Ductal carcinoma in situ and cause-specific mortality among younger and older postmenopausal women: the Women's Health Initiative.

BACKGROUND: Whether DCIS is associated with higher breast cancer-specific and all-cause mortality is unclear with few studies in older women. Therefore, we examined DCIS and breast cancer-specific, cardiovascular (CVD)-specific, and all-cause mortality among Women's Health Initiative (WHI) Clinical Trial participants overall and by age (< 70 versus ≥ 70 years). METHODS: Of 68,132 WHI participants, included were 781 postmenopausal women with incident DCIS and 781 matched controls. Serial screening mammography was mandated with high adherence. DCIS cases were confirmed by central medical record review. Adjusted multivariable Cox proportional hazard regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CI). Kaplan Meier (KM) plots were used to assess 10-year and 20-year mortality rates. RESULTS: After 20.3 years total, and 13.2 years median post-diagnosis follow-up, compared to controls, DCIS was associated with higher breast cancer-specific mortality (HR 3.29; CI = 1.32-8.22, P = 0.01). The absolute difference in 20-year breast cancer mortality was 1.2% without DCIS and 3.4% after DCIS, log-rank P = 0.026. Findings were similar by age (< 70 versus ≥ 70 years) with no interaction (P interaction = 0.80). Incident DCIS was not associated with CVD-specific mortality (HR 0.77; CI-0.54-1.09, P = 0.14) or with all-cause mortality (HR 0.96; CI = 0.80-1.16, P = 0.68) with similar findings by age. CONCLUSIONS: In postmenopausal women, incident DCIS was associated with over three-fold higher breast cancer-specific mortality, with similar findings in younger and older postmenopausal women. These finding suggest caution in using age to adjust DCIS clinical management or research strategies.

Breast cancer incidence and mortality by metabolic syndrome and obesity: The Women's Health Initiative.

BACKGROUND: In the Women's Health Initiative (WHI) randomized trial, dietary intervention significantly reduced breast cancer mortality, especially in women with more metabolic syndrome (MetS) components. Therefore, this study investigated the associations of MetS and obesity with postmenopausal breast cancer after long-term follow-up in the WHI clinical trials. METHODS: A total of 68,132 postmenopausal women, without prior breast cancer and with normal mammogram, were entered into WHI randomized clinical trials; 63,330 women with an entry MetS score comprised the study population. At entry, body mass index (BMI) was determined; MetS score (0, 1-2, and 3-4) included the following: (1) high waist circumference (≥88 cm), (2) high blood pressure (systolic ≥130 mm Hg and/or diastolic ≥85 mm Hg, or hypertension history), (3) high-cholesterol history, and (4) diabetes history. Study outcomes included breast cancer incidence, breast cancer mortality, deaths after breast cancer, and results by hormone receptor status. RESULTS: After a >20-year mortality follow-up, a higher MetS score (3-4), adjusted for BMI, was significantly associated with more poor prognosis, estrogen receptor (ER)-positive, progesterone receptor (PR)-negative cancers (p = .03), 53% more deaths after breast cancer (p < .001), and 44% higher breast cancer mortality (p = .03). Obesity status, adjusted for MetS score, was significantly associated with more good prognosis, ER-positive, PR-positive cancers (p < .001), more total breast cancers (p < .001), and more deaths after breast cancer (p < .001), with higher breast cancer mortality only in women with severe obesity (BMI, ≥35 kg/m2; p < .001). CONCLUSIONS: MetS and obesity status have independent, but differential, adverse associations with breast cancer receptor subtypes and breast cancer mortality risk. Both represent separate targets for breast cancer prediction and prevention strategies.

Genetic subtypes of prediabetes, healthy lifestyle, and risk of type 2 diabetes.

Prediabetes is a heterogenous metabolic state with various risk for development of type 2 diabetes (T2D). In this study, we used genetic data on 7,227 US Hispanic/Latinos without diabetes from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) and 400,149 non-Hispanic whites without diabetes from the UK Biobank (UKBB) to calculate five partitioned polygenetic risk scores (pPRSs) representing various pathways related to T2D. Consensus clustering was performed in participants with prediabetes in HCHS/SOL (n=3,677) and UKBB (n=16,284) separately, based on these pPRSs. Six clusters of individuals with prediabetes with distinctive patterns of pPRSs and corresponding metabolic traits were identified in the HCHS/SOL, five of which were confirmed in the UKBB. Although baseline glycemic traits were similar across clusters, individuals in Cluster 5 and Cluster 6 showed elevated risk of T2D during follow-up compared to Cluster 1 (RR=1.29 [95% CI 1.08-1.53] and1.34 [1.13-1.60], respectively). Inverse associations between a healthy lifestyle score and risk of T2D were observed across different clusters, with a suggestively stronger association observed in Cluster 5 compared to Cluster 1. Among individuals with healthy lifestyle, those in Cluster 5 had a similar risk of T2D compared to those in Cluster 1 (RR=1.03 [0.91-1.18]). This study identified genetic subtypes of prediabetes which differed in risk of progression to T2D and in benefits from healthy lifestyle.

Associations of Lifestyle and Genetic Risks with Obesity and Related Chronic Diseases in the UK Biobank: A Prospective Cohort Study.

BACKGROUND: Interplay between lifestyle risk scores (LRSs) and genetic risk scores (GRSs) on obesity and related chronic diseases are underinvestigated and necessary for understanding obesity causes and developing prevention strategies. OBJECTIVES: This study aimed to investigate independent and joint associations and interactions of LRS and GRS with obesity prevalence and risks of diabetes, cardiovascular disease (CVD), and obesity-related cancer. METHODS: In this cohort study of 444,957 UK Biobank participants [age: 56.5 ± 8.1 y; BMI (in kg/m2): 27.4 ± 4.7], LRS included physical activity, dietary score, sedentary behavior, sleep duration, and smoking (range: 0-20, each factor had 5 levels). GRS was calculated based on 941 genetic variants related to BMI. Both scores were categorized into quintiles. Obesity (n = 106,301) was defined as baseline BMI ≥30. Incident diabetes (n = 16,311), CVD (n = 18,076), and obesity-related cancer (n = 17,325) were ascertained through linkage to registries over a median of 12-y follow-up. RESULTS: The LRS and GRS were independently positively associated with all outcomes. Additive interactions of LRS and GRS were observed for all outcomes (P < 0.021). Comparing the top with bottom LRS quintile, prevalence differences (95% CIs) for obesity were 17.8% (15.9%, 19.7%) in the top GRS quintile and 10.7% (8.3%, 13.1%) in the bottom GRS quintile; for diabetes, CVD, and obesity-related cancer, incidence rate differences associated with per SD increase in LRS were greater in the top than that in the bottom GRS quintile. Participants from top quintiles of both LRS and GRS had 6.16-fold, 3.81-fold, 1.56-fold, and 1.44-fold higher odds/risks of obesity, diabetes, CVD, and obesity-related cancer, respectively, than those from bottom quintiles of both scores. CONCLUSIONS: Higher LRS was associated with higher obesity prevalence and risks of related chronic diseases regardless of GRS, highlighting the broad benefits of healthy lifestyles. Additive gene-lifestyle interactions emphasize the public health importance of lifestyle interventions among people with high genetic risks.

Long-Term Effect of Randomization to Calcium and Vitamin D Supplementation on Health in Older Women : Postintervention Follow-up of a Randomized Clinical Trial.

BACKGROUND: Although calcium and vitamin D (CaD) supplementation may affect chronic disease in older women, evidence of long-term effects on health outcomes is limited. OBJECTIVE: To evaluate long-term health outcomes among postmenopausal women in the Women's Health Initiative CaD trial. DESIGN: Post hoc analysis of long-term postintervention follow-up of the 7-year randomized intervention trial of CaD. (ClinicalTrials.gov: NCT00000611). SETTING: A multicenter (n = 40) trial across the United States. PARTICIPANTS: 36 282 postmenopausal women with no history of breast or colorectal cancer. INTERVENTION: Random 1:1 assignment to 1000 mg of calcium carbonate (400 mg of elemental calcium) with 400 IU of vitamin D3 daily or placebo. MEASUREMENTS: Incidence of colorectal, invasive breast, and total cancer; disease-specific and all-cause mortality; total cardiovascular disease (CVD); and hip fracture by randomization assignment (through December 2020). Analyses were stratified on personal supplement use. RESULTS: For women randomly assigned to CaD versus placebo, a 7% reduction in cancer mortality was observed after a median cumulative follow-up of 22.3 years (1817 vs. 1943 deaths; hazard ratio [HR], 0.93 [95% CI, 0.87 to 0.99]), along with a 6% increase in CVD mortality (2621 vs. 2420 deaths; HR, 1.06 [CI, 1.01 to 1.12]). There was no overall effect on other measures, including all-cause mortality (7834 vs. 7748 deaths; HR, 1.00 [CI, 0.97 to 1.03]). Estimates for cancer incidence varied widely when stratified by whether participants reported supplement use before randomization, whereas estimates on mortality did not vary, except for CVD mortality. LIMITATION: Hip fracture and CVD outcomes were available on only a subset of participants, and effects of calcium versus vitamin D versus joint supplementation could not be disentangled. CONCLUSION: Calcium and vitamin D supplements seemed to reduce cancer mortality and increase CVD mortality after more than 20 years of follow-up among postmenopausal women, with no effect on all-cause mortality. PRIMARY FUNDING SOURCE: National Heart, Lung, and Blood Institute of the National Institutes of Health.

Temporal changes in mammographic breast density and breast cancer risk among women with benign breast disease.

INTRODUCTION: Benign breast disease (BBD) and high mammographic breast density (MBD) are prevalent and independent risk factors for invasive breast cancer. It has been suggested that temporal changes in MBD may impact future invasive breast cancer risk, but this has not been studied among women with BBD. METHODS: We undertook a nested case-control study within a cohort of 15,395 women with BBD in Kaiser Permanente Northwest (KPNW; 1970-2012, followed through mid-2015). Cases (n = 261) developed invasive breast cancer > 1 year after BBD diagnosis, whereas controls (n = 249) did not have breast cancer by the case diagnosis date. Cases and controls were individually matched on BBD diagnosis age and plan membership duration. Standardized %MBD change (per 2 years), categorized as stable/any increase (≥ 0%), minimal decrease of less than 5% or a decrease greater than or equal to 5%, was determined from baseline and follow-up mammograms. Associations between MBD change and breast cancer risk were examined using adjusted unconditional logistic regression. RESULTS: Overall, 64.5% (n = 329) of BBD patients had non-proliferative and 35.5% (n = 181) had proliferative disease with/without atypia. Women with an MBD decrease (≤ - 5%) were less likely to develop breast cancer (Odds Ratio (OR) 0.64; 95% Confidence Interval (CI) 0.38, 1.07) compared with women with minimal decreases. Associations were stronger among women ≥ 50 years at BBD diagnosis (OR 0.48; 95% CI 0.25, 0.92) and with proliferative BBD (OR 0.32; 95% CI 0.11, 0.99). DISCUSSION: Assessment of temporal MBD changes may inform risk monitoring among women with BBD, and strategies to actively reduce MBD may help decrease future breast cancer risk.

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.

Uncovering the genetic architecture and evolutionary roots of androgenetic alopecia in African men.

Androgenetic alopecia is a highly heritable trait. However, much of our understanding about the genetics of male pattern baldness comes from individuals of European descent. Here, we examined a novel dataset comprising 2,136 men from Ghana, Nigeria, Senegal, and South Africa that were genotyped using a custom array. We first tested how genetic predictions of baldness generalize from Europe to Africa, finding that polygenic scores from European GWAS yielded AUC statistics that ranged from 0.513 to 0.546, indicating that genetic predictions of baldness in African populations performed notably worse than in European populations. Subsequently, we conducted the first African GWAS of androgenetic alopecia, focusing on self-reported baldness patterns at age 45. After correcting for present age, population structure, and study site, we identified 266 moderately significant associations, 51 of which were independent (p-value < 10-5, r2 < 0.2). Most baldness associations were autosomal, and the X chromosomes does not appear to have a large impact on baldness in African men. Finally, we examined the evolutionary causes of continental differences in genetic architecture. Although Neanderthal alleles have previously been associated with skin and hair phenotypes, we did not find evidence that European-ascertained baldness hits were enriched for signatures of ancient introgression. Most loci that are associated with androgenetic alopecia are evolving neutrally. However, multiple baldness-associated SNPs near the EDA2R and AR genes have large allele frequency differences between continents. Collectively, our findings illustrate how evolutionary history contributes to the limited portability of genetic predictions across ancestries.

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.

The Breast Microbiome in Breast Cancer Risk and Progression: A Narrative Review.

A decade ago, studies in human populations first revealed the existence of a unique microbial community in the breast, a tissue historically viewed as sterile, with microbial origins seeded through the nipple and/or translocation from other body sites. Since then, research efforts have been made to characterize the microbiome in healthy and cancerous breast tissues. The purpose of this review is to summarize the current evidence for the association of the breast microbiome with breast cancer risk and progression. Briefly, while many studies have examined the breast microbiome in patients with breast cancer, and compared it with the microbiome of benign breast disease tissue or normal breast tissue, these studies have varied widely in their sample sizes, methods, and quality of evidence. Thus, while several large and rigorous cross-sectional studies have provided key evidence of an altered microbiome in breast tumors compared with normal adjacent and healthy control tissue, there are few consistent patterns of perturbed microbial taxa. In addition, only one large prospective study has provided evidence of a relationship between the breast tumor microbiota and cancer prognosis. Future research studies featuring large, well-characterized cohorts with prospective follow-up for breast cancer incidence, progression, and response to treatment are warranted.

Circulating levels of biomarkers and risk of ductal carcinoma in situ of the breast in the UK Biobank study.

Observational studies have shown associations between circulating levels of various biomarkers (eg, total cholesterol [TC], low-density lipoprotein cholesterol [LDL], insulin-like growth factor-1 [IGF-1], C-reactive protein [CRP] and glycated hemoglobin-1c [HbA1c]) and the risk of invasive breast cancer (IBC). Ductal carcinoma in situ of the breast (DCIS) is a nonobligate precursor of IBC and shares several risk factors with it. However, the relationship between these biomarkers and DCIS risk remains unexplored. We studied the association between circulating levels of TC, LDL-C, high-density lipoprotein cholesterol (HDL-C), Lipoprotein (a) (Lp-(a)), IGF-1, CRP and HbA1c, with the risk of DCIS in 156801women aged 40 to 69 years and breast cancer-free at enrolment when blood samples and information on demographic and health-related factors were collected. Incident cases of DCIS were ascertained during the follow-up via linkage to the UK cancer registries Multivariable-adjusted Cox proportional hazards models were used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations of interest. In all, 969 DCIS incident cases were diagnosed during 11.4 years of follow-up. Total cholesterol was inversely associated with the risk of DCIS (HRquintile(Q)5vsQ1 = 0.47, 95% CI: 0.27-0.82, Ptrend = .008). Conversely, LDL-C was positively associated with DCIS risk (HRQ3vsQ1 = 1.43, 95% CI: 1.01-2.04, HRQ4vsQ1 = 1.60, 95% CI: 1.04-2.47, HRQ5vsQ1 = 2.29, 95% CI: 1.36-3.88, Ptrend = .004). In postmenopausal women, CRP had a weak positive association with DCIS risk, while HbA1c showed a nonlinear association with the risk. These results, in conjunction with those from previous studies on IBC, provide support for the association of several biomarkers with the risk of an early stage of breast cancer.

Metabolic Syndrome and the Risk of Ductal Carcinoma In Situ of the Breast in the UK Biobank.

BACKGROUND: Metabolic syndrome (MetS), defined by the presence of three of more metabolic dysregulations such as hyperlipidemia, hyperinsulinemia, central obesity, and hypertension, has been associated with increased risk of cardiovascular disease, diabetes, and various cancers, including invasive breast cancer (IBC). Whether MetS is a risk factor for ductal carcinoma in situ of the breast (DCIS), a nonobligate precursor of IBC, remains unknown. METHODS: A total of 198,748 women ages 40 to 69 years, DCIS- and IBC-free at enrolment in UK Biobank, were included in the current study. Multivariable-adjusted Cox proportional hazards models were used to estimate the association between MetS and DCIS. RESULTS: A total of 1,251 DCIS cases were ascertained during an average follow-up of 11.4 years. There was no association between MetS and the risk of DCIS overall, or by menopausal status. Analysis of individual components of MetS showed an association between central obesity (waist circumference ≥88 cm) and increased DCIS risk in postmenopausal women. CONCLUSIONS: In this prospective study, we found no association between MetS and DCIS risk. IMPACT: The study findings do not support an association between MetS and this breast cancer precursor.

Hysterectomy, oophorectomy and risk of non-Hodgkin's lymphoma.

Hysterectomy is associated with an increased risk for adverse health outcomes. However, its connection to the risk of non-Hodgkin's lymphoma (NHL) remains unclear. The aims of our study were to investigate the associations between hysterectomy, oophorectomy and risk of NHL and its major subtypes (eg, diffuse large B-cell lymphoma [DLBCL]), and whether these associations were modified by exogenous hormone use. Postmenopausal women (n = 141,621) aged 50-79 years at enrollment (1993-1998) from the Women's Health Initiative were followed for an average of 17.2 years. Hysterectomy and oophorectomy were self-reported at baseline. Incident NHL cases were confirmed by central review of medical records and pathology reports. During the follow-up period, a total of 1719 women were diagnosed with NHL. Hysterectomy, regardless of oophorectomy status, was associated with an increased risk of NHL (hazard ratio [HR] = 1.23, 95% confidence interval [CI]: 1.05-1.44). Oophorectomy was not independently associated with NHL risk after adjusting for hysterectomy. When stratified by hormone use, the association between hysterectomy and NHL risk was confined to women who had never used hormone therapy (HR = 1.35, 95% CI: 1.06-1.71), especially for DLBCL subtype (P for interaction = .01), and to those who had undergone hysterectomy before the age of 55. Our large prospective study showed that hysterectomy was a risk factor of NHL. Findings varied by hormone use. Future studies incorporating detailed information on the types and indications of hysterectomy may deepen our understanding of the mechanisms underlying DLBCL development and its potential interactions with hormone use.

Heterogeneous genetic architectures and evolutionary genomics of prostate cancer in Sub-Saharan Africa.

Men of African descent have the highest prostate cancer (CaP) incidence and mortality rates, yet the genetic basis of CaP in African men has been understudied. We used genomic data from 3,963 CaP cases and 3,509 controls recruited in Ghana, Nigeria, Senegal, South Africa, and Uganda, to infer ancestry-specific genetic architectures and fine-mapped disease associations. Fifteen independent associations at 8q24.21, 6q22.1, and 11q13.3 reached genome-wide significance, including four novel associations. Intriguingly, multiple lead SNPs are private alleles, a pattern arising from recent mutations and the out-of-Africa bottleneck. These African-specific alleles contribute to haplotypes with odds ratios above 2.4. We found that the genetic architecture of CaP differs across Africa, with effect size differences contributing more to this heterogeneity than allele frequency differences. Population genetic analyses reveal that African CaP associations are largely governed by neutral evolution. Collectively, our findings emphasize the utility of conducting genetic studies that use diverse populations.

The association of the healthy eating index with risk of colorectal cancers (overall and by subsite) among Canadians.

BACKGROUND: Healthy dietary patterns characterized by high intake of fruits and vegetables, grains/cereals, and lean meat/fish, and low intake of red/processed meats and refined carbohydrates, have been shown to be associated with reduced risk of colorectal cancer, but evidence regarding their association with colorectal cancer subsites is limited. Hence, this study was conducted to assess the association of a healthy dietary pattern, as reflected in the Healthy Eating Index (HEI) (a composite score based on consumption of various food groups), with risk of colorectal cancer, overall and by subsite. METHODS: We conducted a case-cohort study in the Canadian Study of Diet, Lifestyle and Health (CSDLH). The study included all cases of incident colorectal cancer in the entire cohort, and an age-stratified subcohort of 3185 women and 2622 men. Cox regression models were used to estimate hazard ratios (HR) for the association between the HEI and the risk of colorectal cancer, overall and by subsite. We also assessed the association by sex and by selected metabolic factors. RESULTS: For both sexes combined, the highest quintile of the HEI score was inversely associated with risk of colorectal cancer, colon cancer and proximal colon cancer (HR: 0.65; 95% CI: 0. 49-0.85, HR: 0.60, 95% CI: 0.44-0.83 and HR: 0.54, 95% CI: 0.35-0.85, respectively). However, these associations were mostly observed among men (HR: 0.56; 95% CI: 0.38-0.81, HR: 0.44, 95% CI: 0.28-0.69 and HR: 0.26; 95% CI: 0.12-0.56, for colorectal cancer, colon cancer and proximal colon cancer, respectively; p-interactions=0.029, 0.032 and 0.063, respectively). An inverse association was also observed between the HEI and risk of colorectal cancer among normal weight participants, overweight/obese participants, non-smokers, non-alcohol drinkers and participants who were physically inactive. CONCLUSION: A healthy dietary pattern may reduce risk of colorectal cancer, particularly among men.