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Ganna S, Rahimi S, Lu A, Laborde K, Trivedi M. Interventions to improve oral endocrine therapy adherence in breast cancer patients. J Cancer Surviv 2025; 19:930-939. [PMID: 38233637 PMCID: PMC12081578 DOI: 10.1007/s11764-023-01513-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Accepted: 12/13/2023] [Indexed: 01/19/2024]
Abstract
PURPOSE Oral endocrine therapy (OET) is recommended in prevention and treatment of hormone receptor-positive breast cancer (HR+ BC). Despite the reduced incidence, recurrence, and mortality, OET adherence is poor in this patient population. The aim of this study was to review the latest literature to identify effective interventions to improve medication adherence in patients taking OET for prevention or treatment of HR+ BC. METHODS The Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) framework was used to perform this review. We utilized PubMed, SCOPUS, EMBASE, Cochrane, and Web of Science to acquire articles using search terms including breast cancer, adherence, persistence, and acceptability. Inclusion criteria included publication in peer-reviewed journal, primary data source, longitudinal, patients on OET such as aromatase inhibitors (AIs) or selective estrogen receptor modulators (SERMs), measuring adherence, persistence, or acceptability. RESULTS Out of 895 articles identified, 10 articles were included. Majority of patients had early-stage HR+ BC. Two out of two studies incorporating technological intervention, two out of three studies with text communication-based intervention, and three out of five studies with verbal communication-based intervention reported significant improvement in OET adherence and/or persistence. CONCLUSIONS While the interventions tested so far have shown to improve OET adherence in HR+ BC patients in some studies, there is a need to design combination interventions addressing multiple barriers in this population. IMPLICATIONS FOR CANCER SURVIVORS This study showcases effectiveness of novel interventions to improve OET adherence and the need to further develop patient-centered strategies to benefit all patients with HR+ BC.
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Affiliation(s)
- Sourab Ganna
- Department of Pharmaceutical Health Outcomes and Policy, University of Houston College of Pharmacy, Houston, TX, 77204, USA
| | - Sama Rahimi
- West Penn Hospital, Pittsburg, PA, 15224, USA
| | - Anh Lu
- Department of Pharmacy Practice and Translational Research, University of Houston College of Pharmacy, Health 2, 4349 Martin Luther King Blvd, Houston, TX, 77204-5000, USA
| | - Krista Laborde
- Department of Pharmacy Practice and Translational Research, University of Houston College of Pharmacy, Health 2, 4349 Martin Luther King Blvd, Houston, TX, 77204-5000, USA
| | - Meghana Trivedi
- Department of Pharmacy Practice and Translational Research, University of Houston College of Pharmacy, Health 2, 4349 Martin Luther King Blvd, Houston, TX, 77204-5000, USA.
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2
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Ren J, Yan G, Yang L, Kong L, Guan Y, Sun H, Liu C, Liu L, Han Y, Wang X. Cancer chemoprevention: signaling pathways and strategic approaches. Signal Transduct Target Ther 2025; 10:113. [PMID: 40246868 PMCID: PMC12006474 DOI: 10.1038/s41392-025-02167-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2024] [Revised: 12/01/2024] [Accepted: 02/04/2025] [Indexed: 04/19/2025] Open
Abstract
Although cancer chemopreventive agents have been confirmed to effectively protect high-risk populations from cancer invasion or recurrence, only over ten drugs have been approved by the U.S. Food and Drug Administration. Therefore, screening potent cancer chemopreventive agents is crucial to reduce the constantly increasing incidence and mortality rate of cancer. Considering the lengthy prevention process, an ideal chemopreventive agent should be nontoxic, inexpensive, and oral. Natural compounds have become a natural treasure reservoir for cancer chemoprevention because of their superior ease of availability, cost-effectiveness, and safety. The benefits of natural compounds as chemopreventive agents in cancer prevention have been confirmed in various studies. In light of this, the present review is intended to fully delineate the entire scope of cancer chemoprevention, and primarily focuses on various aspects of cancer chemoprevention based on natural compounds, specifically focusing on the mechanism of action of natural compounds in cancer prevention, and discussing in detail how they exert cancer prevention effects by affecting classical signaling pathways, immune checkpoints, and gut microbiome. We also introduce novel cancer chemoprevention strategies and summarize the role of natural compounds in improving chemotherapy regimens. Furthermore, we describe strategies for discovering anticancer compounds with low abundance and high activity, revealing the broad prospects of natural compounds in drug discovery for cancer chemoprevention. Moreover, we associate cancer chemoprevention with precision medicine, and discuss the challenges encountered in cancer chemoprevention. Finally, we emphasize the transformative potential of natural compounds in advancing the field of cancer chemoprevention and their ability to introduce more effective and less toxic preventive options for oncology.
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Affiliation(s)
- Junling Ren
- State key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, National Chinmedomics Research Center, National TCM Key Laboratory of Serum Pharmacochemistry, Metabolomics Laboratory, Department of Pharmaceutical Analysis, Heilongjiang University of Chinese Medicine, Heping Road 24, Harbin, 150040, China
| | - Guangli Yan
- State key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, National Chinmedomics Research Center, National TCM Key Laboratory of Serum Pharmacochemistry, Metabolomics Laboratory, Department of Pharmaceutical Analysis, Heilongjiang University of Chinese Medicine, Heping Road 24, Harbin, 150040, China
| | - Le Yang
- State Key Laboratory of Dampness Syndrome, The Second Affiliated Hospital Guangzhou University of Chinese Medicine, Dade Road 111, Guangzhou, China
| | - Ling Kong
- State key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, National Chinmedomics Research Center, National TCM Key Laboratory of Serum Pharmacochemistry, Metabolomics Laboratory, Department of Pharmaceutical Analysis, Heilongjiang University of Chinese Medicine, Heping Road 24, Harbin, 150040, China
| | - Yu Guan
- State key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, National Chinmedomics Research Center, National TCM Key Laboratory of Serum Pharmacochemistry, Metabolomics Laboratory, Department of Pharmaceutical Analysis, Heilongjiang University of Chinese Medicine, Heping Road 24, Harbin, 150040, China
| | - Hui Sun
- State key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, National Chinmedomics Research Center, National TCM Key Laboratory of Serum Pharmacochemistry, Metabolomics Laboratory, Department of Pharmaceutical Analysis, Heilongjiang University of Chinese Medicine, Heping Road 24, Harbin, 150040, China.
| | - Chang Liu
- State key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, National Chinmedomics Research Center, National TCM Key Laboratory of Serum Pharmacochemistry, Metabolomics Laboratory, Department of Pharmaceutical Analysis, Heilongjiang University of Chinese Medicine, Heping Road 24, Harbin, 150040, China
| | - Lei Liu
- State key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, National Chinmedomics Research Center, National TCM Key Laboratory of Serum Pharmacochemistry, Metabolomics Laboratory, Department of Pharmaceutical Analysis, Heilongjiang University of Chinese Medicine, Heping Road 24, Harbin, 150040, China
| | - Ying Han
- State key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, National Chinmedomics Research Center, National TCM Key Laboratory of Serum Pharmacochemistry, Metabolomics Laboratory, Department of Pharmaceutical Analysis, Heilongjiang University of Chinese Medicine, Heping Road 24, Harbin, 150040, China
| | - Xijun Wang
- State key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, National Chinmedomics Research Center, National TCM Key Laboratory of Serum Pharmacochemistry, Metabolomics Laboratory, Department of Pharmaceutical Analysis, Heilongjiang University of Chinese Medicine, Heping Road 24, Harbin, 150040, China.
- State Key Laboratory of Dampness Syndrome, The Second Affiliated Hospital Guangzhou University of Chinese Medicine, Dade Road 111, Guangzhou, China.
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3
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Gheller A, Tuttle R, Oxenberg J. Breast Cancer Risk, Screening, and Risk Reduction in Young Females. Am Surg 2025:31348251331294. [PMID: 40228550 DOI: 10.1177/00031348251331294] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/16/2025]
Abstract
Screening and prevention strategies for breast cancer (BC) have focused on women over 40 years of age. While BC prevalence under 40 is low, affected patients have more aggressive cancers and a poorer prognosis. Those with identifiable risk factors may benefit from screening for early detection and prevention strategies. This paper reviews the current literature and guidelines regarding BC risk. Screening guidelines and prevention strategies are also reviewed, with a focus on females under the age of 40.
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Affiliation(s)
- April Gheller
- Department of Surgical Oncology, Lehigh Valley Hospital- Pocono, East Stroudsburg, PA, USA
| | - Rebecca Tuttle
- Department of Surgery, Kettering Medical Center, Wright State University Boonshoft School of Medicine, Dayton, OH, USA
| | - Jacqueline Oxenberg
- Department of Surgical Oncology, Lehigh Valley Hospital- Pocono, East Stroudsburg, PA, USA
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4
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García-Sancha N, Corchado-Cobos R, Pérez-Losada J. Understanding Susceptibility to Breast Cancer: From Risk Factors to Prevention Strategies. Int J Mol Sci 2025; 26:2993. [PMID: 40243654 PMCID: PMC11988588 DOI: 10.3390/ijms26072993] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2025] [Revised: 03/23/2025] [Accepted: 03/24/2025] [Indexed: 04/18/2025] Open
Abstract
Breast cancer is the most common malignancy among women globally, with incidence rates continuing to rise. A comprehensive understanding of its risk factors and the underlying biological mechanisms that drive tumor initiation is essential for developing effective prevention strategies. This review examines key non-modifiable risk factors, such as genetic predisposition, demographic characteristics, family history, mammographic density, and reproductive milestones, as well as modifiable risk factors like exogenous hormone exposure, obesity, diet, and physical inactivity. Importantly, reproductive history plays a dual role, providing long-term protection while temporarily increasing breast cancer risk shortly after pregnancy. Current chemoprevention strategies primarily depend on selective estrogen receptor modulators (SERMs), including tamoxifen and raloxifene, which have demonstrated efficacy in reducing the incidence of estrogen receptor-positive breast cancer but remain underutilized due to adverse effects. Emerging approaches such as aromatase inhibitors, RANKL inhibitors, progesterone antagonists, PI3K inhibitors, and immunoprevention strategies show promise for expanding preventive options. Understanding the interactions between risk factors, hormonal influences, and tumorigenesis is critical for optimizing breast cancer prevention and advancing safer, more targeted chemopreventive interventions.
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Affiliation(s)
- Natalia García-Sancha
- Institute of Molecular and Cellular Biology of Cancer (IBMCC-CIC), CSIC-University of Salamanca, 37007 Salamanca, Spain; (R.C.-C.); (J.P.-L.)
- Institute of Biomedical Research of Salamanca (IBSAL), 37007 Salamanca, Spain
| | - Roberto Corchado-Cobos
- Institute of Molecular and Cellular Biology of Cancer (IBMCC-CIC), CSIC-University of Salamanca, 37007 Salamanca, Spain; (R.C.-C.); (J.P.-L.)
- Institute of Biomedical Research of Salamanca (IBSAL), 37007 Salamanca, Spain
| | - Jesús Pérez-Losada
- Institute of Molecular and Cellular Biology of Cancer (IBMCC-CIC), CSIC-University of Salamanca, 37007 Salamanca, Spain; (R.C.-C.); (J.P.-L.)
- Institute of Biomedical Research of Salamanca (IBSAL), 37007 Salamanca, Spain
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5
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Messina M, Nechuta S. A Review of the Clinical and Epidemiologic Evidence Relevant to the Impact of Postdiagnosis Isoflavone Intake on Breast Cancer Outcomes. Curr Nutr Rep 2025; 14:50. [PMID: 40131602 PMCID: PMC11937148 DOI: 10.1007/s13668-025-00640-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/10/2025] [Indexed: 03/27/2025]
Abstract
PURPOSE OF REVIEW This narrative review aims to determine the impact of postdiagnosis isoflavone intake, via supplements and foods, on breast cancer outcomes. Foods derived from soybeans are uniquely rich sources of isoflavones, naturally occurring compounds that can bind to estrogen receptors although the extent to which they exert estrogen-like effects in humans is unclear. Isoflavones have been rigorously investigated for a wide range of health benefits including breast cancer prevention. However, their classification as phytoestrogens has led to concern that isoflavones and hence, soy food consumption, could worsen the prognosis of women with breast cancer and interfere with the efficacy of endocrine therapy for this disease. RECENT FINDINGS Research in athymic ovariectomized mice shows isoflavones stimulate the growth of existing estrogen-sensitive mammary tumors. However, extensive clinical research indicates that neither soy foods nor isolated isoflavones affect markers of breast cancer risk including mammographic density and breast cell proliferation. No effects are observed even when isoflavone exposure greatly exceeds typical intake in Asian countries. Furthermore, the results from epidemiologic studies indicate postdiagnosis isoflavone intake from soy foods reduces recurrence and possibly mortality from breast cancer. Additionally, the limited observational data do not show that isoflavones interfere with the efficacy of tamoxifen or aromatase inhibitors. Regardless of their treatment status, evidence indicates that women with breast cancer can safely consume soy foods. Limiting intake to no more than two servings of traditional Asian soy foods daily, an amount that provides approximately 50 mg isoflavones, is recommended, not because data indicate exceeding this amount is harmful, but because few population-based studies involved participants consuming more than this intake recommendation.
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Affiliation(s)
- Mark Messina
- Soy Nutrition Institute Global, Jefferson, MO, USA.
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Guo Z, Zhu Z, Lin X, Zhang KM, Wu Q, Wang S, Luo M, Lin X, Wang L, Zhou J. Conception and Concern: A Review of Breast Cancer Risk in Assisted Reproductive Technology. Int J Biol Sci 2025; 21:2647-2671. [PMID: 40303287 PMCID: PMC12035894 DOI: 10.7150/ijbs.105357] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2024] [Accepted: 02/25/2025] [Indexed: 05/02/2025] Open
Abstract
This review examines the complex relationship between assisted reproductive technology (ART) and the potential risk of breast cancer. Through a thorough analysis, we explore various aspects of this association, considering both the theoretical and mechanistic overlap between ART and breast cancer, as well as the growing body of empirical research aimed at elucidating this relationship. Theoretical analysis suggests that ART exposure inevitably increases levels of reproductive hormones over a relatively short period, potentially elevating susceptibility to breast cancer. However, current clinical evidence does not strongly support this hypothesis, and no direct correlation between ART and breast cancer development has been established. Our study lays the groundwork for informed discussion and offers recommendations for further research in this area of women's health, based on a comprehensive review of both theoretical and clinical research. The findings provide valuable information to guide both specialists and patients in decision-making regarding ART treatment. As we navigate the complexities surrounding conception, this manuscript serves as an essential resource for understanding and addressing the potential risks of breast cancer in the context of ART.
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Affiliation(s)
- Zijie Guo
- Department of Surgical Oncology, Affiliated Sir Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310016, China
- Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, Zhejiang, 310016, China
| | - Ziyu Zhu
- Department of Surgical Oncology, Affiliated Sir Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310016, China
- Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, Zhejiang, 310016, China
| | - Xixi Lin
- Department of Surgical Oncology, Affiliated Sir Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310016, China
- Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, Zhejiang, 310016, China
| | | | - Qingliang Wu
- Department of Surgical Oncology, Affiliated Sir Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310016, China
- Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, Zhejiang, 310016, China
- The Ninth People's Hospital of Hangzhou, Hangzhou, Zhejiang, 310014, China
| | - Shenkangle Wang
- Department of Surgical Oncology, Affiliated Sir Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310016, China
- Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, Zhejiang, 310016, China
| | - Mingpeng Luo
- Department of Surgical Oncology, Affiliated Sir Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310016, China
- Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, Zhejiang, 310016, China
- The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310014, China
| | - Xiaona Lin
- Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Affiliated Sir Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310016, China
| | - Linbo Wang
- Department of Surgical Oncology, Affiliated Sir Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310016, China
- Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, Zhejiang, 310016, China
| | - Jichun Zhou
- Department of Surgical Oncology, Affiliated Sir Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310016, China
- Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, Zhejiang, 310016, China
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7
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Ren HL, Zhang SH, Li PY. The multifaceted role of phosphodiesterase 4 in tumor: from tumorigenesis to immunotherapy. Front Immunol 2025; 16:1528932. [PMID: 40129976 PMCID: PMC11931042 DOI: 10.3389/fimmu.2025.1528932] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2024] [Accepted: 02/24/2025] [Indexed: 03/26/2025] Open
Abstract
Phosphodiesterase 4 (PDE4) is an enzyme that specifically hydrolyzes the second messenger cAMP and has a critical role in the regulation of a variety of cellular functions. In recent years, PDE4 has attracted great interest in cancer research, and its role in tumorigenesis and development has been gradually elucidated. Research indicates that abnormal expression or heightened activity of PDE4 is associated with the initiation and progression of multiple cancers, including lung, colorectal, and hematological cancers, by facilitating cell proliferation, migration, invasion, and anti-apoptosis. Moreover, PDE4 also influences the tumor immune microenvironment, significantly immune evasion by suppressing anti-tumor immune responses, reducing T-cell activation, and promoting the polarization of tumor-associated macrophages toward a pro-tumorigenic phenotype. However, the PDE4 family may have both oncogenic and tumor-suppressive effects, which could depend on the specific type and grade of the tumor. PDE4 inhibitors have garnered substantial interest as potential anti-cancer therapeutics, directly inhibiting tumor cell growth and restoring immune surveillance capabilities to enhance the clearance of tumor cells. Several PDE4 inhibitors are currently under investigation with the aim of exploring their potential in cancer therapy, particularly in combination strategies with immune checkpoint inhibitors, to improve therapeutic efficacy and mitigate the side effects of conventional chemotherapy. This review provides an overview of PDE4 in tumorigenesis, drug resistance, immunotherapy, and the anti-tumor actions of its inhibitors, intending to guide the exploration of PDE4 as a new target in tumor therapy.
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Affiliation(s)
- Huili-li Ren
- Department of Pharmacy, Traditional Chinese and Western Medicine Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shao-hui Zhang
- Department of Pharmacy, Traditional Chinese and Western Medicine Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Pei-yuan Li
- Division of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Department of Gastroenterology, Wenchang People’s Hospital, Wenchang, Hainan, China
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Patel Y, Alsaedi H, Majd Z, Altaie I, Rahimi S, Fatima B, Ononogbu O, Abughosh S, Trivedi MV. Group-Based Trajectory Modeling to Identify Patterns and Predictors of Adherence to Oral Endocrine Therapies in Underserved Population of Greater Houston Area. Patient Prefer Adherence 2025; 19:473-484. [PMID: 40052001 PMCID: PMC11882467 DOI: 10.2147/ppa.s467892] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2024] [Accepted: 12/17/2024] [Indexed: 03/09/2025] Open
Abstract
Background Poor adherence to oral endocrine therapy (OET) is a significant problem among patients with hormone receptor-positive breast cancer as it results in higher risk of recurrence and mortality. Non-adherence to OET is prevalent among underserved patients, often attributable to socioeconomic factors and limited healthcare access. We evaluated OET adherence patterns over time using group-based trajectory modeling (GBTM) and identified predictors of suboptimal adherence trajectory among patients seen at Harris Health System, serving underserved patients in Houston, Texas. Methods A single-center, retrospective study was conducted from October 2019 through December 2020. OET adherence was measured using proportion of days covered (PDC). A logistic GBTM was conducted using 2-5 adherence groups considering the Bayesian information criteria, clinical relevance, and a 5% minimum membership requirement. Multinomial logistic regression was used to assess the predictors of non-adherence trajectories. Results Among 496 patients, majority were Hispanic (62.50%) or African American (15.12%) and <65 years of age (82.66%). Four distinct adherence trajectories were identified: consistent high adherence (41.4%); constant PDC at ~0.6 (32.6%); rapid decline (14.6%); low adherence with gradual decline (11.5%). African Americans had higher likelihood of having low adherence with gradual decline [odds ratio (OR): 2.462 (confidence interval (CI): 1.1149-5.276), p=0.0205]. Patients with diabetes were more likely to have constant PDC at ~0.6 [OR: 1.714 (CI: 1.042-2.820), p=0.0338]. Longer time (4 or greater years) on therapy predicted low adherence with gradual decline [OR: 2.463 (CI: 1.266-4.793), p=0.008) and constant PDC at ~0.6 (OR: 1.966 (CI: 1.141-3.388), p=0.0149] trajectories. Conclusion The identified predictors, including comorbidities like diabetes, African American descent, and longer OET treatment are crucial considerations when developing patient-centered interventions to enhance OET adherence among underserved populations. These insights can guide the implementation of initiatives such as mobile health applications, community-based educational programs, and financial aid efforts.
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Affiliation(s)
- Yashvi Patel
- Department of Pharmacy Practice and Translational Research, University of Houston College of Pharmacy, Houston, TX, USA
| | - Hasan Alsaedi
- Department of Pharmacy Practice and Translational Research, University of Houston College of Pharmacy, Houston, TX, USA
| | - Zahra Majd
- Department of Pharmaceutical Health Outcomes and Policy, University of Houston College of Pharmacy, Houston, TX, USA
| | - Issra Altaie
- Department of Pharmacy Practice and Translational Research, University of Houston College of Pharmacy, Houston, TX, USA
| | - Sama Rahimi
- Department of Pharmacy Practice and Translational Research, University of Houston College of Pharmacy, Houston, TX, USA
| | - Bilqees Fatima
- Department of Pharmaceutical Health Outcomes and Policy, University of Houston College of Pharmacy, Houston, TX, USA
| | - Onyebuchi Ononogbu
- Department of Pharmacy Practice and Translational Research, University of Houston College of Pharmacy, Houston, TX, USA
| | - Susan Abughosh
- Department of Pharmaceutical Health Outcomes and Policy, University of Houston College of Pharmacy, Houston, TX, USA
| | - Meghana V Trivedi
- Department of Pharmacy Practice and Translational Research, University of Houston College of Pharmacy, Houston, TX, USA
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9
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Weis LN, Bychkovsky BL, Hernandez AR, Barroso-Sousa R, Sandoval RL. CHEK2-related breast cancer: real-world challenges. Fam Cancer 2025; 24:23. [PMID: 39966186 DOI: 10.1007/s10689-025-00448-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2024] [Accepted: 02/09/2025] [Indexed: 02/20/2025]
Abstract
PURPOSE Management of cancer risks associated with the CHEK2 gene, a moderate penetrance breast cancer gene, is challenging in real-world practice. Family history, traditional breast cancer risk factors, and specific genetic CHEK2 variants are risk modifiers in this setting and add complexity for surveillance and risk-reduction decisions. Here, we present a case series of Brazilian CHEK2 carriers affected by breast cancer. METHODS Patients evaluated in the Oncogenetics Department of Hospital Sírio-Libanês (Brasília, Brazil) between November 2017 and September 2021, who had a personal history of breast cancer and a germline genetic test with a pathogenic or likely pathogenic CHEK2 variant, were selected for case description. Clinical pearls and knowledge gaps were highlighted for each case. RESULTS Twelve women were included in this descriptive analysis. All patients had early-stage breast cancer. Most of them were diagnosed with breast cancer prior to age 50 (9/12) and had a close relative affected by breast cancer (9/12). Seven patients harbored intronic pathogenic variants. Clinical pearls included the following: lack of risk estimates for intronic CHEK2 variants among non-European ancestry CHEK2 carriers, environmental exposures as a risk modifier, notable non-breast cancer diagnosis at young ages, incidental germline finding during tumor profiling, breast cancer diagnosis before the recommended age of breast cancer screening, family history of breast cancer as a risk modifier, and clinical outcomes after breast cancer treatment. CONCLUSIONS Improvements in cancer risk assessment and cancer prevention for CHEK2 carriers are still needed to overcome current clinical challenges on the management of these patients.
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Affiliation(s)
- Luiza N Weis
- Dasa Oncology, Hospital Brasília, Brasília, Brazil
| | - Brittany L Bychkovsky
- Division of Cancer Genetics and Prevention, Dana-Farber Cancer Institute, SGAS 613, S/N 94, Via L2 Sul, 70.200 - Asa Sul Brasília-DF, Boston, MA, 70200-730, USA
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Breast Oncology Program, Dana-Farber Brigham Cancer Center, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Adela Rodríguez Hernandez
- Division of Cancer Genetics and Prevention, Dana-Farber Cancer Institute, SGAS 613, S/N 94, Via L2 Sul, 70.200 - Asa Sul Brasília-DF, Boston, MA, 70200-730, USA
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
- Translational Genomics and Targeted Therapies in Solid Tumors Group, August Pi I Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain
- Department of Medicine, University of Barcelona, Barcelona, Spain
| | | | - Renata L Sandoval
- Division of Cancer Genetics and Prevention, Dana-Farber Cancer Institute, SGAS 613, S/N 94, Via L2 Sul, 70.200 - Asa Sul Brasília-DF, Boston, MA, 70200-730, USA.
- Hospital Sírio-Libanês, Oncology Center, Brasília, Brazil.
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10
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Singh P, Agnese DM, Amin M, Barrio AV, van den Bruele AB, Burke EE, Danforth DN, Dirbas FM, Eladoumikdachi F, Fayanju OM, Kantor O, Kumar S, Lee MC, Matsen C, Nguyen TT, Ozmen T, Park KU, Plichta JK, Reyna C, Showalter SL, Styblo T, Tranakas N, Weiss A, Woodfin A, Laronga C, Boughey JC. Society of Surgical Oncology Breast Disease Site Working Group Statement on Bilateral Risk-Reducing Mastectomy: Indications, Outcomes, and Risks. Ann Surg Oncol 2025; 32:899-911. [PMID: 39538100 DOI: 10.1245/s10434-024-16484-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2024] [Accepted: 10/29/2024] [Indexed: 11/16/2024]
Abstract
Bilateral risk-reducing mastectomy (BRRM) is the surgical removal of both breasts to reduce the risk of cancer. In this Society of Surgical Oncology position statement, we review the literature addressing the indications, outcomes, and risks of BRRM to update the society's 2017 statement. We held a virtual meeting to outline key topics and conducted a literature search using PubMed to identify relevant articles. After literature review, recommendations were made according to group consensus. Individuals with a high lifetime risk of breast cancer due to pathogenic variants in high penetrance breast cancer-predisposition genes, early chest or breast radiation exposure, or a compelling family history should be counseled on the option of BRRM. However, BRRM is not recommended for most patients with high-risk lesions and may be contraindicated in patients who have other competing cancers and/or a high risk of surgical complications. BRRM effectively reduces the risk of breast cancer development, although the survival benefit is unclear. For patients with low-to-moderate breast cancer risk, alternative management strategies should be encouraged, including lifestyle modifications, high-risk screening, and risk-reducing medications. Discussions of BRRM should cover: (1) breast-cancer risk estimates; (2) the procedure's degree of risk reduction and impact on survival; (3) surgical techniques, potential surgical complications and long-term sequelae; and (4) alternatives to surgery. Surgeons should encourage shared and informed decision making with patients who have an elevated lifetime risk of developing breast cancer.
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Affiliation(s)
- Puneet Singh
- Department of Breast Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
| | | | | | - Andrea V Barrio
- Memorial Sloan Kettering Cancer Center, New York City, NY, USA
| | | | | | | | | | | | | | - Olga Kantor
- Brigham and Women's Hospital, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Shicha Kumar
- Rutgers Cancer Institute, New Brunswick, NJ, USA
| | | | | | | | - Tolga Ozmen
- Massachusetts General Hospital, Boston, MA, USA
| | - Ko Un Park
- Brigham and Women's Hospital, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | | | | | | | | | | | - Anna Weiss
- University of Rochester Medical Center, Rochester, NY, USA
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11
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Howell SJ, Howell A. Targeting Oestrogen Receptor Signalling in Breast Cancer Therapy. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2025; 1464:449-474. [PMID: 39821038 DOI: 10.1007/978-3-031-70875-6_22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/19/2025]
Abstract
There has been over 130 years of research into the treatment of breast cancer using approaches that target oestrogen receptor signalling. Here, we summarise the development of the key pillars of such endocrine therapy, namely, oestrogen deprivation, achieved through ovarian suppression and/or aromatase inhibition, and oestrogen receptor blockade, through selective oestrogen receptor modulators, downregulators and novel compounds entering early phase development. The translation of these compounds from advanced to early breast cancer settings is discussed with a focus on the placebo-controlled breast cancer prevention studies to most accurately describe the side effect profiles of the main approaches.
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Affiliation(s)
- Sacha J Howell
- Division of Cancer Sciences, University of Manchester, Manchester, UK.
- Manchester University NHS Foundation Trust, Manchester, UK.
- The Christie NHS Foundation Trust, Manchester, UK.
| | - Anthony Howell
- Division of Cancer Sciences, University of Manchester, Manchester, UK
- Manchester University NHS Foundation Trust, Manchester, UK
- The Christie NHS Foundation Trust, Manchester, UK
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12
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Pleasant V, Manorot A, Pearlman M. Identification and management of patients at increased risk for breast cancer. CONTEMPORARY OB/GYN 2025; 70:16-23. [PMID: 40083976 PMCID: PMC11906169] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Subscribe] [Scholar Register] [Indexed: 03/16/2025]
Abstract
Breast cancer is the most diagnosed invasive cancer in the United States, with 1 in 8 people assigned female at birth (AFAB) being affected.1 It is imperative that health care practitioners remain current and well-versed in identifying individuals at high risk for developing breast cancer. This article outlines an approach for obstetrics/gynecology practitioners to identify high-risk patients and to counsel on appropriate breast cancer screening, prevention, and risk-reduction options.
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Affiliation(s)
- Versha Pleasant
- Department of Obstetrics & Gynecology at the University of Michigan in Ann Arbor
| | - Amanda Manorot
- Department of Obstetrics & Gynecology at the University of Michigan in Ann Arbor
| | - Mark Pearlman
- Department of Obstetrics & Gynecology at the University of Michigan in Ann Arbor
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13
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Connors BM, Thompson JL, Miodonski MA, Sinco B, Pleasant VA, Williams-Morad MA, Hughes TM, Pilewskie ML. Has the Option of Low-Dose Tamoxifen Impacted Chemoprevention Uptake Among Women with Breast Intra-Epithelial Neoplasia? Ann Surg Oncol 2024; 31:8866-8872. [PMID: 39287905 DOI: 10.1245/s10434-024-16025-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2024] [Accepted: 07/31/2024] [Indexed: 09/19/2024]
Affiliation(s)
- Bess M Connors
- Department of Surgery, Trinity Health, Grand Rapids, MI, USA.
| | | | | | - Brandy Sinco
- Center for Healthcare Outcomes and Policy, Michigan Medicine, Ann Arbor, MI, USA
| | - Versha A Pleasant
- Department of Obstetrics and Gynecology, Michigan Medicine, Ann Arbor, MI, USA
| | | | - Tasha M Hughes
- Department of Surgery, Michigan Medicine, Ann Arbor, MI, USA
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14
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Michel AM, Yi H, Amenta J, Collins N, Vaynrub A, Umakanth S, Anderson G, Arnold K, Law C, Pruthi S, Sandoval-Leon A, Shirley R, Perdekamp MG, Colonna S, Krisher S, King T, Yee LD, Ballinger TJ, Braun-Inglis C, Mangino DA, Wisinski K, DeYoung CA, Ross M, Floyd J, Kaster A, VanderWalde L, Saphner TJ, Zarwan C, Lo S, Graham C, Conlin A, Yost K, Agnese D, Jernigan C, Hershman DL, Neuhouser ML, Arun B, Crew KD, Kukafka R. Use of web-based decision support to improve informed choice for chemoprevention: a qualitative analysis of pre-implementation interviews (SWOG S1904). BMC Med Inform Decis Mak 2024; 24:272. [PMID: 39334347 PMCID: PMC11430334 DOI: 10.1186/s12911-024-02691-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Accepted: 09/18/2024] [Indexed: 09/30/2024] Open
Abstract
BACKGROUND Women with high-risk breast lesions, such as atypical hyperplasia (AH) or lobular carcinoma in situ (LCIS), have a 4- to tenfold increased risk of breast cancer compared to women with non-proliferative breast disease. Despite high-quality data supporting chemoprevention, uptake remains low. Interventions are needed to break down barriers. METHODS The parent trial, MiCHOICE, is a cluster randomized controlled trial evaluating the effectiveness and implementation of patient and provider decision support tools to improve informed choice about chemoprevention among women with AH or LCIS. For this pre-implementation analysis, 25 providers participated in semi-structured interviews prior to accessing decision support tools. Interviews sought to understand attitudes/beliefs and barriers/facilitators to chemoprevention. RESULTS Interviews with 25 providers (18 physicians and 7 advanced practice providers) were included. Providers were predominantly female (84%), white (72%), and non-Hispanic (88%). Nearly all providers (96%) had prescribed chemoprevention for eligible patients. Three themes emerged in qualitative analysis. The first theme describes providers' confidence in chemoprevention and the utility of decision support tools. The second theme elucidates barriers to chemoprevention, including time constraints, risk communication and perceptions of patients' fear of side effects and anxiety. The third theme is the need for early implementation of decision support tools. CONCLUSIONS This qualitative study suggests that providers were interested in the early inclusion of decision aids (DA) in their chemoprevention discussion workflow. The DAs may help overcome certain barriers which were elucidated in these interviews, including patient level concerns about side effects, clinic time constraints and difficulty communicating risk. A multi-faceted intervention with a DA as one active component may be needed. TRIAL REGISTRATION This trial was registered with the NIH clinical trial registry, clinicaltrials.gov, NCT04496739.
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Affiliation(s)
- Alissa M Michel
- Columbia University Irving Medical Center, 177 Fort Washington Ave, Suite 6-435, New York, NY, 10032, USA.
| | - Haeseung Yi
- Columbia University Irving Medical Center, 177 Fort Washington Ave, Suite 6-435, New York, NY, 10032, USA
| | - Jacquelyn Amenta
- Columbia University Irving Medical Center, 177 Fort Washington Ave, Suite 6-435, New York, NY, 10032, USA
| | - Nicole Collins
- Columbia University Irving Medical Center, 177 Fort Washington Ave, Suite 6-435, New York, NY, 10032, USA
| | - Anna Vaynrub
- Columbia University Irving Medical Center, 177 Fort Washington Ave, Suite 6-435, New York, NY, 10032, USA
| | - Subiksha Umakanth
- Columbia University Irving Medical Center, 177 Fort Washington Ave, Suite 6-435, New York, NY, 10032, USA
| | - Garnet Anderson
- SWOG Statistics and Data Management Center, Seattle, WA, USA
| | - Katie Arnold
- SWOG Statistics and Data Management Center, Seattle, WA, USA
| | - Cynthia Law
- Columbia University Irving Medical Center, 177 Fort Washington Ave, Suite 6-435, New York, NY, 10032, USA
| | | | - Ana Sandoval-Leon
- Miami Cancer Institute at Baptist Health South Florida, Miami, FL, USA
| | | | | | - Sarah Colonna
- Huntsman Cancer Institute / University of Utah Medical Center, Salt Lake City, UT, USA
| | - Stacy Krisher
- Holy Redeemer Hospital and Medical Center, Meadowbrook, PA, USA
| | - Tari King
- Dana-Farber Brigham Cancer Center, Brigham and Women's Hospital, Boston, MA, USA
| | - Lisa D Yee
- City of Hope Comprehensive Cancer Center, Duarte, CA, USA
| | - Tarah J Ballinger
- Indiana University Simon Comprehensive Cancer Center, Indianapolis, IN, USA
| | | | | | - Kari Wisinski
- University of Wisconsin Carbone Cancer Center, Madison, WI, USA
| | | | - Masey Ross
- Virginia Commonwealth University, Richmond, VA, USA
| | - Justin Floyd
- Cancer Care Specialists of Illinois, Heartland NCORP, Decatur, IL, USA
| | | | | | | | | | - Shelly Lo
- Loyola University Stritch School of Medicine, Maywood, IL, USA
| | - Cathy Graham
- Emory University Hospital/Winship Cancer Institute, Atlanta, GA, USA
| | | | - Kathleen Yost
- Cancer Research Consortium of West Michigan NCORP, Kalamazoo, MI, USA
| | - Doreen Agnese
- The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA
| | | | - Dawn L Hershman
- Columbia University Irving Medical Center, 177 Fort Washington Ave, Suite 6-435, New York, NY, 10032, USA
| | | | - Banu Arun
- The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Katherine D Crew
- Columbia University Irving Medical Center, 177 Fort Washington Ave, Suite 6-435, New York, NY, 10032, USA
| | - Rita Kukafka
- Columbia University Irving Medical Center, 177 Fort Washington Ave, Suite 6-435, New York, NY, 10032, USA
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15
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Choradia N, Szabo E. Repurposing Drugs for Cancer Prevention: Targeting Mechanisms Common to Chronic Diseases. Cancer J 2024; 30:345-351. [PMID: 39312454 PMCID: PMC11424023 DOI: 10.1097/ppo.0000000000000746] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/25/2024]
Abstract
ABSTRACT The development of agents for cancer prevention is a lengthy process requiring a delicate balance between the safety and tolerability of potential interventions and effectiveness in preventing future cancer. Individuals at risk for a specific cancer are frequently at risk for multiple types of cancer as well as other chronic diseases, especially ones associated with aging. Shared environmental exposures, genetic predisposition, metabolic factors, and commonalities in pathogenesis suggest opportunities for combined targeting of cancer and other chronic diseases. Examples discussed here include mechanisms shared between various cancers and obesity, diabetes, and cardiovascular disease.
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Affiliation(s)
- Nirmal Choradia
- From the Medical Oncology Service, Center for Cancer Research, National Cancer Institute, National Institutes of Health
| | - Eva Szabo
- Lung and Upper Aerodigestive Cancer Research Group, Division of Cancer Prevention, National Cancer Institute, Bethesda, MD
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16
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McGuinness JE, Anderson GL, Mutasa S, Hershman DL, Terry MB, Tehranifar P, Lew DL, Yee M, Brown EA, Kairouz SS, Kuwajerwala N, Bevers TB, Doster JE, Zarwan C, Kruper L, Minasian LM, Ford L, Arun B, Neuhouser ML, Goodman GE, Brown PH, Ha R, Crew KD. Effects of vitamin D supplementation on a deep learning-based mammographic evaluation in SWOG S0812. JNCI Cancer Spectr 2024; 8:pkae042. [PMID: 38814817 PMCID: PMC11216724 DOI: 10.1093/jncics/pkae042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Revised: 03/04/2024] [Accepted: 05/22/2024] [Indexed: 06/01/2024] Open
Abstract
Deep learning-based mammographic evaluations could noninvasively assess response to breast cancer chemoprevention. We evaluated change in a convolutional neural network-based breast cancer risk model applied to mammograms among women enrolled in SWOG S0812, which randomly assigned 208 premenopausal high-risk women to receive oral vitamin D3 20 000 IU weekly or placebo for 12 months. We applied the convolutional neural network model to mammograms collected at baseline (n = 109), 12 months (n = 97), and 24 months (n = 67) and compared changes in convolutional neural network-based risk score between treatment groups. Change in convolutional neural network-based risk score was not statistically significantly different between vitamin D and placebo groups at 12 months (0.005 vs 0.002, P = .875) or at 24 months (0.020 vs 0.001, P = .563). The findings are consistent with the primary analysis of S0812, which did not demonstrate statistically significant changes in mammographic density with vitamin D supplementation compared with placebo. There is an ongoing need to evaluate biomarkers of response to novel breast cancer chemopreventive agents.
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Affiliation(s)
- Julia E McGuinness
- Department of Medicine, Columbia University Irving Medical Center and the Herbert Irving Comprehensive Cancer Center, New York, NY, USA
| | - Garnet L Anderson
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, USA
- SWOG Cancer Research Network, Statistics and Data Management Center, Seattle, WA, USA
| | - Simukayi Mutasa
- Department of Radiology, Lenox Hill Hospital, New York, NY, USA
| | - Dawn L Hershman
- Department of Medicine, Columbia University Irving Medical Center and the Herbert Irving Comprehensive Cancer Center, New York, NY, USA
| | - Mary Beth Terry
- Department of Medicine, Columbia University Irving Medical Center and the Herbert Irving Comprehensive Cancer Center, New York, NY, USA
| | - Parisa Tehranifar
- Department of Medicine, Columbia University Irving Medical Center and the Herbert Irving Comprehensive Cancer Center, New York, NY, USA
| | - Danika L Lew
- SWOG Cancer Research Network, Statistics and Data Management Center, Seattle, WA, USA
| | - Monica Yee
- SWOG Cancer Research Network, Statistics and Data Management Center, Seattle, WA, USA
| | - Eric A Brown
- William Beaumont Hospital, Beaumont National Cancer Institute Community Oncology Research Program, Troy, MI, USA
| | - Sebastien S Kairouz
- Cancer Care Specialists of Central Illinois, Heartland National Cancer Institute Community Oncology Research Program, Decatur, IL, USA
| | - Nafisa Kuwajerwala
- William Beaumont Hospital, Beaumont National Cancer Institute Community Oncology Research Program, Troy, MI, USA
| | - Therese B Bevers
- Department of Clinical Cancer Prevention, MD Anderson Cancer Center, Houston, TX, USA
| | - John E Doster
- Anderson Area Cancer Center, Southeast Clinical Oncology Research Consortium National Cancer Institute Community Oncology Research Program, Anderson, SC, USA
| | | | - Laura Kruper
- Department of Breast Oncology, City of Hope Medical Center, Duarte, CA, USA
| | - Lori M Minasian
- Division of Cancer Prevention, National Cancer Institute, Bethesda, MD, USA
| | - Leslie Ford
- Division of Cancer Prevention, National Cancer Institute, Bethesda, MD, USA
| | - Banu Arun
- Department of Clinical Cancer Prevention, MD Anderson Cancer Center, Houston, TX, USA
| | - Marian L Neuhouser
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, USA
| | - Gary E Goodman
- Swedish Cancer Institute, Pacific Cancer Research Consortium National Cancer Institute Community Oncology Research Program, Seattle, WA, USA
| | - Powel H Brown
- Department of Clinical Cancer Prevention, MD Anderson Cancer Center, Houston, TX, USA
| | - Richard Ha
- Department of Medicine, Columbia University Irving Medical Center and the Herbert Irving Comprehensive Cancer Center, New York, NY, USA
| | - Katherine D Crew
- Department of Medicine, Columbia University Irving Medical Center and the Herbert Irving Comprehensive Cancer Center, New York, NY, USA
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17
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Sahni SK, Fraker JL, Cornell LF, Klassen CL. Hormone therapy in women with benign breast disease - What little is known and suggestions for clinical implementation. Maturitas 2024; 185:107992. [PMID: 38705054 DOI: 10.1016/j.maturitas.2024.107992] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Revised: 03/27/2024] [Accepted: 04/05/2024] [Indexed: 05/07/2024]
Abstract
Benign breast disease encompasses a spectrum of lesions within the breast. While some lesions pose no increase in risk, others may elevate the likelihood of developing breast cancer by four- to five-fold. This necessitates a personalized approach to screening and lifestyle optimization for women. The menopausal transition is a critical time for the development of benign breast lesions. Increased detection can be attributed to the heightened precision and utilization of screening mammography, with or without the use of supplemental imaging. While it is widely acknowledged that combined hormone therapy involving estrogen and progesterone may elevate the risk of breast cancer, data from the Women's Health Initiative (WHI) indicates that estrogen-alone therapies may actually reduce the overall risk of cancer. Despite this general understanding, there is a notable gap in information regarding the impact of hormone therapy on the risk profile of women with specific benign breast lesions. This review comprehensively examines various benign breast lesions, delving into their pathophysiology and management. The goal is to enhance our understanding of when and how to judiciously prescribe hormone therapy, particularly in the context of specific benign breast conditions. By bridging this knowledge gap, the review provides valuable insights into optimizing healthcare strategies for women with benign breast disease, and offers a foundation for more informed decision-making regarding hormone therapy.
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Affiliation(s)
- Sabrina K Sahni
- Jacoby Center for Breast Health, Mayo Clinic, Jacksonville, 4500 San Pablo Road S. Jacksonville, FL 32221, USA.
| | - Jessica L Fraker
- Division of Women's Health Internal Medicine, Mayo Clinic, Scottsdale, 13737 N. 92nd St. Scottsdale, AZ 85260, USA.
| | - Lauren F Cornell
- Jacoby Center for Breast Health, Mayo Clinic, Jacksonville, 4500 San Pablo Road S. Jacksonville, FL 32221, USA.
| | - Christine L Klassen
- Division of Internal Medicine, Mayo Clinic, Rochester, 200 1st St. SW, Rochester, MN 55905, USA.
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18
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Crew KD, Anderson GL, Arnold KB, Stieb AP, Amenta JN, Collins N, Law CW, Pruthi S, Sandoval-Leon A, Bertoni D, Grosse Perdekamp MT, Colonna S, Krisher S, King T, Yee LD, Ballinger TJ, Braun-Inglis C, Mangino D, Wisinski KB, DeYoung CA, Ross M, Floyd J, Kaster A, Vander Walde L, Saphner T, Zarwan C, Lo S, Graham C, Conlin A, Yost K, Agnese D, Jernigan C, Hershman DL, Neuhouser ML, Arun B, Kukafka R. Making Informed Choices On Incorporating Chemoprevention into carE (MiCHOICE, SWOG 1904): Design and methods of a cluster randomized controlled trial. Contemp Clin Trials 2024; 142:107564. [PMID: 38704119 PMCID: PMC11180561 DOI: 10.1016/j.cct.2024.107564] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Revised: 04/15/2024] [Accepted: 05/01/2024] [Indexed: 05/06/2024]
Abstract
INTRODUCTION Women 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/DESIGN We 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/DISCUSSION With 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 REGISTRATION NCT04496739.
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Affiliation(s)
- K D Crew
- Columbia University Irving Medical Center, New York, NY, USA.
| | - G L Anderson
- SWOG Statistics and Data Management Center, Seattle, WA, USA
| | - K B Arnold
- SWOG Statistics and Data Management Center, Seattle, WA, USA
| | - A P Stieb
- Columbia University Irving Medical Center, New York, NY, USA
| | - J N Amenta
- Columbia University Irving Medical Center, New York, NY, USA
| | - N Collins
- Columbia University Irving Medical Center, New York, NY, USA
| | - C W Law
- Columbia University Irving Medical Center, New York, NY, USA
| | - S Pruthi
- Mayo Clinic, Rochester, MN, United States of America
| | - A Sandoval-Leon
- Miami Cancer Institute at Baptist Health South Florida, Miami, FL, USA
| | - D Bertoni
- Good Samaritan Hospital Corvallis, Corvallis, OR , USA
| | | | - S Colonna
- Huntsman Cancer Institute / University of Utah Medical Center, Salt Lake City, UT, USA
| | - S Krisher
- Holy Redeemer Hospital and Medical Center, Meadowbrook, PA, USA
| | - T King
- Dana-Farber Brigham Cancer Center, Brigham and Women's Hospital, Boston, MA, USA
| | - L D Yee
- City of Hope Comprehensive Cancer Center, Duarte, CA, USA
| | - T J Ballinger
- Indiana University Simon Comprehensive Cancer Center, Indianapolis, IN, USA
| | | | - D Mangino
- Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - K B Wisinski
- University of Wisconsin Carbone Cancer Center, Madison, WI, USA
| | | | - M Ross
- Virginia Commonwealth University, Richmond, VA, USA
| | - J Floyd
- Cancer Care Specialists of Illinois, Heartland NCORP, Decatur, IL, USA
| | - A Kaster
- Sanford Roger Maris Cancer Center, Fargo, ND, United States of America
| | - L Vander Walde
- Baptist Memorial Health Care, Memphis, TN, United States of America
| | | | - C Zarwan
- Lahey Hospital & Medical Center, Burlington, MA, USA
| | - S Lo
- Loyola University Stritch School of Medicine, Maywood, IL, USA
| | - C Graham
- Emory University Hospital/Winship Cancer Institute, Atlanta, GA, USA
| | - A Conlin
- Providence Cancer Institute, Portland, OR, USA
| | - K Yost
- Cancer Research Consortium of West Michigan NCORP, Kalamazoo, MI, USA
| | - D Agnese
- The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA
| | - C Jernigan
- SWOG Statistics and Data Management Center, Seattle, WA, USA
| | - D L Hershman
- Columbia University Irving Medical Center, New York, NY, USA
| | | | - B Arun
- The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - R Kukafka
- Columbia University Irving Medical Center, New York, NY, USA
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19
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Ferro A, Campora M, Caldara A, De Lisi D, Lorenzi M, Monteverdi S, Mihai R, Bisio A, Dipasquale M, Caffo O, Ciribilli Y. Novel Treatment Strategies for Hormone Receptor (HR)-Positive, HER2-Negative Metastatic Breast Cancer. J Clin Med 2024; 13:3611. [PMID: 38930141 PMCID: PMC11204965 DOI: 10.3390/jcm13123611] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2024] [Revised: 06/11/2024] [Accepted: 06/18/2024] [Indexed: 06/28/2024] Open
Abstract
Estrogen receptor (ER)-positive breast cancer (BC) is the most common BC subtype. Endocrine therapy (ET) targeting ER signaling still remains the mainstay treatment option for hormone receptor (HR)-positive BC either in the early or in advanced setting, including different strategies, such as the suppression of estrogen production or directly blocking the ER pathway through SERMs-selective estrogen receptor modulators-or SERDs-selective estrogen receptor degraders. Nevertheless, the development of de novo or acquired endocrine resistance still remains challenging for oncologists. The use of novel ET combined with targeted drugs, such as cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors, has significantly improved long-term outcome rates, thus changing the therapeutic algorithm for metastatic BC (MBC) and recently the therapeutic strategy in the adjuvant setting for early high-risk BC. Eluding the resistance to CDK4/6 inhibitors combined with ET is currently an unmet medical need, and there is disagreement concerning the best course of action for patients who continue to progress after this combination approach. Genetic changes in the tumor along its growth uncovered by genomic profiling of recurrent and/or metastatic lesions through tumor and/or liquid biopsies may predict the response or resistance to specific agents, suggesting the best therapeutic strategy for each patient by targeting the altered ER-dependent pathway (novel oral SERDs and a new generation of anti-estrogen agents) or alternative ER-independent signaling pathways such as PI3K/AKT/mTOR or tyrosine kinase receptors (HER2 mutations or HER2 low status) or by inhibiting pathways weakened through germline BRCA1/2 mutations. These agents are being investigated as single molecules and in combination with other target therapies, offering promising weapons to overcome or avoid treatment failure and propose increasingly more personalized treatment approaches. This review presents novel insights into ET and other targeted therapies for managing metastatic HR+/HER2- BC by exploring potential strategies based on clinical evidence and genomic profiling following the failure of the CDK4/6i and ET combination.
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Affiliation(s)
- Antonella Ferro
- Medical Oncology and Breast Unit, Santa Chiara Hospital, APSS Trento, 38122 Trento, Italy; (A.C.); (D.D.L.); (M.L.); (S.M.); (M.D.)
| | - Michela Campora
- Department of Pathology, Santa Chiara Hospital, APSS Trento, 38122 Trento, Italy;
| | - Alessia Caldara
- Medical Oncology and Breast Unit, Santa Chiara Hospital, APSS Trento, 38122 Trento, Italy; (A.C.); (D.D.L.); (M.L.); (S.M.); (M.D.)
| | - Delia De Lisi
- Medical Oncology and Breast Unit, Santa Chiara Hospital, APSS Trento, 38122 Trento, Italy; (A.C.); (D.D.L.); (M.L.); (S.M.); (M.D.)
| | - Martina Lorenzi
- Medical Oncology and Breast Unit, Santa Chiara Hospital, APSS Trento, 38122 Trento, Italy; (A.C.); (D.D.L.); (M.L.); (S.M.); (M.D.)
| | - Sara Monteverdi
- Medical Oncology and Breast Unit, Santa Chiara Hospital, APSS Trento, 38122 Trento, Italy; (A.C.); (D.D.L.); (M.L.); (S.M.); (M.D.)
| | - Raluca Mihai
- Department of Pathology, Queen Elizabeth University Hospital, Glasgow G51 4TF, UK;
| | - Alessandra Bisio
- Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, 38123 Trento, Italy; (A.B.); (Y.C.)
| | - Mariachiara Dipasquale
- Medical Oncology and Breast Unit, Santa Chiara Hospital, APSS Trento, 38122 Trento, Italy; (A.C.); (D.D.L.); (M.L.); (S.M.); (M.D.)
| | - Orazio Caffo
- Medical Oncology, Santa Chiara Hospital, APSS Trento, 38122 Trento, Italy;
| | - Yari Ciribilli
- Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, 38123 Trento, Italy; (A.B.); (Y.C.)
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20
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Yadav M, Vaishkiar I, Sharma A, Shukla A, Mohan A, Girdhar M, Kumar A, Malik T, Mohan A. Oestrogen receptor positive breast cancer and its embedded mechanism: breast cancer resistance to conventional drugs and related therapies, a review. Open Biol 2024; 14:230272. [PMID: 38889771 DOI: 10.1098/rsob.230272] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2023] [Accepted: 03/14/2024] [Indexed: 06/20/2024] Open
Abstract
Traditional medication and alternative therapies have long been used to treat breast cancer. One of the main problems with current treatments is that there is an increase in drug resistance in the cancer cells owing to genetic differences such as mutational changes, epigenetic changes and miRNA (microRNA) alterations such as miR-1246, miR-298, miR-27b and miR-33a, along with epigenetic modifications, such as Histone3 acetylation and CCCTC-Binding Factor (CTCF) hypermethylation for drug resistance in breast cancer cell lines. Certain forms of conventional drug resistance have been linked to genetic changes in genes such as ABCB1, AKT, S100A8/A9, TAGLN2 and NPM. This review aims to explore the current approaches to counter breast cancer, the action mechanism, along with novel therapeutic methods endowing potential drug resistance. The investigation of novel therapeutic approaches sheds light on the phenomenon of drug resistance including genetic variations that impact distinct forms of oestrogen receptor (ER) cancer, genetic changes, epigenetics-reported resistance and their identification in patients. Long-term effective therapy for breast cancer includes selective oestrogen receptor modulators, selective oestrogen receptor degraders and genetic variations, such as mutations in nuclear genes, epigenetic modifications and miRNA alterations in target proteins. Novel research addressing combinational therapies including maytansine, photodynamic therapy, guajadiol, talazoparib, COX2 inhibitors and miRNA 1246 inhibitors have been developed to improve patient survival rates.
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Affiliation(s)
- Manu Yadav
- Division of Genetics, ICAR- Indian Agricultural Research Institute , Pusa, New Delhi, India
| | - Ishita Vaishkiar
- Amity Institute of Biotechnology (AIB) University, Amity University Noida , Noida, India
| | - Ananya Sharma
- Department: Botany and Microbiology, Hemwati Nandan Bahuguna Garhwal University , Srinagar, India
| | - Akanksha Shukla
- School of Bioengineering and Biosciences, Lovely Professional University , Phagwara, Punjab, India
| | - Aradhana Mohan
- Department of Biomedical Engineering, University of Michigan , Ann Arbor, MI, USA
| | - Madhuri Girdhar
- Division of Research and Development, Lovely Professional University , Phagwara, Punjab, India
| | - Anil Kumar
- Gene Regulation Laboratory, National Institute of Immunology , New Delhi, India
| | - Tabarak Malik
- Department of Biomedical Sciences, Institute of Health, Jimma University , Jimma, Oromia 378, Ethiopia
| | - Anand Mohan
- School of Bioengineering and Biosciences, Lovely Professional University , Phagwara, Punjab, India
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21
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Filip CI, Cătană A, Kutasi E, Roman SA, Militaru MS, Risteiu GA, Dindelengan GC. Breast Cancer Screening and Prophylactic Mastectomy for High-Risk Women in Romania. MEDICINA (KAUNAS, LITHUANIA) 2024; 60:570. [PMID: 38674216 PMCID: PMC11052261 DOI: 10.3390/medicina60040570] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 02/12/2024] [Revised: 03/10/2024] [Accepted: 03/26/2024] [Indexed: 04/28/2024]
Abstract
Breast cancer remains a significant contributor to morbidity and mortality within oncology. Risk factors, encompassing genetic and environmental influences, significantly contribute to its prevalence. While germline mutations, notably within the BRCA genes, are commonly associated with heightened breast cancer risk, a spectrum of other variants exists among affected individuals. Diagnosis relies on imaging techniques, biopsies, biomarkers, and genetic testing, facilitating personalised risk assessment through specific scoring systems. Breast cancer screening programs employing mammography and other imaging modalities play a crucial role in early detection and management, leading to improved outcomes for affected individuals. Regular screening enables the identification of suspicious lesions or abnormalities at earlier stages, facilitating timely intervention and potentially reducing mortality rates associated with breast cancer. Genetic mutations guide screening protocols, prophylactic interventions, treatment modalities, and patient prognosis. Prophylactic measures encompass a range of interventions, including chemoprevention, hormonal inhibition, oophorectomy, and mastectomy. Despite their efficacy in mitigating breast cancer incidence, these interventions carry potential side effects and psychological implications, necessitating comprehensive counselling tailored to individual cases.
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Affiliation(s)
- Claudiu Ioan Filip
- Department of Plastic Surgery and Burn Unit, Emergency District Hospital, 400535 Cluj-Napoca, Romania; (C.I.F.); (G.C.D.)
- First Surgical Clinic, Faculty of Medicine, University of Medicine and Pharmacy “Iuliu Hatieganu”, 400012 Cluj-Napoca, Romania
| | - Andreea Cătană
- Department of Molecular Sciences, Faculty of Medicine, University of Medicine and Pharmacy “Iuliu Hatieganu”, 400012 Cluj-Napoca, Romania; (A.C.); (E.K.); (S.A.R.); (G.A.R.)
- Department of Oncogeneticcs, Institute of Oncology, “Prof. Dr. I. Chiricuță”, 400015 Cluj-Napoca, Romania
- Regional Laboratory Cluj-Napoca, Department of Medical Genetics, Regina Maria Health Network, 400363 Cluj-Napoca, Romania
| | - Eniko Kutasi
- Department of Molecular Sciences, Faculty of Medicine, University of Medicine and Pharmacy “Iuliu Hatieganu”, 400012 Cluj-Napoca, Romania; (A.C.); (E.K.); (S.A.R.); (G.A.R.)
| | - Sara Alexia Roman
- Department of Molecular Sciences, Faculty of Medicine, University of Medicine and Pharmacy “Iuliu Hatieganu”, 400012 Cluj-Napoca, Romania; (A.C.); (E.K.); (S.A.R.); (G.A.R.)
| | - Mariela Sanda Militaru
- Department of Molecular Sciences, Faculty of Medicine, University of Medicine and Pharmacy “Iuliu Hatieganu”, 400012 Cluj-Napoca, Romania; (A.C.); (E.K.); (S.A.R.); (G.A.R.)
- Regional Laboratory Cluj-Napoca, Department of Medical Genetics, Regina Maria Health Network, 400363 Cluj-Napoca, Romania
| | - Giulia Andreea Risteiu
- Department of Molecular Sciences, Faculty of Medicine, University of Medicine and Pharmacy “Iuliu Hatieganu”, 400012 Cluj-Napoca, Romania; (A.C.); (E.K.); (S.A.R.); (G.A.R.)
| | - George Călin Dindelengan
- Department of Plastic Surgery and Burn Unit, Emergency District Hospital, 400535 Cluj-Napoca, Romania; (C.I.F.); (G.C.D.)
- First Surgical Clinic, Faculty of Medicine, University of Medicine and Pharmacy “Iuliu Hatieganu”, 400012 Cluj-Napoca, Romania
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22
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Pegington M, Zhen Tam H, Brentnall A, Sestak I, Adams J, Blake GM, Gareth Evans D, Howell A, Cuzick J, Harvie M. Body composition changes during breast cancer preventive treatment with anastrozole: Findings from the IBIS-II trial. Prev Med Rep 2024; 38:102620. [PMID: 38375161 PMCID: PMC10874867 DOI: 10.1016/j.pmedr.2024.102620] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2023] [Revised: 01/15/2024] [Accepted: 01/17/2024] [Indexed: 02/21/2024] Open
Abstract
Background Uptake to anastrozole for breast cancer prevention is low, partly due to women's concerns about side effects including gains in weight and specifically gains in body fat. Previous evidence does not link anastrozole with gains in weight, but there is a lack of data on any effects on body composition i.e. changes in fat and fat free mass. Here we assess association of anastrozole with body composition changes in a prospective sub-study from the second international breast intervention trial (IBIS-II). Methods Participants had DXA scans at baseline and for five years of anastrozole/placebo and beyond (between March 2004 and September 2017. Primary outcomes were changes in body weight, body fat and fat free mass at 9-18 months. A linear model was used to estimate the size of a differential effect in these outcomes by randomised treatment allocation adjusted for baseline value and time since last scan, age, 10-year breast cancer risk, smoking and HRT status. Results 203 postmenopausal women were recruited (n = 95 anastrozole, n = 108 placebo), mean age 58 years (SD = 5.4), BMI 28.0 kg/m2 (SD = 5.5). There was no evidence of a strong association between anastrozole or placebo and endpoints at 9-18 months; effect size (95 %CI) for anastrozole minus placebo for body weight (per/kg) -0.11 (-1.29-1.08); body fat 0.11 (-0.75-0.96) and fat free mass -0.30 (-0.79-0.19). Conclusions There is unlikely to be a clinically significant change to body composition with anastrozole for breast cancer prevention.
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Affiliation(s)
- Mary Pegington
- The Prevent Breast Cancer Research Unit, The Nightingale Centre, Manchester University NHS Foundation Trust, Manchester, UK
- Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Wilmslow Road, Manchester M20 4BX, UK
| | - Hui Zhen Tam
- Centre for Evaluation and Methods, Wolfson Institute of Population Health, Queen Mary University of London, UK
| | - Adam Brentnall
- Centre for Evaluation and Methods, Wolfson Institute of Population Health, Queen Mary University of London, UK
| | - Ivana Sestak
- Centre for Prevention, Detection and Diagnosis, Wolfson Institute of Population Health, Queen Mary University of London, UK
| | - Judith Adams
- Centre for Imaging Sciences, University of Manchester, Manchester, UK
| | - Glen M. Blake
- School of Biomedical Engineering and Imaging Sciences, King’s College London, St Thomas' Hospital, London, UK
| | - D. Gareth Evans
- The Prevent Breast Cancer Research Unit, The Nightingale Centre, Manchester University NHS Foundation Trust, Manchester, UK
- Manchester Breast Centre, Manchester Cancer Research Centre, University of Manchester, 555 Wilmslow Rd, Manchester, UK
- Division of Informatics, Imaging and Data Sciences, School of Health Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
- NW Genomic Laboratory Hub, Manchester Centre for Genomic Medicine, Manchester University Hospitals NHS Foundation Trust, UK
- Genomic Medicine, Division of Evolution and Genomic Sciences, The University of Manchester, St Mary’s Hospital, Manchester University NHS Foundation Trust, Oxford Road, Manchester, UK
| | - Anthony Howell
- The Prevent Breast Cancer Research Unit, The Nightingale Centre, Manchester University NHS Foundation Trust, Manchester, UK
- Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Wilmslow Road, Manchester M20 4BX, UK
- Manchester Breast Centre, Manchester Cancer Research Centre, University of Manchester, 555 Wilmslow Rd, Manchester, UK
- Department of Medical Oncology, The Christie NHS Foundation Trust, Wilmslow Rd, Manchester, UK
| | - Jack Cuzick
- Centre for Prevention, Detection and Diagnosis, Wolfson Institute of Population Health, Queen Mary University of London, UK
| | - Michelle Harvie
- The Prevent Breast Cancer Research Unit, The Nightingale Centre, Manchester University NHS Foundation Trust, Manchester, UK
- Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Wilmslow Road, Manchester M20 4BX, UK
- Manchester Breast Centre, Manchester Cancer Research Centre, University of Manchester, 555 Wilmslow Rd, Manchester, UK
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23
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Li PC, Zhu YF, Cao WM, Li B. ER-positive and BRCA2-mutated breast cancer: a literature review. Eur J Med Res 2024; 29:30. [PMID: 38184581 PMCID: PMC10770892 DOI: 10.1186/s40001-023-01618-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Accepted: 12/24/2023] [Indexed: 01/08/2024] Open
Abstract
BRCA2-mutated carriers have a high lifetime risk of breast cancer (BC), an early age of onset, and an increased risk of other cancers (including ovarian, pancreatic, and prostate cancer). Almost 70-80% of BRCA2-mutated BC are estrogen receptor (ER)-positive, which is a particular type of ER-positive BC that differs from sporadic ER-positive BC. This article reviews the clinicopathological features, treatment, and prognosis of ER-positive and BRCA2-mutated BC to provide a reference for clinical decision-making.
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Affiliation(s)
- Pu-Chun Li
- Postgraduate Training Base Alliance of Wenzhou Medical University (Zhejiang Cancer Hospital), Hangzhou, 310022, China
- Department of Breast Medical Oncology, Zhejiang Cancer Hospital, Hangzhou, 310022, China
| | - Yi-Fan Zhu
- Postgraduate Training Base Alliance of Wenzhou Medical University (Zhejiang Cancer Hospital), Hangzhou, 310022, China
- Department of Breast Medical Oncology, Zhejiang Cancer Hospital, Hangzhou, 310022, China
| | - Wen-Ming Cao
- Department of Breast Medical Oncology, Zhejiang Cancer Hospital, Hangzhou, 310022, China.
| | - Bei Li
- Department of Geriatric, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, 310006, China.
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24
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Zaluzec EK, Sempere LF. Systemic and Local Strategies for Primary Prevention of Breast Cancer. Cancers (Basel) 2024; 16:248. [PMID: 38254741 PMCID: PMC10814018 DOI: 10.3390/cancers16020248] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2023] [Revised: 12/29/2023] [Accepted: 12/31/2023] [Indexed: 01/24/2024] Open
Abstract
One in eight women will develop breast cancer in the US. For women with moderate (15-20%) to average (12.5%) risk of breast cancer, there are few options available for risk reduction. For high-risk (>20%) women, such as BRCA mutation carriers, primary prevention strategies are limited to evidence-based surgical removal of breasts and/or ovaries and anti-estrogen treatment. Despite their effectiveness in risk reduction, not many high-risk individuals opt for surgical or hormonal interventions due to severe side effects and potentially life-changing outcomes as key deterrents. Thus, better communication about the benefits of existing strategies and the development of new strategies with minimal side effects are needed to offer women adequate risk-reducing interventions. We extensively review and discuss innovative investigational strategies for primary prevention. Most of these investigational strategies are at the pre-clinical stage, but some are already being evaluated in clinical trials and others are expected to lead to first-in-human clinical trials within 5 years. Likely, these strategies would be initially tested in high-risk individuals but may be applicable to lower-risk women, if shown to decrease risk at a similar rate to existing strategies, but with minimal side effects.
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Affiliation(s)
- Erin K. Zaluzec
- Precision Health Program, Michigan State University, East Lansing, MI 48824, USA;
- Department of Pharmacology & Toxicology, College of Veterinary Medicine, Michigan State University, East Lansing, MI 48824, USA
| | - Lorenzo F. Sempere
- Precision Health Program, Michigan State University, East Lansing, MI 48824, USA;
- Department of Radiology, College of Human Medicine, Michigan State University, East Lansing, MI 48824, USA
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25
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Abstract
Breast cancer is the most common cancer among U.S. women and its incidence increases with age. Endogenous estrogen exposure, proliferative benign breast disease, breast density, and family history may also indicate increased risk for breast cancer. Early detection with screening mammography reduces breast cancer mortality, but the net benefits vary by age. Assessing a patient's individual breast cancer risk can guide decisions regarding breast cancer screening. All women benefit from healthy behaviors which may reduce breast cancer risk. Some women at increased risk for breast cancer may benefit from risk-reducing medications. Use of screening measures remains suboptimal, especially for uninsured women.
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Affiliation(s)
- Amy H Farkas
- Medical College of Wisconsin, Milwaukee, Wisconsin (A.H.F., A.B.N.)
| | - Ann B Nattinger
- Medical College of Wisconsin, Milwaukee, Wisconsin (A.H.F., A.B.N.)
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26
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Parvizpour S, Elengoe A, Alizadeh E, Razmara J, Shamsir MS. In silico targeting breast cancer biomarkers by applying rambutan ( Nephelium lappaceum) phytocompounds. J Biomol Struct Dyn 2023; 41:10037-10050. [PMID: 36451602 DOI: 10.1080/07391102.2022.2152868] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Accepted: 11/23/2022] [Indexed: 12/03/2022]
Abstract
Worldwide, breast cancer is the leading type of cancer among women. Overexpression of various prognostic indicators, including nuclear receptors, is linked to breast cancer features. To date, no effective drug has been discovered to block the proliferation of breast cancer cells. This study has been designed to discover target-based small molecular-like natural drug candidates that have anti-cancer potential without causing any serious side effects. A comprehensive substrate-based drug design was carried out to discover the potential plant compounds against the target breast cancer biomarkers including phytochemicals screening, active site identification, molecular docking, pharmacokinetic (PK) properties prediction, toxicity prediction, and molecular dynamics (MD) simulation approaches. Twenty plant compounds extracted from the rambutan (Nephelium lappaceum) were obtained from PubChem Database; and screened against the breast cancer biomarkers including estrogen receptor (ER), progesterone receptor (PR), and androgen receptor (AR). The best docking interaction was chosen based on the higher binding affinity. Analyzing the pharmacokinetic properties and toxicity prediction results indicated that the fifteen selected plant compounds have good potency without toxicity and are safe for humans. Four phytochemicals with a higher binding affinity were chosen for each breast cancer biomarker to study their stability in interaction with the target proteins using MD simulation. Among the above compounds, Ellagic acid showed the high binding affinity against all three breast cancer biomarkers.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Sepideh Parvizpour
- Research Center for Pharmaceutical Nanotechnology, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Asita Elengoe
- Department of Biotechnology, Faculty of Science, Lincoln University College Malaysia, Petaling Jaya, Selangor, Malaysia
| | - Effat Alizadeh
- Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Jafar Razmara
- Department of Computer Science, Faculty of Mathematics, Statistics, and Computer Science, University of Tabriz, Tabriz, Iran
| | - Mohd Shahir Shamsir
- Bioinformatics Research Group (BIRG), Department of Biosciences, Faculty of Science, Universiti Teknologi Malaysia, Skudai, Johor, Malaysia
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27
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Akkoc Mustafayev FN, Liu DD, Gutierrez AM, Lewis JE, Ibrahim NK, Valero V, Booser DJ, Litton JK, Koenig K, Yu D, Sneige N, Arun BK. Short-Term Biomarker Modulation Study of Dasatinib for Estrogen Receptor-Negative Breast Cancer Chemoprevention. Eur J Breast Health 2023; 19:267-273. [PMID: 37795002 PMCID: PMC10546803 DOI: 10.4274/ejbh.galenos.2023.2023-7-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Accepted: 08/26/2023] [Indexed: 10/06/2023]
Abstract
Objective Risk-reducing therapy with selective estrogen receptor (ER) modulators and aromatase inhibitors reduce breast cancer risk. However, the effects are limited to ER-positive breast cancer. Therefore, new agents with improved toxicity profiles that reduce the risk in ER-negative breast cancers are urgently needed. The aim of this prospective, short-term, prevention study was to evaluate the effect of dasatinib, an inhibitor of the tyrosine kinase Src, on biomarkers in normal (but increased risk) breast tissue and serum of women at high risk for a second, contralateral primary breast cancer. Materials and Methods Women with a history of unilateral stage I, II, or III ER-negative breast cancer, having no active disease, and who completed all adjuvant therapies were eligible. Patients underwent baseline fine-needle aspiration (FNA) of the contralateral breast and serum collection for biomarker analysis and were randomized to receive either no treatment (control) or dasatinib at 40 or 80 mg/day for three months. After three months, serum collection and breast FNA were repeated. Planned biomarker analysis consisted of changes in cytology and Ki-67 on breast FNA, and changes in serum levels of insulin-like growth factor 1 (IGF-1), IGF-binding protein 1, and IGF-binding protein 3. The primary objective was to evaluate changes in Ki-67 and secondary objective included changes in cytology in breast tissue and IGF-related serum biomarkers. Toxicity was also evaluated. Results Twenty-three patients started their assigned treatments. Compliance during the study was high, with 86.9% (20/23) of patients completing their assigned doses. Dasatinib was well tolerated and no drug-related grade 3 and 4 adverse events were observed. Since only one patient met the adequacy criteria for the paired FNA sample, we could not evaluate Ki-67 level or cytological changes. No significant change in serum biomarkers was observed among the three groups. Conclusion Dasatinib was well tolerated but did not induce any significant changes in serum biomarkers. The study could not fulfill its primary objective due to an inadequate number of paired FNA samples. Further, larger studies are needed to evaluate the effectiveness of Src inhibitors in breast cancer prevention.
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Affiliation(s)
| | - Diane D. Liu
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Texas, USA
| | - Angelica M. Gutierrez
- Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Texas, USA
| | - John E. Lewis
- Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Texas, USA
| | - Nuhad K. Ibrahim
- Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Texas, USA
| | - Vicente Valero
- Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Texas, USA
| | - Daniel J. Booser
- Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Texas, USA
| | - Jennifer K. Litton
- Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Texas, USA
| | - Kimberly Koenig
- Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Texas, USA
| | - Dihua Yu
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Texas, USA
| | - Nour Sneige
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Texas, USA
| | - Banu K. Arun
- Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Texas, USA
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28
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Khan SA. Breast Cancer Risk Reduction: Current Status and Emerging Trends to Increase Efficacy and Reduce Toxicity of Preventive Medication. Surg Oncol Clin N Am 2023; 32:631-646. [PMID: 37714633 DOI: 10.1016/j.soc.2023.05.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/17/2023]
Abstract
The primary prevention of breast cancer is a worthwhile goal for which the efficacy of antiestrogens is well established. However, implementation has been problematic related to low prioritization by providers and the reluctance of high-risk women to experience medication side effects. Emerging solutions include improved risk estimation through the use of polygenic risk scores and the application of radiomics to screening mammograms; and optimization of medication dose to limit toxicity. The identification of agents to prevent estrogen receptor negative or HER2-positive tumors is being pursued, but personalization of medical risk reduction requires the prediction of tumor subtypes.
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Affiliation(s)
- Seema Ahsan Khan
- Department of Surgery, Feinberg School of Medicine of Northwestern University, 303 East Superior Street, Chicago, IL 60614, USA.
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29
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Cao J, Ma X, Yan X, Zhang G, Hong S, Ma R, Wang Y, Ma M. Kaempferol induces mitochondrial dysfunction and mitophagy by activating the LKB1/AMPK/MFF pathway in breast precancerous lesions. Phytother Res 2023; 37:3602-3616. [PMID: 37086359 DOI: 10.1002/ptr.7838] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Revised: 03/22/2023] [Accepted: 04/04/2023] [Indexed: 04/23/2023]
Abstract
Kaempferol has been suggested to be an effective anticancer agent in several malignant tumors. However, its function and mechanisms in breast precancerous lesions remain largely elusive. Here, we showed that kaempferol induced excessive mitochondrial fission and mitochondrial damage with activated mitochondrial fission factor (MFF)-mediated dynamin-related protein (DRP) 1 mitochondrial translocation. As a result, the PTEN-induced putative kinase 1 (PINK1)/Parkin signaling pathway was activated, accompanied by excessive mitophagy and reduced mitochondrial mass in cells. We also revealed that kaempferol-induced lethal mitophagy contributed to inhibiting breast precancerous lesion growth in vitro and in vivo. Furthermore, we verified serine/threonine kinase 11 (STK11/LKB1)/AMP-activated protein kinase (AMPK) pathway deficiency in breast precancerous lesions. Moreover, LKB1/AMPK pathway reactivation by kaempferol was required for excessive mitochondrial fission and lethal mitophagy. Taken together, our findings shed new light on the molecular mechanisms related to breast cancer prevention by kaempferol and provide evidence for its potential clinical application.
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Affiliation(s)
- Jingyu Cao
- Department of Oncology, The First Affiliated Hospital, Jinan University, Guangzhou, China
| | - Xinyi Ma
- The First Clinical Medical College, Southern Medical University (No: 3210090112), Guangzhou, China
| | - Xianxin Yan
- College of Traditional Chinese Medicine, Institute of Integrated Traditional Chinese and Western Medicine, Jinan University, Guangzhou, China
| | - Guijuan Zhang
- School of Nursing of Jinan University, Guangzhou, China
| | - Shouyi Hong
- College of Traditional Chinese Medicine, Institute of Integrated Traditional Chinese and Western Medicine, Jinan University, Guangzhou, China
| | - Ruirui Ma
- College of Traditional Chinese Medicine, Institute of Integrated Traditional Chinese and Western Medicine, Jinan University, Guangzhou, China
| | - Yanqiu Wang
- College of Traditional Chinese Medicine, Institute of Integrated Traditional Chinese and Western Medicine, Jinan University, Guangzhou, China
| | - Min Ma
- College of Traditional Chinese Medicine, Institute of Integrated Traditional Chinese and Western Medicine, Jinan University, Guangzhou, China
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30
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Moyer CL, Brown PH. Targeting nuclear hormone receptors for the prevention of breast cancer. Front Med (Lausanne) 2023; 10:1200947. [PMID: 37583424 PMCID: PMC10424511 DOI: 10.3389/fmed.2023.1200947] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Accepted: 06/30/2023] [Indexed: 08/17/2023] Open
Abstract
Advancements in research have led to the steady decline of breast cancer mortality over the past thirty years. However, breast cancer incidence has continued to rise, resulting in an undue burden on healthcare costs and highlighting a great need for more effective breast cancer prevention strategies, including targeted chemo preventative agents. Efforts to understand the etiology of breast cancer have uncovered important roles for nuclear receptors in the development and progression of breast cancer. Targeted therapies to inhibit estrogen receptor (ER) and progesterone receptor (PR) signaling (selective ER modulators, aromatase inhibitors and selective PR modulators) have shown great promise for the treatment and prevention of hormone receptor (HR)-positive breast cancer. However, these drugs do not prevent HR-negative disease. Therefore, recent efforts have focused on novel targeted therapies with the potential to prevent both HR-positive and HR-negative breast cancer. Among these include drugs that target other nuclear receptors, such as retinoic acid receptor (RAR), retinoid X receptor (RXR) and vitamin D receptor (VDR). In this review we provide an overview of recent preclinical and clinical trials targeting members of the nuclear receptor superfamily for the prevention of breast cancer.
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Affiliation(s)
- Cassandra L. Moyer
- Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Powel H. Brown
- Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, United States
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31
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Lee O, Wang M, Hosseini O, Bosland MC, Muzzio M, Helenowski I, Khan SA. Z-Endoxifen prevents aggressive mammary cancers in mice by inhibiting cell proliferation and creating a tumor suppressive microenvironment. Biomed Pharmacother 2023; 162:114607. [PMID: 37001185 DOI: 10.1016/j.biopha.2023.114607] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Revised: 03/24/2023] [Accepted: 03/24/2023] [Indexed: 03/31/2023] Open
Abstract
Aggressive estrogen receptor (ER) positive breast cancer is frequently tamoxifen-resistant; alternative endocrine approaches exist for therapy, but not for prevention, particularly in premenopausal women. We examined the efficacy of the selective ER modulator (Z-endoxifen) as monotherapy and in combination with the selective progesterone receptor modulators (onapristone and ulipristal acetate) in the tamoxifen-insensitive C3(1)/SV40TAg mouse mammary tumorigenesis model. Unlike tamoxifen at human equivalent dose (HED) 101 mg/day, endoxifen at HED 24 mg/day significantly increased latency and reduced tumor growth relative to untreated controls. Ulipristal acetate (UPA) at HED 81 mg/day also significantly increased latency however failed to inhibit tumor growth, while onapristone (HED 98 mg/day) had no tumor prevention efficacy in this model. Addition of UPA to endoxifen did not enhance preventive efficacy over endoxifen alone. The expression of genes associated with cell cycle, cell proliferation and extracellular matrix remodeling was similarly repressed by endoxifen and UPA however only endoxifen significantly downregulated prominent genes associated with poor prognosis (Col11a1, Il17b, Pdgfa, Tnfrsf11a). Our results indicate that endoxifen can prevent breast cancers, even when tamoxifen-resistant, through its role in favorable tissue remodeling and immunomodulation.
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Affiliation(s)
- Oukseub Lee
- Department of Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
| | - Minhua Wang
- Department of Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Omid Hosseini
- Department of Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Maarten C Bosland
- Department of Pathology, University of Illinois at Chicago, Chicago, IL, USA
| | - Miguel Muzzio
- Analytical Chemistry Division, Illinois Institute of Technology Research Institute, Chicago, IL, USA
| | - Irene Helenowski
- Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Seema A Khan
- Department of Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
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Fraker JL, Clune CG, Sahni SK, Yaganti A, Vegunta S. Prevalence, Impact, and Diagnostic Challenges of Benign Breast Disease: A Narrative Review. Int J Womens Health 2023; 15:765-778. [PMID: 37223067 PMCID: PMC10202205 DOI: 10.2147/ijwh.s351095] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2022] [Accepted: 05/05/2023] [Indexed: 05/25/2023] Open
Abstract
Benign breast diseases, which are commonly seen in clinical practice, have various clinical presentations and implications, as well as management strategies. This article describes common benign breast lesions, presentations of these lesions, and typical radiographic and histologic findings. Also included in this review are the most recent data and guideline-based recommendations for the management of benign breast diseases at diagnosis, including surgical referral, medical management, and ongoing surveillance.
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Affiliation(s)
- Jessica L Fraker
- Division of Women’s Health Internal Medicine, Mayo Clinic, Scottsdale, AZ, USA
| | - Caroline G Clune
- Center for Breast Care, Mayo Clinic Health System — Southwest Wisconsin Region, La Crosse, WI, USA
- Division of General Internal Medicine, Mayo Clinic, Rochester, MN, USA
| | - Sabrina K Sahni
- Jacoby Center for Breast Health, Mayo Clinic, Jacksonville, FL, USA
| | - Avani Yaganti
- Southern Illinois University School of Medicine, Springfield, IL, USA
| | - Suneela Vegunta
- Division of Women’s Health Internal Medicine, Mayo Clinic, Scottsdale, AZ, USA
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Laws A, Punglia RS. Endocrine Therapy for Primary and Secondary Prevention After Diagnosis of High-Risk Breast Lesions or Preinvasive Breast Cancer. J Clin Oncol 2023:JCO2300455. [PMID: 37126767 DOI: 10.1200/jco.23.00455] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/03/2023] Open
Abstract
The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors' suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology, to patients seen in their own clinical practice.Patients with high-risk breast lesions (HRLs) or preinvasive breast cancers face an elevated risk of future breast cancer diagnoses. Endocrine therapy in this setting reduces the risk of a future diagnosis but does not confer improved survival, thus the side effects of primary/secondary prevention must be considered relative to the benefits. Here, we discuss the available chemoprevention regimens for patients with HRLs and considerations for selecting a regimen, as well as the decision making surrounding use of adjuvant endocrine therapy for patients with ductal carcinoma in situ (DCIS). For patients with HRLs, available chemoprevention regimens differ by menopausal status, including tamoxifen 20 mg once daily for 5 years and more recently tamoxifen 5 mg once daily for 3 years in both premenopausal and postmenopausal women as well as raloxifene or aromatase inhibitors for postmenopausal women. We recommend a shared decision-making approach with attention to patient preferences related to risk tolerance and side-effect profiles. Low-dose tamoxifen appears to be a particularly favorable choice that is well tolerated, without risk of serious adverse events and offers comparable risk reduction to other regimens. For DCIS, the benefit of endocrine therapy in addition to radiation is small, and appears to be driven mainly by a reduction in contralateral breast diagnoses or new breast cancers. A strategy that reduces the side-effect profile of chemoprevention such as low-dose tamoxifen may be especially appealing in the setting of secondary prevention.
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Affiliation(s)
- Alison Laws
- Division of Breast Surgery, Department of Surgery, Brigham and Women's Hospital/Dana-Farber Cancer Institute, Boston, MA
| | - Rinaa S Punglia
- Department of Radiation Oncology, Brigham and Women's Hospital/Dana-Farber Cancer Institute, Boston, MA
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34
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Michaels E, Worthington RO, Rusiecki J. Breast Cancer: Risk Assessment, Screening, and Primary Prevention. Med Clin North Am 2023; 107:271-284. [PMID: 36759097 DOI: 10.1016/j.mcna.2022.10.007] [Citation(s) in RCA: 44] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/10/2023]
Abstract
This review provides an outline of a risk-based approach to breast cancer screening and prevention. All women should be assessed for breast cancer risk starting at age 18 with identification of modifiable and non-modifiable risk factors. Patients can then be stratified into average, moderate, and high-risk groups with personalized screening and prevention plans. Counseling on breast awareness and lifestyle changes is recommended for all women, regardless of risk category. High-risk individuals may benefit from additional screening modalities such as MRI and chemoprevention and should be managed closely by a multidisciplinary team.
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Affiliation(s)
- Elena Michaels
- Department of Medicine, University of Chicago, 5841 South Maryland Avenue, MC 3051, Chicago, IL 60637, USA
| | - Rebeca Ortiz Worthington
- Department of Medicine, University of Chicago, 5841 South Maryland Avenue, MC 3051, Chicago, IL 60637, USA
| | - Jennifer Rusiecki
- Department of Medicine, University of Chicago, 5841 South Maryland Avenue, MC 3051, Chicago, IL 60637, USA.
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Elson NC, Lewis JD, Shaughnessy EA, Reyna C. Lessons from other fields of medicine, Part 1: Breast cancer. HANDBOOK OF CLINICAL NEUROLOGY 2023; 192:101-118. [PMID: 36796936 DOI: 10.1016/b978-0-323-85538-9.00003-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/16/2023]
Abstract
Through the understanding of multiple etiologies, pathologies, and disease progression trajectories, breast cancer shifted historically from a singular malignancy of the breast to a complex of molecular/biological entities, translating into individualized disease-modifying treatments. As a result, this led to various de-escalations of treatment compared with the gold standard in the era preceding systems biology: radical mastectomy. Targeted therapies have minimized morbidity from the treatments and mortality from the disease. Biomarkers further individualized tumor genetics and molecular biology to optimize treatments targeting specific cancer cells. Landmark discoveries in breast cancer management have evolved through histology, hormone receptors, human epidermal growth factor, single-gene prognostic markers, and multigene prognostic markers. Relevant to the reliance on histopathology in neurodegenerative disorders, histopathology evaluation in breast cancer can serve as a marker of overall prognosis rather than predict response to therapies. This chapter reviews the successes and failures of breast cancer research through history, with focus on the transition from a universal approach for all patients to divergent biomarker development and individualized targeted therapies, discussing future areas of growth in the field that may apply to neurodegenerative disorders.
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Affiliation(s)
- Nora C Elson
- Department of Surgery, Good Samaritan TriHealth Hospitals, Cincinnati, OH, United States
| | - Jaime D Lewis
- Department of Surgery, University of Cincinnati Medical Center, Cincinnati, OH, United States
| | - Elizabeth A Shaughnessy
- Department of Surgery, University of Cincinnati Medical Center, Cincinnati, OH, United States
| | - Chantal Reyna
- Department of Surgery, Crozer Health Hospitals, Springfield, PA, United States.
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Seitzman RL, Pushkin J, Berg WA. Effect of an Educational Intervention on Women's Health Care Provider Knowledge Gaps About Breast Cancer Risk Model Use and High-risk Screening Recommendations. JOURNAL OF BREAST IMAGING 2023; 5:30-39. [PMID: 38416962 DOI: 10.1093/jbi/wbac072] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Indexed: 03/01/2024]
Abstract
OBJECTIVE To assess effectiveness of a web-based educational intervention on women's health care provider knowledge of breast cancer risk models and high-risk screening recommendations. METHODS A web-based pre- and post-test study including 177 U.S.-based women's health care providers was conducted in 2019. Knowledge gaps were defined as fewer than 75% of respondents answering correctly. Pre- and post-test knowledge differences (McNemar test) and associations of baseline characteristics with pre-test knowledge gaps (logistic regression) were evaluated. RESULTS Respondents included 131/177 (74.0%) physicians; 127/177 (71.8%) practiced obstetrics/gynecology. Pre-test, 118/177 (66.7%) knew the Gail model predicts lifetime invasive breast cancer risk; this knowledge gap persisted post-test [(121/177, 68.4%); P = 0.77]. Just 39.0% (69/177) knew the Gail model identifies women eligible for risk-reducing medications; this knowledge gap resolved. Only 48.6% (86/177) knew the Gail model should not be used to identify women meeting high-risk MRI screening guidelines; this deficiency decreased to 66.1% (117/177) post-test (P = 0.001). Pre-test, 47.5% (84/177) knew the Tyrer-Cuzick model is used to identify women meeting high-risk screening MRI criteria, 42.9% (76/177) to predict BRCA1/2 pathogenic mutation risk, and 26.0% (46/177) to predict lifetime invasive breast cancer risk. These knowledge gaps persisted but improved. For a high-risk 30-year-old, 67.8% (120/177) and 54.2% (96/177) pre-test knew screening MRI and mammography/tomosynthesis are recommended, respectively; 19.2% (34/177) knew both are recommended; and 53% (94/177) knew US is not recommended. These knowledge gaps resolved or reduced. CONCLUSION Web-based education can reduce important provider knowledge gaps about breast cancer risk models and high-risk screening recommendations.
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Affiliation(s)
| | | | - Wendie A Berg
- DenseBreast-info, Inc, Deer Park, NY, USA
- University of Pittsburgh School of Medicine, Magee-Womens Hospital of UPMC, Department of Radiology, Pittsburgh, PA, USA
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37
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Cuzick J. The importance of long-term follow up of participants in clinical trials. Br J Cancer 2023; 128:432-438. [PMID: 36456713 PMCID: PMC9938165 DOI: 10.1038/s41416-022-02038-4] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Revised: 10/13/2022] [Accepted: 10/18/2022] [Indexed: 12/05/2022] Open
Affiliation(s)
- Jack Cuzick
- Wolfson Institute of Population Health, Queen Mary University of London, London, UK.
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38
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Jayasekera J, Zhao A, Schechter C, Lowry K, Yeh JM, Schwartz MD, O'Neill S, Wernli KJ, Stout N, Mandelblatt J, Kurian AW, Isaacs C. Reassessing the Benefits and Harms of Risk-Reducing Medication Considering the Persistent Risk of Breast Cancer Mortality in Estrogen Receptor-Positive Breast Cancer. J Clin Oncol 2023; 41:859-870. [PMID: 36455167 PMCID: PMC9901948 DOI: 10.1200/jco.22.01342] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Revised: 09/26/2022] [Accepted: 10/19/2022] [Indexed: 12/03/2022] Open
Abstract
PURPOSE Recent studies, including a meta-analysis of 88 trials, have shown higher than expected rates of recurrence and death in hormone receptor-positive breast cancer. These new findings suggest a need to re-evaluate the use of risk-reducing medication to avoid invasive breast cancer and breast cancer death in high-risk women. METHODS We adapted an established Cancer Intervention and Surveillance Modeling Network model to evaluate the lifetime benefits and harms of risk-reducing medication in women with a ≥ 3% 5-year risk of developing breast cancer according to the Breast Cancer Surveillance Consortium risk calculator. Model input parameters were derived from meta-analyses, clinical trials, and large observational data. We evaluated the effects of 5 years of risk-reducing medication (tamoxifen/aromatase inhibitors) with annual screening mammography ± magnetic resonance imaging (MRI) compared with no screening, MRI, or risk-reducing medication. The modeled outcomes included invasive breast cancer, breast cancer death, side effects, false positives, and overdiagnosis. We conducted subgroup analyses for individual risk factors such as age, family history, and prior biopsy. RESULTS Risk-reducing tamoxifen with annual screening (± MRI) decreased the risk of invasive breast cancer by 40% and breast cancer death by 57%, compared with no tamoxifen or screening. This is equivalent to an absolute reduction of 95 invasive breast cancers, and 42 breast cancer deaths per 1,000 high-risk women. However, these drugs are associated with side effects. For example, tamoxifen could increase the number of endometrial cancers up to 11 per 1,000 high-risk women. Benefits and harms varied by individual characteristics. CONCLUSION The addition of risk-reducing medication to screening could further decrease the risk of breast cancer death. Clinical guidelines for high-risk women should consider integrating shared decision making for risk-reducing medication and screening on the basis of individual risk factors.
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Affiliation(s)
- Jinani Jayasekera
- Population and Community Health Sciences Branch, Intramural Research Program, National Institute on Minority Health and Health Disparities, National Institutes of Health, Bethesda, MD
| | - Amy Zhao
- Department of Oncology, Georgetown University Medical Center and Cancer Prevention and Control Program, Georgetown-Lombardi Comprehensive Cancer Center, Washington, DC
| | - Clyde Schechter
- Departments of Family and Social Medicine and Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY
| | - Kathryn Lowry
- Department of Radiology, University of Washington, Seattle Cancer Care Alliance, Seattle, WA
| | - Jennifer M. Yeh
- Department of Pediatrics, Harvard Medical School, Boston Children's Hospital, Boston, MA
| | - Marc D. Schwartz
- Department of Oncology, Georgetown University Medical Center and Cancer Prevention and Control Program, Georgetown-Lombardi Comprehensive Cancer Center, Washington, DC
| | - Suzanne O'Neill
- Department of Oncology, Georgetown University Medical Center and Cancer Prevention and Control Program, Georgetown-Lombardi Comprehensive Cancer Center, Washington, DC
| | - Karen J. Wernli
- Kaiser Permanente Washington Health Research Institute, Seattle, WA
| | - Natasha Stout
- Department of Population Medicine, Harvard Medical School, Harvard Pilgrim Healthcare Institute, Boston, MA
| | - Jeanne Mandelblatt
- Department of Oncology, Georgetown University Medical Center and Cancer Prevention and Control Program, Georgetown-Lombardi Comprehensive Cancer Center, Washington, DC
| | - Allison W. Kurian
- Departments of Medicine and of Epidemiology and Population Health, Stanford University School of Medicine, Stanford, CA
| | - Claudine Isaacs
- Department of Oncology, Georgetown University Medical Center and Cancer Prevention and Control Program, Georgetown-Lombardi Comprehensive Cancer Center, Washington, DC
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39
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Takeuchi Y, Gotoh N. Inflammatory cytokine-enriched microenvironment plays key roles in the development of breast cancers. Cancer Sci 2023; 114:1792-1799. [PMID: 36704829 PMCID: PMC10154879 DOI: 10.1111/cas.15734] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Revised: 12/29/2022] [Accepted: 01/20/2023] [Indexed: 01/28/2023] Open
Abstract
As the incidence of breast cancer continues to increase, it is critical to develop prevention strategies for this disease. Inflammation underlies the onset of the disease, and NF-κB is a master transcription factor for inflammation. Nuclear factor-κB (NF-κB) is activated in a variety of cell types, including normal epithelial cells, cancer cells, cancer-associated fibroblasts (CAFs), and immune cells. Ductal carcinoma in situ (DCIS) is the earliest stage of breast cancer, and not all DCIS lesions develop into invasive breast cancers (IBC). Currently, most patients with DCIS undergo surgery with postoperative therapy, although there is a risk of overtreatment. In BRCA mutants, receptor activator of NF-κB (RANK)-positive progenitors serve as the cell of origin, and treatment using the RANK monoclonal antibody reduces the risk of IBC. There is still an unmet need to diagnose malignant DCIS, which has the potential to progress to IBC, and to establish appropriate prevention strategies. We recently demonstrated novel molecular mechanisms for NF-κB activation in premalignant mammary tissues, which include DCIS, and the resultant cytokine-enriched microenvironment is essential for breast cancer development. On the early endosomes in a few epithelial cells, the adaptor protein FRS2β, forming a complex with ErbB2, carries the IκB kinase (IKK) complex and leads to the activation of NF-κB, thereby inducing a variety of cytokines. Therefore, the FRS2β-NFκB axis in the inflammatory premalignant environment could be targetable to prevent IBC. Further analysis of the molecular mechanisms of inflammation in the premalignant microenvironment is necessary to prevent the risk of IBC.
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Affiliation(s)
- Yasuto Takeuchi
- Division of Cancer Cell Biology, Cancer Research Institute, Kanazawa University, Kanazawa City, Japan.,Institute for Frontier Science Initiative, Kanazawa University, Kanazawa City, Japan
| | - Noriko Gotoh
- Division of Cancer Cell Biology, Cancer Research Institute, Kanazawa University, Kanazawa City, Japan.,Institute for Frontier Science Initiative, Kanazawa University, Kanazawa City, Japan
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40
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Trapani D, Sandoval J, Aliaga PT, Ascione L, Maria Berton Giachetti PP, Curigliano G, Ginsburg O. Screening Programs for Breast Cancer: Toward Individualized, Risk-Adapted Strategies of Early Detection. Cancer Treat Res 2023; 188:63-88. [PMID: 38175342 DOI: 10.1007/978-3-031-33602-7_3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2024]
Abstract
Early detection of breast cancer (BC) comprises two approaches: screening of asymptomatic women in a specified target population at risk (usually a target age range for women at average risk), and early diagnosis for women with BC signs and symptoms. Screening for BC is a key health intervention for early detection. While population-based screening programs have been implemented for age-selected women, the pivotal clinical trials have not addressed the global utility nor the improvement of screening performance by utilizing more refined parameters for patient eligibility, such as individualized risk stratification. In addition, with the exception of the subset of women known to carry germline pathogenetic mutations in (high- or moderately-penetrant) cancer predisposition genes, such as BRCA1 and BRCA2, there has been less success in outreach and service provision for the unaffected relatives of women found to carry a high-risk mutation (i.e., "cascade testing") as it is in these individuals for whom such actionable information can result in cancers (and/or cancer deaths) being averted. Moreover, even in the absence of clinical cancer genetics services, as is the case for the immediate and at least near-term in most countries globally, the capacity to stratify the risk of an individual to develop BC has existed for many years, is available for free online at various sites/platforms, and is increasingly being validated for non-Caucasian populations. Ultimately, a precision approach to BC screening is largely missing. In the present chapter, we aim to address the concept of risk-adapted screening of BC, in multiple facets, and understand if there is a value in the implementation of adapted screening strategies in selected women, outside the established screening prescriptions, in the terms of age-range, screening modality and schedules of imaging.
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Affiliation(s)
- Dario Trapani
- Division of New Drug Development for Innovative Therapies, European Institute of Oncology IRCCS, Milan, Italy.
| | - Josè Sandoval
- Department of Oncology, Geneva University Hospitals, Geneva, Switzerland
- Unit of Population Epidemiology, Division and Department of Primary Care Medicine, Geneva University Hospitals, Geneva, Switzerland
| | - Pamela Trillo Aliaga
- Division of New Drug Development for Innovative Therapies, European Institute of Oncology IRCCS, Milan, Italy
- Department of Oncology and Hematology, University of Milan, Milan, Italy
| | - Liliana Ascione
- Division of New Drug Development for Innovative Therapies, European Institute of Oncology IRCCS, Milan, Italy
- Department of Oncology and Hematology, University of Milan, Milan, Italy
| | - Pier Paolo Maria Berton Giachetti
- Division of New Drug Development for Innovative Therapies, European Institute of Oncology IRCCS, Milan, Italy
- Department of Oncology and Hematology, University of Milan, Milan, Italy
| | - Giuseppe Curigliano
- Division of New Drug Development for Innovative Therapies, European Institute of Oncology IRCCS, Milan, Italy
- Department of Oncology and Hematology, University of Milan, Milan, Italy
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41
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Kuba MG, Brogi E. Update on lobular lesions of the breast. Histopathology 2023; 82:36-52. [PMID: 36482279 PMCID: PMC9752180 DOI: 10.1111/his.14829] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2022] [Revised: 10/09/2022] [Accepted: 10/12/2022] [Indexed: 12/13/2022]
Abstract
The current histological classification of in-situ and invasive lobular carcinomas (ILCs) includes different morphological variants, some of which have been recently described. In this review, we will focus upon: (i) the diagnostic criteria of non-invasive lobular neoplasia and treatment implications across different countries; (ii) utility and limitations of immunohistochemistry; (iii) recently described variants of ILC; and (iv) the significance of lobular differentiation in invasive carcinoma for clinical management.
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Affiliation(s)
- Maria Gabriela Kuba
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Edi Brogi
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
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Naorem R, Ghogale KS, Waghmare CM. Multiple malignant primary tumors (non-head and neck): Contemplation needed. J Cancer Res Ther 2023; 19:S752-S757. [PMID: 38384051 DOI: 10.4103/jcrt.jcrt_155_22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Accepted: 08/06/2022] [Indexed: 02/23/2024]
Abstract
BACKGROUND The incidence of multiple malignant primary tumors (MMPT) is increasing which needs attention. Hence, we undertook this study to analyze clinico-demographic details and treatment outcomes in patients with non-head and neck MMPT. MATERIALS AND METHODS Hospital case records of patients with histopathology proven MMPT registered in the radiation oncology department from January 1, 2008 to December 31, 2020 were retrospectively studied. Modified Warren-Gates criteria were used to define MMPT. Patients with MMPT of the head and neck (both an index and second primary as head-neck) were excluded from the study. Demographic and clinical details were recorded and analyzed. RESULTS Forty-two eligible cases of non-head and neck MMPT were studied. The median age at diagnosis of an index case was 55 years (minimum 21, maximum 85) with a male to a female sex ratio of 5:37. Twelve patients had synchronous (28.57%) and 30 had metachronous (71.42%) MMPT. The average period between metachronous tumors was 77.77 months (minimum 12, maximum 312). The most common site of an index and second primary tumor was the breast (26; 61.90% and 23; 54.76%, respectively). Seventeen (65.38%) out of 26 index breast cancer were bilateral breast cancer and nine were others. In six cases of MMPT, there was an association between the breast and cervix. CONCLUSION Breast cancer was the most common site for both an index and second primary malignancy followed by genital cancers. With cautious monitoring and patient education, second primary tumor could be detected earlier and managed better giving a good quality of life to patients.
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Affiliation(s)
- Raphel Naorem
- Department of Radiation Oncology, Dr. Balasaheb Vikhe Patil Rural Medical College and Dr. Vitthalrao Vikhe Patil Pravara Rural Hospital, PIMS-DU, Loni, Ahmadnagar, Maharashtra, India
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Crew KD, Bhatkhande G, Silverman T, Amenta J, Jones T, McGuinness JE, Mata J, Guzman A, He T, Dimond J, Tsai WY, Kukafka R. Patient and Provider Web-Based Decision Support for Breast Cancer Chemoprevention: A Randomized Controlled Trial. Cancer Prev Res (Phila) 2022; 15:689-700. [PMID: 35679576 PMCID: PMC9532364 DOI: 10.1158/1940-6207.capr-22-0013] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Revised: 05/09/2022] [Accepted: 06/06/2022] [Indexed: 11/16/2022]
Abstract
Significant underutilization of breast cancer chemoprevention remains, despite guidelines stating that physicians should recommend chemoprevention with antiestrogen therapy to high-risk women. We randomized women, ages 35 to 75 years, who met high-risk criteria for breast cancer, without a personal history of breast cancer or prior chemoprevention use, to standard educational materials alone or combined with a web-based decision aid. All healthcare providers, including primary care providers and breast specialists, were given access to a web-based decision support tool. The primary endpoint was chemoprevention uptake at 6 months. Secondary outcomes included decision antecedents (perceived breast cancer risk/worry, chemoprevention knowledge, self-efficacy) and decision quality (decision conflict, chemoprevention informed choice) based upon patient surveys administered at baseline, 1 and 6 months after randomization. Among 282 evaluable high-risk women enrolled from November 2016 to March 2020, mean age was 57 years (SD, 9.9) and mean 5-year invasive breast cancer risk was 2.98% (SD, 1.42). There was no significant difference in chemoprevention uptake at 6 months between the intervention and control groups (2.1% vs. 3.5%). Comparing the intervention and control arms at 1 month, there were significant differences among high-risk women in accurate breast cancer risk perceptions (56% vs. 39%, P = 0.017), adequate chemoprevention knowledge (49% vs. 27%, P < 0.001), mean decision conflict (34.0 vs. 47.0, P < 0.001), and informed choice (41% vs. 23%, P = 0.003). These differences were no longer significant at 6 months. Although our decision support tools did not result in a significant increase in chemoprevention uptake, we did observe improvements in decision antecedents and decision quality measures. PREVENTION RELEVANCE In this randomized controlled trial of decision support for 300 high-risk women and 50 healthcare providers, we did not observe a significant increase in chemoprevention uptake, which remained low at under 5%. However, these decision support tools may increase knowledge and informed choice about breast cancer chemoprevention.
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Affiliation(s)
- Katherine D. Crew
- Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY
- Department of Epidemiology, Mailman School of Public Health, Columbia University Irving Medical Center, New York, NY
- Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY
| | - Gauri Bhatkhande
- Department of Epidemiology, Mailman School of Public Health, Columbia University Irving Medical Center, New York, NY
| | - Thomas Silverman
- Department of Biomedical Informatics, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY
| | - Jacquelyn Amenta
- Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY
| | - Tarsha Jones
- Christine E. Lynn College of Nursing, Florida Atlantic University, Boca Raton, FL
| | - Julia E. McGuinness
- Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY
- Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY
| | - Jennie Mata
- Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY
- Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY
| | - Ashlee Guzman
- Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY
- Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY
| | - Ting He
- Department of Biomedical Informatics and Data Sciences, Johns Hopkins University, Baltimore, MD
| | | | - Wei-Yann Tsai
- Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY
- Department of Biostatistics, Mailman School of Public Health, Columbia University Irving Medical Center, New York, NY
| | - Rita Kukafka
- Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY
- Department of Biomedical Informatics, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY
- Department of Sociomedical Sciences, Mailman School of Public Health, Columbia University Irving Medical Center, New York, NY
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44
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Hong R, Xu B. Breast cancer: an up-to-date review and future perspectives. Cancer Commun (Lond) 2022; 42:913-936. [PMID: 36074908 PMCID: PMC9558690 DOI: 10.1002/cac2.12358] [Citation(s) in RCA: 159] [Impact Index Per Article: 53.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Revised: 06/16/2022] [Accepted: 08/21/2022] [Indexed: 11/10/2022] Open
Abstract
Breast cancer is the most common cancer worldwide. The occurrence of breast cancer is associated with many risk factors, including genetic and hereditary predisposition. Breast cancers are highly heterogeneous. Treatment strategies for breast cancer vary by molecular features, including activation of human epidermal growth factor receptor 2 (HER2), hormonal receptors (estrogen receptor [ER] and progesterone receptor [PR]), gene mutations (e.g., mutations of breast cancer 1/2 [BRCA1/2] and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha [PIK3CA]) and markers of the immune microenvironment (e.g., tumor-infiltrating lymphocyte [TIL] and programmed death-ligand 1 [PD-L1]). Early-stage breast cancer is considered curable, for which local-regional therapies (surgery and radiotherapy) are the cornerstone, with systemic therapy given before or after surgery when necessary. Preoperative or neoadjuvant therapy, including targeted drugs or immune checkpoint inhibitors, has become the standard of care for most early-stage HER2-positive and triple-negative breast cancer, followed by risk-adapted post-surgical strategies. For ER-positive early breast cancer, endocrine therapy for 5-10 years is essential. Advanced breast cancer with distant metastases is currently considered incurable. Systemic therapies in this setting include endocrine therapy with targeted agents, such as CDK4/6 inhibitors and phosphoinositide 3-kinase (PI3K) inhibitors for hormone receptor-positive disease, anti-HER2 targeted therapy for HER2-positive disease, poly(ADP-ribose) polymerase inhibitors for BRCA1/2 mutation carriers and immunotherapy currently for part of triple-negative disease. Innovation technologies of precision medicine may guide individualized treatment escalation or de-escalation in the future. In this review, we summarized the latest scientific information and discussed the future perspectives on breast cancer.
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Affiliation(s)
- Ruoxi Hong
- Department of Medical OncologySun Yat‐Sen University Cancer CenterState Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineGuangzhouGuangdong510060P. R. China
| | - Binghe Xu
- State Key Laboratory of Molecular Oncology and Department of Medical OncologyCancer Hospital Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing100006P. R. China
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45
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Ergun MA, Hajjar A, Alagoz O, Rampurwala M. Optimal breast cancer risk reduction policies tailored to personal risk level. Health Care Manag Sci 2022; 25:363-388. [PMID: 35687269 PMCID: PMC10445480 DOI: 10.1007/s10729-022-09596-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2021] [Accepted: 03/17/2022] [Indexed: 11/04/2022]
Abstract
Depending on personal and hereditary factors, each woman has a different risk of developing breast cancer, one of the leading causes of death for women. For women with a high-risk of breast cancer, their risk can be reduced by two main therapeutic approaches: 1) preventive treatments such as hormonal therapies (i.e., tamoxifen, raloxifene, exemestane); or 2) a risk reduction surgery (i.e., mastectomy). Existing national clinical guidelines either fail to incorporate or have limited use of the personal risk of developing breast cancer in their proposed risk reduction strategies. As a result, they do not provide enough resolution on the benefit-risk trade-off of an intervention policy as personal risk changes. In addressing this problem, we develop a discrete-time, finite-horizon Markov decision process (MDP) model with the objective of maximizing the patient's total expected quality-adjusted life years. We find several useful insights some of which contradict the existing national breast cancer risk reduction recommendations. For example, we find that mastectomy is the optimal choice for the border-line high-risk women who are between ages 22 and 38. Additionally, in contrast to the National Comprehensive Cancer Network recommendations, we find that exemestane is a plausible, in fact, the best, option for high-risk postmenopausal women.
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Affiliation(s)
- Mehmet A Ergun
- Department of Industrial and Systems Engineering, University of Wisconsin-Madison, 3242 Mechanical Engineering Building, 1513 University Avenue, Madison, WI, 53706, USA
- Department of Industrial Engineering, Istanbul Technical University, Istanbul, Turkey
| | - Ali Hajjar
- Harvard Medical School, Boston, Massachusetts, Boston, USA
- Massachusetts General Hospital Institute for Technology Assessment, Boston, USA
| | - Oguzhan Alagoz
- Department of Industrial and Systems Engineering, University of Wisconsin-Madison, 3242 Mechanical Engineering Building, 1513 University Avenue, Madison, WI, 53706, USA.
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46
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Shalabi SF, LaBarge MA. Cellular and molecular mechanisms of breast cancer susceptibility. Clin Sci (Lond) 2022; 136:1025-1043. [PMID: 35786748 DOI: 10.1042/cs20211158] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Revised: 06/16/2022] [Accepted: 06/22/2022] [Indexed: 11/17/2022]
Abstract
There is a plethora of recognized risk factors for breast cancer (BC) with poorly understood or speculative biological mechanisms. The lack of prevention options highlights the importance of understanding the mechanistic basis of cancer susceptibility and finding new targets for breast cancer prevention. Until now, we have understood risk and cancer susceptibility primarily through the application of epidemiology and assessing outcomes in large human cohorts. Relative risks are assigned to various human behaviors and conditions, but in general the associations are weak and there is little understanding of mechanism. Aging is by far the greatest risk factor for BC, and there are specific forms of inherited genetic risk that are well-understood to cause BC. We propose that bringing focus to the biology underlying these forms of risk will illuminate biological mechanisms of BC susceptibility.
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Affiliation(s)
- Sundus F Shalabi
- Department of Population Sciences, Beckman Research Institute, City of Hope, Duarte, CA, U.S.A
- Medical Research Center, Al-Quds University, Jerusalem, Palestine
| | - Mark A LaBarge
- Department of Population Sciences, Beckman Research Institute, City of Hope, Duarte, CA, U.S.A
- Center for Cancer and Aging, Beckman Research Institute, City of Hope, Duarte, CA, U.S.A
- Center for Cancer Biomarkers Research (CCBIO), Bergen, Norway
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47
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Bychkovsky B, Laws A, Katlin F, Hans M, Knust Graichen M, Pace LE, Scheib R, Garber JE, King TA. Initiation and tolerance of chemoprevention among women with high-risk breast lesions: the potential of low-dose tamoxifen. Breast Cancer Res Treat 2022; 193:417-427. [PMID: 35378642 PMCID: PMC8978759 DOI: 10.1007/s10549-022-06577-5] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Accepted: 03/17/2022] [Indexed: 11/05/2022]
Abstract
PURPOSE High-risk lesions (HRLs) of the breast are an indication for chemoprevention, yet uptake is low, largely due to concerns about side effects. In 2019, low-dose (5 mg) tamoxifen was demonstrated to reduce breast cancer risk with improved tolerance. We describe chemoprevention uptake in an academic clinic before and after the introduction of low-dose tamoxifen. METHODS Females age ≥ 35 with HRLs who established care from April 2017 through January 2020 and eligible for chemoprevention were included. Rates of chemoprevention initiation before and after the introduction of low-dose tamoxifen (pre-2019 vs. post-2019) were compared with chi-squared tests. Logistic regression identified demographic and clinical factors associated with chemoprevention initiation. Kaplan-Meier methods determined the rates of discontinuation. RESULTS Among 660 eligible females with HRLs, 22.7% initiated chemoprevention. Median time from first visit to chemoprevention initiation was 54 days (interquartile range (IQR): 0-209); 31.0% (46/150) started chemoprevention > 6 months after their initial visit. Chemoprevention uptake was not significantly different pre-2019 vs. post-2019 (21.2% vs. 26.3%, p = 0.16); however, post-2019, low-dose tamoxifen became the most popular option (41.5%, 34/82). On multivariable analyses, age and breast cancer family history were significantly associated with chemoprevention initiation. Discontinuation rates at 1 year were lowest for low-dose tamoxifen (6.7%) vs. tamoxifen 20 mg (15.0%), raloxifene (20.4%), or an aromatase inhibitor (20.0%). CONCLUSION In this modern cohort, 22.7% of females with HRLs initiated chemoprevention with 31.0% initiating chemoprevention > 6 months after their first visit. Low-dose tamoxifen is now the most popular choice for chemoprevention, with low discontinuation rates at 1 year.
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Affiliation(s)
- Brittany Bychkovsky
- Harvard Medical School, Boston, MA, USA
- Breast Oncology Program, Dana-Farber/Brigham and Women's Cancer Center, Boston, MA, USA
- Division of Cancer Genetics and Prevention, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Alison Laws
- Harvard Medical School, Boston, MA, USA
- Breast Oncology Program, Dana-Farber/Brigham and Women's Cancer Center, Boston, MA, USA
- Division of Breast Surgery, Department of Surgery, Brigham and Women's Hospital, Boston, MA, USA
| | - Fisher Katlin
- Division of Breast Surgery, Department of Surgery, Brigham and Women's Hospital, Boston, MA, USA
| | - Marybeth Hans
- Division of Breast Surgery, Department of Surgery, Brigham and Women's Hospital, Boston, MA, USA
| | - Mary Knust Graichen
- Division of Breast Surgery, Department of Surgery, Brigham and Women's Hospital, Boston, MA, USA
| | - Lydia E Pace
- Harvard Medical School, Boston, MA, USA
- Division of Women's Health, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA
| | - Rochelle Scheib
- Harvard Medical School, Boston, MA, USA
- Breast Oncology Program, Dana-Farber/Brigham and Women's Cancer Center, Boston, MA, USA
- Division of Cancer Genetics and Prevention, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Judy E Garber
- Harvard Medical School, Boston, MA, USA
- Breast Oncology Program, Dana-Farber/Brigham and Women's Cancer Center, Boston, MA, USA
- Division of Cancer Genetics and Prevention, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Tari A King
- Harvard Medical School, Boston, MA, USA.
- Breast Oncology Program, Dana-Farber/Brigham and Women's Cancer Center, Boston, MA, USA.
- Division of Breast Surgery, Department of Surgery, Brigham and Women's Hospital, Boston, MA, USA.
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48
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Abderrahman B, Jordan VC. Estrogen for the Treatment and Prevention of Breast Cancer: A Tale of 2 Karnofsky Lectures. Cancer J 2022; 28:163-168. [PMID: 35594462 PMCID: PMC9179096 DOI: 10.1097/ppo.0000000000000600] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
ABSTRACT In 1971, Sir Alexander Haddow et al. delivered the inaugural David A. Karnofsky lecture at the American Society for Clinical Oncology. This award was designated American Society for Clinical Oncology's highest, as he had used translational research to identify the first clinical therapy, that is, synthetic estrogens to treat breast cancer. His lecture was entitled "Thoughts on Chemical Therapy." For 40 years, high-dose synthetic estrogens were used as palliative therapy, for some advanced breast cancer patients 5 years following menopause. Mechanisms were unknown. Tamoxifen, a failed "morning-after pill," is an antiestrogen in estrogen receptor-positive breast cancer, which was subsequently used to treat all stages of breast cancer and to prevent breast cancer. In 2008, Jordan was selected to present the 38th Karnofsky lecture entitled: "The Paradoxical Action of Estrogen in Breast Cancer-Survival or Death?" Unexpectedly, through a study of acquired resistance to long-term tamoxifen therapy, estrogen-induced apoptosis in long-term estrogen-deprived breast cancer was deciphered in Jordan's laboratory. These data and the biological rules established under laboratory conditions provided molecular mechanisms to aid in the interpretation of the Women's Health initiative in the United States and the Million Women Study in the United Kingdom. In addition, by establishing laboratory models to understand mechanisms of estrogen-induced apoptosis, new estrogen derivatives were successfully evaluated in the laboratory and tested as candidates for women after the therapeutic failure of antiestrogenic strategies to treat breast cancer. For the future, the knowledge obtained about estrogen-induced apoptosis in cancer holds the promise of discovering new therapies to control or cure cancer in general.
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Affiliation(s)
- Balkees Abderrahman
- From the Department of Breast Medical Oncology, University of Texas, MD Anderson Cancer Center, Houston, TX
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49
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Gao W, Hu H, Dai L, He M, Yuan H, Zhang H, Liao J, Wen B, Li Y, Palmisano M, Traore MDM, Zhou S, Sun D. Structure‒tissue exposure/selectivity relationship (STR) correlates with clinical efficacy/safety. Acta Pharm Sin B 2022; 12:2462-2478. [PMID: 35646532 PMCID: PMC9136610 DOI: 10.1016/j.apsb.2022.02.015] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2021] [Revised: 01/23/2022] [Accepted: 02/12/2022] [Indexed: 11/17/2022] Open
Abstract
Drug optimization, which improves drug potency/specificity by structure‒activity relationship (SAR) and drug-like properties, is rigorously performed to select drug candidates for clinical trials. However, the current drug optimization may overlook the structure‒tissue exposure/selectivity-relationship (STR) in disease-targeted tissues vs. normal tissues, which may mislead the drug candidate selection and impact the balance of clinical efficacy/toxicity. In this study, we investigated the STR in correlation with observed clinical efficacy/toxicity using seven selective estrogen receptor modulators (SERMs) that have similar structures, same molecular target, and similar/different pharmacokinetics. The results showed that drug's plasma exposure was not correlated with drug's exposures in the target tissues (tumor, fat pad, bone, uterus), while tissue exposure/selectivity of SERMs was correlated with clinical efficacy/safety. Slight structure modifications of four SERMs did not change drug's plasma exposure but altered drug's tissue exposure/selectivity. Seven SERMs with high protein binding showed higher accumulation in tumors compared to surrounding normal tissues, which is likely due to tumor EPR effect of protein-bound drugs. These suggest that STR alters drug's tissue exposure/selectivity in disease-targeted tissues vs. normal tissues impacting clinical efficacy/toxicity. Drug optimization needs to balance the SAR and STR in selecting drug candidate for clinical trial to improve success of clinical drug development.
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Affiliation(s)
- Wei Gao
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA
| | - Hongxiang Hu
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA
| | - Lipeng Dai
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA
| | - Miao He
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA
| | - Hebao Yuan
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA
| | - Huixia Zhang
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA
| | - Jinhui Liao
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA
| | - Bo Wen
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA
| | - Yan Li
- Translational Development and Clinical Pharmacology, Bristol Myers Squibb, Summit, NJ 07920, USA
| | - Maria Palmisano
- Translational Development and Clinical Pharmacology, Bristol Myers Squibb, Summit, NJ 07920, USA
| | - Mohamed Dit Mady Traore
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA
| | - Simon Zhou
- Translational Development and Clinical Pharmacology, Bristol Myers Squibb, Summit, NJ 07920, USA
| | - Duxin Sun
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA
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50
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McGuinness JE, Bhatkhande G, Amenta J, Silverman T, Mata J, Guzman A, He T, Dimond J, Jones T, Kukafka R, Crew KD. Strategies to Identify and Recruit Women at High Risk for Breast Cancer to a Randomized Controlled Trial of Web-based Decision Support Tools. Cancer Prev Res (Phila) 2022; 15:399-406. [PMID: 35412592 DOI: 10.1158/1940-6207.capr-21-0593] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2021] [Revised: 02/03/2022] [Accepted: 03/28/2022] [Indexed: 11/16/2022]
Abstract
We evaluated strategies to identify and recruit a racially/ethnically diverse cohort of women at high-risk for breast cancer to a randomized controlled trial (RCT). We enrolled 300 high-risk women and 50 healthcare providers to a RCT of standard educational materials alone or in combination with web-based decision support tools. We implemented five strategies to identify high-risk women: (i) recruitment among patients previously enrolled in a study evaluating breast cancer risk; (ii) automated breast cancer risk calculation using information extracted from the electronic health record (EHR); (iii) identification of women with atypical hyperplasia or lobular carcinoma in situ (LCIS) using International Classification of Diseases (ICD)-9/10 diagnostic codes; (iv) clinical encounters with enrolled healthcare providers; (v) recruitment flyers/online resources. Breast cancer risk was calculated using either the Gail or Breast Cancer Surveillance Consortium (BCSC) models. We identified 6,229 high-risk women and contacted 3,459 (56%), of whom 17.2% were identified from prior study cohort, 37.5% through EHR risk information, 14.8% with atypical hyperplasia/LCIS, 29.0% by clinical encounters, and 1.5% through recruitment flyers. Women from the different recruitment sources varied by age and 5-year invasive breast cancer risk. Of 300 enrolled high-risk women, 44.7% came from clinical encounters and 27.3% from prior study cohort. Comparing enrolled with not-enrolled participants, there were significant differences in mean age (57.2 vs. 59.1 years), proportion of non-Whites (41.5% vs. 54.8%), and mean 5-year breast cancer risk (3.0% vs. 2.3%). We identified and successfully recruited diverse high-risk women from multiple sources. These strategies may be implemented in future breast cancer chemoprevention trials. PREVENTION RELEVANCE We describe five strategies to identify and successfully recruit a large cohort of racially/ethnically diverse high-risk women from multiple sources to a randomized controlled trial evaluating interventions to increase chemoprevention uptake. Findings could inform recruitment efforts for future breast cancer prevention trials to increase recruitment yield of high-risk women.
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Affiliation(s)
- Julia E McGuinness
- Division of Hematology and Oncology, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, New York.,Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, New York
| | - Gauri Bhatkhande
- Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, New York
| | - Jacquelyn Amenta
- Division of Hematology and Oncology, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, New York.,Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, New York
| | - Thomas Silverman
- Department of Biomedical Informatics, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, New York
| | - Jennie Mata
- Division of Hematology and Oncology, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, New York.,Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, New York
| | - Ashlee Guzman
- Division of Hematology and Oncology, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, New York.,Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, New York
| | - Ting He
- Department of Biomedical Informatics and Data Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Jill Dimond
- Sassafras Tech Collective, Ann Arbor, Michigan
| | - Tarsha Jones
- Christine E Lynn College of Nursing, Florida Atlantic University, Boca Raton, Florida
| | - Rita Kukafka
- Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, New York.,Department of Biomedical Informatics, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, New York.,Department of Sociomedical Sciences, Mailman School of Public Health, Columbia University, New York, New York
| | - Katherine D Crew
- Division of Hematology and Oncology, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, New York.,Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, New York.,Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, New York
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