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1
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Kavazis C, Ekmektzoglou A, Kokolakis A, Liappis T, Douganiotis G, Natsiopoulos I. The role of PIK3CA mutation in lobular breast cancer in the era of precision oncology - a systematic review. Crit Rev Oncol Hematol 2025:104805. [PMID: 40513789 DOI: 10.1016/j.critrevonc.2025.104805] [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: 02/28/2025] [Revised: 06/06/2025] [Accepted: 06/06/2025] [Indexed: 06/16/2025] Open
Abstract
BACKGROUND Ιnvasive lobular carcinoma (ILC) is a distinct subtype of breast cancer with unique clinical and molecular features. Although ILC generally responds to endocrine therapy, it tends to exhibit lower chemotherapy sensitivity, underscoring the need for tailored therapeutic approaches. PIK3CA mutations are frequently observed in ILC. This systematic review evaluates the prevalence of PIK3CA mutations in ILC and examines their prognostic and predictive significance. METHODS We searched PubMed and Scopus for studies reporting PIK3CA mutations in lobular breast cancer. Inclusion criteria encompassed studies on stage I-III ILC examining mutation frequency, prognosis, or predictive value. Data on mutation prevalence in ILC (and comparisons to invasive ductal carcinoma, IDC) and associated outcomes were extracted. Meta-analyses were performed with assessment of heterogeneity and publication bias. RESULTS Ten relevant studies (nine cohorts) were included. The prevalence of PIK3CA mutations in ILC ranged from ~30% to ~50%. Statistic analysis showed that nearly half of ILCs harbor PIK3CA mutations. Mutation rates in ILC were generally higher than in IDC. No significant association between PIK3CA mutation status and patient prognosis was observed in the available studies. There were limited data ontreatment response. CONCLUSIONS PIK3CA is a commonly mutated gene in ILC, but current evidence does not demonstrate a clear impact on prognosis or definite predictive value for therapy response in this subtype. Nonetheless, the high mutation frequency provides a rationale for targeted therapeutic approaches. PIK3CA testing may be considered in advanced ILC to identify candidates for PI3K inhibitor therapy, although further research is needed.
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Affiliation(s)
| | | | | | - Triantafyllos Liappis
- Department of Breast Surgery, Interbalkan European Medical Center, Thessaloniki, Greece
| | | | - Ioannis Natsiopoulos
- Department of Breast Surgery, Interbalkan European Medical Center, Thessaloniki, Greece
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2
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Singh R, Patel K, Xu H, Adeniyi A, Upshaw JN, Van Buren P, Kaufman PA, Dittus K, Landry KK. Cardio-Oncology and Breast Cancer Therapies. Curr Treat Options Oncol 2025; 26:385-397. [PMID: 40257669 DOI: 10.1007/s11864-025-01311-x] [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] [Accepted: 03/17/2025] [Indexed: 04/22/2025]
Abstract
OPINION STATEMENT Assessing cardiac risk prior to initiating breast cancer treatment, monitoring cardiac function during treatment, and implementing appropriate follow-up strategies are essential components of managing cardiotoxicity in breast cancer patients. A comprehensive cardiovascular evaluation should be conducted before treatment, including a detailed medical history, physical examination, and baseline cardiac imaging. Risk stratification tools can aid in determining the individual patient's risk profile. Close monitoring of cardiac function, including regular assessment of left ventricular ejection fraction (LVEF) and monitoring for signs and symptoms of cardiac dysfunction, is crucial during treatment. Prompt action should be taken if an adverse cardiovascular event is detected, including considering discontinuing or modifying the treatment regimen. Appropriate follow-up care is essential to monitor for long-term cardiac effects and optimize cardiovascular health in breast cancer survivors. Regular cardiovascular assessments, lifestyle modifications, and collaboration between healthcare professionals are important in managing cardiotoxicity effectively.
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Affiliation(s)
- Rohit Singh
- Division of Hematology/Oncology, Department of Medicine, Larner College of Medicine, University of Vermont, Burlington, VT, USA
- University of Vermont Cancer Center, Burlington, VT, USA
| | - Krina Patel
- Division of Cardiology, Department of Medicine, Tufts Medical Center, Boston, MA, USA
| | - Haze Xu
- Division of Hematology/Oncology, Department of Medicine, Larner College of Medicine, University of Vermont, Burlington, VT, USA
- University of Vermont Cancer Center, Burlington, VT, USA
| | - Aderonke Adeniyi
- Division of Cardiology, Department of Medicine, Wake Forest Baptist Medical Center, Winston-Salem, NC, USA
| | - Jenica N Upshaw
- Division of Cardiology, Department of Medicine, Tufts Medical Center, Boston, MA, USA
| | - Peter Van Buren
- Division of Cardiology, Department of Medicine, Larner College of Medicine, University of Vermont, Burlington, VT, USA
| | - Peter A Kaufman
- Division of Hematology/Oncology, Department of Medicine, Larner College of Medicine, University of Vermont, Burlington, VT, USA
- University of Vermont Cancer Center, Burlington, VT, USA
| | - Kim Dittus
- Division of Hematology/Oncology, Department of Medicine, University of Wisconsin, Madison, WI, USA
| | - Kara K Landry
- Division of Hematology/Oncology, Department of Medicine, Larner College of Medicine, University of Vermont, Burlington, VT, USA.
- University of Vermont Cancer Center, Burlington, VT, USA.
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Panda VK, Mishra B, Mahapatra S, Swain B, Malhotra D, Saha S, Khanra S, Mishra P, Majhi S, Kumari K, Nath AN, Saha S, Jena S, Kundu GC. Molecular Insights on Signaling Cascades in Breast Cancer: A Comprehensive Review. Cancers (Basel) 2025; 17:234. [PMID: 39858015 PMCID: PMC11763662 DOI: 10.3390/cancers17020234] [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: 11/22/2024] [Revised: 12/27/2024] [Accepted: 01/01/2025] [Indexed: 01/27/2025] Open
Abstract
The complex signaling network within the breast tumor microenvironment is crucial for its growth, metastasis, angiogenesis, therapy escape, stem cell maintenance, and immunomodulation. An array of secretory factors and their receptors activate downstream signaling cascades regulating breast cancer progression and metastasis. Among various signaling pathways, the EGFR, ER, Notch, and Hedgehog signaling pathways have recently been identified as crucial in terms of breast cancer proliferation, survival, differentiation, maintenance of CSCs, and therapy failure. These receptors mediate various downstream signaling pathways such as MAPK, including MEK/ERK signaling pathways that promote common pro-oncogenic signaling, whereas dysregulation of PI3K/Akt, Wnt/β-catenin, and JAK/STAT activates key oncogenic events such as drug resistance, CSC enrichment, and metabolic reprogramming. Additionally, these cascades orchestrate an intricate interplay between stromal cells, immune cells, and tumor cells. Metabolic reprogramming and adaptations contribute to aggressive breast cancer and are unresponsive to therapy. Herein, recent insights into the novel signaling pathways operating within the breast TME that aid in their advancement are emphasized and current developments in practices targeting the breast TME to enhance treatment efficacy are reviewed.
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Affiliation(s)
- Venketesh K. Panda
- School of Biotechnology, KIIT Deemed to Be University, Bhubaneswar 751024, India; (V.K.P.); (B.M.); (S.M.); (B.S.); (D.M.); (S.S.); (S.K.); (P.M.); (S.M.); (K.K.); (A.N.N.); (S.S.); (S.J.)
- School of Applied Sciences, KIIT Deemed to Be University, Bhubaneswar 751024, India
| | - Barnalee Mishra
- School of Biotechnology, KIIT Deemed to Be University, Bhubaneswar 751024, India; (V.K.P.); (B.M.); (S.M.); (B.S.); (D.M.); (S.S.); (S.K.); (P.M.); (S.M.); (K.K.); (A.N.N.); (S.S.); (S.J.)
| | - Samikshya Mahapatra
- School of Biotechnology, KIIT Deemed to Be University, Bhubaneswar 751024, India; (V.K.P.); (B.M.); (S.M.); (B.S.); (D.M.); (S.S.); (S.K.); (P.M.); (S.M.); (K.K.); (A.N.N.); (S.S.); (S.J.)
| | - Biswajit Swain
- School of Biotechnology, KIIT Deemed to Be University, Bhubaneswar 751024, India; (V.K.P.); (B.M.); (S.M.); (B.S.); (D.M.); (S.S.); (S.K.); (P.M.); (S.M.); (K.K.); (A.N.N.); (S.S.); (S.J.)
| | - Diksha Malhotra
- School of Biotechnology, KIIT Deemed to Be University, Bhubaneswar 751024, India; (V.K.P.); (B.M.); (S.M.); (B.S.); (D.M.); (S.S.); (S.K.); (P.M.); (S.M.); (K.K.); (A.N.N.); (S.S.); (S.J.)
| | - Suryendu Saha
- School of Biotechnology, KIIT Deemed to Be University, Bhubaneswar 751024, India; (V.K.P.); (B.M.); (S.M.); (B.S.); (D.M.); (S.S.); (S.K.); (P.M.); (S.M.); (K.K.); (A.N.N.); (S.S.); (S.J.)
| | - Sinjan Khanra
- School of Biotechnology, KIIT Deemed to Be University, Bhubaneswar 751024, India; (V.K.P.); (B.M.); (S.M.); (B.S.); (D.M.); (S.S.); (S.K.); (P.M.); (S.M.); (K.K.); (A.N.N.); (S.S.); (S.J.)
| | - Priyanka Mishra
- School of Biotechnology, KIIT Deemed to Be University, Bhubaneswar 751024, India; (V.K.P.); (B.M.); (S.M.); (B.S.); (D.M.); (S.S.); (S.K.); (P.M.); (S.M.); (K.K.); (A.N.N.); (S.S.); (S.J.)
| | - Sambhunath Majhi
- School of Biotechnology, KIIT Deemed to Be University, Bhubaneswar 751024, India; (V.K.P.); (B.M.); (S.M.); (B.S.); (D.M.); (S.S.); (S.K.); (P.M.); (S.M.); (K.K.); (A.N.N.); (S.S.); (S.J.)
| | - Kavita Kumari
- School of Biotechnology, KIIT Deemed to Be University, Bhubaneswar 751024, India; (V.K.P.); (B.M.); (S.M.); (B.S.); (D.M.); (S.S.); (S.K.); (P.M.); (S.M.); (K.K.); (A.N.N.); (S.S.); (S.J.)
| | - Angitha N. Nath
- School of Biotechnology, KIIT Deemed to Be University, Bhubaneswar 751024, India; (V.K.P.); (B.M.); (S.M.); (B.S.); (D.M.); (S.S.); (S.K.); (P.M.); (S.M.); (K.K.); (A.N.N.); (S.S.); (S.J.)
| | - Swarnali Saha
- School of Biotechnology, KIIT Deemed to Be University, Bhubaneswar 751024, India; (V.K.P.); (B.M.); (S.M.); (B.S.); (D.M.); (S.S.); (S.K.); (P.M.); (S.M.); (K.K.); (A.N.N.); (S.S.); (S.J.)
| | - Sarmistha Jena
- School of Biotechnology, KIIT Deemed to Be University, Bhubaneswar 751024, India; (V.K.P.); (B.M.); (S.M.); (B.S.); (D.M.); (S.S.); (S.K.); (P.M.); (S.M.); (K.K.); (A.N.N.); (S.S.); (S.J.)
| | - Gopal C. Kundu
- School of Biotechnology, KIIT Deemed to Be University, Bhubaneswar 751024, India; (V.K.P.); (B.M.); (S.M.); (B.S.); (D.M.); (S.S.); (S.K.); (P.M.); (S.M.); (K.K.); (A.N.N.); (S.S.); (S.J.)
- School of Applied Sciences, KIIT Deemed to Be University, Bhubaneswar 751024, India
- Kalinga Institute of Medical Sciences (KIMS), KIIT Deemed to Be University, Bhubaneswar 751024, India
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Liao Y, Tan Y, Li Y, Ma F, Wang J, Zhang P, Li Q, Li Q, Luo Y, Lan B, Chen S, Xu B, Jiang H, Zhao W, Fan Y. The different sequences of CDK4/6 inhibitor and mTOR inhibitor in HR+/HER2-advanced breast cancer: A multicenter real-world study. Heliyon 2024; 10:e38147. [PMID: 39386840 PMCID: PMC11462034 DOI: 10.1016/j.heliyon.2024.e38147] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Revised: 09/09/2024] [Accepted: 09/18/2024] [Indexed: 10/12/2024] Open
Abstract
Background Cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) and everolimus (EVE) are effective for patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC). However, the efficacy of different sequences of CDK4/6i and EVE are largely unknown. The study aimed to explore the efficacy of different sequences in China. Methods 146 patients with HR+/HER2- MBC who received both CDK4/6i and EVE in salvage setting were collected. Objective response rate (ORR), clinical benefit rate (CBR), progression-free survival (PFS), and overall survival (OS) were investigated. Results 56 patients received CDK4/6i prior to EVE (Group A), 90 patients received CDK4/6i subsequent to EVE (Group B). The median PFS of CDK4/6i and EVE in Group A vs Group B were 8.4m and 2.5m vs 4.6m and 6.1m respectively. The total PFS of first-line and second-line endocrine therapy were not different between Group A and Group B [13.1m vs 17.7m (P = 0.330, HR = 0.738, 95%CI: 0.399-1.365)]. The 5y OS of patients in Group A or Group B were 62.0 % vs 57.4 %, P = 0.569. Conclusions We found that no matter CDK4/6i or EVE was used first, the survival were not significantly different between Group A and Group B. Both can be clinical options.
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Affiliation(s)
- Yuqian Liao
- Department of Oncology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi Province, 330006, China
| | - Yujing Tan
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Yipeng Li
- Department of Medical Oncology, People's Hospital of DengFeng City, Zhengzhou, Henan Province, 452470, China
| | - Fei Ma
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Jiayu Wang
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Pin Zhang
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Qing Li
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Qiao Li
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Yang Luo
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Bo Lan
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Shanshan Chen
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Binghe Xu
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Hanfang Jiang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Breast Oncology, Peking University Cancer Hospital & Institute, Beijing, 100142,China
| | - Weihong Zhao
- Department of Medical Oncology, Chinese PLA General Hospital, Beijing, 100853, China
| | - Ying Fan
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
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Rubovszky G. The role of everolimus in metastatic breast cancer and possibilities of moving forward-a narrative review. ANNALS OF TRANSLATIONAL MEDICINE 2024; 12:68. [PMID: 39118946 PMCID: PMC11304436 DOI: 10.21037/atm-23-1583] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Accepted: 09/17/2023] [Indexed: 08/10/2024]
Abstract
Background and Objective In hormone-receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer endocrine-based therapies are preferred over chemotherapy. One of the treatment options is the combination of everolimus with exemestane or other endocrine drug in later lines mainly based on progression-free survival (PFS) results of the phase 3 BOLERO-2 trial. Altogether, clinical trials did not prove an overall survival (OS) benefit and considerable side effects hampered its application in the day-by-day practice. In recent years CDK4/6-inhibitors became a first-choice combination partner to the endocrine treatment, everolimus still has a place within the treatment armamentarium. Although everolimus is a targeted drug, there is no accepted predictive biomarker and further patient selection is not possible. However, several directions can be defined how to optimally use everolimus. For update information on everolimus treatment in breast cancer I have performed a literature search. Methods I used the keywords "breast cancer" and "everolimus" and extended the search in PubMed from 01/01/2014 to 10/02/2023. I considered all phase 3 trials, the phase 1-2 trials with not repetitive information, studies with biomarker results and I also checked review articles to identify potential relevant other clinical trial reports. I also have made a search in clinicaltrials.gov for recently completed and ongoing trials. Key Content and Findings I summarized the search results in this concise and brief report focusing on main trial results and ongoing research with everolimus. Conclusions The most promising research directions seem to be further investigations for useable predictive biomarkers, for combinations with other targeted drugs (even in a triple combination) and for the feasibility of pharmacologically guided dosing method.
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Affiliation(s)
- Gabor Rubovszky
- Department of Thoracic and Abdominal Tumors and Clinical Pharmacology and the National Tumor Biology Laboratory, National Institute of Oncology, Budapest, Hungary
- Department of Oncology, Semmelweis University, Budapest, Hungary
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De-Leon-Covarrubias UE, Perez-Trujillo JJ, Villa-Cedillo SA, Martinez-Perez AG, Montes-de-Oca-Saucedo CR, Loera-Arias MDJ, Garcia-Garcia A, Saucedo-Cardenas O, Montes-de-Oca-Luna R. Unlocking the Potential: Caloric Restriction, Caloric Restriction Mimetics, and Their Impact on Cancer Prevention and Treatment. Metabolites 2024; 14:418. [PMID: 39195514 DOI: 10.3390/metabo14080418] [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: 06/25/2024] [Revised: 07/16/2024] [Accepted: 07/17/2024] [Indexed: 08/29/2024] Open
Abstract
Caloric restriction (CR) and its related alternatives have been shown to be the only interventions capable of extending lifespan and decreasing the risk of cancer, along with a reduction in burden in pre-clinical trials. Nevertheless, the results from clinical trials have not been as conclusive as the pre-clinical results. Recognizing the challenges associated with long-term fasting, the application of caloric restriction mimetics (CRMs), pharmacological agents that mimic the molecular effects of CR, to harness the potential benefits while overcoming the practical limitations of fasting has resulted in an interesting alternative. This review synthesizes the findings of diverse clinical trials evaluating the safety and efficacy of CR and CRMs. In dietary interventions, a fast-mimicking diet was the most tolerated to reduce tumoral growth markers and chemotherapy side effects. CRMs were well tolerated, and metformin and aspirin showed the most promising effect in reducing cancer risk in a selected group of patients. The application of CR and/or CRMs shows promising effects in anti-cancer therapy; however, there is a need for more evidence to safely include these interventions in standard-of-care therapies.
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Affiliation(s)
| | - Jose Juan Perez-Trujillo
- Histology Department, Faculty of Medicine, Universidad Autonoma de Nuevo Leon (UANL), Monterrey 64460, Mexico
| | - Sheila Adela Villa-Cedillo
- Histology Department, Faculty of Medicine, Universidad Autonoma de Nuevo Leon (UANL), Monterrey 64460, Mexico
| | | | | | - Maria de Jesus Loera-Arias
- Histology Department, Faculty of Medicine, Universidad Autonoma de Nuevo Leon (UANL), Monterrey 64460, Mexico
| | - Aracely Garcia-Garcia
- Histology Department, Faculty of Medicine, Universidad Autonoma de Nuevo Leon (UANL), Monterrey 64460, Mexico
| | - Odila Saucedo-Cardenas
- Histology Department, Faculty of Medicine, Universidad Autonoma de Nuevo Leon (UANL), Monterrey 64460, Mexico
| | - Roberto Montes-de-Oca-Luna
- Histology Department, Faculty of Medicine, Universidad Autonoma de Nuevo Leon (UANL), Monterrey 64460, Mexico
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7
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Zhang HP, Jiang RY, Zhu JY, Sun KN, Huang Y, Zhou HH, Zheng YB, Wang XJ. PI3K/AKT/mTOR signaling pathway: an important driver and therapeutic target in triple-negative breast cancer. Breast Cancer 2024; 31:539-551. [PMID: 38630392 PMCID: PMC11194209 DOI: 10.1007/s12282-024-01567-5] [Citation(s) in RCA: 37] [Impact Index Per Article: 37.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2023] [Accepted: 03/10/2024] [Indexed: 06/24/2024]
Abstract
Triple-negative breast cancer (TNBC) is a highly heterogeneous tumor lacking estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression. It has higher aggressiveness and metastasis than other subtypes, with limited effective therapeutic strategies, leading to a poor prognosis. The phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mechanistic target of rapamycin (mTOR) signaling pathway is prevalently over-activated in human cancers and contributes to breast cancer (BC) growth, survival, proliferation, and angiogenesis, which could be an interesting therapeutic target. This review summarizes the PI3K/AKT/mTOR signaling pathway activation mechanism in TNBC and discusses the relationship between its activation and various TNBC subtypes. We also report the latest clinical studies on kinase inhibitors related to this pathway for treating TNBC. Our review discusses the issues that need to be addressed in the clinical application of these inhibitors.
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Affiliation(s)
- Huan-Ping Zhang
- Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310000, Zhejiang, China
- Wenzhou Medical University, No. 270, Xueyuan West Road, Lucheng District, Wenzhou, 325027, Zhejiang, China
| | - Rui-Yuan Jiang
- Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310000, Zhejiang, China
- Zhejiang Chinese Medical University, No. 548, Binwen Road, Binjiang District, Hangzhou, 310000, Zhejiang, China
| | - Jia-Yu Zhu
- Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310000, Zhejiang, China
- Zhejiang Chinese Medical University, No. 548, Binwen Road, Binjiang District, Hangzhou, 310000, Zhejiang, China
| | - Ke-Na Sun
- Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310000, Zhejiang, China
- Wenzhou Medical University, No. 270, Xueyuan West Road, Lucheng District, Wenzhou, 325027, Zhejiang, China
| | - Yuan Huang
- Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310000, Zhejiang, China
| | - Huan-Huan Zhou
- Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310000, Zhejiang, China
| | - Ya-Bing Zheng
- Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310000, Zhejiang, China.
| | - Xiao-Jia Wang
- Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310000, Zhejiang, China.
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8
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Guidelines for diagnosis and treatment of advanced breast cancer in China (2022 edition). JOURNAL OF THE NATIONAL CANCER CENTER 2024; 4:107-127. [PMID: 39282589 PMCID: PMC11390704 DOI: 10.1016/j.jncc.2023.12.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Revised: 12/06/2023] [Accepted: 12/06/2023] [Indexed: 09/19/2024] Open
Abstract
Breast cancer is the most common cancer among women worldwide. It has been estimated that about 416 000 new cases and over 117 000 deaths of breast cancer occurred in China in 2020. Among the new cases of breast cancer diagnosed each year, 3-10% have distant metastasis at the time of initial diagnosis. In addition, approximately 30% of patients with early-stage breast cancer may eventually experience recurrence or metastases. The 5-year survival rate of patients with advanced breast cancer is only 20% with a median overall survival of 2-3 years. Although advanced breast cancer remains incurable at present, new therapeutic options and multidisciplinary treatment could be utilized to alleviate symptoms, improve quality of life, and prolong patients' survival. The choice of treatment regimens for patients with advanced breast cancer is very important, and the optimal treatment strategy beyond the first- and second-line therapy is often lacking. Herein, the China Advanced Breast Cancer Guideline Panel discussed and summarized recent clinical evidence, updated the guidelines for the diagnosis and treatment of advanced breast cancer based on the 2020 edition, and formulated the "Guidelines for diagnosis and treatment of advanced breast cancer in China (2022 edition)" for clinicians' reference.
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9
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Duan XP, Qin BD, Jiao XD, Liu K, Wang Z, Zang YS. New clinical trial design in precision medicine: discovery, development and direction. Signal Transduct Target Ther 2024; 9:57. [PMID: 38438349 PMCID: PMC10912713 DOI: 10.1038/s41392-024-01760-0] [Citation(s) in RCA: 52] [Impact Index Per Article: 52.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Revised: 01/25/2024] [Accepted: 01/29/2024] [Indexed: 03/06/2024] Open
Abstract
In the era of precision medicine, it has been increasingly recognized that individuals with a certain disease are complex and different from each other. Due to the underestimation of the significant heterogeneity across participants in traditional "one-size-fits-all" trials, patient-centered trials that could provide optimal therapy customization to individuals with specific biomarkers were developed including the basket, umbrella, and platform trial designs under the master protocol framework. In recent years, the successive FDA approval of indications based on biomarker-guided master protocol designs has demonstrated that these new clinical trials are ushering in tremendous opportunities. Despite the rapid increase in the number of basket, umbrella, and platform trials, the current clinical and research understanding of these new trial designs, as compared with traditional trial designs, remains limited. The majority of the research focuses on methodologies, and there is a lack of in-depth insight concerning the underlying biological logic of these new clinical trial designs. Therefore, we provide this comprehensive review of the discovery and development of basket, umbrella, and platform trials and their underlying logic from the perspective of precision medicine. Meanwhile, we discuss future directions on the potential development of these new clinical design in view of the "Precision Pro", "Dynamic Precision", and "Intelligent Precision". This review would assist trial-related researchers to enhance the innovation and feasibility of clinical trial designs by expounding the underlying logic, which be essential to accelerate the progression of precision medicine.
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Affiliation(s)
- Xiao-Peng Duan
- Department of Medical Oncology, Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Bao-Dong Qin
- Department of Medical Oncology, Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Xiao-Dong Jiao
- Department of Medical Oncology, Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Ke Liu
- Department of Medical Oncology, Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Zhan Wang
- Department of Medical Oncology, Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Yuan-Sheng Zang
- Department of Medical Oncology, Changzheng Hospital, Naval Medical University, Shanghai, China.
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10
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Sun Y, Cheng J, Nie D, Fang Q, Li C, Zhang Y. Metformin inhibits cell proliferation and ACTH secretion in AtT20 cells via regulating the MAPK pathway. Mol Cell Endocrinol 2024; 582:112140. [PMID: 38147953 DOI: 10.1016/j.mce.2023.112140] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2023] [Revised: 12/17/2023] [Accepted: 12/19/2023] [Indexed: 12/28/2023]
Abstract
We investigated the impact of metformin on ACTH secretion and tumorigenesis in pituitary corticotroph tumors. The mouse pituitary tumor AtT20 cell line was treated with varying concentrations of metformin. Cell viability was assessed using the CCK-8 assay, ACTH secretion was measured using an ELISA kit, changes in the cell cycle were analyzed using flow cytometry, and the expression of related proteins was evaluated using western blotting. RNA sequencing was performed on metformin-treated cells. Additionally, an in vivo BALB/c nude xenograft tumor model was established in nude mice, and immunohistochemical staining was conducted for further verification. Following metformin treatment, cell proliferation was inhibited, ACTH secretion decreased, and G1/S phase arrest occurred. Analysis of differentially expressed genes revealed cancer-related pathways, including the MAPK pathway. Western blotting confirmed a decrease in phosphorylated ERK1/2 and phosphorylated JNK. Combining metformin with the ERK1/2 inhibitor Ulixertinib resulted in a stronger inhibitory effect on cell proliferation and POMC (Precursors of ACTH) expression. In vivo studies confirmed that metformin inhibited tumor growth and reduced ACTH secretion. In conclusion, metformin inhibits tumor progression and ACTH secretion, potentially through suppression of the MAPK pathway in AtT20 cell lines. These findings suggest metformin as a potential drug for the treatment of Cushing's disease.
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Affiliation(s)
- Yingxuan Sun
- Beijing Neurosurgical Institute, Capital Medical University, Beijing, China
| | - Jianhua Cheng
- Beijing Neurosurgical Institute, Capital Medical University, Beijing, China
| | - Ding Nie
- Beijing Neurosurgical Institute, Capital Medical University, Beijing, China
| | - Qiuyue Fang
- Beijing Neurosurgical Institute, Capital Medical University, Beijing, China
| | - Chuzhong Li
- Beijing Neurosurgical Institute, Capital Medical University, Beijing, China.
| | - Yazhuo Zhang
- Beijing Neurosurgical Institute, Capital Medical University, Beijing, China; Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
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11
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Cao LQ, Sun H, Xie Y, Patel H, Bo L, Lin H, Chen ZS. Therapeutic evolution in HR+/HER2- breast cancer: from targeted therapy to endocrine therapy. Front Pharmacol 2024; 15:1340764. [PMID: 38327984 PMCID: PMC10847323 DOI: 10.3389/fphar.2024.1340764] [Citation(s) in RCA: 13] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2023] [Accepted: 01/08/2024] [Indexed: 02/09/2024] Open
Abstract
Breast cancer, a complex and varied disease, has four distinct subtypes based on estrogen receptor and human epidermal growth factor receptor 2 (HER2) levels, among which a significant subtype known as HR+/HER2-breast cancer that has spurred numerous research. The prevalence of breast cancer and breast cancer-related death are the most serious threats to women's health worldwide. Current progress in treatment strategies for HR+/HER2-breast cancer encompasses targeted therapy, endocrine therapy, genomic immunotherapy, and supplementing traditional methods like surgical resection and radiotherapy. This review article summarizes the current epidemiology of HR+/HER2-breast cancer, introduces the classification of HR+/HER2-breast cancer and the commonly used treatment methods. The mechanisms of action of various drugs, including targeted therapy drugs and endocrine hormone therapy drugs, and their potential synergistic effects are deeply discussed. In addition, clinical trials of these drugs that have been completed or are still in progress are included.
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Affiliation(s)
- Lu-Qi Cao
- Institute for Biotechnology, St. John’s University, Queens, NY, United States
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John’s University, Queens, NY, United States
| | - Haidong Sun
- Shenzhen Hospital (Futian) of Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Yuhao Xie
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John’s University, Queens, NY, United States
| | - Harsh Patel
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John’s University, Queens, NY, United States
| | - Letao Bo
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John’s University, Queens, NY, United States
| | - Hanli Lin
- Shenzhen Hospital (Futian) of Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Zhe-Sheng Chen
- Institute for Biotechnology, St. John’s University, Queens, NY, United States
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John’s University, Queens, NY, United States
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12
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Nelson ED, Benesch MGK, Wu R, Ishikawa T, Takabe K. High EIF4EBP1 expression reflects mTOR pathway activity and cancer cell proliferation and is a biomarker for poor breast cancer prognosis. Am J Cancer Res 2024; 14:227-242. [PMID: 38323277 PMCID: PMC10839327] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2023] [Accepted: 12/21/2023] [Indexed: 02/08/2024] Open
Abstract
Eukaryotic translation initiation factor 4E binding protein 1 (EIF4EBP1) is regulated by the mTOR (mammalian target of rapamycin) signaling pathway. Phosphorylated EIF4EBP1 protein leads to pathway activation and correlates with aggressive breast cancer features. However, the clinical relevance of EIF4EBP1 gene expression as a prognostic biomarker in bulk breast tumors is not understood. In this study, EIF4EBP1 expression was analyzed in over 5000 breast cancers from three large independent cohorts, TCGA, METABRIC, and SCAN-B (GSE96058), and expression was dichotomized into low and high groups by the median. We also performed gene set enrichment analysis (GSEA) and cell cybersorting via the xCell algorithm to investigate EIF4EBP1 biology and expression patterns within the tumor microenvironment (TME). We additionally confirmed EIF4EBP1 expression location in the TME via single cell RNA sequencing. EIF4EBP1 expression was highest in both triple negative and high-grade tumors (both P<0.001), and tumor mutational burden scores were highest in the high EIF4EBP1-expression groups (all P<0.001). High EIF4EBP1 expression significantly correlated to worse overall survival in all three cohorts (hazard ratios (HR) 1.4-1.9), and worse distant relapse-free survival in patients treated with neoadjuvant taxane-anthracycline chemotherapy (HR 2.4). GSEA demonstrated enriched mTOR and cell proliferation-related gene sets, including, MYC, G2M checkpoint, and E2F targets across all three bulk tumor and single cell RNA sequencing cohorts. Phenotypically, these pathways were reflected by increased Ki67 gene expression and signaling via pharmacologically-activated mTOR gene sets in EIF4EBP1 high-expressing tumors (all P<0.001). EIF4EBP1 expression was increased in whole breast tumors compared to normal breast tissue (P<0.001), and was expressed predominantly in cancer epithelial cells, particularly in basal epithelial cell subclasses. EIF4EBP1 expression did not correlate to a consistent immune system phenotype across all three cohorts. Overall, these findings support that high EIF4EBP1 gene expression in bulk breast tumors could represent a poor prognostic marker via mTOR signaling pathways activation and upregulation of cell cycling, ultimately leading to increased tumorigenesis.
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Affiliation(s)
- Erek D Nelson
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer CenterBuffalo, NY 14263, USA
| | - Matthew GK Benesch
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer CenterBuffalo, NY 14263, USA
| | - Rongrong Wu
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer CenterBuffalo, NY 14263, USA
- Department of Breast Surgery and Oncology, Tokyo Medical UniversityTokyo 160-8402, Japan
| | - Takashi Ishikawa
- Department of Breast Surgery and Oncology, Tokyo Medical UniversityTokyo 160-8402, Japan
| | - Kazuaki Takabe
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer CenterBuffalo, NY 14263, USA
- Department of Breast Surgery and Oncology, Tokyo Medical UniversityTokyo 160-8402, Japan
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of MedicineYokohama 236-0004, Japan
- Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental SciencesNiigata 951-8520, Japan
- Department of Breast Surgery, Fukushima Medical University School of MedicineFukushima 960-1295, Japan
- Department of Surgery, University at Buffalo Jacobs School of Medicine and Biomedical Sciences, State University of New YorkBuffalo, NY 14263, USA
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13
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Gou X, Kim BJ, Anurag M, Lei JT, Young MN, Holt MV, Fandino D, Vollert CT, Singh P, Alzubi MA, Malovannaya A, Dobrolecki LE, Lewis MT, Li S, Foulds CE, Ellis MJ. Kinome Reprogramming Is a Targetable Vulnerability in ESR1 Fusion-Driven Breast Cancer. Cancer Res 2023; 83:3237-3251. [PMID: 37071495 PMCID: PMC10543968 DOI: 10.1158/0008-5472.can-22-3484] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Revised: 02/20/2023] [Accepted: 04/12/2023] [Indexed: 04/19/2023]
Abstract
Transcriptionally active ESR1 fusions (ESR1-TAF) are a potent cause of breast cancer endocrine therapy (ET) resistance. ESR1-TAFs are not directly druggable because the C-terminal estrogen/anti-estrogen-binding domain is replaced with translocated in-frame partner gene sequences that confer constitutive transactivation. To discover alternative treatments, a mass spectrometry (MS)-based kinase inhibitor pulldown assay (KIPA) was deployed to identify druggable kinases that are upregulated by diverse ESR1-TAFs. Subsequent explorations of drug sensitivity validated RET kinase as a common therapeutic vulnerability despite remarkable ESR1-TAF C-terminal sequence and structural diversity. Organoids and xenografts from a pan-ET-resistant patient-derived xenograft model that harbors the ESR1-e6>YAP1 TAF were concordantly inhibited by the selective RET inhibitor pralsetinib to a similar extent as the CDK4/6 inhibitor palbociclib. Together, these findings provide preclinical rationale for clinical evaluation of RET inhibition for the treatment of ESR1-TAF-driven ET-resistant breast cancer. SIGNIFICANCE Kinome analysis of ESR1 translocated and mutated breast tumors using drug bead-based mass spectrometry followed by drug-sensitivity studies nominates RET as a therapeutic target. See related commentary by Wu and Subbiah, p. 3159.
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Affiliation(s)
- Xuxu Gou
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas
- Graduate Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston Texas
- UCSF Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California
| | - Beom-Jun Kim
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas
- Department of Medicine, Baylor College of Medicine, Houston, Texas
| | - Meenakshi Anurag
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas
- Department of Medicine, Baylor College of Medicine, Houston, Texas
| | - Jonathan T. Lei
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas
- Department of Human and Molecular Genetics, Baylor College of Medicine, Houston, Texas
| | - Meggie N. Young
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas
- Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas
| | - Matthew V. Holt
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas
| | - Diana Fandino
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas
| | - Craig T. Vollert
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas
- Employee of Adrienne Helis Malvin Medical Research Foundation, New Orleans, Los Angeles
| | - Purba Singh
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas
| | - Mohammad A. Alzubi
- Employee of Adrienne Helis Malvin Medical Research Foundation, New Orleans, Los Angeles
| | - Anna Malovannaya
- Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas
| | - Lacey E. Dobrolecki
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas
| | - Michael T. Lewis
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas
- Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas
- Department of Radiology, Baylor College of Medicine, Houston, Texas
| | - Shunqiang Li
- Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri
| | - Charles E. Foulds
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas
- Department of Medicine, Baylor College of Medicine, Houston, Texas
- Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas
| | - Matthew J. Ellis
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas
- Graduate Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston Texas
- Department of Medicine, Baylor College of Medicine, Houston, Texas
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas
- Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas
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14
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Wen J, Yi Z, Chen Y, Huang J, Mao X, Zhang L, Zeng Y, Cheng Q, Ye W, Liu Z, Liu F, Liu J. Efficacy of metformin therapy in patients with cancer: a meta-analysis of 22 randomised controlled trials. BMC Med 2022; 20:402. [PMID: 36280839 PMCID: PMC9594974 DOI: 10.1186/s12916-022-02599-4] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Accepted: 10/10/2022] [Indexed: 11/30/2022] Open
Abstract
BACKGROUND To investigate whether metformin monotherapy or adjunctive therapy improves the prognosis in patients with any type of cancer compared to non-metformin users (age ≥18). METHODS Databases (Medline, Embase, and the Cochrane Central Register of Controlled Trials) and clinical trial registries ( ClinicalTrials.gov ; the World Health Organization International Clinical Trials Registry Platform) were screened for randomized, controlled trials (RCT) reporting at least progression-free survival (PFS) and/or overall survival (OS). Main outcome measures included hazard ratios (HR), and combined HRs and 95% confidence intervals (CI) were calculated using random-effects models. RESULTS Of the 8419 records screened, 22 RCTs comprising 5943 participants were included. Pooled HRs were not statistically significant in both PFS (HR 0.97, 95% CI 0.82-1.15, I2 = 50%) and OS (HR 0.98, 95% CI 0.86-1.13, I2 = 33%) for patients with cancer between the metformin and control groups. Subgroup analyses demonstrated that metformin treatment was associated with a marginally significant improvement in PFS in reproductive system cancers (HR 0.86, 95% CI 0.74-1.00) and a significantly worse PFS in digestive system cancers (HR 1.45, 95% CI 1.03-2.04). The PFS or OS was observed consistently across maintenance dose, diabetes exclusion, median follow-up, risk of bias, and combined antitumoral therapies. CONCLUSION Metformin treatment was not associated with cancer-related mortality in adults compared with placebo or no treatment. However, metformin implied beneficial effects in the PFS of the patients with reproductive system cancers but was related to a worse PFS in digestive system cancers. SYSTEMATIC REVIEW REGISTRATION PROSPERO registration number CRD42022324672.
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Affiliation(s)
- Jie Wen
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan, China.,Hypothalamic Pituitary Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Zhenjie Yi
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan, China.,Hypothalamic Pituitary Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Yuyao Chen
- Department of Epidemiology and Health Statistics, Xiangya School of Public Health, Central South University, Changsha, Hunan, China
| | - Jing Huang
- National Clinical Research Center for Mental Disorders and Department of Psychiatry, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Xueyi Mao
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Liyang Zhang
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan, China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Yu Zeng
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan, China.,Hypothalamic Pituitary Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Quan Cheng
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan, China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Wenrui Ye
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan, China.,Hypothalamic Pituitary Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Zhixiong Liu
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan, China.,Hypothalamic Pituitary Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Fangkun Liu
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan, China. .,Hypothalamic Pituitary Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, China.
| | - Jingfang Liu
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan, China. .,Hypothalamic Pituitary Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, China.
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15
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Curtaz CJ, Kiesel L, Meybohm P, Wöckel A, Burek M. Anti-Hormonal Therapy in Breast Cancer and Its Effect on the Blood-Brain Barrier. Cancers (Basel) 2022; 14:cancers14205132. [PMID: 36291916 PMCID: PMC9599962 DOI: 10.3390/cancers14205132] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2022] [Revised: 10/17/2022] [Accepted: 10/18/2022] [Indexed: 11/16/2022] Open
Abstract
The molecular receptor status of breast cancer has implications for prognosis and long-term metastasis. Although metastatic luminal B-like, hormone-receptor-positive, HER2−negative, breast cancer causes brain metastases less frequently than other subtypes, though tumor metastases in the brain are increasingly being detected of this patient group. Despite the many years of tried and tested use of a wide variety of anti-hormonal therapeutic agents, there is insufficient data on their intracerebral effectiveness and their ability to cross the blood-brain barrier. In this review, we therefore summarize the current state of knowledge on anti-hormonal therapy and its intracerebral impact and effects on the blood-brain barrier in breast cancer.
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Affiliation(s)
- Carolin J. Curtaz
- Department of Gynecology and Obstetrics, University Hospital Würzburg, 97080 Würzburg, Germany
- Correspondence:
| | - Ludwig Kiesel
- Department of Gynecology and Obstetrics, University Hospital of Münster, 48143 Münster, Germany
| | - Patrick Meybohm
- Department of Anaesthesiology, Intensive Care, Emergency and Pain Medicine, University Hospital Würzburg, 97080 Würzburg, Germany
| | - Achim Wöckel
- Department of Gynecology and Obstetrics, University Hospital Würzburg, 97080 Würzburg, Germany
| | - Malgorzata Burek
- Department of Anaesthesiology, Intensive Care, Emergency and Pain Medicine, University Hospital Würzburg, 97080 Würzburg, Germany
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16
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Wang Y, Minden A. Current Molecular Combination Therapies Used for the Treatment of Breast Cancer. Int J Mol Sci 2022; 23:ijms231911046. [PMID: 36232349 PMCID: PMC9569555 DOI: 10.3390/ijms231911046] [Citation(s) in RCA: 51] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Revised: 09/13/2022] [Accepted: 09/15/2022] [Indexed: 11/23/2022] Open
Abstract
Breast cancer is the second leading cause of death for women worldwide. While monotherapy (single agent) treatments have been used for many years, they are not always effective, and many patients relapse after initial treatment. Moreover, in some patients the response to therapy becomes weaker, or resistance to monotherapy develops over time. This is especially problematic for metastatic breast cancer or triple-negative breast cancer. Recently, combination therapies (in which two or more drugs are used to target two or more pathways) have emerged as promising new treatment options. Combination therapies are often more effective than monotherapies and demonstrate lower levels of toxicity during long-term treatment. In this review, we provide a comprehensive overview of current combination therapies, including molecular-targeted therapy, hormone therapy, immunotherapy, and chemotherapy. We also describe the molecular basis of breast cancer and the various treatment options for different breast cancer subtypes. While combination therapies are promising, we also discuss some of the challenges. Despite these challenges, the use of innovative combination therapy holds great promise compared with traditional monotherapies. In addition, the use of multidisciplinary technologies (such as nanotechnology and computer technology) has the potential to optimize combination therapies even further.
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17
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Xu H, Wang Y, Han Y, Wu Y, Wang J, Xu B. CDK4/6 inhibitors versus PI3K/AKT/mTOR inhibitors in women with hormone receptor-positive, HER2-negative metastatic breast cancer: An updated systematic review and network meta-analysis of 28 randomized controlled trials. Front Oncol 2022; 12:956464. [PMID: 36091147 PMCID: PMC9449843 DOI: 10.3389/fonc.2022.956464] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Accepted: 07/18/2022] [Indexed: 11/17/2022] Open
Abstract
Background Updated evidence was required to compare the efficacy and safety of cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) inhibitors for patients with hormone receptor-positive and HER2-negative metastatic breast cancer. Methods A systematic review and network meta-analysis was conducted utilizing data from randomized controlled trials (RCTs) that contained interventions of CDK4/6 inhibitors or PI3K/AKT/mTOR inhibitors. Progression-free survival (PFS), overall survival (OS), and treatment-related adverse events (TRAEs) were primary outcomes of interest. Pooled hazard ratios (HRs) and odds ratios (ORs) with 95% credible intervals (CrIs) were used to assess the survival outcomes and safety profiles, respectively. Results A total of 28 RCTs with 12,129 participants were included. Pooled analysis showed that CDK4/6 inhibitors significantly prolonged PFS than PI3K/AKT/mTOR inhibitors (HR, 0.81; 95% CrI, 0.69–0.94), whereas no significant differences were detected regarding OS. After balancing the treatment lines and metastatic sites, the superiority of CDK4/6 inhibitors only appeared in the visceral and non-visceral subgroups. Among CDK4/6 inhibitors, abemaciclib was significantly better than others in ≥3 grade neutropenia (OR, 0.04; 95% CrI, 0.01–0.15). The incidence of stomatitis and digestive disorders was different among diverse kinds of PI3K/AKT/mTOR inhibitors. Discrepancies appeared regarding TRAEs of hepatotoxicity, diarrhea, and hyperglycemia among different interventions. Conclusions CDK4/6 inhibitors showed better efficacy in PFS, but the benefits disappeared when taking treatment line into consideration. Specific and discrepant safety profiles were found in two categories of agents. Systematic Review Registration https://www.crd.york.ac.uk/PROSPERO, identifier CRD42022321172.
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Affiliation(s)
| | | | | | | | - Jiayu Wang
- *Correspondence: Binghe Xu, ; Jiayu Wang,
| | - Binghe Xu
- *Correspondence: Binghe Xu, ; Jiayu Wang,
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18
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Predictive biomarkers for molecularly targeted therapies and immunotherapies in breast cancer. Arch Pharm Res 2022; 45:597-617. [PMID: 35982262 DOI: 10.1007/s12272-022-01402-5] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Accepted: 08/14/2022] [Indexed: 11/02/2022]
Abstract
Globally, breast cancer is the most common malignancy in women. Substantial efforts have been made to develop novel therapies, including targeted therapies and immunotherapies, for patients with breast cancer who do not respond to standard therapies. Consequently, new targeted therapies, such as cyclin-dependent kinase 4 and 6 inhibitors, poly (ADP-ribose) polymerase inhibitors, phosphoinositide 3-kinase inhibitor, and antibody-drug conjugates targeting human epidermal growth factor receptor 2 or trophoblast cell surface antigen-2, and immune checkpoint inhibitor targeting programmed cell death-1, have been developed and are now in clinical use. However, only some patients have benefited from these novel therapies; therefore, the identification and validation of reliable or more accurate biomarkers for predicting responses to these agents remain a major challenge. This review summarizes the currently available predictive biomarkers for breast cancer and describes recent efforts undertaken to identify potential predictive markers for molecularly targeted therapies and immune checkpoint inhibitors.
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19
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Muñoz-Ayala A, Chimal-Vega B, García-González V. Translation initiation and its relationship with metabolic mechanisms in cancer development, progression and chemoresistance. ADVANCES IN PROTEIN CHEMISTRY AND STRUCTURAL BIOLOGY 2022; 132:111-141. [PMID: 36088073 DOI: 10.1016/bs.apcsb.2022.05.011] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
Pathways that regulate protein homeostasis (proteostasis) in cells range from mRNA processing to protein degradation; perturbations in regulatory mechanisms of these pathways can lead to oncogenic cellular processes. Protein synthesis modulation failures are common phenomena in cancer cells, wherein specific conditions that promote the translation of protein factors promoting carcinogenesis are present. These specific conditions may be favored by metabolic lipid alterations like those found in metabolic syndrome and obesity. Protein translation modifications have been described in obesity, favoring the translation of protein targets that benefit lipid accumulation; a determining factor is the activity of the cap-binding eukaryotic translation initiation factor 4E (eIF4E), a crosstalk in protein translation and lipogenesis. Besides, alterations of protein translation initiation steps are critical participants for the development of both pathogenic conditions, cancer, and obesity. This chapter is focused on the regulation of recognition and processing of carcinogenic-mRNA and the connections among lipid metabolism and cell signaling pathways that promote oncogenesis, tumoral microenvironment generation and potentially the development of chemoresistance. We performed an in-depth analysis of events, such as those occurring in obesity and dyslipidemias, that may influence protein translation, driving the recognition of certain mRNAs and favoring cancer development and chemoresistance.
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Affiliation(s)
- Andrea Muñoz-Ayala
- Departamento de Bioquímica, Facultad de Medicina Mexicali, Universidad Autónoma de Baja California, Mexicali, México; Laboratorio Multidisciplinario de Estudios Metabólicos y Cáncer, Universidad Autónoma de Baja California, Mexicali, México
| | - Brenda Chimal-Vega
- Departamento de Bioquímica, Facultad de Medicina Mexicali, Universidad Autónoma de Baja California, Mexicali, México; Laboratorio Multidisciplinario de Estudios Metabólicos y Cáncer, Universidad Autónoma de Baja California, Mexicali, México
| | - Victor García-González
- Departamento de Bioquímica, Facultad de Medicina Mexicali, Universidad Autónoma de Baja California, Mexicali, México; Laboratorio Multidisciplinario de Estudios Metabólicos y Cáncer, Universidad Autónoma de Baja California, Mexicali, México.
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20
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Basu N, Narad P, Guptasarma ML, Tandon C, Das BC, Tandon S. Computational and In Vitro Approaches to Elucidate the Anti-cancer Effects of Arnica montana in Hormone-Dependent Breast Cancer. HOMEOPATHY 2022; 111:288-300. [PMID: 35790192 DOI: 10.1055/s-0042-1743565] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
BACKGROUND Breast cancer is the most common cancer in women worldwide. Use of homeopathic medicines for the treatment of cancers has increased in the last several years. Arnica montana is an anti-inflammatory homeopathic medicine used in traumatic conditions and because of this property we performed investigations for its potential as a chemotherapeutic agent against breast cancer. METHODS An ethanolic extract of Arnica montana (mother tincture, MT), prepared according to the Homoeopathic Pharmacopoeia of India, was characterized by gas chromatography-mass spectroscopy (GC-MS), followed by computational (in silico) analysis using molecular docking, to identify specific compounds that can bind and modulate the activity of key proteins involved in breast cancer survival and progression. To validate the in silico findings, in a controlled experiment breast cancer cells (MCF7) were treated in vitro with Arnica montana and the cytotoxic effects assessed by flowcytometry, fluorescence microscopy, scratch assay, clonogenic potential and gene expression analysis. RESULTS Phytochemical characterization of ethanolic extract of Arn MT by GC-MS allowed identification of several compounds. Caryophyllene oxide and 7-hydroxycadalene were selected for molecular docking studies, based on their potential drug-like properties. These compounds displayed selective binding affinity to some of the recognized target proteins of breast cancer, which included estrogen receptor alpha (ERα), progesterone receptor (PR), epidermal growth factor receptor (EGFR), mTOR (mechanistic target of rapamycin) and E-cadherin. In vitro studies revealed induction of apoptosis in MCF7 cells following treatment with Arn MT. Furthermore, treatment with Arn MT revealed its ability to inhibit migration and colony forming abilities of the cancer cells. CONCLUSION Considering the apoptotic and anti-migratory effects of Arnica montana in breast cancer cells in vitro, there is a need for this medicine to be further validated in an in vivo model.
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Affiliation(s)
- Nilanjana Basu
- Amity Institute of Molecular Medicine and Stem Cell Research, Amity University, Noida, Uttar Pradesh, India
| | - Priyanka Narad
- Amity Institute of Biotechnology, Amity University, Noida, Uttar Pradesh, India
| | - Manni Luthra Guptasarma
- Department of Immunopathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | | | - Bhudev Chandra Das
- Amity Institute of Molecular Medicine and Stem Cell Research, Amity University, Noida, Uttar Pradesh, India
| | - Simran Tandon
- Amity Institute of Molecular Medicine and Stem Cell Research, Amity University, Noida, Uttar Pradesh, India.,Amity University Punjab, Mohali, India
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21
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Kim Y, Ahn I, Cho HN, Gwon H, Kang HJ, Seo H, Choi H, Kim KP, Jun TJ, Kim YH. RIDAB: Electronic medical record-integrated real world data platform for predicting and summarizing interactions in biomedical research from heterogeneous data resources. COMPUTER METHODS AND PROGRAMS IN BIOMEDICINE 2022; 221:106866. [PMID: 35594580 DOI: 10.1016/j.cmpb.2022.106866] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Revised: 04/27/2022] [Accepted: 05/07/2022] [Indexed: 06/15/2023]
Abstract
BACKGROUND AND OBJECTIVE With the advent of bioinformatics, biological databases have been constructed to computerize data. Biological systems can be described as interactions and relationships between elements constituting the systems, and they are organized in various biomedical open databases. These open databases have been used in approaches to predict functional interactions such as protein-protein interactions (PPI), drug-drug interactions (DDI) and disease-disease relationships (DDR). However, just combining interaction data has limited effectiveness in predicting the complex relationships occurring in a whole context. Each contributing source contains information on each element in a specific field of knowledge but there is a lack of inter-disciplinary insight in combining them. METHODS In this study, we propose the RWD Integrated platform for Discovering Associations in Biomedical research (RIDAB) to predict interactions between biomedical entities. RIDAB is established as a graph network to construct a platform that predicts the interactions of target entities. Biomedical open database is combined with EMRs each representing a biomedical network and a real-world data. To integrate databases from different domains to build the platform, mapping of the vocabularies was required. In addition, the appropriate structure of the network and the graph embedding method to be used were needed to be selected to fit the tasks. RESULTS The feasibility of the platform was evaluated using node similarity and link prediction for drug repositioning task, a commonly used task for biomedical network. In addition, we compared the US Food and Drug Administration (FDA)-approved repositioned drugs with the predicted result. By integrating EMR database with biomedical networks, the platform showed increased f1 score in predicting repositioned drugs, from 45.62% to 57.26%, compared to platforms based on biomedical networks alone. CONCLUSIONS This study demonstrates that the elements of biomedical research findings can be reflected by integrating EMR data with open-source biomedical networks. In addition, showed the feasibility of using the established platform to represent the integration of biomedical networks and reflected the relationship between real world networks.
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Affiliation(s)
- Yunha Kim
- Department of Medical Science, Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea.
| | - Imjin Ahn
- Department of Medical Science, Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea.
| | - Ha Na Cho
- Division of Cardiology, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea.
| | - Hansle Gwon
- Department of Medical Science, Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea.
| | - Hee Jun Kang
- Division of Cardiology, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea.
| | - Hyeram Seo
- Department of Medical Science, Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea.
| | - Heejung Choi
- Department of Medical Science, Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea.
| | - Kyu-Pyo Kim
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea.
| | - Tae Joon Jun
- Big Data Research Center, Asan Institute for Life Sciences, Asan Medical Center, Seoul 05505, Republic of Korea.
| | - Young-Hak Kim
- Division of Cardiology, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea.
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22
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Expert consensus on the clinical application of PI3K/AKT/mTOR inhibitors in the treatment of advanced breast cancer. CANCER INNOVATION 2022; 1:25-54. [PMID: 38089455 PMCID: PMC10686175 DOI: 10.1002/cai2.10] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Accepted: 05/05/2022] [Indexed: 04/07/2024]
Abstract
Phosphoinositide 3-kinase (PI3K)/protein kinase B (PKB or AKT)/mammalian target of rapamycin (mTOR) signaling pathway (PAM pathway) plays an important role in the development of breast cancer and are closely associated with the resistance to endocrine therapy in advanced breast cancer. Therefore, anticancer treatment targeting key molecules in this signaling pathway has become a research hotspot in recent years. Randomized clinical trials have demonstrated that PI3K/AKT/mTOR inhibitors bring significant clinical benefit to patients with advanced breast cancer, especially to those with hormone receptor (HR)-positive, human epidermal growth factor receptor (HER) 2-negative advanced breast cancer. Alpelisib, a PI3K inhibitor, and everolimus, an mTOR inhibitor, have been approved by FDA. Based on their high efficacy and relatively good safety profile, an expanded indication of everolimus in breast cancer has been approved by National Medical Products Administration (NMPA). Alpelisib is expected to be approved in China in the near future. The members of the consensus expert panel reached this consensus to comprehensively define the role of PI3K/AKT/mTOR signaling pathway in breast cancer, efficacy and clinical applications of PI3K/AKT/mTOR inhibitors, management of adverse reactions, and PIK3CA mutation detection, to promote the understanding of PI3K/AKT/mTOR inhibitors for Chinese oncologists, improve clinical decision-making, and prolong the survival of target patient population.
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23
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Kirwan CC, Blower EL. Contemporary breast cancer treatment-associated thrombosis. Thromb Res 2022; 213 Suppl 1:S8-S15. [DOI: 10.1016/j.thromres.2021.12.025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Revised: 12/07/2021] [Accepted: 12/24/2021] [Indexed: 10/18/2022]
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Skolariki A, D’Costa J, Little M, Lord S. Role of PI3K/Akt/mTOR pathway in mediating endocrine resistance: concept to clinic. EXPLORATION OF TARGETED ANTI-TUMOR THERAPY 2022; 3:172-199. [PMID: 36046843 PMCID: PMC9400772 DOI: 10.37349/etat.2022.00078] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2021] [Accepted: 02/11/2022] [Indexed: 01/06/2023] Open
Abstract
The majority of breast cancers express the estrogen receptor (ER) and for this group of patients, endocrine therapy is the cornerstone of systemic treatment. However, drug resistance is common and a focus for breast cancer preclinical and clinical research. Over the past 2 decades, the PI3K/Akt/mTOR axis has emerged as an important driver of treatment failure, and inhibitors of mTOR and PI3K are now licensed for the treatment of women with advanced ER-positive breast cancer who have relapsed on first-line hormonal therapy. This review presents the preclinical and clinical data that led to this new treatment paradigm and discusses future directions.
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Affiliation(s)
- Aglaia Skolariki
- Department of Oncology, University of Oxford, Churchill Hospital, OX3 7LE Oxford, UK
| | - Jamie D’Costa
- Department of Oncology, University of Oxford, Churchill Hospital, OX3 7LE Oxford, UK
| | - Martin Little
- Department of Oncology, Churchill Hospital, OX3 7LE Oxford, UK
| | - Simon Lord
- Department of Oncology, University of Oxford, Churchill Hospital, OX3 7LE Oxford, UK
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25
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Beavers CJ, Rodgers JE, Bagnola AJ, Beckie TM, Campia U, Di Palo KE, Okwuosa TM, Przespolewski ER, Dent S. Cardio-Oncology Drug Interactions: A Scientific Statement From the American Heart Association. Circulation 2022; 145:e811-e838. [PMID: 35249373 DOI: 10.1161/cir.0000000000001056] [Citation(s) in RCA: 52] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
In the cardio-oncology population, drug interactions are of particular importance given the complex pharmacological profile, narrow therapeutic index, and inherent risk of therapies used to manage cardiovascular disease and cancer. Drug interactions may be beneficial or detrimental to the desired therapeutic effect. Clinicians in both cardiology and oncology should be cognizant of these potential drug-drug interactions that may reduce the efficacy or safety of either cardiovascular or cancer therapies. These risks can be mitigated through increased recognition of potential drug-drug interaction, use of alternative medications when possible, and careful monitoring. This scientific statement provides clinicians with an overview of pharmacodynamic and pharmacokinetic drug-drug interactions in patients with cancer exposed to common cardiovascular and cancer medications.
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26
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Murugan NJ, Voutsadakis IA. Proteasome regulators in pancreatic cancer. World J Gastrointest Oncol 2022; 14:38-54. [PMID: 35116102 PMCID: PMC8790418 DOI: 10.4251/wjgo.v14.i1.38] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 04/14/2021] [Accepted: 12/02/2021] [Indexed: 02/06/2023] Open
Abstract
Pancreatic adenocarcinoma is one of the most lethal cancers with rising incidence. Despite progress in its treatment, with the introduction of more effective chemotherapy regimens in the last decade, prognosis of metastatic disease remains inferior to other cancers with long term survival being the exception. Molecular characterization of pancreatic cancer has elucidated the landscape of the disease and has revealed common lesions that contribute to pancreatic carcinogenesis. Regulation of proteostasis is critical in cancers due to increased protein turnover required to support the intense metabolism of cancer cells. The proteasome is an integral part of this regulation and is regulated, in its turn, by key transcription factors, which induce transcription of proteasome structural units. These include FOXO family transcription factors, NFE2L2, hHSF1 and hHSF2, and NF-Y. Networks that encompass proteasome regulators and transduction pathways dysregulated in pancreatic cancer such as the KRAS/ BRAF/MAPK and the Transforming growth factor beta/SMAD pathway contribute to pancreatic cancer progression. This review discusses the proteasome and its transcription factors within the pancreatic cancer cellular micro-environment. We also consider the role of stemness in carcinogenesis and the use of proteasome inhibitors as therapeutic agents.
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Affiliation(s)
- Nirosha J Murugan
- Department of Biology, Algoma University, Sault Sainte Marie P6A3T6, ON, Canada
| | - Ioannis A Voutsadakis
- Department of Medical Oncology, Sault Area Hospital, Sault Sainte Marie P6A3T6, ON, Canada
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Saatci O, Huynh-Dam KT, Sahin O. Endocrine resistance in breast cancer: from molecular mechanisms to therapeutic strategies. J Mol Med (Berl) 2021; 99:1691-1710. [PMID: 34623477 PMCID: PMC8611518 DOI: 10.1007/s00109-021-02136-5] [Citation(s) in RCA: 74] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Revised: 08/20/2021] [Accepted: 09/06/2021] [Indexed: 12/31/2022]
Abstract
Estrogen receptor-positive (ER +) breast cancer accounts for approximately 75% of all breast cancers. Endocrine therapies, including selective ER modulators (SERMs), aromatase inhibitors (AIs), and selective ER down-regulators (SERDs) provide substantial clinical benefit by reducing the risk of disease recurrence and mortality. However, resistance to endocrine therapies represents a major challenge, limiting the success of ER + breast cancer treatment. Mechanisms of endocrine resistance involve alterations in ER signaling via modulation of ER (e.g., ER downregulation, ESR1 mutations or fusions); alterations in ER coactivators/corepressors, transcription factors (TFs), nuclear receptors and epigenetic modulators; regulation of signaling pathways; modulation of cell cycle regulators; stress signaling; and alterations in tumor microenvironment, nutrient stress, and metabolic regulation. Current therapeutic strategies to improve outcome of endocrine-resistant patients in clinics include inhibitors against mechanistic target of rapamycin (mTOR), cyclin-dependent kinase (CDK) 4/6, and the phosphoinositide 3-kinase (PI3K) subunit, p110α. Preclinical studies reveal novel therapeutic targets, some of which are currently tested in clinical trials as single agents or in combination with endocrine therapies, such as ER partial agonists, ER proteolysis targeting chimeras (PROTACs), next-generation SERDs, AKT inhibitors, epidermal growth factor receptor 1 and 2 (EGFR/HER2) dual inhibitors, HER2 targeting antibody-drug conjugates (ADCs) and histone deacetylase (HDAC) inhibitors. In this review, we summarize the established and emerging mechanisms of endocrine resistance, alterations during metastatic recurrence, and discuss the approved therapies and ongoing clinical trials testing the combination of novel targeted therapies with endocrine therapy in endocrine-resistant ER + breast cancer patients.
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Affiliation(s)
- Ozge Saatci
- Department of Drug Discovery and Biomedical Sciences, University of South Carolina, 715, Sumter Street, CLS609D, Columbia, SC, 29208, USA
| | - Kim-Tuyen Huynh-Dam
- Department of Drug Discovery and Biomedical Sciences, University of South Carolina, 715, Sumter Street, CLS609D, Columbia, SC, 29208, USA
| | - Ozgur Sahin
- Department of Drug Discovery and Biomedical Sciences, University of South Carolina, 715, Sumter Street, CLS609D, Columbia, SC, 29208, USA.
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Kunc M, Popęda M, Biernat W, Senkus E. Lost but Not Least-Novel Insights into Progesterone Receptor Loss in Estrogen Receptor-Positive Breast Cancer. Cancers (Basel) 2021; 13:cancers13194755. [PMID: 34638241 PMCID: PMC8507533 DOI: 10.3390/cancers13194755] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Revised: 09/20/2021] [Accepted: 09/21/2021] [Indexed: 12/28/2022] Open
Abstract
Estrogen receptor α (ERα) and progesterone receptor (PgR) are crucial prognostic and predictive biomarkers that are usually co-expressed in breast cancer (BC). However, 12-24% of BCs present ERα(+)/PgR(-) phenotype at immunohistochemical evaluation. In fact, BC may either show primary PgR(-) status (in chemonaïve tumor sample), lose PgR expression during neoadjuvant treatment, or acquire PgR(-) phenotype in local relapse or metastasis. The loss of PgR expression in ERα(+) breast cancer may signify resistance to endocrine therapy and poorer outcomes. On the other hand, ERα(+)/PgR(-) BCs may have a better response to neoadjuvant chemotherapy than double-positive tumors. Loss of PgR expression may be a result of pre-transcriptional alterations (copy number loss, mutation, epigenetic modifications), decreased transcription of the PGR gene (e.g., by microRNAs), and post-translational modifications (e.g., phosphorylation, sumoylation). Various processes involved in the down-regulation of PgR have distinct consequences on the biology of cancer cells. Occasionally, negative PgR status detected by immunohistochemical analysis is paradoxically associated with enhanced transcriptional activity of PgR that might be inhibited by antiprogestin treatment. Identification of the mechanism of PgR loss in each patient seems challenging, yet it may provide important information on the biology of the tumor and predict its responsiveness to the therapy.
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Affiliation(s)
- Michał Kunc
- Department of Pathomorphology, Medical University of Gdańsk, 80-214 Gdańsk, Poland; (M.K.); (W.B.)
| | - Marta Popęda
- Laboratory of Translational Oncology, Intercollegiate Faculty of Biotechnology, Medical University of Gdańsk, 80-211 Gdańsk, Poland;
| | - Wojciech Biernat
- Department of Pathomorphology, Medical University of Gdańsk, 80-214 Gdańsk, Poland; (M.K.); (W.B.)
| | - Elżbieta Senkus
- Department of Oncology and Radiotherapy, Medical University of Gdańsk, 80-214 Gdańsk, Poland
- Correspondence: ; Tel.: +48-58-584-4481
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Shen XB, Li GL, Zheng YB, Chen ZH, Cao WM, Wang XJ, Shao XY. Combined everolimus and endocrine therapy in advanced HR-positive, HER2-negative Chinese breast cancer patients: a retrospective study. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:1334. [PMID: 34532471 PMCID: PMC8422157 DOI: 10.21037/atm-21-3840] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Accepted: 08/12/2021] [Indexed: 11/16/2022]
Abstract
Background Everolimus (EVE) is an inhibitor of the mammalian target of rapamycin (mTOR) pathway, and it is approved for the treatment of advanced breast cancer (ABC). However, there is still little real-world data on using EVE in Chinese breast cancer patients. We retrospectively analyzed real-world data to determine the factors affecting EVE treatment efficacy and patient outcomes. Methods We retrospectively collected the treatment information of ABC patients treated with EVE from 2013 to 2020 in Zhejiang Cancer Hospital. Kaplan-Meier analysis and Cox regression methods were used to calculate and compare the progression-free survival (PFS), and identify the factors associated with EVE treatment efficacy. Results The study finally enrolled 84 patients meeting the requirement; the median PFS in all 84 patients was 6.87 months. Multivariate analysis showed that liver metastasis [hazard ratio, 1.69; 95% confidence interval (CI), 1.00–2.84; P=0.049], and brain metastasis (hazard ratio, 2.65; 95% CI, 1.07–6.58; P=0.036) were independent risk factors. Subgroup analyses demonstrated EVE + fulvestrant (FUL) was not superior to EVE + aromatase inhibitors (AIs) for PFS (5.77 vs. 7.97 months, P=0.0735). Furthermore, it showed EVE + AI was superior to EVE + FUL in some subgroups: postmenopausal group (hazard ratio, 0.50; 95% CI, 0.26–0.98); without bone metastasis group (hazard ratio, 0.22; 95% CI, 0.06–0.80); visceral disease group (hazard ratio, 0.37; 95% CI, 0.20–0.69). Conclusions EVE combined with endocrine therapy is an effective treatment option for Chinese patients with hormone-receptor-positive (HR+), human epidermal growth factor receptor-2-negative (HER2−) breast cancer, although EVE + FUL was not superior to EVE + AI. Liver metastasis and brain metastasis were independent risk factors for successful EVE + endocrine therapy.
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Affiliation(s)
- Xia-Bo Shen
- Department of Breast Medical Oncology, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, China.,Institute of Cancer and Basic Medicine (IBMC), Chinese Academy of Sciences, Hangzhou, China
| | - Guang-Liang Li
- Department of Breast Medical Oncology, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, China.,Institute of Cancer and Basic Medicine (IBMC), Chinese Academy of Sciences, Hangzhou, China
| | - Ya-Bing Zheng
- Department of Breast Medical Oncology, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, China.,Institute of Cancer and Basic Medicine (IBMC), Chinese Academy of Sciences, Hangzhou, China
| | - Zhan-Hong Chen
- Department of Breast Medical Oncology, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, China.,Institute of Cancer and Basic Medicine (IBMC), Chinese Academy of Sciences, Hangzhou, China
| | - Wen-Ming Cao
- Department of Breast Medical Oncology, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, China.,Institute of Cancer and Basic Medicine (IBMC), Chinese Academy of Sciences, Hangzhou, China
| | - Xiao-Jia Wang
- Department of Breast Medical Oncology, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, China.,Institute of Cancer and Basic Medicine (IBMC), Chinese Academy of Sciences, Hangzhou, China
| | - Xi-Ying Shao
- Department of Breast Medical Oncology, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, China.,Institute of Cancer and Basic Medicine (IBMC), Chinese Academy of Sciences, Hangzhou, China
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Dawood S, Konstantionva M, Dent R, Perazzo F, Kim SB, Villarreal-Garza C, Franco S, Dai MS, Simon S. Optimizing treatment selection, and sequencing decisions for Management of HR-Positive, HER2-Negative advanced breast cancer - Proceedings from breast cancer expert group meeting. BMC Proc 2021; 15:15. [PMID: 34372853 PMCID: PMC8351081 DOI: 10.1186/s12919-021-00224-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/24/2021] [Indexed: 12/24/2022] Open
Abstract
PURPOSE The therapeutic landscape of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (mBC) has evolved considerably with the introduction of newer targeted agents and their combinations with endocrine therapies. In this scenario, optimizing treatment selection and sequencing is daunting for clinicians. The purpose of this review is to provide evidence-based answers to key clinical questions on treatment selection and sequencing for the management of HR + HER2 - mBC. DESIGN A panel of nine key opinion leaders from Argentina, Brazil, Colombia, Mexico, Moscow, Singapore, South Korea, Taiwan, and UAE convened in October 2018. They reviewed the literature and formulated answers to clinical questions on optimizing the management of HR + HER2 - mBC. RESULTS Evidence-based answers were formulated for: (1) optimal initial treatment choice; (2) ovarian function suppression, optimal endocrine partner, and role of cyclin-dependent kinase 4/6 (CDK4/6) inhibitors (in premenopausal women); (3) better first-line standard of care than aromatase inhibitors; (4) preferred second-line treatment; (5) treatment of oligometastatic disease; (6) factors influencing first-line single-agent endocrine therapy choice; (7) influence of endocrine resistance on treatment selection; (8) optimal maintenance regimen in visceral crisis; and (9) need for a breast cancer registry for patients with HR + HER2 - mBC. The panel also proposed a treatment-sequencing algorithm for the management of HR + HER2 - mBC. CONCLUSION The current article will serve as a comprehensive guide for optimizing the management of HR + HER2 - mBC. The proposed breast cancer registry will help identify unmet needs and develop strategic regional policies to help improve access to optimized care for HR + HER2 - mBC.
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Affiliation(s)
- Shaheenah Dawood
- Dubai Health Care City, Consultant Medical Oncologist, Mediclinic City Hospital - North Wing, Dubai, UAE.
| | - Maria Konstantionva
- Head of the Department of antitumor drug therapy, F. VladimirskIy Moscow Regional Research Clinical Institute (MONIKI), Moscow, Russia
| | - Rebecca Dent
- Head, Breast Medical Oncology Team, National Cancer Center Singapore, Singapore, Singapore
| | - Florencia Perazzo
- Department of Oncology, Centro de Educación Médicae Investigaciones Clínicas (CEMIC), Ciudad de Buenos Aires, Argentina
| | - Sung-Bae Kim
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Songpa-gu, Seoul, South Korea
| | - Cynthia Villarreal-Garza
- Centro de Cancer de Mama, Hospital Zambrano Hellion, Tecnologico de Monterrey, San Pedro Garza García, NL, Mexico
- Depto. de Investigacion, Instituto Nacional de Cancerologia, Mexico city, Mexico
| | - Sandra Franco
- Head of Oncology, Clínica del Country, Bogotá, Colombia
| | - Ming-Shen Dai
- Department of Hematology/Oncology, Tri-Service General Hospital, National Defense Medical Center, Taipei City, Taiwan
| | - Sergio Simon
- Centro Paulista de Oncologia (CPO), Sao Paulo, Brazil
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Wu W, Chen J, Deng H, Jin L, He Z, Rao N, Nie Y, Yao Y, Yang Y, Su F, Liu J. Neoadjuvant everolimus plus letrozole versus fluorouracil, epirubicin and cyclophosphamide for ER-positive, HER2-negative breast cancer: a randomized pilot trial. BMC Cancer 2021; 21:862. [PMID: 34315439 PMCID: PMC8317384 DOI: 10.1186/s12885-021-08612-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Accepted: 07/16/2021] [Indexed: 11/10/2022] Open
Abstract
Background Here we evaluated the feasibility, efficacy, tolerability, and treatment-mediated immune modulation of neoadjuvant everolimus plus letrozole versus chemotherapy in treating postmenopausal patients with ER-positive, HER2-negative breast cancer. Methods Postmenopausal women with ER-positive, HER2-negative breast cancer who had a primary tumor > 2 cm or positive axillary lymph node(s) proofed by biopsy were randomly (1,1) enrolled to receive neoadjuvant everolimus plus letrozole for 18 weeks or fluorouracil, epirubicin plus cyclophosphamide (FEC) for 6 cycles before surgery. Primary outcome was feasibility of the trial. Secondary outcome included ultrasound response rate, pathological complete response rate, breast-conserving surgery rate, toxicities, treatment-mediated immune modulation and biomarkers. Results Forty patients were randomized. Completion rate was 90.0% in the neoadjuvant endocrine therapy (NET) arm but 70.0% in the neoadjuvant chemotherapy (NAC) arm. The ultrasound response rate was 65.0% in NET arm and 40.0% in FEC arm, respectively. In terms of the adverse events, clearly favored NET arm. Everolimus plus letrozole increased the ratio of peripheral Tregs to CD4+ T cells and tumor PD-L1 expression, and decreased Ki67 index and tumor-infiltrating Tregs, and patients with a greater increase of tumor-specific CTLs showed more sensitive to NET. Conclusion This pilot trial showed that neoadjuvant everolimus plus letrozole might achieve a favorable ultrasound response rate with low toxicities in treating postmenopausal ER-positive, HER2-negative breast cancer patients. Everolimus plus letrozole might have positive antitumoral immunity effects. Further large randomized controlled trials are needed to confirm our findings. Trail registration A Trial of Neoadjuvant Everolimus Plus Letrozole Versus FEC in Women With ER-positive, HER2-negative Breast Cancer, registered on 07/04/2016 and first posted on 18/04/2016, NCT02742051. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-021-08612-y.
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Affiliation(s)
- Wei Wu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Breast Tumor Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Yanjiang West Road 107#, Guangzhou, China
| | - Jiewen Chen
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Breast Tumor Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Yanjiang West Road 107#, Guangzhou, China
| | - Heran Deng
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Breast Tumor Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Yanjiang West Road 107#, Guangzhou, China
| | - Liang Jin
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Breast Tumor Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Yanjiang West Road 107#, Guangzhou, China
| | - Zhanghai He
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Department of Pathology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Nanyan Rao
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Breast Tumor Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Yanjiang West Road 107#, Guangzhou, China
| | - Yan Nie
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Breast Tumor Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Yanjiang West Road 107#, Guangzhou, China
| | - Yandan Yao
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Breast Tumor Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Yanjiang West Road 107#, Guangzhou, China
| | - Yaping Yang
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Breast Tumor Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Yanjiang West Road 107#, Guangzhou, China
| | - Fengxi Su
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Breast Tumor Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Yanjiang West Road 107#, Guangzhou, China
| | - Jieqiong Liu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Breast Tumor Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Yanjiang West Road 107#, Guangzhou, China.
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Gandhi N, Oturkar CC, Das GM. Estrogen Receptor-Alpha and p53 Status as Regulators of AMPK and mTOR in Luminal Breast Cancer. Cancers (Basel) 2021; 13:3612. [PMID: 34298826 PMCID: PMC8306694 DOI: 10.3390/cancers13143612] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Revised: 07/10/2021] [Accepted: 07/14/2021] [Indexed: 12/12/2022] Open
Abstract
Luminal breast cancer (LBC) driven by dysregulated estrogen receptor-alpha (ERα) signaling accounts for 70% of the breast cancer cases diagnosed. Although endocrine therapy (ET) is effective against LBC, about one-third of these patients fail to respond to therapy owing to acquired or inherent resistance mechanisms. Aberrant signaling via ERα, oncogenes, growth factor receptors, and mutations in tumor suppressors such as p53 impinge on downstream regulators such as AMPK and mTOR. While both AMPK and mTOR have been reported to play important roles in determining sensitivity of LBC to ET, how the ERα-p53 crosstalk impinges on regulation of AMPK and mTOR, thereby influencing therapeutic efficacy remains unknown. Here, we have addressed this important issue using isogenic breast cancer cell lines, siRNA-mediated RNA knockdown, and different modes of drug treatments. Interaction of p53 with ERα and AMPK was determined by in situ proximity ligation assay (PLA), and endogenous gene transcripts were analyzed by quantitative real-time polymerase chain reaction (qRT-PCR). Further, the effect of concurrent and sequential administration of Fulvestrant-Everolimus combination on colony formation was determined. The studies showed that in cells expressing wild type p53, as well as in cells devoid of p53, ERα represses AMPK, whereas in cells harboring mutant p53, repression of AMPK is sustained even in the absence of ERα. AMPK is a major negative regulator of mTOR, and to our knowledge, this is the first study on the contribution of AMPK-dependent regulation of mTOR by ERα. Furthermore, the studies revealed that independent of the p53 mutation status, combination of Fulvestrant and Everolimus may be a viable first line therapeutic strategy for potentially delaying resistance of ERα+/HER2- LBC to ET.
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Affiliation(s)
| | | | - Gokul M. Das
- Center for Genetics & Pharmacology, Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA; (N.G.); (C.C.O.)
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Li H, Prever L, Hirsch E, Gulluni F. Targeting PI3K/AKT/mTOR Signaling Pathway in Breast Cancer. Cancers (Basel) 2021; 13:3517. [PMID: 34298731 PMCID: PMC8304822 DOI: 10.3390/cancers13143517] [Citation(s) in RCA: 99] [Impact Index Per Article: 24.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Revised: 07/06/2021] [Accepted: 07/10/2021] [Indexed: 12/19/2022] Open
Abstract
Breast cancer is the most frequently diagnosed cancer and the primary cause of cancer death in women worldwide. Although early diagnosis and cancer growth inhibition has significantly improved breast cancer survival rate over the years, there is a current need to develop more effective systemic treatments to prevent metastasis. One of the most commonly altered pathways driving breast cancer cell growth, survival, and motility is the PI3K/AKT/mTOR signaling cascade. In the past 30 years, a great surge of inhibitors targeting these key players has been developed at a rapid pace, leading to effective preclinical studies for cancer therapeutics. However, the central role of PI3K/AKT/mTOR signaling varies among diverse biological processes, suggesting the need for more specific and sophisticated strategies for their use in cancer therapy. In this review, we provide a perspective on the role of the PI3K signaling pathway and the most recently developed PI3K-targeting breast cancer therapies.
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Affiliation(s)
| | | | | | - Federico Gulluni
- Department of Molecular Biotechnology and Health Sciences, University of Turin, 10126 Turin, Italy; (H.L.); (L.P.); (E.H.)
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Jeong JH, Kim JE, Ahn JH, Jung KH, Koh SJ, Cheon J, Sohn J, Kim GM, Lee KS, Sim SH, Park IH, Kim SB. Leuprorelin combined with letrozole with/without everolimus in ovarian-suppressed premenopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer: The LEO study. Eur J Cancer 2021; 144:341-350. [DOI: 10.1016/j.ejca.2020.11.044] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Revised: 11/12/2020] [Accepted: 11/24/2020] [Indexed: 12/09/2022]
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Rozenblit M, Mun S, Soulos P, Adelson K, Pusztai L, Mougalian S. Patterns of treatment with everolimus exemestane in hormone receptor-positive HER2-negative metastatic breast cancer in the era of targeted therapy. Breast Cancer Res 2021; 23:14. [PMID: 33514405 PMCID: PMC7844919 DOI: 10.1186/s13058-021-01394-y] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Accepted: 01/17/2021] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND There is currently no clinical trial data regarding the efficacy of everolimus exemestane (EE) following prior treatment with CDK4/6 inhibitors (CDK4/6i). This study assesses the use and efficacy of everolimus exemestane in patients with metastatic HR+ HER2- breast cancer previously treated with endocrine therapy (ET) or endocrine therapy + CDK4/6i. METHODS Retrospective analysis of electronic health record-derived data for HR+ HER2- metastatic breast cancer from 2012 to 2018. The proportion of patients receiving EE first-line, second-line, or third-line, and the median duration of EE prior to next line of treatment (TTNT) by line of therapy was calculated. OS for patients receiving EE first-line, second-line, or third-line, indexed to the date of first-line therapy initiation and stratified by prior treatment received, was calculated with Kaplan-Meier method with multivariable Cox proportional hazards regression analysis. RESULTS Six hundred twenty-two patients received EE first-line (n = 104, 16.7%), second-line (n = 273, 43.9%) or third-line (n = 245, 39.4%). Median TTNT was 8.3 months, 5.5 months, and 4.8 months respectively. Median TTNT of EE second-line was longer following prior ET alone compared to prior ET + CDK4/6i (6.2 months (95% CI 5.2, 7.3) vs 4.3 months (95% CI 3.2, 5.7) respectively, p = 0.03). Similarly, EE third-line following ET alone vs ET + CDK4/6i in first- or second-line resulted in median TTNT 5.6 months (95% CI 4.4, 6.9) vs 4.1 months (95% CI 3.6, 6.1) respectively, although this was not statistically significant (p = 0.08). Median OS was longer for patients who received EE following prior ET + CDK4/6i. EE second-line following ET + CDK 4/6i vs ET alone resulted in median OS 37.7 months vs. 32.7 months (p = 0.449). EE third-line following ET + CDK4/6i vs prior ET alone resulted in median OS 59.2 months vs. 40.8 months (p < 0.010). This difference in OS was not statistically significant when indexed to the start of EE therapy. CONCLUSION This study suggests that EE remains an effective treatment option after prior ET or ET + CDK4/6i use. Median TTNT of EE was longer for patients who received prior ET, whereas median OS was longer for patients who received prior ET + CDK4/6i. However, this improvement in OS was not statistically significant when indexed to the start of EE therapy suggesting that OS benefit is primarily driven by prior CDK4/6i use. EE remains an effective treatment option regardless of prior treatment option.
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Affiliation(s)
- Mariya Rozenblit
- Yale School of Medicine, 333 Cedar St., PO Box 208032, New Haven, CT, 05620, USA
| | - Sophia Mun
- Yale COPPER, Harkness Office Building, 367 Cedar Street, New Haven, CT, 06510, USA
| | - Pamela Soulos
- Yale COPPER, Harkness Office Building, 367 Cedar Street, New Haven, CT, 06510, USA
| | - Kerin Adelson
- Yale School of Medicine, 333 Cedar St., PO Box 208032, New Haven, CT, 05620, USA
| | - Lajos Pusztai
- Yale School of Medicine, 333 Cedar St., PO Box 208032, New Haven, CT, 05620, USA
| | - Sarah Mougalian
- Yale School of Medicine, 333 Cedar St., PO Box 208032, New Haven, CT, 05620, USA.
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Samidurai A, Ockaili R, Cain C, Roh SK, Filippone SM, Kraskauskas D, Kukreja RC, Das A. Differential Regulation of mTOR Complexes with miR-302a Attenuates Myocardial Reperfusion Injury in Diabetes. iScience 2020; 23:101863. [PMID: 33319180 PMCID: PMC7725936 DOI: 10.1016/j.isci.2020.101863] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Revised: 09/07/2020] [Accepted: 11/20/2020] [Indexed: 01/11/2023] Open
Abstract
Persistent activation of mTOR (mammalian target of rapamycin) in diabetes increases the vulnerability of the heart to ischemia/reperfusion (I/R) injury. We show here that infusion of rapamycin (mTOR inhibitor) at reperfusion following ischemia reduced myocardial infarct size and apoptosis with restoration of cardiac function in type 1 diabetic rabbits. Likewise, treatment with rapamycin protected hyperglycemic human-pluripotent-stem-cells-derived cardiomyocytes (HG-hiPSC-CMs) following simulated ischemia (SI) and reoxygenation (RO). Phosphorylation of S6 (mTORC1 marker) was increased, whereas AKT phosphorylation (mTORC2 marker) and microRNA-302a were reduced with concomitant increase of its target, PTEN, following I/R injury in diabetic heart and HG-hiPSC-CMs. Rapamycin inhibited mTORC1 and PTEN, but augmented mTORC2 with restoration of miRNA-302a under diabetic conditions. Inhibition of miRNA-302a blocked mTORC2 and abolished rapamycin-induced protection against SI/RO injury in HG-hiPSC-CMs. We conclude that rapamycin attenuates reperfusion injury in diabetic heart through inhibition of PTEN and mTORC1 with restoration of miR-302a-mTORC2 signaling.
miR-302a and AKT phosphorylation are suppressed in post-ischemic diabetic heart Negative regulator of insulin signaling, PTEN, is induced after ischemia reperfusion miRNA-302a-mimic abolishes ischemic injury in hyperglycemic human iPS cardiocytes Rapamycin treatment restores miR-302a-mTORC2 cardioprotective signaling in diabetes
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Affiliation(s)
- Arun Samidurai
- Division of Cardiology, Pauley Heart Center, Box 980204, Virginia Commonwealth University Medical Center, 1101 East Marshall Street, Sanger Hall, Room 7020d & 7020b, Richmond, VA 23298-0204, USA
| | - Ramzi Ockaili
- Division of Cardiology, Pauley Heart Center, Box 980204, Virginia Commonwealth University Medical Center, 1101 East Marshall Street, Sanger Hall, Room 7020d & 7020b, Richmond, VA 23298-0204, USA
| | - Chad Cain
- Division of Cardiology, Pauley Heart Center, Box 980204, Virginia Commonwealth University Medical Center, 1101 East Marshall Street, Sanger Hall, Room 7020d & 7020b, Richmond, VA 23298-0204, USA
| | - Sean K Roh
- Division of Cardiology, Pauley Heart Center, Box 980204, Virginia Commonwealth University Medical Center, 1101 East Marshall Street, Sanger Hall, Room 7020d & 7020b, Richmond, VA 23298-0204, USA
| | - Scott M Filippone
- Division of Cardiology, Pauley Heart Center, Box 980204, Virginia Commonwealth University Medical Center, 1101 East Marshall Street, Sanger Hall, Room 7020d & 7020b, Richmond, VA 23298-0204, USA
| | - Donatas Kraskauskas
- Division of Cardiology, Pauley Heart Center, Box 980204, Virginia Commonwealth University Medical Center, 1101 East Marshall Street, Sanger Hall, Room 7020d & 7020b, Richmond, VA 23298-0204, USA
| | - Rakesh C Kukreja
- Division of Cardiology, Pauley Heart Center, Box 980204, Virginia Commonwealth University Medical Center, 1101 East Marshall Street, Sanger Hall, Room 7020d & 7020b, Richmond, VA 23298-0204, USA
| | - Anindita Das
- Division of Cardiology, Pauley Heart Center, Box 980204, Virginia Commonwealth University Medical Center, 1101 East Marshall Street, Sanger Hall, Room 7020d & 7020b, Richmond, VA 23298-0204, USA
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Han Y, Wang J, Wang Z, Xu B. Comparative efficacy and safety of CDK4/6 and PI3K/AKT/mTOR inhibitors in women with hormone receptor-positive, HER2-negative metastatic breast cancer: a systematic review and network meta-analysis. Curr Probl Cancer 2020; 44:100606. [DOI: 10.1016/j.currproblcancer.2020.100606] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Revised: 04/15/2020] [Accepted: 05/04/2020] [Indexed: 10/24/2022]
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De Palma FDE, Del Monaco V, Pol JG, Kremer M, D’Argenio V, Stoll G, Montanaro D, Uszczyńska-Ratajczak B, Klein CC, Vlasova A, Botti G, D’Aiuto M, Baldi A, Guigó R, Kroemer G, Maiuri MC, Salvatore F. The abundance of the long intergenic non-coding RNA 01087 differentiates between luminal and triple-negative breast cancers and predicts patient outcome. Pharmacol Res 2020; 161:105249. [DOI: 10.1016/j.phrs.2020.105249] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Revised: 10/08/2020] [Accepted: 10/08/2020] [Indexed: 02/07/2023]
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Bardia A, Modi S, Oliveira M, Cortes J, Campone M, Ma B, Dirix L, Weise A, Hewes B, Diaz-Padilla I, Han Y, Deshpande P, Samant TS, Lorenc KR, He W, Su F, Chavez-MacGregor M. Phase Ib Dose-escalation/Expansion Trial of Ribociclib in Combination With Everolimus and Exemestane in Postmenopausal Women with HR+, HER2− Advanced Breast Cancer. Clin Cancer Res 2020; 26:6417-6428. [DOI: 10.1158/1078-0432.ccr-20-1068] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2020] [Revised: 07/04/2020] [Accepted: 09/25/2020] [Indexed: 11/16/2022]
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Simon J, Chaix M, Billa O, Kamga AM, Roignot P, Ladoire S, Coutant C, Arveux P, Quantin C, Dabakuyo-Yonli TS. Survival in patients with HR+/HER2- metastatic breast cancer treated with initial endocrine therapy versus initial chemotherapy. A French population-based study. Br J Cancer 2020; 123:1071-1077. [PMID: 32678278 PMCID: PMC7525445 DOI: 10.1038/s41416-020-0979-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2020] [Revised: 06/12/2020] [Accepted: 06/23/2020] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND According to international guidelines, endocrine therapy (ET) is the preferred option for hormone receptor-positive (HR+) HER2-negative (HER2-) metastatic breast cancer. In spite of clear recommendations, these are not strictly followed in daily practice. The objectives of this study were to investigate the effect of the first anti-metastatic treatment therapy choice on progression-free survival (PFS) and overall survival (OS). METHODS In this population-based study, we included patients with HR+/HER2- metastatic breast cancer recorded in the Côte d'Or Breast Cancer Registry. Differences in PFS and OS between patients initially treated with chemotherapy (CT) or ET were analysed in Cox proportional hazards models. In a sensitivity analysis, we used a propensity score (PS) to limit the indication bias. RESULTS Altogether, 557 cases were included, 280 received initial ET and 277 received initial CT. PFS and OS in patients initially treated with ET was improved significantly when compared to patients with initial CT (respectively, HR = 0.83 (95% CI 0.69-0.99) and HR = 0.71 (95% CI 0.58-0.86)). The results of the sensitivity analysis supported these findings. CONCLUSION This study shows that treating patients with HR+/HER2- metastatic breast cancer with initial ET could provide a survival advantage in comparison with initial CT.
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Affiliation(s)
- Julien Simon
- Breast and Gynecologic Cancer Registry of Côte d'Or, Georges-François Leclerc Comprehensive Cancer Care Centre, 1 rue Professeur Marion, Dijon, France
- Biostatistics, Biomathematics, Pharmacoepidemiology and Infectious Diseases, Inserm U1181, Villejuif, France
| | - Marie Chaix
- Medical Oncology Department, Georges-François Leclerc Comprehensive Cancer Care Centre, 1 rue Professeur Marion, Dijon, France
| | - Oumar Billa
- Breast and Gynecologic Cancer Registry of Côte d'Or, Georges-François Leclerc Comprehensive Cancer Care Centre, 1 rue Professeur Marion, Dijon, France
| | - Ariane Mamguem Kamga
- Breast and Gynecologic Cancer Registry of Côte d'Or, Georges-François Leclerc Comprehensive Cancer Care Centre, 1 rue Professeur Marion, Dijon, France
| | | | - Sylvain Ladoire
- Medical Oncology Department, Georges-François Leclerc Comprehensive Cancer Care Centre, 1 rue Professeur Marion, Dijon, France
| | - Charles Coutant
- Surgical Oncology Department, Georges-François Leclerc Comprehensive Cancer Care Centre, 1 rue Professeur Marion, Dijon, France
| | - Patrick Arveux
- Breast and Gynecologic Cancer Registry of Côte d'Or, Georges-François Leclerc Comprehensive Cancer Care Centre, 1 rue Professeur Marion, Dijon, France
- Center for Research in Epidemiology and Population Health, Inserm U1018, Villejuif, France
| | - Catherine Quantin
- Biostatistics, Biomathematics, Pharmacoepidemiology and Infectious Diseases, Inserm U1181, Villejuif, France
- CHRU Dijon, Service de Biostatistiques et d'Information Médicale (DIM), Dijon, 21000, France
- INSERM, CIC 1432, Univ Bourgogne Franche Comte, Dijon, France
| | - Tienhan Sandrine Dabakuyo-Yonli
- Breast and Gynecologic Cancer Registry of Côte d'Or, Georges-François Leclerc Comprehensive Cancer Care Centre, 1 rue Professeur Marion, Dijon, France.
- Inserm U1231 Lipids, Nutrition, Cancer Research Center, Dijon, France.
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Dhakal A, Antony Thomas R, Levine EG, Brufsky A, Takabe K, Hanna MG, Attwood K, Miller A, Khoury T, Early AP, Soniwala S, O'Connor T, Opyrchal M. Outcome of Everolimus-Based Therapy in Hormone-Receptor-Positive Metastatic Breast Cancer Patients After Progression on Palbociclib. BREAST CANCER-BASIC AND CLINICAL RESEARCH 2020; 14:1178223420944864. [PMID: 32753876 PMCID: PMC7378710 DOI: 10.1177/1178223420944864] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Accepted: 07/02/2020] [Indexed: 12/31/2022]
Abstract
Background Despite the approval of mTOR inhibitor everolimus and CDK4/6 inhibitors in the management of hormone-receptor-positive HER2 non-amplified metastatic breast cancer (HR+ HER2-MBC), the optimal sequence of therapy is unclear. There are no clinical data on efficacy of everolimus in HR+ HER2-MBC after cancer progresses on CDK4/6 inhibitors. Objective The objective of this study is to find the efficacy of everolimus in HR+ HER2-MBC after they progress on a CDK4/6 inhibitor palbociclib. Methods This is a retrospective, 2-institute review of HR+ HER2-MBC from Jan 2015 to March 2018 treated with everolimus after progression on palbociclib. Primary end point was median progression-free survival (PFS), secondary end points objective response rate (ORR), clinical benefit ratio (CBR), and overall survival (OS). Results Out of 41 women with median age 61 years (33, 87) enrolled, 66% had received adjuvant systemic therapy, 61% had visceral disease, and 95% had prior nonsteroidal aromatase inhibitors. About 83% women had 3 or more chemotherapy or hormonal therapies prior to everolimus. Kaplan-Meier estimates showed a median PFS of 4.2 months (95% confidence interval [CI]: 3.2-6.2). The median OS was 18.7 months (95% CI 9.5 to not reached). Objective response rate and CBR were both 17.1%. Conclusion Everolimus was associated with modest PFS and ORR in HR+ HER2-MBCs postprogression on palbociclib.
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Affiliation(s)
- Ajay Dhakal
- Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA
| | - Roby Antony Thomas
- Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Ellis G Levine
- Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Adam Brufsky
- Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Kazuaki Takabe
- Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Matthew G Hanna
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Kristopher Attwood
- Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Austin Miller
- Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Thaer Khoury
- Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Amy P Early
- Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Saif Soniwala
- Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Tracy O'Connor
- Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Mateusz Opyrchal
- Department of Medicine, Washington University in St. Louis, St. Louis, MO, USA
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Efficacy and toxicity of everolimus plus exemestane in third and later lines treatment of hormone receptor-positive, HER2-negative metastatic breast cancer. JOURNAL OF SURGERY AND MEDICINE 2020. [DOI: 10.28982/josam.745731] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
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Vernieri C, Corti F, Nichetti F, Ligorio F, Manglaviti S, Zattarin E, Rea CG, Capri G, Bianchi GV, de Braud F. Everolimus versus alpelisib in advanced hormone receptor-positive HER2-negative breast cancer: targeting different nodes of the PI3K/AKT/mTORC1 pathway with different clinical implications. Breast Cancer Res 2020; 22:33. [PMID: 32252811 PMCID: PMC7137211 DOI: 10.1186/s13058-020-01271-0] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2019] [Accepted: 03/25/2020] [Indexed: 12/22/2022] Open
Abstract
Background The PI3K/AKT/mTORC1 axis is implicated in hormone receptor-positive HER2-negative metastatic breast cancer (HR+ HER2− mBC) resistance to anti-estrogen treatments. Based on results of the BOLERO-2 trial, the mTORC1 inhibitor everolimus in combination with the steroidal aromatase inhibitor (AI) exemestane has become a standard treatment for patients with HR+ HER2− mBC resistant to prior non-steroidal AI therapy. In the recent SOLAR-1 trial, the inhibitor of the PI3K alpha subunit (p110α) alpelisib in combination with fulvestrant prolonged progression-free survival (PFS) when compared to fulvestrant alone in patients with PIK3CA-mutated HR+ HER2− mBC that progressed after/on previous AI treatment. Therefore, two different molecules targeting the PI3K/AKT/mTORC1 axis, namely everolimus and alpelisib, are available for patients progressing on/after previous AI treatment, but it is unclear how to optimize their use in the clinical practice. Main body of the abstract Here, we reviewed the available clinical evidence deriving from the BOLERO-2 and SOLAR-1 trials to compare efficacy and safety profiles of everolimus and alpelisib in advanced HR+ HER2− BC treatment. Adding either compound to standard endocrine therapy provided similar absolute and relative PFS advantage. In the SOLAR-1 trial, a 76% incidence of grade (G) 3 or 4 (G3/G4) adverse events was reported, while G3/G4 toxicities occurred in 42% of patients in the BOLERO-2 trial. While alpelisib was only effective in patients with PIK3CA-mutated neoplasms, retrospective analyses indicate that everolimus improves exemestane efficacy independently of PIK3CA mutational status. Conclusions Based on the available efficacy and safety data, the “new” alpelisib may be burdened by higher incidence of severe adverse events, higher costs, and anticancer efficacy that is limited to PIK3CA-mutated tumors when compared to the “old” everolimus. Therefore, the everolimus-exemestane combination remains an effective and reasonably well-tolerated therapeutic option for HR+ HER2− mBC patients progressing after/on previous AI treatment, independently of PIK3CA mutational status.
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Affiliation(s)
- Claudio Vernieri
- IFOM, the FIRC Institute of Molecular Oncology, Via Adamello 16, 20139, Milan, Italy. .,Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian, 1, 20133, Milan, Italy.
| | - Francesca Corti
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian, 1, 20133, Milan, Italy
| | - Federico Nichetti
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian, 1, 20133, Milan, Italy
| | - Francesca Ligorio
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian, 1, 20133, Milan, Italy
| | - Sara Manglaviti
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian, 1, 20133, Milan, Italy
| | - Emma Zattarin
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian, 1, 20133, Milan, Italy
| | - Carmen G Rea
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian, 1, 20133, Milan, Italy
| | - Giuseppe Capri
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian, 1, 20133, Milan, Italy
| | - Giulia V Bianchi
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian, 1, 20133, Milan, Italy
| | - Filippo de Braud
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian, 1, 20133, Milan, Italy.,Oncology and Hemato-Oncology Department, University of Milan, 20122, Milan, Italy
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Soliman PT, Westin SN, Iglesias DA, Fellman BM, Yuan Y, Zhang Q, Yates MS, Broaddus RR, Slomovitz BM, Lu KH, Coleman RL. Everolimus, Letrozole, and Metformin in Women with Advanced or Recurrent Endometrioid Endometrial Cancer: A Multi-Center, Single Arm, Phase II Study. Clin Cancer Res 2020; 26:581-587. [PMID: 31628143 PMCID: PMC7002216 DOI: 10.1158/1078-0432.ccr-19-0471] [Citation(s) in RCA: 60] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2019] [Revised: 06/12/2019] [Accepted: 10/14/2019] [Indexed: 12/18/2022]
Abstract
PURPOSE Treatment for patients with recurrent endometrioid endometrial cancer (EEC) are limited as paclitaxel is the only second-line chemotherapy with a response rate >13%. Targeting PIK3/mTOR in combination with hormonal therapy has shown promise. The addition of metformin may enhance this response. We conducted a phase II study evaluating everolimus, letrozole, and metformin in advanced/recurrent EEC. PATIENTS AND METHODS A Simon two-stage design was employed. Women with ≤2 prior chemotherapy regimens for recurrence were eligible. Pretreatment biopsy was required, followed by everolimus 10 mg orally, letrozole 2.5 mg orally, and metformin 500 mg orally twice a day on a 4-week cycle. The primary endpoint was clinical benefit (CB), defined as complete response (CR), partial response (PR), or stable disease (SD) confirmed at 16 weeks. Patients were treated until progression or toxicity. RESULTS Sixty-two patients were enrolled. Median age was 62 years (40-77) with 401 cycles completed, median of 6 cycles (1-31). Fifty-four patients were evaluable for response with a CB rate of 50% (27/54). Best overall response (OR) was PR 28% (15/54) and SD 22% (12/54). Thirteen patients received >12 cycles. Median follow-up was 17.9 months (2-47). Median progression-free survival was 5.7 [95% confidence interval (CI), 3.0-8.1] and OS was 19.6 months (95% CI, 14.2-26.3). Positive progesterone receptor expression was associated with CB (89.5% vs. 27.3%, P = 0.001). CONCLUSIONS Everolimus, letrozole, and metformin resulted in 50% CB and 28% OR in women with recurrent EEC. Progesterone receptor-positive tumors may have better response; validation studies are needed.See related commentary by Madariaga et al., p. 523.
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Affiliation(s)
- Pamela T Soliman
- Department of Gynecologic Oncology and Reproductive Medicine, University of Texas, M.D. Anderson Cancer Center, Houston, Texas.
| | - Shannon N Westin
- Department of Gynecologic Oncology and Reproductive Medicine, University of Texas, M.D. Anderson Cancer Center, Houston, Texas
| | - David A Iglesias
- Department of Obstetrics and Gynecology, Virginia Tech Carilion School of Medicine, Roanoke, Virginia
| | - Bryan M Fellman
- Division of Biostatistics, University of Texas, M.D. Anderson Cancer Center, Houston, Texas
| | - Ying Yuan
- Division of Biostatistics, University of Texas, M.D. Anderson Cancer Center, Houston, Texas
| | - Qian Zhang
- Department of Gynecologic Oncology and Reproductive Medicine, University of Texas, M.D. Anderson Cancer Center, Houston, Texas
| | - Melinda S Yates
- Department of Gynecologic Oncology and Reproductive Medicine, University of Texas, M.D. Anderson Cancer Center, Houston, Texas
| | - Russell R Broaddus
- Department of Pathology, University of Texas, M.D. Anderson Cancer Center, Houston, Texas
| | - Brian M Slomovitz
- Sylvester Comprehensive Cancer Center, Department of Obstetrics and Gynecology, Miller School of Medicine, University of Miami, Miami, Florida
| | - Karen H Lu
- Department of Gynecologic Oncology and Reproductive Medicine, University of Texas, M.D. Anderson Cancer Center, Houston, Texas
| | - Robert L Coleman
- Department of Gynecologic Oncology and Reproductive Medicine, University of Texas, M.D. Anderson Cancer Center, Houston, Texas
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Greenwalt I, Zaza N, Das S, Li BD. Precision Medicine and Targeted Therapies in Breast Cancer. Surg Oncol Clin N Am 2020; 29:51-62. [DOI: 10.1016/j.soc.2019.08.004] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
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46
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Yeo W, Ueno T, Lin CH, Liu Q, Lee KH, Leung R, Naito Y, Park YH, Im SA, Li H, Yap YS, Lu YS. Treating HR+/HER2- breast cancer in premenopausal Asian women: Asian Breast Cancer Cooperative Group 2019 Consensus and position on ovarian suppression. Breast Cancer Res Treat 2019; 177:549-559. [PMID: 31270763 DOI: 10.1007/s10549-019-05318-5] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2019] [Accepted: 06/08/2019] [Indexed: 12/19/2022]
Abstract
PURPOSE Breast cancer in young Asian women has distinctive clinicopathological characteristics; hence, we question the universal generalizability of treatment recommendations based on data from predominantly non-Asian postmenopausal women. METHODS The Asian Breast Cancer Cooperative Group (ABCCG) reviewed current ESO-ESMO and St. Gallen recommendations for treating hormone receptor positive/human epidermal growth factor receptor 2 negative (HR+/HER2-) breast cancer in premenopausal women. Points disputed by ≥ 3/12 members were discussed, and statements on contentious issues formulated for anonymous voting; consensus required a ≥ 75% majority. RESULTS The ABCCG contends that: (1) Trials in premenopausal women are not only necessary, but also worthwhile if performed separately from others that also enroll postmenopausal participants. (2) Not all premenopausal women with HR+ early breast cancer need adjuvant ovarian function suppression (OFS). (3) Certain clinical factors might influence decision-making about prescribing OFS. (4) For early HR+/HER2- breast cancer in premenopausal patients with OFS, tamoxifen is preferred for intermediate-risk cases; for high risk, near-consensus supported aromatase inhibitor, despite no clear overall survival benefit versus tamoxifen. (5) Oncotype DX Breast Recurrence Score® has different treatment implications in patients aged ≤ 50 versus > 50 years. (6) High-risk patients (if premenopausal after chemotherapy) should receive adjuvant chemotherapy and OFS plus aromatase inhibitor. (7) For patients with advanced disease receiving OFS on a backbone of tamoxifen, gonadotrophin-releasing hormone agonists may be given 12-weekly. (8) For premenopausal women who decline OFS or oophorectomy, tamoxifen alone is still an option but is considered less effective; other monotherapies are also less effective than OFS plus such treatments. CONCLUSION Premenopausal Asian women with breast cancer have unique disease characteristics and may benefit from treatment that differs somewhat from international guidelines. Given the great diversity of patients and clinical settings worldwide, the ABCCG advocates evidence-based yet flexible and individualized use of all potential options to improve breast cancer outcomes.
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Affiliation(s)
- Winnie Yeo
- State Key Laboratory of Translational Oncology, Department of Clinical Oncology, Faculty of Medicine, Prince of Wales Hospital, Hong Kong Cancer Institute, Chinese University of Hong Kong, 30-32 Ngan Shing St., Shatin, NT, Hong Kong SAR, China
| | - Takayuki Ueno
- Breast Surgical Oncology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, 3-8-31 Ariake Koto-ku, Tokyo, 135-8550, Japan
| | - Ching-Hung Lin
- Department of Oncology, National Taiwan University Hospital, 7 Chung-Shan South Rd., Taipei, 10016, Taiwan
| | - Qiang Liu
- Breast Tumor Center, Sun-Yat Sen Memorial Hospital, Sun-Yat Sen University, 107 Yanjiang West Rd., Guangzhou, 510120, China
| | - Kyung-Hun Lee
- Department of Internal Medicine, Cancer Research Institute, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea
| | - Roland Leung
- Division of Haematology, Medical Oncology and BMT, Department of Medicine, Queen Mary Hospital, The University of Hong Kong, 102 Pokfulam Rd., Hong Kong SAR, China
| | - Yoichi Naito
- Department of Breast and Medical Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
| | - Yeon Hee Park
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, 81 Irwon-ro, Seoul, 06351, Republic of Korea
| | - Seock-Ah Im
- Department of Internal Medicine, Cancer Research Institute, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea
| | - Huiping Li
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Breast Oncology, Peking University Cancer Hospital & Institute, 52 Fucheng Rd., Beijing, 100142, China
| | - Yoon Sim Yap
- Division of Medical Oncology, National Cancer Centre Singapore, 11 Hospital Drive, Singapore, 169610, Singapore
| | - Yen-Shen Lu
- Department of Oncology, National Taiwan University Hospital, 7 Chung-Shan South Rd., Taipei, 10016, Taiwan.
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Presti D, Quaquarini E. The PI3K/AKT/mTOR and CDK4/6 Pathways in Endocrine Resistant HR+/HER2- Metastatic Breast Cancer: Biological Mechanisms and New Treatments. Cancers (Basel) 2019; 11:E1242. [PMID: 31450618 PMCID: PMC6770492 DOI: 10.3390/cancers11091242] [Citation(s) in RCA: 75] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2019] [Revised: 08/17/2019] [Accepted: 08/20/2019] [Indexed: 12/30/2022] Open
Abstract
Endocrine-based treatments are the normal standard-of-care in women with hormone receptor-positive/Human Epidermal growth factor Receptor 2-negative metastatic breast cancer. Despite the well-known efficacy of these drugs as first-line therapies, about 50% of women develop endocrine resistance and disease progression. The treatment of these patients has represented one of the most important research fields in the last few years, with several multicenter phase II/III trials published or still ongoing. Novel therapies, such as cyclin-dependent kinase (CDK)4/6 and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) inhibitors, have significantly changed the prognosis of patients progressing to a previous endocrine treatment, allowing a great benefit in terms of progression-free survival and, in some cases, of overall survival. However, identifying response predictors is essential for the rational use of these drugs to avoid unnecessary toxicity and costs, and to ensure the optimal therapeutic sequence is used. In this review, we analyze the PI3K/AKT/mTOR and CDK4/6 pathways and their roles in endocrine resistant metastatic breast cancer. We then focus on the new treatments developed and the roles of these drugs in overcoming endocrine resistance, describing the latest clinical trials that led to the approval of the drugs in clinical practice.
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Affiliation(s)
- Daniele Presti
- Department of Internal Medicine and Therapeutics, University of Pavia, 27100 Pavia, Italy
- Medical Oncology Unit, IRCCS ICS Maugeri SpA SB, 27100 Pavia, Italy
| | - Erica Quaquarini
- Medical Oncology Unit, IRCCS ICS Maugeri SpA SB, 27100 Pavia, Italy.
- Experimental Medicine, University of Pavia, 27100 Pavia, Italy.
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Ai B, Kong X, Wang X, Zhang K, Yang X, Zhai J, Gao R, Qi Y, Wang J, Wang Z, Fang Y. LINC01355 suppresses breast cancer growth through FOXO3-mediated transcriptional repression of CCND1. Cell Death Dis 2019; 10:502. [PMID: 31243265 PMCID: PMC6594972 DOI: 10.1038/s41419-019-1741-8] [Citation(s) in RCA: 48] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2019] [Revised: 05/16/2019] [Accepted: 05/16/2019] [Indexed: 01/19/2023]
Abstract
Previously, several protein-coding tumor suppressors localized at 1p36 have been reported. In the present work, we focus on functional long non-coding RNAs (lncRNAs) embedded in this locus. Small interfering RNA was used to identify lncRNA candidates with growth-suppressive activities in breast cancer. The mechanism involved was also explored. LINC01355 were downregulated in breast cancer cells relative to non-malignant breast epithelial cells. Overexpression of LINC01355 significantly inhibited proliferation, colony formation, and tumorigenesis of breast cancer cells. LINC01355 arrested breast cancer cells at the G0/G1 phase by repressing CCND1. Moreover, LINC01355 interacted with and stabilized FOXO3 protein, leading to transcriptional repression of CCND1. Importantly, LINC01355-mediated suppression of breast cancer growth was reversed by knockdown of FOXO3 or overexpression of CCND1. Clinically, LINC01355 was downregulated in breast cancer specimens and correlated with more aggressive features. There was a negative correlation between LINC01355 and CCND1 expression in breast cancer samples. LINC01355 acts as a tumor suppressor in breast cancer, which is ascribed to enhancement of FOXO3-mediated transcriptional repression of CCND1. Re-expression of LINC01355 may provide a potential therapeutic strategy to block breast cancer growth and progression.
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Affiliation(s)
- Bolun Ai
- Department of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xiangyi Kong
- Department of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xiangyu Wang
- Department of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Kai Zhang
- Department of Cancer Prevention, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xue Yang
- Department of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jie Zhai
- Department of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Ran Gao
- Department of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yihang Qi
- Department of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jing Wang
- Department of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
| | - Zhongzhao Wang
- Department of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
| | - Yi Fang
- Department of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
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Cazzaniga ME, Danesi R, Girmenia C, Invernizzi P, Elvevi A, Uguccioni M. Management of toxicities associated with targeted therapies for HR-positive metastatic breast cancer: a multidisciplinary approach is the key to success. Breast Cancer Res Treat 2019; 176:483-494. [PMID: 31065872 PMCID: PMC6586706 DOI: 10.1007/s10549-019-05261-5] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2019] [Accepted: 04/26/2019] [Indexed: 02/07/2023]
Abstract
Purpose Agents targeting HR-positive, HER2-negative locally advanced or metastatic breast cancer have improved patient outcomes compared with conventional single-agent endocrine therapy. Currently, approved targeted agents include everolimus and three CDK4/6 inhibitors, palbociclib, ribociclib, and abemaciclib. Unlike the well-characterized and easily manageable safety profile of endocrine therapies, adverse events associated with targeted therapies are complex and potentially severe. Their prompt recognition and treatment, crucial for prolonged endocrine sensitivity and survival, may be challenging and requires a multidisciplinary effort and a good knowledge of drug interactions. Methods We reviewed the current evidence on the drug safety of targeted agents for metastatic breast cancer currently used in clinical practice in Italy, supported by the clinical experience of Italian oncologists with expertise in the field. Results All oncologists had used CDK4/6 inhibitors in clinical practice and/or within a clinical trial. The clinical management of toxicities, including dose adjustments, treatment interruptions, and concerns regarding special populations is discussed, and the management of relevant adverse events, related to individual agents and class-specific, toxicities is reviewed. Hematologic toxicities have the greatest impact on clinical management of the disease and on patients. Although toxicities associated with the new treatments result in more visits to the physician and more time and attention with patients, they are manageable, with no need for the oncologist to consult with specialist physicians. Conclusions Based on the available evidence and current guidelines, we propose a series of practical recommendations for multidisciplinary clinical management of the various toxicities associated with the addition of targeted agents to endocrine therapy.
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Affiliation(s)
- Marina Elena Cazzaniga
- Department of Medical Oncology & Phase 1 Research Centre ASST-Monza, Via Pergolesi 33, 20900, Monza, Italy.
| | - Romano Danesi
- Unit of Clinical Pharmacology and Pharmacogenetics, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Corrado Girmenia
- Department of Hematology, Oncology and Dermatology, Azienda Policlinico Umberto I, Sapienza University, Rome, Italy
| | - Pietro Invernizzi
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milan Bicocca, Monza, Italy
| | - Alessandra Elvevi
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milan Bicocca, Monza, Italy
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Ottestad L, Fronth L, Rajendiran S, Hege Aksnes L, Eikesdal HP, Støre Blix E, Ewertz M. Observational study of everolimus plus exemestane in postmenopausal women with hormone receptor-positive, HER2-negative advanced breast cancer. Acta Oncol 2019; 58:385-387. [PMID: 30798641 DOI: 10.1080/0284186x.2019.1566771] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Affiliation(s)
- Lars Ottestad
- Department of Oncology, Østfold Hospital Trust, Kalnes, Norway
| | - Line Fronth
- Department of internal medicine, Vestre Viken, Bærum Hospital, Gjettum, Norway
| | | | - Liv Hege Aksnes
- Department of Internal Medicine, Vestre Viken, Ringerike Hospital, Hønefoss, Norway
| | | | - Egil Støre Blix
- Institute of Medical Biology, UiT The Arctic University of Norway, Tromsø, Norway
- Department of Oncology, University Hospital of North Norway, Tromsø, Norway
| | - Marianne Ewertz
- Department of Oncology, Odense University Hospital, Institute of Clinical Research, University of Southern Denmark, Odense, Denmark
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