with 3-4 MS components (n = 4,246), HR 0.31, 95% CI 0.14-0.69 (interaction P = 0.01). Conclusions While postmenopausal women with 3-4 MS components were at higher risk of death from breast cancer, those randomised to a low-fat dietary intervention more likely had reduction in this risk. Registry ClinicalTrials.gov (NCT00000611).

Compositional and functional differences in gut bacteria exist between adults with normal glucose tolerance, IGT and type 2 diabetes and can change with dietary factors. We compared the gut microbiome between adults with impaired fasting glucose (IFG), impaired glucose tolerance (IGT) and IFG+IGT and evaluated the impact of dietary glycemic index (GI) on the gut microbiome. The study enrolled 53 adults (mean±SEM: age 53.0±1.4 y, BMI 32.5±0.9 kg/m2) with IFG (n=20), IGT (n=10) or both IFG+IGT (n=23). Stool samples were collected in RNAlater after 2 weeks on a control, moderate GI diet (GI 55-58) and again after a 4 week dietary intervention of a low GI (GI70, n=18 on placebo and n=17 on the antioxidant N-acetyl-cysteine 1200 mg po BID). Diets had the same macronutrient composition (55%carbohydrate/30% fat/15% protein) but more fiber in the LGI (65.1±2.2 g/d) vs. HGI diet (25.8±0.8 g/d). The stool microbiome was analyzed using 16S rRNA gene sequencing (V1-V3). Results: α diversity was significantly higher in IGT vs. IFG+IGT (7.2±0.08 vs. 7.0±0.06, p Conclusions: Differences in microbiota were observed between IGT and IFG+IGT. These associations may contribute to poorer metabolic function in IFG+IGT, but would need further testing to determine cause and effect. The LGI diet was associated with higher Anaerostipes, a butyrate producing bacteria with beneficial anti-inflammatory effects. This may be related to the higher fiber content of the LGI diet. Disclosure K. Utzschneider: Other Relationship; Self; Medtronic. M.L. Neuhouser: None. K.M. Newton: None. K. Breymeyer: None. M.A. Hullar: None. Funding National Institutes of Health (R01DK092568, P30DK017047, UL1TR002319, P30CA015704, KL2TR002317, TL1TR002318)

PURPOSE Observational studies of dietary fat intake and breast cancer have reported inconsistent findings. This topic was addressed in additional analyses of the Women’s Health Initiative (WHI) Dietary Modification (DM) clinical trial that evaluated a low-fat dietary pattern influence on breast cancer incidence. METHODS In the WHI DM trial, 48,835 postmenopausal women, ages 50-79 years, with no prior breast cancer, and a dietary fat intake of ≥ 32% of energy were randomly assigned at 40 US centers to a usual diet comparison group (60%) or dietary intervention group (40%). The goals were to reduce fat intake to 20% of energy and increase vegetable, fruit, and grain intake. Breast cancers were confirmed after central medical record review and serial National Death Index linkages to enhance mortality findings. RESULTS During 8.5 years of dietary intervention, breast cancer incidence and deaths as a result of breast cancer were nonsignificantly lower in the intervention group, while deaths after breast cancer were statistically significantly lower both during intervention and through a 16.1-year (median) follow-up. Now, after a long-term, cumulative 19.6-year (median) follow-up, the significant reduction in deaths after breast cancer persists (359 [0.12%] v 652 [0.14%] deaths; hazard ratio [HR], 0.85; 95% CI, 0.74 to 0.96; P = .01), and a statistically significant reduction in deaths as a result of breast cancer (breast cancer followed by death attributed to the breast cancer) emerged (132 [0.037%, annualized risk] v 251 [0.047%] deaths, respectively; HR, 0.79; 95% CI, 0.64 to 0.97; P = .02). CONCLUSION Adoption of a low-fat dietary pattern associated with increased vegetable, fruit, and grain intake, demonstrably achievable by many, may reduce the risk of death as a result of breast cancer in postmenopausal women.

Oscillating glucose levels can increase oxidative stress and may contribute to β-cell dysfunction. We tested the hypothesis that increased glycemic variability contributes to β-cell dysfunction by experimentally altering glucose variability with controlled diets varying in glycemic index (GI). Fifty-two adults with prediabetes received a 2-week moderate GI (GI = 55–58) control diet followed by randomization to a four-week low GI (LGI: GI < 35) or high GI (HGI HI > 70) diet. Those on the HGI diet were randomized to placebo or the antioxidant N-acetylcysteine (NAC). Participants underwent blinded CGMS, fasting oxidative stress markers and an intravenous glucose tolerance test to estimate β-cell function (disposition index: DI). On the control diet, DI was inversely correlated with SD glucose (r = −0.314, p = 0.03), but neither DI nor glucose variability were associated with oxidative stress markers. The LGI diet decreased SD glucose (Control 0.96 ± 0.08 vs. LGI 0.79 ± 0.06, p = 0.02) while the HGI diet increased it (Control 0.88 ± 0.06 vs. HGI 1.06 ± 0.07, p = 0.03). Neither DI nor oxidative stress markers changed after the LGI or HGI diets. NAC had no effect on DI, glucose variability or oxidative stress markers. We conclude small changes in glucose variability induced by dietary GI in adults with pre-diabetes are unlikely to contribute to β-cell dysfunction.

Author(s): Van Horn, Linda; Aragaki, Aaron K; Howard, Barbara V; Allison, Matthew A; Isasi, Carmen R; Manson, JoAnn E; Neuhouser, Marian L; Mossavar-Rahmani, Yasmin; Thomson, Cynthia A; Vitolin, Mara Z; Wallace, Robert B; Prentice, Ross L; WHI Investigators | Abstract: BackgroundWomen without cardiovascular disease (CVD) or hypertension at baseline assigned to intervention in the Women's Health Initiative Dietary Modification (DM) trial experienced 30% lower risk of coronary heart disease (CHD), whereas results in women with hypertension or prior CVD could have been confounded by postrandomization use of statins.ObjectivesIntervention participants reported various self-selected changes to achieve the 20% total fat goals. Reviewed are intervention compared with comparison group HRs for CHD, stroke, and total CVD in relation to specific dietary changes in normotensive participants.MethodsDietary change was assessed by comparing baseline with year 1 FFQ data in women (nn=n10,371) without hypertension or CVD at baseline with intake of total fat above the median to minimize biases due to use of the FFQ in trial eligibility screening.ResultsIntervention participants self-reported compensating reduced energy intake from total fat by increasing carbohydrate and protein. Specifically they increased plant protein, with those in the upper quartile (increased total protein by ≥3.3% of energy) having a CHD HR of 0.39 (95% CI: 0.22, 0.71), compared with 0.92 (95% CI: 0.57, 1.48) for those in the lower quartile of change (decreased total protein ≥0.6% of energy), with P-trend of 0.04. CHD HR did not vary significantly with change in percentage energy from carbohydrate, and stroke HR did not vary significantly with any macronutrient changes. Scores reflecting adherence to recommended dietary patterns including the Dietary Approaches to Stop Hypertension Trial and the Healthy Eating Index showed favorable changes in the intervention group.ConclusionsIntervention group total fat reduction replaced with increased carbohydrate and some protein, especially plant-based protein, was related to lower CHD risk in normotensive women without CVD who reported high baseline total fat intake. This trial was registered at clinicaltrials.gov as NCT00000611. Link to the WHI trial protocol: https://www.whi.org/about/SitePages/Dietary%20Trial.aspx.

BACKGROUND: Choline plays an integral role in one-carbon metabolism in the body, but it is unclear whether genetic polymorphisms are associated with variations in plasma choline and its metabolites. OBJECTIVES: This study aimed to evaluate the association of genetic variants in choline and one-carbon metabolism with plasma choline and its metabolites. METHODS: We analyzed data from 1423 postmenopausal women in a case-control study nested within the Women's Health Initiative Observational Study. Plasma concentrations of choline, betaine, dimethylglycine (DMG), and trimethylamine N-oxide were determined in 12-h fasting blood samples collected at baseline (1993–1998). Candidate and tagging single-nucleotide polymorphisms (SNPs) were genotyped in betaine-homocysteine S-methyltransferase (BHMT), BHMT2, 5,10-methylenetetrahydrofolate reductase (MTHFR), methylenetetrahydrofolate dehydrogenase (NADP+ dependent 1) (MTHFD1), 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR), and 5-methyltetrahydrofolate-homocysteine methyltransferase reductase (MTRR). Linear regression was used to derive percentage difference in plasma concentrations per variant allele, adjusting for confounders, including B-vitamin biomarkers. Potential effect modification by plasma vitamin B-12, vitamin B-6, and folate concentrations and folic-acid fortification periods was examined. RESULTS: The candidate SNP BHMT R239Q (rs3733890) was associated with lower concentrations of plasma betaine and DMG concentrations (−4.00% and −6.75% per variant allele, respectively; both nominal P G, was associated with higher plasma DMG concentration (13.0%; P < 0.0001). Several tagSNPs in these 2 genes were associated with plasma concentrations after correction for multiple comparisons. Vitamin B-12 status was a significant effect modifier of the association between the genetic variant BHMT2 rs626105 A>G and plasma DMG concentration. CONCLUSIONS: Genetic variations in metabolic enzymes were associated with plasma concentrations of choline and its metabolites. Our findings contribute to the knowledge on the variation in blood nutrient concentrations in postmenopausal women.

The association between consumption of added or concentrated sugars and prostate cancer risk is unclear. We examined the association between concentrated sugars in beverages and desserts and prostate cancer risk among 22 720 men in the usual-care arm of the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial, enrolled during 1993–2001. After a median follow-up of 9 years, 1996 men were diagnosed with prostate cancer. Cox proportional hazards regression models were used to estimate hazard ratios (HR) for prostate cancer risk and 95 % CI, adjusting for potential confounding factors. Increased consumption of sugars from sugar-sweetened beverages was associated with increased risk of prostate cancer for men in the highest quartile of sugar consumption (HR: 1·21; 95 % CI 1·06, 1·39), and there was a linear trend (P

Background: Although some familial cancer syndromes include biliary tract cancers (BTCs; cancers of the gallbladder, intrahepatic and extrahepatic bile ducts, and ampulla of Vater), the few studies that have examined the relationships between family history of cancer (FHC) and BTCs have reported inconclusive findings. The objective of this study was to investigate the associations of FHC with risk of BTC in the Biliary Tract Cancers Pooling Project (BiTCaPP). Methods: We used Cox proportional hazards regressions models to estimate HRs and 95% confidence intervals for associations between FHC (any, first-degree, in female relative, in male relative, relative with gastrointestinal cancer, and relative with hormonally related cancer) and BTC risk by anatomic site within the biliary tract, adjusting for sex and race/ethnicity. Sensitivity analyses were conducted that restricted to studies reporting cholecystectomy data and to people without a history of cholecystectomy. Results: Data on FHC were available from 12 prospective studies within BiTCaPP, which collectively contributed 2,246 cases (729 gallbladder, 345 intrahepatic and 615 extrahepatic bile duct, and 385 ampulla of Vater cancers) with 21,706,107 person-years of follow-up. A marginal, inverse association between FHC and gallbladder cancer was driven to the null when analysis was restricted to studies reporting cholecystectomy data and to people without a history of cholecystectomy. FHC was not associated with risk of BTC at the other anatomic sites. Conclusions: These findings do not support an association between FHC and BTCs. Impact: In a study of 1.5 million people, FHC is not a risk factor for BTCs. Cancer Epidemiol Biomarkers Prev; 27(3); 348–51. ©2018 AACR.

Inconsistent results from epidemiologic studies of circulating fatty acids and prostate cancer risk may be partly due to use of blood concentrations as surrogate biomarkers of prostate tissue concentrations. To determine whether blood concentrations reflect prostate tissue fatty acid profiles, we evaluated associations between phospholipid fatty acid (PLFA) profiles measured in plasma and prostate tissue from 20 patients who underwent prostatectomy. For each patient, three prostate tissue specimens varying in size and location were collected. Correlations were calculated between a) tissue specimens by size ( ≤ 20 mg, > 20 mg); b) individual tissue samples [Intraclass Correlation Coefficient (ICC)]; and c) plasma and mean tissue PLFA concentrations. PLFA concentrations from ≤ 20 mg and > 20 mg tissues were nearly identical. For most PLFAs, intra-individual correlations between tissue specimens were moderate to strong (linoleic acid = 0.66, eicosapentaenoic acid = 0.96), with only one ICC below 0.50 (trans-fatty acid 18:2, ICC = 0.28). Most correlations of mean tissue and plasma concentrations were moderate to strong (α-linoleic acid = 0.47, eicosapentaenoic acid = 0.93). PLFA concentrations are largely homogeneous within the prostate and can be reliably measured in small quantities of tissue. The overall strong correlations between plasma and tissue suggest that for most individual PLFAs, plasma concentrations are adequate surrogate markers of prostate tissue concentrations.

Excess body weight is a poor prognostic factor in women with early breast cancer, but the effect of weight loss on the risk of breast cancer recurrence and mortality in women who are overweight or obese at the time of breast cancer diagnosis has not been evaluated. The Alliance for Clinical Trials in Oncology Breast Cancer Weight Loss trial, also known as A011401, is testing the impact of a telephone-based weight loss program on invasive disease-free survival in 3136 women with a body mass index ≥27 kg/m2 who have recently been diagnosed with stage II-III, HER-2 negative breast cancer. Secondary outcomes of the trial include the impact of the weight loss intervention on overall survival, body weight, physical activity, dietary intakes, incidence of comorbidities, serum biomarkers and patient reported outcomes. Participants are randomized 1:1 to a 2-year, telephone-based weight loss intervention or to an education control group. The intervention is delivered through 42 telephone calls, delivered by health coaches based at the Dana-Farber Cancer Institute. Calls are supplemented by an intervention workbook, as well as a number of tools to help facilitate weight loss. Intervention goals include loss of 10% of baseline body weight, achieved through caloric restriction and increased physical activity. This large-scale study testing the impact of purposeful weight loss after cancer diagnosis on the risk of breast cancer recurrence and mortality has the potential to make weight loss programs a standard part of breast cancer treatment.

Background: Biomarkers of macronutrient intake are lacking. Controlled human feeding studies that preserve the normal variation in nutrient and food consumption are necessary for the development and validation of robust nutritional biomarkers.Objective: We aimed to assess the utility of serum phospholipid fatty acids (PLFAs) as biomarkers of dietary intakes of fatty acids, total fat, and carbohydrate.Design: We used an individualized controlled feeding study in which 153 postmenopausal women from the Women's Health Initiative (WHI) were provided with a 2-wk controlled diet that mimicked each individual's habitual food intake. A total of 41 PLFAs were measured with the use of gas chromatography in end-of-feeding-period fasting serum samples and expressed in both relative and absolute concentrations. R2 values (percentages of variation explained) from linear regressions of (ln-transformed) consumed fatty acids (individual, groups, and broad categories) on (ln-transformed) corresponding measures of serum PLFAs alone and together with selected participant-related variables (age, race/ethnicity, body mass index, season of study participation, education level, and estimated energy intake from doubly labeled water) were used for evaluation against established urinary recovery biomarkers of energy and protein intake as benchmarks. Models to predict intakes of other nutrients were also explored.Results: Intakes of eicosapentaenoic acid and docosahexaenoic acid achieved the benchmark of R2 > 36% with or without covariates. When all 41 serum PLFAs and participant-related covariates were initially included in the model for selection, cross-validated R2 achieved >36% for consumed total carbohydrate (grams per day), total saturated fatty acids (SFAs), percentage of energy from SFAs, and total trans fatty acids with serum PLFAs in both relative and absolute concentrations.Conclusions: Serum PLFA biomarkers perform similarly to established energy and protein urinary recovery biomarkers in describing intake variations for several nutrients and, thus, appear suitable for application in this population of postmenopausal women. This approach represents an important methodologic contribution toward the utilization of nutritional biomarkers to assess macronutrient intake. This trial was registered at clinicaltrials.gov as NCT00000611.

Recent long-term prospective cohort studies found inverse associations between chocolate consumption and the risk of type 2 diabetes, but provided conflicting evidence on the nature of the association among women. To assess this association in a large cohort of American women. Multivariable Cox regression was used with the data from 92 678 postmenopausal women in the prospective Women’s Health Initiative study. Chocolate intake was assessed by food frequency questionnaire. Incidence of type 2 diabetes was determined by self-report of the first treatment with oral medication or insulin. Among women free of diabetes at baseline, there were 10 804 cases, representing an incidence rate of 11.7% during 13.1 years and 1 164 498 person-years of follow-up. There was no significant linear association between long-term chocolate intake and type 2 diabetes risk, but there was significantly reduced risk at moderate levels of intake. Compared to women who ate 1 oz. of chocolate

Laboratory and animal studies suggest an inverse association between chocolate consumption and the risk of cancer. Epidemiological studies have yielded inconsistent evidence.To assess the association of chocolate candy consumption with incident, invasive total, breast, colorectal, and lung cancers in a large cohort of postmenopausal American women.Prospective cohort study with a mean 14.8-year follow-up. Chocolate candy intake was assessed by food frequency questionnaire. Invasive cancer events were assessed by physician adjudication.The Women's Health Initiative Study enrolled 161,808 postmenopausal women at 40 clinical centers nationwide between 1993 and 1998. Of these women, 114,281 with plausible food frequency or biometric data and no missing data on chocolate candy exposure were selected for analysis.Cancer risk in quartiles of chocolate candy consumption with the first quartile as referent.Multivariable Cox regression was used to calculate hazard ratios and 95% confidence intervals.There were 16,164 documented incident invasive cancers, representing an incidence rate of 17.0 per 100 participants and 12.3 per 1000 person years during follow-up among participants without any preexisting cancers or missing outcome data. There were no statistically significant associations for total invasive cancer (P-linear = .47, P-curvature = .14), or invasive breast cancer (P-linear = .77, P-curvature = .26). For colorectal cancer P-linear was .02, P-curvature was .03, and compared with women eating a 1 oz (28.4 g) chocolate candy serving1 time per month, the hazard ratio for ≥1.5 times/wk was 1.18 (95% confidence interval: 1.04-1.35). This result may be attributable to the excess adiposity associated with frequent chocolate candy consumption.In the Women's Health Initiative, there was no significant association between chocolate candy consumption and invasive total or breast cancer. There was a modest 18% higher risk of invasive colorectal cancer for women who ate chocolate candy at least 1.5 times/wk. These results require confirmation.

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.

We and others have reported associations between B vitamins principally involved in one-carbon metabolism and increased lung cancer risk; however, results for women have been inconsistent. Here we report on the association of supplemental vitamins B6 , folic acid and B12 intake and lung cancer risk using data from the Women's Health Initiative (WHI) study of postmenopausal women. Between 1993 and 1998, 161,808 women were recruited to participate in the WHI at 40 clinical centers in the US. After exclusions, 159,232 women were available for analysis and followed prospectively for an average of 18.3 years. Among them, 3,836 incident lung cancer cases were diagnosed. At baseline, supplemental B vitamins from multivitamins, vitamin mixtures and individual supplements were assessed. Adjusted Cox regression models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for associations between supplemental B vitamin intake and lung cancer risk. Relative to no intake, women who took ≥50 mg/day of vitamin B6 had 16% (HR 0.84, 95% CI: 0.71-0.99) reduced lung cancer risk. Associations did not differ significantly by smoking status or lung cancer histology. Intakes of folic acid and vitamin B12 were not associated with risk. There is a need for replication of our findings from other large, prospective studies with similar high-quality measurement of supplement intakes before any recommendations can be made at present on B6 supplementation for lung cancer prevention in women.

Observational studies have reported an inverse association between vitamin D intake and breast cancer risk. We examined whether vitamin D supplementation in high-risk premenopausal women reduces mammographic density (MD), an established breast cancer risk factor. We conducted a multicenter randomized double-blind placebo-controlled trial in premenopausal women at high risk for breast cancer [5-year risk ≥ 1.67%, lifetime risk ≥ 20%, lobular carcinoma in situ, prior stage 0–II breast cancer, hereditary breast cancer syndrome, or high MD (heterogeneously/extremely dense)], with a baseline serum 25-hydroxyvitamin D [25(OH)D] ≤ 32 ng/mL. Participants were randomized to 12 months of vitamin D3 20,000 IU/week or matching placebo. The primary endpoint was change in MD from baseline to 12 months using the Cumulus technique. Secondary endpoints included serial blood biomarkers [25(OH)D, 1,25-dihydroxyvitamin D (1,25(OH)D), insulin-like growth factor (IGF)-1, IGF-binding protein-3] and MD change at 24 months. Among 208 women randomized, median age was 44.6 years, 84% were white, 33% had baseline 25(OH)D < 20 ng/mL, and 78% had high baseline MD. Comparing the active and placebo groups at 12 months, MD changes were small and did not significantly differ. Mean MD changes at 12 and 24 months were −0.3% and −1.2%, respectively, in the active arm and +1.5% and +1.6% with placebo (P > 0.05). We observed a mean change in serum 25(OH)D of +18.9 versus +2.8 ng/mL (P < 0.01) and IGF-1 of −9.8 versus −1.8 ng/mL (P = 0.28), respectively. At 12 months, MD was positively correlated with serum IGF-1 and IGF-1/IGFBP-3 (P < 0.01). This trial does not support the use of vitamin D supplementation for breast cancer risk reduction.

Background Tobacco and alcohol are well-established risk factors for numerous cancers, yet their relationship to biliary tract cancers remains unclear. Methods We pooled data from 26 prospective studies to evaluate associations of cigarette smoking and alcohol consumption with biliary tract cancer risk. Study-specific hazard ratios (HRs) and 95% confidence intervals (CIs) for associations with smoking and alcohol consumption were calculated. Random-effects meta-analysis produced summary estimates. All statistical tests were two-sided. Results Over a period of 38 369 156 person-years of follow-up, 1391 gallbladder, 758 intrahepatic bile duct, 1208 extrahepatic bile duct, and 623 ampulla of Vater cancer cases were identified. Ever, former, and current smoking were associated with increased extrahepatic bile duct and ampulla of Vater cancers risk (eg, current vs never smokers HR = 1.69, 95% CI = 1.34 to 2.13 and 2.22, 95% CI = 1.69 to 2.92, respectively), with dose-response effects for smoking pack-years, duration, and intensity (all Ptrend 40 cigarettes per day vs never smokers HR = 2.15, 95 % CI = 1.15 to 4.00; Ptrend = .001). No convincing association was observed between smoking and gallbladder cancer. Alcohol consumption was only associated with intrahepatic bile duct cancer, with increased risk for individuals consuming five or more vs zero drinks per day (HR = 2.35, 95%CI = 1.46 to 3.78; Ptrend = .04). There was evidence of statistical heterogeneity among several cancer sites, particularly between gallbladder cancer and the other biliary tract cancers. Conclusions Smoking appears to increase the risk of developing all biliary tract cancers except gallbladder cancer. Alcohol may increase the risk of intrahepatic bile duct cancer. Findings highlight etiologic heterogeneity across the biliary tract.

Objective To examine whether changes in diet quality predict changes in central adiposity among postmenopausal women. Methods At baseline and 3-year follow-up, Women's Health Initiative Observational Study participants completed food frequency questionnaires, and waist circumference was measured (WC, n = 67,175). In a subset, trunk fat was measured via dual-energy X-ray absorptiometry (DXA, n = 4,254). Using multivariable linear regression, 3-year changes in dietary patterns (Healthy Eating Index-2010, Alternate Healthy Eating Index-2010, Alternate Mediterranean Diet, and Dietary Approaches to Stop Hypertension) were examined as predictors of concurrent changes in WC and, secondarily, DXA. Results Mean (SD) age and 3-year changes in weight and WC were 63 (7) years, 0.52 (4.26) kg, and 0.94 (6.65) cm. A 10% increase in any dietary pattern score, representing improved diet quality, was associated with 0.07 to 0.43 cm smaller increase in WC over 3 years (all P < 0.05). After adjusting for weight change, associations attenuated to 0.02 to 0.10 cm but remained statistically significant for all patterns except Alternate Mediterranean Diet. Results were similar for DXA trunk fat. Conclusions Three-year improvements in diet quality are modestly protective against gain in WC and partially explained by lesser weight gain. Achieving and maintaining a healthful diet after menopause may protect against gains in central adiposity.

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.

SCOPE High glycemic load diets have been associated with increased breast cancer risk in population-based studies, but the evidence is mixed. This investigation determined whether diets differing in glycemic load affected the carcinogenic process using a preclinical model. METHODS AND RESULTS Human diets, formulated to differ 2-fold in glycemic load, were evaluated in the 1-methyl-nitrosourea-induced (37.5 mg/kg) mammary carcinogenesis model. Cancer incidence (23.3 versus 50.0%, p = 0.032), multiplicity, (0.40 versus 1.03, p = 0.030) and burden, (0.62 versus 1.19 g/rat, p = 0.037) were reduced in the low versus high glycemic load diets, respectively. However, the low glycemic protective effect was attenuated when two purified diets that differed in resistant starch and simulated the glycemic effects of the human diets were fed. Protection was associated with alterations in markers of cell growth regulation. CONCLUSION Our findings show that human low or high glycemic load dietary patterns differentially affect the carcinogenic response in a nondiabetic rodent model for breast cancer. However, factors that are associated with these patterns, in addition to dietary carbohydrate availability, appear to account for the differences observed.

Reports relating meat intake to prostate cancer risk are inconsistent. Associations between these dietary factors and prostate cancer were examined in a consortium of 15 cohort studies. During follow-up, 52,683 incident prostate cancer cases, including 4,924 advanced cases, were identified among 842,149 men. Cox proportional hazard models were used to calculate study-specific relative risks (RR) and then pooled using random effects models. Results do not support a substantial effect of total red, unprocessed red and processed meat for all prostate cancer outcomes, except for a modest positive association for tumors identified as advanced stage at diagnosis (advanced(r)). For seafood, no substantial effect was observed for prostate cancer regardless of stage or grade. Poultry intake was inversely associated with risk of advanced and fatal cancers (pooled multivariable RR [MVRR], 95% confidence interval, comparing ≥ 45 vs.

Background: Mexican immigrants are disproportionally affected by diet-related risk of metabolic dysfunction. Whether adhering to a traditional Mexican diet or adopting a US diet contributes to metabolic changes associated with future risk of type 2 diabetes and other chronic diseases has not been investigated. Objective: The purpose of this study was to test in a randomized crossover feeding trial the metabolic responses to a Mexican diet compared with a commonly consumed US diet. Design: First- and second-generation healthy women of Mexican descent (n = 53) were randomly assigned in a crossover design to consume a Mexican or US diet for 24 d each, separated by a 28-d washout period. Diets were eucaloric and similar in macronutrient composition. The metabolic responses to diets were assessed by measuring fasting serum concentrations of glucose, insulin, insulin-like growth factor 1 (IGF-1), insulin-like growth factor binding protein 3 (IGFBP-3), adiponectin, C-reactive protein (CRP), and interleukin 6 (IL-6), as well as the homeostasis model assessment of insulin resistance (HOMA-IR) at the beginning and end of each period. Linear mixed models tested the intervention effect on the biomarkers, while adjusting for diet sequence, feeding period, baseline and washout biomarker concentrations, age, acculturation, and BMI. Results: Compared with the US diet, the Mexican diet reduced insulin by 14% [geometric means (95% CIs): 9.3 (8.3, 10.3) compared with 8.0 (7.2, 8.9) μU/mL; P = 0.02], HOMA-IR by 15% [2.0 (1.8, 2.3) compared with 1.7 (1.6, 2.0); P = 0.02], and IGFBP-3 by 6% (mean ± SEM: 2420 ± 29 compared with 2299 ± 29 ng/mL; P < 0.01) and tended to reduce circulating concentrations of IGF-1 by 4% (149 ± 2.6 compared with 144 ± 2.5 ng/mL; P = 0.06). There was no significant intervention effect on serum concentrations of glucose, adiponectin, CRP, or IL-6 in the US compared with the Mexican diet. Conclusion: Compared with the commonly consumed US diet, the traditional Mexican diet modestly improved insulin sensitivity under conditions of weight stability in healthy women of Mexican descent, while having no impact on biomarkers of inflammation. This trial was registered at clinicaltrials.gov as {"type":"clinical-trial","attrs":{"text":"NCT01369173","term_id":"NCT01369173"}}NCT01369173.

We and others have reported associations between B vitamins principally involved in one-carbon metabolism and increased lung cancer risk; however results for women have been inconsistent. Here we report on the association of supplemental vitamins B6, folic acid, and B12 intake and lung cancer risk using data from the Women's Health Initiative (WHI) study of postmenopausal women. Between 1993 and 1998, 161,808 women were recruited to participate in the WHI at 40 US clinical centers. After exclusions, 159,232 women were available for analysis and followed prospectively for 18.3 years. Among them, 3,836 incident lung cancer cases were diagnosed. At baseline, supplemental B vitamins from multivitamins, vitamin mixtures, and individual supplements were assessed. Adjusted Cox regression models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for associations between supplemental B vitamin intake and lung cancer risk. Relative to non-users, women who took ≥50 mg/d of vitamin B6 had 18% (HR 0.82, 95% CI: 0.70-0.97) reduced lung cancer risk. Associations did not differ significantly by smoking status or lung cancer histology. Intakes of folic acid and vitamin B12 were not associated with risk. There is a need for replication of our findings from large, prospective studies with high-quality measurement of supplement intakes. As such, no recommendation can be made at present on the use of B6 supplements for lung cancer prevention in women. Citation Format: Theodore M. Brasky, Roberta M. Ray, Sandi L. Navarro, Jeannette M. Schenk, Alison M. Newton, Marian L. Neuhouser. Supplemental one-carbon metabolism related B vitamins and lung cancer risk in the Women's Health Initiative [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4654.

OBJECTIVES: We aimed to evaluate diet quality as reflected by multiple a priori dietary pattern indices in relation to incident PAD. METHODS: We included 138,506 US postmenopausal women aged 50–79 years without known PAD at baseline (1993–1998) of the Women's Health Initiative. Score of 4 dietary pattern indices, including the alternate Mediterranean diet (aMED) index, the alternate Healthy Eating Index (AHEI)-2010, the Dietary Approaches to Stop Hypertension (DASH) diet index, and the Healthy Eating Index (HEI)-2015, were derived using data collected by a validated food frequency questionnaire. Incident cases of symptomatic PAD in the lower extremities were ascertained and adjudicated through March 2019 by reviewing medical record. Hazard ratios (HR) and 95% confidence interval (CI) were estimated using Cox proportional hazards models, with adjustment for multiple potential confounders including known risk factors for PAD (i.e., smoking, high blood pressure, dyslipidemia, and diabetes). RESULTS: During a median 18.6 years of follow-up, 1036 incident cases of PAD were identified. All 4 dietary pattern indices were inversely associated with risk of PAD. The multivariable-adjusted HRs (95% CI) comparing the highest with the lowest score quartiles were 0.74 (0.61–0.91) for aMED index (P-trend across quartile = 0.010), 0.79 (0.65–0.95) for AHEI-2010 (P-trend

1570 Background: Breast cancer (BrCa) is the second leading cause of cancer death and constitutes about 14% of total cancer deaths among US women. Advanced glycation end-products (AGEs) are implicated in chronic diseases including cancer and cardiovascular diseases (CVD). AGEs are naturally found in animal products and processed foods, and preparing food at high temperatures increases AGE formation. Our goal was to assess the association between post-diagnosis dietary NƐ-carboxymethyl-lysine (CML)-AGE intake, a common measure of AGE, and mortality from all-causes, BrCa and CVD among participants with invasive BrCa in the Women’s Health Initiative (WHI). Methods: The WHI enrolled postmenopausal women aged 50 to 79 years from 1993-1998 into randomized controlled trials and a prospective observational study to examine causes of morbidity and mortality. In this analysis, we included 2,073 women diagnosed with invasive BrCa during follow-up who completed a food frequency questionnaire (FFQ) after diagnosis, had energy intakes between ≥600 kcal/day and ≤5000 kcal/day, and had CML-AGE intake data available. Women were followed from BrCa diagnosis until death or censoring through March 2018. Cox proportional hazards regression models estimated the hazard ratios (HR) and 95% CIs of mortality risk from all-causes, BrCa and CVD by tertiles of dietary CML-AGE intake with adjustment for age, income, race/ethnicity, study arm, time from diagnosis to FFQ completion, education, physical activity, smoking, BMI, ER/PR status, diagnosis stage, postmenopausal hormone use, intake of energy, alcohol, fat, red and processed meats. Results: After a median 15.1 years of follow-up, 642 deaths were reported including 198 BrCa-specific and 129 CVD-specific deaths. The average time from BrCa diagnosis to FFQ completion was 1.5 years. Compared to the lowest tertile of CML-AGE intake, there was an increased risk in the highest tertile for all-cause mortality (HR: 1.51, 95% CI: 1.17-1.94), BrCa (HR: 1.86, 95% CI: 1.19-2.91) and CVD (HR: 2.14, 95% CI: 1.19-3.84) mortality. Conclusions: Higher dietary AGE intake after BrCa diagnosis in postmenopausal women was associated with increased risk of mortality from all-causes, BrCa and CVD. Exposure to AGEs could be modified through dietary counseling and evaluated in relation to reduced mortality risk after BrCa diagnosis.

Background: Meta-analyses of observational studies associate adherence to several dietary patterns with cognitive health. However, limited evidence from full scale, randomized controlled trials precludes causal inference regarding dietary effects on cognitive function. Methods: The Women's Health Initiative (WHI) Dietary Modification (DM) randomized trial, in 48,835 postmenopausal women, included a subset of 1,606 WHI Memory Study (WHIMS) participants >= 65 years old, to assess low-fat dietary pattern influence on global cognitive function, evaluated with annual screening (Modified Mini–Mental State Examinations [3MSE]). Participants were randomized by a computerized, permuted block algorithm, stratified by age group and center, to a dietary intervention (40%) to reduce fat intake to 20% of energy and increase fruit, vegetable and grain intake or usual diet comparison groups (60%). The study outcome was possible cognition impairment (failed cognitive function screening) through the 8.5 year (median) dietary intervention. Those failing screening received a comprehensive, multi-phase cognitive function assessment to classify as: no cognitive impairment, mild cognitive impairment, or probable dementia. Exploratory analyses examined the composite endpoint of death after possible cognitive impairment through 18.7 years (median) follow-up. The WHI trials are registered at ClinicalTrials.gov:NCT00000611. Findings: Among the 1,606 WHIMS participants, the dietary intervention statistically significantly reduced the incidence of possible cognitive impairment (n = 126; hazard ratio [HR] 0.59 95% confidence interval [CI] 0.38–0. 91, P = 0.01) with HR for dietary influence on subsequent mild cognitive impairment of 0.65 (95% CI 0.35–1.19) and HR of 0.63 (95% CI 0.19–2.10) for probable dementia (PD). Through 18.7 years, deaths from all-causes after possible cognitive impairment were non-significantly lower in the dietary intervention group (0.56% vs 0.77%, HR 0.83 95% CI 0.35 to 2.00, P = 0.16). Interpretation: Adoption of a low-fat eating pattern, representing dietary moderation, significantly reduced risk of possible cognitive impairment in postmenopausal women. Funding: Several Institutes of the US National Institutes of Health. Keywords: Cognition, Dietary modification, Low-fat dietary pattern, Randomized clinical trial, Women's Health Initiative

ObjectiveWe conducted a gene-environment interaction study to evaluate whether the association of body mass index (BMI) associated meta genome-wide association study single-nucleotide polymorphisms (SNPs) (as a genetic risk score) and BMI is modified by physical activity and age.MethodsIn 8,206 women of European ancestry from the Women's Health Initiative (WHI), we used linear regression to examine main effects of the 95 SNP BMI genetic risk score (GRS) and physical activity on BMI, and evaluated whether genetic associations are modified by physical activity (two-way interaction) and age (three-way interaction).ResultsWe found evidence for modification of the BMI GRS-BMI association according to both physical activity and age. We observed a significant two-way interaction of BMI GRS × physical activity in the crude model (P interaction = 0.05), where a smaller effect of the BMI GRS on BMI with increasing physical activity. The beta coefficient was 0.05 (standard error [SE] = 0.02, P = 0.01) for the high-activity group compared with beta = 0.13 (SE = 0.02, P = 4.8 × 10) for the sedentary group. The three-way interaction was statistically significant (adjusted P interaction = 0.01). Notably, in the 70+ age group, the BMI GRS-BMI association was attenuated and no longer significant in the high-activity group; the beta coefficient for the 70+ high-activity group was relatively small and nonsignificant (beta = 0.02, SE = 0.03, P = 0.58) compared with 70+ sedentary group (beta = 0.17, SE = 0.03, P = 2.5 × 10).ConclusionOur study suggests that physical activity attenuates the influence of genetic predisposition to obesity, and this effect is more profound in the oldest age group.

High glycemic variability has been associated with increased oxidative stress and β-cell dysfunction. To test whether changes in glycemic variability impact β-cell function and oxidative stress markers in adults with prediabetes, we conducted an RCT where we provided study subjects controlled diets varying in glycemic index (GI) to experimentally manipulate post-prandial glucose excursions. After 2 weeks on a control diet (mean GI= 55-58), subjects were randomized to 1 of 3 groups for 4 weeks: low (LGI 70) GI diet plus the anti-oxidant N-acetylcysteine (HGI/NAC) 600 mg BID or HGI diet plus placebo (HGI/PLAC). Subjects underwent CGMS (iPro), fasting markers of oxidative stress (GSH/GSSG and TBARS) and an IVGTT at the end of each diet. Independent t-test was used to test the intervention effect on the change in disposition index (DI), a marker of β-cell function. Fifty-two subjects (26M/26F, age 53±10 y, BMI 32.1±6.2 kg/m2) with IFG and/or IGT completed the study (18 LGI, 17 HGI/NAC, 17 HGI/PLAC). The 3 groups did not differ by sex, age, BMI, A1c, fasting or 2 h glucose (ANOVA). On the control diet, DI was inversely correlated with CGMS mean daily glucose (r=-0.33, p=0.02) and daily SD glucose (r=-0.31, p=0.03) and the GSH/GSSG ratio (r=-0.35, p=0.01), but not TBARS (r=0.13, p=0.4). Compared to LGI, HGI/PLAC increased mean CGMS glucose (change -1.4±1.9 LGI vs. 4.6±2.4 HGI/PLAC mg/dl, p=0.05) and SD (change -2.6±1.3 vs. 5.0±2.2, p=0.005). Results did not differ between HGI/PLAC and HGI/NAC. There were no significant intervention effects on DI, TBARS or GSH/GSSG ratio. Changes in CGMS mean glucose and SD and oxidative stress markers did not correlate with changes in DI. In conclusion, GI diet-induced changes in glucose concentrations and variability did not impact β-cell function or oxidative stress markers. These results suggest that glucose variability may be a consequence of β-cell dysfunction rather than a cause. Disclosure K. Utzschneider: Consultant; Self; Novo Nordisk Inc.. T.N. Johnson: None. K. Breymeyer: None. M.L. Neuhouser: None.

BACKGROUND: Three recent meta-analyses found significant prospective inverse associations between chocolate intake and cardiovascular disease risk. Evidence from these meta-analyses suggests that such inverse associations may only apply to elderly individuals or those with pre-existing major chronic disease. OBJECTIVE: We assessed the association between habitual chocolate intake and subsequent incident coronary heart disease (CHD) and stroke, and the potential effect of modification by age. DESIGN: We conducted multivariable Cox regression analyses using data from 83,310 postmenopausal women free of baseline pre-existing major chronic disease in the prospective Women's Health Initiative cohort. Chocolate intake was assessed using a food-frequency questionnaire. Physician-adjudicated events or deaths were ascertained up to 30 September 2013. RESULTS: After exclusions, there were 3246 CHD and 2624 stroke events or deaths, representing incidence rates of 3.9% and 3.2% during 1,098,091 and 1,101,022 person-years (13.4 y), respectively. We found no association between consumption of chocolate and risk of CHD (P for linear trend = 0.94) or stroke (P = 0.24). The results for CHD and stroke combined were similar (P = 0.30), but were significantly modified by age (P for interaction = 0.02). For women age

Background The prevalence of arthritis in the United States is substantial and on the rise. Long-chain n-3 polyunsaturated fatty acids, which have anti-inflammatory properties, have been shown to provide therapeutic benefit to arthritis patients; however, to date few have examined these associations with arthritis risk. Objective The study objective was to examine the associations of long-chain n-3 polyunsaturated fatty acids intake with osteoarthritis (OA) and rheumatoid arthritis (RA) risk among postmenopausal women. Design This was a prospective cohort study. Participants The sample for this analysis consisted of 80,551 postmenopausal women, aged 55 to 79 years and with no history of arthritis, recruited into the Women's Health Initiative Observational Study and Clinical Trials cohort between 1993 and 1998. Women completed a 120-item food frequency questionnaire at baseline. Main outcome measures After a median follow-up of 8 years, 22,306 incident OA and 3,348 RA cases were identified. Statistical analyses performed Adjusted Cox regression models were used to estimate hazard ratios and 95% CI for the associations between dietary LCn-3PUFA intake and OA and RA risk. Results Individual and total long-chain n-3 polyunsaturated fatty acids (Quintile 5 vs Quintile 1: hazard ratio 1.04, 95% CI 0.99 to 1.09 for OA; hazard ratio 1.01, 95% CI 0.90 to 1.13 for RA) were not associated with OA and RA risk. Further, no associations were observed between n-6 polyunsaturated fatty acids intake and either arthritis outcome. Conclusions This study is the first to examine associations of long-chain n-3 polyunsaturated fatty acids intake with OA risk and the largest to examine associations with RA risk. Despite their therapeutic potential, the study provides no evidence of benefit of these nutrients in relation to arthritis risk.

The aim of this study was to investigate the association between BMI (kg/m) and prostate cancer risk. BMI is a modifiable lifestyle factor and may provide a unique opportunity for primary prevention of prostate cancer if a causal association exists. Data from 11 886 men from the Carotene and Retinol Efficacy Trial (CARET, 1985-1996 with active follow-up through 2005) comprising current and former heavy smokers were analyzed. CARET was a multicenter randomized, double-blind placebo-controlled chemoprevention trial testing daily supplementation of 30 mg β-carotene+25 000 IU retinyl palmitate for primary prevention of lung cancer. Prostate cancer was a secondary outcome. Nonaggressive disease was defined as Gleason less than 7 and stage I/II. Aggressive disease was primarily defined as at least Gleason 7 or stage III/IV, and secondarily by excluding Gleason 3+4 from the first definition. BMI was calculated from measured weight and height. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) for cancer incidence between BMI categories. During follow-up, 883 men were diagnosed with prostate cancer. In the analysis of aggressive disease when Gleason 3+4 was excluded, men with a BMI of at least 35 kg/m had an increased rate of prostate cancer (HR: 1.80, 95% CI: 1.04-3.11, Ptrend=0.04) compared with men with BMI 18-24.9 kg/m. No other differences were seen in risk estimates for overall, nonaggressive or aggressive prostate cancer including all Gleason 7 cases, between BMI categories. Our results show an association between having a BMI of at least 35 kg/m and an increased risk of aggressive prostate cancer (not including Gleason 3+4 tumors), but do not support an association between BMI and risk of overall, aggressive disease including all Gleason 7, or nonaggressive prostate cancer within a population of current and former heavy smokers.

Background: Debate, stimulated recently by the Prospective Urban Rural Epidemiology study, concerns the preferred macronutrient dietary composition. Here we provide a comprehensive overview of health outcomes in the Women's Health Initiative Dietary Modification (DM) trial. Methods: The DM trial was a randomized, controlled trial conducted at 40 centres in the USA. 48,835 postmenopausal women, aged 50-79 years, with baseline intake of ≥32% energy from fat were randomly assigned by a computerized, stratified, permuted block algorithm to a low-fat dietary pattern intervention group (40%) or to a usual diet comparison group (60%) during 1993-8. Intervention goals were to reduce fat intake to 20% of total energy and increase vegetables, fruit, and grains. Invasive breast cancer and colorectal cancer were co-primary outcomes, and coronary heart disease was secondary, with other health outcomes also monitored. Findings: After the 8.5-year (mean) intervention period, intervention versus comparison group differences included lower fat by 8-10% of total energy and higher carbohydrate by 8-10% of total energy with increases in vegetables, fruit, and grains. Intervention and comparison group annual incidences were 0.42 and 0.46 (hazard ratio 0.92, 95% CI - 0.84 to 1.01) for invasive breast cancer, and 0.13 and 0.12 (HR, 1.07, 95% CI - 0.92 to 1.27) for colorectal cancer, with overall unchanged CHD incidence and total mortality. During 17.7-years (mean) cumulative follow-up, statistically significant reduction in deaths following breast cancer, diabetes requiring insulin, and CHD among women who were not hypertensive, emerged in intervention group, primarily among participants who were obese at enrollment. Interpretation: In postmenopausal women, reduction in total dietary fat with commensurate increase in carbohydrate did not increase all-cause mortality or have adverse health consequences, while having some health benefits. Clinical Trial Number: This study is registered with clinicaltrials.gov identifier: NCT00000611. Funding Statement: The development of this paper is partially supported by National Cancer Institute grants R01 CA119171 and R01 CA10921. The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts HHSN268201600018C, HHSN268201600001C, HHSN268201600002C, HHSN268201600003C, and HHSN268201600004C, and these sources also partially support the development of this paper. Declaration of Interests: None of the authors report a conflict of interest related to this study. Ethics Approval Statement: Institutional review board approval was obtained at each individual center, and all participants provided written informed consent.

Substantial preclinical data suggest estrogen’s carcinogenic role in prostate cancer development; however, epidemiological evidence based on circulating estrogen levels is largely null. Compared with circulating estrogen, the intraprostatic estrogen milieu may play a more important role in prostate carcinogenesis. Using a nested case–control design in the Prostate Cancer Prevention Trial (PCPT), we examined associations of genetic variants of genes that are involved in estrogen synthesis, metabolism and function with prostate cancer risk. A total of 25 potentially functional single nucleotide polymorphisms (SNPs) in 13 genes (PGR, ESR1, ESR2, CYP17A1, HSD17B1, CYP19A1, CYP1A1, CYP1B1, COMT, UGT1A6, UGT1A10, UGT2B7, UGT2B15) were examined in whites only. Controls (n = 1380) were frequency matched to cases on age, PCPT treatment arm, and family history (n = 1506). Logistic regression models adjusted for age and family history were used to estimate odds ratios (OR) and 95% confidence intervals (CI) separately in the placebo and finasteride arms. SNPs associated with prostate cancer risk differed by treatment arm. The associations appeared to be modified by circulating estrogen and androgen levels. CYP19A1 was the only gene harboring SNPs that were significantly associated with risk in both the placebo and finasteride arms. Haplotype analysis with all three CYP19A1 SNPs genotyped (rs700518, rs2445765, rs700519) showed that risk-allele haplotypes are associated with the increased prostate cancer risk in both arms when comparing with the non-risk allele haplotype. In conclusion, associations between SNPs in estrogen-related genes and prostate cancer risk are complex and may be modified by circulating hormone levels and finasteride treatment.