|
1
|
Reduced RKIP Expression is Associated With Breast Neoplastic Progression and is Correlated With Poor Outcomes and Aberrant Methylation in Breast Carcinoma. Appl Immunohistochem Mol Morphol 2018; 25:467-474. [PMID: 26894644 DOI: 10.1097/pai.0000000000000323] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Raf kinase inhibitor protein's (RKIP) downregulation can predict poor outcome in patients with various types of malignancy. In this study, we aimed to assess the potential involvement of RKIP in breast carcinogenesis and to evaluate its association with outcome variables and aberrant promoter methylation in breast carcinoma (BC). Tissue microarray sections were immunostained for RKIP in 26 normal breasts, 25 usual ductal hyperplasia, 76 ductal carcinoma in situ, and 198 BC specimens. The methylation status of RKIP was also determined in BC. In addition, the mRNA and protein level of RKIP was analyzed in 8 pairs of BC tissues and surrounding normal tissues by quantitative real-time polymerase chain reaction and Western blot analysis, respectively. RKIP mRNA and protein expression was significantly downregulated in BC tissues compared with the surrounding normal tissues (P<0.05 and P<0.01, respectively). Reduced RKIP expression seemed to increase progressively from normal breast to BC (P<0.001). Reduced RKIP expression was significantly associated with metastatic relapse (P<0.001) and was identified as an independent adverse prognostic indicator for disease-free survival (P=0.003). Reduced RKIP expression in BC was significantly correlated with its aberrant promoter methylation (P<0.05). In conclusion, downregulation of RKIP plays an important role in the breast neoplastic progression and correlates with poor prognosis in patients with BC. Aberrant RKIP methylation is one of the mechanisms that lead to downregulation of RKIP in BC.
Collapse
|
|
2
|
Ramirez G, Proctor AR, Jung KW, Wu TT, Han S, Adams RR, Ren J, Byun DK, Madden KS, Brown EB, Foster TH, Farzam P, Durduran T, Choe R. Chemotherapeutic drug-specific alteration of microvascular blood flow in murine breast cancer as measured by diffuse correlation spectroscopy. BIOMEDICAL OPTICS EXPRESS 2016; 7:3610-3630. [PMID: 27699124 PMCID: PMC5030036 DOI: 10.1364/boe.7.003610] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/01/2016] [Revised: 08/16/2016] [Accepted: 08/17/2016] [Indexed: 05/08/2023]
Abstract
The non-invasive, in vivo measurement of microvascular blood flow has the potential to enhance breast cancer therapy monitoring. Here, longitudinal blood flow of 4T1 murine breast cancer (N=125) under chemotherapy was quantified with diffuse correlation spectroscopy based on layer models. Six different treatment regimens involving doxorubicin, cyclophosphamide, and paclitaxel at clinically relevant doses were investigated. Treatments with cyclophosphamide increased blood flow as early as 3 days after administration, whereas paclitaxel induced a transient blood flow decrease at 1 day after administration. Early blood flow changes correlated strongly with the treatment outcome and distinguished treated from untreated mice individually for effective treatments.
Collapse
Affiliation(s)
- Gabriel Ramirez
- Department of Biomedical Engineering, University of Rochester, Rochester, NY 14627,
USA
| | - Ashley R. Proctor
- Department of Biomedical Engineering, University of Rochester, Rochester, NY 14627,
USA
| | - Ki Won Jung
- Department of Biomedical Engineering, University of Rochester, Rochester, NY 14627,
USA
| | - Tong Tong Wu
- Department of Biostatistics and Computational Biology, University of Rochester Medical Center, Rochester, NY 14642,
USA
| | - Songfeng Han
- The Institute of Optics, University of Rochester, Rochester, NY 14627,
USA
| | - Russell R. Adams
- Department of Biomedical Engineering, University of Rochester, Rochester, NY 14627,
USA
| | - Jingxuan Ren
- Department of Biomedical Engineering, University of Rochester, Rochester, NY 14627,
USA
| | - Daniel K. Byun
- Department of Biomedical Engineering, University of Rochester, Rochester, NY 14627,
USA
| | - Kelley S. Madden
- Department of Biomedical Engineering, University of Rochester, Rochester, NY 14627,
USA
| | - Edward B. Brown
- Department of Biomedical Engineering, University of Rochester, Rochester, NY 14627,
USA
| | - Thomas H. Foster
- Department of Biomedical Engineering, University of Rochester, Rochester, NY 14627,
USA
- The Institute of Optics, University of Rochester, Rochester, NY 14627,
USA
- Department of Imaging Sciences, University of Rochester Medical Center, Rochester, NY 14642,
USA
| | - Parisa Farzam
- ICFO- Institut de Ciències Fotòniques, The Barcelona Institute of Science and Technology, 08860 Castelldefels (Barcelona),
Spain
| | - Turgut Durduran
- ICFO- Institut de Ciències Fotòniques, The Barcelona Institute of Science and Technology, 08860 Castelldefels (Barcelona),
Spain
- Institució Catalana de Recerca i Estudis Avançats (ICREA), 08015 Barcelona,
Spain
| | - Regine Choe
- Department of Biomedical Engineering, University of Rochester, Rochester, NY 14627,
USA
- Department of Electrical and Computer Engineering, University of Rochester, Rochester, NY 14627,
USA
| |
Collapse
|
|
3
|
Huang Y, Ma C, Zhang Q, Ye J, Wang F, Zhang Y, Hunborg P, Varvares MA, Hoft DF, Hsueh EC, Peng G. CD4+ and CD8+ T cells have opposing roles in breast cancer progression and outcome. Oncotarget 2016; 6:17462-78. [PMID: 25968569 PMCID: PMC4627321 DOI: 10.18632/oncotarget.3958] [Citation(s) in RCA: 158] [Impact Index Per Article: 17.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2015] [Accepted: 04/09/2015] [Indexed: 12/13/2022] Open
Abstract
The Cancer Immunoediting concept has provided critical insights suggesting dual functions of immune system during the cancer initiation and development. However, the dynamics and roles of CD4+ and CD8+ T cells in the pathogenesis of breast cancer remain unclear. Here we utilized two murine breast cancer models (4T1 and E0771) and demonstrated that both CD4+ and CD8+ T cells were increased and involved in immune responses, but with distinct dynamic trends in breast cancer development. In addition to cell number increases, CD4+ T cells changed their dominant subsets from Th1 in the early stages to Treg and Th17 cells in the late stages of the cancer progression. We also analyzed CD4+ and CD8+ T cell infiltration in primary breast cancer tissues from cancer patients. We observed that CD8+ T cells are the key effector cell population mediating effective anti-tumor immunity resulting in better clinical outcomes. In contrast, intra-tumoral CD4+ T cells have negative prognostic effects on breast cancer patient outcomes. These studies indicate that CD4+ and CD8+ T cells have opposing roles in breast cancer progression and outcomes, which provides new insights relevant for the development of effective cancer immunotherapeutic approaches.
Collapse
Affiliation(s)
- Yi Huang
- Department of Internal Medicine, Saint Louis University School of Medicine, Saint Louis, MO, USA.,Center for Clinical Molecular Medicine, Children's Hospital of Chongqing Medical University, Chongqing, P. R. China
| | - Chunling Ma
- Department of Internal Medicine, Saint Louis University School of Medicine, Saint Louis, MO, USA.,Department of Laboratory Medicine, Women and Children's Health Care Hospital of Linyi City, Linyi, P. R. China.,Molecular Biology Experimental Center, Shandong Medical College, Linyi, P. R. China
| | - Qunyuan Zhang
- Department of Genetics, Washington University School of Medicine in St. Louis, Saint Louis, MO, USA
| | - Jian Ye
- Department of Internal Medicine, Saint Louis University School of Medicine, Saint Louis, MO, USA
| | - Fang Wang
- Department of Internal Medicine, Saint Louis University School of Medicine, Saint Louis, MO, USA.,Department of Laboratory Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, P. R. China
| | - Yanping Zhang
- Department of Surgery, Saint Louis University School of Medicine, Saint Louis, MO, USA
| | - Pamela Hunborg
- Department of Surgery, Saint Louis University School of Medicine, Saint Louis, MO, USA
| | - Mark A Varvares
- Department of Otolaryngology-Head and Neck Surgery, Saint Louis University School of Medicine, Saint Louis, MO, USA
| | - Daniel F Hoft
- Department of Internal Medicine, Saint Louis University School of Medicine, Saint Louis, MO, USA
| | - Eddy C Hsueh
- Department of Surgery, Saint Louis University School of Medicine, Saint Louis, MO, USA
| | - Guangyong Peng
- Department of Internal Medicine, Saint Louis University School of Medicine, Saint Louis, MO, USA
| |
Collapse
|
|
4
|
Reduced MUC4 Expression is a Late Event in Breast Carcinogenesis and is Correlated With Increased Infiltration of Immune Cells as Well as Promoter Hypermethylation in Invasive Breast Carcinoma. Appl Immunohistochem Mol Morphol 2015; 23:44-53. [DOI: 10.1097/pai.0000000000000041] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
|
|
5
|
Fang Y, Jiang Y, Wang X, Yang X, Gao Y, Wang J. Somatic mutations of the HER2 in metastatic breast cancer. Tumour Biol 2014; 35:11851-4. [PMID: 25326805 DOI: 10.1007/s13277-014-2414-y] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2014] [Accepted: 07/28/2014] [Indexed: 12/28/2022] Open
Abstract
Mutations in the epidermal growth factor receptor gene (EGFR) in lung cancers predict for sensitivity to EGFR kinase inhibitors. HER2 (also known as NEU, EGFR2, or ERBB2) is a member of the EGFR family of receptor tyrosine kinases and plays important roles in the pathogenesis of certain human cancers, and mutations have recently been reported in lung cancers. We sequenced the full length of HER2 in 198 metastatic breast cancers (MBC) as well as 34 other epithelial cancers (bladder, prostate, and colorectal cancers) and compared the mutational status with clinic pathologic features and the presence of EGFR or KRAS mutations. HER2 mutations were present in 11.6 % (23 of 198) of MBC and were absent in other types of cancers. HER2 mutations were located in exon 15 and the in-frame insertions in exon 20 with corresponding region as did EGFR insertions. HER2 mutations were significantly more frequent in patient after the administration of trastuzumab (34.8 %, 8 of 23; P = 0.02). Mutations in exon 15 and 20 were more potent than wild-type HER2 in associating with activating signal transducers and inducing survival, invasiveness, and tumorigenicity.
Collapse
Affiliation(s)
- Yi Fang
- Department of Breast Surgical Oncology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, People's Republic of China
| | | | | | | | | | | |
Collapse
|
|
6
|
Fu W, Wang Y, Zhang Y, Xiong L, Takeda H, Ding L, Xu Q, He L, Tan W, Bethune AN, Zhou L. Insights into HER2 signaling from step-by-step optimization of anti-HER2 antibodies. MAbs 2014; 6:978-90. [PMID: 24838231 PMCID: PMC4171031 DOI: 10.4161/mabs.28786] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2014] [Revised: 04/03/2014] [Accepted: 04/04/2014] [Indexed: 02/04/2023] Open
Abstract
HER2, a ligand-free tyrosine kinase receptor of the HER family, is frequently overexpressed in breast cancer. The anti-HER2 antibody trastuzumab has shown significant clinical benefits in metastatic breast cancer; however, resistance to trastuzumab is common. The development of monoclonal antibodies that have complementary mechanisms of action results in a more comprehensive blockade of ErbB2 signaling, especially HER2/HER3 signaling. Use of such antibodies may have clinical benefits if these antibodies can become widely accepted. Here, we describe a novel anti-HER2 antibody, hHERmAb-F0178C1, which was isolated from a screen of a phage display library. A step-by-step optimization method was employed to maximize the inhibitory effect of this anti-HER2 antibody. Crystallographic analysis was used to determine the three-dimensional structure to 3.5 Å resolution, confirming that the epitope of this antibody is in domain III of HER2. Moreover, this novel anti-HER2 antibody exhibits superior efficacy in blocking HER2/HER3 heterodimerization and signaling, and its use in combination with pertuzumab has a synergistic effect. Characterization of this antibody revealed the important role of a ligand binding site within domain III of HER2. The results of this study clearly indicate the unique potential of hHERmAb-F0178C1, and its complementary inhibition effect on HER2/HER3 signaling warrants its consideration as a promising clinical treatment.
Collapse
MESH Headings
- Animals
- Antibodies, Monoclonal, Humanized/genetics
- Antibodies, Monoclonal, Humanized/immunology
- Antibodies, Monoclonal, Humanized/pharmacology
- Antibodies, Neoplasm/genetics
- Antibodies, Neoplasm/immunology
- Antibodies, Neoplasm/pharmacology
- Antineoplastic Agents/immunology
- Antineoplastic Agents/pharmacology
- Breast Neoplasms/drug therapy
- Breast Neoplasms/immunology
- Breast Neoplasms/pathology
- Cell Line, Tumor
- Female
- Humans
- Mice
- Mice, Inbred BALB C
- Mice, Nude
- Protein Engineering/methods
- Receptor, ErbB-2/antagonists & inhibitors
- Receptor, ErbB-2/immunology
- Receptor, ErbB-3/immunology
- Signal Transduction/drug effects
- Signal Transduction/immunology
- Trastuzumab
Collapse
Affiliation(s)
- Wenyan Fu
- Central Laboratory; Navy General Hospital; Beijing, PR China
- Cancer Center; PLA General Hospital; PLA Postgraduate School of Medicine; Beijing, PR China
| | - Yuxiao Wang
- Central Laboratory; Navy General Hospital; Beijing, PR China
| | - Yunshan Zhang
- Department of Ultrasound in Medicine; Navy General Hospital; Beijing, PR China
| | - Lijuan Xiong
- Central Laboratory; Navy General Hospital; Beijing, PR China
| | - Hiroaki Takeda
- Department of Biochemistry; Norman Institute for Cancer Research; Toronto, ON CA
| | - Li Ding
- Central Laboratory; Navy General Hospital; Beijing, PR China
| | - Qunfang Xu
- The Department of Laboratory Medicine; State Grid Beijing Electric Power Hospital; Beijing, PR China
| | - Lidong He
- Central Laboratory; Navy General Hospital; Beijing, PR China
| | - Wenlong Tan
- Beijing Institute of Radiation Medicine; Beijing, PR China
| | - Augus N. Bethune
- Department of Molecular Oncology; Norman Institute for Cancer Research; Toronto, ON CA
| | - Lijun Zhou
- Central Laboratory; Navy General Hospital; Beijing, PR China
| |
Collapse
|
|
7
|
Cai Z, Li W, Wang H, Yan W, Zhou Y, Wang G, Cui J, Wang F. Anti-tumor and immunomodulating activities of a polysaccharide from the root of Sanguisorba officinalis L. Int J Biol Macromol 2012; 51:484-8. [DOI: 10.1016/j.ijbiomac.2012.05.029] [Citation(s) in RCA: 71] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2012] [Revised: 05/18/2012] [Accepted: 05/24/2012] [Indexed: 12/31/2022]
|
|
8
|
Ma C, Zhang Q, Ye J, Wang F, Zhang Y, Wevers E, Schwartz T, Hunborg P, Varvares MA, Hoft DF, Hsueh EC, Peng G. Tumor-infiltrating γδ T lymphocytes predict clinical outcome in human breast cancer. THE JOURNAL OF IMMUNOLOGY 2012; 189:5029-36. [PMID: 23034170 DOI: 10.4049/jimmunol.1201892] [Citation(s) in RCA: 173] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Understanding and dissecting the role of different subsets of regulatory tumor-infiltrating lymphocytes (TILs) in the immunopathogenesis of individual cancer is a challenge for anti-tumor immunotherapy. High levels of γδ regulatory T cells have been discovered in breast TILs. However, the clinical relevance of these intratumoral γδ T cells is unknown. In this study, γδ T cell populations were analyzed by performing immunohistochemical staining in primary breast cancer tissues from patients with different stages of cancer progression. Retrospective multivariate analyses of the correlations between γδ T cell levels and other prognostic factors and clinical outcomes were completed. We found that γδ T cell infiltration and accumulation in breast tumor sites was a general feature in breast cancer patients. Intratumoral γδ T cell numbers were positively correlated with advanced tumor stages, HER2 expression status, and high lymph node metastasis but inversely correlated with relapse-free survival and overall survival of breast cancer patients. Multivariate and univariate analyses of tumor-infiltrating γδ T cells and other prognostic factors further suggested that intratumoral γδ T cells represented the most significant independent prognostic factor for assessing severity of breast cancer compared with the other known factors. Intratumoral γδ T cells were positively correlated with FOXP3(+) cells and CD4(+) T cells but negatively correlated with CD8(+) T cells in breast cancer tissues. These findings suggest that intratumoral γδ T cells may serve as a valuable and independent prognostic biomarker, as well as a potential therapeutic target for human breast cancer.
Collapse
Affiliation(s)
- Chunling Ma
- Department of Internal Medicine, Saint Louis University School of Medicine, St. Louis, MO 63104, USA
| | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
9
|
Park MH, Lee JS, Yoon JH. High expression of CX3CL1 by tumor cells correlates with a good prognosis and increased tumor-infiltrating CD8+ T cells, natural killer cells, and dendritic cells in breast carcinoma. J Surg Oncol 2012; 106:386-92. [DOI: 10.1002/jso.23095] [Citation(s) in RCA: 72] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2011] [Accepted: 02/21/2012] [Indexed: 02/01/2023]
|
|
10
|
Puente J, López-Tarruella S, Ruiz A, Lluch A, Pastor M, Alba E, de la Haba J, Ramos M, Cirera L, Antón A, Llombart A, Plazaola A, Fernández-Aramburo A, Sastre J, Díaz-Rubio E, Martin M. Practical prognostic index for patients with metastatic recurrent breast cancer: retrospective analysis of 2,322 patients from the GEICAM Spanish El Alamo Register. Breast Cancer Res Treat 2010; 122:591-600. [PMID: 20063196 DOI: 10.1007/s10549-009-0687-4] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2009] [Accepted: 12/11/2009] [Indexed: 11/28/2022]
Abstract
Women with recurrent metastatic breast cancer from a Spanish hospital registry (El Alamo, GEICAM) were analyzed in order to identify the most helpful prognostic factors to predict survival and to ultimately construct a practical prognostic index. The inclusion criteria covered women patients diagnosed with operable invasive breast cancer who had metastatic recurrence between 1990 and 1997 in GEICAM hospitals. Patients with stage IV breast cancer at initial diagnosis or with isolated loco-regional recurrence were excluded from this analysis. Data from 2,322 patients with recurrent breast cancer after primary treatment (surgery, radiation and systemic adjuvant treatment) were used to construct the prognostic index. The prognostic index score for each individual patient was calculated by totalling up the scores of each independent variable. The maximum score obtainable was 26.1. Nine-hundred and sixty-two patients who had complete data for all the variables were used in the computation of the prognostic index score. We were able to stratify them into three prognostic groups based on the prognostic index score: 322 patients in the good risk group (score < or =13.5), 308 patients in the intermediate risk group (score 13.51-15.60) and 332 patients in the poor risk group (score > or =15.61). The median survivals for these groups were 3.69, 2.27 and 1.02 years, respectively (P < 0.0001). In conclusion, risk scores are extraordinarily valuable tools, highly recommendable in the clinical practice.
Collapse
Affiliation(s)
- Javier Puente
- Medical Oncology Department, Hospital Clínico San Carlos, C/Martín Lagos s/n, 28040, Madrid, Spain.
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
11
|
García-Sáenz JA, Martín M, Calles A, Bueno C, Rodríguez L, Bobokova J, Custodio A, Casado A, Díaz-Rubio E. Bevacizumab in combination with metronomic chemotherapy in patients with anthracycline- and taxane-refractory breast cancer. J Chemother 2009; 20:632-9. [PMID: 19028628 DOI: 10.1179/joc.2008.20.5.632] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
A vascular endothelial growth factor (VEGF) inhibitor might enhance metronomic chemotherapy in previously treated metastatic breast cancer (MBC) patients. Anthracycline and taxane refractory MBC patients were given cyclophosphamide 50 mg p.o. daily, methotrexate 1 mg/kg i.v. every 14 days, and bevacizumab 10 mg/kg i.v. every 14 days. Trastuzumab was added in HER2-overexpressing tumors. 24 patients were enrolled and 22 were evaluable. All tumors had histologic grade II-III and most patients had > or =2 metastatic sites. After a median follow-up of 7.7 months the response rates were: complete response (CR) 0%, partial response (PR) 31.8% (95% CI 13.9- 54.9%), stable disease for >or =24 weeks (SD) 31.8% (95% CI 13.9-54.9%). Clinical benefit (CB= CR + PR + SD>24w) 63.6% (95% CI 40.7-82.8%). Median progression-free survival (PFS) was 7.5 months; overall survival (OS) was 13.6 months. HER2-overexpressing or high proliferative-index tumors had better 6-month PFS (75% vs. 34% in HER-negative tumors, P = 0.043; 67% vs. 0% in Ki-67 > or =20% tumors, P = 0.015). Adverse effects were mild. The combination of bevacizumab and a metronomic-based chemotherapy was effective, well tolerated and provided clinical benefit in heavilytreated MBC patients.
Collapse
Affiliation(s)
- J A García-Sáenz
- Service de Oncología Médica, Hospital Clínico San Carlos, Madrid, Spain
| | | | | | | | | | | | | | | | | |
Collapse
|
|
12
|
Twelves C, Trigo JM, Jones R, De Rosa F, Rakhit A, Fettner S, Wright T, Baselga J. Erlotinib in combination with capecitabine and docetaxel in patients with metastatic breast cancer: A dose-escalation study. Eur J Cancer 2008; 44:419-26. [DOI: 10.1016/j.ejca.2007.12.011] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2007] [Revised: 11/15/2007] [Accepted: 12/20/2007] [Indexed: 10/22/2022]
|
|
13
|
Mozaffari F, Lindemalm C, Choudhury A, Granstam-Björneklett H, Helander I, Lekander M, Mikaelsson E, Nilsson B, Ojutkangas ML, Österborg A, Bergkvist L, Mellstedt H. NK-cell and T-cell functions in patients with breast cancer: effects of surgery and adjuvant chemo- and radiotherapy. Br J Cancer 2007; 97:105-11. [PMID: 17551492 PMCID: PMC2359666 DOI: 10.1038/sj.bjc.6603840] [Citation(s) in RCA: 57] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
Abstract
Breast cancer is globally the most common malignancy in women. Her2-targeted monoclonal antibodies are established treatment modalities, and vaccines are in late-stage clinical testing in patients with breast cancer and known to promote tumour-killing through mechanisms like antibody-dependent cellular cytotoxicity. It is therefore increasingly important to study immunological consequences of conventional treatment strategies. In this study, functional tests and four-colour flow cytometry were used to detect natural killer (NK)-cell functions and receptors as well as T-cell signal transduction molecules and intracellular cytokines in preoperative breast cancer patients, and patients who had received adjuvant radiotherapy or adjuvant combined chemo-radiotherapy as well as in age-matched healthy controls. The absolute number of NK cells, the density of NK receptors as well as in vitro quantitation of functional NK cytotoxicity were significantly higher in preoperative patients than the post-treatments group and controls. A similar pattern was seen with regard to T-cell signalling molecules, and preoperative patients produced significantly higher amounts of cytokines in NK and T cells compared to other groups. The results indicate that functions of NK and T cells are well preserved before surgery but decrease following adjuvant therapy, which may speak in favour of early rather than late use of immunotherapeutic agents such as trastuzumab that may depend on intact immune effector functions.
Collapse
Affiliation(s)
- F Mozaffari
- Immune and Gene Therapy Laboratory, Cancer Centre Karolinska, Karolinska University Hospital, SE-17176 Stockholm, Sweden
| | - C Lindemalm
- Immune and Gene Therapy Laboratory, Cancer Centre Karolinska, Karolinska University Hospital, SE-17176 Stockholm, Sweden
| | - A Choudhury
- Immune and Gene Therapy Laboratory, Cancer Centre Karolinska, Karolinska University Hospital, SE-17176 Stockholm, Sweden
| | | | - I Helander
- Immune and Gene Therapy Laboratory, Cancer Centre Karolinska, Karolinska University Hospital, SE-17176 Stockholm, Sweden
| | - M Lekander
- Department of Clinical Neuroscience, Osher Center for Integrative Medicine and Section of Psychology, Karolinska Institutet, SE-17177 Stockholm, Sweden
| | - E Mikaelsson
- Immune and Gene Therapy Laboratory, Cancer Centre Karolinska, Karolinska University Hospital, SE-17176 Stockholm, Sweden
| | - B Nilsson
- Department of Cancer Epidemiology, Karolinska University Hospital, SE-17176 Stockholm, Sweden
| | - M-L Ojutkangas
- Centre for Clinical Research, Uppsala University, Central Hospital, SE-72189 Västerås, Sweden
| | - A Österborg
- Immune and Gene Therapy Laboratory, Cancer Centre Karolinska, Karolinska University Hospital, SE-17176 Stockholm, Sweden
- Departments of Hematology and Oncology, Karolinska University Hospital, SE-17176 Stockholm, Sweden
| | - L Bergkvist
- Centre for Clinical Research, Uppsala University, Central Hospital, SE-72189 Västerås, Sweden
- Department of Surgery and Centre for Clinical Research, Uppsala University, Central Hospital, SE-72189 Västerås, Sweden
| | - H Mellstedt
- Immune and Gene Therapy Laboratory, Cancer Centre Karolinska, Karolinska University Hospital, SE-17176 Stockholm, Sweden
- Departments of Hematology and Oncology, Karolinska University Hospital, SE-17176 Stockholm, Sweden
- Department of Oncology (Radiumhemmet), Karolinska University Hospital, Stockholm SE-17176, Sweden. E-mail:
| |
Collapse
|
|
14
|
Ulrich-Pur H, Kornek GV, Haider K, Kwasny W, Payrits T, Dworan N, Vormittag L, Depisch D, Lang F, Scheithauer W. Phase II trial of pegylated liposomal doxorubicin (Caelyx) plus Gemcitabine in chemotherapeutically pretreated patients with advanced breast cancer. Acta Oncol 2007; 46:208-13. [PMID: 17453371 DOI: 10.1080/02841860600897868] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Abstract
A phase II trial was performed to investigate the efficacy and tolerance of combined gemcitabine and liposomal doxorubicin +/- recombinant human granulocyte colony-stimulating factor (G-CSF) in patients with chemotherapeutically pretreated metastatic breast cancer. Thirty-four patients were entered in this trial. Chemotherapy consisted of gemcitabine and liposomal doxorubicin +/- G-CSF. Twenty seven patients received this regimen as 2nd line therapy, five patients as 3rd line and two patients as 4th line therapy after having failed taxane- and/or anthracycline-based chemotherapy or other drug combinations. After a median of six courses, an overall response rate of 26% (9 PR in 34 enrolled patients) was observed; 14 patients had disease stabilization (41%), and eight (24%) progressed. Three patients were not evaluable for response due to anaphylaxis after the first course and protracted thrombocytopenia. The median TTP was 7.5 months, and median overall survival was 15 months. Myelosuppression was the most frequently observed toxicity. Non-haematological side effects were generally mild to moderate. Our data suggest that gemcitabine and liposomal doxorubicin +/- G-CSF is an effective and fairly well tolerated regimen for chemotherapeutically pretreated patients with advanced breast cancer.
Collapse
Affiliation(s)
- Herbert Ulrich-Pur
- Division of Clinical Oncology, Department of Internal Medicine I, Vienna University Hospital, Waehringer Guertel 18-20, Vienna A-1090, Austria.
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
15
|
Abstract
BACKGROUND A huge clinical research database on adjuvant cancer treatment has verified improvements in breast cancer outcomes such as recurrence and mortality rates. On the other hand, adjuvant therapy with agents such as hormone therapy, chemotherapy and radiotherapy impacts on quality of life due to substantial short- and long-term side effects. OBJECTIVES To assess the effect of aerobic or resistance exercise interventions during adjuvant treatment for breast cancer on treatment-related side effects such as physical deterioration, fatigue, psychosocial distress and physiological, morphological and biological changes. SEARCH STRATEGY We searched the Cochrane Breast Cancer Specialised Register (16 July 2004) and the following electronic databases: MEDLINE (1966 to 2006), EMBASE (1988 to 2004), CINAHL (1982 to 2004), SPORTDiscus (1975 to 2004), PsycINFO (1872 to 2003), SIGLE (1880 to 2004), ProQuest Digital Dissertations (1861 to 2004) and Conference Papers Index (1973 to 2004). Furthermore, we screened references in relevant reviews and clinical trials and handsearched relevant journals. SELECTION CRITERIA We included randomised and non-randomised controlled trials that examined aerobic or resistance exercise, or both, in women undergoing adjuvant treatment for breast cancer. DATA COLLECTION AND ANALYSIS Two authors independently extracted data and assessed methodological quality and adequacy of the training stimulus following a set of standardised criteria. Meta-analyses were performed for physical fitness, fatigue and weight gain using a random-effects model. MAIN RESULTS Nine trials involving 452 women met the inclusion criteria. Meta-analysis for cardiorespiratory fitness (involving 207 participants) suggested that exercise improves cardiorespiratory fitness (SMD 0.66, 95% CI 0.20 to 1.12). Meta-analysis for fatigue (317 participants) found statistically non-significant improvements for participants in the exercise intervention groups compared to control (non-exercising) groups (SMD -0.12, 95% CI -0.37 to 0.13); the same applied for the meta-analysis of weight gain (147 participants) (SMD -1.11, 95% CI -2.44 to 0.22). Evidence for other outcomes remains limited. Adverse effects (lymphedema and shoulder tendonitis) were observed in two trials. The results from non-randomised controlled trials are similar to those of randomised controlled trials and do not appear to produce any bias. This review is based on a small number of trials with a considerable degree of clinical heterogeneity regarding adjuvant cancer treatments and exercise interventions. AUTHORS' CONCLUSIONS Exercise during adjuvant treatment for breast cancer can be regarded as a supportive self-care intervention which results in improved physical fitness and thus the capacity for performing activities of daily life, which may otherwise be impaired due to inactivity during treatment. Improvements in fatigue were ambiguous and there was a lack of evidence for improvement with exercise for other treatment-related side effects. Since exercise interventions (for sedentary participants) require behaviour change, strategies for behaviour change should underpin these interventions. Furthermore, long-term evaluation is required due to possible long-term side effects.
Collapse
Affiliation(s)
- M Markes
- Rehabilitation Research Institute, Lindenstr. 5, Bad Elster, GERMANY.
| | | | | |
Collapse
|
|
16
|
Iijima M, Uhara H, Ide Y, Sakai S, Onuma H, Muto M, Hayashi K, Mitsura F, Kobayashi S, Yoshizawa A, Saida T. Estrogen-Receptor-Alpha-Positive Extramammary Paget’s Disease Treated with Hormonal Therapy. Dermatology 2006; 213:144-6. [PMID: 16902292 DOI: 10.1159/000093854] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2005] [Accepted: 01/21/2006] [Indexed: 11/19/2022] Open
Abstract
The patient was an 80-year-old man with scrotal and penile extramammary Paget's disease and prostate cancer. Both diseases were in advanced stages. Tumor cells of extramammary Paget's disease strongly expressed estrogen receptor alpha. The patient was concurrently treated with two kinds of hormonal therapy: the anti-estrogen tamoxifen (20 mg/day orally) for extramammary Paget's disease and the anti-androgen bicalutamide (80 mg/day orally) for prostate cancer. The toxicity of the therapy was mild. All of the metastatic lesions remained stable for 2 months after initiation of dual hormonal therapy. During a follow-up period of 22 months, performance status was well maintained for 17 months. Hormonal therapy may be an alternative for selected cases of advanced extramammary Paget's disease.
Collapse
Affiliation(s)
- M Iijima
- Department of Dermatology, Shinshu University School of Medicine, Matsumoto, Japan.
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
17
|
Abstract
The Brn-3b POU domain transcription factor is elevated in a significant proportion of breast cancers and in neuroblastoma tumours, where it is associated with increased proliferation, anchorage-independent growth, faster and larger tumour growth in xenograft models, resistance to growth inhibitory stimuli and increased migratory potential. These effects are associated with the ability of Brn-3b to regulate specific genes associated with these processes. Reducing Brn-3b can reverse many of these effects, suggesting that it may be possible to alter the growth and behaviour of tumour cells by abrogating Brn-3b in these cancers. This review discusses the effect of altering Brn-3b in these cancer cells and possible approaches to targeting Brn-3b as a strategy for therapy in treatment of breast cancers.
Collapse
|
|
18
|
Choedon T, Mathan G, Arya S, Kumar VL, Kumar V. Anticancer and cytotoxic properties of the latex of Calotropis procera in a transgenic mouse model of hepatocellular carcinoma. World J Gastroenterol 2006; 12:2517-22. [PMID: 16688796 PMCID: PMC4087983 DOI: 10.3748/wjg.v12.i16.2517] [Citation(s) in RCA: 68] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate the anticancer property of the dried latex (DL) of Calotropis procera, a tropical medicinal plant, in the X15-myc transgenic mouse model of hepatocellular carcinoma and to elucidate its mechanism of action in cell culture.
METHODS: The young transgenic mice were orally fed with the aqueous suspension of DL (400 mg/kg for 5 d/wk) for 15 wk and their liver was examined for histopathological changes at 20 wk. Serum levels of vascular endothelial growth factor (VEGF) were also measured in these animals. To characterize the active fraction, DL was extracted with petroleum ether followed by methanol. The methanolic extract was sub-fractionated on a silica gel G column using a combination of non-polar and polar solvents and eleven fractions were obtained. Each fraction was analysed for cytotoxic effect on hepatoma (Huh7) and non-hepatoma (COS-1) cell lines and non-transformed hepatocytes (AML12) using tetrazolium (MTT) assay. Finally, the mechanism of cell death was investigated by measuring the levels of Bcl2, caspase 3 and DNA fragmentation.
RESULTS: DL treatment of mice showed a complete protection against hepatocarcinogenesis. No adverse effect was observed in these animals. The serum VEGF level was significantly lowered in the treated mice as compared to control animals. Cell culture studies revealed that the methanolic extract of DL as well as its fraction 8 induced extensive cell death in both Huh-7 and COS-1 cells while AML12 cells were spared. This was accompanied by extensive fragmentation of DNA in Huh-7 and COS-1 cells. No change in the levels of canonical markers of apoptosis such as Bcl2 and caspase 3 was observed.
CONCLUSION: DL of C. procera has the potential for anti-cancer therapy due to its differentiable targets and non-interference with regular pathway of apoptosis.
Collapse
Affiliation(s)
- Tenzin Choedon
- International Centre for Genetic Engineering and Biotechnology, Aruna Asaf Ali Marg, New Delhi, India
| | | | | | | | | |
Collapse
|
|
19
|
Norum J, Holtmon M. Adjuvant fluorouracil, epirubicin and cyclophosphamide in early breast cancer: is it cost-effective? Acta Oncol 2006; 44:735-41. [PMID: 16227165 DOI: 10.1080/02841860500247503] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
Adjuvant chemotherapy (ACT) in breast cancer exposes patients to morbidity, but improves survival. The FEC (fluorouracil, epirubicin, cyclophosphamide) regimen has taken over the prior role of CMF (cyclophosphamide, methotrexate, fluorouracil). In this model, efficacy, tolerability and quality of life (QoL) data from the literature were incorporated with Norwegian practice and cost data in a cost-effectiveness approach. The FEC efficacy was calculated 3-7% superior CMF. There was no difference in quality of life. An 80-100% dose intensity range was employed, one Euro was calculated NOK 8.78 and a 3% discount rate was used. The total cost of FEC employing the friction cost method on production loss, including amount spent on drugs, administration and travelling ranged between 3,278-3,850 Euros (human capital approach 12,143-12,715 Euros). Money spent on drugs alone constituted 15-48%, depending on method chosen. A cost-effectiveness analysis revealed a cost per life year (LY) saved replacing FEC by CMF of 3,575-15,125 Euros. Adjuvant FEC is cost effective in Norway.
Collapse
Affiliation(s)
- Jan Norum
- Department of Oncology, University Hospital of North Norway, Norway.
| | | |
Collapse
|
|
20
|
García-Sáenz JA, Martín M, Puente J, López-Tarruella S, Casado A, Moreno F, Grande E, Díaz-Rubio E. Trastuzumab associated with successive cytotoxic therapies beyond disease progression in metastatic breast cancer. Clin Breast Cancer 2006; 6:325-9. [PMID: 16277882 DOI: 10.3816/cbc.2005.n.035] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
PURPOSE To determine the activity of successive trastuzumab-containing regimens in HER2-overexpressing metastatic breast cancer (MBC) as well as the response rate (RR), time to progression (TTP), and predictive factors for response. PATIENTS AND METHODS We performed a descriptive retrospective study of trastuzumab activity in patients with HER2-overexpressing MBC treated at our hospital from October 1999 to October 2003. RESULTS Fifty-eight patients were evaluated, in whom an overall RR (complete response plus partial response) of 39.7% was obtained for first-time administration of trastuzumab; stable disease (SD) was seen in 29.3%, and the clinical benefit rate was 69%. Median TTP was 6 months (range, 1 months to > 39 months). A total of 31 patients (53.4%) received a second trastuzumab-containing regimen, with an RR of 25.8%; SD was seen in 12.9%, and the clinical benefit rate was 38.7%. Median TTP was 3 months (range, 1 months to > 22 months). A total of 8 patients (14.3%) received a third trastuzumab-containing regimen. The RR for the third trastuzumab regimen was 12.5%; SD was seen in 12.5%, and the clinical benefit rate was 25%. Median TTP was 2 months (range, 1 months to > 12 months). A total of 4 patients (7.1%) received a fourth trastuzumab-containing regimen, with an RR of zero and SD in 25%. Predictive factors for response were disease in soft tissue or bone (P = 0.03; odds ratio [OR], 3.25; 95% confidence interval [CI], 1.08-9.8) and metastases at < 2 sites (P = 0.03; OR, 6.2; 95% CI, 1.25-30.9). We observed a better RR in the second trastuzumab-containing regimen when the patient responded to the first regimen (P = 0.03; OR, 13.2; 95% CI, 1.36-126). CONCLUSION Trastuzumab-containing regimens beyond disease progression in MBC show activity even in heavily pretreated patients. The activity noted does not allow us to ascertain the independent contribution of trastuzumab in this setting. There were more responses in patients with few metastases in the soft tissues or bone. Patients who have shown a previous response to trastuzumab can show a response to a second trastuzumab-containing regimen.
Collapse
|
|
21
|
Salceda S, Tang T, Kmet M, Munteanu A, Ghosh M, Macina R, Liu W, Pilkington G, Papkoff J. The immunomodulatory protein B7-H4 is overexpressed in breast and ovarian cancers and promotes epithelial cell transformation. Exp Cell Res 2005; 306:128-41. [PMID: 15878339 DOI: 10.1016/j.yexcr.2005.01.018] [Citation(s) in RCA: 159] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2004] [Revised: 01/14/2005] [Accepted: 01/18/2005] [Indexed: 10/25/2022]
Abstract
B7-H4 protein is expressed on the surface of a variety of immune cells and functions as a negative regulator of T cell responses. We independently identified B7-H4 (DD-O110) through a genomic effort to discover genes upregulated in tumors and here we describe a new functional role for B7-H4 protein in cancer. We show that B7-H4 mRNA and protein are overexpressed in human serous ovarian cancers and breast cancers with relatively little or no expression in normal tissues. B7-H4 protein is extensively glycosylated and displayed on the surface of tumor cells and we provide the first demonstration of a direct role for B7-H4 in promoting malignant transformation of epithelial cells. Overexpression of B7-H4 in a human ovarian cancer cell line with little endogenous B7-H4 expression increased tumor formation in SCID mice. Whereas overexpression of B7-H4 protected epithelial cells from anoikis, siRNA-mediated knockdown of B7-H4 mRNA and protein expression in a breast cancer cell line increased caspase activity and apoptosis. The restricted normal tissue distribution of B7-H4, its overexpression in a majority of breast and ovarian cancers and functional activity in transformation validate this cell surface protein as a new target for therapeutic intervention. A therapeutic antibody strategy aimed at B7-H4 could offer an exciting opportunity to inhibit the growth and progression of human ovarian and breast cancers.
Collapse
Affiliation(s)
- Susana Salceda
- diaDexus, Inc., 343 Oyster Point Boulevard, South San Francisco, CA 94080, USA
| | | | | | | | | | | | | | | | | |
Collapse
|
|
22
|
Markes M, Brockow T, Resch KL. Exercises for women receiving adjuvant therapy for breast cancer. THE COCHRANE DATABASE OF SYSTEMATIC REVIEWS 2004. [DOI: 10.1002/14651858.cd005001] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
|