BMI and breast cancer risk around age at menopause.

BACKGROUND: A high body mass index (BMI, kg/m2) is associated with decreased risk of breast cancer before menopause, but increased risk after menopause. Exactly when this reversal occurs in relation to menopause is unclear. Locating that change point could provide insight into the role of adiposity in breast cancer etiology. METHODS: We examined the association between BMI and breast cancer risk in the Premenopausal Breast Cancer Collaborative Group, from age 45 up to breast cancer diagnosis, loss to follow-up, death, or age 55, whichever came first. Analyses included 609,880 women in 16 prospective studies, including 9956 who developed breast cancer before age 55. We fitted three BMI hazard ratio (HR) models over age-time: constant, linear, or nonlinear (via splines), applying piecewise exponential additive mixed models, with age as the primary time scale. We divided person-time into four strata: premenopause; postmenopause due to natural menopause; postmenopause because of interventional loss of ovarian function (bilateral oophorectomy (BO) or chemotherapy); postmenopause due to hysterectomy without BO. Sensitivity analyses included stratifying by BMI in young adulthood, or excluding women using menopausal hormone therapy. RESULTS: The constant BMI HR model provided the best fit for all four menopausal status groups. Under this model, the estimated association between a five-unit increment in BMI and breast cancer risk was HR=0.87 (95% CI: 0.85, 0.89) before menopause, HR=1.00 (95% CI: 0.96, 1.04) after natural menopause, HR=0.99 (95% CI: 0.93, 1.05) after interventional loss of ovarian function, and HR=0.88 (95% CI: 0.76, 1.02) after hysterectomy without BO. CONCLUSION: The BMI breast cancer HRs remained less than or near one during the 45-55 year age range indicating that the transition to a positive association between BMI and risk occurs after age 55.

International Pooled Analysis of Leisure-Time Physical Activity and Premenopausal Breast Cancer in Women From 19 Cohorts.

PURPOSE: There is strong evidence that leisure-time physical activity is protective against postmenopausal breast cancer risk but the association with premenopausal breast cancer is less clear. The purpose of this study was to examine the association of physical activity with the risk of developing premenopausal breast cancer. METHODS: We pooled individual-level data on self-reported leisure-time physical activity across 19 cohort studies comprising 547,601 premenopausal women, with 10,231 incident cases of breast cancer. Multivariable Cox regression was used to estimate hazard ratios (HRs) and 95% CIs for associations of leisure-time physical activity with breast cancer incidence. HRs for high versus low levels of activity were based on a comparison of risk at the 90th versus 10th percentiles of activity. We assessed the linearity of the relationship and examined subtype-specific associations and effect modification across strata of breast cancer risk factors, including adiposity. RESULTS: Over a median 11.5 years of follow-up (IQR, 8.0-16.1 years), high versus low levels of leisure-time physical activity were associated with a 6% (HR, 0.94 [95% CI, 0.89 to 0.99]) and a 10% (HR, 0.90 [95% CI, 0.85 to 0.95]) reduction in breast cancer risk, before and after adjustment for BMI, respectively. Tests of nonlinearity suggested an approximately linear relationship (Pnonlinearity = .94). The inverse association was particularly strong for human epidermal growth factor receptor 2-enriched breast cancer (HR, 0.57 [95% CI, 0.39 to 0.84]; Phet = .07). Associations did not vary significantly across strata of breast cancer risk factors, including subgroups of adiposity. CONCLUSION: This large, pooled analysis of cohort studies adds to evidence that engagement in higher levels of leisure-time physical activity may lead to reduced premenopausal breast cancer risk.

Prospective analysis of sleep characteristics, chronotype, and risk of breast cancer in the california teachers study.

PURPOSE: Poor sleep quality and evening chronotype were associated with increased risk of breast cancer in a previous retrospective study in the California Teachers Study (CTS). The present analysis examines these sleep factors prospectively in the same cohort of women. METHODS: From the CTS, we included 1,085 incident breast cancer cases and 38,470 cancer-free participants from 2012 through 2019. We calculated time at risk and used Cox proportional hazards regression models to estimate the hazard ratios (HRs) and control for risk factors such as age, race, body mass index, family history of breast cancer, and reproductive history. The sleep factors examined were quality, latency, duration, disturbance, and sleep medication use, based on a shortened version of the Pittsburgh Sleep Quality Index, as well as chronotype (preference for morning or evening activity). This analysis was limited to women who were post-menopausal at the time they answered these sleep-related questions. RESULTS: Measures of sleep quality did not appear to be associated with subsequent breast cancer risk. The HR for evening chronotypes compared to morning chronotypes was somewhat elevated (HR 1.19, 95% CI 1.04, 1.36). CONCLUSION: While the measures of sleep quality and duration were not associated with post-menopausal breast cancer risk in this prospective analysis, the modestly elevated risk observed for evening chronotypes was consistent with the prior retrospective analysis.

Association of hormonal and reproductive factors with differentiated thyroid cancer risk in women: a pooled prospective cohort analysis.

BACKGROUND: The incidence of differentiated thyroid cancer (DTC) is higher in women than in men but whether sex steroid hormones contribute to this difference remains unclear. Studies of reproductive and hormonal factors and thyroid cancer risk have provided inconsistent results. METHODS: Original data from 1 252 907 women in 16 cohorts in North America, Europe, Australia and Asia were combined to evaluate associations of DTC risk with reproductive and hormonal factors. Multivariable-adjusted Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95% CIs. RESULTS: During follow-up, 2142 women were diagnosed with DTC. Factors associated with higher risk of DTC included younger age at menarche (<10 vs 10-11 years; HR, 1.28; 95% CI, 1.00-1.64), younger (<40; HR, 1.31; 95% CI, 1.05-1.62) and older (≥55; HR, 1.33; 95% CI, 1.05-1.68) ages at menopause (vs 40-44 years), ever use of menopausal hormone therapy (HR, 1.16; 95% CI, 1.02-1.33) and previous hysterectomy (HR, 1.25; 95% CI, 1.13-1.39) or bilateral oophorectomy (HR, 1.14; 95% CI, 1.00-1.29). Factors associated with lower risk included longer-term use (≥5 vs <5 years) of oral contraceptives (HR, 0.86; 95% CI, 0.76-0.96) among those who ever used oral contraception and baseline post-menopausal status (HR, 0.82; 95% CI, 0.70-0.96). No associations were observed for parity, duration of menopausal hormone therapy use or lifetime number of reproductive years or ovulatory cycles. CONCLUSIONS: Our study provides some evidence linking reproductive and hormonal factors with risk of DTC. Results should be interpreted cautiously considering the modest strength of the associations and potential for exposure misclassification and detection bias. Prospective studies of pre-diagnostic circulating sex steroid hormone measurements and DTC risk may provide additional insight.

Development and Optimization of a Subtraction-Normalized Immunocyte Profiling Signature for Prostate Cancer Active Surveillance Risk Stratification.

PURPOSE: Less invasive decision support tools are desperately needed to identify occult high-risk disease in men with prostate cancer (PCa) on active surveillance (AS). For a variety of reasons, many men on AS with low- or intermediate-risk disease forgo the necessary repeat surveillance biopsies needed to identify potentially higher-risk PCa. Here, we describe the development of a blood-based immunocyte transcriptomic signature to identify men harboring occult aggressive PCa. We then validate it on a biopsy-positive population with the goal of identifying men who should not be on AS and confirm those men with indolent disease who can safely remain on AS. This model uses subtraction-normalized immunocyte transcriptomic profiles to risk-stratify men with PCa who could be candidates for AS. MATERIALS AND METHODS: Men were eligible for enrollment in the study if they were determined by their physician to have a risk profile that warranted prostate biopsy. Both training (n = 1017) and validation cohort (n = 1198) populations had blood samples drawn coincident to their prostate biopsy. Purified CD2+ and CD14+ immune cells were obtained from peripheral blood mononuclear cells, and RNA was extracted and sequenced. To avoid overfitting and unnecessary complexity, a regularized regression model was built on the training cohort to predict PCa aggressiveness based on the National Comprehensive Cancer Network PCa guidelines. This model was then validated on an independent cohort of biopsy-positive men only, using National Comprehensive Cancer Network unfavorable intermediate risk and worse as an aggressiveness outcome, identifying patients who were not appropriate for AS. RESULTS: The best final model for the AS setting was obtained by combining an immunocyte transcriptomic profile based on 2 cell types with PSA density and age, reaching an AUC of 0.73 (95% CI: 0.69-0.77). The model significantly outperforms (P < .001) PSA density as a biomarker, which has an AUC of 0.69 (95% CI: 0.65-0.73). This model yields an individualized patient risk score with 90% negative predictive value and 50% positive predictive value. CONCLUSIONS: While further validation in an intended-use cohort is needed, the immunocyte transcriptomic model offers a promising tool for risk stratification of individual patients who are being considered for AS.

The Health of Women (HOW) Study®: a web-based survey of breast cancer risk factors, diagnosis, and treatment.

PURPOSE: Although improvements in breast cancer detection and treatment have significantly increased survival, important questions related to breast cancer risk, prognosis, and survivorship remain. This brief report describes the Health of Women (HOW) Study® methodology and characterizes the participants who completed the My Health Overview and My Breast Cancer modules. METHODS: The HOW Study® was a collection of cross-sectional, web-based modules designed to survey a large number of participants with and without breast cancer. RESULTS: A total of 42,540 participants completed the My Health Overview module, of whom 13,285 (31.2%) reported a history of breast cancer. The majority of participants were white (94.3%), female (99.5%), married (74.1%), college educated (73.2%), post-menopausal (91.1%), parous (68.8%), and reported breastfeeding their children (56.0%). A total of 11,670 participants reported a history of breast cancer in the My Breast Cancer module. The majority of survivors reported on their primary breast cancer and were diagnosed over the age of 40 years (83.5%), had either Stage I or Stage II breast cancer (63.1%), and were treated with surgery (98.8%), radiation (64.8%), and/or chemotherapy (62.3%). CONCLUSIONS: The HOW Study® provides an innovative framework for collecting large amounts of epidemiological data in an efficient and minimally invasive way. Data are publicly available to researchers upon request. IMPLICATIONS FOR CANCER SURVIVORS: The HOW Study® can be leveraged to answer important questions about survivorship, and researchers are encouraged to utilize this new data source.

The association of infectious mononucleosis and invasive breast cancer in The Health of Women (HOW) Study®.

BACKGROUND: The link between Epstein-Barr Virus (EBV) and breast cancer (BC) etiology remains unclear. We utilized the Health of Women (HOW) Study® to understand the association between infectious mononucleosis (IM), a surrogate for EBV infection, and invasive BC. METHODS: The HOW Study® was a web-based survey of BC risk factors with > 40, 000 participants; 183 had IM at < 10 years old, 3, 654 had IM between 10 and 22 years old, 764 had IM at > 22 years old, and 17, 026 never developed IM. Of these 21, 627 women, 2093 had Stages I-III BC and 14, 143 were cancer-free. Binary logistic regression ascertained the association between IM and invasive BC risk by controlling for confounders. RESULTS: A history of IM was associated with a lower likelihood of developing invasive BC compared to women who did not develop IM (adjusted OR = 0.83, 95% CI 0.72-0.94). That finding was driven by women who had IM between 10 and 22 years old (adjusted OR = 0.83, 95% CI 0.72-0.97) albeit no linear association between age at developing IM and breast cancer (p-trend > 0.05). Women who had IM between 10 and 22 years old were less likely to develop estrogen receptor positive (ER+ ; adjusted OR = 0.84, 95% CI 0.71-0.99) or hormone receptor positive (HR+ ; adjusted OR = 0.86, 95% CI 0.73-1.01) BC. There was no association between IM and ER- or HR- BC. CONCLUSION: In the HOW Study®, women diagnosed with IM between the ages of 10 and 22 had a lower risk of developing invasive BC compared to women who never developed IM.

Fusion Oncogenes Are Associated With Increased Metastatic Capacity and Persistent Disease in Pediatric Thyroid Cancers.

PURPOSE: In 2014, data from a comprehensive multiplatform analysis of 496 adult papillary thyroid cancer samples reported by The Cancer Genome Atlas project suggested that reclassification of thyroid cancer into molecular subtypes, RAS-like and BRAF-like, better reflects clinical behavior than sole reliance on pathologic classification. The aim of this study was to categorize the common oncogenic variants in pediatric differentiated thyroid cancer (DTC) and investigate whether mutation subtype classification correlated with the risk of metastasis and response to initial therapy in pediatric DTC. METHODS: Somatic cancer gene panel analysis was completed on DTC from 131 pediatric patients. DTC were categorized into RAS-mutant (H-K-NRAS), BRAF-mutant (BRAF p.V600E), and RET/NTRK fusion (RET, NTRK1, and NTRK3 fusions) to determine differences between subtype classification in regard to pathologic data (American Joint Committee on Cancer TNM) as well as response to therapy 1 year after initial treatment had been completed. RESULTS: Mutation-based subtype categories were significant in most variables, including age at diagnosis, metastatic behavior, and the likelihood of remission at 1 year. Patients with RET/NTRK fusions were significantly more likely to have advanced lymph node and distant metastasis and less likely to achieve remission at 1 year than patients within RAS- or BRAF-mut subgroups. CONCLUSION: Our data support that genetic subtyping of pediatric DTC more accurately reflects clinical behavior than sole reliance on pathologic classification with patients with RET/NTRK fusions having worse outcomes than those with BRAF-mutant disease. Future trials should consider inclusion of molecular subtype into risk stratification.

Host characteristics associated with serologic inflammatory biomarkers in women.

BACKGROUND: There is growing evidence that exposure to low-grade inflammation may be associated with adverse health outcomes. METHODS: We conducted a cross-sectional study within the California Teachers Study prospective cohort, among female participants who had completed a questionnaire that asked about their health behaviors (e.g., diabetes, physical activity, body mass index, medication use) and who had donated blood within a year of their questionnaire. 822 women with stored serum were evaluated for 16 immune biomarkers. In addition, four immune pathways were constructed: Th1, pro-inflammatory/macrophage activation, B-cell activation, and T-cell activation. Odds ratios (ORs) and 95% confidence intervals (CI) for the association between host characteristics and immune biomarkers were assessed using logistic regression models. RESULT: Compared to women of a normal BMI, obese women (>30 kg/m2) were positively associated with sTNFR2, CD27, IL6, CXCL13, sIL-2Rα, and IL6Ra levels above the median, with odds ratios ranging from 1.5 to 6.0. The pro-inflammatory/macrophage activation pathway was positively associated with diabetes (OR = 2.12, 95% CI = 1.14-3.95), fueled by individual associations between diabetes and sTNF-R2, TNFα and sCD27. Physical activity was inversely associated with sTNF-R2, TNFα, CXCL13, IL6, IL10, and IFN-γ levels, particularly for the highest category of activity (5.88+ hours/week) (ORs = 0.32-0.69). In pathway-based analyses, the Th1 pathway which includes decreased levels of IL4 and IL10 was positively associated with elevated physical activity (OR = 1.5). In contrast, the pro-inflammatory, B- and T-cell activation pathways were positively associated with higher BMI (OR ranging from 1.6 to 3) and inversely associated with increasing levels of physical activity. CONCLUSIONS: Several host characteristics were associated with circulating levels of immune biomarkers, including markers of inflammation. Further understanding of associations between immune marker profiles with human disease are warranted.

Genetic epidemiology of BRCA1- and BRCA2-associated cancer across Latin America.

The prevalence and contribution of BRCA1/2 (BRCA) pathogenic variants (PVs) to the cancer burden in Latin America are not well understood. This study aims to address this disparity. BRCA analyses were performed on prospectively enrolled Latin American Clinical Cancer Genomics Community Research Network participants via a combination of methods: a Hispanic Mutation Panel (HISPANEL) on MassARRAY; semiconductor sequencing; and copy number variant (CNV) detection. BRCA PV probability was calculated using BRCAPRO. Among 1,627 participants (95.2% with cancer), we detected 236 (14.5%) BRCA PVs; 160 BRCA1 (31% CNVs); 76 BRCA2 PV frequency varied by country: 26% Brazil, 9% Colombia, 13% Peru, and 17% Mexico. Recurrent PVs (seen ≥3 times), some region-specific, represented 42.8% (101/236) of PVs. There was no ClinVar entry for 14% (17/125) of unique PVs, and 57% (111/196) of unique VUS. The area under the ROC curve for BRCAPRO was 0.76. In summary, we implemented a low-cost BRCA testing strategy and documented a significant burden of non-ClinVar reported BRCA PVs among Latin Americans. There are recurrent, population-specific PVs and CNVs, and we note that the BRCAPRO mutation probability model performs adequately. This study helps address the gap in our understanding of BRCA-associated cancer in Latin America.

Chronotype and risk of post-menopausal endometrial cancer in the California Teachers Study.

Working at night causes circadian disruption and it has been classified as a probable carcinogen. An evening chronotype, or preference for late day activity, has been shown to increase risk for several adverse health effects, such as metabolic disorders and recently, breast cancer. To further explore this emerging area of interest, we examined the association between endometrial cancer (EC) risk, another common cancer in women, and chronotype. The women in this study were members of the California Teachers Study cohort, which was established in 1995. Chronotype was reported on a subsequent questionnaire (Q5), administered in 2012-2013. The women included in this analysis were under age 90 years, were post-menopausal at Q5, and had no hysterectomy. The cancer cases, identified through linkages to the California Cancer Registry, were diagnosed between 1996 and 2014. We used unconditional logistic regression models to estimate the odds ratios (ORs) and 95% confidence intervals (CIs) of the associations between chronotype and EC diagnosis. There were 437 EC cases and 26,753 cancer-free controls included in this analysis. Controls were more likely to classify themselves as current morning chronotypes than were cases (39% and 34%, respectively). Compared to morning types, women who were definite evening types had a statistically significantly elevated OR of 1.44 (95% CI 1.09-1.91). This association was more pronounced among obese women as compared to non-obese women. For evening type compared to morning type, the OR among obese women was 2.01 (95% CI 1.23, 3.29) while the OR for non-obese women was 1.12 (95% CI 0.77, 1.63). To our knowledge, the association between EC risk and evening chronotype has not been previously reported, but is consistent with the small body of literature which suggests increased breast cancer risks among evening chronotypes. Because this study was based on a retrospective analysis in a cohort of mostly white female teachers in California, further analysis of chronotype as a potential EC risk factor should be considered in other cohorts and in prospective analyses in order to further explore this relationship.

Chronotype and postmenopausal breast cancer risk among women in the California Teachers Study.

Chronotype is the behavioral manifestation of an individual's underlying circadian rhythm, generally characterized by one's propensity to sleep at a particular time during the 24 hour cycle. Evening chronotypes ("night owls") generally suffer from worse physical and mental health compared to morning chronotypes ("morning larks") - for reasons that have yet to be explained. One hypothesis is that evening chronotypes may be more susceptible to circadian disruption, a condition where the coordinated timing of biologic processes breaks down. The role of chronotype as an independent or modifying risk factor for cancer has not been widely explored. The objective of the current study was to evaluate the risk of breast cancer associated with chronotype in a case-control study nested within the California Teachers Study (CTS) cohort. The study population consisted of 39686 post-menopausal CTS participants who provided information on chronotype by completing a questionnaire in 2012-2013. 2719 cases of primary invasive breast cancer diagnosed from 1995/1996 through completion of the chronotype questionnaire were identified by linkage of the CTS to the California Cancer Registry. 36967 CTS participants who had remained cancer-free during this same time period served as controls. Chronotype was ascertained by responses to an abbreviated version of the Horne-Ostberg Morningness-Eveningness Questionnaire (MEQ) and was characterized into five categories: definite morning, more morning than evening, neither morning or evening, more evening than morning, definite evening. Multivariable unconditional logistic regression analyses were performed to estimate the odds ratios (ORs) and 95% confidence intervals (95% CIs) for each of the chronotypes, adjusted for established breast cancer risk factors. Compared to definite morning types, definite evening types had an increased risk of breast cancer with elevated ORs that were statistically significant in both the crude (OR = 1.24, 95% CI: 1.10-1.40) and fully-adjusted models (OR = 1.20, 95% CI: 1.06-1.35). The risk estimates in the fully-adjusted model for all other chronotypes did not significantly differ from one. These results suggest that evening chronotype may be an independent risk factor for breast cancer among a population of women who are not known to have engaged in any substantial night shift work. Further research in other populations of non-shift workers is warranted.

Urinary Molecular Biomarker Test Impacts Prostate Biopsy Decision Making in Clinical Practice.

INTRODUCTION: There is an unmet need for noninvasive methods to better identify patients at increased risk for clinically significant prostate cancer. SelectMDx® is a molecular urine test validated for the detection of Gleason score 7 and higher cancers (ISUP [International Society of Urological Pathology] Grade Group 2-5). In this multicenter trial we evaluated the test's impact on prostate biopsy decision making in clinical practice. METHODS: The study involved 5 U.S. community urology practices which sequentially enrolled 418 patients who received a SelectMDx test between May 2016 and April 2017 while undergoing evaluation for initial prostate biopsy. All tests were ordered by the urologist for patient management. We determined biopsy and prostate cancer detection rates in patients with SelectMDx positive versus SelectMDx negative results. RESULTS: Of the 418 subjects evaluated with SelectMDx 253 (61%) had negative results and 165 (39%) had positive results. Subsequent biopsy rates for SelectMDx positive and negative cases were 60% (99) and 12% (32), respectively (p <0.001). Time from SelectMDx result to biopsy was shorter for those with positive vs negative results (median 2 vs 5 months, p=0.001). Of patients who underwent biopsy within 3 months of testing 71 (43%) with positive results underwent biopsy and 27 had cancers identified, including 10 greater than Grade Group 2. Of 9 patients with SelectMDx negative results (3.6%) who underwent biopsy 4 were diagnosed with cancer, all Grade Group 2 or less. CONCLUSIONS: SelectMDx had a significant impact on initial prostate biopsy decision making. Biopsy rates in SelectMDx positive cases were fivefold higher than in SelectMDx negative cases. These results describe the clinical utility of SelectMDx in real-world community urology practice.

Metastatic Breast Cancer Collateral Damage Project (MBCCD): Scale development and preliminary results of the Survey of Health, Impact, Needs, and Experiences (SHINE).

PURPOSE: Until recently, people with metastatic breast cancer (MBC) had a very poor prognosis. New treatment approaches have prolonged the time that people with MBC live, but their quality of life has received less attention. Consequently, the needs and concerns across financial, vocational, psychological, social, and physical domains in MBC patients are poorly understood-particularly regarding the collateral damage or longer-term, life-altering impacts of MBC and its treatments. This study's aims were to characterize MBC-related collateral damage, identify groups most likely to experience collateral damage, and examine its associations with psychological health, illness management, and health behaviors. METHODS: Participants (N = 515) with MBC were recruited from Dr. Susan Love Research Foundation's Army of Women® and other advocacy organizations. Participants completed questionnaires of MBC-related collateral damage, depressive symptoms, anxiety, self-efficacy for managing oncologic treatments and physical symptoms, sleep, and physical activity. RESULTS: Eight domains of MBC-related collateral damage, as well as MBC-related benefit finding, were reliably characterized. Concerns about mortality/uncertainty were most prominent. Participants also endorsed high levels of benefit finding. Participants younger than 50 years, with limited financial resources, or with children under 18 at home reported the most collateral damage. Collateral damage was associated significantly with compromised psychological health, lower illness management efficacy, and poorer health behaviors, beyond sociodemographic and medical characteristics. CONCLUSIONS: Subgroups of MBC patients report long-term, life-altering consequences of MBC and its treatments, which relate to important health outcomes. Clinical implications and recommendations are discussed.