Publications by authors named "Thomas E Rohan"

302 Publications

Low-fat dietary pattern and breast cancer mortality by metabolic syndrome components: a secondary analysis of the Women's Health Initiative (WHI) randomised trial.

Br J Cancer 2021 May 18. Epub 2021 May 18.

Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA.

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).
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http://dx.doi.org/10.1038/s41416-021-01379-wDOI Listing
May 2021

Relation of Quantitative Histologic and Radiologic Breast Tissue Composition Metrics With Invasive Breast Cancer Risk.

JNCI Cancer Spectr 2021 Jun 6;5(3):pkab015. Epub 2021 Feb 6.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institute of Health, USA.

Background: Benign breast disease (BBD) is a strong breast cancer risk factor, but identifying patients that might develop invasive breast cancer remains a challenge.

Methods: By applying machine-learning to digitized hematoxylin and eosin-stained biopsies and computer-assisted thresholding to mammograms obtained circa BBD diagnosis, we generated quantitative tissue composition metrics and determined their association with future invasive breast cancer diagnosis. Archival breast biopsies and mammograms were obtained for women (18-86 years of age) in a case-control study, nested within a cohort of 15 395 BBD patients from Kaiser Permanente Northwest (1970-2012), followed through mid-2015. Patients who developed incident invasive breast cancer (ie, cases; n = 514) and those who did not (ie, controls; n = 514) were matched on BBD diagnosis age and plan membership duration. All statistical tests were 2-sided.

Results: Increasing epithelial area on the BBD biopsy was associated with increasing breast cancer risk (odds ratio [OR] = 1.85, 95% confidence interval [CI] = 1.13 to 3.04; = .02). Conversely, increasing stroma was associated with decreased risk in nonproliferative, but not proliferative, BBD ( = .002). Increasing epithelium-to-stroma proportion (OR = 2.06, 95% CI =1.28 to 3.33; = .002) and percent mammographic density (MBD) (OR = 2.20, 95% CI = 1.20 to 4.03; = .01) were independently and strongly predictive of increased breast cancer risk. In combination, women with high epithelium-to-stroma proportion and high MBD had substantially higher risk than those with low epithelium-to-stroma proportion and low MBD (OR = 2.27, 95% CI = 1.27 to 4.06; = .005), particularly among women with nonproliferative ( = .01) vs proliferative ( = .33) BBD.

Conclusion: Among BBD patients, increasing epithelium-to-stroma proportion on BBD biopsies and percent MBD at BBD diagnosis were independently and jointly associated with increasing breast cancer risk. These findings were particularly striking for women with nonproliferative disease (comprising approximately 70% of all BBD patients), for whom relevant predictive biomarkers are lacking.
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http://dx.doi.org/10.1093/jncics/pkab015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8103888PMC
June 2021

Dairy foods, calcium, and risk of breast cancer overall and for subtypes defined by estrogen receptor status: a pooled analysis of 21 cohort studies.

Am J Clin Nutr 2021 May 8. Epub 2021 May 8.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, MD, USA.

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 <1 g/d of yogurt and 0.85, 95% CI: 0.76, 0.95 comparing ≥25 g/d with <1 g/d of cottage/ricotta cheese). Dietary calcium intake was only weakly associated with breast cancer risk (pooled HR = 0.98, 95% CI: 0.97, 0.99 per 350 mg/d).

Conclusion: Our study shows that adult dairy or calcium consumption is unlikely to associate with a higher risk of breast cancer and that higher yogurt and cottage/ricotta cheese intakes were inversely associated with the risk of ER-negative breast cancer, a less hormonally dependent subtype with poor prognosis. Future studies on fermented dairy products, earlier life exposures, ER-negative breast cancer, and different racial/ethnic populations may further elucidate the relation.
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http://dx.doi.org/10.1093/ajcn/nqab097DOI Listing
May 2021

Circulating Levels of Testosterone, Sex Hormone Binding Globulin and Colorectal Cancer Risk: Observational and Mendelian Randomization Analyses.

Cancer Epidemiol Biomarkers Prev 2021 Apr 20. Epub 2021 Apr 20.

Section of Nutrition and Metabolism, International Agency for Research on Cancer, Lyon, France.

Background: Epidemiologic studies evaluating associations between sex steroid hormones and colorectal cancer risk have yielded inconsistent results. To elucidate the role of circulating levels of testosterone, and sex hormone-binding globulin (SHBG) in colorectal cancer risk, we conducted observational and Mendelian randomization (MR) analyses.

Methods: The observational analyses included 333,530 participants enrolled in the UK Biobank with testosterone and SHBG measured. HRs and 95% confidence intervals (CI) were estimated using multivariable Cox proportional hazards models. For MR analyses, genetic variants robustly associated with hormone levels were identified and their association with colorectal cancer (42,866 cases/42,752 controls) was examined using two-sample MR.

Results: In the observational analysis, there was little evidence that circulating levels of total testosterone were associated with colorectal cancer risk; the MR analyses showed a greater risk for women (OR per 1-SD = 1.09; 95% CI, 1.01-1.17), although pleiotropy may have biased this result. Higher SHBG concentrations were associated with greater colorectal cancer risk for women (HR per 1-SD = 1.16; 95% CI, 1.05-1.29), but was unsupported by the MR analysis. There was little evidence of associations between free testosterone and colorectal cancer in observational and MR analyses.

Conclusions: Circulating concentrations of sex hormones are unlikely to be causally associated with colorectal cancer. Additional experimental studies are required to better understand the possible role of androgens in colorectal cancer development.

Impact: Our results from large-scale analyses provide little evidence for sex hormone pathways playing a causal role in colorectal cancer development.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-1690DOI Listing
April 2021

Risk factors for breast cancer development by tumor characteristics among women with benign breast disease.

Breast Cancer Res 2021 Mar 18;23(1):34. Epub 2021 Mar 18.

Albert Einstein College of Medicine, Jack and Pearl Resnick Campus, 1300 Morris Park Avenue, Belfer Building, Room 1301, Bronx, NY, 10461, USA.

Background: Among women diagnosed with invasive breast cancer, 30% have a prior diagnosis of benign breast disease (BBD). Thus, it is important to identify factors among BBD patients that elevate invasive cancer risk. In the general population, risk factors differ in their associations by clinical pathologic features; however, whether women with BBD show etiologic heterogeneity in the types of breast cancers they develop remains unknown.

Methods: Using a nested case-control study of BBD and breast cancer risk conducted in a community healthcare plan (Kaiser Permanente Northwest), we assessed relationships of histologic features in BBD biopsies and patient characteristics with subsequent breast cancer risk and tested for heterogeneity of associations by estrogen receptor (ER) status, tumor grade, and size. The study included 514 invasive breast cancer cases (median follow-up of 9 years post-BBD diagnosis) and 514 matched controls, diagnosed with proliferative or non-proliferative BBD between 1971 and 2006, with follow-up through mid-2015. Odds ratios (ORs) and 95% confidence intervals (CIs) were obtained using multivariable polytomous logistic regression models.

Results: Breast cancers were predominantly ER-positive (86%), well or moderately differentiated (73%), small (74% < 20 mm), and stage I/II (91%). Compared to patients with non-proliferative BBD, proliferative BBD with atypia conferred increased risk for ER-positive cancer (OR = 5.48, 95% CI = 2.14-14.01) with only one ER-negative case, P-heterogeneity = 0.45. The presence of columnar cell lesions (CCLs) at BBD diagnosis was associated with a 1.5-fold increase in the risk of both ER-positive and ER-negative tumors, with a 2-fold increase (95% CI = 1.21-3.58) observed among postmenopausal women (56%), independent of proliferative BBD status with and without atypia. We did not identify statistically significant differences in risk factor associations by tumor grade or size.

Conclusion: Most tumors that developed after a BBD diagnosis in this cohort were highly treatable low-stage ER-positive tumors. CCL in BBD biopsies may be associated with moderately increased risk, independent of BBD histology, and irrespective of ER status.
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http://dx.doi.org/10.1186/s13058-021-01410-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7977564PMC
March 2021

The association of body fat composition with risk of breast, endometrial, ovarian and colorectal cancers among normal weight participants in the UK Biobank.

Br J Cancer 2021 Apr 15;124(9):1592-1605. Epub 2021 Mar 15.

Albert Einstein College of Medicine, Bronx, NY, USA.

Background: The association between body fat composition and risk of cancer in normal weight individuals (body mass index (BMI) 18.5-24.9 kg/m) is unclear.

Methods: We examined the association of measures of adiposity with risk of incident cancers of the breast (postmenopausal), endometrium, ovary and colon/rectum among 149,928 normal weight individuals (40-70 years) who were enrolled in the UK Biobank cohort between 2006 and 2010.

Results: All of the body fat measures were positively associated with invasive postmenopausal breast cancer risk (hazard ratios (HR) for the uppermost quintile (Q5) versus the lowest quintile (Q1) ranged from 1.32 (95% CI: 1.09-1.60) for waist circumference (WC) to 1.56 (1.28-1.90) for BMI). Trunk fat mass index (HR: 1.72, 95% CI: 1.02-2.89) and WC (HR: 1.65, 95% CI: 1.01-2.70)) were positively associated with risk of endometrial cancer. Among males, trunk fat:trunk fat free mass ratio, trunk fat:leg fat mass ratio and (HR: 1.63, 95% CI: 1.02-2.60; 1.92, 1.20-3.07 and 1.68, 1.05-2.66, respectively) were positively associated with colon cancer risk. None of the body fat measures was associated with risk of ovarian cancer or colorectal cancer in women.

Conclusion: The findings of this study suggest that the current normal weight category based on BMI includes individuals who are at increased risk of some obesity-related cancers.
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http://dx.doi.org/10.1038/s41416-020-01210-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8076175PMC
April 2021

Sex Hormones, Insulin, and Insulin-like Growth Factors in Recurrence of High-Stage Endometrial Cancer.

Cancer Epidemiol Biomarkers Prev 2021 Apr 23;30(4):719-726. Epub 2021 Feb 23.

Section of Nutrition and Metabolism, International Agency for Research on Cancer, Lyon, France.

Background: The influence of sex hormone and insulin/insulin-like growth factor (IGF) axis signaling on endometrial cancer recurrence is unknown. We evaluated these pathways in a prospective cohort of Gynecologic Oncology Group (GOG)0210 trial endometrial adenocarcinoma patients.

Methods: Stage II-IV patients ( = 816) were included in this study. Pretreatment specimens were tested for tumor mRNA and protein expression of , IGF-binding proteins () and , insulin (IR) and IGF-I receptors (IGF1R), phosphorylated IR/IGF1R (pIGF1R/pIR), and estrogen (ER) and progesterone receptors (PR) using qPCR and IHC. Serum concentrations of insulin, IGF-I, IGFBP-3, estradiol, estrone, and sex hormone binding globulin were measured. HRs and 95% confidence intervals (CI) for progression-free survival were calculated from Cox models adjusting for age, stage, and grade.

Results: Recurrence occurred in 280 (34%) cases during a median of 4.6 years of follow-up. ER positivity (HR, 0.67; 95% CI, 0.47-0.95), IR positivity (HR, 0.53; 95% CI, 0.29-0.98), and circulating IGF-I (highest vs. lowest quartile: HR, 0.66; 95% CI, 0.47-0.92) were inversely associated with recurrence risk. Circulating estradiol (highest vs. lowest tertile: HR, 1.55; 95% CI, 1.02-2.36) and pIGF1R/pIR positivity (HR, 1.40; 95% CI, 1.02-1.92) were associated with increased recurrence risk.

Conclusions: Circulating estradiol and tumor tissue phosphorylated (activated) IGR1R/IR were independently associated with higher risk of recurrence in patients with endometrial cancer.

Impact: This study may inform future clinical trials of endocrine-targeted adjuvant therapies in patients with endometrial cancer that could include baseline assessment of serum and tissue biomarkers of estradiol and insulin signaling pathways.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-1613DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026669PMC
April 2021

The association of prediagnostic circulating levels of cardiometabolic markers, testosterone and sex hormone-binding globulin with risk of breast cancer among normal weight postmenopausal women in the UK Biobank.

Int J Cancer 2021 Jul 24;149(1):42-57. Epub 2021 Feb 24.

Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, New York, USA.

Emerging evidence suggests that normal weight postmenopausal women with a relative excess of body fat are at increased breast cancer risk. However, little is known about the associations between obesity-related blood markers and risk of breast cancer among these individuals. In this prospective study comprising 58 629 normal weight postmenopausal women (body mass index between 18.5 kg/m and 24.9 kg/m ) who were enrolled in the UK Biobank cohort between 2006 and 2010, we examined the associations of glycated hemoglobin, triglycerides, high-density lipoprotein cholesterol, C-reactive protein (CRP), testosterone and sex hormone-binding globulin (SHBG) with risk of breast cancer. A total of 1268 postmenopausal breast cancer cases were ascertained during a median follow-up period of 7 years. Women with CRP, total testosterone and free testosterone (FT) levels in the highest quintile had increased risk of breast cancer compared to those in the lowest quintile (HR : 1.35, 95% confidence interval [CI]: 1.12-1.63, HR : 1.47, 95% CI: 1.20-1.80 and HR : 1.53, 95% CI: 1.23-1.90, respectively), whereas those with SHBG in the highest quintile had reduced risk (HR : 0.70, 95% CI: 0.56-0.88). These associations were attenuated but persisted after additional adjustment for BMI, fat mass index (whole body fat mass [kg]/height [m ]) or waist circumference and after mutual adjustment for testosterone, CRP and/or SHBG. Our study suggests that the risk of postmenopausal breast cancer among normal weight women is increased in association with relatively high levels of CRP and testosterone and with relatively low levels of SHBG.
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http://dx.doi.org/10.1002/ijc.33508DOI Listing
July 2021

Cancer Risk in Normal Weight Individuals with Metabolic Obesity: A Narrative Review.

Cancer Prev Res (Phila) 2021 May 9;14(5):509-520. Epub 2021 Feb 9.

Weill Cornell Medicine, New York, New York.

Obesity represents one of the most significant public health challenges worldwide. Current clinical practice relies on body mass index (BMI) to define the obesity status of an individual, even though the index has long been recognized for its limitations as a measure of body fat. In normal BMI individuals, increased central adiposity has been associated with worse health outcomes, including increased risks of cardiovascular disease and metabolic disorders. The condition leading to these outcomes has been described as metabolic obesity in the normal weight (MONW). More recent evidence suggests that MONW is associated with increased risk of several obesity-related malignancies, including postmenopausal breast, endometrial, colorectal, and liver cancers. In MONW patients, the false reassurance of a normal range BMI can lead to lost opportunities for implementing preventive interventions that may benefit a substantial number of people. A growing body of literature has documented the increased risk profile of MONW individuals and demonstrated practical uses for body composition and biochemical analyses to identify this at-risk population. In this review, we survey the current literature on MONW and cancer, summarize pathophysiology and oncogenic mechanisms, highlight potential strategies for diagnosis and treatment, and suggest directions for future research.
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http://dx.doi.org/10.1158/1940-6207.CAPR-20-0633DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8102335PMC
May 2021

Infiltrating immune cells in benign breast disease and risk of subsequent invasive breast cancer.

Breast Cancer Res 2021 Jan 30;23(1):15. Epub 2021 Jan 30.

Division of Research, Peter MacCallum Cancer Centre, Melbourne, Australia.

Background: It is well established that tumors are antigenic and can induce an immune response by the host, entailing lymphocytic infiltration of the tumor and surrounding stroma. The extent and composition of the immune response to the tumor, assessed through evaluation of tumor-infiltrating lymphocyte counts, has been shown in many studies to have prognostic and predictive value for invasive breast cancer, but currently, there is little evidence regarding the association between infiltrating immune cell counts (IICCs) in women with benign breast disease (BBD) and risk of subsequent invasive breast cancer.

Methods: Using a cohort of 15,395 women biopsied for BBD at Kaiser Permanente Northwest, we conducted a nested case-control study in which cases were women who developed a subsequent invasive breast cancer during follow-up and controls were individually matched to cases on age at BBD diagnosis. We assessed IICCs in normal tissue and in the BBD lesions, and we used unconditional logistic regression to estimate the multivariable odds ratios (OR) and 95% confidence intervals (CI) for the associations between IICCs and breast cancer risk.

Results: There was no association between the IICC in normal tissue (multivariable OR per 5% increase in IICC = 1.05, 95% CI = 0.96-1.16) or in the BBD lesion (OR per 5% increase in IICC = 1.06, 95% CI = 0.96-1.18) and risk of subsequent invasive breast cancer. Also, there were no associations within subgroups defined by menopausal status, BBD histology, BMI, and history of smoking.

Conclusion: The results of this study suggest that IICCs in BBD tissue are not associated with altered risk of subsequent invasive breast cancer.
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http://dx.doi.org/10.1186/s13058-021-01395-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7846992PMC
January 2021

Association of Oily and Nonoily Fish Consumption and Fish Oil Supplements With Incident Type 2 Diabetes: A Large Population-Based Prospective Study.

Diabetes Care 2021 Mar 11;44(3):672-680. Epub 2021 Jan 11.

Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY

Objective: To evaluate associations of oily and nonoily fish consumption and fish oil supplements with incident type 2 diabetes (T2D).

Research Design And Methods: We included 392,287 middle-aged and older participants (55.0% women) in the UK Biobank who were free of diabetes, major cardiovascular disease, and cancer and had information on habitual intake of major food groups and use of fish oil supplements at baseline (2006-2010). Of these, 163,706 participated in one to five rounds of 24-h dietary recalls during 2009-2012.

Results: During a median 10.1 years of follow-up, 7,262 incident cases of T2D were identified. Compared with participants who reported never consumption of oily fish, the multivariable-adjusted hazard ratios of T2D were 0.84 (95% CI 0.78-0.91), 0.78 (0.72-0.85), and 0.78 (0.71-0.86) for those who reported <1 serving/week, weekly, and ≥2 servings/week of oily fish consumption, respectively (-trend < 0.001). Consumption of nonoily fish was not associated with risk of T2D (-trend = 0.45). Participants who reported regular fish oil use at baseline had a 9% (95% CI 4-14%) lower risk of T2D compared with nonusers. Baseline regular users of fish oil who also reported fish oil use during at least one of the 24-h dietary recalls had an 18% (8-27%) lower risk of T2D compared with constant nonusers.

Conclusions: Our findings suggest that consumption of oily fish but not nonoily fish was associated with a lower risk of T2D. Use of fish oil supplements, especially constant use over time, was also associated with a lower risk of T2D.
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http://dx.doi.org/10.2337/dc20-2328DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7896269PMC
March 2021

Protein Intake by Source and Breast Cancer Incidence and Mortality: The Women's Health Initiative.

JNCI Cancer Spectr 2020 Dec 7;4(6):pkaa101. Epub 2020 Nov 7.

Lundquist Institute for Biomedical Innovation at Harbor, UCLA Medical Center, Torrance, CA, USA.

Background: Prior studies of dietary protein intake and breast cancer have been mixed and were limited by dietary self-report measurement error.

Methods: Biomarker-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.

Results: After 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, = .006) and statistically significantly lower risk of death after breast cancer (HR = 0.93, 95% CI = 0.91 to 0.97 < .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, = .02) but not with deaths from or after breast cancer.

Conclusions: Calibrated 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.
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http://dx.doi.org/10.1093/jncics/pkaa101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7768926PMC
December 2020

Hysterectomy, Oophorectomy, and Risk of Renal Cell Carcinoma.

Cancer Epidemiol Biomarkers Prev 2021 Mar 17;30(3):499-506. Epub 2020 Dec 17.

Department of Environmental and Occupational Health, School of Public Health, Indiana University, Bloomington, Indiana.

Background: Female hormones may play roles during renal cell carcinoma (RCC) carcinogenesis. The aims of this study were to investigate associations between hysterectomy, oophorectomy, and risk of RCC and to assess whether the associations were modified by exogenous estrogen, commonly used among women who have undergone hysterectomy.

Methods: Postmenopausal women ( = 144,599) ages 50-79 years at enrollment (1993-1998) in the Women's Health Initiative were followed for a mean of 15.9 years. Hysterectomy and oophorectomy were self-reported. Incident RCC cases were confirmed by physician review of medical records and pathology reports. Multivariable Cox proportional hazards modeling was used to estimate hazard ratios (HR) and 95% confidence intervals (CI), adjusting for potential confounders.

Results: A total of 583 women developed RCC during follow-up. We observed that hysterectomy, regardless of oophorectomy status, was significantly associated with an increased risk of RCC (HR, 1.28; 95% CI, 1.03-1.60). The association appeared to be more pronounced in women with age at hysterectomy younger than 40 years (HR, 1.34; 95% CI, 1.01-1.80) or older than 55 years (HR, 1.52; 95% CI, 1.01-2.29). Oophorectomy was not significantly associated with risk of RCC. There was no evidence that exogenous estrogen use modified the association between hysterectomy and risk of RCC.

Conclusions: In this large prospective study, we showed that women with a history of hysterectomy had 28% increased risk of RCC, and this finding was not modified by exogenous hormone use.

Impact: If our findings are confirmed, women should be made aware of increased risk of RCC when considering hysterectomy.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-1373DOI Listing
March 2021

Alignment of Dietary Patterns With the Dietary Guidelines for Americans 2015-2020 and Risk of All-Cause and Cause-Specific Mortality in the Women's Health Initiative Observational Study.

Am J Epidemiol 2021 05;190(5):886-892

Poor diet quality is a leading risk factor for death in the United States. We examined the association between Healthy Eating Index-2015 (HEI-2015) scores and death from all causes, cardiovascular disease (CVD), cancer, Alzheimer disease, and dementia not otherwise specified (NOS) among postmenopausal women in the Women's Health Initiative Observational Study (1993-2017). This analysis included 59,388 participants who completed a food frequency questionnaire and were free of cancer, CVD, and diabetes at enrollment. Stratified Cox proportional hazards models were fit using person-years from enrollment as the underlying time metric. We estimated multivariable adjusted hazard ratios and 95% confidence intervals for risk of death associated with HEI-2015 quintiles, with higher scores reflecting more optimal diet quality. Over a median of 18.2 years, 9,679 total deaths 3,303 cancer deaths, 2,362 CVD deaths, and 488 deaths from Alzheimer disease and dementia NOS occurred. Compared with those with lower scores, women with higher HEI-2015 scores had an 18% lower risk of all-cause death and 21% lower risk of cancer death. HEI-2015 scores were not associated with death due to CVD, Alzheimer disease, and dementia NOS. Consuming a diet aligned with 2015-2020 US dietary guidelines may have beneficial impacts for preventing overall causes of death and death from cancer.
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http://dx.doi.org/10.1093/aje/kwaa268DOI Listing
May 2021

Sugar-containing beverages and their association with risk of breast, endometrial, ovarian and colorectal cancers among Canadian women.

Cancer Epidemiol 2021 02 18;70:101855. Epub 2020 Nov 18.

Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, 10461, United States.

Background: The association of sugar containing beverages (SCBs) with risk of breast, endometrial, ovarian and colorectal cancers is unclear. Therefore, we investigated these associations in the Canadian Study of Diet, Lifestyle, and Health.

Methods: The study population comprised an age-stratified subcohort of 3185 women and 848, 161, 91 and 243 breast, endometrial, ovarian and colorectal cancer cases, respectively. We used Cox proportional hazards regression models modified for the case-cohort design to assess the associations of SCBs with risk of the aforementioned cancers.

Results: Compared to SCB intake in the lowest tertile, SCB intake in the highest tertile was positively associated with endometrial cancer risk (HR = 1.58, 95 % CI = 1.08-2.33 and 1.78, 95 % CI = 1.12-2.81 for overall and Type 1 endometrial cancer, respectively) and ovarian cancer (HR = 1.76, 95 % CI: 1.09-2.83). Fruit juice intake was also positively associated with risk of Type 1endometrial (HR = 1.63, 95 % CI = 1.03-2.60). After excluding women with diabetes or cardiovascular diseases, we also observed sugar-sweetened beverages (SSBs) intake in the highest tertile was associated with higher risk of Type 1 endometrial cancer (HR = 1.65; 95 % CI: 1.03-2.64). None of the beverages was associated with risk of breast or colorectal cancer.

Conclusion: We conclude that, in this cohort, relatively high SCB intake was associated with higher risk of endometrial and ovarian cancers, but not of breast or colorectal cancers. Our findings also suggest that relatively high SSB and fruit juice intake are associated with higher risk of Type 1 endometrial cancer.
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http://dx.doi.org/10.1016/j.canep.2020.101855DOI Listing
February 2021

Body size and weight change over adulthood and risk of breast cancer by menopausal and hormone receptor status: a pooled analysis of 20 prospective cohort studies.

Eur J Epidemiol 2021 Jan 30;36(1):37-55. Epub 2020 Oct 30.

Epidemiology and Prevention Group, Research Center for Cancer Prevention and Screening, National Cancer Center, Tokyo, Japan.

Associations between anthropometric factors and breast cancer (BC) risk have varied inconsistently by estrogen and/or progesterone receptor (ER/PR) status. Associations between prediagnostic anthropometric factors and risk of premenopausal and postmenopausal BC overall and ER/PR status subtypes were investigated in a pooled analysis of 20 prospective cohorts, including 36,297 BC cases among 1,061,915 women, using multivariable Cox regression analyses, controlling for reproductive factors, diet and other risk factors. We estimated dose-response relationships and tested for nonlinear associations using restricted cubic splines. Height showed positive, linear associations for premenopausal and postmenopausal BC risk (6-7% RR increase per 5 cm increment), with stronger associations for receptor-positive subtypes. Body mass index (BMI) at cohort baseline was strongly inversely associated with premenopausal BC risk, and strongly positively-and nonlinearly-associated with postmenopausal BC (especially among women who never used hormone replacement therapy). This was primarily observed for receptor-positive subtypes. Early adult BMI (at 18-20 years) showed inverse, linear associations for premenopausal and postmenopausal BC risk (21% and 11% RR decrease per 5 kg/m, respectively) with stronger associations for receptor-negative subtypes. Adult weight gain since 18-20 years was positively associated with postmenopausal BC risk, stronger for receptor-positive subtypes, and among women who were leaner in early adulthood. Women heavier in early adulthood generally had reduced premenopausal BC risk, independent of later weight gain. Positive associations between height, baseline (adult) BMI, adult weight gain and postmenopausal BC risk were substantially stronger for hormone receptor-positive versus negative subtypes. Premenopausal BC risk was positively associated with height, but inversely with baseline BMI and weight gain (mostly in receptor-positive subtypes). Inverse associations with early adult BMI seemed stronger in receptor-negative subtypes of premenopausal and postmenopausal BC.
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http://dx.doi.org/10.1007/s10654-020-00688-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7847460PMC
January 2021

Pregnancy outcomes and risk of endometrial cancer: A pooled analysis of individual participant data in the Epidemiology of Endometrial Cancer Consortium.

Int J Cancer 2021 May 17;148(9):2068-2078. Epub 2020 Nov 17.

Department of Clinical and Biological Sciences, University of Turin, Orbassano, Italy.

A full-term pregnancy is associated with reduced endometrial cancer risk; however, whether the effect of additional pregnancies is independent of age at last pregnancy is unknown. The associations between other pregnancy-related factors and endometrial cancer risk are less clear. We pooled individual participant data from 11 cohort and 19 case-control studies participating in the Epidemiology of Endometrial Cancer Consortium (E2C2) including 16 986 women with endometrial cancer and 39 538 control women. We used one- and two-stage meta-analytic approaches to estimate pooled odds ratios (ORs) for the association between exposures and endometrial cancer risk. Ever having a full-term pregnancy was associated with a 41% reduction in risk of endometrial cancer compared to never having a full-term pregnancy (OR = 0.59, 95% confidence interval [CI] 0.56-0.63). The risk reduction appeared the greatest for the first full-term pregnancy (OR = 0.78, 95% CI 0.72-0.84), with a further ~15% reduction per pregnancy up to eight pregnancies (OR = 0.20, 95% CI 0.14-0.28) that was independent of age at last full-term pregnancy. Incomplete pregnancy was also associated with decreased endometrial cancer risk (7%-9% reduction per pregnancy). Twin births appeared to have the same effect as singleton pregnancies. Our pooled analysis shows that, while the magnitude of the risk reduction is greater for a full-term pregnancy than an incomplete pregnancy, each additional pregnancy is associated with further reduction in endometrial cancer risk, independent of age at last full-term pregnancy. These results suggest that the very high progesterone level in the last trimester of pregnancy is not the sole explanation for the protective effect of pregnancy.
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http://dx.doi.org/10.1002/ijc.33360DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7969437PMC
May 2021

Sex hormones, SHBG and risk of colon and rectal cancer among men and women in the UK Biobank.

Cancer Epidemiol 2020 12 7;69:101831. Epub 2020 Oct 7.

Albert Einstein College of Medicine, Bronx, NY, United States.

Background: Experimental studies have suggested a role for sex hormones in the etiology of colorectal cancer (CRC) but epidemiological data are inconclusive.

Methods: We examined the associations of testosterone, estradiol, and sex hormone binding globulin (SHBG), with risk of CRC (n = 3,247) in 206,508 men and 219,106 women enrolled in the UK Biobank. Participants were followed for a median of 7.1 years. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95 % confidence intervals (CIs) for CRC risk.

Results: In men, in multivariable adjusted models testosterone and SHBG were not associated with CRC. Among men in the highest tertile of physical activity, SHBG was inversely associated with risk (HRvs 0.75, 0.56-0.99,). In women, testosterone and SHBG were not associated with CRC risk. There were no differences in the associations between testosterone, SHBG and CRC risk in the analyses stratified by menopausal status. We did not observe an association between estradiol and CRC risk; however, given the limited number of individuals with detectable values of estradiol (13.2 % of the total sample) we are unable to draw a firm conclusions regarding this association.

Conclusion: The results of this study did not provide support for associations of sex hormones and SHBG with CRC risk.
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http://dx.doi.org/10.1016/j.canep.2020.101831DOI Listing
December 2020

Recommended Definitions of Aggressive Prostate Cancer for Etiologic Epidemiologic Research.

J Natl Cancer Inst 2021 Jun;113(6):727-734

Behavioral and Epidemiology Research Group, American Cancer Society, Atlanta, GA, USA.

Background: In the era of widespread prostate-specific antigen testing, it is important to focus etiologic research on the outcome of aggressive prostate cancer, but studies have defined this outcome differently. We aimed to develop an evidence-based consensus definition of aggressive prostate cancer using clinical features at diagnosis for etiologic epidemiologic research.

Methods: Among prostate cancer cases diagnosed in 2007 in the National Cancer Institute's Surveillance, Epidemiology, and End Results-18 database with follow-up through 2017, we compared the performance of categorizations of aggressive prostate cancer in discriminating fatal prostate cancer within 10 years of diagnosis, placing the most emphasis on sensitivity and positive predictive value (PPV).

Results: In our case population (n = 55 900), 3073 men died of prostate cancer within 10 years. Among 12 definitions that included TNM staging and Gleason score, sensitivities ranged from 0.64 to 0.89 and PPVs ranged from 0.09 to 0.23. We propose defining aggressive prostate cancer as diagnosis of category T4 or N1 or M1 or Gleason score of 8 or greater prostate cancer, because this definition had one of the higher PPVs (0.23, 95% confidence interval = 0.22 to 0.24) and reasonable sensitivity (0.66, 95% confidence interval = 0.64 to 0.67) for prostate cancer death within 10 years. Results were similar across sensitivity analyses.

Conclusions: We recommend that etiologic epidemiologic studies of prostate cancer report results for this definition of aggressive prostate cancer. We also recommend that studies separately report results for advanced category (T4 or N1 or M1), high-grade (Gleason score ≥8), and fatal prostate cancer. Use of this comprehensive set of endpoints will facilitate comparison of results from different studies and help elucidate prostate cancer etiology.
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http://dx.doi.org/10.1093/jnci/djaa154DOI Listing
June 2021

Association of Menopausal Hormone Therapy With Breast Cancer Incidence and Mortality During Long-term Follow-up of the Women's Health Initiative Randomized Clinical Trials.

JAMA 2020 07;324(4):369-380

Fred Hutchinson Cancer Research Center, Division of Public Health Sciences, Seattle, Washington.

Importance: The influence of menopausal hormone therapy on breast cancer remains unsettled with discordant findings from observational studies and randomized clinical trials.

Objective: To assess the association of prior randomized use of estrogen plus progestin or prior randomized use of estrogen alone with breast cancer incidence and mortality in the Women's Health Initiative clinical trials.

Design, Setting, And Participants: Long-term follow-up of 2 placebo-controlled randomized clinical trials that involved 27 347 postmenopausal women aged 50 through 79 years with no prior breast cancer and negative baseline screening mammogram. Women were enrolled at 40 US centers from 1993 to 1998 with follow-up through December 31, 2017.

Interventions: In the trial involving 16 608 women with a uterus, 8506 were randomized to receive 0.625 mg/d of conjugated equine estrogen (CEE) plus 2.5 mg/d of medroxyprogesterone acetate (MPA) and 8102, placebo. In the trial involving 10 739 women with prior hysterectomy, 5310 were randomized to receive 0.625 mg/d of CEE alone and 5429, placebo. The CEE-plus-MPA trial was stopped in 2002 after 5.6 years' median intervention duration, and the CEE-only trial was stopped in 2004 after 7.2 years' median intervention duration.

Main Outcomes And Measures: The primary outcome was breast cancer incidence (protocol prespecified primary monitoring outcome for harm) and secondary outcomes were deaths from breast cancer and deaths after breast cancer.

Results: Among 27 347 postmenopausal women who were randomized in both trials (baseline mean [SD] age, 63.4 years [7.2 years]), after more than 20 years of median cumulative follow-up, mortality information was available for more than 98%. CEE alone compared with placebo among 10 739 women with a prior hysterectomy was associated with statistically significantly lower breast cancer incidence with 238 cases (annualized rate, 0.30%) vs 296 cases (annualized rate, 0.37%; hazard ratio [HR], 0.78; 95% CI, 0.65-0.93; P = .005) and was associated with statistically significantly lower breast cancer mortality with 30 deaths (annualized mortality rate, 0.031%) vs 46 deaths (annualized mortality rate, 0.046%; HR, 0.60; 95% CI, 0.37-0.97; P = .04). In contrast, CEE plus MPA compared with placebo among 16 608 women with a uterus was associated with statistically significantly higher breast cancer incidence with 584 cases (annualized rate, 0.45%) vs 447 cases (annualized rate, 0.36%; HR, 1.28; 95% CI, 1.13-1.45; P < .001) and no significant difference in breast cancer mortality with 71 deaths (annualized mortality rate, 0.045%) vs 53 deaths (annualized mortality rate, 0.035%; HR, 1.35; 95% CI, 0.94-1.95; P= .11).

Conclusions And Relevance: In this long-term follow-up study of 2 randomized trials, prior randomized use of CEE alone, compared with placebo, among women who had a previous hysterectomy, was significantly associated with lower breast cancer incidence and lower breast cancer mortality, whereas prior randomized use of CEE plus MPA, compared with placebo, among women who had an intact uterus, was significantly associated with a higher breast cancer incidence but no significant difference in breast cancer mortality.
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http://dx.doi.org/10.1001/jama.2020.9482DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7388026PMC
July 2020

Risk of Breast Cancer Associated with Estrogen DNA Adduct Biomarker.

Cancer Epidemiol Biomarkers Prev 2020 10 22;29(10):2096-2099. Epub 2020 Jul 22.

Fred Hutch Cancer Research Center Public Health Sciences, Seattle, Washington.

Background: It is biologically plausible that genotoxic estrogens, namely estrogen DNA adducts (EDA), have a role in breast cancer development. Support comes from three prior studies that reported elevated concentrations of EDA relative to estrogen metabolites and conjugates (EDA:EMC) in women with breast cancer relative to control women.

Methods: In postmenopausal women in the Women's Health Initiative (WHI), EDA:EMC in 191 controls was compared with findings in 194 prediagnosis urine samples from breast cancer cases. EDA:EMC determinations were by mass spectrometry as previously described, and logistic regression was employed to estimate ORs.

Results: EDA:EMC did not differ in breast cancer cases compared with controls overall [0.93 (95% confidence interval, 0.71-1.23)], with a mean (SD) of 2.3 (0.8) and 2.4 (1.1) in cases and controls, respectively. Similarly, the ratio did not differ when examined by estrogen receptor or recency of biospecimen collection prior to breast cancer.

Conclusions: Despite the demonstrated genotoxic properties of certain catechol estrogens resulting in EDAs, this analysis did not provide evidence for an increased breast cancer risk in relation to an elevated EDA:EMC.

Impact: This analysis, conducted prospectively within postmenopausal women in the WHI study, suggests that a strong association between EDA:EMC and breast cancer could be ruled out, as this study was powered to detect an OR of 2.2 or greater.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-0133DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7541674PMC
October 2020

Association of Sex Hormones with Risk of Cancers of the Pancreas, Kidney, and Brain in the UK Biobank Cohort Study.

Cancer Epidemiol Biomarkers Prev 2020 09 24;29(9):1832-1836. Epub 2020 Jun 24.

Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, New York.

Background: There is some evidence to suggest that endogenous levels of sex hormones might influence the etiology of cancers of the pancreas, kidney, and brain, but epidemiologic data are lacking.

Methods: We evaluated the association of circulating levels of total and free testosterone, and of sex hormone-binding globulin (SHBG), with the risk of cancers of the pancreas, kidney, and brain, and of total and free estradiol with the risk of kidney cancer, in the UK Biobank cohort study ( = 425,793; 225 pancreatic cancers, 749 kidney cancers, 467 brain cancers). Multivariable Cox proportional hazards models were used to estimate HRs and 95% confidence intervals for the associations.

Results: Testosterone and SHBG levels were not associated with risk of pancreatic cancer. Most of the associations for the other two anatomic sites were null. There were inverse associations between total testosterone and brain cancer in men and between SHBG and risk of kidney cancer in the total sample and in women. Estradiol was not associated with the risk of kidney cancer.

Conclusions: The results of this study provide little support for associations between sex hormones/SHBG and risk of cancers of the pancreas, kidney, and brain. Larger studies are warranted.

Impact: Although these results provide little support for roles for sex hormones and SHBG in the etiology of cancers of the pancreas, kidney, and brain, there is a need for studies with larger numbers of cases.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-0246DOI Listing
September 2020

Associations between reproductive factors and biliary tract cancers in women from the Biliary Tract Cancers Pooling Project.

J Hepatol 2020 10 11;73(4):863-872. Epub 2020 May 11.

Epidemiology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA.

Background & Aims: Gallbladder cancer (GBC) is known to have a female predominance while other biliary tract cancers (BTCs) have a male predominance. However, the role of female reproductive factors in BTC etiology remains unclear.

Methods: We pooled data from 19 studies of >1.5 million women participating in the Biliary Tract Cancers Pooling Project to examine the associations of parity, age at menarche, reproductive years, and age at menopause with BTC. Associations for age at menarche and reproductive years with BTC were analyzed separately for Asian and non-Asian women. Hazard ratios (HRs) and 95% CIs were estimated using Cox proportional hazards models, stratified by study.

Results: During 21,681,798 person-years of follow-up, 875 cases of GBC, 379 of intrahepatic bile duct cancer (IHBDC), 450 of extrahepatic bile duct cancer (EHBDC), and 261 of ampulla of Vater cancer (AVC) occurred. High parity was associated with risk of GBC (HR ≥5 vs. 0 births 1.72; 95% CI 1.25-2.38). Age at menarche (HR per year increase 1.15; 95% CI 1.06-1.24) was associated with GBC risk in Asian women while reproductive years were associated with GBC risk (HR per 5 years 1.13; 95% CI 1.04-1.22) in non-Asian women. Later age at menarche was associated with IHBDC (HR 1.19; 95% CI 1.09-1.31) and EHBDC (HR 1.11; 95% CI 1.01-1.22) in Asian women only.

Conclusion: We observed an increased risk of GBC with increasing parity. Among Asian women, older age at menarche was associated with increased risk for GBC, IHBDC, and EHBDC, while increasing reproductive years was associated with GBC in non-Asian women. These results suggest that sex hormones have distinct effects on cancers across the biliary tract that vary by geography.

Lay Summary: Our findings show that the risk of gallbladder cancer is increased among women who have given birth (especially women with 5 or more children). In women from Asian countries, later age at menarche increases the risk of gallbladder cancer, intrahepatic bile duct cancer and extrahepatic bile duct cancer. We did not see this same association in women from Western countries. Age at menopause was not associated with the risk of any biliary tract cancers.
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http://dx.doi.org/10.1016/j.jhep.2020.04.046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7901003PMC
October 2020

Exogenous hormone use, reproductive factors and risk of intrahepatic cholangiocarcinoma among women: results from cohort studies in the Liver Cancer Pooling Project and the UK Biobank.

Br J Cancer 2020 07 7;123(2):316-324. Epub 2020 May 7.

Division of Medical Oncology, National Cancer Centre, Singapore, Singapore.

Background: Intrahepatic cholangiocarcinoma (ICC) arises from cholangiocytes in the intrahepatic bile duct and is the second most common type of liver cancer. Cholangiocytes express both oestrogen receptor-α and -β, and oestrogens positively modulate cholangiocyte proliferation. Studies in women and men have reported higher circulating oestradiol is associated with increased ICC risk, further supporting a hormonal aetiology. However, no observational studies have examined the associations between exogenous hormone use and reproductive factors, as proxies of endogenous hormone levels, and risk of ICC.

Methods: We harmonised data from 1,107,498 women who enroled in 12 North American-based cohort studies (in the Liver Cancer Pooling Project, LCPP) and the UK Biobank between 1980-1998 and 2006-2010, respectively. Cox proportional hazards regression models were used to generate hazard ratios (HR) and 95% confidence internals (CI). Then, meta-analytic techniques were used to combine the estimates from the LCPP (n = 180 cases) and the UK Biobank (n = 57 cases).

Results: Hysterectomy was associated with a doubling of ICC risk (HR = 1.98, 95% CI: 1.27-3.09), compared to women aged 50-54 at natural menopause. Long-term oral contraceptive use (9+ years) was associated with a 62% increased ICC risk (HR = 1.62, 95% CI: 1.03-2.55). There was no association between ICC risk and other exogenous hormone use or reproductive factors.

Conclusions: This study suggests that hysterectomy and long-term oral contraceptive use may be associated with an increased ICC risk.
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http://dx.doi.org/10.1038/s41416-020-0835-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7374167PMC
July 2020

Validation of an Automated Quantitative Digital Pathology Approach for Scoring TMEM, a Prognostic Biomarker for Metastasis.

Cancers (Basel) 2020 Mar 31;12(4). Epub 2020 Mar 31.

Department of Anatomy and Structural Biology, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY 10461, USA.

Metastasis causes ~90% of breast cancer mortality. However, standard prognostic tests based mostly on proliferation genes do not measure metastatic potential. Tumor MicroEnvironment of Metastasis (TMEM), an immunohistochemical biomarker for doorways on blood vessels that support tumor cell dissemination is prognostic for metastatic outcome in breast cancer patients. Studies quantifying TMEM doorways have involved manual scoring by pathologists utilizing static digital microscopy: a labor-intensive process unsuitable for use in clinical practice. We report here a validation study evaluating a new quantitative digital pathology (QDP) tool (TMEM-DP) for identification and quantification of TMEM doorways that closely mimics pathologists' workflow and reduces pathologists' variability to levels suitable for use in a clinical setting. Blinded to outcome, QDP was applied to a nested case-control study consisting of 259 matched case-control pairs. Sixty subjects of these were manually scored by five pathologists, digitally recorded using whole slide imaging (WSI), and then used for algorithm development and optimization. Validation was performed on the remainder of the cohort. TMEM-DP shows excellent reproducibility and concordance and reduces pathologist time from ~60 min to ~5 min per case. Concordance between manual scoring and TMEM-DP was found to be >0.79. These results show that TMEM-DP is capable of accurately identifying and scoring TMEM doorways (also known as MetaSite score) equivalent to pathologists.
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http://dx.doi.org/10.3390/cancers12040846DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226227PMC
March 2020

Diabetes, Glycated Hemoglobin, and Risk of Cancer in the UK Biobank Study.

Cancer Epidemiol Biomarkers Prev 2020 06 16;29(6):1107-1119. Epub 2020 Mar 16.

Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, New York.

Background: Evidence suggest that diabetes and glycated hemoglobin (HbA1c) levels are associated with cancer risk. However, previous studies have been limited variably by failure to adjust for cancer-specific risk factors (e.g., body mass index), inattention to diabetes duration and use of antidiabetic medications, and failure to stratify by obesity.

Methods: We examined the association between diabetes, HbA1c, and cancer risk in the UK Biobank, using data from 476,517 participants (54% women), followed for an average period of 7.1 years. Diabetes was defined on the basis of baseline self-reported diagnosis of diabetes and/or use of diabetes medication, while HbA1c measured at baseline was categorized as low (<31 mmol/mol), normal (31-<39 mmol/mol), increased risk (39-<48 mmol/mol), and high risk for diabetes (≥48 mmol/mol). Multivariable Cox proportional hazards models were used to estimate the association of diabetes and cancer at different anatomical sites, with adjustment for cancer-specific risk factors.

Results: Diabetes was associated with increased risk of cancers of the stomach, liver, bladder, endometrium, and lung among smokers, and with decreased risk of prostate cancer. Compared with the normal HbA1c category, the increased risk category was positively associated with risk of cancers of the colon, liver, bladder, and lung among smokers, and the high-risk category was associated with increased risk of cancers of the esophagus, liver, pancreas, and bladder, and with decreased risk of prostate cancer.

Conclusions: These results suggest that both diabetes and/or elevated HbA1c are associated with risk of cancer at several anatomic sites.

Impact: The associations of diabetes and HbA1c levels with cancer suggest their importance in cancer prevention.
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http://dx.doi.org/10.1158/1055-9965.EPI-19-1623DOI Listing
June 2020

Prediagnostic Circulating Levels of Sex Steroid Hormones and SHBG in Relation to Risk of Ductal Carcinoma of the Breast among UK Women.

Cancer Epidemiol Biomarkers Prev 2020 05 3;29(5):1058-1066. Epub 2020 Mar 3.

Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, New York.

Background: Sex steroid hormones and sex hormone-binding globulin (SHBG) have been implicated in the etiology of invasive breast cancer, but their associations with risk of the precursor lesion, ductal carcinoma (DCIS) of the breast, remain unclear.

Methods: We used Cox proportional hazards regression models to estimate the associations of serum levels of estradiol (premenopausal women only), testosterone, and/or SHBG with DCIS risk among 182,935 women. After a median follow-up of 7.1 years, 186 and 531 DCIS cases were ascertained in premenopausal and postmenopausal women, respectively.

Results: Total and free estradiol were positively associated with risk of DCIS among premenopausal women. The HRs for the highest versus the lowest tertiles were 1.54 (1.06-2.23) and 1.72 [95% confidence interval (CI), 1.15-2.57], respectively. Among postmenopausal women, elevated levels of free testosterone (FT), and to a lesser extent, total testosterone, were positively associated with DCIS risk. The HRs for the highest versus the lowest quartiles were 1.42 (95% CI, 1.09-1.85) and 1.16 (95% CI, 0.91-1.48), respectively. Serum SHBG levels were inversely associated with risk of DCIS among postmenopausal women (HR: 0.75; 95% CI, 0.56-0.99).

Conclusions: This study suggests that elevated levels of estradiol are associated with increased risk of DCIS among premenopausal women, and that among postmenopausal women, elevated levels of testosterone, and particularly those of FT, are associated with increased DCIS risk, while elevated levels of SHBG are associated with reduced risk.

Impact: These findings may be helpful in developing prevention strategies aimed at reducing breast cancer risk among premenopausal and postmenopausal women.
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http://dx.doi.org/10.1158/1055-9965.EPI-19-1302DOI Listing
May 2020

Dietary Modification and Breast Cancer Mortality: Long-Term Follow-Up of the Women's Health Initiative Randomized Trial.

J Clin Oncol 2020 05 7;38(13):1419-1428. Epub 2020 Feb 7.

Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA.

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%] 652 [0.14%] deaths; hazard ratio [HR], 0.85; 95% CI, 0.74 to 0.96; = .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] 251 [0.047%] deaths, respectively; HR, 0.79; 95% CI, 0.64 to 0.97; = .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.
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http://dx.doi.org/10.1200/JCO.19.00435DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7193750PMC
May 2020

Adult weight change and premenopausal breast cancer risk: A prospective pooled analysis of data from 628,463 women.

Int J Cancer 2020 09 15;147(5):1306-1314. Epub 2020 Feb 15.

Albert Einstein College of Medicine, Bronx, NY.

Early-adulthood body size is strongly inversely associated with risk of premenopausal breast cancer. It is unclear whether subsequent changes in weight affect risk. We pooled individual-level data from 17 prospective studies to investigate the association of weight change with premenopausal breast cancer risk, considering strata of initial weight, timing of weight change, other breast cancer risk factors and breast cancer subtype. Hazard ratios (HR) and 95% confidence intervals (CI) were obtained using Cox regression. Among 628,463 women, 10,886 were diagnosed with breast cancer before menopause. Models adjusted for initial weight at ages 18-24 years and other breast cancer risk factors showed that weight gain from ages 18-24 to 35-44 or to 45-54 years was inversely associated with breast cancer overall (e.g., HR per 5 kg to ages 45-54: 0.96, 95% CI: 0.95-0.98) and with oestrogen-receptor(ER)-positive breast cancer (HR per 5 kg to ages 45-54: 0.96, 95% CI: 0.94-0.98). Weight gain from ages 25-34 was inversely associated with ER-positive breast cancer only and weight gain from ages 35-44 was not associated with risk. None of these weight gains were associated with ER-negative breast cancer. Weight loss was not consistently associated with overall or ER-specific risk after adjusting for initial weight. Weight increase from early-adulthood to ages 45-54 years is associated with a reduced premenopausal breast cancer risk independently of early-adulthood weight. Biological explanations are needed to account for these two separate factors.
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http://dx.doi.org/10.1002/ijc.32892DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7365745PMC
September 2020

The Risk of Ovarian Cancer Increases with an Increase in the Lifetime Number of Ovulatory Cycles: An Analysis from the Ovarian Cancer Cohort Consortium (OC3).

Cancer Res 2020 03 13;80(5):1210-1218. Epub 2020 Jan 13.

Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, University Utrecht, Utrecht, the Netherlands.

Repeated exposure to the acute proinflammatory environment that follows ovulation at the ovarian surface and distal fallopian tube over a woman's reproductive years may increase ovarian cancer risk. To address this, analyses included individual-level data from 558,709 naturally menopausal women across 20 prospective cohorts, among whom 3,246 developed invasive epithelial ovarian cancer (2,045 serous, 319 endometrioid, 184 mucinous, 121 clear cell, 577 other/unknown). Cox models were used to estimate multivariable-adjusted HRs between lifetime ovulatory cycles (LOC) and its components and ovarian cancer risk overall and by histotype. Women in the 90th percentile of LOC (>514 cycles) were almost twice as likely to be diagnosed with ovarian cancer than women in the 10th percentile (<294) [HR (95% confidence interval): 1.92 (1.60-2.30)]. Risk increased 14% per 5-year increase in LOC (60 cycles) [(1.10-1.17)]; this association remained after adjustment for LOC components: number of pregnancies and oral contraceptive use [1.08 (1.04-1.12)]. The association varied by histotype, with increased risk of serous [1.13 (1.09-1.17)], endometrioid [1.20 (1.10-1.32)], and clear cell [1.37 (1.18-1.58)], but not mucinous [0.99 (0.88-1.10), P-heterogeneity = 0.01] tumors. Heterogeneity across histotypes was reduced [P-heterogeneity = 0.15] with adjustment for LOC components [1.08 serous, 1.11 endometrioid, 1.26 clear cell, 0.94 mucinous]. Although the 10-year absolute risk of ovarian cancer is small, it roughly doubles as the number of LOC rises from approximately 300 to 500. The consistency and linearity of effects strongly support the hypothesis that each ovulation leads to small increases in the risk of most ovarian cancers, a risk that cumulates through life, suggesting this as an important area for identifying intervention strategies. SIGNIFICANCE: Although ovarian cancer is rare, risk of most ovarian cancers doubles as the number of lifetime ovulatory cycles increases from approximately 300 to 500. Thus, identifying an important area for cancer prevention research.
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http://dx.doi.org/10.1158/0008-5472.CAN-19-2850DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7056529PMC
March 2020