|
1
|
Silva CR, Vieira DP, de Freitas AZ, Ribeiro MS. Photodynamic therapy as a strategic ally in radiotherapy for triple-negative breast cancer: the importance of treatment order. Breast Cancer Res Treat 2025; 210:687-697. [PMID: 39776332 DOI: 10.1007/s10549-024-07607-0] [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: 10/22/2024] [Accepted: 12/30/2024] [Indexed: 01/11/2025]
Abstract
PURPOSE Triple-negative breast cancer (TNBC) accounts for 20% of all breast cancer cases and is notably resistant to radiotherapy (RT). Photodynamic therapy (PDT) using porphyrins or their derivatives has shown promise as a potential cancer treatment and immune activator. This study evaluated the effects of combining PDT and RT in sublethal conditions for TNBC using in vitro and in vivo models. METHODS In vitro, PDT was combined with RT (2.5 Gy) using a porphyrin (TMPyP, 32 μmolL-1) and red light (660 ± 15 nm) with a dose of 50 Jcm-2. We assessed cell viability, survival, apoptosis, ROS, singlet oxygen, and GSH/GSSG ratio. In vivo, we used a TNBC-bearing mouse model and combined PDT with RT in four sessions, comparing treatment sequences. We evaluated tumor volume, clinical manifestations, survival, metastasis in the lungs, ROS, singlet oxygen, and glutathione levels. RESULTS Cells treated with PDT + RT had a lower survival fraction, although PDT alone showed higher apoptosis and singlet oxygen levels than RT-treated groups. In vivo, the treatment sequence plays a crucial role: PDT after RT resulted in better clinical outcomes, prolonged survival, and fewer lung nodules compared to RT, with higher singlet oxygen levels likely stimulating an immune response. CONCLUSION Our results show that PDT can be a valuable adjunct in the RT of TNBC, with the treatment sequence playing a crucial role in enhancing efficacy.
Collapse
Affiliation(s)
- Camila Ramos Silva
- Center for Lasers and Applications, Energy and Nuclear Research Institute (IPEN-CNEN), Av. Lineu Prestes, 2242, São Paulo, Brazil
| | - Daniel Perez Vieira
- Center of Biotechnology, Energy and Nuclear Research Institute (IPEN-CNEN), Av. Lineu Prestes, 2242, São Paulo, Brazil
| | - Anderson Zanardi de Freitas
- Center for Lasers and Applications, Energy and Nuclear Research Institute (IPEN-CNEN), Av. Lineu Prestes, 2242, São Paulo, Brazil
| | - Martha Simões Ribeiro
- Center for Lasers and Applications, Energy and Nuclear Research Institute (IPEN-CNEN), Av. Lineu Prestes, 2242, São Paulo, Brazil.
| |
Collapse
|
|
2
|
Sheva K, Roy Chowdhury S, Kravchenko-Balasha N, Meirovitz A. Molecular Changes in Breast Cancer Induced by Radiation Therapy. Int J Radiat Oncol Biol Phys 2024; 120:465-481. [PMID: 38508467 DOI: 10.1016/j.ijrobp.2024.03.019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Revised: 02/29/2024] [Accepted: 03/10/2024] [Indexed: 03/22/2024]
Abstract
PURPOSE Breast cancer treatments are based on prognostic clinicopathologic features that form the basis for therapeutic guidelines. Although the utilization of these guidelines has decreased breast cancer-associated mortality rates over the past three decades, they are not adequate for individualized therapy. Radiation therapy (RT) is the backbone of breast cancer treatment. Although a highly successful therapeutic modality clinically, from a biological perspective, preclinical studies have shown RT to have the potential to alter tumor cell phenotype, immunogenicity, and the surrounding microenvironment, potentially changing the behavior of cancer cells and resulting in a significant variation in RT response. This review presents the recent advances in revealing the complex molecular changes induced by RT in the treatment of breast cancer and highlights the complexities of translating this information into clinically relevant tools for improved prognostic insights and the revelation of novel approaches for optimizing RT. METHODS AND MATERIALS Current literature was reviewed with a focus on recent advances made in the elucidation of tumor-associated radiation-induced molecular changes across molecular, genetic, and proteomic bases. This review was structured with the aim of providing an up-to-date overview over the very broad and complex subject matter of radiation-induced molecular changes and radioresistance, familiarizing the reader with the broader issue at hand. RESULTS The subject of radiation-induced molecular changes in breast cancer has been broached from various physiological focal points including that of the immune system, immunogenicity and the abscopal effect, tumor hypoxia, breast cancer classification and subtyping, molecular heterogeneity, and molecular plasticity. It is becoming increasingly apparent that breast cancer clinical subtyping alone does not adequately account for variation in RT response or radioresistance. Multiple components of the tumor microenvironment and immune system, delivered RT dose and fractionation schedules, radiation-induced bystander effects, and intrinsic tumor physiology and heterogeneity all contribute to the resultant RT outcome. CONCLUSIONS Despite recent advances and improvements in anticancer therapies, tumor resistance remains a significant challenge. As new analytical techniques and technologies continue to provide crucial insight into the complex molecular mechanisms of breast cancer and its treatment responses, it is becoming more evident that personalized anticancer treatment regimens may be vital in overcoming radioresistance.
Collapse
Affiliation(s)
- Kim Sheva
- The Legacy Heritage Oncology Center & Dr Larry Norton Institute, Soroka University Medical Center, Ben Gurion University of the Negev, Faculty of Medicine, Be'er Sheva, Israel.
| | - Sangita Roy Chowdhury
- The Institute of Biomedical and Oral Research, The Hebrew University of Jerusalem, Jerusalem, Israel
| | - Nataly Kravchenko-Balasha
- The Institute of Biomedical and Oral Research, The Hebrew University of Jerusalem, Jerusalem, Israel.
| | - Amichay Meirovitz
- The Legacy Heritage Oncology Center & Dr Larry Norton Institute, Soroka University Medical Center, Ben Gurion University of the Negev, Faculty of Medicine, Be'er Sheva, Israel.
| |
Collapse
|
|
3
|
Musielak M, Graczyk K, Liszka M, Christou A, Rosochowicz MA, Lach MS, Adamczyk B, Suchorska WM, Piotrowski T, Stenerlöw B, Malicki J. Impact of Proton Irradiation Depending on Breast Cancer Subtype in Patient-Derived Cell Lines. Int J Mol Sci 2024; 25:10494. [PMID: 39408826 PMCID: PMC11477436 DOI: 10.3390/ijms251910494] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2024] [Revised: 09/26/2024] [Accepted: 09/27/2024] [Indexed: 10/20/2024] Open
Abstract
Research on different types of ionizing radiation's effects has been ongoing for years, revealing its efficacy in damaging cancer cells. Solid tumors comprise diverse cell types, each being able to respond differently to radiation. This study evaluated the radiobiological response of established (MDA-MB-231 (Triple negative breast cancer, TNBC), MCF-7 (Luminal A)) and patient-derived malignant cell lines, cancer-associated fibroblasts, and skin fibroblasts following proton IRR. All cell line types were irradiated with the proton dose of 2, 4, and 6 Gy. The radiobiological response was assessed using clonogenic assay, γH2AX, and p53 staining. It was noticeable that breast cancer lines of different molecular subtypes displayed no significant variations in their response to proton IRR. In terms of cancer-associated fibroblasts extracted from the tumor tissue, the line derived from a TNBC subtype tumor demonstrated higher resistance to ionizing radiation compared to lines isolated from luminal A tumors. Fibroblasts extracted from patients' skin responded identically to all doses of proton radiation. This study emphasizes that tumor response is not exclusively determined by the elimination of breast cancer cells, but also takes into account tumor microenvironmental variables and skin reactions.
Collapse
Affiliation(s)
- Marika Musielak
- Department of Electroradiology, Poznan University of Medical Sciences, 61-701 Poznan, Poland; (W.M.S.); (T.P.); (J.M.)
- Doctoral School, Poznan University of Medical Sciences, 61-701 Poznan, Poland;
- Radiobiology Laboratory, Department of Medical Physics, Greater Poland Cancer Centre, 61-866 Poznan, Poland;
| | - Kinga Graczyk
- Clinical Dosimetry, Department of Medical Physics, Greater Poland Cancer Centre, 61-866 Poznan, Poland;
- The Skandion Clinic, 751 23 Uppsala, Sweden; (M.L.); (A.C.)
| | | | | | - Monika A. Rosochowicz
- Doctoral School, Poznan University of Medical Sciences, 61-701 Poznan, Poland;
- Radiobiology Laboratory, Department of Medical Physics, Greater Poland Cancer Centre, 61-866 Poznan, Poland;
- Department of Orthopaedics and Traumatology, Poznan University of Medical Sciences, 61-701 Poznan, Poland
| | - Michał S. Lach
- Radiobiology Laboratory, Department of Medical Physics, Greater Poland Cancer Centre, 61-866 Poznan, Poland;
| | - Beata Adamczyk
- Breast Surgical Oncology Department, Greater Poland Cancer Centre, 61-866 Poznan, Poland;
| | - Wiktoria M. Suchorska
- Department of Electroradiology, Poznan University of Medical Sciences, 61-701 Poznan, Poland; (W.M.S.); (T.P.); (J.M.)
- Radiobiology Laboratory, Department of Medical Physics, Greater Poland Cancer Centre, 61-866 Poznan, Poland;
| | - Tomasz Piotrowski
- Department of Electroradiology, Poznan University of Medical Sciences, 61-701 Poznan, Poland; (W.M.S.); (T.P.); (J.M.)
- Department of Medical Physics, Greater Poland Cancer Centre, 61-866 Poznan, Poland
| | - Bo Stenerlöw
- Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, 753 10 Uppsala, Sweden;
| | - Julian Malicki
- Department of Electroradiology, Poznan University of Medical Sciences, 61-701 Poznan, Poland; (W.M.S.); (T.P.); (J.M.)
- Department of Medical Physics, Greater Poland Cancer Centre, 61-866 Poznan, Poland
| |
Collapse
|
|
4
|
Tang J, Li J, Lian J, Huang Y, Zhang Y, Lu Y, Zhong G, Wang Y, Zhang Z, Bai X, Fang M, Wu L, Shen H, Wu J, Wang Y, Zhang L, Zhang H. CDK2-activated TRIM32 phosphorylation and nuclear translocation promotes radioresistance in triple-negative breast cancer. J Adv Res 2024; 61:239-251. [PMID: 37734566 PMCID: PMC11258662 DOI: 10.1016/j.jare.2023.09.011] [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: 06/19/2023] [Revised: 09/04/2023] [Accepted: 09/14/2023] [Indexed: 09/23/2023] Open
Abstract
INTRODUCTION Despite radiotherapy being one of the major treatments for triple-negative breast cancer (TNBC), new molecular targets for its treatment are still required due to radioresistance. CDK2 plays a critical role in TNBC. However, the mechanism by which CDK2 promotes TNBC radioresistance remains to be clearly elucidated. OBJECTIVES We aimed to elucidate the relationship between CDK2 and TRIM32 and the regulation mechanism in TNBC. METHODS We performed immunohistochemical staining to detect nuclear TRIM32, CDK2 and STAT3 on TNBC tissues. Western blot assays and PCR were used to detect the protein and mRNA level changes. CRISPR/Cas9 used to knock out CDK2. shRNA-knockdown and transfection assays also used to knock out target genes. GST pull-down analysis, immunoprecipitation (IP) assay and in vitro isomerization analysis also used. Tumorigenesis studies also used to verify the results in vitro. RESULTS Herein, tripartite motif-containing protein 32 (TRIM32) is revealed as a substrate of CDK2. Radiotherapy promotes the binding of CDK2 and TRIM32, thus leading to increased CDK2-dependent phosphorylation of TRIM32 at serines 328 and 339. This causes the recruitment of PIN1, involved in cis-trans isomerization of TRIM32, resulting in importin α3 binding to TRIM32 and contributing to its nuclear translocation. Nuclear TRIM32 inhibits TC45-dephosphorylated STAT3, Leading to increased transcription of STAT3 and radioresistance in TNBC. These results were validated by clinical prognosis confirmed by the correlative expressions of the critical components of the CDK2/TRIM32/STAT3 signaling pathway. CONCLUSIONS Our findings demonstrate that regulating the CDK2/TRIM32/STAT3 pathway is a promising strategy for reducing radioresistance in TNBC.
Collapse
Affiliation(s)
- Jianming Tang
- Department of Radiation Oncology, The First Hospital of Lanzhou University, Lanzhou University, Lanzhou, Gansu 730000, PR China; The First School of Clinical Medicine, Lanzhou University, Lanzhou, Gansu 730000, PR China.
| | - Jing Li
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, Gansu 730000, PR China
| | - Jiayan Lian
- Department of Pathology, The 7th Affiliated Hospital of Sun Yat-Sen University, Shenzhen 510275, Guandong, PR China
| | - Yumei Huang
- Cancer Center, Department of Medical Oncology, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Shangtang Road 158, Hangzhou, Zhejiang 310014, PR China
| | - Yaqing Zhang
- Department of Obstetrics and Gynecology, Gansu Provincial Maternity and Child-care Hospital, Lanzhou, Gansu 730050, PR China
| | - Yanwei Lu
- Cancer Center, Department of Radiation Oncology, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, Zhejiang 310014, PR China
| | - Guansheng Zhong
- Department of Breast Surgery, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, PR China
| | - Yaqi Wang
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, Gansu 730000, PR China
| | - Zhitao Zhang
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, Gansu 730000, PR China
| | - Xin Bai
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, Gansu 730000, PR China
| | - Min Fang
- Cancer Center, Department of Radiation Oncology, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, Zhejiang 310014, PR China
| | - Luming Wu
- Gansu International Scientific and Technological Cooperation Base of Reproductive Medicine Transformation Application, The First Hospital of Lanzhou University, Lanzhou University, Lanzhou, Gansu 730000, PR China
| | - Haofei Shen
- Gansu International Scientific and Technological Cooperation Base of Reproductive Medicine Transformation Application, The First Hospital of Lanzhou University, Lanzhou University, Lanzhou, Gansu 730000, PR China
| | - Jingyuan Wu
- Gansu International Scientific and Technological Cooperation Base of Reproductive Medicine Transformation Application, The First Hospital of Lanzhou University, Lanzhou University, Lanzhou, Gansu 730000, PR China
| | - Yiqing Wang
- Gansu International Scientific and Technological Cooperation Base of Reproductive Medicine Transformation Application, The First Hospital of Lanzhou University, Lanzhou University, Lanzhou, Gansu 730000, PR China.
| | - Lei Zhang
- Department of Radiation Oncology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, PR China.
| | - Haibo Zhang
- Cancer Center, Department of Radiation Oncology, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, Zhejiang 310014, PR China.
| |
Collapse
|
|
5
|
Liu D, Chang L, Hao Q, Ren X, Liu P, Liu X, Wei Y, Wang M, Wu H, Kang H, Lin S. Is neoadjuvant chemotherapy necessary for T2N0-1M0 hormone receptor-positive/HER2-negative breast cancer patients undergoing breast-conserving surgery? J Cancer Res Clin Oncol 2024; 150:285. [PMID: 38814494 PMCID: PMC11139699 DOI: 10.1007/s00432-024-05810-6] [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: 05/09/2024] [Accepted: 05/17/2024] [Indexed: 05/31/2024]
Abstract
INTRODUCTION For HR-positive/HER2-negative patients who can undergo breast-conserving surgery (BCS) but have a tumor size of 2-5 cm or 1-3 lymph node metastases, neoadjuvant chemotherapy (NAC) is still controversial. METHODS Patients with T2N0-1M0 HR-positive/HER2-negative BC who underwent BCS between 2010 and 2017 were selected from the SEER database. Propensity score matching (PSM) was used to minimize the influence of confounding factors. The overall survival (OS) and breast cancer-specific survival (BCSS) of patients were estimated by Kaplan‒Meier curves and Cox proportional hazard models. Independent prognostic factors were included to construct a nomogram prediction model. RESULTS A total of 6475 BC patients were enrolled, of whom 553 received NAC and 5922 received adjuvant chemotherapy (AC). In the T2N0-1M0 population and T2N1M0 subgroup, AC patients before PSM had better OS and BCSS than NAC patients. After PSM, there was no significant difference in OS or BCSS between the two groups. However, in the T2N0M0 subgroup, there was no difference in survival between the AC and NAC groups before and after PSM. Stratified analysis revealed that for complete response (CR) patients, survival was roughly equivalent between the NAC and AC groups. However, the survival of no response (NR) and partial response (PR) patients was significantly worse than that of AC patients. Cox analysis revealed that radiotherapy after BCS was an independent protective factor for OS. NAC is an independent risk factor for NR and PR patients. The nomogram has good prediction efficiency. CONCLUSION NAC before BCS is not necessary for T2N0-1M0 HR-positive/HER2-negative BC patients.
Collapse
Affiliation(s)
- Dandan Liu
- The Comprehensive Breast Care Center, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China
| | - Lidan Chang
- The Comprehensive Breast Care Center, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China
| | - Qian Hao
- The Comprehensive Breast Care Center, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China
| | - Xueting Ren
- The Comprehensive Breast Care Center, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China
| | - Peinan Liu
- The Comprehensive Breast Care Center, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China
| | - Xingyu Liu
- The Comprehensive Breast Care Center, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China
| | - Yumeng Wei
- The Comprehensive Breast Care Center, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China
| | - Meng Wang
- The Comprehensive Breast Care Center, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China
| | - Hao Wu
- School of Basic Medical Sciences, Xi'an Key Laboratory of Immune Related Diseases, Xi'an Jiaotong University, Xi'an, Shaanxi, China.
| | - Huafeng Kang
- The Comprehensive Breast Care Center, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China.
| | - Shuai Lin
- The Comprehensive Breast Care Center, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China.
| |
Collapse
|
|
6
|
Hung SK, Yang HJ, Lee MS, Liu DW, Chen LC, Chew CH, Lin CH, Lee CH, Li SC, Hong CL, Yu CC, Yu BH, Hsu FC, Chiou WY, Lin HY. Molecular subtypes of breast cancer predicting clinical benefits of radiotherapy after breast-conserving surgery: a propensity-score-matched cohort study. Breast Cancer Res 2023; 25:149. [PMID: 38066611 PMCID: PMC10709935 DOI: 10.1186/s13058-023-01747-9] [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: 06/26/2023] [Accepted: 11/28/2023] [Indexed: 12/18/2023] Open
Abstract
BACKGROUND Based on the molecular expression of cancer cells, molecular subtypes of breast cancer have been applied to classify patients for predicting clinical outcomes and prognosis. However, further evidence is needed regarding the influence of molecular subtypes on the efficacy of radiotherapy (RT) after breast-conserving surgery (BCS), particularly in a population-based context. Hence, the present study employed a propensity-score-matched cohort design to investigate the potential role of molecular subtypes in stratifying patient outcomes for post-BCS RT and to identify the specific clinical benefits that may emerge. METHODS From 2006 to 2019, the present study included 59,502 breast cancer patients who underwent BCS from the Taiwan National Health Insurance Research Database. Propensity scores were utilized to match confounding variables between patients with and without RT within each subtype of breast cancer, namely luminal A, luminal B/HER2-negative, luminal B/HER2-positive, basal-like, and HER2-enriched ones. Several clinical outcomes were assessed, in terms of local recurrence (LR), regional recurrence (RR), distant metastasis (DM), disease-free survival (DFS), and overall survival (OS). RESULTS After post-BCS RT, patients with luminal A and luminal B/HER2-positive breast cancers exhibited a decrease in LR (adjusted hazard ratio [aHR] = 0.18, p < 0.0001; and, 0.24, p = 0.0049, respectively). Furthermore, reduced RR and improved DFS were observed in patients with luminal A (aHR = 0.15, p = 0.0004; and 0.29, p < 0.0001), luminal B/HER2-negative (aHR = 0.06, p = 0.0093; and, 0.46, p = 0.028), and luminal B/HER2-positive (aHR = 0.14, p = 0.01; and, 0.38, p < 0.0001) breast cancers. Notably, OS benefits were found in patients with luminal A (aHR = 0.62, p = 0.002), luminal B/HER2-negative (aHR = 0.30, p < 0.0001), basal-like (aHR = 0.40, p < 0.0001), and HER2-enriched (aHR = 0.50, p = 0.03), but not luminal B/HER2-positive diseases. Remarkably, when considering DM, luminal A patients who received RT demonstrated a lower cumulative incidence of DM than those without RT (p = 0.02). CONCLUSION In patients with luminal A breast cancer who undergo BCS, RT could decrease the likelihood of tumor metastasis. After RT, the tumor's hormone receptor status may predict tumor control regarding LR, RR, and DFS. Besides, the HER2 status of luminal breast cancer patients may serve as an additional predictor of OS after post-BCS RT. However, further prospective studies are required to validate these findings.
Collapse
Affiliation(s)
- Shih-Kai Hung
- Department of Radiation Oncology, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chiayi, Taiwan
- School of Medicine, Tzu Chi University, Hualien, Taiwan
| | - Hsuan-Ju Yang
- Department of Radiation Oncology, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chiayi, Taiwan
| | - Moon-Sing Lee
- Department of Radiation Oncology, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chiayi, Taiwan
- School of Medicine, Tzu Chi University, Hualien, Taiwan
| | - Dai-Wei Liu
- School of Medicine, Tzu Chi University, Hualien, Taiwan
- Departments of Radiation Oncology, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan
| | - Liang-Cheng Chen
- Department of Radiation Oncology, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chiayi, Taiwan
- School of Medicine, Tzu Chi University, Hualien, Taiwan
- Department of Computer Science and Information Engineering, National Cheng Kung University, Tainan, Taiwan
| | - Chia-Hui Chew
- Department of Radiation Oncology, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chiayi, Taiwan
| | - Chun-Hung Lin
- School of Medicine, Tzu Chi University, Hualien, Taiwan
- Department of General Surgery, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chiayi, Taiwan
| | - Cheng-Hung Lee
- School of Medicine, Tzu Chi University, Hualien, Taiwan
- Department of General Surgery, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chiayi, Taiwan
| | - Szu-Chin Li
- School of Medicine, Tzu Chi University, Hualien, Taiwan
- Division of Hematology-Oncology, Department of Internal Medicine, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chiayi, Taiwan
| | - Chung-Lin Hong
- Division of Hematology-Oncology, Department of Internal Medicine, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chiayi, Taiwan
| | - Chih-Chia Yu
- Department of Medical Research, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chiayi, Taiwan
| | - Ben-Hui Yu
- Department of Radiation Oncology, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chiayi, Taiwan
| | - Feng-Chun Hsu
- Department of Radiation Oncology, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chiayi, Taiwan
| | - Wen-Yen Chiou
- Department of Radiation Oncology, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chiayi, Taiwan.
- School of Medicine, Tzu Chi University, Hualien, Taiwan.
| | - Hon-Yi Lin
- Department of Radiation Oncology, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chiayi, Taiwan.
- School of Medicine, Tzu Chi University, Hualien, Taiwan.
- Department of Biomedical Sciences, National Chung Cheng University, Min-Hsiung, Chiayi, Taiwan.
| |
Collapse
|
|
7
|
Cheng X, Jiang J, Liang X, Zheng X. Development of a prognostic nomogram for lymph node positive HR +/HER2 - breast cancer patients: a study of SEER database and a Chinese cohort. Gland Surg 2023; 12:1541-1553. [PMID: 38107492 PMCID: PMC10721557 DOI: 10.21037/gs-23-177] [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: 05/05/2023] [Accepted: 10/26/2023] [Indexed: 12/19/2023]
Abstract
Background The hormone receptor+/human epidermal growth factor receptor 2- (HR+/HER2-) breast cancer (BC) patients account for the largest proportion in all patients and are still at high risk of long-range recurrence. This current study aimed to construct a prognostic nomogram to predict 3-year and 5-year BC-specific survival (BCSS) in HR+/HER2- BC patients with axillary lymph node metastasis. Methods A total of 25,338 HR+/HER2- patients with axillary lymph node-positive BC were enrolled from the Surveillance, Epidemiology and End Results (SEER) database and randomly divided into the training (n=17,738) and validation (n=7,600) cohorts using a ratio of 7:3. Univariate and multivariable Cox regression hazards were used to build a prognostic nomogram based on the training cohort. The nomogram was validated with two independent cohorts. Receiver operating characteristic (ROC) curves and calibration plots were used to evaluate the performance of the model, and Kaplan-Meier survival analyses were applied to test the clinical utility of the risk stratification system. Results Twelve factors including age, race, marital status, grade, T stage, N stage, radiotherapy, chemotherapy, and metastasis to the bone, brain, lung and liver were identified and incorporated to construct the nomogram (P<0.001). The area under the ROC curve (AUC) values at 3- and 5-year in the training and internal validation sets were 0.800, 0.800, 0.831 and 0.819, respectively, while those of the external set were 0.765 and 0.735, indicating a satisfactory discrimination with our nomogram. The calibration curves showed highly consistent results for the actual and predicted survival probabilities. Furthermore, patients were divided into three risk groups according to the total scores of the nomogram. The risk stratification system accurately differentiated between patients with different BCSS rates. Conclusions We constructed the first nomogram and corresponding risk stratification system to predict the 3-year and 5-year BCSS for HR+/HER2- patients with lymph node-positive BC, indicating a satisfactory accuracy and clinical application.
Collapse
Affiliation(s)
- Xiaoqi Cheng
- Department of Breast Surgery, The First Hospital of China Medical University, Shenyang, China
| | - Junhan Jiang
- Department of Breast Surgery, The First Hospital of China Medical University, Shenyang, China
| | - Xinzhi Liang
- Department of Operation Room, The First Hospital of China Medical University, Shenyang, China
| | - Xinyu Zheng
- Department of Breast Surgery, The First Hospital of China Medical University, Shenyang, China
- Lab 1, Cancer Institute, The First Hospital of China Medical University, Shenyang, China
| |
Collapse
|
|
8
|
da Silva FC, Brandão DC, Ferreira EA, Siqueira RP, Ferreira HSV, Da Silva Filho AA, Araújo TG. Tailoring Potential Natural Compounds for the Treatment of Luminal Breast Cancer. Pharmaceuticals (Basel) 2023; 16:1466. [PMID: 37895937 PMCID: PMC10610388 DOI: 10.3390/ph16101466] [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: 08/29/2023] [Revised: 09/24/2023] [Accepted: 09/29/2023] [Indexed: 10/29/2023] Open
Abstract
Breast cancer (BC) is the most diagnosed cancer worldwide, mainly affecting the epithelial cells from the mammary glands. When it expresses the estrogen receptor (ER), the tumor is called luminal BC, which is eligible for endocrine therapy with hormone signaling blockade. Hormone therapy is essential for the survival of patients, but therapeutic resistance has been shown to be worrying, significantly compromising the prognosis. In this context, the need to explore new compounds emerges, especially compounds of plant origin, since they are biologically active and particularly promising. Natural products are being continuously screened for treating cancer due to their chemical diversity, reduced toxicity, lower side effects, and low price. This review summarizes natural compounds for the treatment of luminal BC, emphasizing the activities of these compounds in ER-positive cells. Moreover, their potential as an alternative to endocrine resistance is explored, opening new opportunities for the design of optimized therapies.
Collapse
Affiliation(s)
- Fernanda Cardoso da Silva
- Laboratory of Genetics and Biotechnology, Institute of Biotechnology, Universidade Federal de Uberlândia, Patos de Minas 38700-002, MG, Brazil; (F.C.d.S.); (D.C.B.); (R.P.S.); (H.S.V.F.)
| | - Douglas Cardoso Brandão
- Laboratory of Genetics and Biotechnology, Institute of Biotechnology, Universidade Federal de Uberlândia, Patos de Minas 38700-002, MG, Brazil; (F.C.d.S.); (D.C.B.); (R.P.S.); (H.S.V.F.)
| | - Everton Allan Ferreira
- Department of Pharmaceutical Sciences, Faculty of Pharmacy, Federal University of Juiz de Fora, Juiz de Fora 36036-900, MG, Brazil; (E.A.F.); (A.A.D.S.F.)
| | - Raoni Pais Siqueira
- Laboratory of Genetics and Biotechnology, Institute of Biotechnology, Universidade Federal de Uberlândia, Patos de Minas 38700-002, MG, Brazil; (F.C.d.S.); (D.C.B.); (R.P.S.); (H.S.V.F.)
| | - Helen Soares Valença Ferreira
- Laboratory of Genetics and Biotechnology, Institute of Biotechnology, Universidade Federal de Uberlândia, Patos de Minas 38700-002, MG, Brazil; (F.C.d.S.); (D.C.B.); (R.P.S.); (H.S.V.F.)
| | - Ademar Alves Da Silva Filho
- Department of Pharmaceutical Sciences, Faculty of Pharmacy, Federal University of Juiz de Fora, Juiz de Fora 36036-900, MG, Brazil; (E.A.F.); (A.A.D.S.F.)
| | - Thaise Gonçalves Araújo
- Laboratory of Genetics and Biotechnology, Institute of Biotechnology, Universidade Federal de Uberlândia, Patos de Minas 38700-002, MG, Brazil; (F.C.d.S.); (D.C.B.); (R.P.S.); (H.S.V.F.)
- Laboratory of Nanobiotechnology Prof. Dr. Luiz Ricardo Goulart Filho, Institute of Biotechnology, Universidade Federal de Uberlândia, Uberlandia 38405-302, MG, Brazil
| |
Collapse
|
|
9
|
Lin J, Luo S, Zhang J, Song C. The trade-off of post-mastectomy radiotherapy usage for the breast cancer patients aged 70 years or older: a study based on SEER database. BMC Geriatr 2023; 23:625. [PMID: 37803254 PMCID: PMC10557241 DOI: 10.1186/s12877-023-04341-y] [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: 07/04/2022] [Accepted: 09/21/2023] [Indexed: 10/08/2023] Open
Abstract
BACKGROUND This study aimed to investigate the role of post-mastectomy radiotherapy (PMRT) in the female aged 70 years or older diagnosed with breast cancer, which is still controversial. METHODS This retrospective study enrolled female breast cancer women aged 70 + years following mastectomy from the Surveillance, Epidemiology, and End Results (SEER) database. Propensity score matching (PSM) was performed to reduce covariable imbalance. A nomogram was created to predict the 1,3,5-years overall survival (OS) and divide patients into three risk groups. RESULTS After matching, PMRT were associated with significant improvement in breast cancer-specific survival (BCSS) and OS (p < 0.001). By contrast, the BCSS and OS benefit from PMRT were not significant in patients with T1N1 tumor (BCSS: HR = 0.716, p = 0.249;OS:HR = 0.908, p = 0.572), and T2N1 tumor (BCSS:HR = 0.866, p = 0.289;OS:HR = 0.879, p = 0.166). Stratified by subtype, the HR+/HER-2- subtype and the HR-/HER-2- subtype (all p < 0.001) have a significant prolonged survival, yet not significant BCSS difference are shown in the HER-2 + tumor. In the low-risk group as determined by the nomogram, the use of PMRT did not significantly improve OS (p = 0.203). CONCLUSIONS This study demonstrated that PMRT improves the survival of females with elderly breast cancer, while for T1-2N1 breast cancer patients, the omission of PMRT could be considered. Furthermore, the nomogram we constructed could be used as a decision tool for the omission of PMRT in low-risk elderly patients.
Collapse
Affiliation(s)
- Jingyi Lin
- Department of Breast Surgery, Fujian Medical University Union Hospital, No.29, Xin Quan Road, Gulou District, Fuzhou, Fujian Province, 350001, China
- Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian Province, 350001, China
- Breast Cancer Institute, Fujian Medical University, Fuzhou, Fujian Province, 350001, China
| | - Shiping Luo
- Department of Breast Surgery, Fujian Medical University Union Hospital, No.29, Xin Quan Road, Gulou District, Fuzhou, Fujian Province, 350001, China
- Breast Cancer Institute, Fujian Medical University, Fuzhou, Fujian Province, 350001, China
| | - Jie Zhang
- Department of Breast Surgery, Fujian Medical University Union Hospital, No.29, Xin Quan Road, Gulou District, Fuzhou, Fujian Province, 350001, China
- Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian Province, 350001, China
- Breast Cancer Institute, Fujian Medical University, Fuzhou, Fujian Province, 350001, China
| | - Chuangui Song
- Department of Breast Surgery, Fujian Medical University Union Hospital, No.29, Xin Quan Road, Gulou District, Fuzhou, Fujian Province, 350001, China.
- Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian Province, 350001, China.
- Breast Cancer Institute, Fujian Medical University, Fuzhou, Fujian Province, 350001, China.
| |
Collapse
|
|
10
|
Silva CR, Pereira ST, Silva DFT, De Pretto LR, Freitas AZ, Zeituni CA, Rostelato MECM, Ribeiro MS. Noninvasive Red Laser Intervention before Radiotherapy of Triple-negative Breast Cancer in a Murine Model. Radiat Res 2023; 200:366-373. [PMID: 37772737 DOI: 10.1667/rade-23-00050.1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Accepted: 07/31/2023] [Indexed: 09/30/2023]
Abstract
Radiotherapy is a well-established cancer treatment; it is estimated that approximately 52% of oncology patients will require this treatment modality at least once. However, some tumors, such as triple-negative breast cancer (TNBC), may present as radioresistant and thus require high doses of ionizing radiation and a prolonged period of treatment, which may result in more severe side effects. Moreover, such tumors show a high incidence of metastases and decreased survival expectancy of the patient. Thus, new strategies for radiosensitizing TNBC are urgently needed. Red light therapy, photobiomodulation, has been used in clinical practice to mitigate the adverse side effects usually associated with radiotherapy. However, no studies have explored its use as a radiosensitizer of TNBC. Here, we used TNBC-bearing mice as a radioresistant cancer model. Red light treatment was applied in three different protocols before a high dose of radiation (60 Gy split in 4 fractions) was administered. We evaluated tumor growth, mouse clinical signs, total blood cell counts, lung metastasis, survival, and levels of glutathione in the blood. Our data showed that the highest laser dose in combination with radiation arrested tumor progression, likely due to inhibition of GSH synthesis. In addition, red light treatment before each fraction of radiation, regardless of the light dose, improved the health status of the animals, prevented anemia, reduced metastases, and improved survival. Collectively, these results indicate that red light treatment in combination with radiation could prove useful in the treatment of TNBC.
Collapse
Affiliation(s)
- Camila R Silva
- Center for Lasers and Applications, São Paulo, SP, Brazil
| | | | | | | | | | - Carlos A Zeituni
- Radiation Technology Center, Nuclear and Energy Research Institute (IPEN-CNEN), São Paulo, SP, Brazil
| | - Maria E C M Rostelato
- Radiation Technology Center, Nuclear and Energy Research Institute (IPEN-CNEN), São Paulo, SP, Brazil
| | | |
Collapse
|
|
11
|
Beyer SJ, Tallman M, Jhawar SR, White JR, Bazan JG. The Prognostic and Predictive Value of Genomic Assays in Guiding Adjuvant Breast Radiation Therapy. Biomedicines 2022; 11:biomedicines11010098. [PMID: 36672606 PMCID: PMC9855532 DOI: 10.3390/biomedicines11010098] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Revised: 12/16/2022] [Accepted: 12/21/2022] [Indexed: 01/01/2023] Open
Abstract
Many patients with non-metastatic breast cancer benefit from adjuvant radiation therapy after lumpectomy or mastectomy on the basis of many randomized trials. However, there are many patients that have such low risks of recurrence after surgery that de-intensification of therapy by either reducing the treatment volume or omitting radiation altogether may be appropriate options. On the other hand, dose intensification may be necessary for more aggressive breast cancers. Until recently, these treatment decisions were based solely on clinicopathologic factors. Here, we review the current literature on the role of genomic assays as prognostic and/or predictive biomarkers to help guide adjuvant radiation therapy decision-making.
Collapse
Affiliation(s)
- Sasha J. Beyer
- Department of Radiation Oncology, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
| | - Miranda Tallman
- Department of Radiation Oncology, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
| | - Sachin R. Jhawar
- Department of Radiation Oncology, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
| | - Julia R. White
- Department of Radiation Oncology, The University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Jose G. Bazan
- Department of Radiation Oncology, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA
- Correspondence:
| |
Collapse
|
|
12
|
Ansar M, Thu LTA, Hung CS, Su CM, Huang MH, Liao LM, Chung YM, Lin RK. Promoter hypomethylation and overexpression of TSTD1 mediate poor treatment response in breast cancer. Front Oncol 2022; 12:1004261. [PMID: 36419875 PMCID: PMC9676938 DOI: 10.3389/fonc.2022.1004261] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Accepted: 10/19/2022] [Indexed: 11/09/2022] Open
Abstract
Epigenetic alterations play a pivotal role in cancer treatment outcomes. Using the methylation array data and The Cancer Genome Atlas (TCGA) dataset, we observed the hypomethylation and upregulation of thiosulfate sulfurtransferase–like domain containing 1 (TSTD1) in patients with breast cancer. We examined paired tissues from Taiwanese patients and observed that 65.09% and 68.25% of patients exhibited TSTD1 hypomethylation and overexpression, respectively. A significant correlation was found between TSTD1 hypomethylation and overexpression in Taiwanese (74.2%, p = 0.040) and Western (88.0%, p < 0.001) cohorts. High expression of TSTD1 protein was observed in 68.8% of Taiwanese and Korean breast cancer patients. Overexpression of TSTD1 in tumors of breast cancer patients was significantly associated with poor 5-year overall survival (p = 0.021) and poor chemotherapy response (p = 0.008). T47D cells treated with TSTD1 siRNA exhibited lower proliferation than the control group, and transfection of TSTD1 in MDA-MB-231 induced the growth of MDA-MB-231 cells compared to the vector control. Additionally, overexpression of TSTD1 in MCF7 cells mediated a poor response to chemotherapy by epirubicin (p < 0.001) and docetaxel (p < 0.001) and hormone therapy by tamoxifen (p =0.025). Circulating cell-free hypomethylated TSTD1 was detected in plasma of Taiwanese breast cancer patients with disease progression and poor chemotherapy efficacy. Our results indicate that promoter hypomethylation and overexpression of TSTD1 in patients with breast cancer are potential biomarkers for poor 5-year overall survival and poor treatment response.
Collapse
Affiliation(s)
- Muhamad Ansar
- Ph.D Program in the Clinical Drug Development of Herbal Medicine, Taipei Medical University, Taipei, Taiwan
| | - Le Thi Anh Thu
- Graduate Institute of Pharmacognosy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan
- Quang Tri Medical College, Dong Ha, Quang Tri, Vietnam
| | - Chin-Sheng Hung
- Division of Breast Surgery, Department of Surgery, Taipei Medical University Hospital, Taipei, Taiwan
- Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
- Division of General Surgery, Department of Surgery, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan
| | - Chih-Ming Su
- Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
- Division of General Surgery, Department of Surgery, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan
| | - Man-Hsu Huang
- Department of Pathology, Shuang-Ho Hospital, Taipei Medical University, New Taipei City, Taiwan
| | - Li-Min Liao
- Division of General Surgery, Department of Surgery, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan
| | - Yu-Mei Chung
- Master Program in Clinical Genomics and Proteomics; Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei, Taiwan
| | - Ruo-Kai Lin
- Ph.D Program in the Clinical Drug Development of Herbal Medicine, Taipei Medical University, Taipei, Taiwan
- Graduate Institute of Pharmacognosy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan
- Master Program in Clinical Genomics and Proteomics; Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei, Taiwan
- Clinical Trial Center, Taipei Medical University Hospital, Taipei, Taiwan
- *Correspondence: Ruo-Kai Lin,
| |
Collapse
|
|
13
|
Xu L, Zhou C, Qiu J, Lv Q, Du Z. Can Radiotherapy After Breast-Conserving Surgery be Omitted in Elderly Patients with Early-Stage, Hormone-Receptor Negative Breast Cancer? A Population-Based Study and Proposed Nomogram. Adv Ther 2022; 39:4707-4722. [PMID: 35953665 DOI: 10.1007/s12325-022-02279-y] [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: 04/09/2022] [Accepted: 07/20/2022] [Indexed: 01/30/2023]
Abstract
INTRODUCTION We aimed to evaluate whether radiotherapy (RT) after breast-conserving surgery (BCS) can be omitted in elderly patients with early-stage, hormone receptor-negative breast cancer. METHODS Patients aged 65 years and older with T1-2N0-1, hormone receptor-negative breast cancer in 2010-2015 were extracted from the Surveillance, Epidemiology, and End Results program. Propensity score matching was used to balance the baseline of different groups. Survival analysis was performed using Kaplan-Meier plot and log-rank test. Independent risk factors were identified by multivariate Cox analysis. A nomogram predicting breast cancer-specific survival (BCSS) and a risk stratification model were constructed and validated. RESULTS A total of 4465 patients were included and 27.7% (1237/4465) patients did not receive postoperative RT. RT was significantly associated with improved overall survival (OS) (HR = 0.552 P < 0.001) and BCSS (HR = 0.559, P < 0.001) in the matched cohort. The same results were found after adjusting independent risk factors by multivariate analysis. On the basis of the nomogram predicting BCSS of patients without RT by incorporating independent risk factors (age, race, HER2 status, T stage, and N stage), we built a risk stratification model which indicated that RT improved OS (HR = 0.511, P < 0.001) and BCSS (HR = 0.517, P < 0.001) in the high-risk group (total score > 150), but not in the low-risk group (total score ≤ 120). The C-index and all calibration curves demonstrated sufficient accuracies and good predictive capabilities. CONCLUSIONS RT is indeed beneficial for the whole cohort in this study. However, it may be omitted in the low-risk subgroup without significantly sacrificing survival. For patients in the high-risk group, RT following BCS remained beneficial. This study highlights the need for prospective randomized trials to study RT de-escalation strategies.
Collapse
Affiliation(s)
- Li Xu
- Department of Breast Surgery, West China Hospital, Sichuan University, 37 Guoxue Street, Chengdu, China
| | - Chen Zhou
- Department of Breast Surgery, West China Hospital, Sichuan University, 37 Guoxue Street, Chengdu, China
| | - Juanjuan Qiu
- Department of Breast Surgery, West China Hospital, Sichuan University, 37 Guoxue Street, Chengdu, China
| | - Qing Lv
- Department of Breast Surgery, West China Hospital, Sichuan University, 37 Guoxue Street, Chengdu, China
| | - Zhenggui Du
- Department of Breast Surgery, West China Hospital, Sichuan University, 37 Guoxue Street, Chengdu, China.
| |
Collapse
|
|
14
|
He L, Deng C. Recent advances in organotypic tissue slice cultures for anticancer drug development. Int J Biol Sci 2022; 18:5885-5896. [PMID: 36263166 PMCID: PMC9576528 DOI: 10.7150/ijbs.78997] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Accepted: 09/19/2022] [Indexed: 01/12/2023] Open
Abstract
Organotypic tissue slice culture is established from animal or patient tissues and cultivated in an in vitro ecosystem. This technique has made countless contributions to anticancer drug development due to the vast number of advantages, such as the preservation of the cell repertoire and immune components, identification of invasive ability of tumors, toxicity determination of compounds, quick assessment of therapeutic efficacy, and high predictive performance of drug responses. Importantly, it serves as a reliable tool to stratify therapeutic responders from nonresponders and select the optimal standard-of-care treatment regimens for personalized medicine, which is expected to become a potent platform and even the gold standard for anticancer drug screening of individualization in the near future.
Collapse
Affiliation(s)
- Lin He
- Cancer Center, Faculty of Health Sciences, University of Macau, Macau SAR, China.,Centre for Precision Medicine Research and Training, Faculty of Health Sciences, University of Macau, Macau SAR, China.,MOE Frontier Science Centre for Precision Oncology, University of Macau, Macau SAR, China
| | - Chuxia Deng
- Cancer Center, Faculty of Health Sciences, University of Macau, Macau SAR, China.,Centre for Precision Medicine Research and Training, Faculty of Health Sciences, University of Macau, Macau SAR, China.,MOE Frontier Science Centre for Precision Oncology, University of Macau, Macau SAR, China.,✉ Corresponding author: Chu-Xia Deng, Ph.D. Dean and Chair Professor, E12, Room 4041, Faculty of Health Sciences, University of Macau, Macau SAR, China. Phone: (853) 8822 4997; Fax: 8822 2314; E-mail:
| |
Collapse
|
|
15
|
Ye S, Hu W. Effect of postmastectomy radiotherapy on pT1-2N1 breast cancer patients with different molecular subtypes: A real-world study based on the inverse probability of treatment weighting method. Medicine (Baltimore) 2022; 101:e30610. [PMID: 36123865 PMCID: PMC9478234 DOI: 10.1097/md.0000000000030610] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
To investigate the significance of postmastectomy radiotherapy (PMRT) for different molecular subtypes of female breast cancer T1-2N1M0 based on inverse probability of treatment weighting (IPTW). The data of breast cancer patients diagnosed between 2010 and 2014 from the Surveillance, Epidemiology, and End Results (SEER) database were extracted. According to the status of hormone receptor (HR) and human epidermal growth factor receptor-2 (HER2), the patients were classified into luminal-A (HR+/HER2-), luminal-B (HR+/HER2+), HER2-enriched (HR-/HER2+), and TNBC (HR-/HER2-) subtypes. The association between radiation therapy and breast cancer-specific survival (BCSS) and Overall survival (OS) was retrospectively analyzed. Inverse probability of treatment weighting (IPTW) was applied to balance measurable confounders. Among the 16 894 patients, 6 055 (35.8%) were in the PMRT group and 10 839 (64.2%) were in the nonPMRT group, with a median follow-up of 48 months. There were 1003 deaths from breast cancer and 754 deaths from other causes. After IPTW, the covariates between groups reached complete equilibrium, the multifactorial Cox regression analysis showed that PMRT significantly prolonged OS and BCSS in Luminal-A and TNBC subtype breast cancer patients, yet it brought little significant survival advantage in Luminal-B and HER2-enriched subtype patients. Our study demonstrates a beneficial impact for PMRT on OS and BCSS among Luminal-A and TNBC subtype breast cancer patients with T1-2N1 disease.
Collapse
Affiliation(s)
- Shangyue Ye
- Department of oncological radiotherapy, Shaoxing Second Hospital, Shaoxing, China
- *Correspondence: Shangyue Ye (e-mail: )
| | - Weixian Hu
- Department of oncological surgery, Shaoxing Second Hospital, Shaoxing, China
| |
Collapse
|
|
16
|
Zhang Y, Xu Z, Chen H, Sun X, Zhang Z. Survival comparison between postoperative and preoperative radiotherapy for stage I-III non-inflammatory breast cancer. Sci Rep 2022; 12:14288. [PMID: 35995985 PMCID: PMC9395522 DOI: 10.1038/s41598-022-18251-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2022] [Accepted: 08/08/2022] [Indexed: 11/09/2022] Open
Abstract
To compare the survival benefit between preoperative and postoperative radiotherapy for stage I-III non-inflammatory breast cancer patients, we conducted a retrospective cohort study using surveillance, epidemiology and end results databases. Our study recruited patients who had been diagnosed with stage I-III breast cancer and underwent surgery and radiotherapy. The overall survival was calculated by Kaplan-Meier method. Cox risk model was used to determine the impact of radiotherapy according to stage, molecular subtype and other risk factors. Propensity score matching was used to balance measurable confounding factors. Of all the 411,279 enrolled patients varying from 1975 to 2016, 1712 patients received preoperative radiotherapy, and 409,567 patients received postoperative radiotherapy. Compared with the postoperative radiotherapy group, the preoperative radiotherapy group showed significantly higher risks of overall mortality and breast cancer-specific mortality. Survival differences in treatment sequences were correlated with stage, molecular subtypes and other risk factors. According to the results of this study, preoperative radiotherapy did not show a survival advantage, and postoperative radiotherapy is still the primary treatment. However, preoperative radiotherapy also has some theoretical advantages, such as phase reduction and recurrence reduction. Therefore, it is still worthy of further exploration.
Collapse
Affiliation(s)
- Yuxi Zhang
- The First School of Clinical Medicine, Nanjing Medical University, Nanjing, China
| | - Zhipeng Xu
- Department of Urology, Affiliated Zhongda Hospital of Southeast University, Nanjing, Jiangsu, China
| | - Hui Chen
- Department of Radiation Oncology, Jiangsu Province Hospital, Nanjing, China
| | - Xinchen Sun
- Department of Radiation Oncology, Jiangsu Province Hospital, Nanjing, China.
| | - Zhaoyue Zhang
- Department of Radiation Oncology, Jiangsu Province Hospital, Nanjing, China.
| |
Collapse
|
|
17
|
Español A, Sanchez Y, Salem A, Obregon J, Sales ME. Nicotinic receptors modulate antitumor therapy response in triple negative breast cancer cells. World J Clin Oncol 2022; 13:505-519. [PMID: 35949430 PMCID: PMC9244968 DOI: 10.5306/wjco.v13.i6.505] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2021] [Revised: 02/24/2022] [Accepted: 04/26/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Triple negative breast cancer is more aggressive than other breast cancer subtypes and constitutes a public health problem worldwide since it has high morbidity and mortality due to the lack of defined therapeutic targets. Resistance to chemotherapy complicates the course of patients’ treatment. Several authors have highlighted the participation of nicotinic acetylcholine receptors (nAChR) in the modulation of conventional chemotherapy treatment in cancers of the airways. However, in breast cancer, less is known about the effect of nAChR activation by nicotine on chemotherapy treatment in smoking patients.
AIM To investigate the effect of nicotine on paclitaxel treatment and the signaling pathways involved in human breast MDA-MB-231 tumor cells.
METHODS Cells were treated with paclitaxel alone or in combination with nicotine, administered for one or three 48-h cycles. The effect of the addition of nicotine (at a concentration similar to that found in passive smokers’ blood) on the treatment with paclitaxel (at a therapeutic concentration) was determined using the 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. The signaling mediators involved in this effect were determined using selective inhibitors. We also investigated nAChR expression, and ATP “binding cassette” G2 drug transporter (ABCG2) expression and its modulation by the different treatments with Western blot. The effect of the treatments on apoptosis induction was determined by flow cytometry using annexin-V and 7AAD markers.
RESULTS Our results confirmed that treatment with paclitaxel reduced MDA-MB-231 cell viability in a concentration-dependent manner and that the presence of nicotine reversed the cytotoxic effect induced by paclitaxel by involving the expression of functional α7 and α9 nAChRs in these cells. The action of nicotine on paclitaxel treatment was linked to modulation of the protein kinase C, mitogen-activated protein kinase, extracellular signal-regulated kinase, and NF-κB signaling pathways, and to an up-regulation of ABCG2 protein expression. We also detected that nicotine significantly reduced the increase in cell apoptosis induced by paclitaxel treatment. Moreover, the presence of nicotine reduced the efficacy of paclitaxel treatment administered in three cycles to MDA-MB-231 tumor cells.
CONCLUSION Our findings point to nAChRs as responsible for the decrease in the chemotherapeutic effect of paclitaxel in triple negative tumors. Thus, nAChRs should be considered as targets in smoking patients.
Collapse
Affiliation(s)
- Alejandro Español
- Laboratory of Immunopharmacology and Tumor Biology, CEFYBO CONICET University of Buenos Aires, Buenos Aires C1121ABG, Argentina
| | - Yamila Sanchez
- Laboratory of Immunopharmacology and Tumor Biology, CEFYBO CONICET University of Buenos Aires, Buenos Aires C1121ABG, Argentina
| | - Agustina Salem
- Laboratory of Immunopharmacology and Tumor Biology, CEFYBO CONICET University of Buenos Aires, Buenos Aires C1121ABG, Argentina
| | - Jaqueline Obregon
- Laboratory of Immunopharmacology and Tumor Biology, CEFYBO CONICET University of Buenos Aires, Buenos Aires C1121ABG, Argentina
| | - Maria Elena Sales
- Laboratory of Immunopharmacology and Tumor Biology, CEFYBO CONICET University of Buenos Aires, Buenos Aires C1121ABG, Argentina
| |
Collapse
|
|
18
|
Luz FACD, Marinho EDC, Nascimento CP, Marques LDA, Duarte MBO, Delfino PFR, Antonioli RM, Araújo RAD, Silva MJB. The effectiveness of radiotherapy in preventing disease recurrence after breast cancer surgery. Surg Oncol 2022; 41:101709. [PMID: 35124329 DOI: 10.1016/j.suronc.2022.101709] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2021] [Revised: 01/17/2022] [Accepted: 01/29/2022] [Indexed: 01/11/2023]
Abstract
BACKGROUND AND OBJECTIVES The locoregional management of breast cancer has a critical impact on prognosis. This study aimed to analyze the effectiveness of radiotherapy against the deleterious effect of positive surgical margins on disease outcomes. METHODS Retrospective, single-center study enrolled 721 breast cancer patients with a median follow-up of approximately 64.50 months (3.67-247.40). Analyses were performed considering the end of adjuvant therapy, except endocrine therapy. Kaplan-Meier and Cox regression were performed to obtain the predictive value of treatments. RESULTS The minimally adequate radiotherapy (≥45 cGy) was associated with improved outcomes in breast cancer patients compared to inadequate radiotherapy (<45 cGy/no) by controlling locoregional relapses and distant metastasis. In patients with positive surgical margins (n = 53), radiotherapy was associated with an approximate decrease of 90% in locoregional relapse risk [adjusted HR: 0.108 (0.012-0.932), p = 0.043]. Radiotherapy did not alter the adverse effect of positive surgical margins, especially in patients with a higher risk of poorly differentiated tumors (n = 146), presence of lymphovascular invasion (n = 163), and triple-negative subtype (n = 113). Notwithstanding, radiotherapy was associated with respective decreases of distant metastasis risk of 75.2% [adjusted HR: 0.248 (0.081-0.762), p = 0.015] and 67.8% [adjusted HR: 0.322 (0.101-1.029), p = 0.056] in patients with triple-negative tumors or with lymphovascular invasion. CONCLUSION Adequate radiotherapy is associated with better outcomes in breast cancer. Despite improving locoregional relapse-free survival, radiotherapy does not ablate positive surgical margins, a factor of poorer prognosis that prevails mainly in patients with factors of higher relapse risk.
Collapse
Affiliation(s)
- Felipe Andrés Cordero da Luz
- Center for Cancer Prevention and Research, Uberlandia Cancer Hospital, Minas Gerais, Brazil; Laboratory of Tumor Biomarkers and Osteoimmunology, Institute of Biomedical Sciences, Federal University of Uberlandia, Minas Gerais, Brazil.
| | | | | | | | - Mateus Bringel Oliveira Duarte
- Department of Radiotherapy, Oncology Sector, Clinical Hospital of the Federal University of Uberlandia, Minas Gerais, Brazil
| | | | | | - Rogério Agenor de Araújo
- Center for Cancer Prevention and Research, Uberlandia Cancer Hospital, Minas Gerais, Brazil; Medical Faculty, Federal University of Uberlandia, Minas Gerais, Brazil
| | - Marcelo José Barbosa Silva
- Laboratory of Tumor Biomarkers and Osteoimmunology, Institute of Biomedical Sciences, Federal University of Uberlandia, Minas Gerais, Brazil
| |
Collapse
|
|
19
|
TRIM32 promotes radioresistance by disrupting TC45-STAT3 interaction in triple-negative breast cancer. Oncogene 2022; 41:1589-1599. [PMID: 35091679 DOI: 10.1038/s41388-022-02204-1] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Revised: 01/05/2022] [Accepted: 01/19/2022] [Indexed: 11/08/2022]
Abstract
Radioresistance is common in the treatment of triple-negative breast cancer (TNBC), but the molecular mechanisms involved remain unclear. Herein, we reveal that tripartite motif-containing protein 32 (TRIM32) is upregulated in TNBC and is negatively associated with survival of TNBC patients. Radiotherapy resulted in enhanced expression of TRIM32, whereas TRIM32 depletion reduced TNBC radioresistance in vitro and in vivo. Mechanistically, radiotherapy promoted the association between TRIM32 and nuclear STAT3, which suppressed TC45-induced dephosphorylation of STAT3, resulting in increased STAT3 transcriptional activation and TNBC radioresistance. Finally, we demonstrated that TRIM32 and STAT3 phosphorylation are co-expressed in TNBC tissues. Moreover, high expression of TRIM32 and STAT3 phosphorylation is positively linked to poor prognosis of TNBC patients. Our study demonstrates that TRIM32 is a novel target for predicting radioresistance in TNBC patients.
Collapse
|
|
20
|
Blomain ES, Moding EJ. Liquid Biopsies for Molecular Biology-Based Radiotherapy. Int J Mol Sci 2021; 22:11267. [PMID: 34681925 PMCID: PMC8538046 DOI: 10.3390/ijms222011267] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Revised: 10/13/2021] [Accepted: 10/15/2021] [Indexed: 11/29/2022] Open
Abstract
Molecular alterations drive cancer initiation and evolution during development and in response to therapy. Radiotherapy is one of the most commonly employed cancer treatment modalities, but radiobiologic approaches for personalizing therapy based on tumor biology and individual risks remain to be defined. In recent years, analysis of circulating nucleic acids has emerged as a non-invasive approach to leverage tumor molecular abnormalities as biomarkers of prognosis and treatment response. Here, we evaluate the roles of circulating tumor DNA and related analyses as powerful tools for precision radiotherapy. We highlight emerging work advancing liquid biopsies beyond biomarker studies into translational research investigating tumor clonal evolution and acquired resistance.
Collapse
Affiliation(s)
- Erik S. Blomain
- Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA;
| | - Everett J. Moding
- Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA;
- Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305, USA
| |
Collapse
|
|
21
|
Grabarska A, Wróblewska-Łuczka P, Kukula-Koch W, Łuszczki JJ, Kalpoutzakis E, Adamczuk G, Skaltsounis AL, Stepulak A. Palmatine, a Bioactive Protoberberine Alkaloid Isolated from Berberis cretica, Inhibits the Growth of Human Estrogen Receptor-Positive Breast Cancer Cells and Acts Synergistically and Additively with Doxorubicin. Molecules 2021; 26:molecules26206253. [PMID: 34684834 PMCID: PMC8538708 DOI: 10.3390/molecules26206253] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Revised: 10/01/2021] [Accepted: 10/08/2021] [Indexed: 12/24/2022] Open
Abstract
Palmatine (PLT) is a natural isoquinoline alkaloid that belongs to the class of protoberberines and exhibits a wide spectrum of pharmacological and biological properties, including anti-cancer activity. The aim of our study was to isolate PLT from the roots of Berberis cretica and investigate its cytotoxic and anti-proliferative effects in vitro alone and in combination with doxorubicine (DOX) using human ER+/HER2− breast cancer cell lines. The alkaloid was purified by column chromatography filled with silica gel NP and Sephadex LH-20 resin developed in the mixture of methanol: water (50:50 v/v) that provided high-purity alkaloid for bioactivity studies. The purity of the alkaloid was confirmed by high resolution mass measurement and MS/MS fragmentation analysis in the HPLC-ESI-QTOF-MS/MS-based analysis. It was found that PLT treatment inhibited the viability and proliferation of breast cancer cells in a dose-dependent manner as demonstrated by MTT and BrdU assays. PLT showed a quite similar growth inhibition on breast cancer cells with IC50 values ranging from 5.126 to 5.805 µg/mL. In contrast, growth of normal human breast epithelial cells was not affected by PLT. The growth inhibitory activity of PLT was related to the induction of apoptosis, as determined by Annexin V/PI staining. Moreover, PLT sensitized breast cancer cells to DOX. Isobolographic analysis revealed synergistic and additive interactions between studied agents. Our studies suggest that PLT can be a potential candidate agent for preventing and treating breast cancer.
Collapse
Affiliation(s)
- Aneta Grabarska
- Department of Biochemistry and Molecular Biology, Medical University of Lublin, Chodzki 1, 20-093 Lublin, Poland;
- Correspondence: ; Tel.: +48-81448-6350
| | - Paula Wróblewska-Łuczka
- Department of Pathophysiology, Medical University of Lublin, Jaczewskiego 8b, 20-090 Lublin, Poland; (P.W.-Ł.); (J.J.Ł.)
| | - Wirginia Kukula-Koch
- Department of Pharmacognosy with Medicinal Plants Garden, Medical University of Lublin, Chodzki 1, 20-093 Lublin, Poland;
| | - Jarogniew J. Łuszczki
- Department of Pathophysiology, Medical University of Lublin, Jaczewskiego 8b, 20-090 Lublin, Poland; (P.W.-Ł.); (J.J.Ł.)
| | - Eleftherios Kalpoutzakis
- Laboratory of Pharmacognosy and Natural Products Chemistry, School of Pharmacy, National and Kapodistrian University of Athens, Panepistimioupoli Zografou, 15771 Athens, Greece; (E.K.); (A.L.S.)
| | - Grzegorz Adamczuk
- Independent Medical Biology Unit, Medical University of Lublin, Jaczewskiego 8b, 20-090 Lublin, Poland;
| | - Alexios Leandros Skaltsounis
- Laboratory of Pharmacognosy and Natural Products Chemistry, School of Pharmacy, National and Kapodistrian University of Athens, Panepistimioupoli Zografou, 15771 Athens, Greece; (E.K.); (A.L.S.)
| | - Andrzej Stepulak
- Department of Biochemistry and Molecular Biology, Medical University of Lublin, Chodzki 1, 20-093 Lublin, Poland;
| |
Collapse
|
|
22
|
Li Y, Ma L. Nomograms predict survival of patients with lymph node-positive, luminal a breast cancer. BMC Cancer 2021; 21:965. [PMID: 34454451 PMCID: PMC8401066 DOI: 10.1186/s12885-021-08642-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Accepted: 07/26/2021] [Indexed: 12/12/2022] Open
Abstract
Background To develop nomograms for the prediction of the 1-, 3-, and 5-year overall survival (OS) and breast cancer-specific survival (BCSS) for patients with lymph node positive, luminal A breast cancer. Methods Thirty-nine thousand fifty-one patients from The Surveillance, Epidemiology, and End Results (SEER) database were included in our study and were set into a training group (n = 19,526) and a validation group (n = 19,525). Univariate analysis and Cox proportional hazards analysis were used to select variables and set up nomogram models on the basis of the training group. Kaplan-Meier curves and the log-rank test were adopted in the survival analysis and curves plotting. C-index, calibration plots and ROC curves were used to performed internal and external validation on the training group and validation group. Results Following independent factors were included in our nomograms: Age, marital status, grade, ethnic group, T stage, positive lymph nodes numbers, Metastasis, surgery, radiotherapy, chemotherapy. In both the training group and testing group, the calibration plots show that the actual and nomogram-predicted survival probabilities are consistent greatly. The C-index values of the nomograms in the training and validation cohorts were 0.782 and 0.806 for OS and 0.783 and 0.804 for BCSS, respectively. The ROC curves show that our nomograms have good discrimination. Conclusions The nomograms may assist clinicians predict the 1-, 3-, and 5-year OS and BCSS of patients with lymph node positive, luminal A breast cancer.
Collapse
Affiliation(s)
- Yilun Li
- The Fourth Hospital of Hebei Medical University, No. 169 Tianshan Street, Yuhua District, Shi Jiazhuang City, Hebei Province, China
| | - Li Ma
- The Fourth Hospital of Hebei Medical University, No. 169 Tianshan Street, Yuhua District, Shi Jiazhuang City, Hebei Province, China.
| |
Collapse
|
|
23
|
Dastmalchi N, Safaralizadeh R, Latifi-Navid S, Banan Khojasteh SM, Mahmud Hussen B, Teimourian S. An updated review of the role of lncRNAs and their contribution in various molecular subtypes of breast cancer. Expert Rev Mol Diagn 2021; 21:1025-1036. [PMID: 34334086 DOI: 10.1080/14737159.2021.1962707] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Introduction: Breast cancer (BC) is the most significant threat to women's life. To demonstrate its molecular mechanisms, which results in BC progression, it is crucial to develop approaches to enhance prognosis and survival in BC cases.Areas covered: In the current study, we aimed to highlight the updated data on the oncogenic and tumor suppressive roles of lncRNAs in the progression of various subtypes of BC by specifically putting importance on the functional characteristics, modulatory agents, therapeutic potential, future perspectives and challenges of lncRNAs in BC. We reviewed recent studies published between 2019 and 2020.Expert opinion: The latest investigations have demonstrated that the long non-coding RNAs (lncRNAs) participate in different BC molecular subtypes via different molecular mechanisms; however, the exact functional information of the lncRNAs has yet to be elucidated. The studied lncRNAs could be more applicable as therapeutic targets in BC treatment after pre-clinical and clinical studies.
Collapse
Affiliation(s)
- Narges Dastmalchi
- Department of Animal Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran
| | - Reza Safaralizadeh
- Department of Animal Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran
| | - Saeid Latifi-Navid
- Department of Biology, Faculty of Sciences, University of Mohaghegh Ardabili, Ardabil, Iran
| | | | - Bashdar Mahmud Hussen
- Pharmacognosy Department, College of Pharmacy, Hawler Medical University, Erbil, Kurdistan Region, Iraq
| | - Shahram Teimourian
- Department of Medical Genetics, Iran University of Medical Sciences, Tehran, Iran
| |
Collapse
|
|
24
|
Luz FAC, Araújo RA, Silva MJB. Decreased Survival of Invasive Ductal Breast Cancer Patients With Two Macrometastatic Lymph Nodes Among Few Resected Ones: Should Current Sentinel-Lymph-Node Guidelines Be Revised? Front Oncol 2021; 11:669890. [PMID: 34350113 PMCID: PMC8327777 DOI: 10.3389/fonc.2021.669890] [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: 02/19/2021] [Accepted: 07/02/2021] [Indexed: 11/29/2022] Open
Abstract
Purpose Sentinel-lymph-node (SLN) biopsy (SLB) is an efficient and safe axillary surgical approach with decreased morbidity than total axillary lymph node dissection (ALND) in initial patients (T1–T2). Current guidelines strongly suggest avoiding completion of ALND in patients with one or two positive SLNs that will be submitted to whole-breast radiation therapy, but must be done when three SLNs are affected. Methods We performed a SEER-based study with breast invasive ductal carcinoma patients treated between 2010 and 2015. Optimal cutoffs of positive LNs predictive of survival were obtained with ROC curves and survival as a continuous variable. Bias was reduced through propensity score matching. Cox regression was employed to estimate prognosis. Nomograms were constructed to analyze the predictive value of clinicopathological factors for axillary burden. Results Of 43,239 initial patients that had one to three analyzed LNs, only 425 had two positive LNs and matched analysis demonstrated no survival difference versus pN2 patients [HR: 0.960 (0.635–1.452), p = 0.846]. The positive-to-analyzed LN proportion demonstrated a strong prognostic factor for a low rate (1 positive to ≤1.5 analyzed) [HR = 1.567 (1.156–2.126), p = 0.004], and analysis derived from the results demonstrated that a “negative LN margin” improves survival. Nomograms shows that tumor size is the main factor of axillary burden. Conclusion Macrometastasis of two LNs is a poor prognostic factor, similar to pN2, in SLNB (-like) patients; more extensive studies including preconized therapies must be done in order to corroborate or refute the resistance of this prognostic difference in patients with two macrometastatic lymph nodes within few resected.
Collapse
Affiliation(s)
- Felipe A C Luz
- Center for Projects, Prevention and Research in Cancer at the Hospital do Câncer in Uberlândia, Uberlândia, Brazil.,Laboratory of Tumors Osteoimmunology and Immunology, Institute of Biomedical Sciences, Federal University of Uberlândia, Uberlândia, Brazil
| | - Rogério A Araújo
- Laboratory of Tumors Osteoimmunology and Immunology, Institute of Biomedical Sciences, Federal University of Uberlândia, Uberlândia, Brazil.,Department of Clinical Medicine, Faculty of Medicine, Federal University of Uberlândia, Uberlândia, Brazil
| | - Marcelo J B Silva
- Laboratory of Tumors Osteoimmunology and Immunology, Institute of Biomedical Sciences, Federal University of Uberlândia, Uberlândia, Brazil
| |
Collapse
|
|
25
|
Durrani IA, Bhatti A, John P. The prognostic outcome of 'type 2 diabetes mellitus and breast cancer' association pivots on hypoxia-hyperglycemia axis. Cancer Cell Int 2021; 21:351. [PMID: 34225729 PMCID: PMC8259382 DOI: 10.1186/s12935-021-02040-5] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Accepted: 06/24/2021] [Indexed: 12/24/2022] Open
Abstract
Type 2 diabetes mellitus and breast cancer are complex, chronic, heterogeneous, and multi-factorial diseases; with common risk factors including but not limited to diet, obesity, and age. They also share mutually inclusive phenotypic features such as the metabolic deregulations resulting from hyperglycemia, hypoxic conditions and hormonal imbalances. Although, the association between diabetes and cancer has long been speculated; however, the exact molecular nature of this link remains to be fully elucidated. Both the diseases are leading causes of death worldwide and a causal relationship between the two if not addressed, may translate into a major global health concern. Previous studies have hypothesized hyperglycemia, hyperinsulinemia, hormonal imbalances and chronic inflammation, as some of the possible grounds for explaining how diabetes may lead to cancer initiation, yet further research still needs to be done to validate these proposed mechanisms. At the crux of this dilemma, hyperglycemia and hypoxia are two intimately related states involving an intricate level of crosstalk and hypoxia inducible factor 1, at the center of this, plays a key role in mediating an aggressive disease state, particularly in solid tumors such as breast cancer. Subsequently, elucidating the role of HIF1 in establishing the diabetes-breast cancer link on hypoxia-hyperglycemia axis may not only provide an insight into the molecular mechanisms underlying the association but also, illuminate on the prognostic outcome of the therapeutic targeting of HIF1 signaling in diabetic patients with breast cancer or vice versa. Hence, this review highlights the critical role of HIF1 signaling in patients with both T2DM and breast cancer, potentiates its significance as a prognostic marker in comorbid patients, and further discusses the potential prognostic outcome of targeting HIF1, subsequently establishing the pressing need for HIF1 molecular profiling-based patient selection leading to more effective therapeutic strategies emerging from personalized medicine.
Collapse
Affiliation(s)
- Ilhaam Ayaz Durrani
- Atta-ur-Rehman School of Applied Biosciences (ASAB), National University of Sciences and Technology (NUST), H-12, Islamabad, Pakistan
| | - Attya Bhatti
- Atta-ur-Rehman School of Applied Biosciences (ASAB), National University of Sciences and Technology (NUST), H-12, Islamabad, Pakistan.
| | - Peter John
- Atta-ur-Rehman School of Applied Biosciences (ASAB), National University of Sciences and Technology (NUST), H-12, Islamabad, Pakistan
| |
Collapse
|
|
26
|
Español A, Salem A, Sanchez Y, Sales ME. Breast cancer: Muscarinic receptors as new targets for tumor therapy. World J Clin Oncol 2021; 12:404-428. [PMID: 34189066 PMCID: PMC8223712 DOI: 10.5306/wjco.v12.i6.404] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Revised: 03/26/2021] [Accepted: 06/02/2021] [Indexed: 02/06/2023] Open
Abstract
The development of breast cancer is a complex process that involves the participation of different factors. Several authors have demonstrated the overexpression of muscarinic acetylcholine receptors (mAChRs) in different tumor tissues and their role in the modulation of tumor biology, positioning them as therapeutic targets in cancer. The conventional treatment for breast cancer involves surgery, radiotherapy, and/or chemotherapy. The latter presents disadvantages such as limited specificity, the appearance of resistance to treatment and other side effects. To prevent these side effects, several schedules of drug administration, like metronomic therapy, have been developed. Metronomic therapy is a type of chemotherapy in which one or more drugs are administered at low concentrations repetitively. Recently, two chemotherapeutic agents usually used to treat breast cancer have been considered able to activate mAChRs. The combination of low concentrations of these chemotherapeutic agents with muscarinic agonists could be a useful option to be applied in breast cancer treatment, since this combination not only reduces tumor cell survival without affecting normal cells, but also decreases pathological neo-angiogenesis, the expression of drug extrusion proteins and the cancer stem cell fraction. In this review, we focus on the previous evidences that have positioned mAChRs as relevant therapeutic targets in breast cancer and analyze the effects of administering muscarinic agonists in combination with conventional chemotherapeutic agents in a metronomic schedule.
Collapse
Affiliation(s)
- Alejandro Español
- Laboratory of Immunopharmacology and Tumor Biology, CEFYBO CONICET University of Buenos Aires, Buenos Aires C1121ABG, Argentina
| | - Agustina Salem
- Laboratory of Immunopharmacology and Tumor Biology, CEFYBO CONICET University of Buenos Aires, Buenos Aires C1121ABG, Argentina
| | - Yamila Sanchez
- Laboratory of Immunopharmacology and Tumor Biology, CEFYBO CONICET University of Buenos Aires, Buenos Aires C1121ABG, Argentina
| | - María Elena Sales
- Laboratory of Immunopharmacology and Tumor Biology, CEFYBO CONICET University of Buenos Aires, Buenos Aires C1121ABG, Argentina
| |
Collapse
|
|
27
|
Photobiomodulation therapy combined with radiotherapy in the treatment of triple-negative breast cancer-bearing mice. JOURNAL OF PHOTOCHEMISTRY AND PHOTOBIOLOGY B-BIOLOGY 2021; 220:112215. [PMID: 34029847 DOI: 10.1016/j.jphotobiol.2021.112215] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 03/31/2021] [Accepted: 05/14/2021] [Indexed: 12/24/2022]
Abstract
This work investigated the effect of photobiomodulation therapy (PBM) combined with radiotherapy (RT) on triple-negative breast cancer (TNBC)-bearing mice. Female BALB/c mice received 4 T1 cells into a mammary fat pad. Local RT was performed with a total dose of 60 Gy divided into 4 consecutive sessions of 15 Gy. For PBM, a red laser was used in three different protocols: i-) single exposure delivering 150 J.cm-2 (24 h after the last RT session), and ii-) radiant exposure of 150 J.cm-2 or iii-) fractionated radiant exposure of 37.5 J.cm-2 (after each RT session). Tumor volume, complete blood cell count, clinical condition, metastasis, and survival of animals were monitored during 3 weeks post-RT. Our results demonstrated that regardless of the protocol, PBM arrested the tumor growth, improved the clinical condition, and prevented hemolytic anemia. Besides, although PBM groups have exhibited a high neutrophil:lymphocyte ratio (NLR), they decreased the number of lung metastases and enhanced mouse survival. Worthy of note, PBM should be used along with the RT sessions in higher radiant exposures, since PBM at 150 J.cm-2 per session significantly extended the survival rate. Together, these data suggest PBM could be a potential ally to RT to fight TNBC.
Collapse
|
|
28
|
Ma JC, Zhong XR, Luo T, Xiang ZZ, Li JY, Luo C, Yan X, He P, Tian TL, Liu F, Liu L, Zheng H. The Effect of Postmastectomy Radiotherapy on Breast Cancer Patients After Neoadjuvant Chemotherapy by Molecular Subtype. Ann Surg Oncol 2021; 28:5084-5095. [PMID: 33580420 DOI: 10.1245/s10434-020-09523-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2020] [Accepted: 12/08/2020] [Indexed: 02/05/2023]
Abstract
BACKGROUND The effect of postmastectomy radiotherapy (PMRT) on patient outcomes after neoadjuvant chemotherapy (NAC) remains controversial. We aimed to establish a model to identify the subsets benefiting from PMRT and to examine the effect of PMRT according to molecular subtype. PATIENTS AND METHODS We retrospectively analyzed 1118 cT1-4cN0-3M0 breast cancer patients treated with NAC and mastectomy. A nomogram predicting locoregional recurrence (LRR) was established based on 418 unirradiated patients, and X-tile analysis was performed to divide the patients into two risk groups. The effect of PMRT on LRR, distant recurrence (DR), and breast cancer mortality (BCM) was estimated for patients with different molecular subtypes in two risk groups. RESULTS A nomogram predicting LRR was developed using six factors: histologic classification, lymphovascular invasion, ypT stage, ypN stage, estrogen receptor status, and Ki-67 expression. Our study found that PMRT correlated with lower 5-year LRR, DR, and BCM rates for the high-risk group; however, no significant improvement in these endpoints was observed in the low-risk group. Among patients with high risk, subgroup analysis showed that LRR control was improved after PMRT for the human epidermal growth factor receptor 2 (HER2)-negative/hormone receptor (HR)-positive (HER2-/HR+), HER2-positive (HER2+)/HR+, and HER2-/HR-negative (HR-) subtypes, with hazard ratios of 0.113 (95% confidence [CI] 0.034-0.379; p < 0.001), 0.159 (95% CI 0.038-0.671; p = 0.017), and 0.243 (95% CI 0.088-0.676; p = 0.007), respectively, but not for the HER2+/HR- subtype (p = 0.468). CONCLUSIONS We built a nomogram showing favorable risk quantification and patient stratification. Patients in the high-risk group benefited from PMRT, but patients in the low-risk group did not. PMRT may show different benefits for each molecular subtype.
Collapse
Affiliation(s)
- Jia-Chun Ma
- Department of Head and Neck Oncology, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Xiao-Rong Zhong
- Department of Head, Neck and Mammary Gland Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Ting Luo
- Department of Head, Neck and Mammary Gland Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Zhong-Zheng Xiang
- Department of Head and Neck Oncology, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Jia-Yuan Li
- Department of Epidemiology and Biostatistics, West China School of Public Health, Sichuan University, Chengdu, China
| | - Chuanxu Luo
- Department of Head, Neck and Mammary Gland Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Xi Yan
- Department of Head, Neck and Mammary Gland Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Ping He
- Department of Head, Neck and Mammary Gland Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Ting-Lun Tian
- Department of Head, Neck and Mammary Gland Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Fang Liu
- Department of Head and Neck Oncology, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Lei Liu
- Department of Head and Neck Oncology, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.
| | - Hong Zheng
- Department of Head, Neck and Mammary Gland Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| |
Collapse
|
|
29
|
Kolarova I, Melichar B, Vanasek J, Ryska A, Horackova K, Petera J, Vosmik M, Sirak I, Dolezel M. Controversies of radiotherapy in human epidermal growth factor receptor (HER)-2 positive breast cancer patients. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2021; 165:19-25. [PMID: 33542544 DOI: 10.5507/bp.2021.007] [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: 10/08/2020] [Accepted: 01/15/2021] [Indexed: 11/23/2022] Open
Abstract
Tumor biology plays a crucial role in the systemic treatment, specifically in HER2-positive tumors. Distinct biological behavior of breast cancer subtypes is associated with different rates of locoregional recurrence (LRR). HER2- positive breast cancer patients treated with surgery in combination with radiation, without trastuzumab have poor outcome, including high LRR. The efficacy of radiotherapy in HER-2-positive breast cancer appears to be associated with the expression of estrogen receptors. In patients with HER-2-positive breast cancer, studies conducted before the introduction of trastuzumab indicated higher benefit of adjuvant radiation in patients with hormone receptor-positive tumors compared to patients with tumors not expressing hormone receptors. The introduction of agents targeting HER-2 has transformed the management of these patients, resulting in improved outcomes. The data of clinical studies show that the administration of trastuzumab as part of a multimodality approach (with radiation based on standard guidelines) results in improved outcomes, including lower locoregional recurrence. The risk of cardiac toxicity associated with radiation to the heart and administration of potential cardiotoxic trastuzumab is not clear. In patients treated concomitantly with regional lymph node irradiation and anti-HER-2 agents after prior anthracycline-based chemotherapy minimizing the dose to the myocardium, e.g. respiratory gating or proton beam radiotherapy, have been suggested.
Collapse
Affiliation(s)
- Iveta Kolarova
- Department of Oncology and Radiotherapy, University Hospital Hradec Kralove, Czech Republic.,Faculty of Health Studies, Pardubice University, Pardubice, Czech Republic
| | - Bohuslav Melichar
- Department of Oncology and Radiotherapy, University Hospital Hradec Kralove, Czech Republic.,Department of Oncology, Faculty of Medicine and Dentistry, Palacky University and University Hospital Olomouc, Czech Republic.,Department of Oncology and Radiotherapy, Faculty of Medicine in Hradec Kralove, Charles University, Czech Republic
| | - Jaroslav Vanasek
- Faculty of Health Studies, Pardubice University, Pardubice, Czech Republic.,Oncology Centre, Multiscan, Pardubice, Czech Republic
| | - Ales Ryska
- The Fingerland Department of Pathology, Charles University Medical Faculty and University Hospital Hradec Kralove, Czech Republic
| | - Katerina Horackova
- Faculty of Health Studies, Pardubice University, Pardubice, Czech Republic
| | - Jiri Petera
- Department of Oncology and Radiotherapy, University Hospital Hradec Kralove, Czech Republic.,Department of Oncology and Radiotherapy, Faculty of Medicine in Hradec Kralove, Charles University, Czech Republic
| | - Milan Vosmik
- Department of Oncology and Radiotherapy, University Hospital Hradec Kralove, Czech Republic.,Department of Oncology and Radiotherapy, Faculty of Medicine in Hradec Kralove, Charles University, Czech Republic
| | - Igor Sirak
- Department of Oncology and Radiotherapy, University Hospital Hradec Kralove, Czech Republic.,Department of Oncology and Radiotherapy, Faculty of Medicine in Hradec Kralove, Charles University, Czech Republic
| | - Martin Dolezel
- Department of Oncology, Faculty of Medicine and Dentistry, Palacky University and University Hospital Olomouc, Czech Republic.,Department of Oncology, First Faculty of Medicine, Charles University, Prague, Czech Republic
| |
Collapse
|
|
30
|
Abstract
ABSTRACT Triple-negative breast cancer, compared with other molecular subtypes, poses particular challenges for optimizing the timing and the extent of locoregional treatments. In the past, the combination of increased rates of both locoregional and distant recurrences led to a preference of radical surgery and extensive radiation therapy; however, since the introduction of more effective chemotherapy, a sharp de-escalation in the extent of locoregional treatments followed. Current evidence confirms that less aggressive surgery in combination with tailored radiation therapy offers improved oncological outcomes combined with better quality of life. However, further research is required to optimize locoregional treatments, considering the significant heterogeneity in biological behavior and tumor response to systemic treatments.
Collapse
|
|
31
|
Wei J, Jiang Y, Shao Z. The survival benefit of postmastectomy radiotherapy for breast cancer patients with T1-2N1 disease according to molecular subtype. Breast 2020; 51:40-49. [PMID: 32200207 PMCID: PMC7375676 DOI: 10.1016/j.breast.2020.03.003] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Revised: 02/19/2020] [Accepted: 03/09/2020] [Indexed: 02/07/2023] Open
Abstract
OBJECTIVE To evaluate the significance of postmastectomy radiotherapy (PMRT) in female breast cancer patients with T1-2N1M0 disease according to molecular subtypes and other risk factors. METHOD We conducted a retrospective cohort-based study utilizing the Surveillance, Epidemiology, and End Results database. Patients who were diagnosed with T1-2N1M0 invasive breast cancer and received mastectomy between 2010 and 2014 were enrolled in our study. Overall survival (OS) was calculated with Kaplan-Meier method, and multivariant Cox hazard model was conducted to identify the impact of PMRT according to molecular subtypes and other risk factors. Propensity score matching (PSM) was applied to balance measurable confounders. RESULTS Of all the 16,521 enrolled patients, 5775 (35.0%) cases received PMRT. The distribution of molecular subtype is 71.4% for Luminal A, 13.2% for Luminal B, 5.1% for HER2 enriched, and 10.3% for TNBC. The OS was significantly better for patients in PMRT group than the Non-PMRT group (P < 0.0001). Stratified by molecular subtype, PMRT significantly prolonged survival in Luminal A patients (HR: 0.759, 95% CI: 0.651-0.884, P < 0.001), Yet it brought no significant survival advantage in Luminal B, TNBC or HER2 enriched subtype (P = 0.914, P = 0.124, P = 0.103, respectively). Also, PMRT bore prognostic significance among those patients who were older than 56 years old, single, white, exempt from reconstruction and chemotherapy, and were with ductal, GradeⅡtumor (all P < 0.05). After PSM, the survival benefit of PRMT sustained in Luminal A patients with T1 tumor concomitant with one positive lymph node. CONCLUSION Our study demonstrates a beneficial impact for PMRT on overall survival among Luminal A subtype breast cancer patients with T1-2N1 disease. The selection of PMRT should be stratified by molecular subtype and other risk factors.
Collapse
Affiliation(s)
- Jinli Wei
- Department of Breast Surgery, Fudan University Shanghai Cancer Center, Cancer Institute, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, PR China
| | - Yizhou Jiang
- Department of Breast Surgery, Fudan University Shanghai Cancer Center, Cancer Institute, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, PR China
| | - Zhimin Shao
- Department of Breast Surgery, Fudan University Shanghai Cancer Center, Cancer Institute, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, PR China.
| |
Collapse
|