Postmenopausal Breast Cancer Incidence Research Articles

Multi-Trait Body Shape Phenotypes and Breast Cancer Risk in Postmenopausal Women: A Causal Mediation Analysis in the UK Biobank Cohort

Body shape phenotypes combining multiple anthropometric traits have been linked to postmenopausal breast cancer (BC). However, underlying biological pathways remain poorly understood. This study investigated to what extent the associations of body shapes with postmenopausal BC risk is mediated by biochemical markers. The study included 176,686 postmenopausal women from UK Biobank. Four body shape phenotypes were derived from principal component (PC) analysis of height, weight, body mass index, waist and hip circumferences, and waist-to-hip ratio (WHR). The four-way decomposition of the total effect was used to estimate mediation and interaction effects simultaneously as well as the mediated proportions. After 10.9 years median follow-up, 6,396 incident postmenopausal BC were diagnosed. There was strong evidence of positive associations between PC1 (general obesity) and PC2 (tall, low WHR), and BC risk. The association of PC1 with BC risk was positively mediated by testosterone and negatively by insulin-like growth factor-1 (IGF-1), with the overall proportion mediated (sum of the mediated interaction and pure indirect effect (PIE)) accounting for 11.4% (95% confidence intervals: 5.1 to 17.8%) and -12.2% (-20.5% to -4.0%) of the total effect, respectively. Small proportions of the association between PC2 and BC were mediated by IGF-1 (PIE: 2.8% (0.6 to 4.9%)), and sex hormone-binding globulin (SHBG) (PIE: -6.1% (-10.9% to -1.3%)). Our findings are consistent with differential pathways linking different body shapes with BC risk, with a suggestive mediation through testosterone and IGF-1 in the relationship of a generally obese body shape and BC risk, while IGF-1 and SHBG may mediate a tall/lean body shape-BC risk association.

Infertility and risk of postmenopausal breast cancer in the women's health initiative.

Although infertility (i.e., failure to conceive after ≥ 12months of trying) is strongly correlated with established breast cancer risk factors (e.g., nulliparity, number of pregnancies, and age at first pregnancy), its association with breast cancer incidence is not fully understood. Previous studies were primarily small clinic-based or registry studies with short follow-up and predominantly focused on premenopausal breast cancer. The objective of this study was to assess the relationship between infertility and postmenopausal breast cancer risk among participants in the Women's Health Initiative (analytic sample = 131,784; > 25years of follow-up). At study entry, participants were asked about their pregnancy history, infertility history, and diagnosed reasons for infertility. Incident breast cancers were self-reported with adjudication by trained physicians reviewing medical records. Cox proportional hazards models were used to estimate risk of incident postmenopausal breast cancer for women with infertility (overall and specific infertility diagnoses) compared to parous women with no history of infertility. We examined mediation of these associations by parity, age at first term pregnancy, postmenopausal hormone therapy use at baseline, age at menopause, breastfeeding, and oophorectomy. We observed a modest association between infertility (n = 23,406) and risk of postmenopausal breast cancer (HR = 1.07; 95% CI 1.02-1.13). The association was largely mediated by age at first term pregnancy (natural indirect effect: 46.4% mediated, CI 12.2-84.3%). These findings suggest that infertility may be modestly associated with future risk of postmenopausal breast cancer due to age at first pregnancy and highlight the importance of incorporating reproductive history across the life course into breast cancer analyses.

How does weight gain since the age of 18 years affect breast cancer risk in later life? A meta-analysis

Early life factors are important risk factors for breast cancer. The association between weight gain after age 18 and breast cancer risk is inconsistent across previous epidemiologic studies. To evaluate this association, we conducted a meta-analysis according to PRISMA guidelines and the established inclusion criteria. We performed a comprehensive literature search using Medline (Ovid), Embase, Scopus, Cochrane Library, and ClinicalTrials.gov to identify relevant studies published before June 3, 2022. Two reviewers independently reviewed the articles for final inclusion. Seventeen out of 4,725 unique studies met the selection criteria. The quality of studies was assessed using the Newcastle-Ottawa Scale (NOS), and all were of moderate to high quality with NOS scores ranging from 5 to 8. We included 17 studies (11 case-control, 6 cohort) in final analysis. In case-control studies, weight gain after age 18 was associated with an increased risk of breast cancer (odds ratio [OR] = 1.25; 95% CI = 1.07–1.48), when comparing the highest versus the lowest categories of weight gain. Menopausal status was a source of heterogeneity, with weight gain after age 18 associated with an increased risk of breast cancer in postmenopausal women (OR = 1.53; 95% CI = 1.40–1.68), but not in premenopausal women (OR = 1.01; 95% CI = 0.92–1.12). Additionally, a 5 kg increase in weight was positively associated with postmenopausal breast cancer risk (OR = 1.12; 95%CI = 1.05–1.21) in case-control studies. Findings from cohort studies were identical, with a positive association between weight gain after age 18 and breast cancer incidence in postmenopausal women (relative risk [RR] = 1.30; 95% CI = 1.09–1.36), but not in premenopausal women (RR = 1.06; 95% CI = 0.92–1.22). Weight gain after age 18 is a risk factor for postmenopausal breast cancer, highlighting the importance of weight control from early adulthood to reduce the incidence of postmenopausal breast cancer.

The risk of developing postmenopausal breast cancer from ambient exposures to selected volatile organic compounds

ObjectivesTo estimate associations between incident postmenopausal breast cancer and environmental concentrations of five ambient volatile organic compounds (VOCs): benzene, hexane; ethylbenzene; n-decane; and 1,2,4-trimethylbenzene. MethodsWe conducted in Montreal a hospital-based case-control study between 1996 and 1997 and a population-based study between 2008 and 2011 of incident postmenopausal breast cancer. We measured five VOCs at about 130 locations during three sampling periods in 2005–2006 and we then used Bayesian geostatistical models to estimate concentrations of the VOCs at residential locations of participants in the two studies at the time of recruitment. We developed a directed acyclic graph to account for confounding but because of concerns with mis-specified models we used a series of unconditional logistic regression models to adjust for different combinations of personal risk factors, occupational exposures attributed by experts, air pollution data, and contextual variables. We estimated odds ratios (OR) for increases in concentrations across the interquartile ranges of the VOCs and associated 95% confidence intervals (CI). ResultsIn each study, we found that the ORs for each VOC were similar across the statistical models. In the hospital-based study, the ORs for the five VOCs varied between 0.77 and 1.04. In the population-based study, higher ORs were found for three VOCs: benzene, ORModel-7 = 1.12 (95%CI: 0.95, 1.31); hexane, ORModel-7 = 1.11 (95%CI: 0.97, 1.27); and 1,2,4-trimethyl-benzene, ORModel-7 = 1.07 (95%CI: 0.88, 1.31). We did not find important differences in sub-analyses by hormonal phenotype. ConclusionsIn the hospital-based study we did not find evidence of associations with these VOCs but in the population-based study there were indications of positive associations for environmental exposures to benzene and hexane.

The association between the incidence of postmenopausal breast cancer and occupational exposure to selected organic solvents, Montreal, Canada, 2008-2011.

Breast cancer is the most diagnosed cancer among women and recognized risk factors explain 25%-47% of cases. Organic solvents are used widely in the workplace and exposure may increase the risk of developing breast cancer, yet there are insufficient data to confirm this hypothesis. We sought to determine whether past occupational exposures to selected organic solvents were associated with the incidence of invasive breast cancer in postmenopausal women in Montréal, Canada. From a population-based case-control study (2008-2011), using in-depth interviews we elicited information on risk factors and lifetime occupational histories. Industrial hygienists and chemists translated job descriptions into specific chemical and physical exposures. We assessed 11 individual solvents and four solvent groups. Unconditional logistic regression was used to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for metrics of past exposures to selected solvents. Exposure metrics included any previous exposure, average frequency in hours per week, duration in years, and average cumulative concentration weighted by hours per workweek exposed. We enrolled 695 cases and 608 controls. We found increased ORs for average cumulative concentration of exposure to mononuclear aromatic hydrocarbons (OR: 1.52, 95%CI: 1.04, 2.28), chlorinated alkanes (OR: 2.42, 95%CI: 1.23, 5.68), toluene (OR: 1.59, 95%CI: 1.02, 2.59), and a group of organic solvents with reactive metabolites (OR: 1.53, 95%CI: 1.08, 2.24). Positive associations were found across all exposure metrics and were higher among women with estrogen-positive/progesterone-negative tumors. Our findings suggest occupational exposure to certain organic solvents may increase the risk of incident postmenopausal breast cancer.

Combining machine learning with Cox models to identify predictors for incident post-menopausal breast cancer in the UK Biobank

We aimed to identify potential novel predictors for breast cancer among post-menopausal women, with pre-specified interest in the role of polygenic risk scores (PRS) for risk prediction. We utilised an analysis pipeline where machine learning was used for feature selection, prior to risk prediction by classical statistical models. An “extreme gradient boosting” (XGBoost) machine with Shapley feature-importance measures were used for feature selection among approx 1.7 k features in 104,313 post-menopausal women from the UK Biobank. We constructed and compared the “augmented” Cox model (incorporating the two PRS, known and novel predictors) with a “baseline” Cox model (incorporating the two PRS and known predictors) for risk prediction. Both of the two PRS were significant in the augmented Cox model (p<0.001). XGBoost identified 10 novel features, among which five showed significant associations with post-menopausal breast cancer: plasma urea (HR = 0.95, 95% CI 0.92–0.98, p<0.001), plasma phosphate (HR = 0.68, 95% CI 0.53–0.88, p=0.003), basal metabolic rate (HR = 1.17, 95% CI 1.11–1.24, p<0.001), red blood cell count (HR = 1.21, 95% CI 1.08–1.35, p<0.001), and creatinine in urine (HR = 1.05, 95% CI 1.01–1.09, p=0.006). Risk discrimination was maintained in the augmented Cox model, yielding C-index 0.673 vs 0.667 (baseline Cox model) with the training data and 0.665 vs 0.664 with the test data. We identified blood/urine biomarkers as potential novel predictors for post-menopausal breast cancer. Our findings provide new insights to breast cancer risk. Future research should validate novel predictors, investigate using multiple PRS and more precise anthropometry measures for better breast cancer risk prediction.

Metabolically defined body size and body shape phenotypes and risk of postmenopausal breast cancer in the European Prospective Investigation into Cancer and Nutrition.

Excess body fatness and hyperinsulinemia are both associated with an increased risk of postmenopausal breast cancer. However, whether women with high body fatness but normal insulin levels or those with normal body fatness and high levels of insulin are at elevated risk of breast cancer is not known. We investigated the associations of metabolically defined body size and shape phenotypes with the risk of postmenopausal breast cancer in a nested case-control study within the European Prospective Investigation into Cancer and Nutrition. Concentrations of C-peptide-a marker for insulin secretion-were measured at inclusion prior to cancer diagnosis in serum from 610 incident postmenopausal breast cancer cases and 1130 matched controls. C-peptide concentrations among the control participants were used to define metabolically healthy (MH; in first tertile) and metabolically unhealthy (MU; >1st tertile) status. We created four metabolic health/body size phenotype categories by combining the metabolic health definitions with normal weight (NW; BMI < 25 kg/m2 , or WC < 80 cm, or WHR < 0.8) and overweight or obese (OW/OB; BMI ≥ 25 kg/m2 , or WC ≥ 80 cm, or WHR ≥ 0.8) status for each of the three anthropometric measures separately: (1) MHNW, (2) MHOW/OB, (3) MUNW, and (4) MUOW/OB. Conditional logistic regression was used to compute odds ratios (ORs) and 95% confidence intervals (CIs). Women classified as MUOW/OB were at higher risk of postmenopausal breast cancer compared to MHNW women considering BMI (OR = 1.58, 95% CI = 1.14-2.19) and WC (OR = 1.51, 95% CI = 1.09-2.08) cut points and there was also a suggestive increased risk for the WHR (OR = 1.29, 95% CI = 0.94-1.77) definition. Conversely, women with the MHOW/OB and MUNW were not at statistically significant elevated risk of postmenopausal breast cancer risk compared to MHNW women. These findings suggest that being overweight or obese and metabolically unhealthy raises risk of postmenopausal breast cancer while overweight or obese women with normal insulin levels are not at higher risk. Additional research should consider the combined utility of anthropometric measures with metabolic parameters in predicting breast cancer risk.

Associations of body fat mass and fat-free mass with breast cancer incidence in postmenopausal women: A Danish prospective cohort study.

Previous studies have established associations between body mass index and breast cancer, but fat mass is a more direct measure of the amount of fat tissue in the body than body mass index. This study examined the association between body fat mass, fat-free mass, and other anthropometric measures and breast cancer in postmenopausal women according to use of hormone replacement therapy (HRT). From the Danish Diet, Cancer and Health cohort established during 1993-1997, 24,219 postmenopausal women were included who had anthropometric and bioimpedance measurements performed by a laboratory technician at baseline. Information on breast cancer incidence (outcome), other cancer diagnoses, and vital status (censoring variables) through 2016 was obtained from nationwide registers. Cox regression models were used to estimate hazard ratios (HR) and 95% confidence intervals (CIs) while adjusting for known breast cancer risk factors and stratifying by HRT use and running age. During a total of 431,104 person-years, 1919 women developed breast cancer. Among never-users of HRT, the HR for breast cancer at or after age 65 years was 1.06 (95% CI, 1.03-1.08) per 1kg/m2 higher body fat mass index (BFMI), and 1.30 (95% CI, 1.14-1.47) per 10% higher body fat percentage.Thecorresponding HRs for breast cancer before age 65 years were close to unity. The HRs were 1.11 (95% CI, 1.02-1.21) and 1.17 (95% CI, 1.10-1.23) for each 1kg/m2 increase in fat-free mass index, respectively, for breast cancer below and above age 65 years. Mutual adjustment attenuated the HRs for BFMI and body fat percentage, whereas the HRs for fat-free mass index were largely unaffected. Among ever-users of HRT, there was no statistical significant association between any of the body composition measures and breast cancer incidence in the two age groups. Among postmenopausal women who never used HRT, BFMI was associated with breast cancer in women aged 65 years or older. Fat-free mass index was found to be more strongly associated with postmenopausal breast cancer incidence than BFMI independently of age in never-users of HRT.

Accelerometer-measured physical activity and postmenopausal breast cancer incidence in the Women's Health Accelerometry Collaboration.

Few studies have examined accelerometer-measured physical activity and incident breast cancer (BC). Thus, this study examined associations between accelerometer-measured vector magnitude counts per 15 seconds (VM/15s) and average daily minutes of light physical activity (LPA), moderate-to-vigorous PA (MVPA), and total PA (TPA) and BC risk among women in the Women's Health Accelerometry Collaboration (WHAC). The WHAC comprised 21,089 postmenopausal women (15,375 from the Women's Health Study [WHS]; 5714 from the Women's Health Initiative Objective Physical Activity and Cardiovascular Health Study [OPACH]). Women wore an ActiGraph GT3X+on the hip for ≥4days and were followed for 7.4 average years to identify physician-adjudicated in situ (n=94) or invasive (n=546) BCs. Multivariable stratified Cox regression estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for tertiles of physical activity measures in association with incident BC overall and by cohort. Effect measure modification wasexaminedby age, race/ethnicity, and body mass index (BMI). In covariate-adjusted models, the highest (vs. lowest) tertiles of VM/15s, TPA, LPA, and MVPA were associated with BC HRs of 0.80 (95% CI, 0.64-0.99), 0.84 (95% CI,0.69-1.02), 0.89 (95% CI,0.73-1.08), and 0.81 (95% CI,0.64-1.01), respectively. Further adjustment for BMI or physical function attenuated these associations. Associations were more pronounced among OPACH than WHS women for VM/15s, MVPA, and TPA; younger than older women for MVPA; and women with BMI ≥30 than <30kg/m2 for LPA. Greater levels of accelerometer-assessed PA were associated with lower BC risk. Associations varied by age and obesity and were not independent of BMI or physical function.

Body Mass Index Is Inversely Associated with Risk of Postmenopausal Interval Breast Cancer: Results from the Women's Health Initiative.

Simple SummaryBreast cancer diagnosed between a negative screening mammogram and the next regularly scheduled mammographic exam is called interval breast cancer. It is often diagnosed at more advanced stages than screening-detected cancers. While body mass index (BMI) is a risk factor for postmenopausal breast cancer overall and can influence the accuracy of mammography, the association of BMI with postmenopausal interval breast cancer is unclear. Using data from the Women’s Health Initiative, a national study among postmenopausal women, we found that lower BMI was significantly associated with a higher risk of interval breast cancers diagnosed within 1 year of a negative mammogram after adjustment for multiple risk factors. These findings suggest that obesity is associated with a lower risk of postmenopausal interval breast cancer. Future research using body composition measures is warranted to confirm our findings.Interval breast cancer refers to cancer diagnosed after a negative screening mammogram and before the next scheduled screening mammogram. Interval breast cancer has worse prognosis than screening-detected cancer. Body mass index (BMI) influences the accuracy of mammography and overall postmenopausal breast cancer risk, yet how is obesity associated with postmenopausal interval breast cancer incidence is unclear. The current study included cancer-free postmenopausal women aged 50–79 years at enrollment in the Women’s Health Initiative who were diagnosed with breast cancer during follow-up. Analyses include 324 interval breast cancer cases diagnosed within one year after the participant’s last negative screening mammogram and 1969 screening-detected breast cancer patients. Obesity (BMI ≥ 30 kg/m2) was measured at baseline. Associations between obesity and incidence of interval cancer were determined by sequential logistic regression analyses. In multivariable-adjusted models, obesity was inversely associated with interval breast cancer risk [OR (95% CI) = 0.65 (0.46, 0.92)]. The inverse association persisted after excluding women diagnosed within 2 years [OR (95% CI) = 0.60 (0.42, 0.87)] or 4 years [OR (95% CI) = 0.56 (0.37, 0.86)] of enrollment, suggesting consistency of the association regardless of screening practices prior to trial entry. These findings warrant confirmation in studies with body composition measures.

Increase in postmenopausal women with distant stage breast cancer in the United States over the last 18 years: Who is the most at risk?

10537 Background: In the United States, Asian women have traditionally been considered at low risk for breast cancer; yet it is unknown how distant stage disease has trended by geographic, demographic, and modifiable risk factors since 2001. Methods: Data were obtained from the United States Cancer Statistics (USCS) program from 2001-2018, the Behavioral Risk Factor Surveillance System (BRFSS) from 2000-2018. SEER*Stat 8.3.9.2 and the Joinpoint regression program 4.9.0.0 were used to calculate the incidences and trends of distant stage breast cancer per 100,000 women. The trend was presented as average annual or biennial percent change (AAPC or ABPC). Results: Using the USCS program, the overall incidence of postmenopausal breast cancer decreased from 367.90 to 345.07 (per 100,000); however, the incidence of distant stage cancer increased from 16.75 to 19.77 (per 100,000) over 18 years. The incidence is the highest for Black, followed by White, Hispanic, and Asian women at 27.14, 19.86, 14.15, and 11.98 (per 100,000) in 2018, respectively. The annual increase is highest in Asian, followed by Black, White, and Hispanic women at 2.28%, 1.44%, 1.17%, and 0.87% (P &lt; 0.001), respectively. On intersection analysis, postmenopausal Asian women living in the Northeast have the highest annual rise at 2.54% (P = 0.004). BRFSS data revealed that the proportion of women non-compliant with screening mammograms decreased from 36.03% in 2000 to 20.93% in 2018. In 2018, Asian women were the most non-compliant followed by Hispanic, Black, and White women at 40.99%, 40.06%, 21.67%, and 18.17%, respectively. Over time, White, Black, and Hispanic women improved on compliance by 3.43%, 3.32%, and 1.24% (p &lt; 0.05) on screening rates biennially; however, Asian women have not made any improvement (ABPC 0.80%, p = 0.410). On intersectional analysis, the most non-compliant group in 2018 were Asian women in the Midwest at 54.48%. We then evaluated upstream social determinants of breast cancer, such as obesity. While the baseline incidence of obesity in Asian Americans is low compared to other racial groups, it has increased from 9.22 in 2001 to 13.67 (per 100,000) in 2016. Specifically, the incidence of obesity increased the most in postmenopausal Asian 65 to 74-year-olds at 3% compared to White, Hispanic, and Black Americans of the same age group at 2.5%, 2.2%, and 1.1% (p &lt; 0.05), respectively. Conclusions: Although the incidence of breast cancer has decreased in the United States since 2001, the rate of distant stage breast cancer continues to rise. Postmenopausal Asian women with distant stage breast cancer are increasing at the highest rate compared to other racial groups. Further, Asian women are more non-compliant with screening mammograms and have an increased rate of obesity. Tailored interventions are warranted to enhance primary and secondary prevention and decrease distant stage cancer in this high-risk group.

Increase in incidence of advanced-stage breast cancer in Asian women versus White women: Can this be explained by the lower utilization of mammograms?

10524 Background: To examine trends in postmenopausal breast cancer and mammogram utilization in Asian and White women in the United States. Methods: Data on postmenopausal breast cancer was obtained from the United States Cancer Statistics Public Use Database from 2001 and 2018. Rates of mammogram screening for women ages 18 and older were evaluated using the Behavioral Risk Factor Surveillance System (BRFSS) between 2000 and 2018. Obesity rates for women ages 18 and older were extracted from BRFSS between 2001 and 2016. SEER*Stat 8.3.8 and Joinpoint regression program 4.8.0.1 were used to calculate incidence trends. Breast cancer incidence and trends were described using average annual percent change (AAPC). Mammogram screening trends were described using average biennial percent change (ABPC). Obesity trends were described using AAPC. Age groups were divided into five-year or ten-year intervals. Results: The incidence of metastatic postmenopausal breast cancer in women was 19.48/100,000 in 2018 has increased by 1.03% annually over the past eighteen years (p = 0.000). In 2018, the incidence of advanced-stage breast cancer in Asian and White women was 12.17/100,000 and 19.17/100,000 respectively. Over time, the incidence of advanced-stage breast cancer has increased in Asian women by 2.19% annually (p = 0.000), but remained stable in White women. In a subset analysis of early-stage breast cancer, there was no difference in both Asian and White women. Using the BRFSS data, we evaluated the utilization of mammograms. In the overall population, 20.92% were newer screened and this was higher in Asian women at 40.99% compared to 18.17% in White women in the year 2018. Given the potential association of obesity and breast cancer, we then evaluated the rate of obesity in these two groups. Our data showed that the incidence of obesity was low in Asian women at 12.8% compared to 28.13% in White women. Conclusions: There is an increased incidence of advanced-stage breast cancer in Asian women in the U.S. Although Asian women are less obese but they are also less likely to undergo screening compared to White women.

Uric Acid Mediated the Association Between BMI and Postmenopausal Breast Cancer Incidence: A Bidirectional Mendelian Randomization Analysis and Prospective Cohort Study.

BackgroundObservational epidemiological studies have reported the associations of high body mass index (BMI) with elevated serum uric acid (UA) level and increased risk of postmenopausal breast cancer. However, whether UA is causally induced by BMI and functioned in the BMI–breast cancer relationship remains unclear.MethodsTo elucidate the causality direction between BMI and serum UA, the bidirectional Mendelian randomization (MR) analyses were performed by using summarized data from the largest Asian genome-wide association studies (GWAS) of BMI and UA carried out in over 150,000 Japanese populations. Then, a total of 19,518 postmenopausal women from the Dongfeng–Tongji (DFTJ) cohort (with a mean 8.2-year follow-up) were included and analyzed on the associations of BMI and serum UA with incidence risk of postmenopausal breast cancer by using multivariable Cox proportional hazard regression models. Mediation analysis was further conducted among DFTJ cohort to assess the intermediate role of serum UA in the BMI–breast cancer association.ResultsIn the bidirectional MR analyses, we observed that genetically determined BMI was causally associated with elevated serum UA [β(95% CI) = 0.225(0.111, 0.339), p < 0.001], but not vice versa. In the DFTJ cohort, each standard deviation (SD) increment in BMI (3.5 kg/m2) and UA (75.4 μmol/l) was associated with a separate 24% and 22% increased risk of postmenopausal breast cancer [HR(95% CI) = 1.24(1.07, 1.44) and 1.22(1.05, 1.42), respectively]. More importantly, serum UA could mediate 16.9% of the association between BMI and incident postmenopausal breast cancer.ConclusionsThe current findings revealed a causal effect of BMI on increasing serum UA and highlighted the mediating role of UA in the BMI–breast cancer relationship. Controlling the serum level of UA among overweight postmenopausal women may help to decrease their incident risk of breast cancer.

C/EBPB-dependent adaptation to palmitic acid promotes tumor formation in hormone receptor negative breast cancer

Epidemiological studies have established a positive association between obesity and the incidence of postmenopausal breast cancer. Moreover, it is known that obesity promotes stem cell-like properties of breast cancer cells. However, the cancer cell-autonomous mechanisms underlying this correlation are not well defined. Here we demonstrate that obesity-associated tumor formation is driven by cellular adaptation rather than expansion of pre-existing clones within the cancer cell population. While there is no correlation with specific mutations, cellular adaptation to obesity is governed by palmitic acid (PA) and leads to enhanced tumor formation capacity of breast cancer cells. This process is governed epigenetically through increased chromatin occupancy of the transcription factor CCAAT/enhancer-binding protein beta (C/EBPB). Obesity-induced epigenetic activation of C/EBPB regulates cancer stem-like properties by modulating the expression of key downstream regulators including CLDN1 and LCN2. Collectively, our findings demonstrate that obesity drives cellular adaptation to PA drives tumor initiation in the obese setting through activation of a C/EBPB dependent transcriptional network.

The association between the incidence of post-menopausal breast cancer and residential greenness

BackgroundThere is little data as to whether exposure to residential greenness is associated with the incidence of breast cancer. Lack of physical activity and obesity are two of the accepted risk factors for postmenopausal breast cancer and living near green areas may contribute to an active lifestyle and maintaining a normal body mass index and, consequently, residential greenness may be associated with lower incidence rates. ObjectivesThe objective of this study was to determine whether there was an association between past exposure to residential greenness and the incidence of invasive postmenopausal breast cancer among Canadian women living in Montreal, Quebec, in the mid-2000s. MethodsWe conducted a population-based, case-control study of incident postmenopausal breast cancer in Montreal, Canada, and herein we show analyses by level of greenness surrounding participants’ homes. Incident cases were identified between 2008 and 2011 from all but one hospital that treated breast cancer in the Montreal area. Population controls were identified from provincial electoral lists of Montreal residents and frequency-matched to cases on age. Residential greenness was estimated using the maximum daily normalized difference vegetation index averaged over the growing season (“maximum NDVI”). Maximum NDVI was assigned at the home address of recruitment for the years 1992–1998 (about 15 years before diagnosis), and we measured subjects’ personal information, exposure to NO2 and ultrafine particles, and area-wide variables to control for potential confounding effects. Odds ratios (OR) and 95% confidence intervals (CI) for breast cancer associated with residential greenness were estimated using logistic regression models adjusting for various combinations of potential confounders. We assessed the functional form of maximum NDVI using natural cubic splines. ResultsWe found that the response functions between incident postmenopausal breast cancer and maximum NDVI were consistent with linearity. The age-adjusted and fully-adjusted ORs, per increase in the interquartile range (IQR=0.13) of maximum NDVI measured with a 250 m buffer around residences, were 0.95 (95%CI: 0.86–1.04) and 1.00 (95%CI: 0.84–1.11), respectively. For maximum NDVI measured using a 1000 m buffer (IQR=0.05), these were 0.98 (95%CI: 0.94–1.02) and 0.99 (95%CI: 0.95–1.03), respectively. ConclusionsOur findings suggest that exposure to NDVI evaluated where participants were interviewed is not associated with the risk of incident postmenopausal breast cancer.

Can population breast screening programs be leveraged to reduce the burden of breast cancer?

Breast cancer (BC) is the most common cancer in women. A study of the temporal trends (1998–2012) in the age-standardised incidence rate in 41 countries showed that increased BC incidence rates had occurred in pre- and post-menopausal women [[1]Heer E. Harper A. Escandor N. Sung H. McCormack V. Fidler-Benaoudia M.M. Global burden and trends in premenopausal and postmenopausal breast cancer: a population-based study.Lancet Global Health. 2020; 8: e1027-e1037Abstract Full Text Full Text PDF PubMed Scopus (207) Google Scholar]. However, increases exclusively in premenopausal ages were observed mainly in high-income countries, whereas the largest increases in the incidence of postmenopausal BC were observed predominantly in countries undergoing socioeconomic transitions. These findings probably reflect changes in the prevalence of various lifestyle factors that are known to increase BC risk, many of which are inherent in the social and economic circumstances of a population. Although many of these factors, such as reproductive history, alcohol, and (lack of) physical activity, are associated with BC risk across the lifespan, some, for example body fat/obesity and weight gain in adulthood, are associated with post-menopausal BC [[2]World Cancer Research Fund/American Institute for Cancer ResearchDiet, nutrition, physical activity and cancer: a global perspective. Continuous update project expert report 2018.2018Google Scholar]. Mammography screening reduces the risk of BC death through detection and treatment of early-stage disease. Population-based programs have been providing mammography screening to women aged ≥40 years for decades, but screening represents secondary prevention so cannot curb the growing incidence of BC. The interplay of BC risk factors throughout an individual's lifetime renders primary prevention difficult at a population level. Therefore, prevention efforts have focused on subgroups at substantially increased BC risk in whom effective strategies, such as risk-reducing surgery or chemoprevention, may be appropriate. Neither of these strategies can be recommended to the majority of women who are at average BC risk or thereabouts, who routinely present for screening. Contemplation of a new approach to screening, namely risk-stratified screening, has progressed to formal trialling and includes an element of prevention for those at increased BC risk [[3]Pashayan N. Antoniou A.C. Ivanus U. et al.Personalized early detection and prevention of breast cancer: ENVISION consensus statement.Nat Rev Clin Oncol. 2020; 17: 687-705Crossref PubMed Scopus (76) Google Scholar,[4]Esserman L.J. WISDOM Study and Athena InvestigatorsThe WISDOM Study: breaking the deadlock in the breast cancer screening debate.NPJ Breast Cancer. 2017; 3: 34Crossref PubMed Google Scholar]. While results from risk-stratified screening trials are awaited, BC screening programs could be leveraged from now to explore primary prevention in the broader female population participating at periodic intervals and starting screening at an age potentially amenable to lifestyle-related prevention. The development, evaluation, and uptake of lifestyle-related (prevention) interventions will prove to be challenging and would require additional investments to be integrated into existing screening programs, however this approach has the potential to be offered to all screening program participants. Most BC screening programs have data collection and follow-up processes to monitor outcomes which could be expanded to capture data on lifestyle-related risk factors (eg BMI). Program-embedded pilot studies could be established as a first step to investigate the feasibility of integrating primary prevention strategies alongside mammography screening and to assess specific interventions. Consensus on meaningful surrogate outcomes would be needed because changes in incidence, or mortality outcomes, require 10–20 years or longer to be observed. Essential to this proposed approach is funding and a broadly collaborative approach between population screening programs, BC stakeholders including consumers and researchers, and co-designed interventions to ensure acceptability to women and cultural appropriateness. None to declare. I receive research funding via the NBCF Chair in Breast Cancer Prevention (grant #EC-21-001).

Association between overall diet quality and postmenopausal breast cancer risk in five Finnish cohort studies

There is limited evidence for any dietary factor, except alcohol, in breast cancer (BC) risk. Therefore, studies on a whole diet, using diet quality indices, can broaden our insight. We examined associations of the Nordic Diet (mNDI), Mediterranean diet (mMEDI) and Alternative Healthy Eating Index (mAHEI) with postmenopausal BC risk. Five Finnish cohorts were combined including 6374 postmenopausal women with dietary information. In all, 8–9 dietary components were aggregated in each index, higher total score indicating higher adherence to a healthy diet. Cox proportional hazards regression was used to estimate the combined hazard ratio (HR) and 95% confidence interval (CI) for BC risk. During an average 10-year follow-up period, 274 incident postmenopausal BC cases were diagnosed. In multivariable models, the HR for highest vs. lowest quintile of index was 0.67 (95 %CI 0.48–1.01) for mNDI, 0.88 (0.59–1.30) for mMEDI and 0.89 (0.60–1.32) for mAHEI. In this combined dataset, a borderline preventive finding of high adherence to mNDI on postmenopausal BC risk was found. Of the indices, mNDI was more based on the local food culture than the others. Although a healthy diet has beneficially been related to several chronic diseases, the link with the etiology of postmenopausal BC does not seem to be that obvious.

Combined Lifestyle Behaviors and the Incidence of Common Cancer Types in the Norwegian Women and Cancer Study (NOWAC).

IntroductionOnly a small number of studies have examined the impact of combined lifestyle behaviors on cancer incidence, and never in a Norwegian population.PurposeTo examine linear and nonlinear associations of combined lifestyle factors, assessed through a healthy lifestyle index (HLI), with the incidence of postmenopausal breast, colorectal, lung, postmenopausal endometrial, postmenopausal ovarian, pancreatic, and kidney cancer among women in Norway.MethodsThis prospective study included 96,869 women enrolled in the Norwegian Women and Cancer (NOWAC) cohort. Baseline information on lifestyle factors was collected between 1996 and 2004. The HLI was constructed from five lifestyle factors: physical activity level, body mass index, smoking, alcohol consumption, and diet. Each factor contributed 0 to 4 points to the HLI score, which ranged from 0 to 20, with higher scores representing a healthier lifestyle. Multiple imputation was used to handle missing data. Cox proportional hazard regression models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI). Restricted cubic splines were used to examine nonlinearity in the associations.ResultsThe HRs for a one-point increment on the HLI score were 0.97 (95% CI: 0.96–0.98) for postmenopausal breast cancer, 0.98 (0.96–1.00) for colorectal cancer, 0.86 (0.84–0.87) for lung cancer, 0.93 (0.91–0.95) for postmenopausal endometrial cancer, 0.99 (0.96–1.02) for postmenopausal ovarian cancer, 0.92 (0.89–0.95) for pancreatic cancer, and 0.94 (0.91–0.97) for kidney cancer. Nonlinearity was observed for the inverse associations between HLI score and the incidence of lung cancer and postmenopausal breast cancer.ConclusionBased on our results, healthier lifestyle, as assessed by the HLI score, was associated with lower incidence of postmenopausal breast, colorectal, lung, postmenopausal endometrial, pancreatic, and kidney cancer among women, although the magnitude and linearity varied. Adoption of healthier lifestyle behaviors should be a public health priority to reduce the cancer burden among Norwegian women.

Role of physical activity and metabolic syndrome in determining the risk of postmenopausal breast cancer: a systematic review

Physical activity (PA) and metabolic syndrome (MetS) have emerged as crucial factors in facilitating the incidence of postmenopausal (PM) breast cancer (BC). The association of PA, MetS and its components with PM BC was explored in this study. PRISMA guideline was followed and online databases were searched comprehensively to find relevant cohort and case-control studies until 18 February 2021 using keywords such as “physical activity”, “metabolic syndrome” and “breast cancer”. Eligible studies evaluating BC in postmenopausal women with a clear definition and measure of PA, MetS and its individual components were selected. A total of twenty-three articles related to PA and fifteen articles for MetS met the eligibility criteria and were assessed thoroughly. PA and MetS were significantly associated with PM BC. There was evidence of dose-response effect of PA and Mets on PM BC. Obesity, diabetes and dyslipidaemia were independently associated with PM BC and posed an increased risk on PM BC whereas the association of HPTN with PM BC was not prominent. Consistent and sustained long term PA throughout one’s lifetime was observed to decrease PM BC risk whereas increasing number of MetS components increased the risk of PM BC. Routine screening for PM women with ≥2 MetS components and obese or overweight women with any of the MetS components may be beneficial in early BC detection. Lifestyle modifications with emphasis on long term PA would be beneficial to public health in preventing and improving MetS outcomes as well as a primary prevention of sporadic PM BC.

Invited Perspective: Air Pollution and Breast Cancer Risk: Current State of the Evidence and Next Steps.

Invited Perspective: Air Pollution and Breast Cancer Risk: Current State of the Evidence and Next Steps.