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Tao X, Han J, Li Y, Tian Y, Li ZJ, Li J, Guo X, Zhao J. The Difference of RCB 0 and RCB I in Prognosis of Breast Cancer After Neoadjuvant Therapy: A Meta-Analysis. Clin Breast Cancer 2025; 25:299-306.e1. [PMID: 39721893 DOI: 10.1016/j.clbc.2024.11.023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2024] [Revised: 10/15/2024] [Accepted: 11/28/2024] [Indexed: 12/28/2024]
Abstract
BACKGROUND The use of the residual cancer burden (RCB) for assessing breast cancer after neoadjuvant therapy (NAT) is increasingly common, but the prognostic difference between RCB 0 and RCB I is unclear. METHODS We systematically reviewed literature from PubMed, Embase, Web of Science, and oncology conferences until September 24, 2023. We used fixed- and random-effects models to calculate hazard ratio (HR) with 95% confidence interval (CI) for event-free survival (EFS), overall survival (OS), and distant disease-free survival (DDFS). RESULTS Our meta-analysis, encompassing 19 studies with 5894 patients, revealed that in the general population, RCB I had worse EFS (HR = 2.13; 95% CI: 1.75-2.58), OS (HR = 2.08; 95% CI: 1.48-2.93), and DDFS (HR = 2.10; 95% CI: 1.65-2.67) than RCB 0. Consistent with results from the general population, RCB I exhibited poorer EFS, OS, and DDFS in human epidermal growth factor 2-positive (HER2+) subtype and triple-negative breast cancer (TNBC) compared to RCB 0. Conversely, luminal subtype with RCB 0 and RCB I showed similar EFS (HR = 1.04; 95% CI: 0.62-1.72). CONCLUSIONS RCB I experienced a poorer prognosis compared to RCB 0 in the general population, a pattern also observed in the HER2+ subtype and TNBC. However, no significant prognostic disparity was noted between RCB 0 and RCB I in the luminal subtype.
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Affiliation(s)
- Xinlong Tao
- Breast Disease Diagnosis and Treatment Center of Affiliated Hospital of Qinghai University and Affiliated Cancer Hospital of Qinghai University, Xining, 810000, China.
| | - Jingqi Han
- Department of Pathology, Affiliated Hospital of Qinghai University, Xining, 810000, China.
| | - Yongxin Li
- Breast Disease Diagnosis and Treatment Center of Affiliated Hospital of Qinghai University and Affiliated Cancer Hospital of Qinghai University, Xining, 810000, China.
| | - Yaming Tian
- Department of Imaging, Affiliated Hospital of Qinghai University, Xining, 810000, China.
| | - Zhou Juan Li
- Breast Disease Diagnosis and Treatment Center of Affiliated Hospital of Qinghai University and Affiliated Cancer Hospital of Qinghai University, Xining, 810000, China.
| | - Jinming Li
- Breast Disease Diagnosis and Treatment Center of Affiliated Hospital of Qinghai University and Affiliated Cancer Hospital of Qinghai University, Xining, 810000, China.
| | - Xinjian Guo
- Department of Pathology, Affiliated Hospital of Qinghai University, Xining, 810000, China.
| | - Jiuda Zhao
- Breast Disease Diagnosis and Treatment Center of Affiliated Hospital of Qinghai University and Affiliated Cancer Hospital of Qinghai University, Xining, 810000, China.
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2
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Majmudar PR, Keri RA. The neural stem cell gene PAFAH1B1 controls cell cycle progression, DNA integrity, and paclitaxel sensitivity of triple-negative breast cancer cells. J Biol Chem 2025:110235. [PMID: 40378956 DOI: 10.1016/j.jbc.2025.110235] [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: 01/16/2025] [Revised: 04/19/2025] [Accepted: 05/02/2025] [Indexed: 05/19/2025] Open
Abstract
Triple-negative breast cancer (TNBC) is a highly aggressive disease with limited approved therapeutic options. The rapid growth and genomic instability of TNBC cells makes mitosis a compelling target, and a current mainstay of treatment is paclitaxel (Ptx), a taxane that stabilizes microtubules during mitosis. While initially effective, acquired resistance to Ptx is common, and other antimitotic therapies can be similarly rendered ineffective due to the development of resistance or systemic toxicity underscoring the need for new therapeutic approaches. Interrogating CRISPR essentiality screens in TNBC cell lines, we identified PAFAH1B1 (LIS1) as a potential vulnerability in this disease. PAFAH1B1 regulates mitotic spindle orientation, proliferation, and cell migration during neurodevelopment, yet little is known regarding its function in breast cancer. We found that suppressing PAFAH1B1 expression in TNBC cells reduces cell number, while non-malignant cells remain unaffected. PAFAH1B1 suppression alters cell cycle dynamics, increasing mitotic duration and accumulation of cells in the G2/M phase. The suppression of PAFAH1B1 expression also increases DNA double-strand breaks, indicating a requirement for sustained PAFAH1B1 expression to maintain the genomic integrity of TNBC cells. Lastly, PAFAH1B1 silencing substantially enhances these defects in cells that are taxane-resistant and sensitizes both parental and Ptx-resistant TNBC cells to Ptx. These results indicate that LIS1/PAFAH1B1 may be a novel target for the development of new anti-mitotic agents for treating TNBC, particularly in the context of paclitaxel resistance.
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Affiliation(s)
- Parth R Majmudar
- Department of Pharmacology, Case Western Reserve University School of Medicine, 2109 Adelbert Road, Cleveland, OH 44106, United States; Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, United States
| | - Ruth A Keri
- Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, United States.
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Ciringione A, Rizzi F. Facing the Challenge to Mimic Breast Cancer Heterogeneity: Established and Emerging Experimental Preclinical Models Integrated with Omics Technologies. Int J Mol Sci 2025; 26:4572. [PMID: 40429718 PMCID: PMC12111172 DOI: 10.3390/ijms26104572] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2025] [Revised: 05/05/2025] [Accepted: 05/09/2025] [Indexed: 05/29/2025] Open
Abstract
Breast cancer (BC) is among the most common neoplasms globally and is the leading cause of cancer-related mortality in women. Despite significant advancements in prevention, early diagnosis, and treatment strategies made over the past two decades, breast cancer continues to pose a significant global health challenge. One of the major obstacles in the clinical management of breast cancer patients is the high intertumoral and intratumoral heterogeneity that influences disease progression and therapeutic outcomes. The inability of preclinical experimental models to replicate this diversity has hindered the comprehensive understanding of BC pathogenesis and the development of new therapeutic strategies. An ideal experimental model must recapitulate every aspect of human BC to maintain the highest predictive validity. Therefore, a thorough understanding of each model's inherent characteristics and limitations is essential to bridging the gap between basic research and translational medicine. In this context, omics technologies serve as powerful tools for establishing comparisons between experimental models and human tumors, which may help address BC heterogeneity and vulnerabilities. This review examines the BC models currently used in preclinical research, including cell lines, patient-derived organoids (PDOs), organ-on-chip technologies, carcinogen-induced mouse models, genetically engineered mouse models (GEMMs), and xenograft mouse models. We emphasize the advantages and disadvantages of each model and outline the most important applications of omics techniques to aid researchers in selecting the most relevant model to address their specific research questions.
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Affiliation(s)
- Alessia Ciringione
- Laboratory of Biochemistry, Molecular Biology and Oncometabolism, Department of Medicine and Surgery, University of Parma, Via Volturno 39, 43125 Parma, Italy;
| | - Federica Rizzi
- Laboratory of Biochemistry, Molecular Biology and Oncometabolism, Department of Medicine and Surgery, University of Parma, Via Volturno 39, 43125 Parma, Italy;
- National Institute of Biostructure and Biosystems (INBB), 00165 Rome, Italy
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4
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Pesapane F, Rotili A, Scalco E, Pupo D, Carriero S, Corso F, De Marco P, Origgi D, Nicosia L, Ferrari F, Penco S, Pizzamiglio M, Rizzo G, Cassano E. Predictive value of tumoral and peritumoral radiomic features in neoadjuvant chemotherapy response for breast cancer: a retrospective study. LA RADIOLOGIA MEDICA 2025; 130:598-612. [PMID: 39992329 DOI: 10.1007/s11547-025-01969-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/01/2024] [Accepted: 02/05/2025] [Indexed: 02/25/2025]
Abstract
BACKGROUND Neoadjuvant chemotherapy (NACT) improves surgical outcomes for breast cancer patients, with pathologic complete response (pCR) correlated with enhanced survival. The role of radiomics, particularly from peritumoral tissue, in predicting pCR remains under investigation. METHODS This retrospective study analyzed radiomic features from pretreatment dynamic contrast-enhanced breast MRI scans of 150 patients undergoing NACT. A proportional approach was used to define peritumoral zones, assessed both with a 10% and 30% extension, allowing more standardized assessments relative to the tumor size. Radiomic features were evaluated alongside clinical and biological data to predict pCR. The association of clinical/biological and radiomic features with pCR to NACT was evaluated using univariate and multivariate analysis, logistic regression, and a random forest model. A clinical/biological model, a radiomic model, and a combined clinical/biological and 4 radiomic models for predicting the response to NACT were constructed. Area under the curve (AUC) and 95% confidence intervals (CIs) were used to assess the performance of the models. RESULTS Ninety-five patients (average age 47 years) were finally included. HER2 + , basal-like molecular subtypes, and a high level of Ki67 (≥ 20%) were associated with a higher likelihood of pCR to NACT. The combined clinical-biological-radiomic model, especially with a 10% peritumoral extension, showed improved predictive accuracy (AUC 0.76, CI 0.65-0.85) compared to models using clinical-biological data alone (AUC 0.73, CI 0.63-0.83). CONCLUSIONS Integrating peritumoral radiomic features with clinical and biological data enhances the prediction of pCR to NACT, underscoring the potential of a multifaceted approach in treatment personalization.
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Affiliation(s)
- Filippo Pesapane
- Breast Imaging Division, Radiology Department, IEO European Institute of Oncology IRCCS, Milan, Italy.
| | - Anna Rotili
- Breast Imaging Division, Radiology Department, IEO European Institute of Oncology IRCCS, Milan, Italy
| | - Elisa Scalco
- Istituto di Tecnologie Biomediche, Consiglio Nazionale delle Ricerche (ITB-CNR), Segrate, MI, Italy
| | - Davide Pupo
- Breast Imaging Division, Radiology Department, IEO European Institute of Oncology IRCCS, Milan, Italy
| | - Serena Carriero
- Department of Radiology and Interventional Radiology, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Federica Corso
- Department of Experimental Oncology, IEO European Institute of Oncology IRCCS, Milan, Italy
| | - Paolo De Marco
- Medical Physics Unit, European Institute of Oncology, IRCCS, Milan, Italy
| | - Daniela Origgi
- Medical Physics Unit, European Institute of Oncology, IRCCS, Milan, Italy
| | - Luca Nicosia
- Breast Imaging Division, Radiology Department, IEO European Institute of Oncology IRCCS, Milan, Italy
| | - Federica Ferrari
- Breast Imaging Division, Radiology Department, IEO European Institute of Oncology IRCCS, Milan, Italy
| | - Silvia Penco
- Breast Imaging Division, Radiology Department, IEO European Institute of Oncology IRCCS, Milan, Italy
| | - Maria Pizzamiglio
- Breast Imaging Division, Radiology Department, IEO European Institute of Oncology IRCCS, Milan, Italy
| | - Giovanna Rizzo
- Istituto di Sistemi e Tecnologie Industriali Intelligenti per il Manifatturiero Avanzato (STIIMA), CNR, Segrate, MI, Italy
| | - Enrico Cassano
- Breast Imaging Division, Radiology Department, IEO European Institute of Oncology IRCCS, Milan, Italy
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Li C, Tang Y, Zhang R, Shi L, Chen J, Zhang P, Zhang N, Li W. Inhibiting glycolysis facilitated checkpoint blockade therapy for triple-negative breast cancer. Discov Oncol 2025; 16:550. [PMID: 40244544 PMCID: PMC12006572 DOI: 10.1007/s12672-025-02320-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2024] [Accepted: 04/07/2025] [Indexed: 04/18/2025] Open
Abstract
Cancer cells are characterized by their altered energy metabolism. A hallmark of cancer metabolism is aerobic glycolysis, also called the Warburg effect. Hexokinase 2 (HK2), a crucial glycolytic enzyme converting glucose to glucose-6-phosphate, has been identified as a central player in the Warburg effect. Deletion of HK2 decreases cancer cell proliferation in animal models without explicit side effects, suggesting that targeting HK2 is a promising strategy for cancer therapy. In this study, we discovered a correlation between HK2 and the tumor immune response in triple-negative breast cancer. Inhibition of HK2 led to a reduction in G-CSF expression in 4T1 cells and a decrease in the development of myeloid-derived suppressor cells which, in turn, enhanced T cell immunity and prolonged the survival of 4T1 tumor-bearing mice. Furthermore, the HK2 inhibitor 3-BrPA improved the therapeutic efficacy of anti-PD-L1 therapy in 4T1 tumor-bearing mouse models. This study highlights the potential of glycolysis-targeting interventions as a novel treatment strategy, which can be combined with immunotherapy for the treatment of triple-negative breast cancer.
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Affiliation(s)
- Chong Li
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yu Tang
- Department of Gastrointestinal Surgery, Zhejiang University School of Medicine First Affiliated Hospital, Hangzhou, China
| | - Ruizhi Zhang
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Liang Shi
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jianying Chen
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Peng Zhang
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ning Zhang
- Department of Thyroid Breast Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| | - Wei Li
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
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Groheux D, Ferrer L, Vargas J, Martineau A, Borgel A, Teixeira L, Menu P, Bertheau P, Gallinato O, Colin T, Lehmann-Che J. FDG-PET/CT and Multimodal Machine Learning Model Prediction of Pathological Complete Response to Neoadjuvant Chemotherapy in Triple-Negative Breast Cancer. Cancers (Basel) 2025; 17:1249. [PMID: 40227836 PMCID: PMC11987901 DOI: 10.3390/cancers17071249] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2025] [Revised: 03/18/2025] [Accepted: 04/01/2025] [Indexed: 04/15/2025] Open
Abstract
Purpose: Triple-negative breast cancer (TNBC) is a biologically and clinically heterogeneous disease, associated with poorer outcomes when compared with other subtypes of breast cancer. Neoadjuvant chemotherapy (NAC) is often given before surgery, and achieving a pathological complete response (pCR) has been associated with patient outcomes. There is thus strong clinical interest in the ability to accurately predict pCR status using baseline data. Materials and Methods: A cohort of 57 TNBC patients who underwent FDG-PET/CT before NAC was analyzed to develop a machine learning (ML) algorithm predictive of pCR. A total of 241 predictors were collected for each patient: 11 clinical features, 11 histopathological features, 13 genomic features, and 206 PET features, including 195 radiomic features. The optimization criterion was the area under the ROC curve (AUC). Event-free survival (EFS) was estimated using the Kaplan-Meier method. Results: The best ML algorithm reached an AUC of 0.82. The features with the highest weight in the algorithm were a mix of PET (including radiomics), histopathological, genomic, and clinical features, highlighting the importance of truly multimodal analysis. Patients with predicted pCR tended to have a longer EFS than patients with predicted non-pCR, even though this difference was not significant, probably due to the small sample size and few events observed (p = 0.09). Conclusions: This study suggests that ML applied to baseline multimodal data can help predict pCR status after NAC for TNBC patients and may identify correlations with long-term outcomes. Patients predicted as non-pCR may benefit from concomitant treatment with immunotherapy or dose intensification.
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Affiliation(s)
- David Groheux
- Department of Nuclear Medicine, AP-HP, Saint-Louis Hospital, F-75010 Paris, France;
- Université Paris Cité, Inserm, Institut de Recherche Saint Louis (IRSL), F-75010 Paris, France; (A.B.); (L.T.); (J.L.-C.)
| | - Loïc Ferrer
- SOPHiA GENETICS, F-33600 Pessac, France; (L.F.); (J.V.); (O.G.); (T.C.)
| | - Jennifer Vargas
- SOPHiA GENETICS, F-33600 Pessac, France; (L.F.); (J.V.); (O.G.); (T.C.)
| | - Antoine Martineau
- Department of Nuclear Medicine, AP-HP, Saint-Louis Hospital, F-75010 Paris, France;
| | - Adrien Borgel
- Université Paris Cité, Inserm, Institut de Recherche Saint Louis (IRSL), F-75010 Paris, France; (A.B.); (L.T.); (J.L.-C.)
- Molecular Oncology Unit, AP-HP, Saint Louis Hospital, F-75010 Paris, France
| | - Luis Teixeira
- Université Paris Cité, Inserm, Institut de Recherche Saint Louis (IRSL), F-75010 Paris, France; (A.B.); (L.T.); (J.L.-C.)
- Breast Diseases Unit, AP-HP, Saint Louis Hospital, F-75010 Paris, France
| | | | - Philippe Bertheau
- Department of Pathology, AP-HP, Saint Louis Hospital, F-75010 Paris, France;
| | - Olivier Gallinato
- SOPHiA GENETICS, F-33600 Pessac, France; (L.F.); (J.V.); (O.G.); (T.C.)
| | - Thierry Colin
- SOPHiA GENETICS, F-33600 Pessac, France; (L.F.); (J.V.); (O.G.); (T.C.)
| | - Jacqueline Lehmann-Che
- Université Paris Cité, Inserm, Institut de Recherche Saint Louis (IRSL), F-75010 Paris, France; (A.B.); (L.T.); (J.L.-C.)
- Molecular Oncology Unit, AP-HP, Saint Louis Hospital, F-75010 Paris, France
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Yao Q, Du Y, Liu W, Liu X, Zhang M, Zha H, Du L, Zha X, Wang J, Li C. Improving Prediction Accuracy of Residual Axillary Lymph Node Metastases in Node-Positive Triple-Negative Breast Cancer: A Radiomics Analysis of Ultrasound-Guided Clip Locations Using the SHAP Method. Acad Radiol 2025; 32:1827-1837. [PMID: 39523140 DOI: 10.1016/j.acra.2024.10.039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2024] [Revised: 10/20/2024] [Accepted: 10/22/2024] [Indexed: 11/16/2024]
Abstract
RATIONALE AND OBJECTIVES To construct a radiomics nomogram derived from multiparametric ultrasound (US) imaging using the SHapley Additive exPlanations (SHAP) method for the accurate identification of residual axillary lymph node metastases post-neoadjuvant chemotherapy (NAC) among patients with triple-negative breast cancer (TNBC). METHODS A total of 405 consecutive patients with pathologically confirmed TNBC between 2016 and 2023 were recruited in the study and were divided into training (n = 284) and validation cohorts (n = 121). Radiomics features capturing detailed tumor characteristics were extracted from pre-NAC gray-scale US images at the locations of US-guided clip placement. The least absolute shrinkage and selection operator and the maximum relevance minimum redundancy algorithm were employed to identify key features and formulate the radiomics signature (RS). A nomogram based on US radiomics was then constructed using multivariable logistic regression analysis. The predictive efficacy of this model was evaluated through receiver operating characteristic curve analysis, calibration assessment, and decision curve analysis. SHAP summary plots were used to visualize the distribution of SHAP values across all features. RESULTS The nomogram integrates clinical and US characteristics with RS, yielded optimal AUC of 0.922 (95% CI, 0.890-0.954) in the training cohort, 0.904 (95% CI, 0.853-0.955) in the validation cohort. The calibration and decision curves confirmed favorable calibration and clinical value of the nomogram. SHAP provided further insight into the contributions of each feature to the model's outcomes. CONCLUSION The combined multiparametric US based radiomics nomogram plays a potential role in predicting residual axillary lymph node metastases after NAC in TNBCs.
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Affiliation(s)
- Qing Yao
- Department of Ultrasound, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China (Q.Y., W.L., X.L., H.Z., L.D., C.L.)
| | - Yu Du
- Department of Ultrasound, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China (Y.D.).
| | - Wei Liu
- Department of Ultrasound, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China (Q.Y., W.L., X.L., H.Z., L.D., C.L.)
| | - Xinpei Liu
- Department of Ultrasound, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China (Q.Y., W.L., X.L., H.Z., L.D., C.L.)
| | - Manqi Zhang
- Department of Ultrasound, Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China (M.Z.)
| | - Hailing Zha
- Department of Ultrasound, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China (Q.Y., W.L., X.L., H.Z., L.D., C.L.)
| | - Liwen Du
- Department of Ultrasound, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China (Q.Y., W.L., X.L., H.Z., L.D., C.L.)
| | - Xiaoming Zha
- Department of Breast Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China (X.Z., J.W.)
| | - Jue Wang
- Department of Breast Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China (X.Z., J.W.)
| | - Cuiying Li
- Department of Ultrasound, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China (Q.Y., W.L., X.L., H.Z., L.D., C.L.)
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8
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Pai S, Murthy SV. Molecular Subtypes and Ki-67 index in Breast Carcinoma with Special Emphasis on Triple Negative Breast Cancer. A 3-year Study in a Tertiary Care Center. Indian J Surg Oncol 2025; 16:478-490. [PMID: 40337051 PMCID: PMC12052743 DOI: 10.1007/s13193-023-01773-1] [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: 04/20/2022] [Accepted: 05/18/2023] [Indexed: 05/09/2025] Open
Abstract
Purpose Molecular subtyping of breast carcinoma and Ki-67 index has gained prominence in the recent past, as conventional factors such as surgical margins, tumor size, grade and lymph node involvement, are not sufficient to assess prognosis and make better therapeutic decisions. These subtypes include Luminal A, Luminal B, Triple Negative breast cancer (TNBC), and HER2-enriched subtypes. This study aimed to analyze the molecular subtypes and Ki-67 index in prognosis of breast carcinoma. Method This retrospective study was conducted in the department of Pathology in a tertiary care center over a period of 3 years. All invasive breast carcinomas (IDC) which were molecularly subtyped and Ki-67 indexed were included in the study. Statistical analysis was done using SPSS software. Results and Discussion Out of 253 cases, 231 cases (91.3%) were IDC-NST and 22 cases (8.7%) were special types. Metaplastic and papillary tumors were associated with higher grade and high Ki-67 value. TNBC (35.2%) showing a majority of high-grade tumors, was the most prevalent subtype followed by Luminal A (32%) showing low grade, unlike other studies which showed luminal A to be most common subtype. The rare PR positive subtype was also observed in our study. Conclusion TNBC and HER 2-positive subtypes exhibited bad prognosis with higher histological grade, high Ki-67 index and higher age at presentation whereas Luminal A subtype, with lower grade and low Ki-67 index showed better prognosis. Thus, this vast array of predictive and prognostic information obtained by molecular subtyping will help clinicians in not only distinguishing between low-risk and high-risk subtypes but also in customization of the treatment and follow-up of the patients.
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Affiliation(s)
- Shweta Pai
- Department of Pathology, ESIC Medical College and Post Graduate Institute of Medical Science and Research, Rajajinagar, Bangalore, India
| | - Srinivasa V Murthy
- Department of Pathology, ESIC Medical College and Post Graduate Institute of Medical Science and Research, Rajajinagar, Bangalore, India
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9
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De K, Jana M, Chowdhury B, Calaf GM, Roy D. Role of PARP Inhibitors: A New Hope for Breast Cancer Therapy. Int J Mol Sci 2025; 26:2773. [PMID: 40141415 PMCID: PMC11942994 DOI: 10.3390/ijms26062773] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2025] [Revised: 03/05/2025] [Accepted: 03/14/2025] [Indexed: 03/28/2025] Open
Abstract
Tumors formed by the unchecked growth of breast cells are known as breast cancer. The second most frequent cancer in the world is breast cancer. It is the most common cancer among females. In 2022, 2,296,840 women were diagnosed with breast cancer. The therapy of breast cancer is evolving through the development of Poly (ADP-ribose) polymerase (PARP) inhibitors, which are offering people with specific genetic profiles new hope as research into the disease continues. It focuses on patients with BRCA1 and BRCA2 mutations. This review summarizes the most recent research on the mechanisms of action of PARP inhibitors and their implications for breast cancer therapy. We review how therapeutic applications are developing and highlight recent studies showing the effectiveness of these medicines whether used alone or in combination. Furthermore, the significance of customized therapy is highlighted in enhancing patient outcomes as we address the function of genetic testing in identifying candidates for PARP inhibition. Recommendations for future research areas to maximize the therapeutic potential of PARP inhibitors are also included, along with challenges and limits in their clinical usage. The objective of this review is to improve our comprehension of the complex interaction between breast cancer biology and PARP inhibition. This knowledge will help to guide screening approaches, improve clinical practice, and support preventive initiatives for people at risk.
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Affiliation(s)
- Kamalendu De
- Department of Biological Sciences (Botany), Midnapore City College, Midnapore 721129, West Bengal, India;
| | - Malabendu Jana
- Department of Neurological Science, Rush University School of Medicine, Chicago, IL 773, USA;
| | - Bhabadeb Chowdhury
- HIV Dynamics and Replication Program, National Institute of Health, Frederick, MD 21702, USA;
| | - Gloria M. Calaf
- Instituto de Alta Investigación, Universidad de Tarapacá, Arica 1000000, Chile
| | - Debasish Roy
- Department of Natural Sciences, Hostos College of The City University of New York, Bronx, NY 718, USA;
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10
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Dent R, Cortés J, Park YH, Muñoz-Couselo E, Kim SB, Sohn J, Im SA, Holgado E, Foukakis T, Kümmel S, Yearley J, Wang A, Nebozhyn M, Huang L, Cristescu R, Jelinic P, Karantza V, Schmid P. Molecular determinants of response to neoadjuvant pembrolizumab plus chemotherapy in patients with high-risk, early-stage, triple-negative breast cancer: exploratory analysis of the open-label, multicohort phase 1b KEYNOTE-173 study. Breast Cancer Res 2025; 27:35. [PMID: 40069763 PMCID: PMC11895130 DOI: 10.1186/s13058-024-01946-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2024] [Accepted: 12/09/2024] [Indexed: 03/15/2025] Open
Abstract
BACKGROUND The multicohort, open-label, phase 1b KEYNOTE-173 study was conducted to investigate pembrolizumab plus chemotherapy as neoadjuvant therapy for triple-negative breast cancer (TNBC). This exploratory analysis evaluated features of the tumor microenvironment that might be predictive of response. METHODS Cell fractions from 20 paired samples collected at baseline and after one cycle of neoadjuvant pembrolizumab prior to chemotherapy initiation were analyzed by spatial localization (tumor compartment, stromal compartment, or sum of tumor and stromal compartments [total tumor]) using three six-plex immunohistochemistry panels with T-cell, myeloid cell, and natural killer cell components. Area under the receiver operating characteristic curve (AUROC) was used to assess associations between immune subsets and gene expression signatures (T-cell-inflamed gene expression profile [TcellinfGEP] and 10 non-TcellinfGEP signatures using RNA sequencing) and pathologic complete response (pCR). RESULTS At baseline, six immune subsets quantitated within the tumor compartment showed AUROC with 95% CIs not crossing 0.5, including CD11c+ cells (macrophage and dendritic cell [DC]: AUROC, 0.85; 95% confidence interval [CI] 0.63-1.00), CD11c+/MHCII+/CD163-/CD68- cells (DC: 0.76; 95% CI, 0.53-0.99), CD11c+/MHCII-/CD163-/CD68- cells (nonactivated/immature DC: 0.80; 95% CI 0.54-1.00), and CD11c+/CD163+ cells (M2 macrophage: 0.77; 95% CI 0.55-0.99). Other associations with pCR included baseline CD11c+/MHCII-/CD163-/CD68- (nonactivated/immature DC) within the total tumor (AUROC, 0.76; 95% CI 0.51-1.00) and the baseline CD11c/CD3 ratio within the tumor compartment (0.75; 95% CI 0.52-0.98). Changes in immune subsets following one cycle of pembrolizumab were not strongly associated with pCR. Although T-cell associations were relatively weak, specific CD8 subsets trended toward association. The AUROC for discriminating pCR based on TcellinfGEP was 0.55 (95% CI 0.25-0.85); when detrended by TcellinfGEP, AUROC varied for the non-TcellinfGEP signatures. TcellinfGEP expression trended higher in responders than in nonresponders when evaluating pCR. CONCLUSIONS Myeloid cell populations within the tumor compartment at baseline and TcellinfGEP show a promising trend toward an association with pCR in a small subgroup of patients with early-stage TNBC treated with neoadjuvant pembrolizumab plus chemotherapy. TRIAL REGISTRATION ClinicalTrials.gov, NCT02622074; registration date, December 2, 2015.
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Affiliation(s)
- Rebecca Dent
- Division of Medical Oncology, National Cancer Centre Singapore, 30 Hospital Blvd, Singapore, 168583, Singapore.
| | - Javier Cortés
- Vall d´Hebron Institute of Oncology (VHIO), Barcelona, Spain
- International Breast Cancer Center, Quironsalud Group, Barcelona, Spain
- Department of Medicine, Faculty of Biomedical and Health Sciences, European University of Madrid, Madrid, Spain
| | - Yeon Hee Park
- Department of Medicine, Division of Hematology-Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Eva Muñoz-Couselo
- Vall d´Hebron Institute of Oncology (VHIO), Barcelona, Spain
- Department of Medical Oncology, Vall d'Hebron Hospital, Barcelona, Spain
| | - Sung-Bae Kim
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Joohyuk Sohn
- Department of Internal Medicine, Division of Medical Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Seock-Ah Im
- Department of Internal Medicine, Cancer Research Institute, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Esther Holgado
- Medical Oncology Service, Ramón y Cajal University Hospital, Madrid, Spain
| | - Theodoros Foukakis
- Department of Oncology-Pathology, Karolinska Comprehensive Cancer Center, Karolinska Institute and Breast Cancer Centre, Cancer Theme, Karolinska University Hospital, Solna, Sweden
| | - Sherko Kümmel
- Interdisciplinary Breast Unit, Essen-Mitte Clinics, Essen, and Charité-Universitätsmedizin Berlin, Berlin, Germany
| | | | | | | | | | | | | | | | - Peter Schmid
- Centre for Experimental Cancer Medicine, Barts Cancer Institute, London, UK
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11
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Xue Q, He N, Gao Y, Zhang X, Li S, Chen F, Ning C, Wu X, Yao J, Zhang Z, Li S, Zhao C. Optimizing Triple-Negative Breast Cancer Therapy via Ultrasound-Enhanced Piezocatalysis for Targeted Chemodrug Release. Int J Nanomedicine 2025; 20:2779-2796. [PMID: 40066325 PMCID: PMC11892375 DOI: 10.2147/ijn.s505526] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2024] [Accepted: 02/23/2025] [Indexed: 05/13/2025] Open
Abstract
Introduction Triple-negative breast cancer (TNBC) is known for its high malignancy, limited clinical treatment options, and poor chemotherapy outcomes. Although some advancements have been made using nanotechnology-based chemotherapy for TNBC treatment, the controlled and on-demand release of chemotherapeutic drugs at the tumor site remains a challenge. Methods We manufactured DOX/BaTiO3@cRGD-Lip (DBRL) nanoparticles as an ultrasound (US)-controlled release platform targeting the delivery of Doxorubicin (DOX) for TNBC treatment. The nanoparticles incorporate DSPE-Se-Se-PEG-NH2 as the liposomal membrane for ROS responsiveness, cRGD peptide for TNBC cell selectivity, and polyethylene glycol for minimized phagocytic cell absorption. Results The DBRL+US group achieved significant tumor inhibition (70.27% compared to control group, p < 0.001), while maintaining excellent biocompatibility with over 90% cell viability in normal cells. The selective cytotoxicity was evidenced by a 55.70% cell death rate in 4T1 cancer cells under US activation. DBRL showed enhanced tumor accumulation with peak fluorescence intensity of (1.01 ± 0.33)×109 at 12 hours post-injection. Conclusion This targeted nanocomposite material paves a new prospect for future precise piezoelectric catalytic therapy for the treatment of TNBC.
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Affiliation(s)
- Qingwen Xue
- Department of Ultrasound, the Affiliated Hospital of Qingdao University, Qingdao, 266003, People’s Republic of China
| | - Ningning He
- School of Basic Medicine, Qingdao Medical College, Qingdao University, Qingdao, 266003, People’s Republic of China
| | - Yuxiu Gao
- Department of Ultrasound, the Affiliated Hospital of Qingdao University, Qingdao, 266003, People’s Republic of China
| | - Xuehui Zhang
- Department of Ultrasound, the Affiliated Hospital of Qingdao University, Qingdao, 266003, People’s Republic of China
| | - Shuao Li
- Department of Ultrasound, the Affiliated Hospital of Qingdao University, Qingdao, 266003, People’s Republic of China
| | - Fang Chen
- Department of Ultrasound, the Affiliated Hospital of Qingdao University, Qingdao, 266003, People’s Republic of China
| | - Chunping Ning
- Department of Ultrasound, the Affiliated Hospital of Qingdao University, Qingdao, 266003, People’s Republic of China
| | - Xiaoyu Wu
- School of Basic Medicine, Qingdao Medical College, Qingdao University, Qingdao, 266003, People’s Republic of China
| | - Jingtong Yao
- School of Basic Medicine, Qingdao Medical College, Qingdao University, Qingdao, 266003, People’s Republic of China
| | - Ziheng Zhang
- School of Basic Medicine, Qingdao Medical College, Qingdao University, Qingdao, 266003, People’s Republic of China
| | - Shangyong Li
- Department of Ultrasound, the Affiliated Hospital of Qingdao University, Qingdao, 266003, People’s Republic of China
- School of Basic Medicine, Qingdao Medical College, Qingdao University, Qingdao, 266003, People’s Republic of China
| | - Cheng Zhao
- Department of Ultrasound, the Affiliated Hospital of Qingdao University, Qingdao, 266003, People’s Republic of China
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12
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Huang Z, Peng Q, Mao L, Ouyang W, Xiong Y, Tan Y, Chen H, Zhang Z, Li T, Hu Y, Wang Y, Zhang W, Yao H, Yu Y. Neoadjuvant Strategies for Triple Negative Breast Cancer: Current Evidence and Future Perspectives. MEDCOMM – FUTURE MEDICINE 2025; 4. [DOI: 10.1002/mef2.70013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/05/2024] [Accepted: 02/10/2025] [Indexed: 04/02/2025]
Abstract
ABSTRACTTriple‐negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer, characterized by poor prognosis and limited therapeutic options. Although neoadjuvant chemotherapy (NACT) remains the established treatment approach, its suboptimal efficacy associated with TNBC highlight the urgent need for optimized treatment strategies to improve pathological complete response (pCR) rates. This review provides a comprehensive overview of recent advancements in neoadjuvant treatment for TNBC, emphasizing pivotal breakthroughs in therapeutic strategies and the ongoing pursuit of innovative approaches to enhance precision medicine. It emphasizes the clinical value of platinum‐based agents, such as carboplatin and cisplatin, which have shown significant improvements in pCR rates, particularly in TNBC patients with BRCA mutations. Additionally, the review explores progress in targeted therapies, including PARP inhibitors, AKT inhibitors, and Antiangiogenic agents, showcasing their potential for personalized treatment approaches. The integration of immunotherapy, particularly immune checkpoint inhibitor like pembrolizumab and atezolizumab, with chemotherapy has demonstrated substantial efficacy in high‐risk TNBC cases. Future research priorities include refining biomarker‐driven strategies, optimizing therapeutic combinations, developing antibody‐drug conjugates (ADCs) targeting TROP2 and other biomarkers, and reducing treatment‐related toxicity to develop safer and highly personalized neoadjuvant therapies. Furthermore, artificial intelligence has also emerged as a transformative tool in predicting treatment response and optimizing therapeutic decision‐making in TNBC. These advancements aim to improve long‐term outcomes and quality of life for patients with TNBC.
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Affiliation(s)
- Zhenjun Huang
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong‐Hong Kong Joint Laboratory for RNA Medicine, Department of Medical Oncology, Breast Tumor Centre, Phase I Clinical Trial Centre, Sun Yat‐sen Memorial Hospital Sun Yat‐sen University Guangzhou China
| | - Qing Peng
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong‐Hong Kong Joint Laboratory for RNA Medicine, Department of Medical Oncology, Breast Tumor Centre, Phase I Clinical Trial Centre, Sun Yat‐sen Memorial Hospital Sun Yat‐sen University Guangzhou China
| | - Luhui Mao
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong‐Hong Kong Joint Laboratory for RNA Medicine, Department of Medical Oncology, Breast Tumor Centre, Phase I Clinical Trial Centre, Sun Yat‐sen Memorial Hospital Sun Yat‐sen University Guangzhou China
| | - Wenhao Ouyang
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong‐Hong Kong Joint Laboratory for RNA Medicine, Department of Medical Oncology, Breast Tumor Centre, Phase I Clinical Trial Centre, Sun Yat‐sen Memorial Hospital Sun Yat‐sen University Guangzhou China
| | - Yunjing Xiong
- The Second Clinical Medical College Nanchang University Nanchang China
| | - Yujie Tan
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong‐Hong Kong Joint Laboratory for RNA Medicine, Department of Medical Oncology, Breast Tumor Centre, Phase I Clinical Trial Centre, Sun Yat‐sen Memorial Hospital Sun Yat‐sen University Guangzhou China
| | - Haizhu Chen
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong‐Hong Kong Joint Laboratory for RNA Medicine, Department of Medical Oncology, Breast Tumor Centre, Phase I Clinical Trial Centre, Sun Yat‐sen Memorial Hospital Sun Yat‐sen University Guangzhou China
| | - Zebang Zhang
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong‐Hong Kong Joint Laboratory for RNA Medicine, Department of Medical Oncology, Breast Tumor Centre, Phase I Clinical Trial Centre, Sun Yat‐sen Memorial Hospital Sun Yat‐sen University Guangzhou China
| | - Tang Li
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong‐Hong Kong Joint Laboratory for RNA Medicine, Department of Medical Oncology, Breast Tumor Centre, Phase I Clinical Trial Centre, Sun Yat‐sen Memorial Hospital Sun Yat‐sen University Guangzhou China
| | - Yuanjia Hu
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences University of Macau Taipa Macau China
| | - Ying Wang
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong‐Hong Kong Joint Laboratory for RNA Medicine, Department of Medical Oncology, Breast Tumor Centre, Phase I Clinical Trial Centre, Sun Yat‐sen Memorial Hospital Sun Yat‐sen University Guangzhou China
| | - Wei Zhang
- Department of Breast Surgery, The First Affiliated Hospital Jinan University Guangzhou China
| | - Herui Yao
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong‐Hong Kong Joint Laboratory for RNA Medicine, Department of Medical Oncology, Breast Tumor Centre, Phase I Clinical Trial Centre, Sun Yat‐sen Memorial Hospital Sun Yat‐sen University Guangzhou China
| | - Yunfang Yu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong‐Hong Kong Joint Laboratory for RNA Medicine, Department of Medical Oncology, Breast Tumor Centre, Phase I Clinical Trial Centre, Sun Yat‐sen Memorial Hospital Sun Yat‐sen University Guangzhou China
- Department of Breast Surgery, The First Affiliated Hospital Jinan University Guangzhou China
- Shenshan Medical Center, Sun Yat‐sen Memorial Hospital Sun Yat‐sen University Guangzhou China
- Faculty of Medicine Macau University of Science and Technology Taipa Macao China
- Guangdong Provincial Key Laboratory IRADS BNU‐HKBU United International College Zhuhai China
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Jacot W, Chateau M, Thezenas S, Guiu S, Firmin N, Lafont V, Lazennec G, Theillet C, Boissière‐Michot F. Prognostic Value of Trop-2 Expression in Nonmetastatic Triple-Negative Breast Cancer and Correlation With Emerging Biomarkers. Cancer Med 2025; 14:e70615. [PMID: 40059728 PMCID: PMC11891490 DOI: 10.1002/cam4.70615] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2024] [Revised: 11/07/2024] [Accepted: 01/06/2025] [Indexed: 05/13/2025] Open
Abstract
INTRODUCTION Triple-Negative Breast Cancer (TNBC) is an aggressive breast cancer subtype, in which targeting the Trophoblast cell-surface antigen-2 (Trop-2), using antibody-drug conjugates (ADC), results in significant clinical improvement. However, clinicopathological correlations with Trop-2 protein expression levels remain limited in TNBC patients. METHODS Here we assessed by immunohistochemistry (IHC) using the mouse monoclonal anti-Trop-2 antibody (Enzo, Cat. ENZ-ABS380) cell membrane Trop-2 expression levels and classified them in 3 H-Score classes, low (< 100), moderate (100-200), and strong (> 200). We also evaluated potential associations with clinicopathological variables including basal-like and molecular apocrine phenotypes, immune infiltrate characteristics, PTEN and PIK3CA alterations in a large retrospective series of 228 nonmetastatic TNBC patients. RESULTS Trop-2 expression was evaluated as low, moderate and strong in 12.3%, 28.9%, and 58.8% of the cases respectively. Only 3 tumors showed no Trop-2 expression. Interestingly, Trop-2 expression was not associated with classical breast cancer clinicopathological variables, HER2 levels or molecular subtype, neither did we observe an association with relapse-free survival. Only a marginal association with pT1 tumors was observed, which tended to express increased levels of Trop-2 protein. In order to determine possible fluctuations of Trop-2 protein expression levels during the course of the disease, we studied a second independent cohort of 18 TNBC comprised of serial tissue samples (diagnostic biopsies, surgical resection specimens and corresponding patients-derived xenografts (PDX)). Trop-2 levels remained globally stable between cognate tumor samples with only one exception corresponding to a Trop-2-negative tumor giving rise to a Trop-2-positive PDX. CONCLUSIONS As Trop-2 expression appears nearly constant and independent of classical TNBC variables and outcome, association of anti-Trop-2 therapies with other targeted therapies can be evaluated without reducing the population in specific TNBC subgroups.
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Affiliation(s)
- William Jacot
- Department of Medical OncologyMontpellier Cancer Institute Val d'AurelleMontpellierFrance
- Translational Research UnitMontpellier Cancer Institute Val d'AurelleMontpellierFrance
- Montpellier UniversityMontpellierFrance
- Institut de Recherche en Cancérologie de Montpellier (IRCM)MontpellierFrance
| | | | - Simon Thezenas
- Biometrics Unit, Institut du Cancer Montpellier (ICM)Université de MontpellierMontpellierFrance
- Institut du Cancer Montpellier (ICM)Université de MontpellierMontpellierFrance
| | - Séverine Guiu
- Department of Medical OncologyMontpellier Cancer Institute Val d'AurelleMontpellierFrance
- Institut de Recherche en Cancérologie de Montpellier (IRCM)MontpellierFrance
| | - Nelly Firmin
- Institut de Recherche en Cancérologie de Montpellier (IRCM)MontpellierFrance
| | - Virginie Lafont
- Montpellier UniversityMontpellierFrance
- Institut de Recherche en Cancérologie de Montpellier (IRCM)MontpellierFrance
| | | | - Charles Theillet
- Institut de Recherche en Cancérologie de Montpellier (IRCM)MontpellierFrance
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Patel SS, Cook RS, Lo JH, Cherry FK, Hoogenboezem EN, Yu F, Francini N, Cassidy NT, McCune JT, Gbur EF, Messier L, Dean TA, Wilson KL, Brantley-Sieders DM, Duvall CL. Induction of Triple-Negative Breast Cancer Cell Death and Chemosensitivity Using mTORC2-Directed RNAi Nanomedicine. CANCER RESEARCH COMMUNICATIONS 2025; 5:458-476. [PMID: 40019775 PMCID: PMC11921867 DOI: 10.1158/2767-9764.crc-24-0261] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/09/2024] [Revised: 11/13/2024] [Accepted: 02/26/2025] [Indexed: 03/01/2025]
Abstract
SIGNIFICANCE We identified an mTORC2/Rictor-directed RNAi nanomedicine that cooperates with chemotherapy to enhance in vivo tumor cell killing in PI3K-active TNBCs.
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Affiliation(s)
- Shrusti S. Patel
- Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee
| | - Rebecca S. Cook
- Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee
| | - Justin H. Lo
- Division of Hematology/Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Fiona K. Cherry
- Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee
| | - Ella N. Hoogenboezem
- Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee
| | - Fang Yu
- Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee
| | - Nora Francini
- Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee
| | - Nina T. Cassidy
- Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee
| | - Joshua T. McCune
- Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee
| | - Eva F. Gbur
- Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee
| | - Lisa Messier
- Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee
| | - Thomas A. Dean
- Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee
| | - Kalin L. Wilson
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
| | | | - Craig L. Duvall
- Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee
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15
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Ghazizadeh M, Khorsandi K, Najafi SMA. Synergic anti-tumor effects of photodynamic therapy and resveratrol on triple-negative breast cancer cells. Photochem Photobiol Sci 2025; 24:451-465. [PMID: 40095354 DOI: 10.1007/s43630-025-00698-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2024] [Accepted: 02/24/2025] [Indexed: 03/19/2025]
Abstract
INTRODUCTION Breast cancer is a widespread type of cancer found across the world. The use of chemotherapy in breast cancer treatment may result in side effects and the emergence of drug resistance. Hence, seeking new and efficient therapies that reduce adverse reactions is imperative. Recently, combination therapy has emerged as a fresh and innovative strategy in contrast to conventional treatment methods. Photodynamic therapy (PDT) serves as a highly effective and minimally invasive technique for addressing breast cancer, providing the option to be utilized either concurrently or in conjunction with other therapeutic approaches. Resveratrol (RES) is a polyphenol found in several food sources. Research has demonstrated that RES can inhibit cell proliferation and metastasis and trigger apoptosis in tumor cells. This research aimed to assess the impact of combining RES and photodynamic therapy on MDA-MB-231 breast cancer cells. METHODS MDA-MB-231 cells were grown in culture and subsequently exposed to different methylene blue (MB) doses while subjected to laser irradiation (PDT). Following this treatment, the cells were exposed to different RES concentrations. Cell viability was assessed utilizing the MTT assay. Light and fluorescence microscopy (AO/EB staining) were employed to observe cell morphological alterations following exposure to RES and MB-PDT. Additionally, flow cytometry was utilized to investigate cell cycle progression and apoptosis induction. RESULTS The findings indicated that the co-administration of MB-PDT and RES resulted in increased cytotoxic effects on MDA-MB-231 breast cancer cells compared to the individual application of either treatment. DISCUSSION The results of this study suggest that MB-PDT can reduce the dose and time of RES treatment and, therefore, can be indicated as a new approach for treating breast cancer cells.
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Affiliation(s)
- Masta Ghazizadeh
- Department of Cell and Molecular Biology, School of Biology, College of Sciences, University of Tehran, Tehran, Iran
| | - Khatereh Khorsandi
- Department of Photodynamic, Medical Laser Research Center, Yara Institute, ACECR, Tehran, Iran.
| | - SMahmoud A Najafi
- Department of Cell and Molecular Biology, School of Biology, College of Sciences, University of Tehran, Tehran, Iran
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Wang J, Wang Y, Zhang S, Hu H, Zhang R, Zi C, Sheng J, Sun P. Prodelphinidin B-2,3,3"-O-gallate via chemical oxidation of epigallocatechin-3-gallate shows high efficacy inhibiting triple-negative breast cancer cells. BMC Pharmacol Toxicol 2025; 26:48. [PMID: 40022263 PMCID: PMC11869402 DOI: 10.1186/s40360-025-00883-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2024] [Accepted: 02/25/2025] [Indexed: 03/03/2025] Open
Abstract
BACKGROUND Triple-negative breast cancer is a clinically aggressive malignancy with poorer outcomes versus other subtypes of breast cancer. Numerous reports have discussed the use of epigallocatechin-3-gallate (EGCG) against various types of cancer. However, the effectiveness of EGCG is limited by its high oxidation and instability. The Notch pathway is critical in breast cancer development and prognosis, and its inhibition is a potential treatment strategy. RESULTS In this study, we investigated the effects of prodelphinidin B-2,3,3''-O-gallate (named PB2,3,3''/OG or compound 2) via chemical oxidation of EGCG on cell viability and the Notch1 signaling pathway in breast cancer cells. We found that compound 2 showed significant cytotoxicity against triple-negative breast cancer cells, with the half maximal inhibitory concentration (IC50) values ranging 20-50 µM. In MDA-MB453 cells, compound 2 inhibited proliferation, clone formation, and the expression of proteins involved in the Notch1 signaling pathway. Furthermore, compound 2 induced cell cycle arrest and apoptosis. Consistent with the results of in-vitro experiments, treatment with compound 2 significantly reduced tumor growth. Mechanistically, compound 2 directly bound to Notch1 with high binding affinity (dissociation constant: KD=4.616 × 10- 6 M). CONCLUSION Our finding suggested that compound 2 may be a promising agent for the development of novel anti-cancer therapy options.
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Affiliation(s)
- Jing Wang
- Key Laboratory of Pu-er Tea Science, Ministry of Education, Yunnan Agricultural University, Kunming, 650201, China
- College of Science, Yunnan Agricultural University, Kunming, 650201, China
| | - Yuna Wang
- Key Laboratory of Pu-er Tea Science, Ministry of Education, Yunnan Agricultural University, Kunming, 650201, China
| | - Shuanggou Zhang
- Key Laboratory of Pu-er Tea Science, Ministry of Education, Yunnan Agricultural University, Kunming, 650201, China
- College of Food Science and Technology, Yunnan Agricultural University, Kunming, 650201, China
| | - Hongtao Hu
- Key Laboratory of Pu-er Tea Science, Ministry of Education, Yunnan Agricultural University, Kunming, 650201, China
- College of Food Science and Technology, Yunnan Agricultural University, Kunming, 650201, China
| | - Ruohan Zhang
- Key Laboratory of Pu-er Tea Science, Ministry of Education, Yunnan Agricultural University, Kunming, 650201, China
- College of Food Science and Technology, Yunnan Agricultural University, Kunming, 650201, China
| | - Chengting Zi
- Key Laboratory of Pu-er Tea Science, Ministry of Education, Yunnan Agricultural University, Kunming, 650201, China.
- College of Food Science and Technology, Yunnan Agricultural University, Kunming, 650201, China.
| | - Jun Sheng
- Key Laboratory of Pu-er Tea Science, Ministry of Education, Yunnan Agricultural University, Kunming, 650201, China.
| | - Peiyuan Sun
- Key Laboratory of Pu-er Tea Science, Ministry of Education, Yunnan Agricultural University, Kunming, 650201, China.
- College of Science, Yunnan Agricultural University, Kunming, 650201, China.
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Tayebi A, TizMaghz A, Gorjizad M, Tavasol A, Tajaddini A, Rashnoo F, Vakili K, Behmanesh M, Olamaeian F, Ashoori M. Evaluating the effect of neoadjuvant chemotherapy on surgical outcomes in breast cancer patients: a systematic review study. J Chemother 2025:1-14. [PMID: 40019128 DOI: 10.1080/1120009x.2025.2468044] [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: 08/29/2024] [Revised: 01/18/2025] [Accepted: 01/22/2025] [Indexed: 03/01/2025]
Abstract
As a systematic review, this study addresses a gap in the literature by evaluating both the short-term and long-term outcomes of breast cancer patients undergoing neoadjuvant chemotherapy (NAC). The purpose of the current study was to evaluate NAC's impact on breast cancer patients' surgical outcomes. We performed a comprehensive search of international databases, including PubMed, Scopus, Embase, and Science Direct, covering studies from 2000 to 2023, using carefully selected keywords. Our search strategy aimed to capture a wide variety of relevant studies. To ensure a structured and unbiased selection, we followed PRISMA guidelines throughout the process. We concentrated on identifying studies that reported on short-term outcomes, like surgical complications (e.g., operation time, blood loss), as well as long-term outcomes, including overall survival, tumor size reduction, metastasis rates, breast conservation surgery, and recurrence rates. The findings highlighted the benefits of NAC in terms of lower recurrence and metastasis rates. The results also emphasized the significance of considering tumor characteristics and nodal involvement for prognostication in this patient population. The findings of this study will contribute to a better understanding of the impact of NAC on surgical outcomes in breast cancer patients, providing valuable insights for treatment planning and optimizing patient care.
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Affiliation(s)
- Ali Tayebi
- Firoozabadi Clinical Research Development Unit (FACRDU), Iran University of Medical Sciences (IUMS), Tehran, Iran
| | - Adnan TizMaghz
- Firoozabadi Clinical Research Development Unit (FACRDU), Iran University of Medical Sciences (IUMS), Tehran, Iran
| | - Mahmood Gorjizad
- Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Arian Tavasol
- Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ali Tajaddini
- Department of Surgery, Shiraz University of Medical Sciences, Tehran, Iran
| | - Fariborz Rashnoo
- Department of General and Minimally Invasive Surgery, Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Kimia Vakili
- Student Research Committee, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohsen Behmanesh
- Firoozabadi Clinical Research Development Unit (FACRDU), Iran University of Medical Sciences (IUMS), Tehran, Iran
| | - Faranak Olamaeian
- Firoozabadi Clinical Research Development Unit (FACRDU), Iran University of Medical Sciences (IUMS), Tehran, Iran
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Alaouna M, Molefi T, Khanyile R, Chauke-Malinga N, Chatziioannou A, Luvhengo TE, Raletsena M, Penny C, Hull R, Dlamini Z. The potential of the South African plant Tulbaghia Violacea Harv for the treatment of triple negative breast cancer. Sci Rep 2025; 15:5737. [PMID: 39962120 PMCID: PMC11832780 DOI: 10.1038/s41598-025-88417-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Accepted: 01/28/2025] [Indexed: 02/20/2025] Open
Abstract
Triple-negative breast cancer (TNBC) is difficult to treat and has a low five-year survival rate. In South Africa, a large percentage of the population still relies on traditional plant-based medicine. To establish the utility of both methanol and water-soluble extracts from the leaves of Tulbaghia violacea, cytotoxicity assays were carried out to establish the IC50 values against a TNBC cell line. Cell cycle and apoptosis assays were carried out using the extracts. To identify the molecular compounds, present in water-soluble leaf extracts, NMR spectroscopy was performed. Compounds of interest were then used in computational docking studies with the anti-apoptotic protein COX-2. The IC50 values for the water- and methanol-soluble extracts were determined to be 400 and 820 µg/mL, respectively. The water-soluble extract induced apoptosis in the TNBC cell line to a greater extent than in the normal cell line. RNAseq indicated that there was an increase in the transcription of pro-apoptotic genes in the TNBC cell line. The crude extract also caused these cells to stall in the S phase. Of the 61 compounds identified in this extract, five demonstrated a high binding affinity for COX-2. Based on these findings, the compounds within the extract show significant potential for further investigation as candidates for the development of cancer therapeutics, particularly for TNBC.
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Affiliation(s)
- Mohammed Alaouna
- Department of Internal Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
- Department of Chemical pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
| | - Thulo Molefi
- Department of Medical Oncology, Steve Biko Academic Hospital, University of Pretoria, Pretoria, 0001, South Africa
- Department of Chemical pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
- SA-MRC Precision Oncology Research Unit (PORU), DSTI/NRF SARChI Chair in Precision Oncology and Cancer Prevention (POCP), Pan African Cancer Research Institute (PACRI), University of Pretoria Hatfield, Pretoria, 0028, South Africa
| | - Richard Khanyile
- Department of Medical Oncology, Steve Biko Academic Hospital, University of Pretoria, Pretoria, 0001, South Africa
- SA-MRC Precision Oncology Research Unit (PORU), DSTI/NRF SARChI Chair in Precision Oncology and Cancer Prevention (POCP), Pan African Cancer Research Institute (PACRI), University of Pretoria Hatfield, Pretoria, 0028, South Africa
| | - Nkhensani Chauke-Malinga
- Papillon Aesthetics, Suite 302b Netcare Linksfield Hospital, 24 12th Ave, Linksfield West, Johannesburg, 2192, South Africa
- Department of Chemical pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
- SA-MRC Precision Oncology Research Unit (PORU), DSTI/NRF SARChI Chair in Precision Oncology and Cancer Prevention (POCP), Pan African Cancer Research Institute (PACRI), University of Pretoria Hatfield, Pretoria, 0028, South Africa
| | - Aristotelis Chatziioannou
- Center of Systems Biology, Biomedical Research Foundation of the Academy of Athens, Athens, 11527, Greece
- Department of Chemical pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
- SA-MRC Precision Oncology Research Unit (PORU), DSTI/NRF SARChI Chair in Precision Oncology and Cancer Prevention (POCP), Pan African Cancer Research Institute (PACRI), University of Pretoria Hatfield, Pretoria, 0028, South Africa
| | - Thifhelimbilu Emmanuel Luvhengo
- Department of Surgery, Charlotte Maxeke Johannesburg Academic Hospital, University of the Witwatersrand, Parktown, Johannesburg, 2193, South Africa
- Department of Chemical pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
| | - Maropeng Raletsena
- Department of Chemical pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
- Department of Chemistry, University of South Africa, Florida Campus, Johannesburg, South Africa
| | - Clement Penny
- Department of Internal Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
- Department of Chemical pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
| | - Rodney Hull
- Department of Chemical pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
- SA-MRC Precision Oncology Research Unit (PORU), DSTI/NRF SARChI Chair in Precision Oncology and Cancer Prevention (POCP), Pan African Cancer Research Institute (PACRI), University of Pretoria Hatfield, Pretoria, 0028, South Africa.
| | - Zodwa Dlamini
- Department of Chemical pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
- SA-MRC Precision Oncology Research Unit (PORU), DSTI/NRF SARChI Chair in Precision Oncology and Cancer Prevention (POCP), Pan African Cancer Research Institute (PACRI), University of Pretoria Hatfield, Pretoria, 0028, South Africa.
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19
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Martín M, Stecklein SR, Gluz O, Villacampa G, Monte-Millán M, Nitz U, Cobo S, Christgen M, Brasó-Maristany F, Álvarez EL, Echavarría I, Conte B, Kuemmel S, Bueno-Muiño C, Jerez Y, Kates R, Cebollero M, Kolberg-Liedtke C, Bueno O, García-Saenz JÁ, Moreno F, Grischke EM, Forstbauer H, Braun M, Warm M, Hackmann J, Uleer C, Aktas B, Schumacher C, Wuerstleins R, Graeser M, Zu Eulenburg C, Kreipe HH, Gómez H, Massarrah T, Herrero B, Paré L, Bohn U, López-Tarruella S, Vivancos A, Sanfeliu E, Parker JS, Perou CM, Villagrasa P, Prat A, Sharma P, Harbeck N. TNBC-DX genomic test in early-stage triple-negative breast cancer treated with neoadjuvant taxane-based therapy. Ann Oncol 2025; 36:158-171. [PMID: 39419289 DOI: 10.1016/j.annonc.2024.10.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2024] [Revised: 09/28/2024] [Accepted: 10/07/2024] [Indexed: 10/19/2024] Open
Abstract
BACKGROUND Identification of biomarkers to optimize treatment strategies for early-stage triple-negative breast cancer (TNBC) is crucial. This study presents the development and validation of TNBC-DX, a novel test aimed at predicting both short- and long-term outcomes in early-stage TNBC. The objective of this study was to evaluate the association between TNBC-DX and efficacy outcomes [pathologic complete response (pCR), distant disease-free survival (DDFS) or event-free survival (EFS), and overall survival (OS)] in the validation cohorts. METHODS Information from 1259 patients with early-stage TNBC (SCAN-B, CALGB-40603, and BrighTNess) was used to establish the TNBC-DX scores. Independent validation of TNBC-DX was carried out in three studies: (i) WSG-ADAPT-TN; (ii) MMJ-CAR-2014-01; and (iii) NeoPACT, including 527 patients with stage I-III TNBC undergoing neoadjuvant chemotherapy. In WSG-ADAPT-TN, patients were randomized to receive nab-paclitaxel plus gemcitabine or carboplatin. In MMJ-CAR-2014-01, patients received carboplatin plus docetaxel. In NeoPACT, patients received carboplatin plus docetaxel and pembrolizumab. RESULTS TNBC-DX test was created incorporating the 10-gene Core Immune Gene module, the 4-gene tumor cell proliferation signature, tumor size, and nodal staging. In the two independent validation cohorts without pembrolizumab, the TNBC-DX pCR score was significantly associated with pCR after adjustment for clinicopathological variables and treatment regimen [odds ratio per 10-unit increment 1.34, 95% confidence interval (CI) 1.20-1.52, P < 0.001]. pCR rates for the TNBC-DX pCR-high, pCR-medium, and pCR-low categories were 56.3%, 53.6%, and 22.5% respectively (odds ratio for pCR-high versus pCR-low 3.48, 95% CI 1.72-7.15, P < 0.001). In addition, the TNBC-DX risk score was significantly associated with DDFS [hazard ratio (HR) high-risk versus low-risk 0.24, 95% CI 0.15-0.41, P < 0.001] and OS (HR 0.19, 95% CI 0.11-0.35, P < 0.001). In the validation cohort with pembrolizumab, the TNBC-DX scores were significantly associated with pCR, EFS, and OS. CONCLUSIONS TNBC-DX predicts pCR to neoadjuvant taxane-carboplatin in stage I-III TNBC and helps to forecast the patient's long-term survival in the absence of neoadjuvant anthracycline-cyclophosphamide, and independent of pembrolizumab use.
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Affiliation(s)
- M Martín
- Department of Medical Oncology, Hospital General Universitario Gregorio Marañón, Madrid, Spain; Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain; Centro de Investigación Biomédica en Red de Cáncer, Madrid, Spain; Grupo Español de Investigación en Cáncer de Mama, Madrid, Spain; Universidad Complutense de Madrid, Madrid, Spain
| | - S R Stecklein
- Department of Internal Medicine, University of Kansas Medical Center, Westwood; Department of Radiation Oncology, University of Kansas Medical Center, Kansas City, USA; Departments of Pathology & Laboratory Medicine, University of Kansas Medical Center, Kansas City, USA; Departments of Cancer Biology, University of Kansas Medical Center, Kansas City, USA
| | - O Gluz
- West German Study Group, Monchengladbach, Germany; Breast Center Niederrhein, Ev. Hospital Bethesda, Moenchengladbach, Germany; University Clinics Cologne, Cologne, Germany
| | - G Villacampa
- SOLTI Cancer Research Group, Barcelona, Spain; Statistics Unit, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
| | - M Monte-Millán
- Department of Medical Oncology, Hospital General Universitario Gregorio Marañón, Madrid, Spain; Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain; Centro de Investigación Biomédica en Red de Cáncer, Madrid, Spain
| | - U Nitz
- West German Study Group, Monchengladbach, Germany; Breast Center Niederrhein, Ev. Hospital Bethesda, Moenchengladbach, Germany
| | - S Cobo
- Translational Genomics and Targeted Therapies in Solid Tumors, August Pi I Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain
| | - M Christgen
- University Clinics Cologne, Cologne, Germany
| | - F Brasó-Maristany
- Translational Genomics and Targeted Therapies in Solid Tumors, August Pi I Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain; Reveal Genomics, Barcelona, Spain
| | - E L Álvarez
- Department of Medical Oncology, Hospital General Universitario Gregorio Marañón, Madrid, Spain; Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain
| | - I Echavarría
- Department of Medical Oncology, Hospital General Universitario Gregorio Marañón, Madrid, Spain; Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain; Centro de Investigación Biomédica en Red de Cáncer, Madrid, Spain
| | - B Conte
- Translational Genomics and Targeted Therapies in Solid Tumors, August Pi I Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain
| | - S Kuemmel
- Medical School Hannover, Institute of Pathology, Hannover; Breast Unit, Clinics Essen Mitte, Breast Center, Essen, Germany
| | - C Bueno-Muiño
- Medical Oncology Department, Hospital Infanta Cristina (Parla), Madrid, Spain
| | - Y Jerez
- Department of Medical Oncology, Hospital General Universitario Gregorio Marañón, Madrid, Spain; Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain; Centro de Investigación Biomédica en Red de Cáncer, Madrid, Spain
| | - R Kates
- West German Study Group, Monchengladbach, Germany
| | - M Cebollero
- Department of Medical Oncology, Hospital General Universitario Gregorio Marañón, Madrid, Spain; Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain
| | - C Kolberg-Liedtke
- Department of Gynecology and Obstetrics, University Hospital Essen, Essen, Germany
| | - O Bueno
- Department of Medical Oncology, Hospital General Universitario Gregorio Marañón, Madrid, Spain; Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain
| | - J Á García-Saenz
- Grupo Español de Investigación en Cáncer de Mama, Madrid, Spain; Department of Medical Oncology, Instituto de Investigación Sanitaria Hospital Clinico San Carlos (IdISSC), Madrid, Spain
| | - F Moreno
- Grupo Español de Investigación en Cáncer de Mama, Madrid, Spain; Department of Medical Oncology, Instituto de Investigación Sanitaria Hospital Clinico San Carlos (IdISSC), Madrid, Spain
| | - E-M Grischke
- Department of Gynecology, Women's Clinic, University Clinics Tuebingen, Tuebingen, Germany
| | | | - M Braun
- Breast Center, Rotkreuz Clinics Munich, Munich, Germany
| | - M Warm
- Breast Center, City Hospital Holweide, Cologne, Germany
| | - J Hackmann
- Breast Center, Marien-Hospital, Witten, Germany
| | - C Uleer
- Practice of Gynecology and Oncology, Hildesheim, Germany
| | - B Aktas
- Women's Clinic, University Clinics Essen, Essen, Germany
| | - C Schumacher
- Breast Center, St. Elisabeth Hospital, Cologne, Germany
| | - R Wuerstleins
- West German Study Group, Monchengladbach, Germany; Breast Center, Department of Obstetrics and Gynecology and CCC Munich, LMU University Hospital, Munich, Germany
| | - M Graeser
- West German Study Group, Monchengladbach, Germany; Breast Center Niederrhein, Ev. Hospital Bethesda, Moenchengladbach, Germany; University Hospital Hamburg-Eppendorf, Hamburg, Germany
| | - C Zu Eulenburg
- West German Study Group, Monchengladbach, Germany; University Hospital Hamburg-Eppendorf, Hamburg, Germany
| | - H H Kreipe
- West German Study Group, Monchengladbach, Germany
| | - H Gómez
- Instituto Nacional de Enfermedades Neoplásicas, Lima, Peru
| | - T Massarrah
- Department of Medical Oncology, Hospital General Universitario Gregorio Marañón, Madrid, Spain; Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain; Centro de Investigación Biomédica en Red de Cáncer, Madrid, Spain
| | - B Herrero
- Department of Medical Oncology, Hospital General Universitario Gregorio Marañón, Madrid, Spain; Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain; Grupo Español de Investigación en Cáncer de Mama, Madrid, Spain
| | - L Paré
- Reveal Genomics, Barcelona, Spain
| | - U Bohn
- Hospital Universitario de Gran Canaria Dr. Negrín, Las Palmas, Spain
| | - S López-Tarruella
- Department of Medical Oncology, Hospital General Universitario Gregorio Marañón, Madrid, Spain; Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain; Centro de Investigación Biomédica en Red de Cáncer, Madrid, Spain; Grupo Español de Investigación en Cáncer de Mama, Madrid, Spain; Universidad Complutense de Madrid, Madrid, Spain
| | | | - E Sanfeliu
- Translational Genomics and Targeted Therapies in Solid Tumors, August Pi I Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain; Pathology Department, Hospital Clínic de Barcelona, Barcelona, Spain
| | - J S Parker
- Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, USA
| | - C M Perou
- Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, USA
| | | | - A Prat
- Translational Genomics and Targeted Therapies in Solid Tumors, August Pi I Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain; Reveal Genomics, Barcelona, Spain; Cancer Institute and Blood Disorders, Hospital Clínic de Barcelona, Barcelona, Spain; Medicine Department, University of Barcelona, Barcelona, Spain; Breast Cancer Unit, IOB-QuirónSalud, Barcelona, Spain.
| | - P Sharma
- Department of Radiation Oncology, University of Kansas Medical Center, Kansas City, USA
| | - N Harbeck
- West German Study Group, Monchengladbach, Germany; Breast Center, Department of Obstetrics and Gynecology and CCC Munich, LMU University Hospital, Munich, Germany
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20
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Ning B, Liu C, Kucukdagli AC, Zhang J, Jing H, Zhou Z, Zhang Y, Dong Y, Chen Y, Guo H, Xu J. Proteomic profiling identifies upregulation of aurora kinases causing resistance to taxane-type chemotherapy in triple negative breast cancer. Sci Rep 2025; 15:3211. [PMID: 39863788 PMCID: PMC11762698 DOI: 10.1038/s41598-025-87315-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2024] [Accepted: 01/17/2025] [Indexed: 01/27/2025] Open
Abstract
Nowadays, chemotherapy and immunotherapy remain the major treatment strategies for Triple-Negative Breast Cancer (TNBC). Identifying biomarkers to pre-select and subclassify TNBC patients with distinct chemotherapy responses is essential. In the current study, we performed an unbiased Reverse Phase Protein Array (RPPA) on TNBC cells treated with chemotherapy compounds and found a leading significant increase of phosphor-AURKA/B/C, AURKA, AURKB, and PLK1, which fall into the mitotic kinase group. The increase of AURKA and AURKB protein was majorly due to a post-transcription level regulation, and Paclitaxel treatment induced Aurora Kinases protein phosphorylation on AURKA(T288)/AURKB(T232) sites and their protein stability. In our UAB TNBC cohort, the expression of AURKA and AURKB was significantly higher in TNBC tumors compared to normal adjacent tissues, and AURKB was found to be highly expressed in African American TNBC patients compared to European Americans. Moreover, Aurora Kinases overexpression in TNBC cells renders resistance to Paclitaxel treatment and attenuates the apoptosis effect triggered by chemotherapy treatment, suggesting Aurora Kinases could mediate the chemo-resistance in TNBC. Hence, a combination of Aurora kinase inhibitors or PROTAC degrader and taxane-type chemotherapy significantly enhanced the chemotherapy effect. In summary, we revealed that Aurora Kinases upregulation after treatment with chemotherapy could confer chemotherapy resistance to TNBC cells, and AURKB could serve as preselection markers for stratifying patients' response to neoadjuvant chemotherapy.
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Affiliation(s)
- Bohan Ning
- Department of Genetics, The University of Alabama at Birmingham, Birmingham, AL, USA
- Department of Pathology, Heersink School of Medicine, The University of Alabama at Birmingham, 720 20th Street South, Birmingham, AL, 35294, USA
| | - Chang Liu
- Department of Genetics, The University of Alabama at Birmingham, Birmingham, AL, USA
| | - Ali Cem Kucukdagli
- Department of Genetics, The University of Alabama at Birmingham, Birmingham, AL, USA
| | - Jiuyi Zhang
- Department of Genetics, The University of Alabama at Birmingham, Birmingham, AL, USA
| | - Han Jing
- Department of Genetics, The University of Alabama at Birmingham, Birmingham, AL, USA
| | - Zhiqian Zhou
- Department of Genetics, The University of Alabama at Birmingham, Birmingham, AL, USA
| | - Yuwei Zhang
- Department of Genetics, The University of Alabama at Birmingham, Birmingham, AL, USA
| | - Ying Dong
- Department of Pathology, Peking University First Hospital, Beijing, China
| | - Yunjia Chen
- Department of Genetics, The University of Alabama at Birmingham, Birmingham, AL, USA
| | - Hua Guo
- Department of Pathology, Heersink School of Medicine, The University of Alabama at Birmingham, 720 20th Street South, Birmingham, AL, 35294, USA.
| | - Jia Xu
- Department of Genetics, The University of Alabama at Birmingham, Birmingham, AL, USA.
- Department of Pathology, Heersink School of Medicine, The University of Alabama at Birmingham, 720 20th Street South, Birmingham, AL, 35294, USA.
- O'Neal Comprehensive Cancer Center, The University of Alabama at Birmingham, Birmingham, AL, USA.
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21
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Marei HE, Bedair K, Hasan A, Al-Mansoori L, Caratelli S, Sconocchia G, Gaiba A, Cenciarelli C. Current status and innovative developments of CAR-T-cell therapy for the treatment of breast cancer. Cancer Cell Int 2025; 25:3. [PMID: 39755633 PMCID: PMC11700463 DOI: 10.1186/s12935-024-03615-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2024] [Accepted: 12/12/2024] [Indexed: 01/06/2025] Open
Abstract
Breast cancer will overtake all other cancers in terms of diagnoses in 2024. Breast cancer counts highest among women in terms of cancer incidence and death rates. Innovative treatment approaches are desperately needed because treatment resistance brought on by current clinical drugs impedes therapeutic efficacy. The T cell-based immunotherapy known as chimeric antigen receptor (CAR) T cell treatment, which uses the patient's immune cells to fight cancer, has demonstrated remarkable efficacy in treating hematologic malignancies; nevertheless, the treatment effects in solid tumors, like breast cancer, have not lived up to expectations. We discuss in detail the role of tumor-associated antigens in breast cancer, current clinical trials, barriers to the intended therapeutic effects of CAR-T cell therapy, and potential ways to increase treatment efficacy. Finally, our review aims to stimulate readers' curiosity by summarizing the most recent advancements in CAR-T cell therapy for breast cancer.
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Affiliation(s)
- Hany E Marei
- Department of Cytology and Histology, Faculty of Veterinary Medicine, Mansoura University, Mansoura, 35116, Egypt.
| | - Khaled Bedair
- Department of Social Sciences, College of Arts and Sciences, Qatar University, P.O. Box 2713, Doha, Qatar
| | - Anwarul Hasan
- Department of Mechanical and Industrial Engineering, College of Engineering, Qatar University, Doha, Qatar
| | - Layla Al-Mansoori
- Biomedical Research Center, Qatar University, P.O. Box 2713, Doha, Qatar
| | - Sara Caratelli
- Institute of Translational Pharmacology-CNR, Rome, Italy
| | | | - Alice Gaiba
- Institute of Translational Pharmacology-CNR, Rome, Italy
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22
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Lyu SY, Meshesha SM, Hong CE. Synergistic Effects of Mistletoe Lectin and Cisplatin on Triple-Negative Breast Cancer Cells: Insights from 2D and 3D In Vitro Models. Int J Mol Sci 2025; 26:366. [PMID: 39796221 PMCID: PMC11719730 DOI: 10.3390/ijms26010366] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2024] [Revised: 12/09/2024] [Accepted: 12/30/2024] [Indexed: 01/13/2025] Open
Abstract
Triple-negative breast cancer (TNBC) remains a challenging subtype due to its aggressive nature and limited treatment options. This study investigated the potential synergistic effects of Korean mistletoe lectin (Viscum album L. var. coloratum agglutinin, VCA) and cisplatin on MDA-MB-231 TNBC cells using both 2D and 3D culture models. In 2D cultures, the combination of VCA and cisplatin synergistically inhibited cell proliferation, induced apoptosis, and arrested the cell cycle at the G2/M phase. Also, the combination treatment significantly reduced cell migration and invasion. Gene expression analysis showed significant changes in specific genes related to apoptosis (Bax, Bcl-2), metastasis (MMP-2, MMP-9), and EMT (E-cadherin, N-cadherin). Three-dimensional spheroid models corroborated these findings, demonstrating enhanced cytotoxicity and reduced invasion with the combination treatment. Significantly, the 3D models exhibited differential drug sensitivity compared to 2D cultures, emphasizing the importance of utilizing physiologically relevant models in preclinical studies. The combination treatment also reduced the expression of angiogenesis-related factors VEGF-A and HIF-1α. This comprehensive study provides substantial evidence for the potential of VCA and cisplatin combination therapy in TNBC treatment and underscores the significance of integrating 2D and 3D models in preclinical cancer research.
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Affiliation(s)
- Su-Yun Lyu
- College of Pharmacy, Sunchon National University, Suncheon 57922, Republic of Korea; (S.-Y.L.)
- Research Institute of Life and Pharmaceutical Sciences, Sunchon National University, Suncheon 57922, Republic of Korea
| | - Saporie Melaku Meshesha
- College of Pharmacy, Sunchon National University, Suncheon 57922, Republic of Korea; (S.-Y.L.)
| | - Chang-Eui Hong
- College of Pharmacy, Sunchon National University, Suncheon 57922, Republic of Korea; (S.-Y.L.)
- Research Institute of Life and Pharmaceutical Sciences, Sunchon National University, Suncheon 57922, Republic of Korea
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23
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Lerévérend C, Kotaich N, Cartier L, De Boni M, Lahire S, Fichel C, Thiebault C, Brabencova E, Maquin C, Barbosa E, Corsois L, Hotton J, Guendouzen S, Guilbert P, Lepagnol-Bestel AM, Cahen-Doidy L, Lehmann-Che J, Devy J, Bensussan A, Le Jan S, Pommier A, Merrouche Y, Le Naour R, Vignot S, Potteaux S. Enhanced expression of galectin-9 in triple negative breast cancer cells following radiotherapy: Implications for targeted therapy. Int J Cancer 2025; 156:229-242. [PMID: 39077999 DOI: 10.1002/ijc.35107] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2024] [Revised: 05/15/2024] [Accepted: 06/27/2024] [Indexed: 07/31/2024]
Abstract
Optimizations are expected in the development of immunotherapy for the treatment of Triple-negative breast cancer (TNBC). We studied the expression of galectin-9 (Gal-9) after irradiation and assessed the differential impacts of its targeting with or without radiotherapy. Tumor resections from TNBC patients who received neoadjuvant radiotherapy revealed higher levels of Gal-9 in comparison to their baseline level, only in non-responder patients. Gal-9 expression was also found to be increased in TNBC tumor biopsies and cell lines after irradiation. We investigated the therapeutic advantage of targeting Gal-9 after radiotherapy in mice. Irradiated 4T1 cells or control non-irradiated 4T1 cells were injected into BALB/c mice. Anti-Gal-9 antibody treatment decreased tumor progression only in mice injected with irradiated 4T1 cells. This proof-of-concept study demonstrates that Gal-9 could be considered as a dynamic biomarker after radiotherapy for TNBC and suggests that Gal-9 induced-overexpression could represent an opportunity to develop new therapeutic strategies for TNBC patients.
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Affiliation(s)
- Cédric Lerévérend
- Université de Reims Champagne Ardenne, IRMAIC UR 7509, Reims, France
| | - Nour Kotaich
- Université de Reims Champagne Ardenne, IRMAIC UR 7509, Reims, France
| | | | - Manon De Boni
- Département de Recherche, Institut Godinot, Reims, France
| | - Sarah Lahire
- Université de Reims Champagne Ardenne, IRMAIC UR 7509, Reims, France
| | - Caroline Fichel
- Université de Reims Champagne Ardenne, IRMAIC UR 7509, Reims, France
| | | | - Eva Brabencova
- Centre de ressources biologiques, Institut Godinot, Reims, France
| | - Célia Maquin
- Centre de ressources biologiques, Institut Godinot, Reims, France
| | - Elodie Barbosa
- Centre de ressources biologiques, Institut Godinot, Reims, France
| | | | - Judicael Hotton
- Département de chirurgie oncologique, Institut Godinot, Reims, France
| | | | | | | | | | - Jacqueline Lehmann-Che
- Université Paris Cité, INSERM, U976 HIPI, Paris, France
- Molecular Oncology Unit, Saint Louis Hospital, APHP, Paris, France
| | - Jérôme Devy
- Matrice Extracellulaire et Dynamique Cellulaire, MEDyC, UMR 7369 CNRS, Reims, France
- Université de Reims Champagne-Ardenne, UFR Sciences Exactes et Naturelles, Reims, Cedex, France
| | | | - Sébastien Le Jan
- Université de Reims Champagne Ardenne, IRMAIC UR 7509, Reims, France
| | - Arnaud Pommier
- Université de Reims Champagne Ardenne, IRMAIC UR 7509, Reims, France
| | - Yacine Merrouche
- Université de Reims Champagne Ardenne, IRMAIC UR 7509, Reims, France
- Département de Recherche, Institut Godinot, Reims, France
| | - Richard Le Naour
- Université de Reims Champagne Ardenne, IRMAIC UR 7509, Reims, France
| | - Stéphane Vignot
- Université de Reims Champagne Ardenne, IRMAIC UR 7509, Reims, France
- Département de Recherche, Institut Godinot, Reims, France
| | - Stephane Potteaux
- Université de Reims Champagne Ardenne, IRMAIC UR 7509, Reims, France
- Département de Recherche, Institut Godinot, Reims, France
- Inserm, Délégation régionale Paris Île-de-France Centre Nord, Paris, France
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24
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Varshini MS, Krishnamurthy PT, Reddy RA, Wadhwani A, Chandrashekar VM. Insights into the Emerging Therapeutic Targets of Triple-negative Breast Cancer. Curr Cancer Drug Targets 2025; 25:3-25. [PMID: 38385495 DOI: 10.2174/0115680096280750240123054936] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2023] [Revised: 12/24/2023] [Accepted: 01/09/2024] [Indexed: 02/23/2024]
Abstract
Triple-negative Breast Cancer (TNBC), the most aggressive breast cancer subtype, is characterized by the non-appearance of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). Clinically, TNBC is marked by its low survival rate, poor therapeutic outcomes, high aggressiveness, and lack of targeted therapies. Over the past few decades, many clinical trials have been ongoing for targeted therapies in TNBC. Although some classes, such as Poly (ADP Ribose) Polymerase (PARP) inhibitors and immunotherapies, have shown positive therapeutic outcomes, however, clinical effects are not much satisfiable. Moreover, the development of drug resistance is the major pattern observed in many targeted monotherapies. The heterogeneity of TNBC might be the cause for limited clinical benefits. Hence,, there is a need for the potential identification of new therapeutic targets to address the above limitations. In this context, some novel targets that can address the above-mentioned concerns are emerging in the era of TNBC therapy, which include Hypoxia Inducible Factor (HIF-1α), Matrix Metalloproteinase 9 (MMP-9), Tumour Necrosis Factor-α (TNF-α), β-Adrenergic Receptor (β-AR), Voltage Gated Sodium Channels (VGSCs), and Cell Cycle Regulators. Currently, we summarize the ongoing clinical trials and discuss the novel therapeutic targets in the management of TNBC.
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Affiliation(s)
- Magham Sai Varshini
- Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Ooty, 643001, TN, India
| | | | - Ramakamma Aishwarya Reddy
- Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Ooty, 643001, TN, India
| | - Ashish Wadhwani
- Department of Pharmaceutical Biotechnology, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Ooty, 643001, TN, India
- Faculty of Health Sciences, School of Pharmacy, JSS Academy of Higher Education and Research, Mauritius, Vacoas, 73304, Mauritius
| | - V M Chandrashekar
- Department of Pharmacology, HSK College of Pharmacy, Bagalkot, 587101, Karnataka, India
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25
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Rios-Hoyo A, Shan NL, Karn PL, Pusztai L. Clinical Implications of Breast Cancer Intrinsic Subtypes. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2025; 1464:435-448. [PMID: 39821037 DOI: 10.1007/978-3-031-70875-6_21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/19/2025]
Abstract
Estrogen receptor-positive (ER+) and estrogen receptor-negative (ER-) breast cancers have different genomic architecture and show large-scale gene expression differences consistent with different cellular origins, which is reflected in the luminal (i.e., ER+) versus basal-like (i.e., ER-) molecular class nomenclature. These two major molecular subtypes have distinct epidemiological risk factors and different clinical behaviors. Luminal cancers can be subdivided further based on proliferative activity and ER signaling. Those with a high expression of proliferation-related genes and a low expression of ER-associated genes, called luminal B, have a high risk of early recurrence (i.e., within 5 years), derive significant benefit from adjuvant chemotherapy, and may benefit from adding immunotherapy to chemotherapy. This subset of luminal cancers is identified as the genomic high-risk ER+ cancers by the MammaPrint, Oncotype DX Recurrence Score, EndoPredict, Prosigna, and several other molecular prognostic assays. Luminal A cancers are characterized by low proliferation and high ER-related gene expression. They tend to have excellent prognosis with adjuvant endocrine therapy. Adjuvant chemotherapy may not improve their outcome further. These cancers correspond to the genomic low-risk categories. However, these cancers remain at risk for distant recurrence for extended periods of time, and over 50% of distant recurrences occur after 5 years. Basal-like cancers are uniformly highly proliferative and tend to recur within 3-5 years of diagnosis. In the absence of therapy, basal-like breast cancers have the worst survival, but these also include many highly chemotherapy-sensitive cancers. Basal-like cancers are often treated with preoperative chemotherapy combined with an immune checkpoint inhibitor which results in 60-65% pathologic complete response rates that herald excellent long-term survival. Patients with residual cancer after neoadjuvant therapy can receive additional postoperative chemotherapy that improves their survival. Currently, there is no clinically actionable molecular subclassification for basal-like cancers, although cancers with high androgen receptor (AR)-related gene expression and those with high levels of immune infiltration have better prognosis, but currently their treatment is not different from basal-like cancers in general. A clinically important, minor subset of breast cancers are characterized by frequent HER2 gene amplification and high expression of a few dozen genes, many residing on the HER2 amplicon. This is an important subset because of the highly effective HER2 targeted therapies which are synergistic with endocrine therapy and chemotherapy. The clinical behavior of HER2-enriched cancers is dominated by the underlying ER subtype. ER+/HER2-enriched cancers tend to have more indolent course and lesser chemotherapy sensitivity than their ER counterparts.
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Affiliation(s)
| | - Naing-Lin Shan
- Yale Cancer Center, Yale School of Medicine, New Haven, CT, USA
| | | | - Lajos Pusztai
- Yale Cancer Center, Yale School of Medicine, New Haven, CT, USA.
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26
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Chen AX, Chen X, Li XX, Guo ZY, Cao XC, Wang X, Zhang B. Impacts of Tumor Stage at Diagnosis and Adjuvant Therapy on Long-Term Survival Outcomes in Patients With Triple-Negative Breast Cancer Achieving Pathologic Complete Response After Neoadjuvant Chemotherapy. Clin Breast Cancer 2025; 25:e30-e39. [PMID: 38987035 DOI: 10.1016/j.clbc.2024.06.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2024] [Revised: 06/12/2024] [Accepted: 06/18/2024] [Indexed: 07/12/2024]
Abstract
BACKGROUND It remains unknown whether the tumor stage at initial diagnosis and adjuvant treatments had any impacts on the long-term survival outcomes of patients with triple-negative breast cancer (TNBC) achieving pathologic complete response (pCR) following neoadjuvant chemotherapy (NACT). METHODS Clinical stage II-III patients with TNBC who achieved pCR after NACT were identified from the Surveillance, Epidemiology, and End Results (SEER) program (SEER cohort) and the National Clinical Research Center for Cancer (Tianjin) in China (TMUCIH cohort). Survival analyses were conducted based on tumor stages and the types of adjuvant treatment received by the patients. The outcomes of interest were overall survival (OS) and breast cancer-specific survival (BCSS). RESULTS The TMUCIH cohort comprised 178 patients with a median follow-up of 55.5 months. Two and 3 patients experienced BCSS and OS events, respectively. The SEER cohort included 1218 patients with a median follow-up of 65.5 months, where 53 and 78 patients experienced BCSS and OS events, respectively. Patients diagnosed with stage III disease had significantly higher hazards of death compared to stage II disease (OS: hazard ratio [HR], 3.34; 95% confidence interval [CI], 1.84-6.07; P < .001; BCSS: HR, 2.86; 95% CI, 1.38-5.92; P < .001). Adjuvant systemic and radiation therapy did not confer additional benefits to OS and BCSS. CONCLUSION Tumor stage at initial diagnosis remains an independent predictor of long-term survival outcomes in patients with TNBC achieving pCR after NACT. Postoperative adjuvant chemotherapy and radiation therapy do not appear to provide additional benefit to their long-term prognosis.
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Affiliation(s)
- Ao-Xiang Chen
- The First Department of Breast Surgery, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China; Key Laboratory of Cancer Prevention and Therapy, Tianjin, China; Tianjin's Clinical Research Center for Cancer, Tianjin, China; Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin, China
| | - Xiao Chen
- The First Department of Breast Surgery, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China; Key Laboratory of Cancer Prevention and Therapy, Tianjin, China; Tianjin's Clinical Research Center for Cancer, Tianjin, China; Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin, China
| | - Xin-Xin Li
- The First Department of Breast Surgery, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China; Key Laboratory of Cancer Prevention and Therapy, Tianjin, China; Tianjin's Clinical Research Center for Cancer, Tianjin, China; Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin, China
| | - Zhang-Yin Guo
- The First Department of Breast Surgery, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China; Key Laboratory of Cancer Prevention and Therapy, Tianjin, China; Tianjin's Clinical Research Center for Cancer, Tianjin, China; Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin, China
| | - Xu-Chen Cao
- The First Department of Breast Surgery, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China; Key Laboratory of Cancer Prevention and Therapy, Tianjin, China; Tianjin's Clinical Research Center for Cancer, Tianjin, China; Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin, China
| | - Xin Wang
- The First Department of Breast Surgery, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China; Key Laboratory of Cancer Prevention and Therapy, Tianjin, China; Tianjin's Clinical Research Center for Cancer, Tianjin, China; Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin, China
| | - Bin Zhang
- The First Department of Breast Surgery, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China; Key Laboratory of Cancer Prevention and Therapy, Tianjin, China; Tianjin's Clinical Research Center for Cancer, Tianjin, China; Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin, China.
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27
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Önder T, Cengiz M, Koçoğlu SS, Ateş Ö, Yazıcı O, İnanç M, Duran AO. Prognostic value of HER2 2 + expression in patients with TNBC receiving adjuvant capecitabine. Clin Transl Oncol 2024:10.1007/s12094-024-03812-x. [PMID: 39709575 DOI: 10.1007/s12094-024-03812-x] [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: 10/05/2024] [Accepted: 11/23/2024] [Indexed: 12/23/2024]
Abstract
BACKGROUND In triple-negative breast cancer (TNBC) patients receiving adjuvant capecitabine, the impact of HER2 expression on survival outcomes is unclear. METHODS Between June 2017 and December 2023, 112 patients with TNBC who received adjuvant capecitabine due to residual masses after neoadjuvant chemotherapy (NACT) in three hospitals were identified. HER2 is analyzed through immunohistochemistry (IHC) and/or in situ hybridization in the core biopsy and/or post-surgical histopathologies. Relapse-free survival (RFS) and overall survival (OS), according to HER2 expression (0, 1 + , 2 +) status, were calculated (Kaplan-Meier method). RESULTS Seventy-eight (69.6%) patients had HER2 zero, 20 (17.9%) patients had HER2 + 1, and 14 (12.5%) patients had HER2 + 2/ISH- BC. The 5-year OS was 62.6%, and the 5-year RFS was 55.8%. HER2 2 + expression was associated with worse OS (27.5 vs. 84.5 months; HR 4.82, 95% CI 2.15-10.80, p < 0.001) and worse RFS (11.90 months vs. not reached; HR 4.30, 95% CI 2.06-8.99, p < 0.001) compared with HER2 0/1 + expression. The 5-year OS rates were 32.7% and 72.1%, and the 5-year RFS rates were 30.6% and 64.7% in the HER2 2 + and HER2 0/1 + groups, respectively. No statistically significant differences were detected in clinicopathologic features or pathologic responses to NACT according to the HER2 expression level. CONCLUSIONS Despite the use of the adjuvant capecitabine in HER2 2 + TNBC patients, these poor results will pave the way for further investigations of anti-HER2 therapeutic agents in adjuvant treatment.
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Affiliation(s)
- Tuğba Önder
- Dr Abdurrahman Yurtaslan Ankara Oncology Education and Research Hospital, Health Sciences University, Ankara, Turkey.
| | - Muhammet Cengiz
- Department of Medical Oncology, Erciyes University, Kayseri, Turkey
| | | | - Öztürk Ateş
- Dr Abdurrahman Yurtaslan Ankara Oncology Education and Research Hospital, Health Sciences University, Ankara, Turkey
| | - Ozan Yazıcı
- Department of Medical Oncology, Gazi University, Ankara, Turkey
| | - Mevlüde İnanç
- Department of Medical Oncology, Erciyes University, Kayseri, Turkey
| | - Ayşe Ocak Duran
- Dr Abdurrahman Yurtaslan Ankara Oncology Education and Research Hospital, Health Sciences University, Ankara, Turkey
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28
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Lin S, Fu B, Khan M. Identifying subgroups deriving the most benefit from PD-1 checkpoint inhibition plus chemotherapy in advanced metastatic triple-negative breast cancer: a systematic review and meta-analysis. World J Surg Oncol 2024; 22:346. [PMID: 39709499 DOI: 10.1186/s12957-024-03424-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2024] [Accepted: 05/21/2024] [Indexed: 12/23/2024] Open
Abstract
BACKGROUND The combination of immunotherapy and chemotherapy has demonstrated an enhancement in progression-free survival (PFS) for individuals with advanced and metastatic triple-negative breast cancer (TNBC) when compared to the use of chemotherapy alone. Nevertheless, the extent to which different subgroups of metastatic TNBC patients experience this benefit remains uncertain. OBJECTIVES Our objective was to conduct subgroup analyses to more precisely identify the factors influencing these outcomes. MATERIALS AND METHODS The PubMed database was searched until Dec 2023 for studies that compared PD-1 checkpoint inhibitors plus chemotherapy (ICT) with chemotherapy (CT) alone. The primary outcome of interest was progression-free survival (PFS). Review Manager (RevMan) version 5.4. was used for the data analysis. RESULTS Four randomized controlled trials (RCTs) comprising 2468 advanced and metastatic TNBC were included in this systematic review and meta-analysis. PFS surge with combined therapy was observed in White (HR 0.80 [0.70, 0.91], p = 0.0007) and Asian ethnicities (HR 0.73 [0.58, 0.93], p = 0.01) but not in Blacks (HR 0.72 [0.42, 1.24], p = 0.24). Overall, patients with distant metastasis demonstrated to derive the PFS benefit from additional immunotherapy (HR 0.87 [0.77, 0.99], p = 0.03); however, metastasis to individual distant site was associated with failure to achieve any treatment difference (Bone: HR 0.79 [0.41, 1.52], p = 0.49; Lung: HR 0.85 [0.70, 1.04], p = 0.11; Liver: HR 0.80 [0.64, 1.01], p = 0.06). While number of metastases > 3 also showed to impact the PFS advantage (HR 0.89 [0.69, 1.16], p = 0.39). While patients, regardless of prior chemotherapy, experienced a notable enhancement in PFS with ICT (Overall: HR 0.79 [0.71, 0.88], p < 0.0001; Yes: HR 0.87 [0.76, 1.00], p = 0.05; No: HR 0.67 [0.56, 0.80], p < 0.00001), those previously exposed to chemotherapy exhibited a significantly smaller PFS advantage compared to those without prior chemotherapy, as evidenced by a significant subgroup difference (Test for subgroup difference: P = 0.02, I2 = 82.2%). Patients lacking PD-L1 expression also failed to achieve any additional benefit from immunotherapy (PD-L1-: HR 0.95 [0.81, 1.12]; p = 0.54; PD-L1+: HR 0.73 [0.64, 0.85], p < 0.0001). Age, ECOG status, and presentation with de novo metastasis/recurrent shown no impact on IT-associated PFS advantage. CONCLUSIONS Patient- and treatment- related factors such as ethnicity, distant metastases, number of metastases (> 3), previous exposure to chemotherapy and PD-L1 expression, seem to influence or restrict the advantage in progression-free survival associated with the addition of immunotherapy to chemotherapy, as opposed to chemotherapy alone, in patients with advanced and metastatic TNBC. Larger studies are warranted to validate these outcomes.
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Affiliation(s)
- Shengfa Lin
- Department of Oncology, Jinshazhou Hospital of Guangzhou University of Chinese Medicine, Guangzhou, 510168, People's Republic of China
| | - Bihe Fu
- Department of Oncology, Jinshazhou Hospital of Guangzhou University of Chinese Medicine, Guangzhou, 510168, People's Republic of China
| | - Muhammad Khan
- Department of Radiation Oncology, Guangzhou Institute of Cancer Research, the Affiliated Cancer Hospital, Guangzhou, Guangdong, 510095, People's Republic of China.
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29
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Nemours S, Solé C, Goicoechea I, Armesto M, Arestin M, Urruticoechea A, Rezola M, López IÁ, Schaapveld R, Schultz I, Zhang L, Lawrie CH. Use of Gain-of-Function Screening to Identify miRNAs Involved in Paclitaxel Resistance in Triple-Negative Breast Cancer. Int J Mol Sci 2024; 25:13630. [PMID: 39769392 PMCID: PMC11728027 DOI: 10.3390/ijms252413630] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2024] [Revised: 12/11/2024] [Accepted: 12/18/2024] [Indexed: 01/30/2025] Open
Abstract
Paclitaxel is a widely used chemotherapeutic agent for the treatment of breast cancer (BC), including as a front-line treatment for triple-negative breast cancer (TNBC) patients. However, resistance to paclitaxel remains one of the major causes of death associated with treatment failure. Multiple studies have demonstrated that miRNAs play a role in paclitaxel resistance and are associated with both disease progression and metastasis. In the present study, we used a miRNA-encoding lentiviral library as a gain-of-function screen for paclitaxel resistance in the MDA-MB-231 TNBC cell line. We identified that miR-181b, miR-29a, miR-30c, miR-196 and miR-1295 conferred a resistant phenotype to cells. The expression of miR-29a also induced resistance to eribulin and vinorelbine, while miR-181b and miR-30c induced resistance to vinorelbine. We measured the levels of these miRNAs in breast cancer patients and observed higher levels of miR-29a in treatment-refractory patients. Taken together, we suggest that miR-29a and miR-181b may be good candidates for miRNA inhibition to overcome resistance to chemotherapy.
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Affiliation(s)
- Stéphane Nemours
- Molecular Oncology Group, Biogipuzkoa Health Research Institute, 20014 San Sebastian, Spain; (S.N.); (C.S.); (M.A.); (M.A.)
| | - Carla Solé
- Molecular Oncology Group, Biogipuzkoa Health Research Institute, 20014 San Sebastian, Spain; (S.N.); (C.S.); (M.A.); (M.A.)
| | - Ibai Goicoechea
- Department of Personalized Medicine, NASERTIC, Government of Navarra, 31011 Pamplona, Spain
| | - María Armesto
- Molecular Oncology Group, Biogipuzkoa Health Research Institute, 20014 San Sebastian, Spain; (S.N.); (C.S.); (M.A.); (M.A.)
| | - María Arestin
- Molecular Oncology Group, Biogipuzkoa Health Research Institute, 20014 San Sebastian, Spain; (S.N.); (C.S.); (M.A.); (M.A.)
| | - Ander Urruticoechea
- Breast Cancer Group, Biogipuzkoa Health Research Institute, 20014 San Sebastian, Spain; (A.U.); (I.Á.L.)
- Gipuzkoa Cancer Unit, OSI Donostialdea—Onkologikoa Foundation, Paseo Dr Begiristain 121, 20014 San Sebastian, Spain
| | - Marta Rezola
- Department of Pathology, Hospital Universitario Donostia Osakidetza, 20014 Donostia, Spain;
| | - Isabel Álvarez López
- Breast Cancer Group, Biogipuzkoa Health Research Institute, 20014 San Sebastian, Spain; (A.U.); (I.Á.L.)
- Gipuzkoa Cancer Unit, OSI Donostialdea—Onkologikoa Foundation, Paseo Dr Begiristain 121, 20014 San Sebastian, Spain
| | - Roel Schaapveld
- InteRNA Technologies, 3584 Utrecht, The Netherlands; (R.S.); (I.S.)
| | - Iman Schultz
- InteRNA Technologies, 3584 Utrecht, The Netherlands; (R.S.); (I.S.)
| | - Lei Zhang
- Sino-Swiss Institute of Advanced Technology (SSIAT), Shanghai University, Shanghai 201800, China;
| | - Charles H. Lawrie
- Molecular Oncology Group, Biogipuzkoa Health Research Institute, 20014 San Sebastian, Spain; (S.N.); (C.S.); (M.A.); (M.A.)
- Sino-Swiss Institute of Advanced Technology (SSIAT), Shanghai University, Shanghai 201800, China;
- IKERBASQUE, Basque Foundation for Science, 48011 Bilbao, Spain
- Radcliffe Department of Medicine, University of Oxford, Oxford OX1 2JD, UK
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30
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Denkert C, Schneeweiss A, Rey J, Karn T, Hattesohl A, Weber KE, Rachakonda S, Braun M, Huober J, Jank P, Sinn HP, Zahm DM, Felder B, Hanusch C, Teply-Szymanski J, Marmé F, Fehm T, Thomalla J, Sinn BV, Stiewe T, Marczyk M, Blohmer JU, van Mackelenbergh M, Schem C, Staib P, Link T, Müller V, Stickeler E, Stover DG, Solbach C, Metzger-Filho O, Jackisch C, Geyer CE, Fasching PA, Pusztai L, Nekljudova V, Untch M, Loibl S. Molecular adaptation to neoadjuvant immunotherapy in triple-negative breast cancer. Cell Rep Med 2024; 5:101825. [PMID: 39566464 PMCID: PMC11604547 DOI: 10.1016/j.xcrm.2024.101825] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2023] [Revised: 06/03/2024] [Accepted: 10/18/2024] [Indexed: 11/22/2024]
Abstract
Therapy-induced molecular adaptation of triple-negative breast cancer is crucial for immunotherapy response and resistance. We analyze tumor biopsies from three different time points in the randomized neoadjuvant GeparNuevo trial (NCT02685059), evaluating the combination of durvalumab with chemotherapy, for longitudinal alterations of gene expression. Durvalumab induces an activation of immune and stromal gene expression as well as a reduction of proliferation-related gene expression. Immune genes are positive prognostic factors irrespective of treatment, while proliferation genes are positive prognostic factors only in the durvalumab arm. We identify stromal-related gene expression as a contributor to immunotherapy resistance and poor therapy response. The results provide evidence from clinical trial cohorts suggesting a role for stromal reorganization in therapy resistance to immunotherapy and in the generation of an immune-suppressive microenvironment, which might be relevant for future therapy approaches targeting the tumor stroma parallel to immunotherapy, such as combinations of immunotherapy with anti-angiogenic therapy.
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Affiliation(s)
- Carsten Denkert
- Institute of Pathology, Philipps University Marburg, Marburg University Hospital (UKGM), and University Cancer Center Frankfurt-Marburg (UCT), Marburg, Germany.
| | - Andreas Schneeweiss
- Nationales Centrum für Tumorerkrankungen, Universitätsklinikum und Deutsches Krebsforschungszentrum, Heidelberg, Germany
| | - Julia Rey
- German Breast Group (GBG) Forschungs GmbH, Neu-Isenburg, Germany
| | - Thomas Karn
- University Hospital, Goethe University, and University Cancer Center Frankfurt-Marburg (UCT), Frankfurt am Main, Germany
| | - Akira Hattesohl
- Institute of Pathology, Philipps University Marburg, Marburg University Hospital (UKGM), and University Cancer Center Frankfurt-Marburg (UCT), Marburg, Germany
| | - Karsten E Weber
- German Breast Group (GBG) Forschungs GmbH, Neu-Isenburg, Germany
| | | | | | - Jens Huober
- Kantonsspital St. Gallen, Brustzentrum, St. Gallen, Switzerland
| | - Paul Jank
- Institute of Pathology, Philipps University Marburg, Marburg University Hospital (UKGM), and University Cancer Center Frankfurt-Marburg (UCT), Marburg, Germany
| | - Hans-Peter Sinn
- Institut für Pathologie, Universitätsklinikum Heidelberg, Heidelberg, Germany
| | | | - Bärbel Felder
- German Breast Group (GBG) Forschungs GmbH, Neu-Isenburg, Germany
| | | | - Julia Teply-Szymanski
- Institute of Pathology, Philipps University Marburg, Marburg University Hospital (UKGM), and University Cancer Center Frankfurt-Marburg (UCT), Marburg, Germany
| | - Frederik Marmé
- Medizinische Fakultät Mannheim, Universität Heidelberg, Universitätsfrauenklinik Mannheim, Mannheim, Germany
| | - Tanja Fehm
- Frauenklinik, Universitätsklinikum Düsseldorf, Center for Integrated Oncology (CIO Aachen, Bonn, Cologne, Düsseldorf), Düsseldorf, Germany
| | - Jörg Thomalla
- Praxis für Hämatologie und Onkologie Koblenz, Germany
| | - Bruno V Sinn
- Institut für Pathologie, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Thorsten Stiewe
- Institute of Molecular Oncology and Genomics Core Facility, Member of the German Center for Lung Research (DZL), Philipps University Marburg, Marburg, Germany; Institute of Lung Health (ILH), Justus Liebig University, Giessen, Germany
| | - Michal Marczyk
- Department of Data Science and Engineering, Silesian University of Technology, Gliwice, Poland; Yale School of Medicine, New Haven, CT, USA
| | - Jens-Uwe Blohmer
- Klinik für Gynäkologie mit Brustzentrum, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | | | - Christian Schem
- Mammazentrum Hamburg, Brustzentrum am Krankenhaus Jerusalem, Hamburg, Germany
| | - Peter Staib
- Klinik für Hämatologie und Onkologie, St.-Antonius Hospital, Eschweiler, Germany
| | - Theresa Link
- Klinik und Poliklinik für Frauenheilkunde und Geburtshilfe, Universitätsklinikum Carl Gustav Carus Dresden, Dresden, Germany
| | - Volkmar Müller
- Klinik und Poliklinik für Gynäkologie, Universitätsklinikum Hamburg Eppendorf, Hamburg, Germany
| | - Elmar Stickeler
- Department of Obstetrics and Gynecology, Center for Integrated Oncology (CIO Aachen, Bonn, Cologne, Düsseldorf), University Hospital of RWTH Aachen, Aachen, Germany
| | - Daniel G Stover
- Department of Internal Medicine, Ohio State University, Columbus, OH, USA
| | | | | | - Christian Jackisch
- Klinik für Gynäkologie und Geburtshilfe, Sana Klinikum Offenbach, Offenbach, Germany
| | - Charles E Geyer
- Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Peter A Fasching
- Department of Gynecology and Obstetrics, University Hospital Erlangen, Comprehensive Cancer Center Erlangen-Nuremberg, National Center for Tumour Diseases, Erlangen, Germany
| | - Lajos Pusztai
- Yale Cancer Center, Yale School of Medicine, New Haven, CT, USA
| | | | - Michael Untch
- Department of Gynecology and Obstetrics, Breast Cancer Center, Helios Klinikum Berlin Buch, Berlin, Germany
| | - Sibylle Loibl
- German Breast Group (GBG) Forschungs GmbH, Neu-Isenburg, Germany.
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31
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Jovanović B, Church SE, Gorman KM, North K, Richardson ET, DiLullo M, Attaya V, Kasparian J, Mohammed-Abreu A, Kirkner G, Hughes ME, Lin NU, Mittendorf EA, Schnitt SJ, Tolaney SM, Goel S. Integrative Multiomic Profiling of Triple-Negative Breast Cancer for Identifying Suitable Therapies. Clin Cancer Res 2024; 30:4768-4779. [PMID: 39136550 PMCID: PMC11474168 DOI: 10.1158/1078-0432.ccr-23-1242] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2023] [Revised: 03/05/2024] [Accepted: 08/08/2024] [Indexed: 10/16/2024]
Abstract
PURPOSE Triple-negative breast cancer (TNBC) is a heterogeneous disease that carries the poorest prognosis of all breast cancers. Although novel TNBC therapies in development are frequently targeted toward tumors carrying a specific genomic, transcriptomic, or protein biomarker, it is poorly understood how these biomarkers are correlated. EXPERIMENTAL DESIGN To better understand the molecular features of TNBC and their correlation with one another, we performed multimodal profiling on a cohort of 95 TNBC. Our approach involved quantifying tumor-infiltrating lymphocytes through hematoxylin and eosin staining, assessing the abundance of retinoblastoma, androgen receptor, and PDL1 proteins through IHC, and carrying out transcriptomic profiling using the NanoString BC360 platform, targeted DNA sequencing on a subset of cases, as well as evaluating associations with overall survival. RESULTS Levels of RB1 mRNA and RB proteins are better correlated with markers of retinoblastoma functionality than RB1 mutational status. Luminal androgen receptor tumors clustered into two groups with transcriptomes that cluster with either basal or mesenchymal tumors. Tumors classified as PDL1-positive by the presence of immune or tumor cells showed similar biological characteristics. HER2-low TNBC showed no distinct biological phenotype when compared with HER2-zero. The majority of TNBC were classified as basal or HER2-enriched by PAM50, the latter showing significantly improved overall survival. CONCLUSIONS Our study contributes new insights into biomarker utility for identifying suitable TNBC therapies and the intercorrelations between genomic, transcriptomic, protein, and cellular biomarkers. Additionally, our rich data resource can be used by other researchers to explore the interplay between DNA, RNA, and protein biomarkers in TNBC.
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Affiliation(s)
- Bojana Jovanović
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
- Breast Oncology Program, Dana-Farber Brigham Cancer Center, Boston, Massachusetts.
- Harvard Medical School, Boston, Massachusetts.
| | | | | | | | - Edward T. Richardson
- Harvard Medical School, Boston, Massachusetts.
- Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts.
| | - Molly DiLullo
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
- Breast Oncology Program, Dana-Farber Brigham Cancer Center, Boston, Massachusetts.
| | - Victoria Attaya
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
- Breast Oncology Program, Dana-Farber Brigham Cancer Center, Boston, Massachusetts.
| | - Julie Kasparian
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
- Breast Oncology Program, Dana-Farber Brigham Cancer Center, Boston, Massachusetts.
| | - Ayesha Mohammed-Abreu
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
- Breast Oncology Program, Dana-Farber Brigham Cancer Center, Boston, Massachusetts.
| | - Gregory Kirkner
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
- Breast Oncology Program, Dana-Farber Brigham Cancer Center, Boston, Massachusetts.
| | - Melissa E. Hughes
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
- Breast Oncology Program, Dana-Farber Brigham Cancer Center, Boston, Massachusetts.
| | - Nancy U. Lin
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
- Breast Oncology Program, Dana-Farber Brigham Cancer Center, Boston, Massachusetts.
- Harvard Medical School, Boston, Massachusetts.
| | - Elizabeth A. Mittendorf
- Breast Oncology Program, Dana-Farber Brigham Cancer Center, Boston, Massachusetts.
- Harvard Medical School, Boston, Massachusetts.
- Division of Breast Surgery, Department of Surgery, Brigham and Women’s Hospital, Boston, Massachusetts.
| | - Stuart J. Schnitt
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
- Harvard Medical School, Boston, Massachusetts.
- Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts.
| | - Sara M. Tolaney
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
- Breast Oncology Program, Dana-Farber Brigham Cancer Center, Boston, Massachusetts.
- Harvard Medical School, Boston, Massachusetts.
| | - Shom Goel
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
- Breast Oncology Program, Dana-Farber Brigham Cancer Center, Boston, Massachusetts.
- Harvard Medical School, Boston, Massachusetts.
- Sir Peter MacCallum Department of Oncology, The University of Melbourne, Victoria, Australia.
- Peter MacCallum Cancer Centre, Victoria, Australia.
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Padzińska-Pruszyńska I, Kucharzewska P, Matejuk A, Górczak M, Kubiak M, Taciak B, Król M. Macrophages: Key Players in the Battle against Triple-Negative Breast Cancer. Int J Mol Sci 2024; 25:10781. [PMID: 39409110 PMCID: PMC11476577 DOI: 10.3390/ijms251910781] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2024] [Revised: 09/30/2024] [Accepted: 10/03/2024] [Indexed: 10/20/2024] Open
Abstract
Triple-negative breast cancer (TNBC) is a challenging subtype of breast cancer characterized by the absence of estrogen and progesterone receptors and HER2 expression, leading to limited treatment options and a poorer prognosis. TNBC is particularly prevalent in premenopausal African-descent women and is associated with aggressive tumor behavior and higher metastatic potential. Tumor-associated macrophages (TAMs) are abundantly present within the TNBC microenvironment and play pivotal roles in promoting tumor growth, progression, and metastasis through various mechanisms, including immune suppression and enhancement of angiogenesis. This review provides an in-depth overview of TNBC, focusing on its epidemiology, its molecular characteristics, and the critical influence of TAMs. It discusses the pathological and molecular aspects that define TNBC's aggressive nature and reviews current and emerging therapeutic strategies aimed at targeting these dynamics. Special attention is given to the role of TAMs, exploring their potential as therapeutic targets due to their significant impact on tumor behavior and patient outcomes. This review aims to highlight the complexities of the TNBC landscape and to present the innovative approaches that are currently being pursued to improve therapeutic efficacy and patient survival.
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Affiliation(s)
- Irena Padzińska-Pruszyńska
- Center of Cellular Immunotherapies, Warsaw University of Life Sciences, 02-787 Warsaw, Poland; (I.P.-P.); (P.K.); (M.G.); (M.K.); (B.T.)
| | - Paulina Kucharzewska
- Center of Cellular Immunotherapies, Warsaw University of Life Sciences, 02-787 Warsaw, Poland; (I.P.-P.); (P.K.); (M.G.); (M.K.); (B.T.)
| | - Agata Matejuk
- Department of Immunology, Collegium Medicum, University of Zielona Góra, 65-417 Zielona Góra, Poland;
| | - Małgorzata Górczak
- Center of Cellular Immunotherapies, Warsaw University of Life Sciences, 02-787 Warsaw, Poland; (I.P.-P.); (P.K.); (M.G.); (M.K.); (B.T.)
| | - Małgorzata Kubiak
- Center of Cellular Immunotherapies, Warsaw University of Life Sciences, 02-787 Warsaw, Poland; (I.P.-P.); (P.K.); (M.G.); (M.K.); (B.T.)
| | - Bartłomiej Taciak
- Center of Cellular Immunotherapies, Warsaw University of Life Sciences, 02-787 Warsaw, Poland; (I.P.-P.); (P.K.); (M.G.); (M.K.); (B.T.)
| | - Magdalena Król
- Center of Cellular Immunotherapies, Warsaw University of Life Sciences, 02-787 Warsaw, Poland; (I.P.-P.); (P.K.); (M.G.); (M.K.); (B.T.)
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Shen Y, Guan X, Li S, Hou X, Yu J, Yin H, Shan X, Han X, Wang L, Zhou B, Li X, Sun L, Zhang Y, Xu H, Yue W. Exploiting a tumor softening targeted bomb for mechanical gene therapy of chemoresistant Triple-Negative breast cancer. CHEMICAL ENGINEERING JOURNAL 2024; 498:155217. [DOI: 10.1016/j.cej.2024.155217] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/11/2025]
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Kim CM, Park KH, Yu YS, Kim JW, Park JY, Park K, Yu JH, Lee JE, Sim SH, Seo BK, Kim JK, Lee ES, Park YH, Kong SY. A 10-Gene Signature to Predict the Prognosis of Early-Stage Triple-Negative Breast Cancer. Cancer Res Treat 2024; 56:1113-1125. [PMID: 38754473 PMCID: PMC11491257 DOI: 10.4143/crt.2024.100] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Accepted: 05/06/2024] [Indexed: 05/18/2024] Open
Abstract
PURPOSE Triple-negative breast cancer (TNBC) is a particularly challenging subtype of breast cancer, with a poorer prognosis compared to other subtypes. Unfortunately, unlike luminal-type cancers, there is no validated biomarker to predict the prognosis of patients with early-stage TNBC. Accurate biomarkers are needed to establish effective therapeutic strategies. MATERIALS AND METHODS In this study, we analyzed gene expression profiles of tumor samples from 184 TNBC patients (training cohort, n=76; validation cohort, n=108) using RNA sequencing. RESULTS By combining weighted gene expression, we identified a 10-gene signature (DGKH, GADD45B, KLF7, LYST, NR6A1, PYCARD, ROBO1, SLC22A20P, SLC24A3, and SLC45A4) that stratified patients by risk score with high sensitivity (92.31%), specificity (92.06%), and accuracy (92.11%) for invasive disease-free survival. The 10-gene signature was validated in a separate institution cohort and supported by meta-analysis for biological relevance to well-known driving pathways in TNBC. Furthermore, the 10-gene signature was the only independent factor for invasive disease-free survival in multivariate analysis when compared to other potential biomarkers of TNBC molecular subtypes and T-cell receptor β diversity. 10-gene signature also further categorized patients classified as molecular subtypes according to risk scores. CONCLUSION Our novel findings may help address the prognostic challenges in TNBC and the 10-gene signature could serve as a novel biomarker for risk-based patient care.
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Affiliation(s)
- Chang Min Kim
- CbsBioscience. Inc., Daejeon, Korea
- Department of Pharmacy, College of Pharmacy, CHA University, Seongnam, Korea
| | - Kyong Hwa Park
- Division of Medical Oncology/Hematology, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | | | - Ju Won Kim
- Division of Medical Oncology/Hematology, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | | | - Kyunghee Park
- Samsung Genome Institute, Samsung Medical Center, Seoul, Korea
| | - Jong-Han Yu
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jeong Eon Lee
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Sung Hoon Sim
- Breast Cancer Center, National Cancer Center, Goyang, Korea
| | - Bo Kyoung Seo
- Department of Radiology, Korea University Ansan Hospital, Korea University College of Medicine, Ansan, Korea
| | - Jin Kyeoung Kim
- Department of Pharmacy, College of Pharmacy, CHA University, Seongnam, Korea
| | - Eun Sook Lee
- Breast Cancer Center, National Cancer Center, Goyang, Korea
| | - Yeon Hee Park
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Sun-Young Kong
- Targeted Therapy Branch, Research Institute, National Cancer Center, Goyang, Korea
- Department of Laboratory Medicine, Hospital, National Cancer Center, Goyang, Korea
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Alaouna M, Hull R, Molefi T, Khanyile R, Mbodi L, Luvhengo TE, Chauke-Malinga N, Phakathi B, Penny C, Dlamini Z. Exploring Water-Soluble South African Tulbaghia violacea Harv Extract as a Therapeutic Approach for Triple-Negative Breast Cancer Metastasis. Curr Issues Mol Biol 2024; 46:10806-10828. [PMID: 39451522 PMCID: PMC11506433 DOI: 10.3390/cimb46100642] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2024] [Revised: 09/12/2024] [Accepted: 09/13/2024] [Indexed: 10/26/2024] Open
Abstract
Triple-negative breast cancer (TNBC) accounts for approximately 20% of all breast cancer cases and is characterized by a lack of estrogen, progesterone, and human epidermal growth factor 2 receptors. Current targeted medicines have been unsuccessful due to this absence of hormone receptors. This study explored the efficacy of Tulbaghia violacea, a South African medicinal plant, for the treatment of TNBC metastasis. Extracts from T. violacea leaves were prepared using water and methanol. However, only the water-soluble extract showed anti-cancer activity and the effects of this water-soluble extract on cell adhesion, invasion, and migration, and its antioxidant activity were assessed using MCF-10A and MDA-MB-231 cells. The T. violacea extract that was soluble in water effectively decreased the movement and penetration of MDA-MB-231 cells through the basement membrane in scratch and invasion tests, while enhancing their attachment to a substance resembling an extracellular matrix. The sample showed mild-to-low antioxidant activity in the antioxidant assy. Nuclear magnetic resonance spectroscopy revealed 61 chemical components in the water-soluble extract, including DDMP, 1,2,4-triazine-3,5(2H,4H)-dione, vanillin, schisandrin, taurolidine, and α-pinene, which are known to have anti-cancer properties. An in-depth examination of the transcriptome showed alterations in genes linked to angiogenesis, metastasis, and proliferation post-treatment, with reduced activity in growth receptor signaling, angiogenesis, and cancer-related pathways, such as the Wnt, Notch, and PI3K pathways. These results indicate that T. violacea may be a beneficial source of lead chemicals for the development of potential therapeutic medicines that target TNBC metastasis. Additional studies are required to identify the precise bioactive chemical components responsible for the observed anti-cancer effects.
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Affiliation(s)
- Mohammed Alaouna
- Department of Internal Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 2193, South Africa; (M.A.); (C.P.)
- SAMRC Precision Oncology Research Unit (PORU), DSI/NRF SARChI Chair in Precision Oncology and Cancer Prevention (POCP), Pan African Cancer Research Institute (PACRI), University of Pretoria, Pretoria 0084, South Africa; (R.H.); (T.M.); (R.K.); (N.C.-M.)
| | - Rodney Hull
- SAMRC Precision Oncology Research Unit (PORU), DSI/NRF SARChI Chair in Precision Oncology and Cancer Prevention (POCP), Pan African Cancer Research Institute (PACRI), University of Pretoria, Pretoria 0084, South Africa; (R.H.); (T.M.); (R.K.); (N.C.-M.)
| | - Thulo Molefi
- SAMRC Precision Oncology Research Unit (PORU), DSI/NRF SARChI Chair in Precision Oncology and Cancer Prevention (POCP), Pan African Cancer Research Institute (PACRI), University of Pretoria, Pretoria 0084, South Africa; (R.H.); (T.M.); (R.K.); (N.C.-M.)
- Department of Medical Oncology, Steve Biko Academic Hospital, University of Pretoria, Pretoria 0084, South Africa
| | - Richard Khanyile
- SAMRC Precision Oncology Research Unit (PORU), DSI/NRF SARChI Chair in Precision Oncology and Cancer Prevention (POCP), Pan African Cancer Research Institute (PACRI), University of Pretoria, Pretoria 0084, South Africa; (R.H.); (T.M.); (R.K.); (N.C.-M.)
- Department of Medical Oncology, Steve Biko Academic Hospital, University of Pretoria, Pretoria 0084, South Africa
| | - Langanani Mbodi
- Gynaecologic Oncology Unit, Department of Obstetrics and Gynaecology, Charlotte Maxeke Johannesburg Academic Hospital, University of the Witwatersrand, Johannesburg 2193, South Africa;
| | - Thifhelimbilu Emmanuel Luvhengo
- Department of Surgery, Charlotte Maxeke Johannesburg Academic Hospital, University of the Witwatersrand, Parktown, Johannesburg 2193, South Africa;
| | - Nkhensani Chauke-Malinga
- SAMRC Precision Oncology Research Unit (PORU), DSI/NRF SARChI Chair in Precision Oncology and Cancer Prevention (POCP), Pan African Cancer Research Institute (PACRI), University of Pretoria, Pretoria 0084, South Africa; (R.H.); (T.M.); (R.K.); (N.C.-M.)
- Papillon Plastic Surgery, Suite 203B, 24 12th Avenue, Linksfield West, Johannesburg 2192, South Africa
| | - Boitumelo Phakathi
- Department of Surgery, Faculty of Health Sciences, University of Kwa-Zulu Natal, Durban 4041, South Africa;
| | - Clement Penny
- Department of Internal Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 2193, South Africa; (M.A.); (C.P.)
| | - Zodwa Dlamini
- SAMRC Precision Oncology Research Unit (PORU), DSI/NRF SARChI Chair in Precision Oncology and Cancer Prevention (POCP), Pan African Cancer Research Institute (PACRI), University of Pretoria, Pretoria 0084, South Africa; (R.H.); (T.M.); (R.K.); (N.C.-M.)
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Park H, Kim H, Park W, Cho WK, Kim N, Kim TG, Im YH, Ahn JS, Park YH, Kim JY, Nam SJ, Kim SW, Lee JE, Yu J, Chae BJ, Lee SK, Ryu JM. Oncological outcomes in patients with residual triple-negative breast cancer after preoperative chemotherapy. Radiat Oncol J 2024; 42:210-217. [PMID: 39354824 PMCID: PMC11467479 DOI: 10.3857/roj.2024.00087] [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: 01/25/2024] [Revised: 06/26/2024] [Accepted: 07/02/2024] [Indexed: 10/03/2024] Open
Abstract
PURPOSE This study aimed to evaluate the clinical outcomes and prognostic implications of regional nodal irradiation (RNI) after neoadjuvant chemotherapy (NAC) in patients with residual triple-negative breast cancer (TNBC). MATERIALS AND METHODS We analyzed 152 patients with residual TNBC who underwent breast-conserving surgery after NAC between December 2008 and December 2017. Most patients (n = 133; 87.5%) received taxane-based chemotherapy. Adjuvant radiotherapy (RT) was administered at a total dose of 45-65 Gy in 15-30 fractions to the whole breast, with some patients also receiving RT to regional nodes. Survival was calculated using the Kaplan-Meier method, and prognostic factors influencing survival were analyzed using the Cox proportional-hazards model. RESULTS During a median follow-up of 66 months (range, 9 to 179 months), the 5-year disease-free survival (DFS) rate was 68.0%. The 5-year locoregional recurrence-free survival, distant metastasis-free survival, and overall survival rates were 83.6%, 72.6%, and 78.7%, respectively. In the univariate analysis, the cN stage, ypT stage, ypN stage, axillary operation type, and RT field were associated with DFS. Multivariate analysis revealed that higher ypT stage (hazard ratio [HR] = 2.0; 95% confidence interval [CI] 1.00-3.82; p = 0.049) and ypN stage (HR = 4.7; 95% CI 1.57-14.24; p = 0.006) were associated with inferior DFS. Among clinically node-positive patients, those who received RT to the breast only had a 5-year DFS of 73.7%, whereas those who received RNI achieved a DFS of 59.6% (p = 0.164). There were no differences between the DFS and RNI. CONCLUSION In patients with residual TNBC, higher ypT and ypN stages were associated with poorer outcomes after NAC. RNI did not appear to improve DFS. More intensive treatments incorporating systemic therapy and RT should be considered for these patients.
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Affiliation(s)
- Hyunki Park
- Department of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Haeyoung Kim
- Department of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Won Park
- Department of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Won Kyung Cho
- Department of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Nalee Kim
- Department of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Tae Gyu Kim
- Department of Radiation Oncology, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon, Republic of Korea
| | - Young-Hyuck Im
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Jin Seok Ahn
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Yeon Hee Park
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Ji-Yeon Kim
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Seok Jin Nam
- Division of Breast Surgery, Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Seok Won Kim
- Division of Breast Surgery, Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Jeong Eon Lee
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Jonghan Yu
- Division of Breast Surgery, Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Byung Joo Chae
- Division of Breast Surgery, Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Sei Kyung Lee
- Division of Breast Surgery, Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Jai-Min Ryu
- Division of Breast Surgery, Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
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Sharma R, Yadav V, Jha S, Dighe S, Jain S. Unveiling the potential of ursolic acid modified hyaluronate nanoparticles for combination drug therapy in triple negative breast cancer. Carbohydr Polym 2024; 338:122196. [PMID: 38763723 DOI: 10.1016/j.carbpol.2024.122196] [Citation(s) in RCA: 10] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Revised: 04/18/2024] [Accepted: 04/21/2024] [Indexed: 05/21/2024]
Abstract
Triple negative breast cancer (TNBC) represents the most aggressive and heterogenous disease, and combination therapy holds promising potential. Here, an enzyme-responsive polymeric prodrug with self-assembly properties was synthesized for targeted co-delivery of paclitaxel (PTX) and ursolic acid (UA). Hyaluronic acid (HA) was conjugated with UA, yielding an amphiphilic prodrug with 13.85 mol% UA and a CMC of 32.3 μg/mL. The HA-UA conjugate exhibited ∼14 % and 47 % hydrolysis at pH 7.4 and in tumor cell lysate. HA-UA/PTX NPs exhibited a spherical structure with 173 nm particle size, and 0.15 PDI. The nanoparticles showed high drug loading (11.58 %) and entrapment efficiency (76.87 %) of PTX. Release experiments revealed accelerated drug release (∼78 %) in the presence of hyaluronidase enzyme. Cellular uptake in MDA-MB-231 cells showed enhanced uptake of HA-UA/PTX NPs through CD44 receptor-mediated endocytosis. In vitro, HA-UA/PTX NPs exhibited higher cytotoxicity, apoptosis, and mitochondrial depolarization compared to PTX alone. In vivo, HA-UA/PTX NPs demonstrated improved pharmacokinetic properties, with 2.18, 2.40, and 2.35-fold higher AUC, t1/2, and MRT compared to free PTX. Notably, HA-UA/PTX NPs exhibited superior antitumor efficacy with a 90 % tumor inhibition rate in 4T1 tumor model and low systemic toxicity, showcasing their significant potential as carriers for TNBC combination therapy.
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Affiliation(s)
- Reena Sharma
- Centre for Pharmaceutical Nanotechnology, Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S.A.S. Nagar, Punjab 160062, India
| | - Vivek Yadav
- Centre for Pharmaceutical Nanotechnology, Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S.A.S. Nagar, Punjab 160062, India
| | - Shikha Jha
- Centre for Pharmaceutical Nanotechnology, Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S.A.S. Nagar, Punjab 160062, India
| | - Sayali Dighe
- Centre for Pharmaceutical Nanotechnology, Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S.A.S. Nagar, Punjab 160062, India
| | - Sanyog Jain
- Centre for Pharmaceutical Nanotechnology, Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S.A.S. Nagar, Punjab 160062, India.
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Hao Q, Dai L, Chang L, Song D, Liu D, Ma X, Wu H, Kang H. Evaluation of neoadjuvant chemotherapy for clinical T1 triple-negative breast cancer. Sci Rep 2024; 14:18055. [PMID: 39103475 PMCID: PMC11300443 DOI: 10.1038/s41598-024-68719-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2024] [Accepted: 07/26/2024] [Indexed: 08/07/2024] Open
Abstract
The role of neoadjuvant chemotherapy and its benefits in patients with triple-negative breast cancer (TNBC) and small tumors are unclear. This study aims to compare survival differences between clinical T1 TNBC receiving neoadjuvant chemotherapy (NAC) and adjuvant chemotherapy (AC). Data for patients with clinical T1 TNBC were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. Patients were categorized according to whether they received chemotherapy before or after surgery. Propensity Score Matching (PSM) was used to minimize the influence of confounding factors. OS and BCSS were compared between the two treatment sequences using Kaplan-Meier and univariate and multivariable Cox proportional hazards regression analyses. The study included 6249 women with T1 TNBC. In multivariate analysis, compared with that in the AC group, the hazard ratio for death in the NAC group was 1.54 (95% confidence interval 1.26-1.89, p < 0.001). NAC offers no additional benefits in any age group or T, N subgroups. Our findings suggest that NAC does not provide additional benefit to patients with clinical T1 TNBC, even in the presence of lymph node metastasis, or T1c.
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Affiliation(s)
- Qian Hao
- The Comprehensive Breast Center, The Second Affiliated Hospital of Xi'an Jiaotong University, 157 West 5th Road, Xi'an, 710061, China
| | - Luyao Dai
- The Comprehensive Breast Center, The Second Affiliated Hospital of Xi'an Jiaotong University, 157 West 5th Road, Xi'an, 710061, China
| | - Lidan Chang
- The Comprehensive Breast Center, The Second Affiliated Hospital of Xi'an Jiaotong University, 157 West 5th Road, Xi'an, 710061, China
| | - Dingli Song
- Department of Thoracic Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710004, China
| | - Dandan Liu
- The Comprehensive Breast Center, The Second Affiliated Hospital of Xi'an Jiaotong University, 157 West 5th Road, Xi'an, 710061, China
| | - Xiaobin Ma
- The Comprehensive Breast Center, The Second Affiliated Hospital of Xi'an Jiaotong University, 157 West 5th Road, Xi'an, 710061, China.
| | - Hao Wu
- School of Basic Medical Sciences, Key Laboratory of Environment and Genes Related to Diseases of Ministry of Education, Xi'an Jiaotong University, 76 Yanta West Road, Xi'an, 710061, China.
| | - Huafeng Kang
- The Comprehensive Breast Center, The Second Affiliated Hospital of Xi'an Jiaotong University, 157 West 5th Road, Xi'an, 710061, China.
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Md Zaki FA, Mohamad Hanif EA. Identifying miRNA as biomarker for breast cancer subtyping using association rule. Comput Biol Med 2024; 178:108696. [PMID: 38850957 DOI: 10.1016/j.compbiomed.2024.108696] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Revised: 05/03/2024] [Accepted: 06/01/2024] [Indexed: 06/10/2024]
Abstract
- This paper presents a comprehensive study focused on breast cancer subtyping, utilizing a multifaceted approach that integrates feature selection, machine learning classifiers, and miRNA regulatory networks. The feature selection process begins with the CFS algorithm, followed by the Apriori algorithm for association rule generation, resulting in the identification of significant features tailored to Luminal A, Luminal B, HER-2 enriched, and Basal-like subtypes. The subsequent application of Random Forest (RF) and Support Vector Machine (SVM) classifiers yielded promising results, with the SVM model achieving an overall accuracy of 76.60 % and the RF model demonstrating robust performance at 80.85 %. Detailed accuracy metrics revealed strengths and areas for refinement, emphasizing the potential for optimizing subtype-specific recall. To explore the regulatory landscape in depth, an analysis of selected miRNAs was conducted using MIENTURNET, a tool for visualizing miRNA-target interactions. While FDR analysis raised concerns for HER-2 and Basal-like subtypes, Luminal A and Luminal B subtypes showcased significant miRNA-gene interactions. Functional enrichment analysis for Luminal A highlighted the role of Ovarian steroidogenesis, implicating specific miRNAs such as hsa-let-7c-5p and hsa-miR-125b-5p as potential diagnostic biomarkers and regulators of Luminal A breast cancer. Luminal B analysis uncovered associations with the MAPK signaling pathway, with miRNAs like hsa-miR-203a-3p and hsa-miR-19a-3p exhibiting potential diagnostic and therapeutic significance. In conclusion, this integrative approach combines machine learning techniques with miRNA analysis to provide a holistic understanding of breast cancer subtypes. The identified miRNAs and associated pathways offer insights into potential diagnostic biomarkers and therapeutic targets, contributing to the ongoing efforts to improve breast cancer diagnostics and personalized treatment strategies.
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Affiliation(s)
- Fatimah Audah Md Zaki
- Department of Internet Engineering & Computer Science, Universiti Tunku Abdul Rahman (UTAR), Selangor, Malaysia.
| | - Ezanee Azlina Mohamad Hanif
- UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia Medical Centre, Kuala Lumpur, Malaysia.
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Yang C, Liu H, Feng X, Shi H, Jiang Y, Li J, Tan J. Research hotspots and frontiers of neoadjuvant therapy in triple-negative breast cancer: a bibliometric analysis of publications between 2002 and 2023. Int J Surg 2024; 110:4976-4992. [PMID: 39143709 PMCID: PMC11326012 DOI: 10.1097/js9.0000000000001586] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2024] [Accepted: 04/25/2024] [Indexed: 08/16/2024]
Abstract
Triple-negative breast cancer (TNBC) is a highly aggressive type of breast cancer with poor prognosis, and neoadjuvant therapy (NAT) has emerged as an important component in managing advanced-stage patients by providing surgical opportunities and improving survival outcomes. A search of publications on NAT for TNBC from 2002 to 2023 was conducted through the Web of Science core collection. A comprehensive bibliometric analysis was conducted on the data using CiteSpace, VOSviewer, and Bibliometrix. The analysis revealed a continuous and steady growth in the number of articles published in this field over the past 20 years. The United States has made significant contributions to this field, with The University of Texas MD Anderson Cancer Center publishing the most articles. Loibl, S. from Germany was found to be the most published author with 54 articles. Analysis of the journals showed that the Journal of Clinical Oncology is the most cited journal. Combined with the keyword co-occurrence analysis and clustering analysis, current research topic focuses on treatment regimens and disease prognosis. Dual-map overlay of the journals indicates that the research trend is gradually shifting from molecular biology and genetics to immunology and clinical research. Combination therapy, including immunotherapy, may be the future direction for NAT treatment of TNBC. Overall, this study provides valuable insights into the current research status, latest advancements, and emerging development trend of NAT for TNBC.
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Affiliation(s)
- Chuang Yang
- Department of Breast and Thyroid Surgery, The First Affiliated Hospital of Chongqing Medical University
| | - Hui Liu
- Department of Breast and Thyroid Surgery, The Second Affiliated Hospital of Chongqing Medical University
| | - Xing Feng
- Department of Breast and Thyroid Surgery, The First Affiliated Hospital of Chongqing Medical University
- Department of Hepatobiliary, Breast and Thyroid Surgery, The People’s Hospital of Liangping District, Chongqing, China
| | - Han Shi
- Department of Breast and Thyroid Surgery, The First Affiliated Hospital of Chongqing Medical University
| | - Yuchan Jiang
- Department of Breast and Thyroid Surgery, The First Affiliated Hospital of Chongqing Medical University
| | - Junfeng Li
- Department of Breast and Thyroid Surgery, The First Affiliated Hospital of Chongqing Medical University
| | - Jinxiang Tan
- Department of Breast and Thyroid Surgery, The First Affiliated Hospital of Chongqing Medical University
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Javed S, Mohamed Noor DA, Md Hanafiah NH, Javed U, Mustafa T, Rehman AU, Harun SN. Investigating the Association Between Type 2 Diabetes Mellitus and Pathological Responses Among Breast Cancer Patients Receiving Neoadjuvant Chemotherapy. J Surg Res 2024; 299:85-93. [PMID: 38718688 DOI: 10.1016/j.jss.2024.04.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2023] [Revised: 03/01/2024] [Accepted: 04/01/2024] [Indexed: 06/22/2024]
Abstract
INTRODUCTION The relationship between type 2 diabetes mellitus (T2DM) and pathological responses after neoadjuvant chemotherapy (NACT) is controversial. In this study, we aim to determine the association of pathological responses in breast cancer women with T2DM after receiving NACT. METHODS Medical records of breast cancer women with T2DM who received NACT from January 2016 to January 2021 at the medical center in the Gujranwala Institute of Nuclear Medicine and Radiotherapy, Pakistan, were identified and retrieved retrospectively. Variables, including pathological responses, diabetes status, and other clinical data, were collected. Patients were grouped as diabetic and nondiabetic based on the doctor's diagnosis or the diabetic's medication history recorded upon the breast cancer diagnosis. Factors influencing the pathological complete response (pCR) were determined using multivariate logistic regression utilizing IBM SPSS Statistics (version 20). RESULTS A total of 1372 patient files who received NACT and breast cancer surgery from January 2016 to January 2021 were selected. Out of 1372 breast cancer women receiving NACT, 345 (25.1%) had pre-existing diabetes, while 1027 (74.85%) were without pre-existing diabetes. The most common molecular subtypes of breast cancer were luminal A and B. Two hundred fifty-eight patients (18.8%) had a pCR after receiving NACT. The pCR in diabetic patients was 3.9%, and in nondiabetes, 14.9%. Most women had a pathological partial response (pPR) after the NACT 672 (48.9%). The pPR in diabetic patients was 11.0%, and in nondiabetic patients, it was 38.0%. In nondiabetics, the odds of achieving pPR increase more than pathological no response after the NACT with odd ratio: 1.71 (95% confidence interval: 1.24-2.37). The probability of pCR in patients with luminal B was 1.67 times higher than that in patients with triple-negative breast cancer with odd ratio: 1.67, 95% confidence interval (1.00-2.79), P = 0.05. CONCLUSIONS The results of the study show that T2DM may have an adverse impact on pCR and pPR following NACT and surgery. Further investigation is needed to explore how changes in blood glucose levels over time impact pathological responses.
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Affiliation(s)
- Saba Javed
- School of Pharmaceutical Sciences, Universiti Sains Malaysia, USM Penang, Malaysia; Faculty of Pharmaceutical Sciences, Department of Pharmacy Practice, Government College University, Faisalabad, Pakistan
| | | | | | - Umar Javed
- Gujranwala Institute of Nuclear Medicine & Radiotherapy (GINUM), Gujranwala, Pakistan
| | - Tanveer Mustafa
- Gujranwala Institute of Nuclear Medicine & Radiotherapy (GINUM), Gujranwala, Pakistan
| | - Anees Ur Rehman
- Faculty of Pharmacy, Department of Pharmacy Practice, Bahauddin Zakariya University Multan, Punjab, Pakistan
| | - Sabariah Noor Harun
- School of Pharmaceutical Sciences, Universiti Sains Malaysia, USM Penang, Malaysia.
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de Bastos DR, Longatto-Filho A, Conceição MPF, Termini L. High Levels of Superoxide Dismutase 2 Are Associated With Worse Prognosis in Patients With Breast Cancer. Eur J Breast Health 2024; 20:185-193. [PMID: 39257010 PMCID: PMC11589296 DOI: 10.4274/ejbh.galenos.2024.2024-3-6] [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: 03/12/2024] [Accepted: 04/16/2024] [Indexed: 09/12/2024]
Abstract
OBJECTIVE Breast cancer is classified based on hormone receptor status and human epidermal growth factor receptor 2 (HER2) expression, including luminal, HER2+, or triple-negative (TNBC). The absence of a therapeutic target in TNBC and the resistance to treatment associated with other subtypes means that research for new biomarkers remains important. In this context, superoxide dismutase 2 (SOD2) has emerged as a potential therapeutic target due to its clinicopathological associations and its ability to predict responses in human tumors. To analyze SOD2 staining in samples obtained from individuals with breast cancer and explore its transcriptional pattern across tumor subtypes. MATERIALS AND METHODS SOD2 staining was assessed using the immunohistochemistry (IHC) in 80 samples from breast cancer patients. To analyze the expression profile at the transcriptional level, international databases such as cBioPortal (1,980 patients) and PrognoScan were accessed. RESULTS Significant differences were observed between SOD2 expression analyzed by IHC, and estrogen (p = 0.0008) and progesterone (p = 0.0003) receptors, as well as tumor subtypes (p<0.0001). These differences were found in conjunction with other associations, including clinical and pathological data, such as tumor stage (p = 0.0129), tumor size (p = 0.0296), and node metastasis (p = 0.0486). Moreover, elevated SOD2 expression correlated with an unfavorable prognosis. The in silico analysis revealed a similar pattern, despite operating at the transcriptional level. Moreover, notable correlations were identified between elevated SOD2 expression and worse survival. CONCLUSION These results highlight the importance of SOD2 in breast cancer, particularly in aggressive subtypes. Increased SOD2 staining correlates with poorer outcomes, suggesting it as a potential therapeutic target.
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Affiliation(s)
- Daniel Rodrigues de Bastos
- Department of Radiology and Oncology, São Paulo University, Institute of Cancer of São Paulo Faculty of Medicine, São Paulo, Brazil
| | - Adhemar Longatto-Filho
- Medical Laboratory of Medical Investigation (LIM) 14, Department of Pathology, São Paulo University Faculty of Medicine, São Paulo, Brazil
- Life and Health Sciences Research Institute (ICVS), Minho University, Braga, Portugal
- Teaching and Research Institute, Molecular Oncology Research Center, Barretos Cancer Hospital - Pio XII Foundation, São Paulo, Brazil
| | | | - Lara Termini
- Department of Radiology and Oncology, São Paulo University, Institute of Cancer of São Paulo Faculty of Medicine, São Paulo, Brazil
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Cabioglu N, Onder S, Karatay H, Bayram A, Oner G, Tukenmez M, Muslumanoglu M, Igci A, Dinccag A, Ozmen V, Aydiner A, Saip P, Yavuz E. New Emerging Chemokine Receptors: CCR5 or CXCR5 on Tumor Is Associated with Poor Response to Chemotherapy and Poor Prognosis in Locally Advanced Triple-Negative Breast Cancer. Cancers (Basel) 2024; 16:2388. [PMID: 39001456 PMCID: PMC11240792 DOI: 10.3390/cancers16132388] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Revised: 06/23/2024] [Accepted: 06/25/2024] [Indexed: 07/16/2024] Open
Abstract
BACKGROUND We aim to investigate any possible associations between chemokine receptor expression and responses to neoadjuvant chemotherapy (NAC) along with outcomes in patients with triple-negative breast cancer (TNBC) with locally advanced disease. METHOD Expressions of chemokine receptors were examined immunohistochemically after staining archival tissue of surgical specimens (n = 63) using specific antibodies for CCR5, CCR7, CXCR4, and CXCR5. RESULTS Patients with high CCR5, CCR7, CXCR4, and CXCR5 expression on tumors and high CXCR4 expression on tumor-infiltrating lymphocytes (TILs) were less likely to have a pathological complete response (pCR) or Class 0-I RCB-Index compared to others. Patients with residual lymph node metastases (ypN-positive), high CCR5TM(tumor), and high CXCR4TM expressions had an increased hazard ratio (HR) compared to others (DFS: HR = 2.655 [1.029-6.852]; DSS: HR = 2.763 [1.008-7.574]), (DFS: HR = 2.036 [0.805-5.148]; DSS: HR = 2.689 [1.020-7.090]), and (DFS: HR = 2.908 [1.080-7.829]; DSS: HR = 2.132 (0.778-5.846)), respectively. However, patients without CXCR5TIL expression had an increased HR compared to those with CXCR5TIL (DFS: 2.838 [1.266-6.362]; DSS: 4.211 [1.770-10.016]). CONCLUSIONS High expression of CXCR4TM and CCR5TM was found to be associated with poor prognosis, and CXCR5TM was associated with poor chemotherapy response in the present cohort with locally advanced TNBC. Our results suggest that patients with TNBC could benefit from a chemokine receptor inhibitor therapy containing neoadjuvant chemotherapy protocols.
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Affiliation(s)
- Neslihan Cabioglu
- Department of General Surgery, Istanbul Faculty of Medicine, Istanbul University, Istanbul 34452, Turkey; (G.O.); (M.T.); (M.M.); (A.I.); (A.D.); (V.O.)
| | - Semen Onder
- Department of Pathology, Istanbul Faculty of Medicine, Istanbul University, Istanbul 34452, Turkey; (S.O.); (H.K.); (A.B.); (E.Y.)
| | - Hüseyin Karatay
- Department of Pathology, Istanbul Faculty of Medicine, Istanbul University, Istanbul 34452, Turkey; (S.O.); (H.K.); (A.B.); (E.Y.)
| | - Aysel Bayram
- Department of Pathology, Istanbul Faculty of Medicine, Istanbul University, Istanbul 34452, Turkey; (S.O.); (H.K.); (A.B.); (E.Y.)
| | - Gizem Oner
- Department of General Surgery, Istanbul Faculty of Medicine, Istanbul University, Istanbul 34452, Turkey; (G.O.); (M.T.); (M.M.); (A.I.); (A.D.); (V.O.)
| | - Mustafa Tukenmez
- Department of General Surgery, Istanbul Faculty of Medicine, Istanbul University, Istanbul 34452, Turkey; (G.O.); (M.T.); (M.M.); (A.I.); (A.D.); (V.O.)
| | - Mahmut Muslumanoglu
- Department of General Surgery, Istanbul Faculty of Medicine, Istanbul University, Istanbul 34452, Turkey; (G.O.); (M.T.); (M.M.); (A.I.); (A.D.); (V.O.)
| | - Abdullah Igci
- Department of General Surgery, Istanbul Faculty of Medicine, Istanbul University, Istanbul 34452, Turkey; (G.O.); (M.T.); (M.M.); (A.I.); (A.D.); (V.O.)
| | - Ahmet Dinccag
- Department of General Surgery, Istanbul Faculty of Medicine, Istanbul University, Istanbul 34452, Turkey; (G.O.); (M.T.); (M.M.); (A.I.); (A.D.); (V.O.)
| | - Vahit Ozmen
- Department of General Surgery, Istanbul Faculty of Medicine, Istanbul University, Istanbul 34452, Turkey; (G.O.); (M.T.); (M.M.); (A.I.); (A.D.); (V.O.)
| | - Adnan Aydiner
- Department of Medical Oncology, Institute of Oncology, Istanbul University, Istanbul 34452, Turkey; (A.A.); (P.S.)
| | - Pınar Saip
- Department of Medical Oncology, Institute of Oncology, Istanbul University, Istanbul 34452, Turkey; (A.A.); (P.S.)
| | - Ekrem Yavuz
- Department of Pathology, Istanbul Faculty of Medicine, Istanbul University, Istanbul 34452, Turkey; (S.O.); (H.K.); (A.B.); (E.Y.)
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Qian X, Yang H, Ye Z, Gao B, Qian Z, Ding Y, Mao Z, Du Y, Wang W. Celecoxib Augments Paclitaxel-Induced Immunogenic Cell Death in Triple-Negative Breast Cancer. ACS NANO 2024; 18:15864-15877. [PMID: 38829727 DOI: 10.1021/acsnano.4c02947] [Citation(s) in RCA: 13] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/05/2024]
Abstract
Triple-negative breast cancer (TNBC) is a highly aggressive malignancy that lacks effective targeted therapies. Inducing immunogenic cell death (ICD) in tumor cells represents a promising strategy to enhance therapeutic efficacy by promoting antitumor immunity. Paclitaxel (PTX), a commonly used chemotherapy drug for TNBC, can induce ICD; however, the resulting immunogenicity is limited. Thus, there is an urgent need to explore strategies that improve the effectiveness of ICD in TNBC by incorporating immunoregulatory agents. This study investigated the potential of celecoxib (CXB) to enhance PTX-induced ICD by blocking the biosynthesis of PGE2 in the tumor cells. We observed that the combination of CXB and PTX promoted the maturation of dendritic cells and primed a T cell-dependent immune response, leading to enhanced tumor rejection in a vaccination assay. To further optimize drug delivery in vivo, we developed cRGD-modified liposomes for the targeted codelivery of CXB and PTX. This delivery system significantly improved drug accumulation and triggered robust antitumor immunity in an orthotopic mouse model of TNBC. Moreover, it served as an in situ vaccine to inhibit tumor recurrence and lung metastasis. Overall, our findings provide in-depth insights into the therapeutic mechanism underlying the combination of CXB and PTX, highlighting their potential as effective immune-based therapies for TNBC.
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Affiliation(s)
- Xiaohui Qian
- Department of Hepatobiliary and Pancreatic Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang, China
- Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, Hangzhou 310009, Zhejiang, China
- Research Center of Diagnosis and Treatment Technology for Hepatocellular Carcinoma of Zhejiang Province, Hangzhou 310009, Zhejiang, China
- National Innovation Center for Fundamental Research on Cancer Medicine, Hangzhou 310009, Zhejiang, China
- Cancer Center, Zhejiang University, Hangzhou 310058, Zhejiang, China
- ZJU-Pujian Research & Development Center of Medical Artificial Intelligence for Hepatobiliary and Pancreatic Disease, Hangzhou 310058, Zhejiang, China
| | - Huang Yang
- MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou 310027, Zhejiang, China
| | - Ziqiang Ye
- MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou 310027, Zhejiang, China
| | - Bingqiang Gao
- Department of Hepatobiliary and Pancreatic Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang, China
- Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, Hangzhou 310009, Zhejiang, China
- Research Center of Diagnosis and Treatment Technology for Hepatocellular Carcinoma of Zhejiang Province, Hangzhou 310009, Zhejiang, China
- National Innovation Center for Fundamental Research on Cancer Medicine, Hangzhou 310009, Zhejiang, China
- Cancer Center, Zhejiang University, Hangzhou 310058, Zhejiang, China
- ZJU-Pujian Research & Development Center of Medical Artificial Intelligence for Hepatobiliary and Pancreatic Disease, Hangzhou 310058, Zhejiang, China
| | - Zhefeng Qian
- Department of Hepatobiliary and Pancreatic Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang, China
- Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, Hangzhou 310009, Zhejiang, China
- Research Center of Diagnosis and Treatment Technology for Hepatocellular Carcinoma of Zhejiang Province, Hangzhou 310009, Zhejiang, China
- National Innovation Center for Fundamental Research on Cancer Medicine, Hangzhou 310009, Zhejiang, China
- Cancer Center, Zhejiang University, Hangzhou 310058, Zhejiang, China
- ZJU-Pujian Research & Development Center of Medical Artificial Intelligence for Hepatobiliary and Pancreatic Disease, Hangzhou 310058, Zhejiang, China
| | - Yuan Ding
- Department of Hepatobiliary and Pancreatic Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang, China
- Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, Hangzhou 310009, Zhejiang, China
- Research Center of Diagnosis and Treatment Technology for Hepatocellular Carcinoma of Zhejiang Province, Hangzhou 310009, Zhejiang, China
- National Innovation Center for Fundamental Research on Cancer Medicine, Hangzhou 310009, Zhejiang, China
- Cancer Center, Zhejiang University, Hangzhou 310058, Zhejiang, China
- ZJU-Pujian Research & Development Center of Medical Artificial Intelligence for Hepatobiliary and Pancreatic Disease, Hangzhou 310058, Zhejiang, China
| | - Zhengwei Mao
- Department of Hepatobiliary and Pancreatic Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang, China
- Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, Hangzhou 310009, Zhejiang, China
- MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou 310027, Zhejiang, China
| | - Yang Du
- Department of Hepatobiliary and Pancreatic Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang, China
- Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, Hangzhou 310009, Zhejiang, China
- Research Center of Diagnosis and Treatment Technology for Hepatocellular Carcinoma of Zhejiang Province, Hangzhou 310009, Zhejiang, China
- National Innovation Center for Fundamental Research on Cancer Medicine, Hangzhou 310009, Zhejiang, China
- Cancer Center, Zhejiang University, Hangzhou 310058, Zhejiang, China
- ZJU-Pujian Research & Development Center of Medical Artificial Intelligence for Hepatobiliary and Pancreatic Disease, Hangzhou 310058, Zhejiang, China
| | - Weilin Wang
- Department of Hepatobiliary and Pancreatic Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang, China
- Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, Hangzhou 310009, Zhejiang, China
- Research Center of Diagnosis and Treatment Technology for Hepatocellular Carcinoma of Zhejiang Province, Hangzhou 310009, Zhejiang, China
- National Innovation Center for Fundamental Research on Cancer Medicine, Hangzhou 310009, Zhejiang, China
- Cancer Center, Zhejiang University, Hangzhou 310058, Zhejiang, China
- ZJU-Pujian Research & Development Center of Medical Artificial Intelligence for Hepatobiliary and Pancreatic Disease, Hangzhou 310058, Zhejiang, China
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Aquino-Acevedo AN, Orengo-Orengo JA, Cruz-Robles ME, Saavedra HI. Mitotic kinases are emerging therapeutic targets against metastatic breast cancer. Cell Div 2024; 19:21. [PMID: 38886738 PMCID: PMC11184769 DOI: 10.1186/s13008-024-00125-x] [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: 12/21/2023] [Accepted: 06/10/2024] [Indexed: 06/20/2024] Open
Abstract
This review aims to outline mitotic kinase inhibitors' roles as potential therapeutic targets and assess their suitability as a stand-alone clinical therapy or in combination with standard treatments for advanced-stage solid tumors, including triple-negative breast cancer (TNBC). Breast cancer poses a significant global health risk, with TNBC standing out as the most aggressive subtype. Comprehending the role of mitosis is crucial for understanding how TNBC advances from a solid tumor to metastasis. Chemotherapy is the primary treatment used to treat TNBC. Some types of chemotherapeutic agents target cells in mitosis, thus highlighting the need to comprehend the molecular mechanisms governing mitosis in cancer. This understanding is essential for devising targeted therapies to disrupt these mitotic processes, prevent or treat metastasis, and improve patient outcomes. Mitotic kinases like Aurora kinase A, Aurora Kinase B, never in mitosis gene A-related kinase 2, Threonine-Tyrosine kinase, and Polo-kinase 1 significantly impact cell cycle progression by contributing to chromosome separation and centrosome homeostasis. When these kinases go awry, they can trigger chromosome instability, increase cell proliferation, and activate different molecular pathways that culminate in a transition from epithelial to mesenchymal cells. Ongoing clinical trials investigate various mitotic kinase inhibitors as potential biological treatments against advanced solid tumors. While clinical trials against mitotic kinases have shown some promise in the clinic, more investigation is necessary, since they induce severe adverse effects, particularly affecting the hematopoietic system.
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Affiliation(s)
- Alexandra N Aquino-Acevedo
- Department of Basic Sciences, Ponce Health Sciences University-Ponce Research Institute, 388 Luis Salas Zona Industrial Reparada 2, P.O. Box 7004, Ponce, Puerto Rico, 00716-2347, USA
| | - Joel A Orengo-Orengo
- Department of Basic Sciences, Ponce Health Sciences University-Ponce Research Institute, 388 Luis Salas Zona Industrial Reparada 2, P.O. Box 7004, Ponce, Puerto Rico, 00716-2347, USA
| | - Melanie E Cruz-Robles
- Department of Basic Sciences, Ponce Health Sciences University-Ponce Research Institute, 388 Luis Salas Zona Industrial Reparada 2, P.O. Box 7004, Ponce, Puerto Rico, 00716-2347, USA
| | - Harold I Saavedra
- Department of Basic Sciences, Ponce Health Sciences University-Ponce Research Institute, 388 Luis Salas Zona Industrial Reparada 2, P.O. Box 7004, Ponce, Puerto Rico, 00716-2347, USA.
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Li Y, Wang Z, Yang J, Sun Y, He Y, Wang Y, Chen X, Liang Y, Zhang N, Wang X, Zhao W, Hu G, Yang Q. CircTRIM1 encodes TRIM1-269aa to promote chemoresistance and metastasis of TNBC via enhancing CaM-dependent MARCKS translocation and PI3K/AKT/mTOR activation. Mol Cancer 2024; 23:102. [PMID: 38755678 PMCID: PMC11097450 DOI: 10.1186/s12943-024-02019-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2024] [Accepted: 05/08/2024] [Indexed: 05/18/2024] Open
Abstract
Peptides and proteins encoded by noncanonical open reading frames (ORFs) of circRNAs have recently been recognized to play important roles in disease progression, but the biological functions and mechanisms of these peptides and proteins are largely unknown. Here, we identified a potential coding circular RNA, circTRIM1, that was upregulated in doxorubicin-resistant TNBC cells by intersecting transcriptome and translatome RNA-seq data, and its expression was correlated with clinicopathological characteristics and poor prognosis in patients with TNBC. CircTRIM1 possesses a functional IRES element along with an 810 nt ORF that can be translated into a novel endogenously expressed protein termed TRIM1-269aa. Functionally, we demonstrated that TRIM1-269aa, which is involved in the biological functions of circTRIM1, promoted chemoresistance and metastasis in TNBC cells both in vitro and in vivo. In addition, we found that TRIM1-269aa can be packaged into exosomes and transmitted between TNBC cells. Mechanistically, TRIM1-269aa enhanced the interaction between MARCKS and calmodulin, thus promoting the calmodulin-dependent translocation of MARCKS, which further initiated the activation of the PI3K/AKT/mTOR pathway. Overall, circTRIM1, which encodes TRIM1-269aa, promoted TNBC chemoresistance and metastasis by enhancing MARCKS translocation and PI3K/AKT/mTOR activation. Our investigation has yielded novel insights into the roles of protein-coding circRNAs and supported circTRIM1/TRIM1-269aa as a novel promising prognostic and therapeutic target for patients with TNBC.
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Affiliation(s)
- Yaming Li
- Department of Breast Surgery, General Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, 250012, China
| | - Zekun Wang
- Department of Breast Surgery, General Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, 250012, China
| | - Jingwen Yang
- Department of Breast Surgery, General Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, 250012, China
| | - Yuhan Sun
- Department of Breast Surgery, General Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, 250012, China
| | - Yinqiao He
- Department of Breast Surgery, General Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, 250012, China
| | - Yuping Wang
- School of Basic Medicine, Jining Medical College, Jining, Shandong, 272067, China
| | - Xi Chen
- Department of Breast Surgery, General Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, 250012, China
| | - Yiran Liang
- Department of Breast Surgery, General Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, 250012, China
| | - Ning Zhang
- Department of Breast Surgery, General Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, 250012, China
| | - Xiaolong Wang
- Department of Breast Surgery, General Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, 250012, China
| | - Wenjing Zhao
- Pathology Tissue Bank, Qilu Hospital of Shandong University, Jinan, Shandong, 250012, China
| | - Guohong Hu
- Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China.
| | - Qifeng Yang
- Department of Breast Surgery, General Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, 250012, China.
- Pathology Tissue Bank, Qilu Hospital of Shandong University, Jinan, Shandong, 250012, China.
- Research Institute of Breast Cancer, Shandong University, Jinan, Shandong, 250012, China.
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47
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Raj-Kumar PK, Lin X, Liu T, Sturtz LA, Gritsenko MA, Petyuk VA, Sagendorf TJ, Deyarmin B, Liu J, Praveen-Kumar A, Wang G, McDermott JE, Shukla AK, Moore RJ, Monroe ME, Webb-Robertson BJM, Hooke JA, Fantacone-Campbell L, Mostoller B, Kvecher L, Kane J, Melley J, Somiari S, Soon-Shiong P, Smith RD, Mural RJ, Rodland KD, Shriver CD, Kovatich AJ, Hu H. Proteogenomic characterization of difficult-to-treat breast cancer with tumor cells enriched through laser microdissection. Breast Cancer Res 2024; 26:76. [PMID: 38745208 PMCID: PMC11094977 DOI: 10.1186/s13058-024-01835-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2024] [Accepted: 05/05/2024] [Indexed: 05/16/2024] Open
Abstract
BACKGROUND Breast cancer (BC) is the most commonly diagnosed cancer and the leading cause of cancer death among women globally. Despite advances, there is considerable variation in clinical outcomes for patients with non-luminal A tumors, classified as difficult-to-treat breast cancers (DTBC). This study aims to delineate the proteogenomic landscape of DTBC tumors compared to luminal A (LumA) tumors. METHODS We retrospectively collected a total of 117 untreated primary breast tumor specimens, focusing on DTBC subtypes. Breast tumors were processed by laser microdissection (LMD) to enrich tumor cells. DNA, RNA, and protein were simultaneously extracted from each tumor preparation, followed by whole genome sequencing, paired-end RNA sequencing, global proteomics and phosphoproteomics. Differential feature analysis, pathway analysis and survival analysis were performed to better understand DTBC and investigate biomarkers. RESULTS We observed distinct variations in gene mutations, structural variations, and chromosomal alterations between DTBC and LumA breast tumors. DTBC tumors predominantly had more mutations in TP53, PLXNB3, Zinc finger genes, and fewer mutations in SDC2, CDH1, PIK3CA, SVIL, and PTEN. Notably, Cytoband 1q21, which contains numerous cell proliferation-related genes, was significantly amplified in the DTBC tumors. LMD successfully minimized stromal components and increased RNA-protein concordance, as evidenced by stromal score comparisons and proteomic analysis. Distinct DTBC and LumA-enriched clusters were observed by proteomic and phosphoproteomic clustering analysis, some with survival differences. Phosphoproteomics identified two distinct phosphoproteomic profiles for high relapse-risk and low relapse-risk basal-like tumors, involving several genes known to be associated with breast cancer oncogenesis and progression, including KIAA1522, DCK, FOXO3, MYO9B, ARID1A, EPRS, ZC3HAV1, and RBM14. Lastly, an integrated pathway analysis of multi-omics data highlighted a robust enrichment of proliferation pathways in DTBC tumors. CONCLUSIONS This study provides an integrated proteogenomic characterization of DTBC vs LumA with tumor cells enriched through laser microdissection. We identified many common features of DTBC tumors and the phosphopeptides that could serve as potential biomarkers for high/low relapse-risk basal-like BC and possibly guide treatment selections.
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Affiliation(s)
- Praveen-Kumar Raj-Kumar
- Chan Soon-Shiong Institute of Molecular Medicine at Windber, Windber, PA, USA
- Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD, USA
| | - Xiaoying Lin
- Chan Soon-Shiong Institute of Molecular Medicine at Windber, Windber, PA, USA
- Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD, USA
| | - Tao Liu
- Pacific Northwest National Laboratory, Richland, WA, USA
| | - Lori A Sturtz
- Chan Soon-Shiong Institute of Molecular Medicine at Windber, Windber, PA, USA
- Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD, USA
| | | | | | | | - Brenda Deyarmin
- Chan Soon-Shiong Institute of Molecular Medicine at Windber, Windber, PA, USA
| | - Jianfang Liu
- Chan Soon-Shiong Institute of Molecular Medicine at Windber, Windber, PA, USA
| | | | - Guisong Wang
- Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD, USA
- The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc, Bethesda, MD, USA
| | | | - Anil K Shukla
- Pacific Northwest National Laboratory, Richland, WA, USA
| | - Ronald J Moore
- Pacific Northwest National Laboratory, Richland, WA, USA
| | | | | | - Jeffrey A Hooke
- Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD, USA
- The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc, Bethesda, MD, USA
| | - Leigh Fantacone-Campbell
- Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD, USA
- The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc, Bethesda, MD, USA
| | - Brad Mostoller
- Chan Soon-Shiong Institute of Molecular Medicine at Windber, Windber, PA, USA
| | - Leonid Kvecher
- Chan Soon-Shiong Institute of Molecular Medicine at Windber, Windber, PA, USA
- Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD, USA
| | - Jennifer Kane
- Chan Soon-Shiong Institute of Molecular Medicine at Windber, Windber, PA, USA
| | - Jennifer Melley
- Chan Soon-Shiong Institute of Molecular Medicine at Windber, Windber, PA, USA
| | - Stella Somiari
- Chan Soon-Shiong Institute of Molecular Medicine at Windber, Windber, PA, USA
| | | | | | - Richard J Mural
- Chan Soon-Shiong Institute of Molecular Medicine at Windber, Windber, PA, USA
| | | | - Craig D Shriver
- Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
- Department of Surgery, Walter Reed National Military Medical Center, Bethesda, MD, USA.
| | - Albert J Kovatich
- Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD, USA
- The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc, Bethesda, MD, USA
| | - Hai Hu
- Chan Soon-Shiong Institute of Molecular Medicine at Windber, Windber, PA, USA.
- Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
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48
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Ho AN, Kiesel VA, Gates CE, Brosnan BH, Connelly SP, Glenny EM, Cozzo AJ, Hursting SD, Coleman MF. Exogenous Metabolic Modulators Improve Response to Carboplatin in Triple-Negative Breast Cancer. Cells 2024; 13:806. [PMID: 38786030 PMCID: PMC11119195 DOI: 10.3390/cells13100806] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2024] [Revised: 05/06/2024] [Accepted: 05/07/2024] [Indexed: 05/25/2024] Open
Abstract
Triple-negative breast cancer (TNBC) lacks targeted therapies, leaving cytotoxic chemotherapy as the current standard treatment. However, chemotherapy resistance remains a major clinical challenge. Increased insulin-like growth factor 1 signaling can potently blunt chemotherapy response, and lysosomal processes including the nutrient scavenging pathway autophagy can enable cancer cells to evade chemotherapy-mediated cell death. Thus, we tested whether inhibition of insulin receptor/insulin-like growth factor 1 receptor with the drug BMS-754807 and/or lysosomal disruption with hydroxychloroquine (HCQ) could sensitize TNBC cells to the chemotherapy drug carboplatin. Using in vitro studies in multiple TNBC cell lines, in concert with in vivo studies employing a murine syngeneic orthotopic transplant model of TNBC, we show that BMS-754807 and HCQ each sensitized TNBC cells and tumors to carboplatin and reveal that exogenous metabolic modulators may work synergistically with carboplatin as indicated by Bliss analysis. Additionally, we demonstrate the lack of overt in vivo toxicity with our combination regimens and, therefore, propose that metabolic targeting of TNBC may be a safe and effective strategy to increase sensitivity to chemotherapy. Thus, we conclude that the use of exogenous metabolic modulators, such as BMS-754807 or HCQ, in combination with chemotherapy warrants additional study as a strategy to improve therapeutic responses in women with TNBC.
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Affiliation(s)
- Alyssa N. Ho
- Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Violet A. Kiesel
- Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Claire E. Gates
- Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
- Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Bennett H. Brosnan
- Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Scott P. Connelly
- Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Elaine M. Glenny
- Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Alyssa J. Cozzo
- Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Stephen D. Hursting
- Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
- Nutrition Research Institute, University of North Carolina at Chapel Hill, Kannapolis, NC 28081, USA
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Michael Francis Coleman
- Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
- Nutrition Research Institute, University of North Carolina at Chapel Hill, Kannapolis, NC 28081, USA
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49
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Čeprnja T, Tomić S, Perić Balja M, Marušić Z, Blažićević V, Spagnoli GC, Juretić A, Čapkun V, Vuger AT, Pogorelić Z, Mrklić I. Prognostic Value of "Basal-like" Morphology, Tumor-Infiltrating Lymphocytes and Multi-MAGE-A Expression in Triple-Negative Breast Cancer. Int J Mol Sci 2024; 25:4513. [PMID: 38674098 PMCID: PMC11050590 DOI: 10.3390/ijms25084513] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2024] [Revised: 04/16/2024] [Accepted: 04/19/2024] [Indexed: 04/28/2024] Open
Abstract
"Basal-like" (BL) morphology and the expression of cancer testis antigens (CTA) in breast cancer still have unclear prognostic significance. The aim of our research was to explore correlations of the morphological characteristics and tumor microenvironment in triple-negative breast carcinomas (TNBCs) with multi-MAGE-A CTA expression and to determine their prognostic significance. Clinical records of breast cancer patients who underwent surgery between January 2017 and December 2018 in four major Croatian clinical centers were analyzed. A total of 97 non-metastatic TNBCs with available tissue samples and treatment information were identified. Cancer tissue sections were additionally stained with programmed death-ligand 1 (PD-L1) Ventana (SP142) and multi-MAGE-A (mAb 57B). BL morphology was detected in 47 (49%) TNBCs and was associated with a higher Ki-67 proliferation index and histologic grade. Expression of multi-MAGE-A was observed in 77 (79%) TNBCs and was significantly associated with BL morphology. Lymphocyte-predominant breast cancer (LPBC) status was detected in 11 cases (11.3%) and significantly correlated with the Ki-67 proliferation index, increased number of intratumoral lymphocytes (itTIL), and PD-L1 expression. No impact of BL morphology, multi-MAGE-A expression, histologic type, or LPBC status on disease-free survival was observed. Our data suggest that tumor morphology could help identify patients with potential benefits from CTA-targeting immunotherapy.
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Affiliation(s)
- Toni Čeprnja
- Department of Pathology, Forensic Medicine and Cytology, University Hospital of Split, 21000 Split, Croatia; (T.Č.); (S.T.); (I.M.)
| | - Snježana Tomić
- Department of Pathology, Forensic Medicine and Cytology, University Hospital of Split, 21000 Split, Croatia; (T.Č.); (S.T.); (I.M.)
- Department of Pathology, School of Medicine, University of Split, 21000 Split, Croatia
| | - Melita Perić Balja
- Department of Pathology, University Hospital Center “Sestre Milosrdnice”, 10000 Zagreb, Croatia
| | - Zlatko Marušić
- Department of Pathology, Zagreb University Hospital Center, 10000 Zagreb, Croatia
| | | | | | - Antonio Juretić
- Department of Oncology, University Hospital Dubrava, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia;
| | - Vesna Čapkun
- Department of Nuclear Medicine, University Hospital of Split, 21000 Split, Croatia
| | - Ana Tečić Vuger
- Department of Oncology, University Hospital “Sestre Milosrdnice”, 10000 Zagreb, Croatia;
| | - Zenon Pogorelić
- Department of Pediatric Surgery, University Hospital of Split, 21000 Split, Croatia
- Department of Surgery, School of Medicine, University of Split, 21000 Split, Croatia
| | - Ivana Mrklić
- Department of Pathology, Forensic Medicine and Cytology, University Hospital of Split, 21000 Split, Croatia; (T.Č.); (S.T.); (I.M.)
- Department of Pathology, School of Medicine, University of Split, 21000 Split, Croatia
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50
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Sunassee ED, Deutsch RJ, D’Agostino VW, Castellano-Escuder P, Siebeneck EA, Ilkayeva O, Crouch BT, Madonna MC, Everitt J, Alvarez JV, Palmer GM, Hirschey MD, Ramanujam N. Optical imaging reveals chemotherapy-induced metabolic reprogramming of residual disease and recurrence. SCIENCE ADVANCES 2024; 10:eadj7540. [PMID: 38579004 PMCID: PMC10997195 DOI: 10.1126/sciadv.adj7540] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Accepted: 03/04/2024] [Indexed: 04/07/2024]
Abstract
Fewer than 20% of triple-negative breast cancer patients experience long-term responses to mainstay chemotherapy. Resistant tumor subpopulations use alternative metabolic pathways to escape therapy, survive, and eventually recur. Here, we show in vivo, longitudinal metabolic reprogramming in residual disease and recurrence of triple-negative breast cancer xenografts with varying sensitivities to the chemotherapeutic drug paclitaxel. Optical imaging coupled with metabolomics reported an increase in non-glucose-driven mitochondrial metabolism and an increase in intratumoral metabolic heterogeneity during regression and residual disease in resistant MDA-MB-231 tumors. Conversely, sensitive HCC-1806 tumors were primarily reliant on glucose uptake and minimal changes in metabolism or heterogeneity were observed over the tumors' therapeutic life cycles. Further, day-matched resistant HCC-1806 tumors revealed a higher reliance on mitochondrial metabolism and elevated metabolic heterogeneity compared to sensitive HCC-1806 tumors. Together, metabolic flexibility, increased reliance on mitochondrial metabolism, and increased metabolic heterogeneity are defining characteristics of persistent residual disease, features that will inform the appropriate type and timing of therapies.
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Affiliation(s)
| | - Riley J. Deutsch
- Department of Biomedical Engineering, Duke University, Durham, NC, USA
| | | | - Pol Castellano-Escuder
- Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Metabolism Center, Durham, NC, USA
- Department of Pharmacology and Cancer Biology, School of Medicine, Duke University, Durham, NC, USA
- Department of Medicine, Division of Endocrinology, Metabolism, and Nutrition, Duke University Medical Center, Durham, NC, USA
| | | | - Olga Ilkayeva
- Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Metabolism Center, Durham, NC, USA
- Department of Medicine, Division of Endocrinology, Metabolism, and Nutrition, Duke University Medical Center, Durham, NC, USA
| | - Brian T. Crouch
- Department of Biomedical Engineering, Duke University, Durham, NC, USA
| | - Megan C. Madonna
- Department of Biomedical Engineering, Duke University, Durham, NC, USA
| | - Jeffrey Everitt
- Department of Pathology, School of Medicine, Duke University, Durham, NC, USA
| | - James V. Alvarez
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, USA
| | | | - Matthew D. Hirschey
- Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Metabolism Center, Durham, NC, USA
- Department of Pharmacology and Cancer Biology, School of Medicine, Duke University, Durham, NC, USA
- Department of Medicine, Division of Endocrinology, Metabolism, and Nutrition, Duke University Medical Center, Durham, NC, USA
| | - Nirmala Ramanujam
- Department of Biomedical Engineering, Duke University, Durham, NC, USA
- Department of Radiation Oncology, Duke University, Durham, NC, USA
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