Breast Cancer Chemoprevention Research Articles

Making informed choices on incorporating chemoprevention into carE (MiCHOICE, SWOG 1904): Design and methods of a cluster randomized controlled trial

IntroductionWomen with atypical hyperplasia (AH) or lobular carcinoma in situ (LCIS) have a significantly increased risk of breast cancer, which can be substantially reduced with antiestrogen therapy for chemoprevention. However, antiestrogen therapy for breast cancer risk reduction remains underutilized. Improving knowledge about breast cancer risk and chemoprevention among high-risk patients and their healthcare providers may enhance informed decision-making about this critical breast cancer risk reduction strategy. Methods/designWe are conducting a cluster randomized controlled trial to evaluate the effectiveness and implementation of patient and provider decision support tools to improve informed choice about chemoprevention among women with AH or LCIS. We have cluster randomized 26 sites across the U.S. through the SWOG Cancer Research Network. A total of 415 patients and 200 healthcare providers are being recruited. They are assigned to standard educational materials alone or combined with the web-based decision support tools. Patient-reported and clinical outcomes are assessed at baseline, after a follow-up visit at 6 months, and yearly for 5 years. The primary outcome is chemoprevention informed choice after the follow-up visit. Secondary endpoints include other patient-reported outcomes, such as chemoprevention knowledge, decision conflict and regret, and self-reported chemoprevention usage. Barriers and facilitators to implementing decision support into clinic workflow are assessed through patient and provider interviews at baseline and mid-implementation. Results/discussionWith this hybrid effectiveness/implementation study, we seek to evaluate if a multi-level intervention effectively promotes informed decision-making about chemoprevention and provide valuable insights on how the intervention is implemented in U.S. clinical settings. Trial RegistrationNCT04496739

Abstract PO2-08-04: Unraveling alterations in the pre-neoplastic breast microenvironment of BRCA1/2 mutation carriers using spatial transcriptomics

Abstract Breast cancer is the most common cancer in females, affecting one in every eight women and accounting for the majority of cancer-related deaths in women worldwide. Germline mutations in the BRCA1 and BRCA2 genes are significant risk factors for specific subtypes of breast cancer. BRCA1 mutations are associated with basal-like breast cancers, whereas BRCA2 mutations are associated with luminal-like disease. There are currently few chemoprevention strategies available for BRCA1/2 mutation carriers, and irreversible prophylactic mastectomy is the primary option. Designing chemo-preventive strategies requires an in-depth understanding of the physiological processes underlying tumor initiation. Here, we employ spatial transcriptomics to investigate defects in mammary epithelial cell differentiation accompanied by distinct microenvironmental alterations in preneoplastic breast tissues from BRCA1/2 mutation carriers and normal breast tissues from non-carrier controls. We uncovered spatially defined receptor-ligand interactions in these tissues for the investigation of autocrine and paracrine signaling. We discovered that β1-integrin-mediated autocrine signaling in BRCA2-deficient mammary epithelial cells differs from BRCA1-deficient mammary epithelial cells. In addition, we found that the epithelial-to-stromal paracrine signaling in the breast tissues of BRCA1/2 mutation carriers is greater than in control tissues. More integrin-ligand pairs were differentially correlated in BRCA1/2-mutant breast tissues than non-carrier breast tissues with more integrin receptor-expressing stromal cells. These results reveal alterations in the communication between mammary epithelial cells and the microenvironment in BRCA1 and BRCA2 mutation carriers, laying the foundation for designing innovative breast cancer chemo-prevention strategies for high-risk patients. Citation Format: Mihriban Karaayvaz, Anthony Caputo, Kavya Vipparthi, Peter Bazeley, Erinn Downs-Kelly, Patrick McIntire, Ying Ni, Bo Hu, Ruth Keri. Unraveling alterations in the pre-neoplastic breast microenvironment of BRCA1/2 mutation carriers using spatial transcriptomics [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-08-04.

Novel carbamodithioate regulates cellular hypoxia through chemical activation of prolyl hydroxylase-2 for breast cancer chemoprevention.

Inhibition of prolylhydroxylase-2 (PHD-2) in both normoxic and hypoxic cells is a critical component of solid tumours. The present study aimed to identify small molecules with PHD-2 activation potential. Virtually screening 4342 chemical compounds for structural similarity to R59949 and docking with PHD-2. To find the best drug candidate, hits were assessed for drug likeliness, antihypoxic and antineoplastic potential. The selected drug candidate's PHD-2 activation, cytotoxic and apoptotic potentials were assessed using 2-oxoglutarate, MTT, AO/EtBr and JC-1 staining. The drug candidate was also tested for its in-vivo chemopreventive efficacy against DMBA-induced mammary gland cancer alone and in combination with Tirapazamine (TPZ). Virtual screening and 2-oxoglutarate assay showed BBAP-6 as lead compound. BBAP-6 exhibited cytotoxic and apoptotic activity against ER+ MCF-7. In carmine staining and histology, BBAP-6 alone or in combination with TPZ restored normal surface morphology of the mammary gland after DMBA produced malignant alterations. Immunoblotting revealed that BBAP-6 reduced NF-κB expression, activated PHD-2 and induced intrinsic apoptotic pathway. Serum metabolomics conducted with 1H NMR confirmed that BBAP-6 prevented HIF-1α and NF-κB-induced metabolic changes in DMBA mammary gland cancer model. In a nutshell, it can be concluded that BBAP-6 activates PHD-2 and exhibits anticancer potential.

Bioactive Natural Products for Breast Cancer Chemoprevention and Treatment

Background: In addition to being one of the deadliest tumors, breast cancer is also one of the most difficult to cure. Due to the serious side effects of current breast cancer treatments and the rise in drug resistance, current drugs are losing their effectiveness. Potential Natural Bioactives: Bioactive natural compounds target various pathophysiological pathways involved in the development and progression of cancer and hence have the ability to prevent both the growth of breast cancer and the advancement of metastatic disease concurrently. : Natural anticancer compounds have been shown to be effective, complementary treatment may be of great assistance in this case. Clinical Outcomes: Nutraceuticals and popular folk remedies may provide benefits over manufactured pharmaceuticals since they have fewer side effects and less toxicity in both in vitro and in vivo studies. A variety of natural compounds have been shown to reduce the aggressiveness of breast cancer, inhibit the growth of malignant cells, and alter the pathways involved in cancer development and progression. Either by directly affecting certain biological targets, such genes, or by indirectly stabilising conjugates that have an impact on metabolic processes, natural compounds called phytochemicals can enhance human health. Mechanistic Pathways: There are many promising bioactive natural products that can be used to treat breast cancer, including those that inhibit aromatase activity, target HIF-1 signaling, inhibit cytoplasmic signaling, modulate epigenetic regulation, modulate estrogen signaling pathways, or work in chemosensitivity/adjuvant therapy (such as resveratrol, epigallocatechin-3-gallate, and eugenol).

Potential of Natural products for Chemoprevention of Breast Cancer

Background: Breast cancer is the most frequent female cancer and one of the leading causes of cancer death in women. There are many chemotherapy agents available for the treatment of breast cancer. Still, the current therapeutic options have not fulfilled the desired outcomes, especially for drug-resistant breast cancer therapy. Thus, there is an urgent need to develop novel anti-breast cancer agents. Objective: This overview targets to portray the new advancement of herbal and artificial derivatives with anti-breast cancer potential, protecting the articles allotted from the ultimate year. Method: We found significant articles of interest in the field of breast cancer and proposed a review based on relevant information. Description of the studies included in the review. Result: Various key components are found in vegetables, fruits, seeds, nuts, coffee, tea, and wine. Therefore, dietary exposure is significant. Natural products having low-cost toxicity, their availability in foods, and their existence in a variety of herbal treatments, caution should be exercised in further assessment of their properties and applications. Conclusion: We tried to analyze the anti-breast cancer potency of quite a few extracts from different plant sources and to compare their antiproliferative efficiency of crude extracts with the action of their purified ingredients while an additional study is required.

Spatial Transcriptomics Suggests That Alterations Occur in the Preneoplastic Breast Microenvironment of BRCA1/2 Mutation Carriers.

These results suggest alterations in the communication between mammary epithelial cells and the microenvironment in BRCA1 and BRCA2 mutation carriers, laying the foundation for designing innovative breast cancer chemo-prevention strategies for high-risk patients.

Comparing Breast Cancer and Cardiovascular Disease Risk and Use of Chemoprevention and Statins among Women with High-risk Breast Lesions.

Among women with high-risk breast lesions, mean absolute risk of breast cancer was higher compared with cardiovascular disease; however, statin use was significantly higher than chemoprevention. To address underutilization of breast cancer chemoprevention, these drugs should be placed in the context of medications used to prevent other chronic diseases.

Women's Health Beliefs and Intention to Use Chemoprevention for Breast Cancer.

To investigate the associations between women's health beliefs and their intention to use chemoprevention. Participants were postmenopausal women (N = 400) aged 50-64 years who were recruited for a study on mammographic breast density. Participants completed a screening mammogram and breast cancer health belief questionnaires. The authors regressed intention to use chemoprevention onto health belief scores (breast cancer fatalism, fear, perceived threat, perceived benefits, barriers, and self-efficacy). Nearly half of the participants indicated that they would be interested in using chemoprevention if they were found to be at high risk for developing breast cancer. Women who reported higher perceived benefits of chemoprevention, higher perceptions of their ability to use chemoprevention (self-efficacy), and fewer logistic barriers to seeking health care had significantly higher intention to use chemoprevention. Interventions aimed at reducing logistic barriers to health care may increase the uptake of chemoprevention among at-risk women. In addition, women at the time of mammography and women with higher levels of education may be motivated to consider using chemoprevention.

Comparative anticancer effects of Annona muricata Linn (Annonaceae) leaves and fruits on DMBA-induced breast cancer in female rats

BackgroundNumerous studies have reported the anti-cancer effects of different parts of Annona muricata Linn, however ; most of them focused on the in vitro evaluation of isolates. In vivo evidence on which part is best suited for breast cancer chemoprevention remains to be demonstrated. This is a comparative study of the effects of A. muricata fruit and leaves extracts on DMBA induced-breast cancer in rats.MethodsRats exposed to DMBA (50 mg/kg, s.c.), were treated with A. muricata fruit aqueous extract at 200 mg/kg BW (3 days/week or daily) and A. muricata Linn leaves ethanolic extract at 200 mg/kg daily. Positive control group received tamoxifen at 3.3 mg/kg, while the normal and diseased controls received vehicle. After 20 weeks of treatment, the tumor incidence, tumor burden, tumor volume, histopathology, protein and CA 15 − 3 levels as well as antioxidant status, pro-inflammatory cytokines were assessed.ResultsThus, 100% of diseased rats presented cribriform ductal carcinoma of SBR grade III. A. muricata extracts (leaves and fruit) and tamoxifen significantly reduced death and tumor incidences, volume and weight of the tumors, total protein and CA15-3 levels compared to the DMBA group. They exhibited antioxidant activity, through an increase in the GSH level and SOD and catalase activities with reduced levels of MDA compared to DMBA group. TNF-α, IL-6 and INF-γ levels reduced with regards to A. muricata treatment.ConclusionThese results confirm the anti-breast cancer effect of A. muricata, however, the aqueous fruit extract was more potent than the ethanolic leaves extract.

An Update on Tamoxifen and the Chemo-Preventive Potential of Vitamin E in Breast Cancer Management.

Breast cancer (BC) is the most common female cancer in terms of incidence and mortality worldwide. Tamoxifen (Nolvadex) is a widely prescribed, oral anti-estrogen drug for the hormonal treatment of estrogen-receptor-positive BC, which represents 70% of all BC subtypes. This review assesses the current knowledge on the molecular pharmacology of tamoxifen in terms of its anticancer and chemo-preventive actions. Due to the importance of vitamin E compounds, which are widely taken as a supplementary dietary component, the review focuses only on the potential importance of vitamin E in BC chemo-prevention. The chemo-preventive and onco-protective effects of tamoxifen combined with the potential effects of vitamin E can alter the anticancer actions of tamoxifen. Therefore, methods involving an individually designed, nutritional intervention for patients with BC warrant further consideration. These data are of great importance for tamoxifen chemo-prevention strategies in future epidemiological studies.

Abstract 5250: Effect of the β-blocker carvedilol in preventing DMBA-induced mammary gland tumor growth

Abstract According to global cancer statistics, breast cancer has now become the most diagnosed cancer and has become the fifth leading cause of cancer-related deaths worldwide. A promising method of retarding cancer-related mortality is cancer chemoprevention. However, there is no drug available that can be used routinely as a breast cancer-preventative agent. As carvedilol (CAR), an FDA-approved beta-adrenergic receptor blocker, reduces breast cancer mortality, we hypothesized that CAR might act as a breast cancer preventative agent. Three protocols were utilized to evaluate the ability of CAR to prevent 7,12-Dimethylbenz(a)anthracene (DMBA)-induced mammary tumors in rats. In protocol 1, two doses of CAR (2 and 10 mg/kg) were administered in drinking water as a 7-day pretreatment and throughout the study. In protocol 2, 10 mg/kg tamoxifen and 10 mg/kg carvedilol were provided as a 7-day pretreatment, and treatment was halted after six weeks. In protocol 3, CAR and the non-β-blocking enantiomer R-carvedilol (10 mg/kg) were given as a 7-day pretreatment and throughout the study. In all studies, animals were palpated weekly beginning at week 5 to detect the presence and location of mammary tumors. Tumors were measured using a caliper, and the experiments terminated at week 13. In protocol 1, only 10 mg/kg CAR was effective in delaying DMBA-mediated tumor occurrence (p = 0.0002); the first appearance of tumors and median tumor appearance in CAR-treated rats were separated from rats receiving DMBA alone by 2 and 4 weeks, respectively. However, tumors that did form grew at the same rate in all groups. In protocol 2, tamoxifen served as a control to prevent DMBA-mediated tumors; only one tamoxifen-treated rat developed a tumor at the end of the study. The tamoxifen-treated rats tumor formation was not statistically different than negative controls; however, the CAR group was not statistically different from the DMBA group. In protocol 3, CAR and R-CAR treatment showed delayed tumor formation and growth compared to the DMBA-only group, although not statistically significant. Combining all DMBA and 1-week pretreatment CAR data (n = 58 and 40, respectively), CAR effectively prevents DMBA-induced tumor incidence (p = 0.001), with a 3-week differential in the median tumor formation between the two groups. Therefore, continuous CAR treatment is essential to achieve the observed chemopreventive effects. As carvedilol is a clinically used beta-blocker, the results provide significant implications in breast cancer chemoprevention. Citation Format: Pabitra Kumar Sardar, Steven Yeung, Ayaz Shahid, Bradley T. Andresen, Ying Huang. Effect of the β-blocker carvedilol in preventing DMBA-induced mammary gland tumor growth. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5250.

Abstract OT1-15-01: SWOG 1904: Cluster-randomized controlled trial of patient and provider decision support to increase chemoprevention informed choice among women with atypical hyperplasia or lobular carcinoma in situ (MiCHOICE)

Abstract Background: Despite evidence of substantial breast cancer risk reduction, few high-risk women adopt chemopreventive medications such as selective estrogen receptor modulators (SERMs) or aromatase inhibitors (AIs). Women with benign breast disease, such as atypical hyperplasia (AH) or lobular carcinoma in situ (LCIS), have an increased risk of developing breast cancer and derive a greater benefit from antiestrogens compared to other high-risk women. Reasons for low uptake of chemoprevention include insufficient patient and clinician knowledge about antiestrogens, time constraints during the clinical encounter, and concerns about side effects. To address these barriers, we have developed patient and provider web-based decision support tools to improve informed choice about breast cancer chemoprevention among women with AH or LCIS. Study design: We are conducting a cluster-randomized controlled trial of clinical decision support to improve chemoprevention informed choice among women with AH or LCIS and their treating providers. Twenty-six U.S. sites through the SWOG Cancer Research Network were randomly assigned 1:1 to standard educational materials alone or in combination with the patient-centered decision aid (RealRisks) and provider decision support tool (BNAV). A total of 415 patients and 200 healthcare providers will be recruited from these sites. RealRisks consists of interactive modules to calculate personalized breast cancer risk and elicit preferences on chemoprevention. The modules are available in English and Spanish. BNAV is comprised of self-directed case-based learning modules on breast cancer risk assessment and chemoprevention. Patients complete questionnaires at baseline, 6 and 12 months. Providers complete surveys at baseline and after their enrolled patient’s 6-month clinical encounter. The primary endpoint is chemoprevention informed choice at 6 months, using a measure combining knowledge, attitude, and intention scales. Secondary endpoints include perceived breast cancer risk/worry, chemoprevention knowledge/intention, decision conflict/regret, shared decision-making, and chemoprevention uptake. For patients who begin chemoprevention, adherence and reasons for discontinuation are assessed annually for up to 5 years. Barriers and facilitators to implementing RealRisks and BNAV into clinic workflow will be assessed by conducting patient and provider interviews at baseline and mid-implementation. Eligibility criteria: Eligible patients include women, age 35-74 years, with AH or LCIS, no history of breast cancer, no prior use of SERMs or AIs, no bilateral mastectomies, English or Spanish-speaking, and access to the internet. Eligible providers include breast surgeons, medical oncologists, primary care providers, and physician extenders who see patients with AH or LCIS. Statistical methods: We have 90% power to detect a 15% increase in the frequency of chemoprevention informed choice with a 1-sided 0.025 level test, assuming an intraclass correlation (ICC) of 0.02 to account for clustering, roughly equal accrual at each site, 10% loss to follow-up, and ≤10% event rate in the control arm. Current/target accrual: The trial was activated on 9/1/2020. As of 7/7/2022, all 26 sites have been randomized, 157/200 providers and 184/415 patients have been enrolled. Discussion: Our hybrid effectiveness/implementation study seeks to evaluate the effectiveness of a multi-level intervention in promoting informed decision-making about breast cancer chemoprevention. Study results will provide valuable insights on how the decision support tools are integrated in diverse clinical settings. Citation Format: Katherine D. Crew, Garnet Anderson, Kathryn Arnold, Andrew Stieb, Jacquelyn N. Amenta, Cynthia Law, Ana Sandoval-Leon, Sarah Colonna, Tari King, Debra Mangino, Sandhya Pruthi, Maria Grosse Perdekamp, Christa Braun-Inglis, Stacy Krisher, Lisa Yee, Danielle Bertoni, Samantha Seaward, Kari B. Wisinski, Justin Floyd, Corrine Zarwan, Tarah J. Ballinger, Lindi VanderWalde, Masey M. Ross, Preston Steen, Shelly Lo, Alison Conlin, Kathleen Yost, John Ellerton, Erin Lin, Holly J. Pederson, Sagar Sardesai, Cheryl Jernigan, Dawn Hershman, Marian L. Neuhouser, Banu K. Arun, Rita Kukafka. SWOG 1904: Cluster-randomized controlled trial of patient and provider decision support to increase chemoprevention informed choice among women with atypical hyperplasia or lobular carcinoma in situ (MiCHOICE) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT1-15-01.

Abstract P4-03-23: Comparison of Breast Cancer vs Cardiovascular Disease Risk and Uptake of Chemoprevention vs Statins in a Cohort of Predominantly Hispanic Women Undergoing Screening Mammography

Abstract Background: Atherosclerotic cardiovascular disease (ASCVD) and breast cancer are two of the most diagnosed chronic diseases among women in the U.S. Although prevention of ASCVD with statins is widely practiced, breast cancer chemoprevention with selective estrogen receptor modulators (SERMs) or aromatase inhibitors (AIs) is underutilized in the primary care setting, despite significant evidence in randomized controlled trials demonstrating its clinical benefits. We compared the risk of ASCVD and breast cancer among predominantly Hispanic women undergoing screening mammography, as well as uptake of statins and SERMs/AIs for ASCVD and breast cancer risk reduction, respectively, among high-risk women. Methods: We conducted a retrospective cohort study among 1,655 English or Spanish-speaking women, age 40-79 years, with no prior history of breast cancer, who underwent screening mammography from 2014 to 2016 at Columbia University Irving Medical Center in New York City. Participants completed a survey collecting data on sociodemographic and breast cancer risk factors and had available data in the electronic health record (EHR) for calculating ASCVD risk, including systolic blood pressure, total and HDL cholesterol, history of diabetes, treatment for hypertension, and current smoking status. The main outcomes included 5-year and lifetime invasive breast cancer risk according to the Gail model, and 10-year and lifetime ASCVD risk score according to the 2013 American College of Cardiology (ACC)/American Heart Association (AHA) ASCVD risk calculator. High-risk was defined as a 5-year invasive breast cancer risk 1.67% and 10-year ASCVD risk 7.5%. Secondary outcomes included uptake of chemoprevention with SERMs or AIs and statins among women at high-risk for breast cancer and ASCVD, respectively, based upon medication lists in the EHR. We compared mean lifetime risk of breast cancer vs ASCVD for the entire cohort using a paired t-test, and the proportion of high-risk women taking statins vs chemoprevention using McNemar’s test. Results: Among 1,655 evaluable women, mean age was 58 years (SD=10.1 years), with 76% Hispanic, 6% non-Hispanic White, 3% non-Hispanic Black, 2% Asian, and 13% other. About half (48%) of women met high-risk criteria for ASCVD compared to 15% who met high-risk criteria for breast cancer. Among all women, mean lifetime ASCVD risk was higher than mean lifetime breast cancer risk (10.71% vs. 5.46%, p< 0.001). Among women at high risk for ASCVD or breast cancer, respectively, statin uptake was higher compared to SERM/AI uptake for breast cancer chemoprevention (84% vs. 7%, p< 0.001). Overall, fewer Hispanic compared to non-Hispanic women met high-risk criteria for ASCVD (47% vs. 51%, respectively) and breast cancer (9% vs. 34%, respectively). Conclusions: In a population of predominantly Hispanic women undergoing screening mammography, we found that more women met high-risk criteria for ASCVD compared to breast cancer. Among women at high risk for ASCVD, statin uptake was about 12-fold higher compared to uptake of breast cancer chemoprevention among women at high risk for breast cancer. Given significant underutilization of breast cancer chemoprevention, placing this in the context of prevention of other chronic diseases, such as statins for ASCVD, may enhance uptake of SERMs or AIs in the primary care setting. Citation Format: Luisa Nilan, Mary M. McDermid, Jacquelyn N. Amenta, Julia E. McGuinness, Katherine D. Crew, Rita Kukafka. Comparison of Breast Cancer vs Cardiovascular Disease Risk and Uptake of Chemoprevention vs Statins in a Cohort of Predominantly Hispanic Women Undergoing Screening Mammography [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-03-23.

Abstract P2-07-01: Hydroxytyrosol, a Component of Olive Oil for Breast Cancer Prevention in Women at High Risk

Abstract Background Breast cancer is the most frequently diagnosed cancer in women in developed countries with increased incidence in women at high risk such as those with strong family history, BRCA mutations, atypical hyperplasia etc. Chemoprevention with drugs like tamoxifen and aromatase inhibitors come with challenges of intolerance and limited efficacy in estrogen receptor negative breast cancers. The purpose of our study was to evaluate the effects of hydroxytyrosol (HT), a component of olive oil on mammographic breast density reduction, which is a validated surrogate biomarker for breast cancer prevention as well as to explore on-target effects on Wingless-related integration site (Wnt) pathway, and alterations in key pathways of proliferation, DNA damage repair and stem cell function. Methods This study was conducted using 25mg/day oral dose of HT for 12 months in both pre- and post-menopausal women who are at increased risk of breast cancer with Gail 5-year risk score ≥ 1.67 and/or > 10% probability of BRCA mutation and had declined standard chemoprevention. These women underwent annual mammograms as well as had the option to have a biopsy of normal breast tissue before and after HT. Maximum volumetric breast density (Max VBD%) was assessed quantitatively using Volpara software (VIS 3.2) and the annualized percent decrease in max VBD% between baseline (BL) and end of treatment (EOT) with HT was analyzed in the study. RNA was extracted from the breast biopsies and RNA sequencing (RNA-Seq) and multiplex analysis of 28 proteins using NanoString nCounter analysis was performed to compare the BL with EOT samples. Results A total of 61 women were screened for the trial, 51 were enrolled and 41 patients completed the study. Median age for the study population was 54 years (range 35-76 years). There were 26 patients with paired BL and EOT mammograms. There were 14 patients with paired BL and EOT breast biopsies and seven patients with only BL and seven with only EOT biopsies. Mammographic density as measured by max VBD% showed a non-significant change of -0.038%, p = 0.49. However, on subgroup analysis in women 60-years or older, the mean decrease in max VBD% was - 3.7% (p = 0.0391), especially in those with high baseline mammographic density (> 10% baseline max VBD%). RNAseq data was generated from 15 BL and 17 EOT samples and pathways were confirmed by NanoString. Our bioinformatics pipeline identified 190 transcripts that were upregulated and 90 that were downregulated in EOT vs. BL by at least 1.5 fold. Reactome pathway R-HSA-195721 (Signaling by WNT) is identified as the top pathway enriched with EOT downregulated genes. On further review of the expression profiles, 82 of 261 member genes had p-value < 0.05 for EOT vs. BL, among which only 4 were upregulated and 78 were downregulated in EOT samples. These 82 genes were highly interactive with each other, with 379 high confidence protein-protein interactions (PPIs) (confidence score > 0.7 from STRING database) involving 81 out of 82 genes. In addition, mitotic telophase/cytokinesis (p = 0.004), ATM signaling (p = 0.007) were some pathways that were upregulated whereas, NOTCH signaling (p = 0.007), oxidative stress induced senescence (p = 0.0001) pathways were downregulated in EOT vs. BL. Conclusions Hydroxytyrosol, a component of olive oil did not show a decrease in breast density in the intention to treat population but showed some reduction in breast density in women 60-years of age and above, especially in those with high baseline breast density. HT showed on target effects by affecting Wnt signaling pathway, as well as decrease in proliferation. This study lays the foundation for future larger studies in exploring a natural compound such as HT for chemoprevention of breast cancer. Citation Format: Akshjot Puri, Zheng Yin, Sergio Granados-Principal, Joe Ensor, Liliana Guzman, Roberto Rosato, Hong Zhao, Stephen Wong, Tejal Patel, Jenny Chang. Hydroxytyrosol, a Component of Olive Oil for Breast Cancer Prevention in Women at High Risk [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-07-01.

Abstract P2-05-01: Addressing barriers to adherence and quality of life among women recommended to receive chemoprevention for breast cancer prevention

Abstract Aims: While women with breast cancer may have increased survival when compared to other cancers, aggressive, multi-modal treatments are often required with significant impact on quality of life and economic cost, highlighting the importance of breast cancer prevention and screening. For the estimated 10 million women in the United States who meet high-risk criteria for breast cancer, evidence-based interventions may be implemented to reduce risk, including long-term chemoprevention. Engaging in preventative care requires a healthy woman to navigate a complicated decision-making process involving the woman’s perception of risk, access to information about risk and prevention strategies, access to care, social support, and the financial ability to manage cost of preventive care. Even with substantial evidence supporting chemoprevention for risk reduction, there is significant lack of uptake and adherence, especially among racial and ethnic minorities and underserved women. Given the missed opportunity for breast cancer prevention that this represents, it is critical to characterize the experience of women with chemoprevention to improve uptake and adherence to chemoprevention. Our aims were to explore the patient experience of women recommended to receive chemoprevention for breast cancer prevention. Methods: Sampling from a unique high-risk specialty care setting, we interviewed a diverse cohort of thirty women recommended to receive chemoprevention for breast cancer to learn about their experience in single semi-structured qualitative interviews. Content analysis was used to describe their experience and identify barriers to chemoprevention uptake and adherence. The MDASI-Breast was used to capture patient reported symptom burden at the time of interview. Results: Mean participant age was 54.6 years (range 34-87 years); 44.0% Hispanic; 20.0% Black; 81.0% receiving a selective estrogen receptor modulator, 19% receiving an aromatase inhibitor. Mean time since initiating chemoprevention was 14.0 months (range 1.1-49.3 months). At the time of the interview, women reported multiple symptoms, with the most severe reports of fatigue (mean severity 3.77, SD 2.91), sleep disturbance (mean severity 2.90, SD 2.47), problems with memory (mean severity 2.48, SD 2.07), drowsiness (mean severity 2.23, SD 2.14), and decrease in sexual interest or activity (mean severity 2.09, SD 2.38). In qualitative interviews, women reported barriers to preventive care related to symptom burden, access to care, access to accurate information, lack of understanding of breast cancer risk, and financial concerns. Content analysis found 20 symptoms related to both risk and preventive treatment, with 8 symptoms reported by ≥ 20% of women. All women described distress related to their risk, with 23.8% of women describing sadness related to their risk. In addition, 33.3% of women reported distress related to the impact of their own risk on their family, primarily on their children. Women (23.8%) described breast changes that were present when their risk was identified, such as a lump or pain. Treatment-related symptoms varied based on type of endocrine therapy received and history of surgery and included sleep disturbance (23.8% of women), pain (28.6%), hot flashes/night sweats (33.3%), fatigue (28.6%), and joint stiffness or soreness (23.8%). Women shared ways in which symptoms impacted daily functioning, work, relationships, and ability to enjoy life. Conclusions: Women at risk for breast cancer recommended to receive chemoprevention experience multiple barriers to adherence including symptoms related to their risk and preventive care, access to care and accurate information, and financial burden. Interventions are needed to improve access to care and symptom management. Citation Format: Jessica T. Jones, Meagan Whisenant, Kelly J. Brassil, Hannah G. Warlick, Emily Solis, Sharvari Kamat, Ann Maliackal, Amie Walters, Darcy Ponce, Anneliese Gonzalez, Denise Rios, Robinson Emily. Addressing barriers to adherence and quality of life among women recommended to receive chemoprevention for breast cancer prevention [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-05-01.

Abstract P001: Frequency and covariates of chemoprevention use among women at high risk for breast cancer

Abstract Purpose: To assess patterns of self-reported use of chemopreventive medications (i.e., tamoxifen, raloxifene) among women with elevated risk for breast cancer. Methods: Women with elevated breast cancer risk (N=134; n=98 BRCA1/2 mutation carriers, n=36 with ≥1.67% 5-year breast cancer per the National Cancer Institute [NCI] Breast Cancer Risk Assessment Tool [BCRAT; https://bcrisktool.cancer.gov/]) were recruited by advertising on social media and through community organizations. Between August 2020 and January 2021, participants completed an online survey assessing demographic characteristics (race, ethnicity, education, employment, income, insurance, and usual healthcare setting), psychosocial characteristics (perceived breast cancer risk, self-efficacy), provider recommendation for breast cancer chemoprevention, and prior/current use of breast cancer chemoprevention. Descriptive statistics characterized the frequency of provider recommendation for and use of breast cancer chemoprevention. Multivariable logistic regression analysis examined demographic and psychosocial characteristics associated with use of breast cancer chemoprevention. Results: Participants were in middle adulthood (M=45) and mostly non-Hispanic White (90%), with ≥ Bachelor’s degree (69%), household income ≥ $50,000/year (67%), and private health insurance (69%). Most were employed outside the home (73%) and typically received medical care at a private doctor’s office (81%). Most (76%) had discussed their breast cancer risk with a healthcare provider. About one-third (33%) reported receiving a provider recommendation for tamoxifen or raloxifene, 16% had previously taken one of these medications, and 10% were currently taking one of these medications. This included 24% of participants with a BRCA1/2 mutation and 35% of participants with a 5-year breast cancer risk ≥1.67%; use of chemoprevention did not differ between these groups (p=0.22). Compared to participants with private health insurance, those who were publicly insured were more likely to have taken chemoprevention medications (OR=8.27, p=0.04, 95% C.I.=1.95-35.11). No other demographic or psychosocial characteristics were associated with chemoprevention use (all p’s≥0.09). Conclusions: Consistent with prior research, few women with elevated breast cancer risk reported currently or previously taking chemopreventive medications. Despite little data on the efficacy of chemoprevention for BRCA1/2 mutation carriers, self-reported use of chemoprevention did not differ based on BRCA1/2 mutation status. Insurance status emerged as a key predictor of chemoprevention use, indicating that cost and insurance coverage may be a barrier for some women and may need to be addressed in interventions aiming to increase use of chemoprevention. Given the homogenous convenience sample, results might not extend to the broader population and need to be replicated in larger, more diverse samples. Citation Format: Claire C. Conley, Jennifer Rodriguez, Suzanne C. O’Neill, Susan T. Vadaparampil. Frequency and covariates of chemoprevention use among women at high risk for breast cancer. [abstract]. In: Proceedings of the AACR Special Conference: Precision Prevention, Early Detection, and Interception of Cancer; 2022 Nov 17-19; Austin, TX. Philadelphia (PA): AACR; Can Prev Res 2023;16(1 Suppl): Abstract nr P001.

Implementation-effectiveness trial of systematic family health history based risk assessment and impact on clinical disease prevention and surveillance activities

BackgroundSystematically assessing disease risk can improve population health by identifying those eligible for enhanced prevention/screening strategies. This study aims to determine the clinical impact of a systematic risk assessment in diverse primary care populations.MethodsHybrid implementation-effectiveness trial of a family health history-based health risk assessment (HRA) tied to risk-based guideline recommendations enrolling from 2014–2017 with 12 months of post-intervention survey data and 24 months of electronic medical record (EMR) data capture. Setting:19 primary care clinics at four geographically and culturally diverse U.S. healthcare systems. Participants: any English or Spanish-speaking adult with an upcoming appointment at an enrolling clinic. Methods: A personal and family health history based HRA with integrated guideline-based clinical decision support (CDS) was completed by each participant prior to their appointment. Risk reports were provided to patients and providers to discuss at their clinical encounter. Outcomes: provider and patient discussion and provider uptake (i.e. ordering) and patient uptake (i.e. recommendation completion) of CDS recommendations. Measures: patient and provider surveys and EMR data.ResultsOne thousand eight hundred twenty nine participants (mean age 56.2 [SD13.9], 69.6% female) completed the HRA and had EMR data available for analysis. 762 (41.6%) received a recommendation (29.7% for genetic counseling (GC); 15.2% for enhanced breast/colon cancer screening). Those with recommendations frequently discussed disease risk with their provider (8.7%-38.2% varied by recommendation, p-values ≤ 0.004). In the GC subgroup, provider discussions increased referrals to counseling (44.4% with vs. 5.9% without, P < 0.001). Recommendation uptake was highest for colon cancer screening (provider = 67.9%; patient = 86.8%) and lowest for breast cancer chemoprevention (0%).ConclusionsSystematic health risk assessment revealed that almost half the population were at increased disease risk based on guidelines. Risk identification resulted in shared discussions between participants and providers but variable clinical action uptake depending upon the recommendation. Understanding the barriers and facilitators to uptake by both patients and providers will be essential for optimizing HRA tools and achieving their promise of improving population health.Trial registrationClinicaltrials.gov number NCT01956773, registered 10/8/2013.

Abstract A015: The β-blocker carvedilol prevents DMBA-induced mammary gland tumors

Abstract Breast cancer is the most diagnosed cancer globally and is the fifth leading cause of cancer related mortality worldwide. Chemoprevention is a promising method of reducing cancer mortality. However, there are no drugs that are used routinely as breast cancer preventative agents. Carvedilol (CAR), a beta-adrenergic receptor blocker, use in humans reduces breast cancer incidence; therefore, we hypothesized that carvedilol acts as a breast cancer preventative agent. Two protocols were used to evaluate the ability of carvedilol to prevent 15 mg 7,12-Dimethylbenz(a)anthracene (DMBA)-induced mammary tumors. In protocol 1, two doses of carvedilol (2 and 10 mg/kg) were provided as a 7-day pretreatment and throughout the study. In protocol 2, 10 mg/kg tamoxifen and 10 mg/kg carvedilol were provided as a 7-day pretreatment and treatment was halted after six weeks. In all studies carvedilol and tamoxifen were administered in the drinking water, animals were palpated weekly beginning at week 5 to detect the presence and location of mammary tumors, tumors were measured via calipers, and the experiments terminated at week 13. In protocol 1, 10 mg/kg, but not 2 mg/kg carvedilol was effective in delaying the tumor occurrence (P = 0.0002); the first appearance of tumors and median tumor appearance were separated by 6 and 4 weeks, respectively, compared to rats receiving DMBA alone. However, the tumors that appeared, grew at similar rate as those in the DMBA group. In protocol 2, tamoxifen prevented all but 1 rat developing a tumor and was similar to the negative control; however, 10 mg/kg carvedilol was indistinguishable from the DMBA group. Although tamoxifen prevented DMBA-induced breast cancer, the rats drank significantly less water resulting in statistically lower body weight than all other groups. The rats also drank significantly less of the carvedilol-laced water, but not to a degree that affected their body weight. Therefore, continuous carvedilol treatment is essential to achieve the observed chemopreventive effects. Our data demonstrates the chemopreventive activity of carvedilol in a rat model of mammary gland carcinogenesis. The results provide significant implications in breast cancer chemoprevention using carvedilol, which is a safe FDA-approved medicine. Citation Format: Pabitra K. Sardar, Ayaz Shahid, Steven Yeung, Bradley T. Andresen, Ying Huang. The β-blocker carvedilol prevents DMBA-induced mammary gland tumors [abstract]. In: Proceedings of the Second Biennial NCI Meeting: Translational Advances in Cancer Prevention Agent Development (TACPAD); 2022 Sep 7-9. Philadelphia (PA): AACR; Can Prev Res 2022;15(12 Suppl_2): Abstract nr A015.

Abstract A003: Identification of a potential chemoprevention agent for BRCA1- mutated cancers

Abstract BRCA1 mutation carriers are predisposed to developing aggressive breast, ovarian, and other cancers at a relatively early age. Unfortunately, these cancers lack an effective chemoprevention option. We have found that cells containing mutant BRCA1 harbor defective repair of oxidative DNA damage, an early trigger to tumorigenesis. Therefore, we sought to target this defect and discover a novel chemoprevention agent for these cancers. High-throughput screening of a chemical library identified a novel class of small-molecules that enhance repair of oxidative DNA damage, which we termed DNA repair-activating agents. One of these agents, benserazide, increased base-excision repair of oxidative DNA damage utilizing a cell-based DNA repair assay, decreased levels of 8-oxo-g (i.e. most common oxidized lesion in human genome) using flow cytometric analysis, and decreased levels of oxidative DNA damage as determined by alkaline comet assay modified for detection of oxidized DNA lesions. These results were observed in mutant but not wild-type BRCA1 breast cancer cells. Benserazide, but not tamoxifen (current FDA-approved breast cancer chemoprevention agent), also decreased in vitro tumorigenesis of mutant BRCA1 or BRCA1-depleted breast cancer cells according to the soft-agar colony formation assay, and delayed tumor formation in vivo using a xenograft mouse model. Lastly, benserazide led to elevated levels of 8-oxo-dG (a by-product of base-excision repair) in conditioned media of mutant BRCA1 breast cancer cells, and concurrently increased serum levels of 8oxodG and decreased tumor burden in mice. Taken together, benserazide is a DNA-repair activating agent that enhances repair of oxidative DNA damage and decreases tumorigenesis in vitro and in vivo, and thus may serve as a potential chemoprevention agent for BRCA1-mutated cancers. Further, circulating levels of 8oxoG/8oxodG may function as a predictive biomarker for the efficacy of benserazide, which would prove useful in the clinical evaluation of benserazide for cancer chemoprevention. Citation Format: Sujeeth Shanmugam, Eboni Hosch, Dipasri Konar, James M. Ford, Elizabeth Alli. Identification of a potential chemoprevention agent for BRCA1- mutated cancers [abstract]. In: Proceedings of the Second Biennial NCI Meeting: Translational Advances in Cancer Prevention Agent Development (TACPAD); 2022 Sep 7-9. Philadelphia (PA): AACR; Can Prev Res 2022;15(12 Suppl_2): Abstract nr A003.

IN SILICO MOLECULAR DOCKING STUDIES OF OVARIAN EXTRACT SINGKARAK LAKE PUFFERFISH (TETRAODON LEIURUS) AGAINST BREAST CANCER

Targets the development of breast cancer chemoprevention by blocking the expression of NaV 1.5 channels and NHE, decreasing the expression of Bcl-2 and Bcl-XL, and increasing the expression of Bax. The ovarian extract Singkarak Lake Pufferfish (Tetraodon leiurus) has the potential as chemoprevention in breast cancer cell lines (MCF-7). This study aimed to analyze the interaction of STX, neoSTX, and dcSTX ligands against NaV1.5, NHE, Bcl-2, Bcl-XL, and Bax receptors. This study used the molecular docking method using STX, neoSTX, and dcSTX ligands against NaV1.5, NHE, Bcl-2, Bcl-XL, and Bax receptors. The result showed that the STX ligand has a more stable interaction with NaV1.5, Bcl-2, Bcl-XL, and Bax receptors with ΔG values of -8.72, -7.32 -6.86, and -6.31 kcal/mol compared to neoSTX and dcSTX ligands. Furthermore, the neoSTX ligand has a more stable interaction with the NHE receptor with an ΔG value of -7.5 kcal/mol compared to the STX and dcSTX ligands. This study shows that the ovarian extract of Singkarak Lake Pufferfish (Tetraodon leiurus) has the potential to be developed as cancer chemoprevention.