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1
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Luca SD, Verdoliva V, Saviano M. Peptide Ligands Specifically Targeting HER2 Receptor and the Role Played by a Synthetic Model System of the Receptor Extracellular Domain: Hypothesized Future Perspectives. J Med Chem 2020; 63:15333-15343. [PMID: 33226807 DOI: 10.1021/acs.jmedchem.0c01340] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
A short (Fab)trastuzumab-derived peptide specific for HER2 receptor was identified. Its affinity for the model system HER2-DIVMP was found in a nanomolar range. The structural determinants responsible for the interaction between this ligand (A9) and HER2-DIVMP were investigated by both computational and NMR analysis. Next, the possibility of using A9 as HER2- specific probe for the nuclear medicine imaging was evaluated by conjugating A9 with the DTPA chelator and radiolabeling it with 111In. The developed probe retained a nanomolar affinity to HER2-overexpressing cancer cells, however, some unspecific binding also occurred. The peptide internalization into cells by receptor-mediated endocytosis was also studied. Future perspectives are aimed at using A9 as a probe for molecular imaging diagnostics as well as active targeting of anticancer drugs. Lead structure optimization is needed to minimize the percentage of A9 unspecific binding and to increase the binding affinity to the receptor.
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Affiliation(s)
- Stefania De Luca
- Institute of Biostructures and Bioimaging, National Research Council, 80134 Naples, Italy
| | - Valentina Verdoliva
- Institute of Biostructures and Bioimaging, National Research Council, 80134 Naples, Italy
| | - Michele Saviano
- Institute of Crystallography, National Research Council, 70126 Bari, Italy
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2
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Use of HER2-Directed Therapy in Metastatic Breast Cancer and How Community Physicians Collaborate to Improve Care. J Clin Med 2020; 9:jcm9061984. [PMID: 32599960 PMCID: PMC7355741 DOI: 10.3390/jcm9061984] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Revised: 06/10/2020] [Accepted: 06/18/2020] [Indexed: 01/18/2023] Open
Abstract
The development of new HER2-directed therapies has resulted in a significant prolongation of survival for women with metastatic HER2-positive breast cancer. Discoveries in the laboratory inform clinical trials which are the basis for improving the standard of care and are also the backbone for quality improvement. Clinical trials can be completed more rapidly by expanding trial enrollment to community sites. In this article we review some of the challenges in treating metastatic breast cancer with HER2-directed therapies and our strategies for incorporating our community partners into the research network.
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3
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De Luca S, Verdoliva V, Saviano M, Fattorusso R, Diana D. SPR and NMR characterization of the molecular interaction between A9 peptide and a model system of HER2 receptor: A fragment approach for selecting peptide structures specific for their target. J Pept Sci 2019; 26:e3231. [PMID: 31749266 DOI: 10.1002/psc.3231] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2019] [Revised: 09/30/2019] [Accepted: 10/22/2019] [Indexed: 01/01/2023]
Abstract
The binding process of A9 peptide toward HER2-DIVMP, a synthetic model of the receptor domain IV, was studied by using the surface plasmon resonance (SPR) technique, with the aim of validating it as a fast and reliable screening method for selecting peptide ligands specifically targeting a domain of their target. To investigate the structural basis of A9 binding to the model of HER2-DIVMP, multiple ligand-based nuclear magnetic resonance (NMR) methods were applied. The use of saturation transfer difference (STD) and WaterLOGSY NMR experiments identified key residues in the peptide for the receptor binding. Moreover, the bound conformation of the A9 peptide was obtained using transferred nuclear Overhauser effect spectroscopy (trNOESY) experiments. The NMR data revealed an extended binding surface that confirms an in silico model previously reported. These structural findings could provide good starting points for future lead structures optimization specific for the receptor target.
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Affiliation(s)
- Stefania De Luca
- Institute of Biostructures and Bioimaging, National Research Council, 80134, Naples, Italy
| | - Valentina Verdoliva
- Institute of Biostructures and Bioimaging, National Research Council, 80134, Naples, Italy
| | - Michele Saviano
- Institute of Crystallography, National Research Council, 70126, Bari, Italy
| | - Roberto Fattorusso
- Department of Environmental, Biological and Pharmaceutical Science and Technology, University of Campania Luigi Vanvitelli, 81100, Caserta, Italy
| | - Donatella Diana
- Institute of Biostructures and Bioimaging, National Research Council, 80134, Naples, Italy
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4
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Evaluation of HER2-specific peptide ligand for its employment as radiolabeled imaging probe. Sci Rep 2018; 8:2998. [PMID: 29445216 PMCID: PMC5812989 DOI: 10.1038/s41598-018-21283-3] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2017] [Accepted: 02/01/2018] [Indexed: 01/19/2023] Open
Abstract
HER2 transmembrane receptor is an important target in immunotherapy treatment of breast and gastroesophageal cancer. Molecular imaging of HER2 expression may provide essential prognostic and predictive information concerning disseminated cancer and aid in selection of an optimal therapy. Radiolabeled low molecular weight peptide ligands are particularly attractive as probes for molecular imaging, since they reach and bind to the target and clear from non-target organs and blood stream faster than bulky antibodies. In this study, we evaluated a potential HER2-imaging probe, an A9 nonapeptide, derived from the trastuzumab-Fab portion. Its cellular uptake was investigated by mass spectrometry analysis of the cytoplasmic cellular extracts. Moreover, based on in-silico modeling, DTPA chelator was conjugated to N-terminus of A9. 111In-labeled A9 demonstrated nanomolar affinity to HER2-expressing BT474 cells and favorable biodistribution profile in NMRI mice. This study suggests that the peptide A9 represents a good lead candidate for development of molecular probe, to be used for imaging purposes and for the delivery of cytotoxic agents.
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dos Santos GT, Camillo ND, Berto MD, Prolla JC, da Cruz IBM, Roehe AV, Brackmann RL, Reiter KC, Bica CG. Impact of Her-2 Overexpression on Survival of Patients with Metastatic Breast Cancer. Asian Pac J Cancer Prev 2017; 18:2673-2678. [PMID: 29072390 PMCID: PMC5747388 DOI: 10.22034/apjcp.2017.18.10.2673] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
Abstract
Introduction: Breast cancer is a complex and heterogeneous disease which is increasingly important as a public
health problem. In Brazil, 57,960 new cases have been estimated to be the burden in 2016 and 2017. Despite advances
in early diagnosis and therapy, approximately 20-30% of patients, even with early stage lesions, will develop distant
metastatic disease. Tumors with similar clinical and pathological presentations may have differing behavior, so it
is important to understand specific biological characteristics. Objective: To investigate tumor markers of primary
tumors featuring pleural metastasis to identify organ-specific characteristics of metastatic breast cancer. Methods:
In a historical cohort study, immunohistochemistry was performed on cell blocks of neoplastic pleural effusions and
results were compared with clinicopathological data. Results: The median survival time with Her-2 overexpression
in malignant pleural effusions was 2.2 months, whereas cases without overexpression survived, on average, for seven
months (p = 0.02). Conclusions: We emphasize that metastases may behave independently of primary tumors, but the
present results indicate that therapeutic agents targeting Her-2 overexpression could increase survival in metastatic
breast cancer cases.
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6
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Stefanovic S, Wirtz R, Deutsch TM, Hartkopf A, Sinn P, Varga Z, Sobottka B, Sotiris L, Taran FA, Domschke C, Hennigs A, Brucker SY, Sohn C, Schuetz F, Schneeweiss A, Wallwiener M. Tumor biomarker conversion between primary and metastatic breast cancer: mRNA assessment and its concordance with immunohistochemistry. Oncotarget 2017; 8:51416-51428. [PMID: 28881657 PMCID: PMC5584258 DOI: 10.18632/oncotarget.18006] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2017] [Accepted: 05/05/2017] [Indexed: 01/09/2023] Open
Abstract
Biomarker changes between primary (PT) and metastatic tumor (MT) site may be significant in individualizing treatment strategies and can result from actual clonal evolution, biomarker conversion, or technical limitations of diagnostic tests. This study explored biomarker conversion during breast cancer (BC) progression in 67 patients with different tumor subtypes and metastatic sites via mRNA quantification and subsequently analyzed the concordance between real-time qPCR and immunohistochemistry (IHC). Immunostaining for estrogen receptor (ER), progesterone receptor (PR), HER2, and Ki-67 was performed on formalin-fixed, paraffin-embedded PT and MT tissue sections. RT-qPCR was performed using a multiplex RT-qPCR kit for ESR1, PGR, ERBB2, and MKI67 and the reference genes B2M and CALM2. Subsequent measurement of tumor biomarker mRNA expression to detect conversion revealed significant decreases in ESR1 and PGR mRNA and MKI67 upregulation (all p < 0.001) in MT compared to PT of all tumor subtypes and ERBB2 upregulation in MT from triple-negative PT patients (p = 0.023). Furthermore, ERBB2 mRNA was upregulated in MT brain biopsies, particularly those from triple-negative PTs (p = 0.023). High concordance between RT-qPCR and IHC was observed for ER/ESR1 (81%(κ 0.51) in PT and 84%(κ 0.34) in MT, PR/PGR (70%(κ 0.10) in PT and 78% (κ -0.32) in MT), and for HER2/ERBB2 (100% in PT and 89% in MT). Discordance between mRNA biomarker assessments of PT and MT resulting from receptor conversion calls for dynamic monitoring of BC tumor biomarkers. Overall, RT-qPCR assessment of BC target genes and their mRNA expression is highly concordant with IHC protein analysis in both primary and metastatic tumor.
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Affiliation(s)
- Stefan Stefanovic
- Department of Gynecology and Obstetrics, Heidelberg University Hospital, 69120 Heidelberg, Germany
- National Center for Tumor Diseases (NCT) Heidelberg, 69120 Heidelberg, Germany
| | - Ralph Wirtz
- Stratifyer Molecular Pathology GmbH, 50935 Cologne, Germany
| | - Thomas M. Deutsch
- National Center for Tumor Diseases (NCT) Heidelberg, 69120 Heidelberg, Germany
| | - Andreas Hartkopf
- Department of Women's Health, University Hospital Tübingen, 72076 Tübingen, Germany
| | - Peter Sinn
- Department of Pathology, Heidelberg University Hospital, 69120 Heidelberg, Germany
| | - Zsuzsanna Varga
- Institute of Surgical Pathology, Zurich University Hospital, 8091 Zurich, Switzerland
| | - Bettina Sobottka
- Institute of Surgical Pathology, Zurich University Hospital, 8091 Zurich, Switzerland
| | - Lakis Sotiris
- Stratifyer Molecular Pathology GmbH, 50935 Cologne, Germany
| | - Florin-Andrei Taran
- Department of Women's Health, University Hospital Tübingen, 72076 Tübingen, Germany
| | - Christoph Domschke
- Department of Gynecology and Obstetrics, Heidelberg University Hospital, 69120 Heidelberg, Germany
- National Center for Tumor Diseases (NCT) Heidelberg, 69120 Heidelberg, Germany
| | - Andre Hennigs
- Department of Gynecology and Obstetrics, Heidelberg University Hospital, 69120 Heidelberg, Germany
- National Center for Tumor Diseases (NCT) Heidelberg, 69120 Heidelberg, Germany
| | - Sara Y. Brucker
- Research Institute for Women's Health, Tübingen University Hospital, 72076 Tübingen, Germany
| | - Christof Sohn
- Department of Gynecology and Obstetrics, Heidelberg University Hospital, 69120 Heidelberg, Germany
- National Center for Tumor Diseases (NCT) Heidelberg, 69120 Heidelberg, Germany
| | - Florian Schuetz
- Department of Gynecology and Obstetrics, Heidelberg University Hospital, 69120 Heidelberg, Germany
- National Center for Tumor Diseases (NCT) Heidelberg, 69120 Heidelberg, Germany
| | - Andreas Schneeweiss
- Department of Gynecology and Obstetrics, Heidelberg University Hospital, 69120 Heidelberg, Germany
- National Center for Tumor Diseases (NCT) Heidelberg, 69120 Heidelberg, Germany
| | - Markus Wallwiener
- Department of Gynecology and Obstetrics, Heidelberg University Hospital, 69120 Heidelberg, Germany
- National Center for Tumor Diseases (NCT) Heidelberg, 69120 Heidelberg, Germany
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Amato M, Perrone G, Righi D, Pellegrini C, Rabitti C, Di Matteo F, Crucitti P, Caputo D, Coppola R, Tonini G, Santini D, Onetti Muda A. HER2 Status in Gastric Cancer: Comparison between Primary and Distant Metastatic Disease. Pathol Oncol Res 2017; 23:55-61. [PMID: 27363700 DOI: 10.1007/s12253-016-0082-5] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2016] [Accepted: 06/14/2016] [Indexed: 01/21/2023]
Abstract
HER2 (human epidermal growth factor receptor-2) assessment in histological samples of gastric cancer is essential to determine which patients might benefit from trastuzumab therapy. HER2 is often evaluated in primary tumor even if trastuzumab therapy is used to treat metastatic disease. However, the exact relationship in terms of HER2 status between primary and metastatic tumors has not been fully clarified. We aimed to evaluate the HER2 status concordance between primary gastric cancer and corresponding distant metastasis. HER2 status was evaluated by IHC (immunohistochemistry) and/or FISH ( fluorescence in situ hybridization) in 41 patients in primary gastric cancer and in paired metastasis. HER2 was assessed according scoring criteria applied in clinical approach. HER2 positivity was found in 14,6 % primary tumors and in 24,4%corresponding metastasis. HER2 concordance rate between primary and metastasis was 80,5 % (K-value = 0,388). Eight/41 (19,5 %)cases resulted discordant: 6 patients with metastatic HER2 positive lesions were found HER2 negative in primary cancers while 2 patient HER2 positive in primary lesion showed a negative conversion in metastasis. Our results showed a good concordance in terms of HER2 status between primary and metastatic lesions, as well as in biopsy and surgical removed specimens. However, the higher rate of HER2 positive status found in metastatic lesions underlined the importance of HER2 assessment in all samples obtained from different sites of gastric cancer disease.
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Affiliation(s)
- Michelina Amato
- Department of Pathology, Campus Bio-Medico University of Rome, Via Alvaro del Portillo, 200, Rome, Italy
| | - Giuseppe Perrone
- Department of Pathology, Campus Bio-Medico University of Rome, Via Alvaro del Portillo, 200, Rome, Italy.
| | - Daniela Righi
- Department of Pathology, Campus Bio-Medico University of Rome, Via Alvaro del Portillo, 200, Rome, Italy
| | - Claudio Pellegrini
- Department of Pathology, Campus Bio-Medico University of Rome, Via Alvaro del Portillo, 200, Rome, Italy
| | - Carla Rabitti
- Department of Pathology, Campus Bio-Medico University of Rome, Via Alvaro del Portillo, 200, Rome, Italy
| | - Francesco Di Matteo
- Endoscopic Unit, Campus Bio-Medico University of Rome, Via Alvaro del Portillo, 200, Rome, Italy
| | - Pierfilippo Crucitti
- Department of Surgery, Campus Bio-Medico University of Rome, Via Alvaro del Portillo, 200, Rome, Italy
| | - Damiano Caputo
- Department of Surgery, Campus Bio-Medico University of Rome, Via Alvaro del Portillo, 200, Rome, Italy
| | - Roberto Coppola
- Department of Surgery, Campus Bio-Medico University of Rome, Via Alvaro del Portillo, 200, Rome, Italy
| | - Giuseppe Tonini
- Oncology Unit, Campus Bio-Medico University of Rome, Via Alvaro del Portillo, 200, Rome, Italy
| | - Daniele Santini
- Oncology Unit, Campus Bio-Medico University of Rome, Via Alvaro del Portillo, 200, Rome, Italy
| | - Andrea Onetti Muda
- Department of Pathology, Campus Bio-Medico University of Rome, Via Alvaro del Portillo, 200, Rome, Italy
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8
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Kameswaran M, Gota V, Ambade R, Gupta S, Dash A. Preparation and preclinical evaluation of 131 I-trastuzumab for breast cancer. J Labelled Comp Radiopharm 2016; 60:12-19. [PMID: 27813128 DOI: 10.1002/jlcr.3465] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2016] [Revised: 08/30/2016] [Accepted: 09/08/2016] [Indexed: 11/10/2022]
Abstract
Trastuzumab that targets the human epidermal growth factor receptor type 2 (HER2) is known to benefit patients with HER2+ metastatic breast cancer. The objective was to explore the potential of 131 I-trastuzumab for treatment of breast cancers. Radioiodination of trastuzumab was carried out by chloramine-T method, purified by using PD-10 column, and characterized by size exclusion high-performance liquid chromatography on a gel column. In vitro studies were carried out in HER2+ cells to determine the specificity of the radioimmunoconjugate. Uptake and retention of 131 I-trastuzumab were determined by biodistribution studies in tumor-bearing non-obese diabetic/severe combined immunodeficiency and normal severe combined immunodeficiency mice. The radiochemical purity (RCP) of 131 I-trastuzumab was 98 ± 0.4% with retention time of 17 minutes by high-performance liquid chromatography. In vitro stability studies exhibited RCP of more than 90% in serum at 37°C after 120 hours of radioiodination. In vitro cell binding with 131 I-trastuzumab in HER2+ cells showed binding of 28% to 35% which was inhibited significantly, with unlabeled trastuzumab confirming its specificity. Kd value of 131 I-trastuzumab was 0.5 nM, while its immunoreactivity was more than 80%. Uptake of more than 12% and retention were observed in the tumors up to 120 hours p.i. 131 I-trastuzumab prepared in-house-exhibited RCP of more than 98%, excellent immunoreactivity, affinity to HER2+ cell lines and good tumor uptake thereby indicating its potential for further evaluation in HER2+ breast cancers.
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Affiliation(s)
- Mythili Kameswaran
- Isotope Production and Applications Division, Bhabha Atomic Research Centre, Mumbai, India
| | - Vikram Gota
- Advanced Centre for Treatment Research and Education in Cancer (ACTREC), Navi Mumbai, India
| | - Rajwardhan Ambade
- Isotope Production and Applications Division, Bhabha Atomic Research Centre, Mumbai, India
| | - Sudeep Gupta
- Advanced Centre for Treatment Research and Education in Cancer (ACTREC), Navi Mumbai, India
| | - Ashutosh Dash
- Isotope Production and Applications Division, Bhabha Atomic Research Centre, Mumbai, India
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9
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Affiliation(s)
- Frank D. Cirisano
- Department of Obstetrics and Gynecology, Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles, California
| | - Beth Y. Karlan
- Cedars-Sinai Medical Center, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, 8700 Beverly Boulevard, #1740, Los Angeles, CA 90048; Department of Obstetrics and Gynecology, Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles, California
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10
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Kaumaya PTP. A paradigm shift: Cancer therapy with peptide-based B-cell epitopes and peptide immunotherapeutics targeting multiple solid tumor types: Emerging concepts and validation of combination immunotherapy. Hum Vaccin Immunother 2016; 11:1368-86. [PMID: 25874884 DOI: 10.1080/21645515.2015.1026495] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
There is a recognizable and urgent need to speed the development and application of novel, more efficacious anti-cancer vaccine therapies that inhibit tumor progression and prevent acquisition of tumor resistance. We have created and established a portfolio of validated peptide epitopes against multiple receptor tyrosine kinases and we have identified the most biologically effective combinations of EGFR (HER-1), HER-2, HER-3, VEGF and IGF-1R peptide vaccines/mimics to selectively inhibit multiple receptors and signaling pathways. The strategy is based on the use of chimeric conformational B-cell epitope peptides incorporating "promiscuous" T-cell epitopes that afford the possibility of generating an enduring immune response, eliciting protein-reactive high-affinity anti-peptide antibodies as potential vaccines and peptide mimics that act as antagonists to receptor signaling that drive cancer metastasis. In this review we will summarize our ongoing studies based on the development of combinatorial immunotherapeutic strategies that act synergistically to enhance immune-mediated tumor killing aimed at addressing mechanisms of tumor resistance for several tumor types.
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Affiliation(s)
- Pravin T P Kaumaya
- a Department of Obstetrics and Gynecology; The Ohio State University Wexner Medical Center ; Columbus , OH , USA
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11
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Abstract
Background Gastric cancer is the fourth most common cancer worldwide. Surgery in combination with multimodal therapy provides the only curative therapy until now. The importance of targeted therapy became clear over the last few years. Due to the implication of HER2 and angiogenesis-directed targeted therapies major advances in the treatment of gastric cancer could be reached. Nevertheless, benefits in survival remain unsatisfactory and the development of resistance to monoclonal antibodies is arising. Methods A comprehensive and comparative literature research was performed to evaluate the status of HER2 and angiogenesis-directed targeted therapy in gastric cancer. Results Up to now, trastuzumab and ramucirumab are the only agents showing remarkable benefits in the therapy for the patients suffering from gastric cancer. The limitations of targeted therapies in gastric cancer are mainly associated with the development of secondary resistance. Conclusion Addition of targeted therapy in second-line treatment is beneficial when compared with chemotherapy alone. Nevertheless, results in first-line treatment remain modest. Therefore, new therapeutic agents and combinations in the first-line treatment of gastric cancer are urgently needed and remain to be validated in clinical trials.
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Affiliation(s)
- G Jomrich
- Department of Surgery, Gastroesophageal Tumor Unit, Comprehensive Cancer Center (CCC), Medical University of Vienna, Spitalgasse 23, 1090 Vienna, Austria
| | - S F Schoppmann
- Department of Surgery, Gastroesophageal Tumor Unit, Comprehensive Cancer Center (CCC), Medical University of Vienna, Spitalgasse 23, 1090 Vienna, Austria
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12
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Abstract
Gastric cancer is one of the most commonly diagnosed and the second leading cause of cancer death worldwide. Surgery combined with multimodal therapy remains the only curative therapy. However, local relapse or distant metastases occur in more than 50% of radically resected patients. Due to molecular therapies, targeting HER2 and angiogenesis, major advances in the treatment of gastric cancer could be achieved. Nevertheless, development of resistance to monoclonal antibodies, such as trastuzumab, is arising. Currently a number of promising new therapeutic are under investigation, combining chemotherapy with newly developed agents to overcome cancer resistance. In this review we report current clinical applications of targeted therapies and overview ongoing trials, investigating the use of monoclonal antibodies in (HER2 positive) gastric cancer.
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Affiliation(s)
- G Jomrich
- a Department of Surgery, Gastroesophageal Tumor Unit, Comprehensive Cancer Center (CCC) , Medical University of Vienna , Vienna , Austria
| | - S F Schoppmann
- a Department of Surgery, Gastroesophageal Tumor Unit, Comprehensive Cancer Center (CCC) , Medical University of Vienna , Vienna , Austria
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13
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Golkar N, Tamaddon AM, Samani SM. Effect of lipid composition on incorporation of trastuzumab-PEG-lipid into nanoliposomes by post-insertion method: physicochemical and cellular characterization. J Liposome Res 2015; 26:113-25. [DOI: 10.3109/08982104.2015.1048692] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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14
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Fernandes E, Ferreira JA, Andreia P, Luís L, Barroso S, Sarmento B, Santos LL. New trends in guided nanotherapies for digestive cancers: A systematic review. J Control Release 2015; 209:288-307. [PMID: 25957905 DOI: 10.1016/j.jconrel.2015.05.003] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2015] [Revised: 05/02/2015] [Accepted: 05/05/2015] [Indexed: 02/06/2023]
Abstract
Digestive tract tumors are among the most common and deadliest malignancies worldwide, mainly due to late diagnosis and lack of efficient therapeutics. Current treatments essentially rely on surgery associated with (neo)adjuvant chemotherapy agents. Despite an upfront response, conventional drugs often fail to eliminate highly aggressive clones endowed with chemoresistant properties, which are responsible for tumor recurrence and disease dissemination. Synthetic drugs also present severe adverse systemic effects, hampering the administration of biologically effective dosages. Nanoencapsulation of chemotherapeutic agents within biocompatible polymeric or lipid matrices holds great potential to improve the pharmacokinetics and efficacy of conventional chemotherapy while reducing systemic toxicity. Tagging nanoparticle surfaces with specific ligands for cancer cells, namely monoclonal antibodies or antibody fragments, has provided means to target more aggressive clones, further improving the selectivity and efficacy of nanodelivery vehicles. In fact, over the past twenty years, significant research has translated into a wide array of guided nanoparticles, providing the molecular background for a new generation of intelligent and more effective anti-cancer agents. Attempting to bring awareness among the medical community to emerging targeted nanopharmaceuticals and foster advances in the field, we have conducted a systematic review about this matter. Emphasis was set on ongoing preclinical and clinical trials for liver, colorectal, gastric and pancreatic cancers. To the best of our knowledge this is the first systematic and integrated overview on this field. Using a specific query, 433 abstracts were gathered and narrowed to 47 manuscripts when matched against inclusion/exclusion criteria. All studies showed that active targeting improves the effectiveness of the nanodrugs alone, while lowering its side effects. The main focus has been on hepatocarcinomas, mainly by exploring glycans as homing molecules. Other ligands such as peptides/small proteins and antibodies/antibody fragments, with affinity to either tumor vasculature or tumor cells, have also been widely and successfully applied to guide nanodrugs to gastrointestinal carcinomas. Conversely, few solutions have been presented for pancreatic tumors. To this date only three nanocomplexes have progressed beyond pre-clinical stages: i) PK2, a galactosamine-functionalized polymeric-DOX formulation for hepatocarcinomas; ii) MCC-465, an anti-(myosin heavy chain a) immunoliposome for advanced stage metastatic solid tumors; and iii) MBP-426, a transferrin-liposome-oxaliplatin conjugate, also for advanced stage tumors. Still, none has been approved for clinical use. However, based on the high amount of pre-clinical studies showing enthusiastic results, the number of clinical trials is expected to increase in the near future. A more profound understanding about the molecular nature of chemoresistant clones and cancer stem cell biology will also contribute to boost the field of guided nanopharmacology towards more effective solutions.
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Affiliation(s)
- Elisabete Fernandes
- Experimental Pathology and Therapeutics Group, Portuguese Institute of Oncology, Porto, Portugal; I3S, Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Portugal and INEB - Instituto de Engenharia Biomédica, University of Porto, Porto, Portugal
| | - José Alexandre Ferreira
- Experimental Pathology and Therapeutics Group, Portuguese Institute of Oncology, Porto, Portugal; Mass Spectrometry Center, QOPNA, Department of Chemistry, University of Aveiro, Aveiro, Portugal.
| | - Peixoto Andreia
- Experimental Pathology and Therapeutics Group, Portuguese Institute of Oncology, Porto, Portugal
| | - Lima Luís
- Experimental Pathology and Therapeutics Group, Portuguese Institute of Oncology, Porto, Portugal; Nucleo de Investigação em Farmácia - Centro de Investigação em Saúde e Ambiente (CISA), Health School of the Polytechnic Institute of Porto, Porto, Portugal
| | - Sérgio Barroso
- Serviço de Oncologia, Hospital de Évora, Évora, Portugal
| | - Bruno Sarmento
- I3S, Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Portugal and INEB - Instituto de Engenharia Biomédica, University of Porto, Porto, Portugal; CESPU, Instituto de Investigação e Formação Avançada em Ciências e Tecnologias da Saúde, Gandra PRD, Portugal
| | - Lúcio Lara Santos
- Experimental Pathology and Therapeutics Group, Portuguese Institute of Oncology, Porto, Portugal; Health School of University of Fernando Pessoa, Porto, Portugal; Department of Surgical Oncology, Portuguese Institute of Oncology, Porto, Portugal
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15
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Indira Chandran V, Eppenberger-Castori S, Venkatesh T, Vine KL, Ranson M. HER2 and uPAR cooperativity contribute to metastatic phenotype of HER2-positive breast cancer. Oncoscience 2015; 2:207-24. [PMID: 25897424 PMCID: PMC4394126 DOI: 10.18632/oncoscience.146] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2015] [Accepted: 03/16/2015] [Indexed: 12/30/2022] Open
Abstract
Human epidermal growth factor receptor type 2 (HER2)-positive breast carcinoma is highly aggressive and mostly metastatic in nature though curable/manageable in part by molecular targeted therapy. Recent evidence suggests a subtype of cells within HER2-positive breast tumors that concomitantly expresses the urokinase plasminogen activator receptor (uPAR) with inherent stem cell/mesenchymal-like properties promoting tumor cell motility and a metastatic phenotype. This HER-positive/uPAR-positive subtype may be partially responsible for the failure of HER2-targeted treatment strategies. Herein we discuss and substantiate the cumulative preclinical and clinical evidence on HER2-uPAR cooperativity in terms of gene co-amplification and/or mRNA/protein co-overexpression. We then propose a regulatory signaling model that we hypothesize to maintain upregulation and cooperativity between HER2 and uPAR in aggressive breast cancer. An improved understanding of the HER2/uPAR interaction in breast cancer will provide critical biomolecular information that may help better predict disease course and response to therapy.
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Affiliation(s)
- Vineesh Indira Chandran
- Department of Clinical Sciences, Section of Oncology and Pathology, Lund University, Lund, Sweden
| | | | - Thejaswini Venkatesh
- Nitte University Centre for Science Education and Research (NUCSER), K. S. Hegde Medical Academy, Nitte University, Deralakatte, Mangalore, Karnataka, India
| | - Kara Lea Vine
- School of Biological Sciences, University of Wollongong, Wollongong, NSW, Australia ; Centre for Medical & Molecular Bioscience, University of Wollongong, Wollongong, NSW, Australia ; Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, NSW, Australia
| | - Marie Ranson
- School of Biological Sciences, University of Wollongong, Wollongong, NSW, Australia ; Centre for Medical & Molecular Bioscience, University of Wollongong, Wollongong, NSW, Australia ; Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, NSW, Australia
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16
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HER2 expression in fine needle aspirates of lymph nodes detected by preoperative axillary ultrasound in breast cancer patients. PLoS One 2014; 9:e113065. [PMID: 25393693 PMCID: PMC4231107 DOI: 10.1371/journal.pone.0113065] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2014] [Accepted: 10/19/2014] [Indexed: 02/05/2023] Open
Abstract
The purpose of this study was to assess the usefulness of HER2 levels in ultrasonographically guided fine-needle aspiration biopsy (US-FNA) aspirates of axillary lymph nodes (ALNs) in the determination of lymph node metastasis or the characterization of primary breast cancer, and to correlate the HER2 levels in US-FNA aspirates (FNA-HER2s) of metastatic ALNs with the HER2 statuses of corresponding primary breast cancers. An institutional review board approved the study. Between January and October 2010, 164 patients with 167 ALNs examined by US-FNA were included. FNA-HER2s of ALNs were measured by chemiluminescence immunoassay, and they were correlated with cytologic/final diagnoses. Receiver operating characteristics (ROC) curve analysis was performed to evaluate the diagnostic ability to differentiate benign and metastatic ALNs. Additionally, FNA-HER2s of metastatic ALNs were correlated with HER2 status and other clinicopathologic variables of the primary breast cancers. Among the 167 ALNs, 138 were metastatic and 29 were benign. The mean FNA-HER2 (6.3 ng/ml) of metastatic ALNs was higher than that of benign ALNs. All 29 benign ALNs showed no measurable value of FNA-HER2 (0.0 ng/ml). The area under the ROC curves of FNA-HER2 of ALNs was 0.679 for the diagnosis of ALN metastasis. The FNA-HER2 statuses of 108 metastatic ALNs (79.4%) were concordant with the HER2 statuses of the corresponding primary breast cancers. In a subgroup analysis of HER2-positive cancers with ALN metastasis, distant metastasis was significantly associated with FNA-HER2-negativity of metastatic ALNs (P = 0.04). Although FNA-HER2 of ALNs did not improve the diagnostic performance of FNA cytology in preoperative diagnosis of ALN metastasis of overall patients, FNA-HER2-positive metastatic ALNs were significantly associated with HER2-positivity of primary breast cancers. Additionally, FNA-HER2 analysis of ALN may help to develop more personalized treatment protocol for breast cancer patients by determining the concordance or discordance of HER2 status between primary cancers and metastatic ALNs.
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Kanthala S, Banappagari S, Gokhale A, Liu YY, Xin G, Zhao Y, Jois S. Novel Peptidomimetics for Inhibition of HER2:HER3 Heterodimerization in HER2-Positive Breast Cancer. Chem Biol Drug Des 2014; 85:702-714. [PMID: 25346057 DOI: 10.1111/cbdd.12453] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2014] [Revised: 09/23/2014] [Accepted: 10/15/2014] [Indexed: 01/06/2023]
Abstract
The current approach to treating HER2-overexpressed breast cancer is the use of monoclonal antibodies or a combination of antibodies with traditional chemotherapeutic agents or kinase inhibitors. Our approach is to target clinically validated HER2 domain IV with peptidomimetics and inhibit the protein-protein interactions (PPI) of HERs. Unlike antibodies, peptidomimetics have advantages in terms of stability, modification, and molecular size. We have designed peptidomimetics (compounds 5 and 9) that bind to HER2 domain IV, inhibit protein-protein interactions, and decrease cell viability in breast cancer cells with HER2 overexpression. We have shown, using enzyme fragment complementation and proximity ligation assays, that peptidomimetics inhibit the PPI of HER2:HER3. Compounds 5 and 9 suppressed the tumor growth in a xenograft mouse model. Furthermore, we have shown that these compounds inhibit PPI of HER2:HER3 and phosphorylation of HER2 as compared to control in tissue samples derived from in vivo studies. The stability of the compounds was also investigated in mouse serum, and the compounds exhibited stability with a half-life of up to 3 h. These results suggest that the novel peptidomimetics we have developed target the extracellular domain of HER2 protein and inhibit HER2:HER3 interaction, providing a novel method to treat HER2-positive cancer.
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Affiliation(s)
- Shanthi Kanthala
- Basic Pharmaceutical Sciences, School of Pharmacy, University of Louisiana at Monroe, Monroe LA 71201
| | - Sashikanth Banappagari
- Basic Pharmaceutical Sciences, School of Pharmacy, University of Louisiana at Monroe, Monroe LA 71201
| | - Ameya Gokhale
- Basic Pharmaceutical Sciences, School of Pharmacy, University of Louisiana at Monroe, Monroe LA 71201
| | - Yong-Yu Liu
- Basic Pharmaceutical Sciences, School of Pharmacy, University of Louisiana at Monroe, Monroe LA 71201
| | - Gu Xin
- Department of Pharmacology, LSU Health Sciences Center, Shreveport, LA 71103
| | - Yunfeng Zhao
- Department of Pharmacology, LSU Health Sciences Center, Shreveport, LA 71103
| | - Seetharama Jois
- Basic Pharmaceutical Sciences, School of Pharmacy, University of Louisiana at Monroe, Monroe LA 71201
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18
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Aoyagi K, Kouhuji K, Kizaki J, Isobe T, Hashimoto K, Shirouzu K. Molecular targeting to treat gastric cancer. World J Gastroenterol 2014; 20:13741-55. [PMID: 25320512 PMCID: PMC4194558 DOI: 10.3748/wjg.v20.i38.13741] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2013] [Revised: 01/13/2014] [Accepted: 05/23/2014] [Indexed: 02/06/2023] Open
Abstract
Trastuzumab that targets human epidermal growth factor receptor 2 (HER2) protein is the only approved molecular targeting agent for treating gastric cancer in Japan and the outcomes have been favorable. However, trastuzumab is effective for only 10% to 20% of the population with gastric cancer that expresses HER2 protein. Molecular targeting therapy with bevacizumab against vascular endothelial growth factors (VEGF) and with cetuximab and panitumumab against the epidermal growth factors pathway that have been approved for treating colorectal cancer are not considered effective for treating gastric cancer according to several clinical trials. However, ramucirumab that targets VEGF receptor-2 prolonged overall survival in a large phase III clinical trial and it might be an effective molecular targeting therapy for gastric cancer. The significance of molecular targeting therapy for gastric cancer remains controversial. A large-scale randomized clinical trial of novel molecular targeting agents with which to treat gastric cancer is needed.
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19
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[Personalized medicine and breast cancer: anticipatory medicine, prognostic evaluation and therapeutic targeting]. Bull Cancer 2014; 100:1295-310. [PMID: 24225763 DOI: 10.1684/bdc.2013.1856] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Breast cancer is now considered as a large collection of distinct biological entities, the management of which is increasingly personalized. Personalized medicine - defined as a medicine, which uses molecular profiles, notably genetic profiles, from patients and/or tumors to tailor therapeutic decisions - is now introduced in the management of breast cancer at any stages: screening and prevention of hereditary forms, prognostic and predictive evaluation of early breast cancer, and, more recently, novel clinical trials in advanced breast cancer, where genetic characterization of tumor tissue based on genomics, including next-generation sequencing tools, is used to drive specific therapeutic targeting.
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20
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Aurilio G, Disalvatore D, Pruneri G, Bagnardi V, Viale G, Curigliano G, Adamoli L, Munzone E, Sciandivasci A, De Vita F, Goldhirsch A, Nolè F. A meta-analysis of oestrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 discordance between primary breast cancer and metastases. Eur J Cancer 2014; 50:277-89. [DOI: 10.1016/j.ejca.2013.10.004] [Citation(s) in RCA: 195] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2013] [Revised: 07/03/2013] [Accepted: 10/07/2013] [Indexed: 02/02/2023]
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21
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Résistance aux traitements du cancer du sein (RPC 2013). ONCOLOGIE 2013. [DOI: 10.1007/s10269-013-2356-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
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22
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Hoefnagel LDC, van der Groep P, van de Vijver MJ, Boers JE, Wesseling P, Wesseling J, van der Wall E, van Diest PJ. Discordance in ERα, PR and HER2 receptor status across different distant breast cancer metastases within the same patient. Ann Oncol 2013; 24:3017-23. [PMID: 24114857 DOI: 10.1093/annonc/mdt390] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND We studied discordance in estrogen receptor alpha (ERα), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) status between multiple distant metastases from the same breast cancer patient. MATERIAL AND METHODS Multiple distant metastases from 55 female patients were stained for ERα, PR and HER2 by immunohistochemistry and in situ hybridization for confirmation of the HER2 status. RESULTS Different metastatic sites within the same patient showed discordance in ERα receptor status in 7.3% or 10.9% of patients (using a 10% or 1% threshold for positivity, respectively). For PR, 29.1% or 30.9% of patients showed discordance. Taking ERα and PR together, 36.4% of cases (both thresholds) showed discrepancy between metastases. In 10.9% (10% threshold) or 14.5% of patients (1% threshold), such discordance could have clinical consequences with regard to hormonal treatment. For HER2, there was 3.6% discordance on the immunohistochemical level but 0% on the gene level. CONCLUSION In a significant proportion of metastatic breast cancer patients, discordance in ERα and PR receptor status between different metastatic sites was observed. This implies that multiple metastases may need to be biopsied to optimally reassess receptors.
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23
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Extended trastuzumab therapy improves the survival of HER2-positive breast cancer patients following surgery and radiotherapy for brain metastases. Mol Clin Oncol 2013; 1:995-1001. [PMID: 24649283 DOI: 10.3892/mco.2013.162] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2013] [Accepted: 07/19/2013] [Indexed: 11/05/2022] Open
Abstract
Brain metastases usually present late during the course of breast cancer and are associated with an unfavorable prognosis. It was previously demonstrated that the status of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor type 2 (HER2) may be altered in the time window between the emergence of the primary breast tumor and the development of metastases. The aim of this study was to compare the expression of ER, PR and HER2 in pathology samples of primary breast cancer and brain metastases in order to evaluate whether previously administered therapy was able to modify this status and determine whether biomarker alterations affect prognosis after the development of brain metastases. Data were collected from 62 patients who were initially diagnosed with breast cancer that had metastasized to the brain. The ER, PR and HER2 status of the samples from the primary tumors and the brain metastases was determined. Differences in the immunohistochemical profiles of ER, PR or HER2 between the primary tumors and the brain metastases in 17 patients (29.3%) were identified. The patients with HER2-positive brain metastases who received trastuzumab had no leptomeningeal metastases and exhibited a longer survival time after brain metastases compared to the HER2-positive patients who did not receive trastuzumab and the patients with HER2-negative brain metastases (P=0.0005). Our results suggested that the patients treated with trastuzumab following surgery and radiotherapy for brain metastases exhibited a better prognosis. Thus, the HER2 status in brain metastases requires re-evaluation and extended trastuzumab therapy is recommended after brain metastases.
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Heitz F, Barinoff J, du Bois O, Hils R, Fisseler-Eckhoff A, Harter P, Heitz J, Willenbrock K, Traut A, du Bois A. Differences in the Receptor Status between Primary and Recurrent Breast Cancer - The Frequency of and the Reasons for Discordance. Oncology 2013; 84:319-25. [DOI: 10.1159/000346184] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2012] [Accepted: 11/26/2012] [Indexed: 11/19/2022]
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25
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Fluorescence study for selecting specific ligands toward HER2 receptor: An example of receptor fragment approach. Eur J Med Chem 2013; 61:116-21. [DOI: 10.1016/j.ejmech.2012.09.024] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2012] [Revised: 09/14/2012] [Accepted: 09/15/2012] [Indexed: 12/14/2022]
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26
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Kaumaya PTP, Foy KC. Peptide vaccines and targeting HER and VEGF proteins may offer a potentially new paradigm in cancer immunotherapy. Future Oncol 2012; 8:961-87. [PMID: 22894670 DOI: 10.2217/fon.12.95] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
The ErbB family (HER-1, HER-2, HER-3 and HER-4) of receptor tyrosine kinases has been the focus of cancer immunotherapeutic strategies while antiangiogenic therapies have focused on VEGF and its receptors VEGFR-1 and VEGFR-2. Agents targeting receptor tyrosine kinases in oncology include therapeutic antibodies to receptor tyrosine kinase ligands or the receptors themselves, and small-molecule inhibitors. Many of the US FDA-approved therapies targeting HER-2 and VEGF exhibit unacceptable toxicities, and show problems of efficacy, development of resistance and unacceptable safety profiles that continue to hamper their clinical progress. The combination of different peptide vaccines and peptidomimetics targeting specific molecular pathways that are dysregulated in tumors may potentiate anticancer immune responses, bypass immune tolerance and circumvent resistance mechanisms. The focus of this review is to discuss efforts in our laboratory spanning two decades of rationally developing peptide vaccines and therapeutics for breast cancer. This review highlights the prospective benefit of a new, untapped category of therapies biologically targeted to EGF receptor (HER-1), HER-2 and VEGF with potential peptide 'blockbusters' that could lay the foundation of a new paradigm in cancer immunotherapy by creating clinical breakthroughs for safe and efficacious cancer cures.
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Affiliation(s)
- Pravin T P Kaumaya
- Departments of Obstetrics & Gynecology, OSU Wexner Medical Center, James Cancer Hospital & Solove Research Institute & the Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA.
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Foukakis T, Åström G, Lindström L, Hatschek T, Bergh J. When to order a biopsy to characterise a metastatic relapse in breast cancer. Ann Oncol 2012; 23 Suppl 10:x349-53. [DOI: 10.1093/annonc/mds297] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
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Jabbour MN, Massad CY, Boulos FI. Variability in hormone and growth factor receptor expression in primary versus recurrent, metastatic, and post-neoadjuvant breast carcinoma. Breast Cancer Res Treat 2012; 135:29-37. [PMID: 22484731 DOI: 10.1007/s10549-012-2047-z] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2012] [Accepted: 03/20/2012] [Indexed: 12/29/2022]
Abstract
The introduction of selective molecular targeted therapy, specifically tamoxifen and trastuzumab, has significantly altered the clinical behavior of breast carcinoma. Several questions remain, however, regarding potential phenotypic drifts in estrogen receptor (ER), progesterone receptor (PR), and epidermal growth factor receptor (Her-2/neu) expression between the primary and metastatic site. Whether patients should be tested for ER, PR, and Her-2/neu expression in the nodal or distant metastatic site, local recurrence and following neoadjuvant therapy, and whether this has an effect on prognosis remains elusive. A review of 45 studies addressing ER, PR, and Her-2/neu expression in lymph node metastasis, distant metastasis, local recurrence, and post-neoadjuvant therapy revealed the following average phenotypic drift in ER, PR, and Her-2/neu expression, respectively: 13.1 % (median = 10.0 %), 13.8 % (median = 16.0 %), and 7.7 % (median = 5.0 %) for lymph node metastasis; 21.8 % (median = 19.5 %), 30.8 % (median = 33.5 %), and 7.6 % (median = 6.1 %) for distant metastasis; 19.8 % (median = 13.4 %), 27.1 % (median = 28.6 %), and 6.6 % (median = 1.6 %) for local recurrence; and 12.9 % (median = 8.0 %), 32.0 % (median = 20.0 %), and 8.9 % (median = 0 %) post-neoadjuvant therapy. The above findings support the notion of re-evaluating ER, PR, and Her-2/neu expression in distant metastasis, lymph node metastasis and to a lesser extent local recurrence. The effects of neoadjuvant therapy on receptor expression are more pronounced for PR, which may have a prognostic role in therapy efficacy.
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Affiliation(s)
- Mark N Jabbour
- Department of Pathology and Laboratory Medicine, American University of Beirut Medical Center, PO Box 11-0236, Beirut 1107 2020, Lebanon.
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29
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Liu J, Deng H, Jia W, Zeng Y, Rao N, Li S, Jin L, Wu J, Song E, Su F. Comparison of ER/PR and HER2 statuses in primary and paired liver metastatic sites of breast carcinoma in patients with or without treatment. J Cancer Res Clin Oncol 2012; 138:837-42. [PMID: 22290394 DOI: 10.1007/s00432-012-1150-1] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
PURPOSE The aim of this study was to determine whether estrogen receptor (ER)/progesterone receptor (PR) and human epidermal growth factor receptor type 2 (HER2) statuses between primary tumors and paired liver metastatic localizations of breast carcinoma were modified by treatment or during the natural metastatic process. METHODS ER, PR, and HER2 expressions were analyzed on paired tissue specimens taken from the primary and the liver metastatic tumors in breast cancer patients. The first group included 46 women who presented with T1-T4, N0-N3, M0 breast carcinoma when first diagnosed and were treated by neoadjuvant therapy or directly underwent surgery, then received postoperative treatment and developed liver metastasis several months/years later. The second group included 12 patients with liver metastatic breast carcinoma when first diagnosed for breast cancer. HER2 status was determined by immunohistochemistry as well as fluorescence in situ hybridization. RESULTS Among the 46 patients in the first group, the ER/PR and HER2 statuses (when considered as a whole histological subtype) were changed between primary tumor and liver metastatic lesions in 12 patients (26.1%). While ER and PR status were modified in 14 (30.4%) and 25 (54.3%) patients, respectively, there were only 5 (10.9%) cases showed a discrepancy in the HER2 status. In the second group, the ER/PR and HER2 statuses (when considered as a whole subtype) were consistent between primary and liver metastatic tumor in 10 of 12 (83.3%) patients. ER, PR, and HER2 statuses were modified in 0 of 12 (0%), 4 of 12 (33.3%), and 1 of 12 (8.3%) cases, respectively. CONCLUSIONS ER/PR and HER2 statuses between primary and liver metastatic lesions of breast carcinoma can be modified after treatment but are stable in most cases during the natural metastatic process.
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MESH Headings
- Adult
- Aged
- Antineoplastic Agents/therapeutic use
- Biomarkers, Tumor/metabolism
- Breast Neoplasms/metabolism
- Breast Neoplasms/pathology
- Breast Neoplasms/therapy
- Carcinoma, Ductal, Breast/metabolism
- Carcinoma, Ductal, Breast/secondary
- Carcinoma, Ductal, Breast/therapy
- Carcinoma, Lobular/metabolism
- Carcinoma, Lobular/secondary
- Carcinoma, Lobular/therapy
- Carcinoma, Medullary/metabolism
- Carcinoma, Medullary/secondary
- Carcinoma, Medullary/therapy
- Chemoradiotherapy
- Female
- Humans
- Immunohistochemistry
- In Situ Hybridization, Fluorescence
- Liver Neoplasms/metabolism
- Liver Neoplasms/pathology
- Liver Neoplasms/secondary
- Liver Neoplasms/therapy
- Lymphatic Metastasis
- Mastectomy
- Mastectomy, Segmental
- Middle Aged
- Receptor, ErbB-2/metabolism
- Receptors, Estrogen/metabolism
- Receptors, Progesterone/metabolism
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Affiliation(s)
- Jieqiong Liu
- Department of Breast Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, People's Republic of China
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Target points in trastuzumab resistance. Int J Breast Cancer 2012; 2012:761917. [PMID: 22482061 PMCID: PMC3299266 DOI: 10.1155/2012/761917] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2011] [Accepted: 11/11/2011] [Indexed: 01/16/2023] Open
Abstract
Epidermal growth factor (EGF) family of receptors is involved in cell growth and differentiation. The human EGF2 (HER2) lacks natural ligands, and correlation between HER2 levels and carcinogenesis makes the receptor an ideal candidate for targeted therapy in breast cancer. Trastuzumab is a humanized antibody applied against HER2-positive breast tumors in clinic. Metastatic tumors respond well to trastuzumab therapy for the first year, but development of antibody resistance helps the tumors to regrow allowing the disease to progress. Trastuzumab resistance is shaped via a range of intracellular signaling pathways that are interconnected and share in key effector molecules. Identification of a common node central to these resistance pathways could provide an ultimate solution for trastuzumab resistance in breast and other cancers.
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Abstract
The presence of circulating tumor cells (CTCs) in the blood as well as disseminated tumor cells (DTCs) in the bone marrow of breast cancer patients is associated with a worsened prognosis in the primary as well as in the metastatic situation. Next to their detection, evaluation of human epidermal growth factor receptor (HER2) expression is a valuable feature of CTCs/DTCs. As the HER2 status may change during disease progression CTCs/DTCs might (1) characterize the phenotype of minimal residual disease in the adjuvant setting and (2) serve as a "real time biopsy" of metastatic breast cancer. Phenotyping of CTCs/DTCs will thus help to understand mechanism of resistance to HER2-directed therapy. Moreover, patients that are likely to benefit from HER2-directed therapy despite a HER2-negative primary tumor might be identified.
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Curigliano G, Bagnardi V, Viale G, Fumagalli L, Rotmensz N, Aurilio G, Locatelli M, Pruneri G, Giudici S, Bellomi M, Della Vigna P, Monfardini L, Orsi F, Nolè F, Munzone E, Goldhirsch A. Should liver metastases of breast cancer be biopsied to improve treatment choice? Ann Oncol 2011; 22:2227-33. [DOI: 10.1093/annonc/mdq751] [Citation(s) in RCA: 93] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
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Houssami N, Macaskill P, Balleine RL, Bilous M, Pegram MD. HER2 discordance between primary breast cancer and its paired metastasis: tumor biology or test artefact? Insights through meta-analysis. Breast Cancer Res Treat 2011; 129:659-74. [PMID: 21698410 DOI: 10.1007/s10549-011-1632-x] [Citation(s) in RCA: 89] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2011] [Accepted: 06/03/2011] [Indexed: 12/31/2022]
Abstract
The proto-oncogene, HER2, has prognostic and predictive relevance in invasive breast cancer (IBC). HER2 testing of primary IBC guides treatment selection and is assumed to reflect HER2 status of associated metastases, although HER2 discordance between IBC and metastasis has been reported. Systematic review and meta-analysis of HER2 status in IBC and its paired loco-regional or distant metastasis were done. Quality appraisal considered whether (within-subject) testing conditions were maintained for paired primary and metastasis. Random effects logistic regression models were used to estimate pooled within-subject HER2 discordant proportions and to examine study-level covariates, including tumor-related and testing-related variables, potentially associated with HER2 discordance differences across (between) studies. Modelled paired HER2 data for primary and metastatic cancer (2520 subjects, 26 studies) showed a pooled HER2 discordance of 5.5% (3.6-8.5%). Sensitivity analysis, excluding the only study not maintaining same conditions for paired testing, gave a pooled estimate of 5.2% (3.5-7.8%). Pooled discordant proportion was not associated with differences between studies in test type, test scoring or interpretation criteria, subjects' median age, study time-frame, or HER2 positivity in primary cancer (all P > 0.05). However, type of metastasis was significantly associated with estimated HER2 discordance (P = 0.0017): studies of primary tumor paired with distant metastases had higher discordance [11.5% (6.9-18.6%)] than studies of primary paired with lymph node metastases only [4.1% (2.4-7.2%)], or those paired with nodal or various metastases [3.3% (2.0-5.6%)]; P < 0.01. HER2 discordant proportion was higher where paired metastases were metachronous relative to synchronous to primary IBC (P = 0.0024). Sensitivity analysis provided weak evidence (P = 0.074) that discordance in the direction of change from HER2-negative primary cancer to HER2-positive paired metastasis was more likely than the reverse. Study-level meta-analysis suggests factors associated with the type of metastasis as underlying mechanisms for observed HER2 discordance between primary IBC and paired metastasis. Test-related factors did not account for differences across studies in the HER2 discordant proportion.
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Affiliation(s)
- Nehmat Houssami
- Screening and Test Evaluation Program, School of Public Health (A27), Sydney Medical School, University of Sydney, Sydney 2006, Australia.
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Zurrida S, Montagna E, Naninato P, Colleoni M, Goldhirsch A. Receptor status (ER, PgR and HER2) discordance between primary tumor and locoregional recurrence in breast cancer. Ann Oncol 2011; 22:479-80. [PMID: 21278222 DOI: 10.1093/annonc/mdq688] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
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35
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Chang HJ, Han SW, Oh DY, Im SA, Jeon YK, Park IA, Han W, Noh DY, Bang YJ, Kim TY. Discordant human epidermal growth factor receptor 2 and hormone receptor status in primary and metastatic breast cancer and response to trastuzumab. Jpn J Clin Oncol 2011; 41:593-599. [PMID: 21406492 DOI: 10.1093/jjco/hyr020] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2025] Open
Abstract
BACKGROUND Recent studies have shown that the human epidermal growth factor receptor 2 status of a metastatic site may differ from that of the primary site. This difference may influence patient prognosis and response to therapy. METHODS We conducted a retrospective study using immunohistochemistry and/or fluorescent in situ hybridization to compare human epidermal growth factor receptor 2 and hormone receptor status in primary and metastatic breast cancers. RESULTS Fifty-six patients were included in this study. Conversion from hormone receptor positive in the primary tumor to hormone receptor negative in the metastasis occurred in 12 patients (21.4%), and hormone receptor negative to hormone receptor positive conversion occurred in two patients (3.6%). Human epidermal growth factor receptor 2 status was discordant between primary and metastatic lesions in seven patients (12.5%). All of the five patients who converted from human epidermal growth factor receptor 2 negative status to human epidermal growth factor receptor positive received trastuzumab-based chemotherapy. Overall response rate and median progression-free survival for concordant human epidermal growth factor receptor 2 positive patients were 69.2% and 16.9 months, whereas that of patients with positive conversion of human epidermal growth factor receptor 2 were 40.0% and 7.6 months, respectively (overall response rate; P = 0.169 and progression-free survival; P = 0.004). CONCLUSION Discordance in human epidermal growth factor receptor 2 and hormone receptor status between primary and metastatic tumors was observed, which led to altered treatment decisions. Evaluation of human epidermal growth factor receptor 2 and hormone receptor in metastatic tumors should be considered in patients with breast cancer.
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Affiliation(s)
- Hye Jung Chang
- Department of Internal Medicine, Seoul National University Hospital, 28 Yongon-Dong, Chongno-Gu, Seoul 110-744, South Korea
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Foy KC, Liu Z, Phillips G, Miller M, Kaumaya PTP. Combination treatment with HER-2 and VEGF peptide mimics induces potent anti-tumor and anti-angiogenic responses in vitro and in vivo. J Biol Chem 2011; 286:13626-37. [PMID: 21325276 PMCID: PMC3075707 DOI: 10.1074/jbc.m110.216820] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2010] [Revised: 02/07/2011] [Indexed: 12/27/2022] Open
Abstract
HER-2 is a member of the EGF receptor family and is overexpressed in 20-30% of breast cancers. HER-2 overexpression causes increased expression of VEGF at both the RNA and protein levels. HER-2 and VEGF are therefore considered good targets for cancer treatment, which has led to the development of two humanized monoclonal antibodies (mAb) pertuzumab and bevacizumab. Although passive immunotherapy with these Abs are approved for treatment of advanced breast cancer, a number of concerns exist. Treatment is expensive, has a limited duration of action, and is usually accompanied by serious side effects. We hypothesized that therapy with conformational peptide mimics aimed at blocking receptor-ligand interaction is potentially safer with little toxicity, cheaper with a longer half-life, and has greater penetrating abilities than mAbs. We designed and synthesized peptides based on the binding of HER-2 with pertuzumab and VEGF with VEGFR2. We show that treatment with the peptide mimics induces potent anti-tumor responses in vitro as determined by cell viability, proliferation, and HER2 phosphorylation assays. We also demonstrate in a transplantable BALB/c mouse tumor model that treatment with the peptide mimics resulted in a greater delay in tumor growth and development. Similarly, treatment with the peptide mimics inhibited angiogenesis in vivo as assessed by a Matrigel plug assay. To address the problem of degradability of L-amino acid peptides in vivo, we synthesized the retro-inverso D-peptide mimics that resulted in higher efficacy in treatment. Our study shows that combination treatment with HER-2 and VEGF peptide mimics provides greater efficacy than individual treatments.
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MESH Headings
- Angiogenesis Inhibitors/chemical synthesis
- Angiogenesis Inhibitors/chemistry
- Angiogenesis Inhibitors/pharmacology
- Animals
- Antibodies, Monoclonal/chemistry
- Antibodies, Monoclonal/pharmacology
- Antibodies, Monoclonal, Humanized
- Antineoplastic Combined Chemotherapy Protocols/chemistry
- Antineoplastic Combined Chemotherapy Protocols/pharmacology
- Biomimetic Materials/chemical synthesis
- Biomimetic Materials/chemistry
- Biomimetic Materials/pharmacokinetics
- Drug Screening Assays, Antitumor/methods
- Female
- Humans
- Mice
- Mice, Inbred BALB C
- Neoplasms, Experimental/drug therapy
- Neoplasms, Experimental/metabolism
- Neoplasms, Experimental/pathology
- Peptides/chemical synthesis
- Peptides/chemistry
- Peptides/pharmacology
- Receptor, ErbB-2
- Vascular Endothelial Growth Factor A
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Affiliation(s)
- Kevin C. Foy
- From the Department of Microbiology
- Department of Obstetrics and Gynecology, and
| | | | - Gary Phillips
- Arthur G. James Comprehensive Cancer Center, Ohio State University, Columbus, Ohio 43210
| | - Megan Miller
- From the Department of Microbiology
- Department of Obstetrics and Gynecology, and
| | - Pravin T. P. Kaumaya
- From the Department of Microbiology
- Ohio State Biochemistry Program
- Department of Obstetrics and Gynecology, and
- Arthur G. James Comprehensive Cancer Center, Ohio State University, Columbus, Ohio 43210
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Fabi A, Di Benedetto A, Metro G, Perracchio L, Nisticò C, Di Filippo F, Ercolani C, Ferretti G, Melucci E, Buglioni S, Sperduti I, Papaldo P, Cognetti F, Mottolese M. HER2 protein and gene variation between primary and metastatic breast cancer: significance and impact on patient care. Clin Cancer Res 2011; 17:2055-64. [PMID: 21307144 DOI: 10.1158/1078-0432.ccr-10-1920] [Citation(s) in RCA: 75] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
PURPOSE To analyze HER2 status in primary breast cancer (PBC) compared with correspondent metachronous metastases and to investigate whether BC phenotype may be predictive of change in HER2 expression. EXPERIMENTAL DESIGN HER2 was investigated by immunohistochemistry, silver in situ hybridization (SISH), and FISH, in a series of 137 tumors, building up a tissue microarray to concurrently analyze each single PBC and metastatic (MBC) on the same slide. RESULTS HER2 status was discordant in 14 cases (10%): 12 negative in PBC and positive in metastases and two positive in PBC and negative in metastases (P = 0.04). These findings were confirmed by a PCR based test termed Multiplex Ligation-dependent Probe Amplification (MLPA). HER2 status changed in hormone receptor-positive BC more frequently than in negative ones (P = 0.002). In addition, we evaluated HER2 gene and chromosome 17 copy number by SISH in the 123 cases with unchanged HER2 status during progression. We found consistent HER2 gene copy number stability in the 100 nonamplified cases. Conversely, of the 23 amplified PBC, 13 (57%) demonstrated a significant increase in the HER2 gene and chromosome 17 copy number in their paired metastases (P = 0.01), as defined by SISH (k = 0.54, P < 0.0001) and MLPA. Patients who changed HER2 status from negative to positive, presented significant longer time to progression when treated with trastuzumab compared to those who were untreated (P = 0.04). CONCLUSIONS When feasible, HER2 reassessment in metastatic lesions should be carefully taken into account, especially for metastases coming from primary hormone receptor-positive BC.
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Affiliation(s)
- Alessandra Fabi
- Medical Oncology, Regina Elena Cancer Institute, Rome, Italy
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Tai W, Mahato R, Cheng K. The role of HER2 in cancer therapy and targeted drug delivery. J Control Release 2010; 146:264-75. [PMID: 20385184 PMCID: PMC2918695 DOI: 10.1016/j.jconrel.2010.04.009] [Citation(s) in RCA: 405] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2010] [Accepted: 04/05/2010] [Indexed: 12/16/2022]
Abstract
HER2 is highly expressed in a significant proportion of breast cancer, ovarian cancer, and gastric cancer. Since the discovery of its role in tumorigenesis, HER2 has received great attention in cancer research during the past two decades. Successful development of the humanized monoclonal anti-HER2 antibody (Trastuzumab) for the treatment of breast cancer further spurred scientists to develop various HER2 specific antibodies, dimerization inhibitors and kinase inhibitors for cancer therapy. On the other hand, the high expression of HER2 and the accessibility of its extracellular domain make HER2 an ideal target for the targeted delivery of anti-tumor drugs as well as imaging agents. Although there is no natural ligand for HER2, artificial ligands targeting HER2 have been developed and applied in various targeted drug delivery systems. The emphasis of this review is to elucidate the roles of HER2 in cancer therapy and targeted drug delivery. The structure and signal pathway of HER2 will be briefly described. The role of HER2 in tumorigenesis and its relationship with other tumor markers will be discussed. For the HER2 targeted cancer therapy, numerous strategies including the blockage of receptor dimerization, inhibition of the tyrosine kinase activity, and interruption of the downstream signal pathway will be summarized. For the targeted drug delivery to HER2 positive tumor cells, various targeting ligands and their delivery systems will be described in details.
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Affiliation(s)
- Wanyi Tai
- Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, 2464 Charlotte Street, Kansas City, MO 64108
| | - Rubi Mahato
- Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, 2464 Charlotte Street, Kansas City, MO 64108
| | - Kun Cheng
- Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, 2464 Charlotte Street, Kansas City, MO 64108
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Aitken S, Thomas J, Langdon S, Harrison D, Faratian D. Quantitative analysis of changes in ER, PR and HER2 expression in primary breast cancer and paired nodal metastases. Ann Oncol 2010; 21:1254-1261. [DOI: 10.1093/annonc/mdp427] [Citation(s) in RCA: 134] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
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Abstract
HER2-positive breast cancer accounts for 20 to 25% of breast cancers. The surexpression of this tyrosine-kinase receptor is often associated with a poor prognosis. However, the management and the outcome of these patients have changed these last ten years with trastuzumab. Despite the encouraging results obtained with this humanized monoclonal antibody directed against the HER2-receptor, used alone or in association with chemotherapy in metastatic patients, progression under trastuzumab are usually observed and resistances to this treatment are described. Thus, many other monoclonal antibodies and tyrosine-kinase inhibitors emerged. These therapeutics, used alone or in association with chemotherapy or trastuzumab have variable properties: anti-HER2 and anti-EGFR such as lapatinib, pertuzumab and neratinib; anti-EGFR such as erlotinib and gefitinib; antiangiogenesis (bevacizumab, pazopanib); anti-mTOR pathway (temsirolimus, everolimus) or inhibitor of HSP90 (tanespimycine). In this paper, we present an overview on validated targeted therapies and those which are currently under investigation and seem promising in first line or after progression under trastuzumab. Data regarding cardiotoxicity and the use of trastuzumab under particular clinical circumstances (brain metastases, pregnancy) are also reviewed.
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41
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Concordance between HER-2 and steroid hormone receptor expression between primary breast cancer, sentinel node metastases, and isolated tumor cells. Pathol Res Pract 2010; 206:253-8. [DOI: 10.1016/j.prp.2009.12.006] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2009] [Revised: 12/07/2009] [Accepted: 12/15/2009] [Indexed: 11/24/2022]
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Targeting trastuzumab-resistant breast cancer cells with a lentivirus engineered to bind antibodies that recognize HER-2. Breast Cancer Res Treat 2010; 125:89-97. [DOI: 10.1007/s10549-010-0828-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2009] [Accepted: 02/26/2010] [Indexed: 10/19/2022]
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Aoyama K, Kamio T, Nishikawa T, Kameoka S. A comparison of HER2/neu gene amplification and its protein overexpression between primary breast cancer and metastatic lymph nodes. Jpn J Clin Oncol 2010; 40:613-9. [PMID: 20202990 DOI: 10.1093/jjco/hyq019] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
OBJECTIVE Breast cancer is a heterogeneous disease. The aim of this prospective study, in which fluorescence in situ hybridization was used to determine human epidermal growth factor receptor 2 status in primary breast cancers and in the lymph node metastases, was to verify the stability of human epidermal growth factor receptor 2 status in the following steps of neoplastic progression of breast cancer, which is fundamental for an appropriate therapeutic approach. METHODS From patients with primary breast cancer, for whom, after January 2003, surgery was performed and involved metastatic lymph nodes were found, we randomly selected four groups of 15 patients, whose human epidermal growth factor receptor 2 score by immunohistochemistry was either 0, 1+, 2+ or 3+, respectively, totaling to 60. For each of those patients, their primary tumors and all of the metastatic lymph nodes were examined. Primary tumors and metastatic lymph nodes in each patient were examined by fluorescence in situ hybridization. RESULTS Of 18 patients with fluorescence in situ hybridization-positive primary tumors, 15 (83.3%) were fluorescence in situ hybridization-positive and 2 (11.1%) were fluorescence in situ hybridization-negative in all of their metastatic lymph nodes, and 1 (5.5%) patient had mixed (fluorescence in situ hybridization-positive or -negative) metastatic lymph nodes. Of 42 patients with fluorescence in situ hybridization-negative primary tumors, 40 (95%) were fluorescence in situ hybridization-negative and 2 (5%) fluorescence in situ hybridization-positive in all of their metastatic lymph nodes. CONCLUSIONS This study revealed that fluorescence in situ hybridization resulted in a high concordance of 83.3% between the human epidermal growth factor receptor 2 manifestation (fluorescence in situ hybridization-positive status) in primary tumors and that in metastatic lymph nodes, demonstrating that it is appropriate to determine whether and how to apply treatment by trastuzumab based on the results of evaluation of human epidermal growth factor receptor 2 expression.
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Affiliation(s)
- Kei Aoyama
- Department of Surgery II, Tokyo Women's Medical University, Tokyo, Japan.
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Idirisinghe PK, Thike AA, Cheok PY, Tse GMK, Lui PCW, Fook-Chong S, Wong NS, Tan PH. Hormone receptor and c-ERBB2 status in distant metastatic and locally recurrent breast cancer. Pathologic correlations and clinical significance. Am J Clin Pathol 2010; 133:416-29. [PMID: 20154280 DOI: 10.1309/ajcpj57flljrxkpv] [Citation(s) in RCA: 78] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Estrogen receptor (ER), progesterone receptor (PR), and c-ERBB2 (HER2/neu) are therapeutically and prognostically important markers in the management of breast carcinoma. They are not always analyzed in distant metastatic and locally recurrent breast cancers. We compared immunohistochemical expression in a series of primary breast carcinomas with their distant metastases (n = 72) and local recurrences (n = 45) and analyzed the impact of any changes on survival. Discordance rates between primary and metastatic and between primary and locally recurrent lesions, respectively, were 18% (13/72) and 13% (6/45) for ER, 42% (30/72) and 33% (15/45) for PR, and 7% (5/72) and 2% (1/45) for c-ERBB2. There was statistically significant discordance between primary and metastatic PR status (P = .017; kappa = 0.201). Among locally recurrent tumors, 15 (33%) of 45 revealed discordance for PR (P = .006; kappa = 0.366). We observed a trend for shorter survival among women with ER- metastatic and locally recurrent tumors regardless of the primary tumor ER status. Our findings suggest a benefit for routine evaluation of ER, PR, and c-ERBB2 status in distant metastatic and locally recurrent breast cancer for therapeutic and prognostic purposes.
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45
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46
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Liedtke C, Broglio K, Moulder S, Hsu L, Kau SW, Symmans WF, Albarracin C, Meric-Bernstam F, Woodward W, Theriault RL, Kiesel L, Hortobagyi GN, Pusztai L, Gonzalez-Angulo AM. Prognostic impact of discordance between triple-receptor measurements in primary and recurrent breast cancer. Ann Oncol 2009; 20:1953-8. [PMID: 19596702 DOI: 10.1093/annonc/mdp263] [Citation(s) in RCA: 226] [Impact Index Per Article: 14.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND We evaluated discordance in expression measurements for estrogen receptor (ER), progesterone receptor (PR), and HER2 between primary and recurrent tumors in patients with recurrent breast cancer and its effect on prognosis. METHODS A total of 789 patients with recurrent breast cancer were studied. ER, PR, and HER2 status were determined by immunohistochemistry (IHC) and/or FISH. Repeat markers for ER, PR, and HER2 were available in 28.9%, 27.6%, and 70.0%, respectively. Primary and recurrent tumors were classified as triple receptor-negative breast cancer (TNBC) or receptor-positive breast cancer (RPBC, i.e. expressing at least one receptor). Discordance was correlated with clinical/pathological parameters. RESULTS Discordance for ER, PR, and HER2 was 18.4%, 40.3%, and 13.6%, respectively. Patients with concordant RPBC had significantly better post-recurrence survival (PRS) than discordant cases; patients with discordant receptor status had similarly unfavorable survival as patients with concordant TNBC. IHC scores for ER and PR showed weak concordance between primary and recurrent tumors. Concordance of HER2-FISH scores was higher. CONCLUSIONS Concordance of quantitative hormone receptor measurements between primary and recurrent tumors is modest consistent with suboptimal reproducibility of measurement methods, particularly for IHC. Discordant cases have poor survival probably due to inappropriate use of targeted therapies. However, biological change in clinical phenotype cannot be completely excluded.
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Affiliation(s)
- C Liedtke
- Department of Breast Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77039, USA
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Kyoda S, Kinoshita S, Takeyama H, Uchida K, Morikawa T. HER-2 protein overexpression in metastatic breast carcinoma found at autopsy. Jpn J Clin Oncol 2008; 38:743-7. [PMID: 18836203 DOI: 10.1093/jjco/hyn103] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
OBJECTIVE The overexpression of HER-2 protein has generally been considered to be consistent in primary and metastatic tumor tissues. We evaluated HER-2 protein overexpression levels in 31 autopsied cases. METHODS Hematoxylin-eosin staining and immunohistological staining Hercep Test II were performed on the primary tumors and the lung, liver, brain and bone metastatic tumors. RESULTS Nine (29%) of the 31 primary tumors were HER-2 score 3+ and HER-2 score 3+ cases were significantly more frequent in carcinomas of nuclear Grade 3 than in those of Grade 1 or 2. In these 31 patients, the HER-2 status in the primary tumors was consistent with the metastatic foci of the lung, liver, brain and bone in 96% (25 of 26), 91% (21 of 23), 100% (12 of 12) and 85% (11 of 13), respectively. With regard to the nine patients with HER-2 score 3+ primary tumors, the HER-2 status in the primary tumors was consistent with the metastatic foci of the lung, liver, brain and bone in 87% (seven of eight), 78% (seven of nine), 100% (only one) and 33% (one of three), respectively. In 11 (92%) of the 12 patients with brain metastasis, the HER-2 was not overexpressed. CONCLUSIONS Even in the far-advanced stages of autopsy, HER-2 status of the primary tumors appeared to be maintained especially in the foci of the lung, liver and brain metastases. As there was a high degree of agreement in HER-2 status between the primary tumors and the metastatic foci to the lung, liver and brain, it is considered to be reasonable to treat patients with such metastatic foci based on the HER-2 status of the primary tumors.
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Affiliation(s)
- Shigeya Kyoda
- Department of Surgery, Jikei University Daisan Hospital, Komae, Tokyo, Japan.
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Jeong JH, An JY, Kwon YT, Li LY, Lee YJ. Quercetin-induced ubiquitination and down-regulation of Her-2/neu. J Cell Biochem 2008; 105:585-95. [PMID: 18655187 PMCID: PMC2575035 DOI: 10.1002/jcb.21859] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Her-2/neu (ErbB2) is a transmembrane tyrosine kinase and acts as a co-receptor for the other EGFR family members. It is well known that high expression of Her-2/neu is associated with a poor prognosis in breast cancer. Quercetin, a flavonoid present in many vegetables and fruits, has been studied extensively as a chemoprevention agent in several cancer models. In this study, we observed that quercetin decreased the level of Her-2/neu protein in time- and dose-dependent manners and also inhibited the downstream survival PI3K-Akt signaling pathway in Her-2/neu-overexpressing breast cancer SK-Br3 cells. We also observed that quercetin induced polyubiquitination of Her-2/neu. When the proteasome pathway was blocked by MG-132 during quercetin treatment, accumulation of the NP-40 insoluble form of Her-2/neu occurred. Interestingly, data from immunocomplex studies revealed that quercetin promoted interaction between Her-2/neu and Hsp90 which is a molecular chaperone involved in stabilization of Her-2/neu. In this condition, inhibition of Hsp90 activity by a specific inhibitor, geldanamycin (GA), or intracellular ATP depletion caused dissociation of Hsp90 from Her-2/neu and promoted ubiquitination and down-regulation of Her-2/neu protein. In addition, the carboxyl terminus of Hsc70-interacting protein (CHIP), a chaperone-dependent E3 ubiquitin ligase, played a crucial role in the quercetin-induced ubiquitination of Her-2/neu. Inhibition of tyrosine kinase activity of Her-2/neu by quercetin could indicate an lateration in the Her-2/neu structure which promotes CHIP recruitments and down-regulation of Her-2/neu. We believe that by using quercetin, new therapeutic strategies can be developed to treat Her-2/neu overexpressing cancers.
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Affiliation(s)
- Jae-Hoon Jeong
- Department of Surgery, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15213
| | - Jee Young An
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania 15261
| | - Yong Tae Kwon
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania 15261
| | - Lu-Yuan Li
- Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15213
| | - Yong J. Lee
- Department of Surgery, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15213
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Kirpotin DB, Park JW, Hong K, Shao Y, Shalaby R, Colbern G, Benz CC, Papahadjopoulos D. Targeting of Liposomes to Solid Tumors: The Case of Sterically Stabilized Anti-Her2 Immunoliposomes. J Liposome Res 2008. [DOI: 10.3109/08982109709035509] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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Papahadjopoulos D, Kirpotin DB, Park JW, Hong K, Shao Y, Shalaby R, Colbern G, Benz CC. Targeting of Drugs to Solid Tumors Using Anti-Her2 Immunoliposomes. J Liposome Res 2008. [DOI: 10.3109/08982109809039930] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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