Elevated Breast Cancer Risk Research Articles

Use of postmenopausal hormone therapies and risk of histology- and hormone receptor-defined breast cancer: results from a 15-year prospective analysis of NIH-AARP cohort

BackgroundMenopausal hormone therapy (MHT) increases breast cancer (BC) risk, but cohort studies largely consider use only at enrollment. Evidence is limited on how changes in MHT use alter the magnitude of risk, and whether risk varies between invasive and in situ cancer, by histology or by hormone receptor status.MethodsWe investigated the roles of estrogen-alone therapy (ET) and estrogen plus progestin therapy (EPT) on BC risk overall, by histology and estrogen receptor (ER) and progesterone receptor (PR) status, and on incidence of in situ disease, in the NIH-AARP cohort. Participants included 118,760 postmenopausal women (50–71 years), of whom 63.5% (n = 75,398) provided MHT use information at baseline in 1996 and in a follow-up survey in 2004, subsequent to the dissemination in 2002 of the Women’s Health Initiative trial safety concerns regarding EPT. ET analyses included 50,476 women with hysterectomy (31,439 with follow-up data); EPT analyses included 68,284 women with intact uteri (43,959 with follow-up data). Adjusted hazard ratios (HRs) were estimated using Cox proportional hazards models using age as the time metric with follow-up through 2011.ResultsEight thousand three hundred thirty-three incident BC cases were accrued, 2479 in women with follow-up data. BC risk was not elevated in current ET users at baseline (HR = 1.05, 95% confidence interval [CI] CI = 0.95–1.16) but was higher in women continuing use through 2004 (HR = 1.35, 95% CI = 1.04–1.75). Ever EPT use at baseline was associated with elevated BC risk overall (HR = 1.54 (1.44–1.64), with a doubling in risk for women with 10 or more years of use, for in situ disease, and across subtypes defined by histology and ER/PR status (all p < 0.004). Risk persisted in women who continued EPT through 2004 (HR = 1.80, 95% CI = 1.39–2.32). In contrast, no association was seen in women who discontinued EPT before 2004 (HR = 1.14, 95% CI = 0.99–1.30).ConclusionsET use was not associated with BC risk in this cohort, although excess risk was suggested in women who continued use through 2004. EPT use was linked to elevated in situ and invasive BC risk, and elevated risk across invasive BC histologic and hormone receptor-defined subtypes, with the highest risk for women who continued use through the 2004 follow-up survey.

Increased Duration of Exercise Decreases Rate of Nonresponse to Exercise but May Not Decrease Risk for Cancer Mortality.

Previous studies have observed an inverse relationship between exercise and breast cancer risk. However, there is interindividual variability in response to exercise training interventions. We investigated whether increasing the dose of aerobic exercise (150 or 300 min·wk-1), while keeping intensity of exercise constant (70%-80% HRmax), decreases the number of exercise nonresponders and further decreases associated risk for cancer mortality in our study population of women genetically predisposed for breast cancer. Healthy premenopausal women at elevated risk of breast cancer were randomized into control (<75 min·wk-1, n = 47), low-dose exercise (150 min·wk-1, n = 39), and high-dose exercise groups (300 min·wk-1, n = 39) for approximately 6 months. We assessed 1) clinical effectiveness (CE), defined as an improvement in predicted V˙O2max of ≥1 mL·kg-1·min-1, and twice the typical error (2× TE) of V˙O2max as thresholds to classify exercise "nonresponders"; 2) CE and 2× TE relative to exercise adherence levels; and 3) related changes in V˙O2max to predicted cancer mortality risk. After our 6-month intervention, we observed that 23.5% of women in the low-dose group and 5.6% of women in the high-dose group were clinical nonresponders (P = 0.04). Clinical nonresponder status was independent of adherence level. Associated reduction in risk for cancer mortality was observed among 87.2% of women in the low-dose group and 94.9% in the high-dose group (P = 0.43). Increasing volume (not intensity) of exercise via time spent exercising significantly decreases the number of "nonresponders." True nonresponders were observed as some women did not improve their fitness capacity despite high exercise adherence levels. Lastly, it appears 150 min·wk-1 is sufficient to decrease the predicted risk of cancer mortality.

TIMP-2 gene rs4789936 polymorphism is associated with increased risk of breast cancer and poor prognosis in Southern Chinese women.

Tissue inhibitor of metalloproteinase-2 (TIMP-2) is an endogenous inhibitor of matrix metalloproteinase-2, and an important regulator of cancer growth and metastasis. Here, we evaluated the relationship between TIMP-2 gene rs4789936 polymorphism and breast cancer risk and prognosis in Southern Chinese women. Analysis of 480 breast cancer cases and 530 healthy controls revealed that compared to the CC genotype, the TT/CT genotypes increased the risk of breast cancer (CT: odds ratio (OR)=1.46, 95%CI: 1.11-1.92; TT: OR=2.57, 95%CI: 1.76-3.77). Stratified and cross-over analyses indicated that the increased risk of the rs4789936 polymorphism was associated with age, smoking, drinking, and the body mass index. The TT and CT genotypes were more common than the CC genotype in patients with lymph node metastases (TT: OR=2.54, 95%CI: 1.54-4.18; CT: OR=2.10, 95%CI: 1.40-3.15), advanced stage (TT: OR=1.91, 95%CI: 1.17-3.14; CT: OR=1.80, 95%CI: 1.20-2.70), or progesterone receptor positive cancer (TT: OR=2.02, 95%CI: 1.23-3.32). Multivariate cox regression indicated the CT and TT genotypes (HR=4.65, 95%CI: 1.26-17.18, P=0.021; HR=6.62, 95%CI: 1.51-29.11, P=0.012) were associated with poor prognosis in breast cancer patients. Thus, the TIMP-2 gene rs4789936 polymorphism is associated with elevated breast cancer risk and may be an independent prognosis factor in breast cancer patients.

10 Oral - Chemoprevention for breast cancer: A survey of the views of Australian women and clinicians

Background: Chemoprevention for women at elevated risk of breast cancer is endorsed by international guidelines. This study examined the uptake of chemoprevention by Australian women at increased risk and aimed to identify modifiable barriers and facilitators for both patients and clinicians. Material and Methods: 1,113 participants enrolled in the Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer Follow-Up Study (kConFab FUS) and at ≥16% lifetime risk of BC (≥1.5 times the average population risk) were mailed a 68-item survey. 130 currently practising breast surgeons and 394 family doctors (FDs) who reportedly provided care for kConFab-FUS participants were sent a 49-item survey. Surveys were developed based on the theoretical domains framework. Results: 725 participants (65%) and 221 (42%) clinicians responded (147 (37%) FDs, 74 (57%) breast surgeons). The median age of participants was 55 years. Most (84%) were at moderately increased risk (<3 times population risk). Ten women (1.4%) had taken chemoprevention. Possible side effects, lack of information and preferring the adoption of a healthy lifestyle alone were the three strongest barriers. The 20-year reduction in BC risk with tamoxifen was the most important facilitator, followed by desire to stay healthy for their family and having an abnormal breast biopsy. Most patients preferred to get information from a cancer genetics centre (CGC) (38%) followed by their FD (33%). Most surgeons knew about chemoprevention (97%), but 35% of FDs did not; 7% and 74%, respectively, were not confident in providing chemoprevention information. The majority of FDs (75%) and breast surgeons (89%) thought discussing chemoprevention should be part of their role. For FDs the strongest barriers were insufficient knowledge and lack of confidence. For breast surgeons, the strongest barriers were medication side-effects and lack of consultation time. Clear guidelines and strong family history were facilitators for both clinician groups. FDs identified that availability of better tools to select suitable patients would be a strong facilitator. Conclusions: Chemoprevention uptake is low in Australia by international standards. This study identified barriers and facilitators not previously noted in the literature and that could suggest interventions. However, as in other studies, improving both clinician and patient knowledge may be the most important driver of interventions. Upskilling FDs is important as, in Australia, moderate risk women are not generally eligible for CGC consultation (despite their preference for one). Providing FDs and patients with tailored education resources and tools (such as iPrevent- www.petermac.org/iprevent) to improve their confidence and awareness of chemoprevention may reduce the gap between evidence and implementation. Conflict of interest: Other Substantive Relationships: KAP has a patent “System and Process of Cancer Risk Estimation” (Australian Innovation Patent) issued regarding iPrevent.

High-sensitivity C-reactive protein, hemoglobin A1c and breast cancer risk: a nested case-control study from Alberta's Tomorrow Project cohort.

Our aim is to examine the associations between high-sensitivity C-reactive protein (hsCRP) and hemoglobin A1c (HbA1c), common biomarkers of inflammation and insulin resistance, respectively, with breast cancer risk, while adjusting for measures of excess body size. We conducted a nested case-control study within the Alberta's Tomorrow Project cohort (Alberta, Canada) including 197 incident breast cancer cases and 394 matched controls. The sample population included both pre- and postmenopausal women. Serum concentrations of hsCRP and HbA1c were measured from blood samples collected at baseline, along with anthropometric measurements, general health and lifestyle data. Conditional logistic regression was used to evaluate associations between hsCRP, HbA1c, and breast cancer risk adjusted for excess body size (body fat percentage) and other risk factors for breast cancer. Higher concentrations of hsCRP were associated with elevated breast cancer risk (odds ratio [OR] 1.27; 95% confidence interval [95% CI] 1.03-1.55). The observed associations were unchanged with adjustment for body fat percentage. Higher HbA1c concentrations were not significantly associated with an increased breast cancer risk (OR 1.22; 95% CI 0.17-8.75). These data suggest that hsCRP may be associated with elevated breast cancer risk, independent of excess body size. However, elevated concentrations of HbA1c did not appear to increase breast cancer risk in apparently healthy women.

Sentinel lymph node biopsy should be considered for clinically node-negative breast cancer regardless of BRCA1/2 mutation status.

BackgroundBRCA1/2 mutations lead to an elevated risk of breast cancer. None involved in whether BRCA1/2 mutation status will affect the first decision-making of sentinel lymph node (SLN) biopsy or not for clinically node-negative breast cancer. We retrospectively investigated whether BRCA1/2 mutation status influenced SLN involvement rate and survival outcomes after sentinel lymph node biopsy (SLNB) for Chinese clinically node-negative breast cancer patients.MethodsPatients who underwent SLNB at initial were enrolled and divided according to BRCA1/2 mutation status. Germline DNA for BRCA1/2 testing was derived from blood samples. SLN involvement rate and clinicopathological characteristics were analyzed using the Chi-square test. Kaplan–Meier univariate and multivariate Cox regression analysis was performed to compare survival between groups.ResultsAccording to BRCA1/2 mutation test criteria, 156 Chinese women receiving initial SLNB with clinically node-negative breast cancer were selected—thirty-one patients identified as BRCA1/2 mutation carriers and 102 as non-carriers were enrolled. Non-carriers seemed to be with a more advanced TNM stage (P<0.01) compared to the non-carrier group. Once SLN involved, the patient will receive axillary lymph node dissection in which BRCA1/2 mutation did not increase the rate (P=0.73). Disease-free survival (DFS) (P=0.48) and recurrence-free survival (RFS) (P=0.79) are comparable between groups, even after adjustment for clinicopathological characteristics, systemic treatment, and surgical management of breast [DFS, hazard ratio (HR) =1.63, confidence interval (CI): 0.48–5.54, P=0.43; RFS, HR =0.75, CI: 0.14–3.89, P=0.73].ConclusionsSLNB should be considered for clinically node-negative breast cancer regardless of BRCA1/2 status.

Implementation of a High-Risk Breast Clinic for Comprehensive Care of Women With Elevated Breast Cancer Risk Identified by Risk Assessment Models in the Community.

Many radiology centers perform risk assessment at time of screening mammography. The Massachusetts General Hospital North Shore Cancer Center (MGHNS) developed a nurse practitioner (NP)-led high-risk breast clinic (HRBC) to provide comprehensive care for patients with elevated breast cancer risk by a validated tool. Patient and administrative data from the MGHNS HRBC was collected to evaluate clinical and implementation outcomes. We compared patients from the HRBC with those identified as having ≥ 20% lifetime risk at 5 community imaging centers. From March 2018 to February 2019, 318 patients were seen in the HRBC; 264 (83%) had ≥ 20% lifetime risk, 13 (4%) had prior atypia/lobular carcinoma in situ, 9 (3%) had ≥ 1.7% 5-year risk, and 32 (10%) had no indication of elevated risk. Genetic testing was recommended for 159 patients (50%); 33 (21%) completed testing with 1 mutation identified. Chemoprevention was discussed with 99 patients (31%); 9 (9%) initiated treatment. Screening magnetic resonance imaging (MRI) was recommended for 284 patients (89%); 184 (65%) had MRI performed with 2 mammographically occult cancers identified. During this time period, 215,112 patients had risk assessment performed at time of breast imaging; of these, 1,170 were found to have ≥ 20% lifetime risk. Compared with those identified as high risk in the community, patients seen in the HRBC were more likely to be white (94.3% v 85.4%; P < .001) and have a family history of ovarian cancer (16.4% v 9.4%; P < .001). We demonstrate the feasibility of an NP-led HRBC. Follow-through of recommendations by patients was highest for screening MRI; use of genetic testing and chemoprevention was lower than anticipated. In our community, uptake of the HRBC by referring providers remains a barrier, with only a minority of identified high-risk patients assessed in our clinic.

Abstract NG15: Investigation of relationships between breast cancer risk factors and bilateral mammographic breast density asymmetry among women undergoing diagnostic image-guided breast biopsies

Introduction: The etiology of breast cancer remains an area of ongoing investigation. Improving our understanding of factors associated with breast cancer development will strengthen the utility of risk prediction strategies and improve risk stratification. Mammographic breast density remains one of the most influential breast cancer risk factors, with 4 to 6 fold elevated risk observed among women with the highest compared to the lowest levels. These associations have consistently been observed irrespective of the method (visual or automated), used to quantify breast density, showing the robustness of the associations. An understudied breast cancer risk factor is the bilateral asymmetry of mammographic features, with prior studies suggesting that women with higher levels of breast asymmetry may be at elevated breast cancer risk. Increasingly, studies are recognizing the potential of bilateral breast asymmetry defined by mammographic breast density in determining breast cancer risk. Recently, Eriksson and colleagues highlighted a strong influence of breast asymmetry within a model they developed to predict short-term breast cancer risk among women attending breast screening. They observed that the contribution to the model of asymmetry in mammographic breast density, microcalcifications, and masses between the breasts was as substantial as the total number of microcalcifications and masses found within a mammogram, indicating that differences between the breasts may be an important risk marker. To help further understand associations between breast cancer risk factors and asymmetry of breast density, particularly among women at elevated risk for breast cancer, we evaluated risk factor relationships with the bilateral asymmetry of volumetric measures of global and local breast density across the spectrum of premalignant and invasive breast cancer diagnoses. Methods: This study included 882 women enrolled as part of the National Cancer Institute9s Breast Radiology Evaluation and Study of Tissues (BREAST)-Stamp Project (2007-2010). The BREAST-Stamp Project is a cross-sectional molecular epidemiologic study that aims to understand how novel breast density measures are related to breast cancer etiology. Women were enrolled if they were referred for diagnostic image-guided breast biopsy following an abnormal mammogram at the University of Vermont Medical Center, and had not previously been diagnosed or treated for cancer, undergone breast surgery within one year or received chemoprevention. Risk factor data were collected at study enrolment via interview and self-administered questionnaires. Breast density measures were estimated using Single X-ray Absorptiometry (SXA), a technique in which an SXA breast density phantom was affixed to the compression paddle of the mammography machine during routine mammography so that it was included in the X-ray field. It served as a reference standard to estimate volumetric breast density. Breast density was assessed using pre-biopsy craniocaudal full-field digital mammograms of both the ipsilateral (affected) and contralateral (unaffected) breast. Firstly, global density from each laterality was determined as percent fibroglandular volume (%FGV). Secondly, localized volumetric density measures were estimated following identification of the biopsy site on the ipsilateral pre-biopsy mammogram by the study radiologist and identifying the corresponding site on the contralateral mammogram. The SXA estimated %FGV in a perilesional volume twice the size of, but excluding, the biopsy target, centered at the biopsy site. Previous estimates of reproducibility for the SXA test phantoms demonstrated a repeatability SD of 2%, with a ±2% accuracy for the entire thickness and density ranges. Breast density asymmetry was defined as an absolute bilateral difference in measures when subtracting the breast density measures of the contralateral breast from the ipsilateral measures. Spearman9s correlations (rho) examined associations between breast density measures of the left and right breasts. To determine relationships between breast cancer risk factors (defined as categorical variables) and measures of bilateral breast density asymmetry, analysis of covariance (ANCOVA) models (PROC GLM) were used. Analyses were conducted at the per woman level using SAS. Probability values of Citation Format: Maeve Mullooly, Shaoqi Fan, Ruth M. Pfeiffer, Brian Sprague, Pamela M. Vacek, Donald L. Weaver, John A. Shepherd, Amir Pasha Mahmoudzadeh, Jeff Wang, Serghei Malkov, Jason M. Johnson, Sally D. Herschorn, Gretchen L. Gierach. Investigation of relationships between breast cancer risk factors and bilateral mammographic breast density asymmetry among women undergoing diagnostic image-guided breast biopsies [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr NG15.

Abstract 3493: Interactions between adiponectin pathway polymorphisms and obesity on breast cancer risk among African American postmenopausal women

Abstract Purpose: A decreased circulating adiponectin concentration is associated with obesity and an increased breast cancer risk among postmenopausal women. Yet, the interplay between adiponectin-associated genetic variants, obesity, and breast cancer risk is unclear in African American (AA) postmenopausal women. We examined adiponectin pathway polymorphisms for their association with breast cancer risk among AA postmenopausal women. We also explored a gene-environment interaction between adiponectin pathway polymorphisms and obesity for the risk of breast cancer. Method: Using the Women's Health Initiative SNP Health Association Resource Study, we identified 37 single-nucleotide polymorphisms (SNPs) in relation to the adiponectin pathway. Body-fat distributions were determined using three independent indices including body mass index (BMI), waist-to-hip ratio (WHR), and waist circumference (WC). We used multiple Cox proportional hazards regression models to estimate hazard ratios and 95% confidence intervals (CIs) for the association with breast cancer. Obesity-stratified analysis and tests for the joint effects with the SNPs were conducted. Results: Of 7,991 AA postmenopausal women, 402 reported of having an invasive breast cancer with a mean follow-up of 14.5 years. The majority were obese, had low WHR (&amp;lt; 0.85), and had high WC (&amp;lt; 88 cm). Of 37 adiponectin pathway-related SNPs, 3 SNPs were significantly associated with breast cancer risk (KCNK9 rs2468677, OR8S1-LALBA rs11168618, and EIF4A2 rs266719). Among women who have under or normal bodyweight, the minor allele GG genotype of NMU rs13434995 had an elevated risk of postmenopausal breast cancer compared to those with the major allele AA genotype. Women who carry the heterozygous TC genotype of OR8S1-LALBA rs11168618 and are obese jointly increased the risk of breast cancer (relative excess risk due to interaction = 0.58, 95% CI = 0.35, 0.80). Conclusion: Our findings revealed the association between the previously confirmed adiponectin pathway-related SNPs and breast cancer risk among AA postmenopausal women. We also demonstrated that obesity plays an important role as an effect modifier in the relationship between the SNPs and breast cancer, suggesting 1) the potential use of metabolic and genetic biomarkers for identifying a greater risk for breast cancer and 2) support for the research to promote interventions to those with risk genotypes, thus reducing breast cancer risk. Citation Format: Gina E. Nam, Zuo-Feng Zhang, Jianyu Rao, Hua Zhou, Su Yon Jung. Interactions between adiponectin pathway polymorphisms and obesity on breast cancer risk among African American postmenopausal women [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3493.

Association of HOTAIR (rs920778 and rs1899663) and NME1 (rs16949649 and rs2302254) gene polymorphisms with breast cancer risk in India

Until now, no study has reported the combined effect of genetic variants of HOTAIR and NME1 towards breast cancer (BC) pathogenesis. Hence, the aim of the present study is to determine the risk of breast cancer development with HOTAIR (rs920778 C>T and rs1899663 G>T) and NME1 (rs16949649 T>C and rs2302254 C>T) genetic polymorphisms in the Indian population for the first time. To investigate the genetic association of these four SNPs, we conducted a population-based case-control study involving 1011 subjects (502 histologically confirmed BC patients and 509 disease-free controls) using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. HOTAIR rs920778 TC genotype elevated the risk of BC (OR=1.39, 95% CI=1.06-1.83, p=0.018) and individuals carrying the mutant allele (T) of rs1899663 had increased BC risk (OR=1.23, 95% CI=1.02-1.47, p=0.026). The presence of the NME1 rs16949649 CC genotype increased the risk of BC (OR=1.76, 95% CI=1.15-2.71, p=0.009). Moreover, the HOTAIR rs920778 variant (TC+CC) increased the risk of BC in pre-menopausal women (OR=5.86; p<0.0001). Women carrying 2 or 3 mutant alleles for the investigated SNPs were observed to have an elevated risk of BC. The results of the present study highlight the presence of significant associations between NME1 rs16949649 and HOTAIR (rs920778 and rs1899663) polymorphisms and breast cancer development in Indian women.

Male Breast Cancer Risk Assessment and Screening Recommendations in High-Risk Men Who Undergo Genetic Counseling and Multigene Panel Testing

BackgroundEmerging data suggest screening mammography may be effective in detecting breast cancer early in high-risk men. We evaluated current screening recommendations as a risk management strategy in men at elevated risk for breast cancer. Patients and MethodsThis institutional review board–approved, Health Insurance Portability and Accountability Act (HIPAA)-compliant study reviewed consecutive men who underwent genetic counseling and multigene panel testing (MGPT) for breast cancer risk assessment at our institution between 2012 and 2018. Patient risk factors, test indications, and MGPT outcomes were recorded, then correlated with screening recommendations by either clinical breast examination or screening mammography. Recommendation consistency among practitioners was evaluated. Patient adherence to screening mammography (defined as undergoing screening mammography as recommended) was assessed. Statistical analysis was performed at the 2-sided 5% significance level. ResultsA total of 414 asymptomatic men underwent both genetic counseling and MGPT (mean age, 47 years; range, 18-91 years) for breast cancer risk assessment. Of this group, 18 (4.3%) of 414 had a personal history of breast cancer, and 159 (38.4%) of 414 had a family history of breast cancer before MGPT. Among 112 men with positive MGPT results, BRCA1/2 mutations were the most common (56.3%, 63/112). Most BRCA mutation carriers (80.9%, 51/63) were recommended clinical breast examination only. Only 5.9% (2/34) BRCA2 and 10.3% (3/29) BRCA1 carriers were recommended screening mammograms (7.9%, 5/63 of all BRCA carriers). Among men with a personal history of breast cancer, only 9 (50%) of 18 were recommended screening mammograms. Overall adherence to screening mammogram in men was 71.4% (10/14), which ultimately yielded two cancers. Breast cancer screening recommendations varied widely among practitioners, with some recommending clinical breast examination only, and others also recommending mammography. ConclusionMen who are found to be at an elevated risk for breast cancer after undergoing genetic counseling and testing currently receive relatively inconsistent screening recommendations.

Breast cancer risk assessment and management programs: A practical guide.

Breast cancer risk assessment continues to evolve as emerging knowledge of breast cancer risk drivers and modifiers enables better identification of high-risk women who may benefit from increased screening or targeted risk-reduction protocols. The ongoing development of breast cancer Risk Assessment and Management Programs (RAMPs) presents an opportunity to decrease breast cancer disease incidence with evidence-based interventions. The goal of this review was to provide a practical guide for providers seeking to establish or update a breast cancer risk assessment and management program. We outline genetic/familial, personal, reproductive, and lifestyle-related factors while discussing the incorporation of risk modeling for precise risk estimate personalization. We further describe the process for determining a risk management plan: information gathering, generation of a risk profile, and articulation and implementation of risk reduction. We also include an overview of clinical workflows in breast cancer management programs and underlines the logistics of establishing a program as well as general principles for guiding the formulation of an individualized risk management plan. We discuss practical considerations, such as clinic structure and operation, allocation of resources, and patient education. Other critical aspects of program design, including identification of the target population, delineation of the core components of the clinical experience, definition of provider roles, description of referral mechanisms, and the launching of a marketing plan are also addressed. The process of risk assessment is both anxiety-provoking and empowering for women at increased risk. New knowledge has enabled strategies to both understand the risk and control it through evidence-based risk management. These benefits can now be realized by an increasing number of unaffected, high-risk patients collaborating with risk management practitioners. Continuation of these efforts will lead to further progress in both risk stratification and risk management of women at elevated breast cancer risk in the near future.

Dynamic contrast-enhanced magnetic resonance imaging for risk-stratified screening in women with BRCA mutations or high familial risk for breast cancer: are we there yet?

Women at an elevated lifetime risk for breast cancer (BC), including carriers of pathogenic mutations in BC predisposition genes, are recommended intensified BC screening that includes annual mammography (MG) and annual breast MRI. Controversy exists regarding the clinical utility of MRI as a screening tool in high-risk women. This paper is intended to review recent advances and remaining areas of uncertainty in order to further facilitate the incorporation of breast MRI into an intensified BC screening protocol for women at high familial risk and BRCA carriers. A multidisciplinary team of medical oncologists and a radiologist specializing in the treatment of BC and high-risk patients searched PubMed to identify studies deemed to have the highest scientific value. Since none of the initial MRI studies were randomized, meta-analyses examining breast MRI screening in high-risk women were prioritized for inclusion. Breast MRI performs well in high-risk women, including mutation carriers. Breast MRI screening allows for the detection of early stage, likely curable invasive BC. It is mandatory that radiologists receive appropriate MRI training to reduce false positives and unnecessary biopsies. MRI screening is cost-effective in the highest risk patients and new clinical trials are open examining abbreviated and ultra-fast MRI techniques as a tool to drive down costs and improve specificity. As breast MRI is recommended as part of an intensified screening program in addition to mammography for high-risk women, it important that health care providers understand the benefits and limitations of this screening modality for high-risk women, as well as areas for further investigation.

T-cell Response To Exercise Training Among Women At Heightened Risk Of Breast Cancer.

Aging causes changes in the peripheral T-cell compartment that may increase susceptibility to cancer and lower immune responses. Fitness is associated with lower frequencies of highly differentiated T-cells, increased naïve T-cells, and elevations in myokines such as IL-7 that contribute to naïve T-cell output, indicating that exercise may help preserve immunity. PURPOSE: Examine the impact of exercise training on the differentiation status of CD4+ and CD8+ T-cells, recent thymic emigrants (RTE), and plasma levels of IL-7 in older women with an elevated risk of breast cancer (obesity status, postmenopausal, elevated Gail and/or lifetime risk score or history of non-invasive breast cancer). METHODS: 44 women (VO2=19.58±3.37 ml/kg/min) were randomized to: high-intensity interval training (HIIT; n=16; 63.73±6.86yrs); moderate continuous exercise (MCE; n=14.; 64.62±12.21yrs); or control (CNT; n=14; 63.35±6.99yrs). Participants completed clinically supervised treadmill exercise 3x/week for 12 weeks using heart rate training. Naive (NA), central memory (CM), effector memory (EM) and CD45RA+ effector memory (EMRA) CD4+ and CD8+ T-cells, and RTE (CD4NA or CD8NA CD31+CD103+) in blood were quantified before and after training. Fold changes (cells/μl) were calculated by (post-pre)/pre and compared across groups via ANOVA with p<0.05 considered significant. RESULTS: 11, 10, and 11 participants completed the HIIT, MCE, and CNT training, respectively. Compared to HIIT, MCE increased total lymphocytes (-0.05±0.13 vs. 0.12±0.12), CD4 (-0.29±0.24 vs. 0.21±0.30), CD4 CM (-0.23±0.20 vs. 0.36±0.27), CD4NA (-0.33±0.32 vs. 0.31±0.39), and CD8EM (-0.16±0.31 vs. 0.32±0.31). The change in number of CD4CM was higher in MCE compared to CNT (0.36±0.27 vs. -0.24±0.42). No changes were found for IL-7 or RTEs. CONCLUSION: Immune responses to exercise training in women with an elevated risk of breast cancer are likely to vary depending on the intensity of exercise. Future research should focus on investigating the potential that exercise may have on T-cell phenotypes and their relation to breast cancer risk. Funded by NCI R25 CA057730, the MD Anderson Cancer Center/Energy Balance Assessment Supplemental Funding, MD Anderson Cancer Center, Center for Energy Balance in Cancer Prevention and Survivorship, UA T32CA009213.

RSK2 Maintains Adult Estrogen Homeostasis by Inhibiting ERK1/2-Mediated Degradation of Estrogen Receptor Alpha

SUMMARYIn response to estrogens, estrogen receptor alpha (ERα), a critical regulator of homeostasis, is degraded through the 26S proteasome. However, despite the continued presence of estrogen before menopause, ERα protein levels are maintained. We discovered that ERK1/2-RSK2 activity oscillates during the estrous cycle. In response to high estrogen levels, ERK1/2 is activated and phosphorylates ERα to drive ERα degradation and estrogen-responsive gene expression. Reduction of estrogen levels results in ERK1/2 deactivation. RSK2 maintains redox homeostasis, which prevents sustained ERK1/2 activation. In juveniles, ERK1/2-RSK2 activity is not required. Mammary gland regeneration demonstrates that ERK1/2-RSK2 regulation of ERα is intrinsic to the epithelium. Reduced RSK2 and enrichment in an estrogen-regulated gene signature occur in individuals taking oral contraceptives. RSK2 loss enhances DNA damage, which may account for the elevated breast cancer risk with the use of exogenous estrogens. These findings implicate RSK2 as a critical component for the preservation of estrogen homeostasis.

In-silico analysis to identify the role of MEN1 missense mutations in breast cancer

Background: The multiple endocrine neoplasia type 1 (MEN1) gene located on chromosome 11q13 encodes menin protein. Previously reported mutations were thought to result in loss of function of menin protein and that they are associated with multiple endocrine neoplasia 1 disorder. However, recently menin has also been characterized as an oncosuppressor protein and it was suggested that mutations in it are associated with various other tumors. Studies indicate that the menin protein stimulates the estrogen receptor (ER) that in turn increases the predisposition for inherited breast cancer. Methods: Here, we used our supervised in-house combinatory in-silico predictor method to investigate the impact of unclassified missense mutations in MEN1 gene found in breast cancer tissue. We also examined the biophysical and biochemical properties to predict the effects of these missense variants on the menin protein stability and interactions. The results are compared with the effects of known pathogenic mutations in menin causing neoplasia. Results: Our analysis indicates that some of the variants found in breast cancer tissue show similar pattern of destabilizing the menin protein and its interactions as the pathogenic variants associated with neoplasia. Taking together with the results of our in-silico consensus predictor, we classify missense mutations in menin protein found in breast cancer tissue into pathogenic and benign, and thus, suggesting as an indicator for early detection of elevated breast cancer risk.

DNA repair genes hOGG1, XRCC1 and ERCC2 polymorphisms and their molecular mapping in breast cancer patients from India.

Identification of modifier genes predisposing to breast cancer (BC) phenotype remains a significant challenge and varies with ethnicity. The genetic variability observed in DNA repair genes may modulate the cell's ability to repair the damaged DNA and hence, evaluation of genetic variants in crucial DNA damage repair genes is of clinical importance. We performed the present study to evaluate the role of ERCC2-Lys751Gln, hOGG1-Ser326Cys, and XRCC1-Arg399Gln gene polymorphisms on the risk of BC development and its molecular profile in Indian women. Three non-synonymous variants (rs13181, rs1052133, and rs25487) were genotyped in 464 BC patients and 450 healthy controls. Logistic regression was employed to evaluate the association of genotypes with BC risk. Also, in silico analysis was carried out to map the Arg399Gln variant on the BRCT1 domain of XRCC1 protein. XRCC1 Gln/Gln genotype frequency was significantly elevated in BC patients [odd ratio (OR) = 1.73; 95% confidence interval (CI) = 1.13-2.65]. No significant association was observed between hOGG1-Ser326Cys and ERCC2-Lys751Gln variants and BC risk. Subgroup analysis revealed that ERCC2-Lys751Gln and XRCC1-Arg399Gln variants contributed towards tumor progression. A positive interaction between the investigated SNPs and BC was revealed by MDR analysis. Arg399Gln variant resulted in a change in the surface charge of XRCC1 protein. The rs25487 variant of XRCC1 might be associated with an elevated risk of BC. Furthermore, we demonstrated that high order gene-gene interaction plays a significant role in BC etiology. Hence, understanding the impact of low penetrant gene polymorphisms might enable a better understanding of the genetic background of breast cancer.

Abstract A058: Examining preferential mode of obtaining health information in African American women with elevated risk for breast cancer

Abstract Background: Breast cancer is the second leading cause of cancer death in the U.S. and is substantially higher in African American (AA) women. Early detection is crucial in decreasing breast cancer mortality and racial disparities. Research shows that low-income minority women are less likely to get breast cancer screening. Previous studies demonstrate that use of technology increases cancer screening rates. However, there are limited studies on the preferred mode of consuming health information for AA women, particularly those with increased risk of developing cancer. Objectives: The objective of this study is to examine preferences in receiving and accessing health information among AA women with a family history of breast and/or ovarian cancer. Methods: We conducted a mixed-methods study to address our research objective. For quantitative data, African American women (aged 26-67) were recruited from a Federally Qualified Health Center in the Southside of Chicago who were identified with elevated breast cancer risk via a risk assessment tool. Women were asked to complete a survey that assessed their preferred method of receiving health information. Data were analyzed using SPSS software. To supplement the quantitative data, qualitative data were collected during two focus groups conducted with AA women aged 25-69 with a family history of breast cancer. Bivariate analyses were performed to determine women's preferences in receiving and accessing health information, and if these preferences differed by age (&amp;lt;40 and ≥40). Results: The analytical sample consisted of 85 AA women with increased breast cancer risk. Sixty-nine women completed the surveys and 16 women attended focus group sessions. The majority of the study participants found reading materials (100%), listening to recordings (73%), and watching videos (96%) or animation (62%) were useful modes of receiving health information. There were no differences in these preferences by age groups. All women aged ≥40 years preferred receiving information explained by a person (p-value = 0.032). Most of the women had a cell phone with texting capabilities (90%). Seventy-eight percent of cell phone owners used their cell phone to access health information on the Internet, and 64% of these women were aged &amp;lt;40 years (p-value = 0.004). Other vital avenues of accessing health information that emerged from the focus groups included social media and health fairs. Conclusion: Understanding African American women's preferences for receiving and accessing health information can inform development of interventions designed to improve adherence to cancer screening recommendations. Additional research is needed to better understand the impact that accessing health information through various media has on cancer screening rates. Citation Format: Tera Ivy, Ifeanyi Chukwudozie, Vida Henderson, Silvia Tejeda, Ganga Vijayasiri, Catherine Balthazar, Robert Winn, Kent Hoskins. Examining preferential mode of obtaining health information in African American women with elevated risk for breast cancer [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr A058.

New mammography screening performance metrics based on the entire screening episode.

Established mammography screening performance metrics use the initial screening mammography assessment because they were developed for radiologist performance auditing, yet these metrics are frequently used to inform health policy and screening decision making. The authors have developed new performance metrics based on the final assessment that consider the entire screening episode, including diagnostic workup. The authors used data from 2,512,577 screening episodes during 2005-2017 at 146 facilities in the United States participating in the Breast Cancer Surveillance Consortium. Screening performance metrics based on the final assessment of the screening episode were compared with conventional metrics defined with the initial assessment. Results were also stratified by breast density and breast cancer risk. The cancer detection rates were similar for the final assessment (4.1 per 1000; 95% confidence interval [CI], 3.8-4.3 per 1000) and the initial assessment (4.1 per 1000; 95% CI, 3.9-4.3 per 1000). The interval cancer rate was 12% higher when it was based on the final assessment (0.77 per 1000; 95% CI, 0.71-0.83 per 1000) versus the initial assessment (0.69 per 1000; 95% CI, 0.64-0.74 per 1000), and this resulted in a modest difference in sensitivity (84.1% [95% CI, 83.0%-85.1%] vs 85.7% [95% CI, 84.8%-86.6%], respectively). Absolute differences in the interval cancer rate between final and initial assessments increased with breast density and breast cancer risk (eg, a difference of 0.29 per 1000 for women with extremely dense breasts and a 5-year risk >2.49%). Established screening performance metrics underestimate the interval cancer rate of a mammography screening episode, particularly for women with dense breasts or an elevated breast cancer risk. Women, clinicians, policymakers, and researchers should use final-assessment performance metrics to support informed screening decisions.

The Women's Health Initiative trials of menopausal hormone therapy: lessons learned.

The Women's Health Initiative (WHI) assessed oral conjugated equine estrogens (CEE) taken with or without medroxyprogesterone acetate (MPA) for prevention of chronic disease in postmenopausal women aged 50-79 years. Women with an intact uterus (n = 16,608) were randomized to CEE+ MPA therapy or placebo for a median of 5.6 years; women with hysterectomy (n = 10,739) were randomized to CEE-alone therapy or placebo for a median of 7.2 years. Both cohorts have been followed for 18 years. In the overall study population (mean age, 63 y), neither estrogen-progestin therapy (EPT) nor estrogen-only therapy prevented coronary heart disease or led to a favorable balance of chronic-disease benefits and risks. Subgroup analyses, however, suggest that timing of hormone therapy (HT) initiation influences the relation between HT and coronary risk, as well as its overall benefit-risk balance, with more favorable effects in women who are younger (age < 60 year) or recently menopausal (within 10 year) than in women who are older or further past the menopausal transition. In younger women who entered the trial of estrogen-only therapy with oophorectomy, the intervention was associated with a significant 32% reduction in all-cause mortality over long-term follow-up. WHI findings indicate important differences in HT-related clinical outcomes by age and time since menopause. Systemic HT has an acceptable safety profile for menopause management when initiated among healthy women who are younger (or recently menopausal) and not at elevated risk for cardiovascular disease or breast cancer. Initiation of treatment in older women who are distant from menopause onset, however, should be avoided. Other HT formulations and routes of delivery warrant further study.(WHI clinicaltrials.gov identifier: NCT00000611).