Breast Cancer Prevention Strategies Research Articles

Real World Cost-Effectiveness Analysis of Population Screening for BRCA Variants among Ashkenazi Jews Compared with Family History-Based Strategies.

Identifying carriers of pathogenic BRCA1/BRCA2 variants reduces cancer morbidity and mortality through surveillance and prevention. We analyzed the cost-effectiveness of BRCA1/BRCA2 population screening (PS) in Ashkenazi Jews (AJ), for whom carrier rate is 2.5%, compared with two existing strategies: cascade testing (CT) in carrier's relatives (≥25% carrier probability) and international family history (IFH)-based guidelines (>10% probability). We used a decision analytic-model to estimate quality-adjusted life-years (QALY) gained, and incremental cost-effectiveness ratio for PS vs. alternative strategies. Analysis was conducted from payer-perspective, based on actual costs. Per 1000 women, the model predicted 21.6 QALYs gained, a lifetime decrease of three breast cancer (BC) and four ovarian cancer (OC) cases for PS vs. CT, and 6.3 QALYs gained, a lifetime decrease of 1 BC and 1 OC cases comparing PS vs. IFH. PS was less costly compared with CT (-3097 USD/QALY), and more costly than IFH (+42,261 USD/QALY), yet still cost-effective, from a public health policy perspective. Our results are robust to sensitivity analysis; PS was the most effective strategy in all analyses. PS is highly cost-effective, and the most effective screening strategy for breast and ovarian cancer prevention. BRCA testing should be available to all AJ women, irrespective of family history.

Association of dietary n - 3 polyunsaturated fatty acids with breast cancer risk: Serial mediating roles of erythrocyte n - 3 polyunsaturated fatty acids

Dietary n - 3 polyunsaturated fatty acids (PUFAs) were found to be inversely associated with breast cancer risk; however, the underlying pathways between them remain uncertain. We aimed to explore serial mediatory roles of erythrocyte n - 3 PUFAs in association between dietary n - 3 PUFAs and breast cancer risk. Using a case-control study, 850 cases and 861 controls completed structured questionnaires with dietary information. Erythrocyte n - 3 PUFAs were measured by gas chromatography. Odds ratios (ORs) and 95% confidence intervals (CIs) were obtained using multiple unconditional logistic regression models to examine association between dietary n - 3 PUFAs and breast cancer risk. Mediation analyses with bootstrapping were conducted to investigate indirect effects. Higher intake of dietary ALA, long-chain n - 3 PUFAs and total n - 3 PUFAs was associated with lower risk of breast cancer. The adjusted OR tertile 3 v.1 (95% CI) was 0.70 (0.55, 0.90) for ALA, 0.76 (0.60, 0.97) for long-chain n - 3 PUFAs and 0.74 (0.58, 0.94) for total n - 3 PUFAs, respectively. Mediation analysis showed that erythrocyte long-chain n - 3 PUFAs served as sequential mediators in the relationship between dietary long-chain or total n - 3 PUFAs and breast cancer risk. In particular, erythrocyte long-chain n - 3 PUFAs completely mediated the association between dietary long-chain n - 3 PUFAs and breast cancer risk [indirect effect (95% CI) = -0.982 (-1.529, -0.508)]. The relationship between dietary total n - 3 PUFAs and breast cancer risk was partly mediated by erythrocyte long-chain n - 3 PUFAs [indirect effect (95% CI) = -0.107 (-0.216, -0.014)], accounting for 19.31%. However, the serial mediation model in dietary ALA and risk of breast cancer was not statistically significant [indirect effect (95% CI) = -0.042 (-0.144, 0.049)]. This study highlights the complexity and inaccuracy in using a simple analysis of individual dietary n - 3 PUFAs to examine their associations with breast cancer risk without considering the variety of metabolic processes. Interventions aimed at increasing erythrocyte long-chain n - 3 PUFAs may represent a promising strategy for breast cancer prevention.

Awareness about preventive measures that reduce the risk of breast cancer among menopausal women

Background: Breast cancer is the most common malignant cancer and the second leading cause of cancer death in women. In 2020, there were 2.3 million women diagnosed with breast cancer and 6,85,000 deaths globally. Mortality due to breast cancer is found to be high in the developing countries because they seek medical attention at advanced stages due to lack of awareness and low socio-economic status. As there is no uniform education policy for breast cancer prevention and there is no acceptable strategy for breast cancer prevention throughout the nation, we thought to assess about awareness of preventive measures that reduce risk of breast cancer in menopausal women.Methods: For data collection, consent was taken from the participants and a questionnaire was given to them through Google form. Once the data was collected, descriptive data analysis was done on it.Results: This study found that 80.6% of women are aware of the term ‘breast cancer’ in general. Women are comparatively more aware about primary preventive measures than about secondary preventive measures. The study also found that some women have myths regarding risk factors and preventive measures of breast cancer.Conclusions: The study found that women are more aware about primary preventive measures than about secondary preventive measures. Also, some women have myths regarding risk factors and preventive measures of breast cancer.

Breast density is strongly associated with multiparametric magnetic resonance imaging biomarkers and pro-tumorigenic proteins in situ

BackgroundHigh mammographic density is an independent risk factor for breast cancer by poorly understood molecular mechanisms. Women with dense breasts often undergo conventional magnetic resonance imaging (MRI) despite its limited specificity, which may be increased by diffusion-weighted imaging (DWI) with apparent diffusion coefficient (ADC) and contrast. How these modalities are affected by breast density per se and their association with the local microenvironment are undetermined.MethodsHealthy postmenopausal women attending mammography screen with extremely dense or entirely fatty breasts underwent multiparametric MRI for analyses of lean tissue fraction (LTF), ADC and perfusion dynamics. Microdialysis was used for extracellular proteomics in situ.ResultsSignificantly increased LTF and ADC and delayed perfusion were detected in dense breasts. In total, 270 proteins were quantified, whereof 124 related to inflammation, angiogenesis, and cellular growth were significantly upregulated in dense breasts. Most of these correlated significantly with LTF, ADC and the perfusion data.ConclusionsADC and perfusion characteristics depend on breast density, which should be considered during the implementation of thresholds for malignant lesions. Dense and nondense breasts are two essentially different biological entities, with a pro-tumorigenic microenvironment in dense breasts. Our data reveal several novel pathways that may be explored for breast cancer prevention strategies.

Modulating Microbiota as a New Strategy for Breast Cancer Prevention and Treatment.

Breast cancer (BC) is the most common cancer in women in the United States. There has been an increasing incidence and decreasing mortality rate of BC cases over the past several decades. Many risk factors are associated with BC, such as diet, aging, personal and family history, obesity, and some environmental factors. Recent studies have shown that healthy individuals and BC patients have different microbiota composition, indicating that microbiome is a new risk factor for BC. Gut and breast microbiota alterations are associated with BC prognosis. This review will evaluate altered microbiota populations in gut, breast tissue, and milk of BC patients, as well as mechanisms of interactions between microbiota modulation and BC. Probiotics and prebiotics are commercially available dietary supplements to alleviate side-effects of cancer therapies. They also shape the population of human gut microbiome. This review evaluates novel means of modulating microbiota by nutritional treatment with probiotics and prebiotics as emerging and promising strategies for prevention and treatment of BC. The mechanistic role of probiotic and prebiotics partially depend on alterations in estrogen metabolism, systematic immune regulation, and epigenetics regulation.

ERα-LBD, an isoform of estrogen receptor alpha, promotes breast cancer proliferation and endocrine resistance

Estrogen receptor alpha (ERα) drives mammary gland development and breast cancer (BC) growth through an evolutionarily conserved linkage of DNA binding and hormone activation functions. Therapeutic targeting of the hormone binding pocket is a widely utilized and successful strategy for breast cancer prevention and treatment. However, resistance to this endocrine therapy is frequently encountered and may occur through bypass or reactivation of ER-regulated transcriptional programs. We now identify the induction of an ERα isoform, ERα-LBD, that is encoded by an alternative ESR1 transcript and lacks the activation function and DNA binding domains. Despite lacking the transcriptional activity, ERα-LBD is found to promote breast cancer growth and resistance to the ERα antagonist fulvestrant. ERα-LBD is predominantly localized to the cytoplasm and mitochondria of BC cells and leads to enhanced glycolysis, respiration and stem-like features. Intriguingly, ERα-LBD expression and function does not appear to be restricted to cancers that express full length ERα but also promotes growth of triple-negative breast cancers and ERα-LBD transcript (ESR1-LBD) is also present in BC samples from both ERα(+) and ERα(−) human tumors. These findings point to ERα-LBD as a potential mediator of breast cancer progression and therapy resistance.

Recombinant human chorionic gonadotropin induces signaling pathways towards cancer prevention in the breast of BRCA1/2 mutation carriers.

Strategies for breast cancer prevention in women with germline BRCA1/2 mutations are limited. We previously showed that recombinant human chorionic gonadotropin (r-hCG) induces mammary gland differentiation and inhibits mammary tumorigenesis in rats. The present study investigated hCG-induced signaling pathways in the breast of young nulliparous women carrying germline BRCA1/2 mutations. We performed RNA-sequencing on breast tissues from 25 BRCA1/2 mutation carriers who received r-hCG treatment for 3 months in a phase II clinical trial, we analyzed the biological processes, reactome pathways, canonical pathways, and upstream regulators associated with genes differentially expressed after r-hCG treatment, and validated genes of interest. We observed that r-hCG induces remarkable transcriptomic changes in the breast of BRCA1/2 carriers, especially in genes related to cell development, cell differentiation, cell cycle, apoptosis, DNA repair, chromatin remodeling, and G protein-coupled receptor signaling. We revealed that r-hCG inhibits Wnt/β-catenin signaling, MYC, HMGA1 , and HOTAIR , whereas activates TGFB/TGFBR-SMAD2/3/4, BRCA1, TP53, and upregulates BRCA1 protein. Our data suggest that the use of r-hCG at young age may reduce the risk of breast cancer in BRCA1/2 carriers by inhibiting pathways associated with stem/progenitor cell maintenance and neoplastic transformation, whereas activating genes crucial for breast epithelial differentiation and lineage commitment, and DNA repair.

Association of lipid profile biomarkers with breast cancer by molecular subtype: analysis of the MEND study

There is conflicting evidence on the role of lipid biomarkers in breast cancer (BC), and no study to our knowledge has examined this association among African women. We estimated odds ratios (ORs) and 95% confidence intervals (95% CI) for the association of lipid biomarkers—total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), and triglycerides—with odds of BC overall and by subtype (Luminal A, Luminal B, HER2-enriched and triple-negative or TNBC) for 296 newly diagnosed BC cases and 116 healthy controls in Nigeria. Each unit standard deviation (SD) increase in triglycerides was associated with 39% increased odds of BC in fully adjusted models (aOR: 1.39; 95% CI: 1.03, 1.86). Among post-menopausal women, higher total cholesterol (aOR: 1.65; 95% CI: 1.06, 2.57), LDL cholesterol (aOR: 1.59; 95% CI: 1.04, 2.41), and triglycerides (aOR: 1.91; 95% CI: 1.21, 3.01) were associated with increased odds of BC. Additionally, each unit SD increase in LDL was associated with 64% increased odds of Luminal B BC (aOR 1.64; 95% CI: 1.06, 2.55). Clinically low HDL was associated with 2.7 times increased odds of TNBC (aOR 2.67; 95% CI: 1.10, 6.49). Among post-menopausal women, higher LDL cholesterol and triglycerides were significantly associated with increased odds of Luminal B BC and HER2 BC, respectively. In conclusion, low HDL and high LDL are associated with increased odds of TN and Luminal B BC, respectively, among African women. Future prospective studies can definitively characterize this association and inform clinical approaches targeting HDL as a BC prevention strategy.

Global Burden of Female Breast Cancer: Age-Period-Cohort Analysis of Incidence Trends From 1990 to 2019 and Forecasts for 2035

IntroductionThis study aimed to describe the latest epidemiology of female breast cancer globally, analyze the change pattern of the incidence rates and the disease’s association with age, period, and birth cohort, and subsequently present a forecast of breast cancer incidence.MethodsData for analysis were obtained from Global Burden of Disease (GBD) Study 2019 and World Population Prospects 2019 revision by the United Nations (UN). We described the age-standardized incidence rates (ASIRs) from 1990 to 2019 and then calculated the relative risks of period and cohort using an age-period-cohort model, and predicted the trends of ASIRs to 2035.ResultsIn 2019, the global incidence of breast cancer in women increased to 1,977,212 (95% uncertainty interval = 1 807 615 to 2 145 215), with an ASIR of 45.86 (41.91 to 49.76) per 100 000 person-year. Among the six selected countries facing burdensome ASIRs, only the USA showed a downward trend from 1990 to 2019, whereas the others showed an increasing or stable trend. The overall net drift was similar in Japan (1.78%), India (1.66%), and Russia (1.27%), reflecting increasing morbidity from 1990 to 2019. The increase in morbidity was particularly striking in China (2.60%) and not significant in Germany (0.42%). The ASIRs were predicted to continue to increase globally, from 45.26 in 2010 to 47.36 in 2035. In most countries and regions, the age specific incidence rate is the highest in those aged over 70 years and will increase in all age groups until 2035. In high-income regions, the age specific incidence rates are expected to decline in women aged over 50 years.ConclusionsThe global burden of female breast cancer is becoming more serious, especially in developing countries. Raising awareness of the risk factors and prevention strategies for female breast cancer is necessary to reduce future burden.

Physical activity and the risk of breast cancer among Nigerian women

BackgroundAlthough physical activity has been associated with a reduced risk of breast cancer risk in high income countries (HIC), its role has not been widely studied in sub-Saharan Africa. Our aim was to investigate the association between physical activity (PA) and the risk of breast cancer in Nigeria. MethodsWe conducted a hospital-based case-control study involving participants from five hospitals in Lagos and Abuja. Women were interviewed in-person between October 2016 and May 2017 using a semi-structured questionnaire. Total PA was estimated by summing occupational, household, transport and leisure PA scores. PA was summarised as metabolic equivalents (MET) hours per week (MET-hr/wk). The putative association between breast cancer incidence and PA was analysed using multivariable logistic regression. Results379 histologically confirmed breast cancer cases and 403 controls took part. Compared to women in the lowest categories, women in the upper middle category of total PA(adjusted OR-AOR 0.44, 95% CI: 0.27, 0.78),uppermost categories of total non-vigorous PA (AOR 0.26, 95%CI:0.09,0.75), household PA(AOR 0.0.38, 95% CI: 0.20, 0.71) and occupational PA (AOR 0.64, 95% 0.40, 1.02) had a reduced risk of breast cancer following adjustment for relevant confounders. Transport and leisure PA were not significantly associated with a reduced risk of breast cancer. ConclusionThe total effect of various PA related to regular activities of Nigerian women was associated with a reduced risk of breast cancer. PA especially at household and occupational environments should be promoted as part of breast cancer prevention strategy in Nigeria.

Assessment of repeated reference measurements to inform the validity of optical breast spectroscopy.

Mammographic breast density is a strong breast cancer risk factor, and its routine clinical measurement could potentially be used to identify women at higher risk of breast cancer and/or monitor primary prevention strategies. Previous reports of optical breast spectroscopy (OBS), a novel approach to measuring breast density, demonstrated that it is safe (no ionizing radiation), portable, low-cost, and does not require image interpretation but have been limited to small, single-center studies. Reference measurements taken on a phantom breast prior to and after each woman's OBS assessment are required for the calibration of the system transfer function as a part of processing participant data. To inform the validity of participant data, a detailed description of the reference measurements and a repeatability analysis of these measurements taken before and after participant assessment is presented. Reference measurements for OBS from 539 women aged 18-40 years were obtained as a part of a high-throughput epidemiological pilot study. Of these, measurements from 20 women with no useable data due to device failure (3.7%) were excluded and from another 12 women due to user error. The intra-class correlation (ICC) within complete pairs of reference data (taken before and after assessment) was high (all ICC > 0.84). The analysis presented here confirms the OBS participant data as valid for use in ongoing epidemiological research, providing further supporting evidence of OBS as a measure of breast density. A novel method of measuring breast density is needed to bridge large gaps in the knowledge of breast density in younger women and its relation to later-life breast cancer risk.

Abstract P2-10-03: Improving breast cancer risk prediction using a convolutional neural network-based mammographic evaluation in combination with clinical risk factors

Abstract Background: Accurate assessment of a woman’s individualized breast cancer risk is necessary to inform shared decision-making regarding screening and risk-reducing strategies. Recently, deep learning techniques, including convolutional neural networks (CNN), have shown better predictive potential for breast cancer risk compared to mammographic density (MD). We evaluated whether combining clinical factors in the Breast Cancer Surveillance Consortium (BCSC) model, including MD, with a novel CNN-based mammographic evaluation more accurately predicts breast cancer risk than the BCSC model alone in a cohort of racially/ethnically diverse women. Methods: We conducted a retrospective cohort study of 23,552 women, age 35-74 years, who underwent screening mammography from 2014 to 2018 at Columbia University Irving Medical Center in New York City. We extracted data from the electronic health record (EHR) on breast cancer risk factors (age, race/ethnicity, prior benign breast biopsy, first degree family history of breast cancer, and MD). From this cohort, we identified 206 women who developed breast cancer by linkage to the tumor registry. We calculated 5-year invasive breast cancer risk using the BCSC model. We applied CNN-based breast cancer risk model to full-field craniocaudal mammographic views of both breasts, with an output of a risk score (range, 0-1). We used logistic regression models with breast cancer status as the outcome and predictors including clinical factors only (BCSC model) or combined with CNN risk score (hybrid model). We compared the prediction performance of these models via area under the receiver operating characteristics curves (AUCs) based on the DeLong test. We also calculated each model’s AUC for subgroups of age and race/ethnicity. Results: Among 23,552 evaluable women, mean age was 55.9 years (standard deviation [SD], 9.5) with 27% non-Hispanic White, 9% non-Hispanic Black, 36% Hispanic, 5% Asian, and 23% Other/Unknown race/ethnicity. Four percent had a first-degree family history of breast cancer, 10% had a prior benign breast biopsy, 45% had heterogeneously or extremely dense breasts on mammography, and 22% met high-risk criteria based upon a 5-year invasive breast cancer risk 1.67% according to the BCSC model. Mean CNN risk score was higher among breast cancer cases compared to unaffected controls (0.477 vs. 0.466, p=0.077). We found that the hybrid model outperformed the BCSC model (AUC of 0.676 vs. 0.640, respectively; p=0.003). In subgroup analyses, the hybrid model more accurately predicted breast cancer risk compared to the BCSC model among women age<50 (AUC of 0.713 vs. 0.645, respectively; p=0.078) and age>=50 (AUC of 0.663 vs. 0.625, respectively; p=0.026); non-Hispanic Black women (AUC of 0.794 vs. 0.663, respectively; p=0.028) and Hispanic women (AUC of 0.666 vs. 0.621, respectively; p=0.060). Conclusion: Among women undergoing screening mammography, a hybrid model incorporating a CNN-based mammography evaluation with clinical factors from the BCSC model more accurately predicted breast cancer risk relative to the BCSC model alone, particularly among racial and ethnic minorities. Combined with clinical risk factors, our CNN model may be used to efficiently predict breast cancer risk and inform risk-stratified breast cancer screening and prevention strategies. Comparing prediction performance for breast cancer risk of the BCSC model vs. hybrid modelBCSC ModelHybrid ModelP-value*AUC95% CIAUC95% CIAll patients0.6400.602-0.6830.6760.640-0.7110.003Age (years)<500.6450.562-0.7280.7130.648-0.7780.078>=500.6250.579-0.6710.6630.623-0.7030.026Race/ethnicityNon-Hispanic White0.6880.623-0.7540.7040.643-0.7660.230Non-Hispanic Black0.6630.539-0.7880.7940.704-0.8830.028Hispanic0.6210.560-0.6860.6660.597-0.7330.060Asian0.6160.440-0.7910.6510.461-0.8410.694 Citation Format: Alissa Michel, Vicky Ro, Julia E McGuinness, Simukayi Mutasa, Richard Ha, Katherine D Crew. Improving breast cancer risk prediction using a convolutional neural network-based mammographic evaluation in combination with clinical risk factors [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-10-03.

Barriers and Facilitators to the Implementation of a Personalized Breast Cancer Screening Program: Views of Spanish Health Professionals.

This study explored the barriers and facilitators to the implementation of a risk-based breast cancer screening program from the point of view of Spanish health professionals. A cross-sectional study with 220 Spanish health professionals was designed. Data were collected in 2020 via a web-based survey and included the advantages and disadvantages of risk-based screening and barriers and facilitators for the implementation of the program. Descriptive statistics and Likert scale responses analyzed as category-ordered data were obtained. The risk-based screening was considered important or very important to reduce breast cancer mortality and promote a more proactive role for women in breast cancer prevention, to increase coverage for women under 50 years, to promote a breast cancer prevention strategy for women at high risk, and to increase efficiency and effectiveness. Switching to a risk-based program from an age-based program was rated as important or very important by 85% of participants. As barriers for implementation, risk communication, the workload of health professionals, and limited human and financial resources were mentioned. Despite the barriers, there is good acceptance, and it seems feasible, from the perspective of health professionals, to implement a risk-based breast cancer screening program in Spain. However, this poses a number of organizational and resource challenges.

Abstract PO-216: Circulating 27-hydroxycholesterol is associated with decreased breast cancer risk: The Multiethnic Cohort Study

Abstract Background: Obesity is one of the most significant risk factors for breast cancer among postmenopausal women. Body fat distribution varies across racial/ethnic groups, which may partially explain the differences in breast cancer incidence across race/ethnicity. Laboratory studies have indicated that a cholesterol metabolite, 27-hydroxycholesterol (27HC), is an endogenous selective estrogen receptor modulator (SERM) and may represent an important obesity-related mechanism in breast cancer etiology. However, epidemiologic evidence for the role of 27HC in breast cancer risk is lacking, particularly in multiethnic populations. Methods: In a nested case-control study of 1,472 cases and 1.472 matched controls within the Multiethnic Cohort Study (MEC), we examined the association of circulating 27HC and lipids with breast cancer risk among African American, Japanese American, Native Hawaiian, Latino, and non-Latino White females. We conducted multivariable conditional logistic regression to assess associations of pre-diagnostic 27HC and lipids (modeled continuously on the log scale) with postmenopausal breast cancer risk adjusting for age at blood draw. Race/ethnicity stratified analyses were also conducted to assess differences in associations across racial/ethnic groups. Results: Among all females, higher levels of circulating 27HC were associated with a reduced risk of breast cancer (OR per log ng/ml: 0.71; 95% confidence interval (CI): 0.51, 0.99). Analyses stratified by race/ethnicity indicate that this association was driven by the Latino (OR: 0.39; 95% CI: 0.16, 0.93) and Japanese American (OR: 0.62; 95% CI: 0.35, 1.08) groups. Inverse associations were also observed with high-density lipoprotein and total cholesterol levels, while low-density lipoprotein levels were positively associated with breast cancer risk among all females. Conclusions: Ours is the first U.S. study to report a protective association between circulating 27HC and breast cancer risk in a multiethnic population. Interestingly, parallel analyses of a sub-cohort of healthy females in the MEC indicate inverse associations of total fat mass and percent subcutaneous fat assessed by dual X-ray absorptiometry and abdominal magnetic resonance imaging, respectively, with circulating 27HC. Ongoing analyses are evaluating joint associations of circulating 27HC, lipids, estrogens, and androgen levels with breast cancer risk. Results from this study will improve our understanding of racial/ethnic differences in breast cancer risk in relation to body fat distribution and inform prevention strategies for postmenopausal breast cancer. Citation Format: Mindy C DeRouen, Juan Yang, Yuqing li, Adrian A. Franke, Anne Tome, Kami White, Brenda Hernandez, Yurii Shvestov, V. Wendy Setiawan, Anna H. Wu, Lynne Wilkens, Loic Le Marchand, Lenora WM Loo, Iona Cheng. Circulating 27-hydroxycholesterol is associated with decreased breast cancer risk: The Multiethnic Cohort Study [abstract]. In: Proceedings of the AACR Virtual Conference: 14th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2021 Oct 6-8. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr PO-216.

A Low-Glucose Eating Pattern Improves Biomarkers of Postmenopausal Breast Cancer Risk: An Exploratory Secondary Analysis of a Randomized Feasibility Trial.

Postmenopausal breast cancer is the most common obesity-related cancer death among women in the U.S. Insulin resistance, which worsens in the setting of obesity, is associated with higher breast cancer incidence and mortality. Maladaptive eating patterns driving insulin resistance represent a key modifiable risk factor for breast cancer. Emerging evidence suggests that time-restricted feeding paradigms (TRF) improve cancer-related metabolic risk factors; however, more flexible approaches could be more feasible and effective. In this exploratory, secondary analysis, we identified participants following a low-glucose eating pattern (LGEP), defined as consuming energy when glucose levels are at or below average fasting levels, as an alternative to TRF. Results show that following an LGEP regimen for at least 40% of reported eating events improves insulin resistance (HOMA-IR) and other cancer-related serum biomarkers. The magnitude of serum biomarkers changes observed here has previously been shown to favorably modulate benign breast tissue in women with overweight and obesity who are at risk for postmenopausal breast cancer. By comparison, the observed effects of LGEP were similar to results from previously published TRF studies in similar populations. These preliminary findings support further testing of LGEP as an alternative to TRF and a postmenopausal breast cancer prevention strategy. However, results should be interpreted with caution, given the exploratory nature of analyses.

Prevention of breast&ovarian cancer in women with BRCA-1/2 mutations - A decision-analytic evaluation

Abstract Background Women who have inherited BRCA-1/2 mutations have substantially elevated lifetime risks for developing breast and/or ovarian cancer and may develop these cancers around age 30. Therefore, breast and ovarian cancer prevention should be administered relatively early in life for those women. We systematically evaluate the long-term effectiveness and cost-effectiveness of different breast and ovarian cancer prevention strategies in women with BRCA-1/2 mutations in Germany. Methods A decision-analytic Markov model simulating lifetime breast and ovarian cancer development in BRCA-1/2 carriers was developed to evaluate different strategies including intensified surveillance (IS), prophylactic bilateral mastectomy (PBM), and prophylactic bilateral oophorectomy (PBSO) alone or in combination at different ages. German clinical, epidemiological and cost (in 2018 Euro) data were used. Outcomes included cancer incidences, mortality, life years (LYs), quality-adjusted life years (QALYs), and discounted incremental cost-effectiveness ratios (ICER). Results All intervention strategies are more effective and less costly than IS alone. Prevention with PBM plus PBSO at age 30 maximizes life expectancy with 6.3 LYs gained, whereas PBM at age 30 with delayed PBSO at age 35 improves quality of life with 11.1 QALYs gained, when compared to IS alone. Both strategies are cost effective with ICER significantly below 10,000 EUR/LY or QALY gained. Conclusions Based on our results, PBM at age 30 plus PBSO between age 30 and 40 prolongs life and is cost effective in women with BRCA-1/2 mutations in Germany. Serial preventive surgeries with delayed PBSO potentially improve quality of life for women. We therefore suggest that efforts should be directed to carefully and thoroughly inform women with BRCA-1/2 mutations about their options to prevent breast and ovarian cancer. Key messages Prophylactic mastectomy at age 30 combined with prophylactic oophorectomy between age 30 and 40 may prolong lives and be cost effective in German women with BRCA- 1/2 mutations. Women’s quality of life might be improved by a delayed prophylactic oophorectomy after a prophylactic mastectomy.

Investigation of the Interplay between Circulating Lipids and IGF-I and Relevance to Breast Cancer Risk: An Observational and Mendelian Randomization Study.

BackgroundCirculating lipids and insulin-like growth factor 1 (IGF-I) have been reliably associated with breast cancer (BCa). Observational studies suggest an interplay between lipids and IGF-I, however, whether these relationships are causal and if pathways from these phenotypes to BCa overlap is unclear.MethodsMendelian Randomisation (MR) was conducted to estimate the relationship between lipids or IGF-I and BCa risk using genetic summary statistics for lipids (low-density lipoprotein cholesterol,LDL-C; high-density lipoprotein cholesterol,HDL-C; triglycerides,TGs), IGF-I and BCa from GLGC/UKBB (N=239,119), CHARGE/UKBB (N=252,547) and BCAC (N=247,173), respectively. Cross-sectional observational and MR analyses were conducted to assess the bi-directional relationship between lipids and IGF-I in SHIP (N=3,812) and UKBB (N=422,389), and using genetic summary statistics from GLGC (N=188,577) and CHARGE/UKBB (N=469,872).ResultsIn multivariable MR (MVMR) analyses, the OR for BCa per 1-SD increase in HDL-C and TG was 1.08 (95%CI: 1.04,1.13) and 0.94 (95%CI: 0.89,0.98), respectively. The OR for BCa per 1-SD increase in IGF-I was 1.09 (95%CI: 1.04,1.15). MR analyses suggested a bi-directional TG-IGF-I relationship (TG-IGF-I beta per 1-SD: -0.13; 95%CI: -0.23,-0.04; and IGF-I-TG beta per 1-SD: -0.11; 95%CI: -0.18,-0.05). There was little evidence for a causal relationship between HDL-C and LDL-C with IGF-I. In MVMR analyses, associations of TG or IGF-I with BCa were robust to adjustment for IGF-I or TG, respectively.ConclusionsOur findings suggest a causal role of HDL-C, TG and IGF-I in BCa. Observational and MR analyses support an interplay between IGF-I and TG, however, MVMR estimates suggest that TG and IGF-I may act independently to influence BCa.ImpactOur findings should be considered in the development of prevention strategies for BCa, where interventions are known to modify circulating lipids and IGF-I.

Cost effectiveness of breast cancer screening and prevention: a systematic review with a focus on risk-adapted strategies.

Benefit and cost effectiveness of breast cancer screening are still matters of controversy. Risk-adapted strategies are proposed to improve its benefit-harm and cost-benefit relations. Our objective was to perform a systematic review on economic breast cancer models evaluating primary and secondary prevention strategies in the European health care setting, with specific focus on model results, model characteristics, and risk-adapted strategies. Literature databases were systematically searched for economic breast cancer models evaluating the cost effectiveness of breast cancer screening and prevention strategies in the European health care context. Characteristics, methodological details and results of the identified studies are reported in evidence tables. Economic model outputs are standardized to achieve comparable cost-effectiveness ratios. Thirty-two economic evaluations of breast cancer screening and seven evaluations of primary breast cancer prevention were included. Five screening studies and none of the prevention studies considered risk-adapted strategies. Studies differed in methodologic features. Only about half of the screening studies modeled overdiagnosis-related harms, most often indirectly and without reporting their magnitude. All models predict gains in life expectancy and/or quality-adjusted life expectancy at acceptable costs. However, risk-adapted screening was shown to be more effective and efficient than conventional screening. Economic models suggest that breast cancer screening and prevention are cost effective in the European setting. All screening models predict gains in life expectancy, which has not yet been confirmed by trials. European models evaluating risk-adapted screening strategies are rare, but suggest that risk-adapted screening is more effective and efficient than conventional screening.

Breast-Specific Molecular Clocks Comprised of ELF5 Expression and Promoter Methylation Identify Individuals Susceptible to Cancer Initiation.

A robust breast cancer prevention strategy requires risk assessment biomarkers for early detection. We show that expression of ELF5, a transcription factor critical for normal mammary development, is downregulated in mammary luminal epithelia with age. DNA methylation of the ELF5 promoter is negatively correlated with expression in an age-dependent manner. Both ELF5 methylation and gene expression were used to build biological clocks to estimate chronological ages of mammary epithelia. ELF5 clock-based estimates of biological age in luminal epithelia from average-risk women were within three years of chronological age. Biological ages of breast epithelia from BRCA1 or BRCA2 mutation carriers, who were high risk for developing breast cancer, suggested they were accelerated by two decades relative to chronological age. The ELF5 DNA methylation clock had better performance at predicting biological age in luminal epithelial cells as compared with two other epigenetic clocks based on whole tissues. We propose that the changes in ELF5 expression or ELF5-proximal DNA methylation in luminal epithelia are emergent properties of at-risk breast tissue and constitute breast-specific biological clocks. PREVENTION RELEVANCE: ELF5 expression or DNA methylation level at the ELF5 promoter region can be used as breast-specific biological clocks to identify women at higher than average risk of breast cancer.

RANK links senescence to stemness in the mammary epithelia, delaying tumor onset but increasing tumor aggressiveness

SummaryRank signaling enhances stemness in mouse and human mammary epithelial cells (MECs) and mediates mammary tumor initiation. Mammary tumors initiated by oncogenes or carcinogen exposure display high levels of Rank and Rank pathway inhibitors have emerged as a new strategy for breast cancer prevention and treatment. Here, we show that ectopic Rank expression in the mammary epithelia unexpectedly delays tumor onset and reduces tumor incidence in the oncogene-driven Neu and PyMT models. Mechanistically, we have found that ectopic expression of Rank or exposure to Rankl induces senescence, even in the absence of other oncogenic mutations. Rank leads to DNA damage and senescence through p16/p19. Moreover, RANK-induced senescence is essential for Rank-driven stemness, and although initially translates into delayed tumor growth, eventually promotes tumor progression and metastasis. We uncover a dual role for Rank in the mammary epithelia: Rank induces senescence and stemness, delaying tumor initiation but increasing tumor aggressiveness.