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Chiang ZC, Xu S, Zhao X, Liu M, Lin J, Chen Q. Generation and characterization of 7DC-DM1: a non-cleavable CD47-targeting antibody-drug conjugates with antitumor effects. Int J Biol Macromol 2025; 310:142844. [PMID: 40187444 DOI: 10.1016/j.ijbiomac.2025.142844] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2024] [Revised: 03/30/2025] [Accepted: 04/02/2025] [Indexed: 04/07/2025]
Abstract
Colorectal cancer is the second leading cause of cancer-related deaths following lung cancer in recent years. Therefore, lung or colorectal cancer therapy is very important for reducing mortality. In this study, we developed and characterized CD47-specific antibody-drug conjugates, namely 7DC-DM1 ADCs, to evaluate their therapeutic effects on lung and colorectal cancer. Both 7DC2-DM1 and 7DC4-DM1 demonstrated good binding affinities of 0.56 nM and 0.49 nM, respectively, and exhibited significant cytotoxicity, though they displayed different penetration effects. These findings suggest that the binding complexes of 7DC2-DM1 and 7DC4-DM1 with CD47 receptors adopt different conformations, leading to variations in their cellular internalized efficiencies. Molecular docking simulations revealed that 7DC2 and 7DC4 bind to CD47 molecules in distinct orientations and epitopes, differing between conserved and non-conserved regions. Furthermore, treatments with 7DC2-DM1 and 7DC4-DM1 displayed notable differences in antitumor effects in murine syngeneic tumor models derived from the MC38 cell line in C57BL/6 mice. In the tumor model treated with 7DC4-DM1, immunofluorescence staining analysis revealed a large area of necrosis in the tumor stroma, accompanied by a significant infiltration of CD11b-expressing immune cells. In summary, these results indicate that 7DC4-DM1 holds promise as a therapeutic agent for colorectal cancer treatment.
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Affiliation(s)
- Zu-Chian Chiang
- Fujian Key Laboratory of Innate Immune Biology, Biomedical Research Center of South China, College of Life Science, Fujian Normal University, Fuzhou, Fujian, China; College of Photonic and Electronic Engineering, Fujian Normal University, Fuzhou, China.
| | - Shan Xu
- Fujian Key Laboratory of Innate Immune Biology, Biomedical Research Center of South China, College of Life Science, Fujian Normal University, Fuzhou, Fujian, China
| | - Xiangqian Zhao
- Fujian Key Laboratory of Innate Immune Biology, Biomedical Research Center of South China, College of Life Science, Fujian Normal University, Fuzhou, Fujian, China
| | - Min Liu
- Fujian Key Laboratory of Innate Immune Biology, Biomedical Research Center of South China, College of Life Science, Fujian Normal University, Fuzhou, Fujian, China.
| | - Jizhen Lin
- The Cancer Center, Union Hospital, Fujian Medical University, Fuzhou, Fujian, China.
| | - Qi Chen
- Fujian Key Laboratory of Innate Immune Biology, Biomedical Research Center of South China, College of Life Science, Fujian Normal University, Fuzhou, Fujian, China.
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Dowsing B, Dehbi HM, Chung R, Pedra J, Worn O, Artico J, Schmid P, Roylance R, Kellman P, Moon JC, Crake T, Westwood M, Ghosh A, Andres MS, Nazir MS, Lyon AR, Chen D, Walker M, Manisty CH. HER-SAFE study design: an open-label, randomised controlled trial to investigate the safety of withdrawal of pharmacological treatment for recovered HER2-targeted therapy-related cardiac dysfunction. BMJ Open 2025; 15:e091917. [PMID: 39909533 PMCID: PMC11800297 DOI: 10.1136/bmjopen-2024-091917] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2024] [Accepted: 01/20/2025] [Indexed: 02/07/2025] Open
Abstract
INTRODUCTION A quarter of breast cancers show human epidermal growth factor-2 (HER2) overexpression, where targeted therapy dramatically improves survival. However, cancer therapy-related cardiac dysfunction (CTRCD) occurs in up to 15% of patients. With the interruption of HER2 therapy, if necessary, and the initiation of heart failure therapy (HFT), HER2 CTRCD recovers in over 80% of cases. The need to continue HFT in 'recovered' HER2 CTRCD following completion of HER2 therapy is unclear and there are potential significant impacts on patient's quality of life (QoL). The Randomised Controlled Trial for the Safety of Withdrawal of Pharmacological Treatment for Recovered HER2 Targeted Therapy Related Cardiac Dysfunction (HER-SAFE) aims to evaluate whether HFT can be safely withdrawn in non-high cardiovascular (CV) risk patients with 'recovered' HER2 CTRCD. METHODS AND ANALYSIS This is a multicentre, open-label randomised controlled trial investigating whether withdrawal of HFT is non-inferior to continuation in non-high CV risk, breast cancer survivors with recovered HER2 CTRCD after cancer treatment completion. The primary endpoint is the incidence of guideline-defined cardiac dysfunction or clinical heart failure. Secondary endpoints include changes in cardiac blood biomarkers, cardiovascular magnetic resonance (CMR)-derived strain and tissue mapping and heart failure symptom questionnaires. The study will recruit 90 participants who will undergo serial clinical assessment over 12 months with advanced cardiovascular imaging (CMR scans with automated analysis at baseline, 6 and 12 months), cardiac biomarker measurement (six time points over 12 months), plus complete heart failure QoL and medication disutility questionnaires. This is the first multicentre study to address this significant clinical issue. ETHICS AND DISSEMINATION This study was approved by the research ethics committee (London-London Bridge, 23/LO/0152). The results will be disseminated in peer-reviewed scientific journals. TRIAL REGISTRATION NUMBER NCT05880160.
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Affiliation(s)
- Benjamin Dowsing
- Institute of Cardiovascular Science, University College London, London, UK
- Saint Bartholomew's Hospital Barts Heart Centre, London, UK
| | | | - Robin Chung
- Saint Bartholomew's Hospital Barts Heart Centre, London, UK
- Whittington Health NHS Trust, London, UK
| | - Joanna Pedra
- Saint Bartholomew's Hospital Barts Heart Centre, London, UK
| | - Orla Worn
- Saint Bartholomew's Hospital Barts Heart Centre, London, UK
| | - Jessica Artico
- Institute of Cardiovascular Science, University College London, London, UK
- Imperial College Healthcare NHS Trust Cardiology Service, London, UK
| | - Peter Schmid
- Queen Mary University of London, London, UK
- Barts Health NHS Trust, London, UK
| | | | - Peter Kellman
- National Heart Lung and Blood Institute, Bethesda, Maryland, USA
| | - James C Moon
- Institute of Cardiovascular Science, University College London, London, UK
- Saint Bartholomew's Hospital Barts Heart Centre, London, UK
| | - Tom Crake
- Saint Bartholomew's Hospital Barts Heart Centre, London, UK
| | - Mark Westwood
- Saint Bartholomew's Hospital Barts Heart Centre, London, UK
| | - Arjun Ghosh
- Institute of Cardiovascular Science, University College London, London, UK
- Saint Bartholomew's Hospital Barts Heart Centre, London, UK
| | - Maria Sol Andres
- Cardio-Oncology Centre of Excellence, Royal Brompton Hospital, London, UK
| | - Muhummad Sohaib Nazir
- King's College London School of Biomedical Engineering & Imaging Sciences, London, UK
- Cardio-Oncology Centre of Excellence, Royal Brompton and Harefield Hospitals, London, UK
| | - Alexander R Lyon
- Cardio-Oncology Centre of Excellence, Royal Brompton Hospital, London, UK
| | - Daniel Chen
- Institute of Cardiovascular Science, University College London, London, UK
- Saint Bartholomew's Hospital Barts Heart Centre, London, UK
| | - Malcolm Walker
- Institute of Cardiovascular Science, University College London, London, UK
| | - Charlotte H Manisty
- Institute of Cardiovascular Science, University College London, London, UK
- Saint Bartholomew's Hospital Barts Heart Centre, London, UK
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Ning W, Yan S, Song Y, Xu H, Zhang J, Wang X. Virus-like particle: a nano-platform that delivers cancer antigens to elicit an anti-tumor immune response. Front Immunol 2025; 15:1504124. [PMID: 39840069 PMCID: PMC11747419 DOI: 10.3389/fimmu.2024.1504124] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2024] [Accepted: 12/16/2024] [Indexed: 01/23/2025] Open
Abstract
Virus-like particles (VLPs), as a unique form of nanocarrier, predominantly encompass hollow protein shells that exhibit analogous morphology and structure to naturally occurring viruses, yet devoid of genetic material. VLPs are considered safe, easily modifiable, and stable, making them suitable for preparation in various expression systems. They serve as precise biological instruments with broad applications in the field of medical biology. Leveraging their unique structural attributes and facile modification capabilities, VLPs can serve as an effective platform for the delivery of tumor antigens, thereby stimulating the immune system and facilitating the eradication of tumor cells.
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Affiliation(s)
- Weisen Ning
- School of Medicine, Wuhan University of Science and Technology, Wuhan, Hubei, China
| | - Sheng Yan
- School of Medicine, Wuhan University of Science and Technology, Wuhan, Hubei, China
| | - Yongyao Song
- School of Medicine, Wuhan University of Science and Technology, Wuhan, Hubei, China
| | - Hanning Xu
- School of Medicine, Wuhan University of Science and Technology, Wuhan, Hubei, China
| | - Jinling Zhang
- Department of Oncology, Wuhan Fourth Hospital, Wuhan Orthopedic Hospital, Wuhan, Hubei, China
| | - Xiaomei Wang
- School of Medicine, Wuhan University of Science and Technology, Wuhan, Hubei, China
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Luo X, Wang N, Xing Y, Gao X, Yu Y, Liu T, Jiang S, Dong M. Pharmacokinetics of trastuzumab and its efficacy and safety in HER2-positive cancer patients. Cancer Chemother Pharmacol 2024; 94:721-732. [PMID: 39177768 DOI: 10.1007/s00280-024-04707-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2024] [Accepted: 08/08/2024] [Indexed: 08/24/2024]
Abstract
Trastuzumab is a potent targeted therapy drug for HER2-positive cancer patients. A comprehensive understanding of trastuzumab's mechanism of action, pharmacokinetic (PK) parameters, and steady-state exposure in different treatment regimens and administration routes is essential for a thorough evaluation of the drug's safety and effectiveness. Due to the distinctive pharmacokinetics, indications, and administration methods of trastuzumab, this understanding becomes crucial. Drug exposure can be assessed by measuring trastuzumab's peak concentration, trough concentration, or area under the curve through assays like enzyme-linked immunosorbent assay (ELISA) or liquid chromatography-tandem mass spectrometry (LC-MS/MS). The dose-response (D-R) and exposure-response (E-R) relationships establish the correlation between drug dosage/exposure and the therapeutic effect and safety. Additionally, various covariates such as body weight, aspartate transaminase, and albumin levels can influence drug exposure. This review provides a comprehensive overview of trastuzumab's mechanism of action, data on steady-state concentration and PK parameters under multiple administration routes and indications, discussions on factors influencing PK parameters, and evaluations of the effectiveness and safety of E-R and D-R in diverse HER2-positive cancer patients.
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Affiliation(s)
- Xinyu Luo
- Department of Pharmacy, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, China
| | - Nan Wang
- Department of Pharmacy, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, China
| | - Yue Xing
- Department of Pharmacy, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, China
| | - Xinyue Gao
- Department of Pharmacy, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, China
| | - Yang Yu
- Department of Pharmacy, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, China
| | - Tong Liu
- Department of Pharmacy, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, China
| | - Shuai Jiang
- Department of Pharmacy, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, China.
| | - Mei Dong
- Department of Pharmacy, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, China.
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Yang M, Huang C, Chang D, Hu F, Huang S, Huang P, Chen I, Chen TW, Lin C, Lu Y. Concurrent epirubicin and trastuzumab use increases complete pathological response rate without additional cardiotoxicity in patients with human epidermal growth factor receptor 2-positive early breast cancer: A meta-regression analysis. Cancer Med 2024; 13:e70005. [PMID: 39046067 PMCID: PMC11267450 DOI: 10.1002/cam4.70005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2024] [Revised: 06/27/2024] [Accepted: 06/30/2024] [Indexed: 07/25/2024] Open
Abstract
BACKGROUND Due to cardiotoxicity concerns, the concurrent use of epirubicin and trastuzumab has not been fully studied. This study aimed to examine the cardiotoxicity and pathological complete response (pCR) rate associated with the concurrent regimens in patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer (EBC). METHODS We conducted a systematic search for relevant literature in the NCBI/PubMed, the Cochrane database, and international conference abstracts for phase II or III randomized controlled trials between January 1, 2000, and February 28, 2021, focusing on the concurrent regimens in patients with HER2-positive EBC. To compare the risk of cardiotoxicity and the odds of the pCR rate, we performed linear meta-regression analyses to investigate the effects of multiple covariates. RESULTS We analyzed 7 neoadjuvant trials involving the concurrent use of epirubicin and trastuzumab with 1797 patients. The median cumulative dose of epirubicin used was 300 mg/m2, with a total of 96 reported adverse cardiac events. The concurrent regimens did not result in a significant increase in cardiotoxicity compared to nonconcurrent regimens (risk ratio [RR] = 1.18, 95% confidence interval [CI] = 0.68-2.05). Compared with nonconcurrent or non-anthracycline-containing regimens, concurrent regimens were associated with a significant increase in the pCR rate (odds ratio = 1.48, 95% CI = 1.04-2.12). The linear fixed-effects meta-regression analysis indicated that in trials including more patients with hormone receptor-positive EBC, the RR of cardiotoxicity significantly increased with concurrent regimens, and the pCR rate became less significant. CONCLUSIONS The combination of trastuzumab and a low dose of epirubicin positively impacted the pCR rate without a significant increase in cardiotoxicity. We recommend exploring concurrent regimens for HR-negative, HER2-positive tumors to enhance pCR rates, with caution advised for HR-positive tumors due to potential cardiotoxicity.
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Affiliation(s)
- Ming‐Han Yang
- Department of OncologyNational Taiwan University HospitalTaipeiTaiwan
| | - Chiun‐Sheng Huang
- Department of SurgeryNational Taiwan UniversityTaipeiTaiwan
- College of MedicineNational Taiwan UniversityTaipeiTaiwan
| | - Dwan‐Ying Chang
- Department of OncologyNational Taiwan University HospitalTaipeiTaiwan
| | - Fu‐Chang Hu
- Graduate Institute of Clinical Medicine and School of Nursing, College of Medicine, National Taiwan UniversityTaipeiTaiwan
- Statistical Consulting Clinic, International‐Harvard (I‐H) Statistical Consulting CompanyTaipeiTaiwan
| | - Shu‐Min Huang
- Department of OncologyNational Taiwan University HospitalTaipeiTaiwan
| | - Po‐Hsiang Huang
- Department of OncologyNational Taiwan University HospitalTaipeiTaiwan
| | - I‐Chun Chen
- Department of OncologyNational Taiwan University HospitalTaipeiTaiwan
- Department of OncologyNational Taiwan University Cancer CenterTaipeiTaiwan
- Graduate Institute of Oncology, College of MedicineNational Taiwan UniversityTaipeiTaiwan
| | - Tom Wei‐Wu Chen
- Department of OncologyNational Taiwan University HospitalTaipeiTaiwan
- Graduate Institute of Oncology, College of MedicineNational Taiwan UniversityTaipeiTaiwan
| | - Ching‐Hung Lin
- Department of OncologyNational Taiwan University HospitalTaipeiTaiwan
- College of MedicineNational Taiwan UniversityTaipeiTaiwan
- Department of OncologyNational Taiwan University Cancer CenterTaipeiTaiwan
| | - Yen‐Shen Lu
- Department of OncologyNational Taiwan University HospitalTaipeiTaiwan
- College of MedicineNational Taiwan UniversityTaipeiTaiwan
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Liu L, Sun B, Cai J, Wang J, Liu W, Hu H, Chen S, Wu J. Simultaneous quantification of co-administered trastuzumab and pertuzumab in serum based on nano-surface and molecular-orientation limited (nSMOL) proteolysis. RSC Adv 2024; 14:19550-19559. [PMID: 38895524 PMCID: PMC11184472 DOI: 10.1039/d4ra03060e] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2024] [Accepted: 06/04/2024] [Indexed: 06/21/2024] Open
Abstract
Monoclonal antibodies (mAbs) are pivotal therapeutic agents for various diseases, and effective treatment hinges on attaining a specific threshold concentration of mAbs in patients. With the rising adoption of combination therapy involving multiple mAbs, there arises a clinical demand for multiplexing assays capable of measuring the concentrations of these mAbs. However, minimizing the complexity of serum samples while achieving rapid and accurate quantification is difficult. In this work, we introduced a novel method termed nano-surface and molecular orientation limited (nSMOL) proteolysis for the fragment of antigen binding (Fab) region-selective proteolysis of co-administered trastuzumab and pertuzumab based on the pore size difference between the protease nanoparticles (∼200 nm) and the resin-captured antibody (∼100 nm). The hydrolyzed peptide fragments were then quantified using liquid chromatography-tandem mass spectrometry (LC-MS/MS). In this process, the digestion time is shortened, and the produced digestive peptides are greatly reduced, thereby minimizing sample complexity and increasing detection accuracy. Assay linearity was confirmed within the ranges of 0.200-200 μg mL-1 for trastuzumab and 0.300-200 μg mL-1 for pertuzumab. The intra- and inter-day precision was within 9.52% and 8.32%, except for 12.5% and 10.8% for the lower limit of quantitation, and the accuracy (bias%) was within 6.3%. Additionally, other validation parameters were evaluated, and all the results met the acceptance criteria of the guiding principles. Our method demonstrated accuracy and selectivity for the simultaneous determination of trastuzumab and pertuzumab in clinical samples, addressing the limitation of ligand binding assays incapable of simultaneously quantifying mAbs targeting the same receptor. This proposed assay provides a promising technical approach for realizing clinical individualized precise treatment, especially for co-administered mAbs.
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Affiliation(s)
- Liang Liu
- Department of Pharmacy, Zhongnan Hospital of Wuhan University, Wuhan University 169 Donghu Road, Wuchang District Wuhan 430071 China
| | - Bo Sun
- Department of Pharmacy, The First People's Hospital of Lianyungang Lianyungang 222000 China
| | - Junlong Cai
- Department of Clinical Trial Center, Zhongnan Hospital of Wuhan University Wuhan 430071 China
| | - Jiajun Wang
- Department of Pharmacy, Zhongnan Hospital of Wuhan University, Wuhan University 169 Donghu Road, Wuchang District Wuhan 430071 China
| | - Wei Liu
- Key Laboratory of Artificial Micro- and Nano-Structures of Ministry of Education, School of Physics and Technology, Wuhan University Wuhan 430072 China
| | - Hankun Hu
- Department of Pharmacy, Zhongnan Hospital of Wuhan University, Wuhan University 169 Donghu Road, Wuchang District Wuhan 430071 China
| | - Siyi Chen
- Department of Pharmacy, Zhongnan Hospital of Wuhan University, Wuhan University 169 Donghu Road, Wuchang District Wuhan 430071 China
| | - Jianhua Wu
- Department of Pharmacy, Zhongnan Hospital of Wuhan University, Wuhan University 169 Donghu Road, Wuchang District Wuhan 430071 China
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Ferreira Almeida C, Correia-da-Silva G, Teixeira N, Amaral C. Influence of tumor microenvironment on the different breast cancer subtypes and applied therapies. Biochem Pharmacol 2024; 223:116178. [PMID: 38561089 DOI: 10.1016/j.bcp.2024.116178] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2023] [Revised: 03/15/2024] [Accepted: 03/28/2024] [Indexed: 04/04/2024]
Abstract
Despite the significant improvements made in breast cancer therapy during the last decades, this disease still has increasing incidence and mortality rates. Different targets involved in general processes, like cell proliferation and survival, have become alternative therapeutic options for this disease, with some of them already used in clinic, like the CDK4/6 inhibitors for luminal A tumors treatment. Nevertheless, there is a demand for novel therapeutic strategies focused not only on tumor cells, but also on their microenvironment. Tumor microenvironment (TME) is a very complex and dynamic system that, more than surrounding and supporting tumor cells, actively participates in tumor development and progression. During the last decades, it has become clear that the cellular and acellular components of TME differ between the various breast cancer subtypes and shape the differences regarding their severity and prognosis. The pivotal role of the TME in controlling tumor growth and influencing responses to therapy represents a potential source for novel targets and therapeutic strategies. In this review, we present a description of the multiple therapeutic options used for different breast cancer subtypes, as well as the influence that the TME may exert on the development of the disease and on the response to the distinct therapies, which in some cases may explain their failure by the occurrence of relapses and resistance. Furthermore, the ongoing studies focused on the use of TME components for developing potential cancer treatments are described.
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Affiliation(s)
- Cristina Ferreira Almeida
- UCIBIO, Laboratory of Biochemistry, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, Rua Jorge Viterbo Ferreira, n° 228, 4050-313 Porto, Portugal; Associate Laboratory i4HB, Institute for Health and Bioeconomy, Faculty of Pharmacy, University of Porto, Rua Jorge Viterbo Ferreira, n° 228, 4050-313 Porto, Portugal
| | - Georgina Correia-da-Silva
- UCIBIO, Laboratory of Biochemistry, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, Rua Jorge Viterbo Ferreira, n° 228, 4050-313 Porto, Portugal; Associate Laboratory i4HB, Institute for Health and Bioeconomy, Faculty of Pharmacy, University of Porto, Rua Jorge Viterbo Ferreira, n° 228, 4050-313 Porto, Portugal.
| | - Natércia Teixeira
- UCIBIO, Laboratory of Biochemistry, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, Rua Jorge Viterbo Ferreira, n° 228, 4050-313 Porto, Portugal; Associate Laboratory i4HB, Institute for Health and Bioeconomy, Faculty of Pharmacy, University of Porto, Rua Jorge Viterbo Ferreira, n° 228, 4050-313 Porto, Portugal
| | - Cristina Amaral
- UCIBIO, Laboratory of Biochemistry, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, Rua Jorge Viterbo Ferreira, n° 228, 4050-313 Porto, Portugal; Associate Laboratory i4HB, Institute for Health and Bioeconomy, Faculty of Pharmacy, University of Porto, Rua Jorge Viterbo Ferreira, n° 228, 4050-313 Porto, Portugal.
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Barroso A, Estevinho F, Hespanhol V, Teixeira E, Ramalho-Carvalho J, Araújo A. Management of infusion-related reactions in cancer therapy: strategies and challenges. ESMO Open 2024; 9:102922. [PMID: 38452439 PMCID: PMC10937241 DOI: 10.1016/j.esmoop.2024.102922] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2023] [Revised: 02/06/2024] [Accepted: 02/06/2024] [Indexed: 03/09/2024] Open
Abstract
Several anticancer therapies have the potential to cause infusion-related reactions (IRRs) in the form of adverse events that typically occur within minutes to hours after drug infusion. IRRs can range in severity from mild to severe anaphylaxis-like reactions. Careful monitoring at infusion initiation, prompt recognition, and appropriate clinical assessment of the IRR and its severity, followed by immediate management, are required to ensure patient safety and optimal outcomes. Lack of standardization in the prevention, management, and reporting of IRRs across cancer-treating institutions represents not only a quality and safety gap but also a disparity in cancer care. The present article, supported by recently published data, was developed to standardize these procedures across institutions and provide a useful tool for health care providers in clinical practice to recognize early signs and symptoms of an IRR and promptly and appropriately manage the event.
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Affiliation(s)
- A Barroso
- Multidisciplinary Unit of Thoracic Tumours, Centro Hospitalar de Vila Nova de Gaia e Espinho, Vila Nova de Gaia, Portugal
| | - F Estevinho
- Hospital Pedro Hispano, Unidade Local de Saúde de Matosinhos, Matosinhos, Portugal
| | - V Hespanhol
- Departamento de Medicina Faculty of Medicine, University of Porto, Porto, Portugal; Department of Pulmonology, Centro Hospitalar de São João, Porto, Portugal
| | - E Teixeira
- Lung Cancer Unit, CUF Descobertas, Lisboa, Portugal
| | | | - A Araújo
- Medical Oncology Department, Centro Hospitalar Universitário do Porto, Porto, Portugal; Oncology Research Unit, UMIB-Unit for Multidisciplinary Research in Biomedicine, ICBAS-School of Medicine and Biomedical Sciences, Universidade do Porto, Porto, Portugal.
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9
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Pourmir I, Van Halteren HK, Elaidi R, Trapani D, Strasser F, Vreugdenhil G, Clarke M. A conceptual framework for cautious escalation of anticancer treatment: How to optimize overall benefit and obviate the need for de-escalation trials. Cancer Treat Rev 2024; 124:102693. [PMID: 38330752 DOI: 10.1016/j.ctrv.2024.102693] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2023] [Revised: 01/24/2024] [Accepted: 01/29/2024] [Indexed: 02/10/2024]
Abstract
BACKGROUND The developmental workflow of the currently performed phase 1, 2 and 3 cancer trial stages lacks essential information required for the determination of the optimal efficacy threshold of new anticancer regimens. Due to this there is a serious risk of overdosing and/or treating for an unnecessary long time, leading to excess toxicity and a higher financial burden for society. But often post-approval de-escalation trials for dose-optimization and treatment de-intensification are not performed due to failing resources and time. Therefore, the developmental workflow needs to be restructured toward cautious systemic cancer treatment escalation, in order to guarantee optimal efficacy and sustainability. METHODS In this manuscript we discuss opportunities to produce the information needed for cautious escalation, based on models of cancer growth and cancer kill kinetics as well as exploratory biomarkers, for the purpose of designing the optimal phase 3 superiority trial. Subsequently, we compare the sample size needed for a phase 3 superiority trial, followed by a necessary de-escalation trial with the sample size needed for a multi-arm phase 3 trial with intervention arms of differing intensity. All essential items are structured within a Framework for Cautious Escalation (FCE). The discussion uses illustrations from the breast cancer setting, but aims to be applicable for all cancers. RESULTS The FCE is a promising model of clinical development in oncology to prevent overtreatment and associated issues, especially with regard to the number of repetitive treatment cycles. It will hopefully increase the relevance and success rate of clinical trials, to deliver improved patient-centric outcomes.
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Affiliation(s)
- I Pourmir
- Department of Thoracic Oncology, European Hospital Georges Pompidou, Paris, France; INSERM U970, Paris Research Cardiovascular Center, Paris, France
| | - H K Van Halteren
- Department of Medical Oncology, Adrz Hospital, Goes, the Netherlands.
| | - R Elaidi
- Consultant/advisor in Clinical Trials Methodology and Biostatistic, Paris, France
| | - D Trapani
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, Milan, Italy; Department of Oncology and Haematology, University of Milan, Milan, Italy
| | - F Strasser
- Center for Integrative Medicine, Cantonal Hospital Gallen, St. Gallen University of Bern, Switzerland
| | - G Vreugdenhil
- Department of Medical Oncology, Maxima Medical Center, Veldhoven, the Netherlands
| | - M Clarke
- Professor and Director of Northern Ireland Methodology Hub, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, Northern Ireland, United Kingdom
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Sun B, Liu J, Cai P, Wu J, Liu W, Hu H, Liu L. Aptamer-based sample purification for mass spectrometric quantification of trastuzumab in human serum. Talanta 2023; 257:124349. [PMID: 36827940 DOI: 10.1016/j.talanta.2023.124349] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Revised: 02/08/2023] [Accepted: 02/10/2023] [Indexed: 02/19/2023]
Abstract
In this study, we developed a simple liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay to quantify trastuzumab in human serum using aptamers for sample purification. Trastuzumab was extracted from serum samples using the capture probe based on its aptamer CH1S-3, followed by reduction, alkylation, trypsin digestion, and quantification using LC-MS/MS. Additionally, a unique peptide, FTISADTSK, was employed as a surrogate peptide and quantified, and *FTISADTSK (13C915N-labeled phenylalanine) was used as an internal standard to minimize variability in detection among the samples. The detection range for this method was 0.5-250 μg/mL, with a high correlation coefficient (r2 > 0.99). The intra- and inter-day precision (%CV, the coefficient of variation) of the quality control samples was less than 12.7%, and the accuracy (%bias) was below 8.64%. After optimization and verification, this assay was used to determine trastuzumab levels in clinical human serum samples. The results indicated that the trastuzumab concentrations had an approximate 4-fold difference among ten patients (range: 11.80-41.90 μg/mL). This study provides a novel approach for the accurate and quantitative monitoring of the mAb-trastuzumab.
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Affiliation(s)
- Bo Sun
- Department of Pharmacy, The First People's Hospital of Lianyungang, Lianyungang, 222000, China
| | - Jiuyang Liu
- Department of Thyroid and Breast Surgery, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
| | - Pei Cai
- School of Pharmacy, Wuhan University, Wuhan, 430071, China
| | - Jianhua Wu
- Department of Pharmacy, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
| | - Wei Liu
- Key Laboratory of Artificial Micro- and Nano-Structures of Ministry of Education, School of Physics and Technology, Wuhan University, Wuhan, 430072, China.
| | - Hankun Hu
- Department of Pharmacy, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China; Hubei Micro-explore Innovative Pharmaceutical Research Co., Ltd, Wuhan, 430074, China.
| | - Liang Liu
- Department of Pharmacy, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China.
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11
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Waliany S, Caswell-Jin J, Riaz F, Myall N, Zhu H, Witteles RM, Neal JW. Pharmacovigilance Analysis of Heart Failure Associated With Anti-HER2 Monotherapies and Combination Regimens for Cancer. JACC CardioOncol 2023; 5:85-98. [PMID: 36875913 PMCID: PMC9982216 DOI: 10.1016/j.jaccao.2022.09.007] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2022] [Revised: 09/08/2022] [Accepted: 09/09/2022] [Indexed: 01/18/2023] Open
Abstract
Background Trastuzumab improves outcomes in patients with HER2-overexpressing malignancies but is associated with decreases in left ventricular ejection fraction. Heart failure (HF) risks from other anti-HER2 therapies are less clear. Objectives Using World Health Organization pharmacovigilance data, the authors compared HF odds across anti-HER2 regimens. Methods In VigiBase, 41,976 patients had adverse drug reactions (ADRs) with anti-HER2 monoclonal antibodies (trastuzumab, n = 16,900; pertuzumab, n = 1,856), antibody-drug conjugates (trastuzumab emtansine [T-DM1], n = 3,983; trastuzumab deruxtecan, n = 947), and tyrosine kinase inhibitors (afatinib, n = 10,424; lapatinib, n = 5,704; neratinib, n = 1,507; tucatinib, n = 655); additionally, 36,052 patients had ADRs with anti-HER2-based combination regimens. Most patients had breast cancer (monotherapies, n = 17,281; combinations, n = 24,095). Outcomes included comparison of HF odds with each monotherapy relative to trastuzumab, within each therapeutic class, and among combination regimens. Results Of 16,900 patients with trastuzumab-associated ADRs, 2,034 (12.04%) had HF reports (median time to onset 5.67 months; IQR: 2.85-9.32 months) compared with 1% to 2% with antibody-drug conjugates. Trastuzumab had higher odds of HF reporting relative to other anti-HER2 therapies collectively in the overall cohort (reporting OR [ROR]: 17.37; 99% CI: 14.30-21.10) and breast cancer subgroup (ROR: 17.10; 99% CI: 13.12-22.27). Pertuzumab/T-DM1 had 3.4 times higher odds of HF reporting than T-DM1 monotherapy; tucatinib/trastuzumab/capecitabine had similar odds as tucatinib. Among metastatic breast cancer regimens, HF odds were highest with trastuzumab/pertuzumab/docetaxel (ROR: 1.42; 99% CI: 1.17-1.72) and lowest with lapatinib/capecitabine (ROR: 0.09; 99% CI: 0.04-0.23). Conclusions Trastuzumab and pertuzumab/T-DM1 had higher odds of HF reporting than other anti-HER2 therapies. These data provide large-scale, real-world insight into which HER2-targeted regimens would benefit from left ventricular ejection fraction monitoring.
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Key Words
- AC-THP, doxorubicin/cyclophosphamide followed by paclitaxel/trastuzumab/pertuzumab
- ACTH, doxorubicin/cyclophosphamide followed by trastuzumab/paclitaxel
- ADC, antibody-drug conjugate
- ADR, adverse drug reaction
- AI, aromatase inhibitor
- FDA, U.S. Food and Drug Administration
- HER2
- HF, heart failure
- IC, information component
- LVEF, left ventricular ejection fraction
- ROR, reporting odds ratio
- T-DM1, trastuzumab emtansine
- T-DXd, trastuzumab deruxtecan
- antibody-drug conjugates
- heart failure
- trastuzumab
- tyrosine kinase inhibitors
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Affiliation(s)
- Sarah Waliany
- Department of Medicine, Stanford University School of Medicine, Palo Alto, California, USA
| | - Jennifer Caswell-Jin
- Division of Oncology, Stanford University School of Medicine, Palo Alto, California, USA.,Stanford Cancer Institute, Palo Alto, California, USA
| | - Fauzia Riaz
- Division of Oncology, Stanford University School of Medicine, Palo Alto, California, USA.,Stanford Cancer Institute, Palo Alto, California, USA
| | - Nathaniel Myall
- Division of Oncology, Stanford University School of Medicine, Palo Alto, California, USA.,Stanford Cancer Institute, Palo Alto, California, USA
| | - Han Zhu
- Division of Cardiovascular Medicine, Stanford University School of Medicine, Palo Alto, California, USA.,Stanford Cardiovascular Institute, Stanford University School of Medicine, Palo Alto, California, USA
| | - Ronald M Witteles
- Department of Medicine, Stanford University School of Medicine, Palo Alto, California, USA.,Division of Cardiovascular Medicine, Stanford University School of Medicine, Palo Alto, California, USA
| | - Joel W Neal
- Division of Oncology, Stanford University School of Medicine, Palo Alto, California, USA.,Stanford Cancer Institute, Palo Alto, California, USA
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12
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Castellanos G, Valbuena DS, Pérez E, Villegas VE, Rondón-Lagos M. Chromosomal Instability as Enabling Feature and Central Hallmark of Breast Cancer. BREAST CANCER (DOVE MEDICAL PRESS) 2023; 15:189-211. [PMID: 36923397 PMCID: PMC10010144 DOI: 10.2147/bctt.s383759] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Accepted: 10/11/2022] [Indexed: 03/11/2023]
Abstract
Chromosomal instability (CIN) has become a topic of great interest in recent years, not only for its implications in cancer diagnosis and prognosis but also for its role as an enabling feature and central hallmark of cancer. CIN describes cell-to-cell variation in the number or structure of chromosomes in a tumor population. Although extensive research in recent decades has identified some associations between CIN with response to therapy, specific associations with other hallmarks of cancer have not been fully evidenced. Such associations place CIN as an enabling feature of the other hallmarks of cancer and highlight the importance of deepening its knowledge to improve the outcome in cancer. In addition, studies conducted to date have shown paradoxical findings about the implications of CIN for therapeutic response, with some studies showing associations between high CIN and better therapeutic response, and others showing the opposite: associations between high CIN and therapeutic resistance. This evidences the complex relationships between CIN with the prognosis and response to treatment in cancer. Considering the above, this review focuses on recent studies on the role of CIN in cancer, the cellular mechanisms leading to CIN, its relationship with other hallmarks of cancer, and the emerging therapeutic approaches that are being developed to target such instability, with a primary focus on breast cancer. Further understanding of the complexity of CIN and its association with other hallmarks of cancer could provide a better understanding of the cellular and molecular mechanisms involved in prognosis and response to treatment in cancer and potentially lead to new drug targets.
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Affiliation(s)
- Giovanny Castellanos
- Maestría en Ciencias Biológicas, Universidad Pedagógica y Tecnológica de Colombia, Tunja, Colombia.,School of Biological Sciences, Universidad Pedagógica y Tecnológica de Colombia, Tunja, Colombia
| | - Duván Sebastián Valbuena
- School of Biological Sciences, Universidad Pedagógica y Tecnológica de Colombia, Tunja, Colombia
| | - Erika Pérez
- School of Biological Sciences, Universidad Pedagógica y Tecnológica de Colombia, Tunja, Colombia
| | - Victoria E Villegas
- Centro de Investigaciones en Microbiología y Biotecnología-UR (CIMBIUR), Facultad de Ciencias Naturales, Universidad del Rosario, Bogotá, Colombia
| | - Milena Rondón-Lagos
- School of Biological Sciences, Universidad Pedagógica y Tecnológica de Colombia, Tunja, Colombia
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13
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Berwanger JD, Lake MA, Ganguly S, Yang J, Welch CJ, Linnes JC, Bruening M. Microporous affinity membranes and their incorporation into microfluidic devices for monitoring of therapeutic antibodies. Talanta 2023; 252:123842. [DOI: 10.1016/j.talanta.2022.123842] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2022] [Revised: 08/08/2022] [Accepted: 08/11/2022] [Indexed: 10/15/2022]
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14
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Aapro M, Cardoso F, Curigliano G, Eniu A, Gligorov J, Harbeck N, Mueller A, Pagani O, Paluch-Shimon S, Senkus E, Thürlimann B, Zaman K. Current challenges and unmet needs in treating patients with human epidermal growth factor receptor 2-positive advanced breast cancer. Breast 2022; 66:145-156. [PMID: 36279803 PMCID: PMC9597182 DOI: 10.1016/j.breast.2022.07.011] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Revised: 07/14/2022] [Accepted: 07/17/2022] [Indexed: 12/27/2022] Open
Abstract
Human epidermal growth factor receptor 2 oncogene (HER2-positive) overexpression/amplification occurs in less than 20% of breast cancers and has traditionally been associated with poor prognosis. Development of therapies that target HER2 has significantly improved outcomes for patients with HER2-positive advanced breast cancer (ABC). Currently available HER2-targeted agents include the monoclonal antibodies trastuzumab, pertuzumab, and margetuximab, the small-molecule inhibitors lapatinib, tucatinib, neratinib, and pyrotinib, as well as the antibody-drug conjugates trastuzumab emtansine and trastuzumab deruxtecan. Optimal sequencing of these agents in the continuum of the disease is critical to maximize treatment outcomes. The large body of clinical evidence generated over the past 2 decades aids clinicians in treatment decision-making. However, patients with HER2-positive ABC and specific disease characteristics and/or comorbidities, such as leptomeningeal disease, brain metastases, or cardiac dysfunction, are generally excluded from large randomized clinical trials, and elderly or frail patients are often underrepresented. In addition, there is great inequality in the accessibility of approved drugs across countries. This article addresses various challenging clinical situations when treating patients with HER2-positive ABC. The objective is to provide guidance to clinicians on how and when HER2-targeted therapies and additional treatments can be best implemented in routine clinical practice, on the basis of existing clinical evidence and expert opinion where needed.
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Affiliation(s)
- Matti Aapro
- Breast Center, Clinique de Genolier, Route du Muids 3, PO Box 100, 1272, Genolier, Switzerland.
| | - Fatima Cardoso
- Breast Unit, Champalimaud Clinical Center/Champalimaud Foundation, Av. De Brasilia - Doca de Pedrouços, 1400-038, Lisbon, Portugal
| | - Giuseppe Curigliano
- Department of Oncology and Haematology, University of Milan, IEO, European Institute of Oncology IRCCS, Via Ripamonti 435, 20141, Milan, Italy
| | - Alexandru Eniu
- Hopital Riviera-Chablais, Vaud-Valais, Route du Vieux-Séquoia 20, 1847, Rennaz, Switzerland; Cancer Institute Ion Chiricuta, Strada Republicii 34-36, 400015, Cluj-Napoca, Romania
| | - Joseph Gligorov
- Institut Universitaire de Cancérologie AP-HP, Sorbonne Université, Oncologie Médicale, Hôpital Tenon, INSERM U-938, 4 Rue de la Chine, 75020, Paris, France
| | - Nadia Harbeck
- LMU Munich, University Hospital, Department of Obstetrics and Gynecology, Breast Center and Comprehensive Cancer Center (CCLMU), Marchioninistrasse 15, 81377, Munich, Germany
| | - Andreas Mueller
- Cantonal Hospital Winterthur, Brauerstrasse 15, 8401, Winterthur, Switzerland
| | - Olivia Pagani
- Hopital Riviera-Chablais, Vaud-Valais, Route du Vieux-Séquoia 20, 1847, Rennaz, Switzerland; Geneva University Hospitals, Rue Gabrielle-Perret-Gentil 4, 1205, Geneva, Switzerland
| | - Shani Paluch-Shimon
- Hadassah University Hospital - Sharett Institute of Oncology, Kiryat Hadassah, POB 12000, 91120, Jerusalem, Israel
| | - Elzbieta Senkus
- Department of Oncology and Radiotherapy, Medical University of Gdańsk, Smoluchowskiego 17, 80214, Gdańsk, Poland
| | - Beat Thürlimann
- Brustzentrum Kantonsspital St. Gallen, Rorschacher Strasse 95, 9007, St. Gallen, Switzerland
| | - Khalil Zaman
- Breast Center, Lausanne University Hospital CHUV, Rue du Bugnon 46, 1011, Lausanne, Switzerland
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15
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Serum LAPTM4B as a Potential Diagnostic and Prognostic Biomarker for Breast Cancer. BIOMED RESEARCH INTERNATIONAL 2022; 2022:6786351. [PMID: 36506911 PMCID: PMC9729050 DOI: 10.1155/2022/6786351] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Revised: 11/05/2022] [Accepted: 11/07/2022] [Indexed: 12/05/2022]
Abstract
Background Lysosome-associated protein transmembrane-4 beta (LAPTM4B) is an integral membrane protein overexpressed in various cancers and may function as a prognostic tumor marker. The present study is aimed at understanding the clinical significance of serum LAPTM4B in breast cancer (BC). Methods Serum LAPTM4B level was evaluated in 426 BC patients, 40 benign breast disease, and 80 healthy controls by ELISA. We used the receiver operator characteristic (ROC) curve to assess the diagnostic significance. 46 BC patients were recruited to monitor the dynamic change of serum LAPTM4B during adjuvant therapy (AT). In addition, sera from a subset of 330 patients undergoing AT, including anti-HER2 treatment, were collected to evaluate the association between LAPTM4B levels and AT efficacy. Descriptive and explorative statistical analyses were used to assess LAPTM4 B's potential as a diagnostic and prognostic marker in BC. Results Serum LAPTM4B level was significantly increased in BC patients than benign group and controls. It could well discriminate BC from healthy controls with diagnostic accuracy with an AUC of 0.912, a sensitivity of 85.9%, and a specificity of 83.8%. Compared with pre-AT, serum LAPTM4B concentration remarkably decreased after AT. In addition, patients in the invalid response group (PD + SD) showed higher LAPTM4B levels than the valid response group (PR + CR). Conclusion Our results proposed that serum LAPTM4B had a high diagnostic and prognostic impact as a circulating biomarker in BC.
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16
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Poon V, Lu D. Performance of Cox proportional hazard models on recovering the ground truth of confounded exposure-response relationships for large-molecule oncology drugs. CPT Pharmacometrics Syst Pharmacol 2022; 11:1511-1526. [PMID: 35988264 PMCID: PMC9662202 DOI: 10.1002/psp4.12859] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Revised: 08/04/2022] [Accepted: 08/06/2022] [Indexed: 12/20/2022] Open
Abstract
A Cox proportional hazard (CoxPH) model is conventionally used to assess exposure-response (E-R), but its performance to uncover the ground truth when only one dose level of data is available has not been systematically evaluated. We established a simulation workflow to generate realistic E-R datasets to assess the performance of the CoxPH model in recovering the E-R ground truth in various scenarios, considering two potential reasons for the confounded E-R relationship. We found that at high doses, when the pharmacological effects are largely saturated, missing important confounders is the major reason for inferring false-positive E-R relationships. At low doses, when a positive E-R slope is the ground truth, either missing important confounders or mis-specifying the interactions can lead to inaccurate estimates of the E-R slope. This work constructed a simulation workflow generally applicable to clinical datasets to generate clinically relevant simulations and provide an in-depth interpretation on the E-R relationships with confounders inferred by the conventional CoxPH model.
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Affiliation(s)
- Victor Poon
- Modeling and Simulation Group, Department of Clinical PharmacologyGenentech, Inc.South San FranciscoCaliforniaUSA
| | - Dan Lu
- Modeling and Simulation Group, Department of Clinical PharmacologyGenentech, Inc.South San FranciscoCaliforniaUSA
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17
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Prevention and Therapy of Metastatic HER-2 + Mammary Carcinoma with a Human Candidate HER-2 Virus-like Particle Vaccine. Biomedicines 2022; 10:biomedicines10102654. [PMID: 36289916 PMCID: PMC9599132 DOI: 10.3390/biomedicines10102654] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Revised: 10/17/2022] [Accepted: 10/17/2022] [Indexed: 11/16/2022] Open
Abstract
Vaccines are a promising therapeutic alternative to monoclonal antibodies against HER-2+ breast cancer. We present the preclinical activity of an ES2B-C001, a VLP-based vaccine being developed for human breast cancer therapy. FVB mice challenged with HER-2+ mammary carcinoma cells QD developed progressive tumors, whereas all mice vaccinated with ES2B-C001+Montanide ISA 51, and 70% of mice vaccinated without adjuvant, remained tumor-free. ES2B-C001 completely inhibited lung metastases in mice challenged intravenously. HER-2 transgenic Delta16 mice developed mammary carcinomas by 4−8 months of age; two administrations of ES2B-C001+Montanide prevented tumor onset for >1 year. Young Delta16 mice challenged intravenously with QD cells developed a mean of 68 lung nodules in 13 weeks, whereas all mice vaccinated with ES2B-C001+Montanide, and 73% of mice vaccinated without adjuvant, remained metastasis-free. ES2B-C001 in adjuvant elicited strong anti-HER-2 antibody responses comprising all Ig isotypes; titers ranging from 1−10 mg/mL persisted for many months. Antibodies inhibited the 3D growth of human HER-2+ trastuzumab-sensitive and -resistant breast cancer cells. Vaccination did not induce cytokine storms; however, it increased the ELISpot frequency of IFN-γ secreting HER-2-specific splenocytes. ES2B-C001 is a promising candidate vaccine for the therapy of tumors expressing HER-2. Preclinical results warrant further development towards human clinical studies.
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18
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Abstract
PURPOSE OF REVIEW Extramammary Paget's Disease (EMPD) is an uncommon intra-epithelial malignancy, affecting primarily apocrine gland-bearing skin. EMPD is often considered an orphan diagnosis given its rarity. This review provides a contemporary overview of EMPD management. RECENT FINDINGS The mainstay of EMPD treatment centers around a high index of suspicion to allow for an early and accurate diagnosis, wide local or Mohs micrographic surgical excision with care paid toward the margin status, and thoughtful consideration for lymphadenectomy in patients with clinically positive regional disease. There is currently no consensus regarding adjuvant therapies or systemic therapies although with ongoing improvements in tumor biology and genomics, including molecular pathways and alterations specific to EMPD, targeted or combinatorial therapies may be on the horizon. SUMMARY Clinicians caring for patients with EMPD should seek consultation from or if feasible, consider referral to high-volume, experienced centers with patients counseled and provided with frequent and close follow-up for disease recurrence or progression. Collaboration with groups such as the Global Society for Rare Genitourinary Tumors, and especially patient groups will be vital to designing trials and collaborative databases.
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Affiliation(s)
- Vikram M Narayan
- Department of Urology, Emory University School of Medicine, Atlanta, Georgia, USA
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19
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Tan HY, Yang J, Linnes JC, Welch CJ, Bruening ML. Quantitation of Trastuzumab and an Antibody to SARS-CoV-2 in Minutes Using Affinity Membranes in 96-Well Plates. Anal Chem 2022; 94:884-891. [PMID: 34982935 PMCID: PMC8751022 DOI: 10.1021/acs.analchem.1c03654] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Accepted: 12/20/2021] [Indexed: 11/28/2022]
Abstract
Quantitation of therapeutic monoclonal antibodies (mAbs) in human serum could ensure that patients have adequate levels of mAbs for effective treatment. This research describes the use of affinity, glass-fiber membranes in a 96-well-plate format for rapid (<5 min) quantitation of the therapeutic mAb trastuzumab and a mAb against the SARS-CoV-2 spike protein. Adsorption of a poly(acrylic acid)-containing film in membrane pores and activation of the -COOH groups in the film enable covalent-linking of affinity peptides or proteins to the membrane. Passage of mAb-containing serum through the affinity membrane results in mAb capture within 1 min. Subsequent rinsing, binding of a secondary antibody conjugated to a fluorophore, and a second rinse yield mAb-concentration-dependent fluorescence intensities in the wells. Calibration curves established from analyses on different days have low variability and allow determination of mAb levels in separately prepared samples with an average error <10%, although errors in single-replicate measurements may reach 40%. The assays can occur in diluted serum with physiologically relevant mAb concentrations, as well as in undiluted serum. Thus, the combination of 96-well plates containing affinity membranes, a microplate reader, and a simple vacuum manifold affords convenient mAb quantitation in <5 min.
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Affiliation(s)
- Hui Yin Tan
- Department
of Chemistry and Biochemistry, University
of Notre Dame, Notre
Dame, Indiana 46556, United States
| | - Junyan Yang
- Department
of Chemical and Biomolecular Engineering, University of Notre Dame, Notre
Dame, Indiana 46556, United States
| | - Jacqueline C. Linnes
- Weldon
School of Bioengineering, Purdue University, West Lafayette, Indiana 47907, United States
| | - Christopher J. Welch
- Indiana
Consortium for Analytical Science & Engineering (ICASE), 410 W. 10th Street, # 1020H, Indianapolis, Indiana 46202, United States
| | - Merlin L. Bruening
- Department
of Chemistry and Biochemistry, University
of Notre Dame, Notre
Dame, Indiana 46556, United States
- Department
of Chemical and Biomolecular Engineering, University of Notre Dame, Notre
Dame, Indiana 46556, United States
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20
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Iwabuchi E, Miki Y, Sasano H. The Visualization of Protein-Protein Interactions in Breast Cancer: Deployment Study in Pathological Examination. Acta Histochem Cytochem 2021; 54:177-183. [PMID: 35023880 PMCID: PMC8727844 DOI: 10.1267/ahc.21-00084] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Accepted: 10/14/2021] [Indexed: 11/22/2022] Open
Abstract
The therapeutic strategy is determined by protein expression using immunohistochemistry of estrogen receptor (ER), progesterone receptor, and human epidermal growth factor receptor 2 (HER2) in formalin-fixed paraffin-embedded (FFPE) breast cancer tissues. However, few proteins function independently, and many of them functions due to protein-protein interactions (PPIs) with other proteins. Therefore, it is important to focus on PPIs. This review summarizes the PPIs of ER and HER2 in breast cancer, especially those using a proximity ligation assay that can visualize PPIs in FFPE tissues. In particular, assessing the interaction of CEACAM6 with HER2 may serve as a surrogate marker for the efficacy of trastuzumab in patients with breast cancer. Therefore, in this review, the technique used to detect the interaction of CEACAM6 and HER2 in routinely processed pathological specimens will be applied to the clinical practice of drug selection. We showed the possibility as a novel pathological examination method using PPIs.
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Affiliation(s)
- Erina Iwabuchi
- Department of Pathology, Tohoku University Graduate School of Medicine
| | - Yasuhiro Miki
- Department of Disaster Obstetrics and Gynecology, International Research Institute of Disaster Science (IRIDes), Tohoku University
| | - Hironobu Sasano
- Department of Pathology, Tohoku University Graduate School of Medicine
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21
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Alsadig A, Vondracek H, Pengo P, Pasquato L, Posocco P, Parisse P, Casalis L. Label-Free, Rapid and Facile Gold-Nanoparticles-Based Assay as a Potential Spectroscopic Tool for Trastuzumab Quantification. NANOMATERIALS (BASEL, SWITZERLAND) 2021; 11:3181. [PMID: 34947531 PMCID: PMC8708960 DOI: 10.3390/nano11123181] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Revised: 11/12/2021] [Accepted: 11/20/2021] [Indexed: 11/17/2022]
Abstract
Monoclonal antibody-based immunotherapy is one of the pillars of cancer treatment. However, for an efficient and personalized approach to the therapy, a quantitative evaluation of the right dose for each patient is required. In this study, we developed a simple, label-free, and rapid approach to quantify Trastuzumab, a humanized IgG1 monoclonal antibody used against human epidermal growth factor receptor 2 (HER2), overexpressed in breast cancer patients, based on localized surface plasmon resonance (LSPR). The central idea of this work was to use gold nanoparticles (AuNPs) as plasmonic scaffolds, decorated with HER2 binders mixed with oligo-ethylene glycol (OEG) molecules, to tune the surface density of the attached macromolecules and to minimize nonspecific binding events. Specifically, we characterized and optimized a self-assembled monolayer of mixed alkylthiols terminated with nitrilotriacetic acid (NTA), and OEG3 as a spacing ligand to achieve both excellent dispersibility and high reliability in protein immobilization. The successful immobilization of histidine-tagged HER2 (His-tagged HER2) on NTA via cobalt (II) chelates was demonstrated, confirming the fully functional attachment of the proteins to the AuNP surface. The proposed design demonstrates the capability of producing a clear readout that enables the transduction of a Trastuzumab/HER2 binding event into optical signals based on the wavelength shifts in LSPR, which allowed for detecting clinically relevant concentrations of Trastuzumab down to 300 ng/mL in the buffer and 2 µg/mL in the diluted serum. This strategy was found to be fast and highly specific to Trastuzumab. These findings make the present platform an auspicious tool for developing affordable bio-nanosensors.
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Affiliation(s)
- Ahmed Alsadig
- Department of Physics, University of Trieste, 34127 Trieste, Italy;
- NanoInnovation Lab, Elettra Sincrotrone Trieste S.C.p.A., 34149 Trieste, Italy; (H.V.); (P.P.)
| | - Hendrik Vondracek
- NanoInnovation Lab, Elettra Sincrotrone Trieste S.C.p.A., 34149 Trieste, Italy; (H.V.); (P.P.)
- Department of Chemical and Pharmaceutical Sciences, University of Trieste, 34127 Trieste, Italy; (P.P.); (L.P.)
| | - Paolo Pengo
- Department of Chemical and Pharmaceutical Sciences, University of Trieste, 34127 Trieste, Italy; (P.P.); (L.P.)
| | - Lucia Pasquato
- Department of Chemical and Pharmaceutical Sciences, University of Trieste, 34127 Trieste, Italy; (P.P.); (L.P.)
| | - Paola Posocco
- Department of Engineering and Architecture, University of Trieste, 34127 Trieste, Italy;
| | - Pietro Parisse
- NanoInnovation Lab, Elettra Sincrotrone Trieste S.C.p.A., 34149 Trieste, Italy; (H.V.); (P.P.)
| | - Loredana Casalis
- NanoInnovation Lab, Elettra Sincrotrone Trieste S.C.p.A., 34149 Trieste, Italy; (H.V.); (P.P.)
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22
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Bou-Dargham MJ, Draughon S, Cantrell V, Khamis ZI, Sang QXA. Advancements in Human Breast Cancer Targeted Therapy and Immunotherapy. J Cancer 2021; 12:6949-6963. [PMID: 34729098 PMCID: PMC8558657 DOI: 10.7150/jca.64205] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Accepted: 09/16/2021] [Indexed: 12/14/2022] Open
Abstract
Human breast cancer treatment regimens have evolved greatly due to the significant advances in understanding the molecular mechanisms and pathways of the common subtypes of breast cancer. In this review, we discuss recent progress in breast cancer targeted therapy and immunotherapy as well as ongoing clinical trials. We also highlight the potential of combination therapies and personalized approaches to improve clinical outcomes. Targeted therapies have surpassed the hormone receptors and the human epidermal growth factor receptor 2 (HER2) to include many other molecules in targetable pathways such as the epidermal growth factor receptor (EGFR), poly (adenosine diphosphate-ribose) polymerase (PARP), and cyclin-dependent kinase 4/6 (CDK4/6). However, resistance to targeted therapy persists, underpinning the need for more efficacious therapies. Immunotherapy is considered a milestone in breast cancer treatments, including the engineered immune cells (CAR-T cell therapy) to better target the tumor cells, vaccines to stimulate the patient's immune system against tumor antigens, and checkpoint inhibitors (PD-1, PD-L1, and CTLA4) to block molecules that mediate immune inhibition. Targeted therapies and immunotherapy tested in breast cancer clinical trials are discussed here, with special emphasis on combinatorial approaches which are believed to maximize treatment efficacy and enhance patient survival.
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Affiliation(s)
- Mayassa J Bou-Dargham
- Department of Chemistry and Biochemistry, Florida State University, Tallahassee, Florida, United States of America
| | - Sophia Draughon
- Department of Chemistry and Biochemistry, Florida State University, Tallahassee, Florida, United States of America
| | - Vance Cantrell
- Department of Chemistry and Biochemistry, Florida State University, Tallahassee, Florida, United States of America
| | - Zahraa I Khamis
- Department of Chemistry and Biochemistry, Florida State University, Tallahassee, Florida, United States of America.,Department of Chemistry and Biochemistry, Faculty of Sciences-I, Lebanese University, Beirut, Lebanon
| | - Qing-Xiang Amy Sang
- Department of Chemistry and Biochemistry, Florida State University, Tallahassee, Florida, United States of America.,Institute of Molecular Biophysics, Florida State University, Tallahassee, Florida, United States of America
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23
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Berwanger JD, Tan HY, Jokhadze G, Bruening ML. Determination of the Serum Concentrations of the Monoclonal Antibodies Bevacizumab, Rituximab, and Panitumumab Using Porous Membranes Containing Immobilized Peptide Mimotopes. Anal Chem 2021; 93:7562-7570. [PMID: 33999602 DOI: 10.1021/acs.analchem.0c04903] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Effective monoclonal antibody (mAb) therapies require a threshold mAb concentration in patient serum. Moreover, the serum concentration of the mAb Bevacizumab should reside in a specific range to avoid side effects. Methods for conveniently determining the levels of mAbs in patient sera could allow for personalized dosage schedules that lead to more successful treatments. This work utilizes microporous nylon membranes functionalized with antibody-binding peptides to capture Bevacizumab, Rituximab, or Panitumumab from diluted (25%) serum. Modification of the capture-peptide terminus is often crucial to creating the affinity necessary for effective binding. The high purity of eluted mAbs allows for their quantitation using native fluorescence, and membranes are effective in spin devices that can be used in any laboratory. The technique is effective over the therapeutic range of Bevacizumab concentrations. Future work aims at further modifications to develop rapid point-of-care devices and decrease detection limits.
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Affiliation(s)
- Joshua D Berwanger
- Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556, United States
| | - Hui Yin Tan
- Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556, United States
| | - Gia Jokhadze
- Takara Bio USA, Inc., Mountain View, California 94043, United States
| | - Merlin L Bruening
- Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556, United States.,Department of Chemical and Biomolecular Engineering, University of Notre Dame, Notre Dame, Indiana 46556, United States
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24
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Jafari F, Safaei AM, Hosseini L, Asadian S, Kamangar TM, Zadehbagheri F, Rezaeian N. The role of cardiac magnetic resonance imaging in the detection and monitoring of cardiotoxicity in patients with breast cancer after treatment: a comprehensive review. Heart Fail Rev 2021; 26:679-697. [PMID: 33029698 DOI: 10.1007/s10741-020-10028-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/15/2020] [Indexed: 01/04/2023]
Abstract
The use of chemotherapy medicines for breast cancer (BC) has been associated with an increased risk of cardiotoxicity. In recent years, there have been growing interests regarding the application of cardiovascular magnetic resonance (CMR) imaging, a safe and noninvasive modality, with the potential to identify subtle morphological and functional changes in the myocardium. In this investigation, we aimed to review the performance of various CMR methods in diagnosing cardiotoxicity in BC, induced by chemotherapy or radiotherapy. For this purpose, we reviewed the literature available in PubMed, MEDLINE, Cochrane, Google Scholar, and Scopus databases. Our literature review showed that CMR is a valuable modality for identifying and predicting subclinical cardiotoxicity induced by chemotherapy. The novel T1, T2, and extracellular volume mapping techniques may provide critical information about cardiotoxicity, in addition to other CMR features such as functional and structural changes. However, further research is needed to verify the exact role of these methods in identifying cardiotoxicity and patient management. Since multiple studies have reported the improvement of left ventricular performance following the termination of chemotherapy regimens, CMR remains an essential imaging tool for the prediction of cardiotoxicity and, consequently, decreases the mortality rate of BC due to heart failure.
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Affiliation(s)
- Fatemeh Jafari
- Department of Radiation Oncology, Cancer Institute, Tehran University of Medical Sciences, Tehran, Iran
- Radiation Oncology Research Center (RORC), Cancer Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Afsane Maddah Safaei
- Radiation Oncology Research Center (RORC), Cancer Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Leila Hosseini
- North Khorasan University of Medical Sciences, Bojnurd, Iran
| | - Sanaz Asadian
- Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Tara Molanaie Kamangar
- Radiation Oncology Research Center (RORC), Cancer Institute, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Nahid Rezaeian
- Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran.
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25
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Hyman DM, Soria JC, Tabernero J. Building bridges between drug development and cancer science: a tribute to José Baselga's legacy. Ann Oncol 2021; 32:825-828. [PMID: 33838220 DOI: 10.1016/j.annonc.2021.03.209] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Accepted: 03/31/2021] [Indexed: 12/01/2022] Open
Affiliation(s)
- D M Hyman
- Loxo Oncology and Eli Lilly, Stamford, USA.
| | - J-C Soria
- Institut Gustave Roussy, Paris, France; Paris-Saclay University, Orsay, France
| | - J Tabernero
- Vall d'Hebron Institute of Oncology, Barcelona, Spain
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26
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Primary Trastuzumab Resistance After (Neo)adjuvant Trastuzumab-containing Treatment for Patients With HER2-positive Breast Cancer in Real-world Practice. Clin Breast Cancer 2021; 21:191-198. [PMID: 33549471 DOI: 10.1016/j.clbc.2020.09.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2020] [Revised: 09/01/2020] [Accepted: 09/03/2020] [Indexed: 11/20/2022]
Abstract
BACKGROUND It is difficult to define patients with primary trastuzumab resistance (PTR) after (neo)adjuvant trastuzumab with minimal data and understanding of the actual prevalence, prognosis, and potential treatment strategies in the real-world setting. PATIENTS AND METHODS The medical records of 1096 patients with human epidermal growth factor receptor 2-positive early-stage breast cancer who had received (neo)adjuvant trastuzumab-containing treatment from 2010 to 2016 in the Cancer Hospital and Chinese Academy of Medical Sciences were reviewed. PTR was defined as recurrence during adjuvant trastuzumab or within 12 months from their last (neo)adjuvant trastuzumab dosage. The cutoff date for data collection was September 1, 2018, with a median follow-up time of 46 months. RESULTS A total of 126 recurrences were observed, and 75 (6.8%; 75/1096) of them were categorized as PTR; the remaining were non-PTR. The prognosis of patients in the PTR group was much inferior to those in the non-PTR group (27 months vs. not reached; P < .01). As expected, patients with PTR did possess a much lower response rate to first-line trastuzumab-containing therapy (27.3% vs. 61.9%; P = .02). Subgroup analyses indicated that patients in the PTR group seemed to get little survival benefit from the reuse of trastuzumab compared with those without trastuzumab (26 months vs. 28 months; P = .80). However, in the non-PTR group, re-treatment with trastuzumab in the metastatic setting prolonged the survival of patients compared to those without trastuzumab (not reached vs. 34 months; P = .04). CONCLUSION This study verified the rationality of present definition of PTR after (neo)adjuvant trastuzumab. Patients with PTR did have a poor prognosis. Further research and clinical trials are required to establish the best treatment patterns for these patients.
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27
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Zhou Q, Dong J, Jiang X, Pan Y, Han X. Trastuzumab-induced thrombocytopenia after eight cycles of trastuzumab treatment. Open Med (Wars) 2020; 15:659-662. [PMID: 33336023 PMCID: PMC7711970 DOI: 10.1515/med-2020-0201] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2019] [Revised: 06/01/2020] [Accepted: 06/01/2020] [Indexed: 11/29/2022] Open
Abstract
Trastuzumab, a humanized monoclonal antibody derived from recombinant DNA, is used in patients with breast cancer with HER2 gene amplification. The survival benefit from trastuzumab has been well established in patients with early and metastatic breast cancer who had over expression of HER2. We reported a case of severe thrombocytopenia after eight cycles of trastuzumab treatment for breast cancer. Before the 9th trastuzumab treatment, the patient’s platelet decreased to 48 × 109/L. Recombinant human thrombopoietin was used, and the platelet level increased to normal level. Before the 10th treatment, the platelet count of the patient was 99 × 109/L. However, during the 10th and 11th trastuzumab treatment, the platelet count decreased to 5 × 109/L in 24 h. After treatment with TPO and corticosteroids, the platelet levels increased to the normal level in 7 days. Trastuzumab-induced thrombocytopenia is rare but still occurred even after 8 cycles of trastuzumab treatment.
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Affiliation(s)
- Qiong Zhou
- Department of Oncology, Provincial Hospital affiliated to Anhui Medical University, Hefei, Anhui Province, 230032, China
| | - Jie Dong
- Department of Oncology, Provincial Hospital affiliated to Anhui Medical University, Hefei, Anhui Province, 230032, China
| | - Xiaodong Jiang
- The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui Province, 230001, China
| | - Yueyin Pan
- The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui Province, 230001, China
| | - Xinghua Han
- Department of Oncology, Provincial Hospital affiliated to Anhui Medical University, Hefei, Anhui Province, 230032, China.,The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui Province, 230001, China
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28
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Che YQ, Zhang Y, Ou KP, Wang D, Shen D, Liu HY, Luo Y. Depth of Response and Early Tumor Shrinkage for Predicting Clinical Outcomes in HER2-Positive Metastatic Breast Cancer Treated with Trastuzumab. Cancer Manag Res 2020; 12:8527-8534. [PMID: 32982445 PMCID: PMC7502405 DOI: 10.2147/cmar.s269067] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2020] [Accepted: 08/14/2020] [Indexed: 12/29/2022] Open
Abstract
Background To evaluate whether the depth of response (DepRe) and early tumor shrinkage (ETS) are predictive factors of clinical outcomes in HER2-positive metastatic breast cancer (mBC) patients treated with trastuzumab. Methods We performed a retrospective study of 100 HER2-positive mBC patients who received trastuzumab combined with chemotherapy as first-line treatment. ETS and DepRe were calculated. We employed Youden’s index to determine the optimal cutoff value of ETS and DepRe for predicting progression-free survival (PFS) and overall survival (OS). We used Kaplan–Meier analysis, Log-rank tests, and Cox proportional hazards regression models to evaluate the impacts of ETS and DepRe on clinical outcomes. Results The optimal cutoff values were 30% for ETS and 40% for DepRe; ETS and DepRe were observed in 51.0% (51/100) and in 56.0% (56/100) of patients, respectively. Both ETS≥30% and DepRe≥40% were significant tumor-size metrics for predicting PFS (ETS: median 1.43 vs 0.69 years, hazard ratio [HR] = 0.384; 95% confidence interval [CI]: 0.245 to 0.601; P=0.000030; DepRe: median 1.43 vs 0.59 years, HR = 0.390; 95% CI: 0.250 to 0.609; P=0.0000034), but only DepRe≥40% was a significant predictor for OS (median 4.02 vs 3.07 years, HR = 0.484; 95% CI: 0.255 to 0.919; P = 0.027). Multivariate analyses also identified DepRe as an independent prognostic factor for PFS (HR = 0.52; 95% CI: 0.29 to 0.93; P = 0.028) and OS (HR=0.37; 95% CI:0.15 to 0.90; P = 0.029). Conclusion ETS≥30% and DepRe≥40% were significant predictors of better clinical outcomes in mBC patients treated with first-line trastuzumab-based chemotherapy. Further validation in prospective trials with larger patient populations is needed.
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Affiliation(s)
- Yi-Qun Che
- Department of Clinical Laboratory, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, People's Republic of China
| | - Yue Zhang
- Department of Clinical Laboratory, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, People's Republic of China
| | - Kai-Ping Ou
- Department of Medical Oncology, Beijing Chaoyang District Sanhuan Cancer Hospital, Beijing 100122, People's Republic of China
| | - Di Wang
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, People's Republic of China
| | - Di Shen
- Department of Clinical Laboratory, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, People's Republic of China
| | - Hui-Ying Liu
- Department of Clinical Laboratory, Jinzhou Central Hospital, Jinzhou 121000, Liaoning Province, People's Republic of China
| | - Yang Luo
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, People's Republic of China
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29
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Li X, Yao L, Wang M, Wang M, Li X, Yu X, Guo J, Dong H, Sun X, Xu Y. Updated Bayesian Network Meta-Analysis of Adjuvant Targeted Treatment Regimens for Early Human Epidermal Growth Factor Receptor-2 Positive Breast Cancer. J Breast Cancer 2020; 23:410-429. [PMID: 32908791 PMCID: PMC7462812 DOI: 10.4048/jbc.2020.23.e45] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2020] [Accepted: 07/28/2020] [Indexed: 11/30/2022] Open
Abstract
Purpose Combining targeted agents with adjuvant chemotherapy prolongs survival in human epidermal growth factor receptor 2 (HER2)-positive breast cancer patients, but also increases the risk of adverse effects. The updated results of 3 randomized controlled trials (RCTs) were reported in 2019. Given the lack of adequate head-to-head pairwise assessment for anti-HER2 agents, network meta-analysis facilitates obtaining more precise inference for evidence-based therapy. Methods RCTs comparing at least 2 anti-HER2 regimens in an adjuvant setting for HER2-positive early-stage breast cancer (EBC) were included. Hazard ratios for overall survival (OS) and disease free survival (DFS), with respective 95% confidence intervals were pooled for assessment of efficacy. A Bayesian statistical model was used, and odds ratios (ORs) for adverse events (AEs) were used to pool effect sizes. Results We demonstrated that 1-year trastuzumab plus chemotherapy had increased efficacy compared to shorter or longer treatment duration. The OR of cardiac events gradually increased from 6 months to 1 and 2-year trastuzumab arms, relative to chemotherapy only. Compared to trastuzumab plus chemotherapy, dual HER2-targeting therapies increased DFS, especially for hormone receptor negative patients. Dual anti-HER2 blockade regimens revealed an increased probability of gastrointestinal reactions. As a second agent, pertuzumab showed significantly higher DFS and OS. Conclusion We conclude that 1-year adjuvant trastuzumab should remain as the standard treatment for HER2-positive EBC patients, as it has greater efficacy and a manageable proportion of AEs. Clinical efficacy can be increased for hormone receptor-negative tumors by including a second HER2-targeted agent to the treatment regimen. For hormone receptor-positive cases with basal disease, it is acceptable to reduce the risk of cardiotoxicity by shortening the duration of trastuzumab.
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Affiliation(s)
- Xinyan Li
- Department of Breast Surgery, The First Affiliated Hospital of China Medical University, Shenyang, China.,Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Litong Yao
- Department of Breast Surgery, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Mozhi Wang
- Department of Breast Surgery, The First Affiliated Hospital of China Medical University, Shenyang, China.,Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Mengshen Wang
- Department of Breast Surgery, The First Affiliated Hospital of China Medical University, Shenyang, China.,Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Xiang Li
- Department of Breast Surgery, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Xueting Yu
- Department of Breast Surgery, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Jingyi Guo
- Department of Breast Surgery, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Haoran Dong
- Department of Breast Surgery, The First Affiliated Hospital of China Medical University, Shenyang, China.,Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Xiangyu Sun
- Department of Breast Surgery, The First Affiliated Hospital of China Medical University, Shenyang, China.,Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Yingying Xu
- Department of Breast Surgery, The First Affiliated Hospital of China Medical University, Shenyang, China
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30
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Ly L, Cheng X, Murthy SRK, Zhuang T, Jones OZ, Basadonna G, Keidar M, Canady J. Canady cold plasma conversion system treatment: An effective inhibitor of cell viability in breast cancer molecular subtypes. CLINICAL PLASMA MEDICINE 2020. [DOI: 10.1016/j.cpme.2020.100109] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
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31
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Zhang M, Li L, Zhang S, Zhu W, Yang S, Di G, Ma X, Yang H. Efficacy of Neoadjuvant Chemotherapy with Epirubicin and Cyclophosphamide and Weekly Paclitaxel and Trastuzumab in Human Epidermal Growth Factor Receptor 2-Positive Breast Carcinoma: A Real-World Study. BIOMED RESEARCH INTERNATIONAL 2020; 2020:3208391. [PMID: 32461977 PMCID: PMC7222597 DOI: 10.1155/2020/3208391] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/14/2019] [Revised: 12/29/2019] [Accepted: 01/16/2020] [Indexed: 11/17/2022]
Abstract
BACKGROUND Trastuzumab has been introduced a decade ago and demonstrated improvement in the prognosis in patients with human epidermal growth factor receptor 2- (HER2-) positive (+) breast carcinoma (BC). This study is aimed at evaluating the efficacy of epirubicin/cyclophosphamide with weekly paclitaxel-trastuzumab as neoadjuvant chemotherapies in HER2+ BC patients. METHODS A total of 234 HER2+ BC patients were given neoadjuvant chemotherapy (NAC) between 2010 and 2016. The primary endpoints were pathologic complete response (pCR) and disease-free survival (DFS). Univariate and multivariate analyses of clinical and pathological factors associated with pCR and DFS were conducted. RESULTS The pCR (30.4% vs. 14.8%; P = 0.004) and DFS (P = 0.036) showed significant differences between patients administered with neoadjuvant trastuzumab therapy and those who did not. Multivariate logistic regression analysis showed that neoadjuvant trastuzumab treatment was regarded as an independent predictor of pCR. Patients with pCR had prolonged DFS (P = 0.025). In patients who did not achieve pCR (non-pCR), those who received trastuzumab had more prolonged DFS (P = 0.046). The luminal B/HER2+ subtypes had prolonged DFS when compared with nonluminal B/HER2+ subtypes (P = 0.010). The luminal B/HER2+ subgroup also showed improved DFS in non-pCR patients (P = 0.010). In the subgroup of non-pCR, the luminal B/HER2+ subgroup administered with trastuzumab showed no superior DFS (P = 0.168). However, a positive result was observed in patients without trastuzumab (P = 0.039). Multivariate analysis showed cT stage (P = 0.006) and tumor grade (P = 0.041), considering them as significant prognostic factors of DFS. CONCLUSIONS HER2+ BC patients showed improvement in pCR and DFS after neoadjuvant trastuzumab treatment. Patients without pCR had prolonged DFS after trastuzumab maintenance. Although the prognosis of luminal B/HER2+ BC showed favorable outcomes in the non-pCR subgroup, those receiving trastuzumab showed no survival advantage.
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Affiliation(s)
- Mengmeng Zhang
- Department of Breast Surgery, The Affiliated Hospital of Guizhou Medical University, Guizhou 550004, China
| | - Ling Li
- Department of Neurology, 925 Hospital of PLA Joint Logistics Support Force, Guizhou 550009, China
| | - Shiyong Zhang
- Department of Breast Surgery, The Affiliated Hospital of Guizhou Medical University, Guizhou 550004, China
| | - Wenlong Zhu
- Department of Breast Surgery, The Affiliated Hospital of Guizhou Medical University, Guizhou 550004, China
| | - Senguo Yang
- Department of Breast Surgery, The Affiliated Hospital of Guizhou Medical University, Guizhou 550004, China
| | - Guangsheng Di
- Department of Breast Surgery, The Affiliated Hospital of Guizhou Medical University, Guizhou 550004, China
| | - Xiaoxia Ma
- Department of Breast Surgery, The Affiliated Hospital of Guizhou Medical University, Guizhou 550004, China
| | - Haisong Yang
- Department of Breast Surgery, The Affiliated Hospital of Guizhou Medical University, Guizhou 550004, China
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32
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Sow HS, Benonisson H, Brouwers C, Linssen MM, Camps M, Breukel C, Claassens J, van Hall T, Ossendorp F, Fransen MF, Verbeek JS. Immunogenicity of rat-neu + mouse mammary tumours determines the T cell-dependent therapeutic efficacy of anti-neu monoclonal antibody treatment. Sci Rep 2020; 10:3933. [PMID: 32127568 PMCID: PMC7054273 DOI: 10.1038/s41598-020-60893-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2019] [Accepted: 02/14/2020] [Indexed: 11/09/2022] Open
Abstract
The use of Trastuzumab (Herceptin), a monoclonal antibody (mAb) targeting HER2/neu, results in an increased median survival in Her2+ breast cancer patients. The tumour mutational burden and the presence of tumour infiltrating lymphocytes (TILs) clearly correlate with response to trastuzumab. Here, we investigated if the immunogenicity of the transplantable rat-neu+ tumour cell line (TUBO) derived from a BALB/c-NeuT primary tumour is associated with the response to anti-neu mAb therapy. We compared the TUBO tumour outgrowth and tumour infiltrating T cells in isogenic (BALB/c-NeuT) and non-isogenic (WT BALB/c) recipient mice. Furthermore, therapeutic efficacy of anti-neu mAb and the contribution of T cells were examined in both mouse strains. The outgrowth of untreated tumours was significantly better in BALB/c-NeuT than WT BALB/c mice. Moreover, tumour infiltrating T cells were more abundantly present in WT BALB/c than BALB/c-NeuT mice, showing that the TUBO tumour was more immunogenic in WT BALB/c mice. In TUBO tumour bearing WT BALB/c mice, anti-neu mAb therapy resulted in an increase of tumour infiltrating T cells and long-term survival. When T cells were depleted, this strong anti-tumour effect was reduced to an outgrowth delay. In contrast, in TUBO tumour bearing BALB/c-NeuT mice, treatment with anti-neu mAb resulted only in tumour outgrowth delay, both in the presence and absence of T cells. We concluded that in immunogenic tumours the response to anti-neu mAb therapy is enhanced by additional T cell involvement compared to the response to anti-neu mAb in non-immunogenic tumours.
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Affiliation(s)
- Heng Sheng Sow
- Department of Human Genetics, Leiden University Medical Centre, Leiden, The Netherlands
| | - Hreinn Benonisson
- Department of Human Genetics, Leiden University Medical Centre, Leiden, The Netherlands
| | - Conny Brouwers
- Department of Human Genetics, Leiden University Medical Centre, Leiden, The Netherlands
| | - Margot M Linssen
- Department of Human Genetics, Leiden University Medical Centre, Leiden, The Netherlands
| | - Marcel Camps
- Department of Immunohematology and Blood Transfusion, Leiden University Medical Centre, Leiden, The Netherlands
| | - Cor Breukel
- Department of Human Genetics, Leiden University Medical Centre, Leiden, The Netherlands
| | - Jill Claassens
- Department of Human Genetics, Leiden University Medical Centre, Leiden, The Netherlands
| | - Thorbald van Hall
- Department of Medical Oncology, Leiden University Medical Centre, Leiden, The Netherlands
| | - Ferry Ossendorp
- Department of Immunohematology and Blood Transfusion, Leiden University Medical Centre, Leiden, The Netherlands
| | - Marieke F Fransen
- Department of Immunohematology and Blood Transfusion, Leiden University Medical Centre, Leiden, The Netherlands.,Department of Pulmonary Diseases, Amsterdam University Medical Centre, Amsterdam, The Netherlands
| | - J Sjef Verbeek
- Department of Human Genetics, Leiden University Medical Centre, Leiden, The Netherlands.
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33
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Laengle J, Kabiljo J, Hunter L, Homola J, Prodinger S, Egger G, Bergmann M. Histone deacetylase inhibitors valproic acid and vorinostat enhance trastuzumab-mediated antibody-dependent cell-mediated phagocytosis. J Immunother Cancer 2020; 8:jitc-2019-000195. [PMID: 31940587 PMCID: PMC7057438 DOI: 10.1136/jitc-2019-000195] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/01/2019] [Indexed: 01/02/2023] Open
Abstract
Background The monoclonal antibody (mAb) trastuzumab is part of the standard of care for patients with human epidermal growth factor receptor 2 (HER2)-overexpressing breast cancer. Antibody-dependent cell-mediated phagocytosis (ADCP) and cytotoxicity (ADCC) are major mechanisms of action of the mAb trastuzumab. Histone deacetylase inhibitors (HDACi), such as valproic acid (VPA) or vorinostat (SAHA), exert several immunostimulatory properties, which contribute at least in part to their anticancer effect. However, the impact of HDACi-induced immunostimulatory effects on trastuzumab-mediated anti-tumor immune response is not well characterized. Methods We analyzed the ADCP and ADCC activity of peripheral blood mononuclear cells (PBMCs) from age and gender-matched healthy volunteers (n=5) against HDACi-treated HER2-overexpressing breast cancer cells (SKBR3), using a well-established in vitro three-color imaging flow cytometry and flow cytometry approach. Results VPA and SAHA enhanced trastuzumab-mediated ADCP and trastuzumab-independent cytotoxicity. Mechanistically, VPA upregulated the activating antibody-binding receptor Fc-gamma receptor (FcγR) IIA (CD32A) on monocytes (CD14+). Moreover, VPA and SAHA downregulated the anti-apoptotic protein myeloid leukemia cell differentiation 1 (MCL1) in breast cancer cells. Additionally, VPA and SAHA induced an immunogenic cell death, characterized by the exposure of calreticulin (CALR), as well as decreased the “do not eat me” signal CD47 on tumor cells. Conclusions HDACi VPA and SAHA increase trastuzumab-mediated phagocytosis and trastuzumab-independent cytotoxicity. The immunomodulatory activities of those HDACi support a rationale combined treatment approach with mAb for cancer treatment.
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Affiliation(s)
- Johannes Laengle
- Division of General Surgery, Department of Surgery, Comprehensive Cancer Center Vienna, Medical University of Vienna, Vienna, Austria.,Ludwig Boltzmann Institute Applied Diagnostics, Medical University of Vienna, Vienna, Austria
| | - Julijan Kabiljo
- Division of General Surgery, Department of Surgery, Comprehensive Cancer Center Vienna, Medical University of Vienna, Vienna, Austria
| | - Leah Hunter
- Division of General Surgery, Department of Surgery, Comprehensive Cancer Center Vienna, Medical University of Vienna, Vienna, Austria
| | - Jakob Homola
- Division of General Surgery, Department of Surgery, Comprehensive Cancer Center Vienna, Medical University of Vienna, Vienna, Austria
| | - Sophie Prodinger
- Division of General Surgery, Department of Surgery, Comprehensive Cancer Center Vienna, Medical University of Vienna, Vienna, Austria
| | - Gerda Egger
- Ludwig Boltzmann Institute Applied Diagnostics, Medical University of Vienna, Vienna, Austria.,Department of Pathology, Comprehensive Cancer Center Vienna, Medical University of Vienna, Vienna, Austria
| | - Michael Bergmann
- Division of General Surgery, Department of Surgery, Comprehensive Cancer Center Vienna, Medical University of Vienna, Vienna, Austria .,Ludwig Boltzmann Institute Applied Diagnostics, Medical University of Vienna, Vienna, Austria
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Styles IK, Feeney OM, Nguyen TH, Brundel DHS, Kang DW, Clift R, McIntosh MP, Porter CJH. Removal of interstitial hyaluronan with recombinant human hyaluronidase improves the systemic and lymphatic uptake of cetuximab in rats. J Control Release 2019; 315:85-96. [PMID: 31655131 DOI: 10.1016/j.jconrel.2019.10.040] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2019] [Revised: 10/08/2019] [Accepted: 10/21/2019] [Indexed: 11/28/2022]
Abstract
Interstitial, e.g. subcutaneous (SC) or intradermal (ID), administration of monoclonal antibodies (mAb) is less invasive than intravenous administration and leads to mAb uptake into both lymphatic and blood capillaries draining the injection site. Interstitial administration, however, is hindered by the presence of hyaluronan (HA), a glycosaminoglycan that is a major fluid barrier in the interstitial space. The transient removal of HA with recombinant human hyaluronidase (rHuPH20) helps facilitate the interstitial administration of often high therapeutic doses of mAb in the clinic. rHuPH20's impact on the systemic pharmacokinetics of several mAbs has been previously described, however effects on route of absorption (lymph vs blood) are unknown. The current study has therefore explored the lymphatic transport and bioavailability of cetuximab and trastuzumab after SC and ID coadministration in the presence and absence of rHuPH20 in rats. After SC administration cetuximab absolute bioavailability increased from 67 % to 80 % in the presence of rHuPH20. Cetuximab recovery in the lymphatics also increased after SC (35.8 % to 49.4 %) and ID (26.7 % to 58.8 %) administration in the presence of rHuPH20. When the injection volume (and therefore dose) was increased 10-fold in the presence of rHuPH20 cetuximab plasma exposure increased approximately linearly (12- and 8.9-fold respectively after SC and ID administration), although the proportional contribution of cetuximab lymphatic transport reduced slightly (6.2-fold increase for both administration routes). In contrast, co-administration with rHuPH20 did not lead to increases in plasma exposure for trastuzumab after SC or ID administration, most likely reflecting the fact that the reported absolute bioavailability of trastuzumab (in the absence of rHuPH20) is high (∼77-99 %). However, lymphatic transport of trastuzumab did increase when coadministered ID with rHuPH20 in spite of the lack of change to overall bioavailability. The data suggest that co-administration with rHuPH20 is able to increase the volume of mAb that can be administered interstitially, and in some instances can increase the amount absorbed into both the blood and the lymph. In the current studies the ability of rHuPH20 to enhance interstitial bioavailability was higher for cetuximab where intrinsic interstitial bioavailability was low, when compared to trastuzumab where interstitial bioavailability was high.
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Affiliation(s)
- Ian K Styles
- Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia; ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia
| | - Orlagh M Feeney
- Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia; ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia
| | - Tri-Hung Nguyen
- Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia
| | - Daniel H S Brundel
- Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia; ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia
| | - David W Kang
- Halozyme Therapeutics Inc, 11388 Sorrento Valley Rd, San Diego, California 92121, USA
| | - Renee Clift
- Halozyme Therapeutics Inc, 11388 Sorrento Valley Rd, San Diego, California 92121, USA
| | - Michelle P McIntosh
- Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia
| | - Christopher J H Porter
- Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia; ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia.
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Feng L, Huang S, An G, Wang G, Gu S, Zhao X. Identification of new cancer stem cell markers and signaling pathways in HER‑2‑positive breast cancer by transcriptome sequencing. Int J Oncol 2019; 55:1003-1018. [PMID: 31545416 PMCID: PMC6776190 DOI: 10.3892/ijo.2019.4876] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2018] [Accepted: 06/06/2019] [Indexed: 12/17/2022] Open
Abstract
Human epidermal growth factor receptor (HER)‑2‑positive breast cancer accounts for ~25% of all breast cancer cases, has a high propensity for relapse, metastasis and drug resistance, and is associated with a poor prognosis. Therefore, it is necessary to develop more effective therapeutic targets for the treatment of HER‑2‑positive breast cancer. CD44+/CD24‑/low is currently the most commonly used marker for breast cancer stem cells (CSCs), which are considered the main cause of drug resistance, relapse and metastasis. In the present study, the ratio of CD44+/CD24‑/low cells was almost zero in SK‑BR‑3 cells; however, it was >90% in MDA‑MB‑231 cells, as determined by flow cytometry. Since SK‑BR‑3 and MDA‑MB‑231 cells both exhibit a strong propensity for invasion and migration, it was hypothesized that there may be other markers of CSCs in SK‑BR‑3 cells. Therefore, transcriptome sequencing was performed for SK‑BR‑3 and MDA‑MB‑231 cells. It was observed that several leukocyte differentiation antigens and other CSC markers were significantly more highly expressed in SK‑BR‑3 cells. Furthermore, the expression of aldehyde dehydrogenase (ALDH)1A3, CD164 and epithelial cell adhesion molecule (EpCAM) was higher in SK‑BR‑3 cells compared with in other subtypes of breast cell lines, as determined by reverse transcription‑polymerase chain reaction and western blot analysis. In addition, the expression levels of ALDH1A3, ALDH3B2 and EpCAM were higher in HER‑2‑positive breast cancer compared with in paracancerous tissues and other subtypes of breast cancer, as determined by immunohistochemistry. The expression of β‑catenin in the Wnt signaling pathway was lower in SK‑BR‑3 cells compared with in MDA‑MB‑231 cells, which may be used as a prognostic indicator for breast cancer. These findings may help identify novel CSC markers and therapeutic targets for HER‑2‑positive breast cancer.
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Affiliation(s)
- Lu Feng
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Shangke Huang
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, P.R. China
| | - Gaili An
- Department of Clinical Oncology, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi 710068, P.R. China
| | - Guanying Wang
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Shanzhi Gu
- College of Forensic Medicine, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi 710061, P.R. China
| | - Xinhan Zhao
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
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Deppenweiler M, Debled M, Robquin JL, Lortal-Canguilhem B. Subcutaneous auto-administration of trastuzumab following therapeutic education: A case report. J Oncol Pharm Pract 2019; 25:1523-1525. [DOI: 10.1177/1078155218792364] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Trastuzumab is a monoclonal antibody used to treat human epidermal growth receptor 2 positive (HER2+) breast cancers either by itself or in combination with other chemotherapy medication. Marketing authorization was granted for a subcutaneous form of the antibody in 2014. In this case report, we discuss our experience with a patient who took part in a therapeutic education program on self-administration of trastuzumab. We demonstrate that these types of self-administered injections are not only possible but also are toxicity-free. Based on the tolerance data and our patient’s experience, we propose that the current regulations be relaxed regarding the availability of trastuzumab subcutaneous form in order to develop a cheaper “city scheme,” i.e. self-administered injections.
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Affiliation(s)
| | - Marc Debled
- Department of Oncology, Institut Bergonié, Bordeaux, France
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Lubbers B, Kazura E, Dawson E, Mernaugh R, Baudenbacher F. Microfabricated calorimeters for thermometric enzyme linked immunosorbent assay in one-Nanoliter droplets. Biomed Microdevices 2019; 21:85. [PMID: 31451947 DOI: 10.1007/s10544-019-0429-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
Advances in microfabrication allow for highly sensitive calorimeters with dramatically reduced volume, decreased response time and increased energy resolution. These calorimeters hold the potential for designs of ELISA platforms competitive with fluorescent and chemiluminescent technologies. We have developed a new assay platform using conventional ELISA reagents to produce a thermal signal quantifiable using calorimetry. Our optimized micromachined calorimeters have nL reaction volumes and a minimum detectable power of 375 pW/Hz1/2. We demonstrate rapid quantification in a model system of trastuzumab, a humanized monoclonal antibody used in the treatment of HER2 overexpressing breast cancers, in human serum using a HER2 peptide mimetic. Trastuzumab concentration and reaction time constant correlated well (R2 = 0.954) and can be used to determine trastuzumab concentrations. The limit of detection for the ThermometricELISA (TELISA) was 10 μg/ml trastuzumab in human serum. TELISA allows for a simple readout, reduction in assay time, sample and reagent volumes and has the potential to become a point of care multiplexed platform technology.
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Affiliation(s)
- Brad Lubbers
- Department of Biomedical Engineering, Vanderbilt University, PMB 351631, 2301 Vanderbilt Place, Nashville, TN, 37235-1631, USA
| | - Evan Kazura
- Department of Biomedical Engineering, Vanderbilt University, PMB 351631, 2301 Vanderbilt Place, Nashville, TN, 37235-1631, USA
| | - Elliott Dawson
- BioVentures, Inc., 1435 Kensington Square Court, P.O. Box 2561, Murfreesboro, TN, 37133-2561, USA
| | - Ray Mernaugh
- Vanderbilt University School of Medicine, PRB 895, Nashville, TN, 37232, USA
| | - Franz Baudenbacher
- Department of Biomedical Engineering, Vanderbilt University, PMB 351631, 2301 Vanderbilt Place, Nashville, TN, 37235-1631, USA.
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Tanese K, Nakamura Y, Hirai I, Funakoshi T. Updates on the Systemic Treatment of Advanced Non-melanoma Skin Cancer. Front Med (Lausanne) 2019; 6:160. [PMID: 31355203 PMCID: PMC6635480 DOI: 10.3389/fmed.2019.00160] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2019] [Accepted: 06/28/2019] [Indexed: 12/21/2022] Open
Abstract
Non-melanoma skin cancers (NMSCs), which represent a diverse group of cutaneous malignancies, are the most common forms of human neoplasia. The incidence of these diseases is increasing due to a number of factors, including that of increasing human lifespans. The majority of NMSCs are basal cell carcinomas (BCC) and cutaneous squamous cell carcinomas (cSCC), with the remainder being various rare skin cancers, including extramammary Paget's disease (EMPD), Merkel cell carcinoma (MCC), and several skin adnexal carcinomas. Of these, MCC usually shows aggressive behavior with a high mortality rate. On the other hand, BCC, cSCC, EMPD, and skin adnexal tumors usually show an indolent clinical course and metastasize only rarely. Nevertheless, the metastatic forms of these tumors commonly lead to poor patient outcome. A definitive management strategy for the treatment of advanced NMSC has not been established, mainly due to their rarity and lack of reliable information based on well-controlled randomized trials. Chemotherapeutic regimens for treatment of these diseases have been mainly based on the observations of isolated, small case series or clinical trials with a limited numbers of patients. However, accumulating evidence regarding their pathobiological backgrounds as well as recent advances in molecular biotechnology have facilitated the development of novel drugs for treatment of these diseases. Over the past decade, the U.S. Food and Drug Administration has approved several molecular targeting therapies, including Hedgehog inhibitors for BCC, monoclonal antibodies targeting anti-programmed death ligand-1 and anti- programmed cell death 1 (PD-1) for MCC, and anti-PD-1 for cSCC. Here, we review their clinical utility and discuss updated systemic treatment strategies for advanced NMSC.
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Affiliation(s)
- Keiji Tanese
- Department of Dermatology, Keio University School of Medicine, Tokyo, Japan
| | - Yoshio Nakamura
- Department of Dermatology, Keio University School of Medicine, Tokyo, Japan
| | - Ikuko Hirai
- Department of Dermatology, Keio University School of Medicine, Tokyo, Japan
| | - Takeru Funakoshi
- Department of Dermatology, Keio University School of Medicine, Tokyo, Japan
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von der Grün J, Rödel F, Brandts C, Fokas E, Guckenberger M, Rödel C, Balermpas P. Targeted Therapies and Immune-Checkpoint Inhibition in Head and Neck Squamous Cell Carcinoma: Where Do We Stand Today and Where to Go? Cancers (Basel) 2019; 11:E472. [PMID: 30987257 PMCID: PMC6521064 DOI: 10.3390/cancers11040472] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2019] [Revised: 03/28/2019] [Accepted: 04/01/2019] [Indexed: 01/12/2023] Open
Abstract
With an increased understanding of the tumor biology of squamous cell carcinoma of the head and neck (SCCHN), targeted therapies have found their way into the clinical treatment routines against this entity. Nevertheless, to date platinum-based cytostatic agents remain the first line choice and targeting the epidermal growth factor-receptor (EGFR) with combined cetuximab and radiation therapy remains the only targeted therapy approved in the curative setting. Investigation of immune checkpoint inhibitors (ICI), such as antibodies targeting programmed cell death protein 1 (PD-1) and its ligand PD-L1, resulted in a change of paradigms in oncology and in the first approval of new drugs for treating SCCHN. Nivolumab and pembrolizumab, two anti-PD-1 antibodies, were the first agents shown to improve overall survival for patients with metastatic/recurrent tumors in recent years. Currently, several clinical trials investigate the role of ICI in different therapeutic settings. A robust set of biomarkers will be an inevitable tool for future individualized treatment approaches including radiation dose de-escalation and escalation strategies. This review aims to summarize achieved goals, the current status and future perspectives regarding targeted therapies and ICI in the management of SCCHN.
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Affiliation(s)
- Jens von der Grün
- Department of Radiation Oncology, Theodor-Stern-Kai 7, University of Frankfurt, 60590 Frankfurt, Germany.
| | - Franz Rödel
- Department of Radiation Oncology, Theodor-Stern-Kai 7, University of Frankfurt, 60590 Frankfurt, Germany.
- Frankfurt Cancer Institute (FCI), Theodor-Stern-Kai 7, University of Frankfurt, 60590 Frankfurt, Germany.
- German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
- German Cancer Consortium (DKTK), partner site: Frankfurt a. M., Theodor-Stern-Kai 7, University of Frankfurt, 60590 Frankfurt, Germany.
| | - Christian Brandts
- German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
- German Cancer Consortium (DKTK), partner site: Frankfurt a. M., Theodor-Stern-Kai 7, University of Frankfurt, 60590 Frankfurt, Germany.
- Department of Medicine, Hematology/Oncology, University Cancer Center Frankfurt (UCT), Theodor-Stern-Kai 7, University of Frankfurt, 60590 Frankfurt, Germany.
| | - Emmanouil Fokas
- Department of Radiation Oncology, Theodor-Stern-Kai 7, University of Frankfurt, 60590 Frankfurt, Germany.
- Frankfurt Cancer Institute (FCI), Theodor-Stern-Kai 7, University of Frankfurt, 60590 Frankfurt, Germany.
- German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
- German Cancer Consortium (DKTK), partner site: Frankfurt a. M., Theodor-Stern-Kai 7, University of Frankfurt, 60590 Frankfurt, Germany.
| | - Matthias Guckenberger
- Department of Radiation Oncology, Rämistrasse 100, University Hospital Zurich, 8091 Zürich, Switzerland.
| | - Claus Rödel
- Department of Radiation Oncology, Theodor-Stern-Kai 7, University of Frankfurt, 60590 Frankfurt, Germany.
- Frankfurt Cancer Institute (FCI), Theodor-Stern-Kai 7, University of Frankfurt, 60590 Frankfurt, Germany.
- German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
- German Cancer Consortium (DKTK), partner site: Frankfurt a. M., Theodor-Stern-Kai 7, University of Frankfurt, 60590 Frankfurt, Germany.
| | - Panagiotis Balermpas
- Department of Radiation Oncology, Rämistrasse 100, University Hospital Zurich, 8091 Zürich, Switzerland.
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Ginzac A, Passildas J, Gadéa E, Abrial C, Molnar I, Trésorier R, Duclos M, Thivat E, Durando X. Treatment-Induced Cardiotoxicity in Breast Cancer: A Review of the Interest of Practicing a Physical Activity. Oncology 2019; 96:223-234. [DOI: 10.1159/000499383] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2019] [Accepted: 03/05/2019] [Indexed: 11/19/2022]
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Oh SY, Lee S, Huh SJ, Lee J, Kim ST, Park SH, Lim HY, Kang WK, Kang BW, Kim JG, Lee HJ, Kim JH, Kang JH, Kim H. Safety and efficacy of trastuzumab administered as a 30-min infusion in patients with HER2-positive advanced gastric cancer. Cancer Chemother Pharmacol 2019; 83:501-508. [PMID: 30535535 DOI: 10.1007/s00280-018-3753-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2018] [Accepted: 12/04/2018] [Indexed: 01/09/2023]
Abstract
PURPOSE To investigate the safety and efficacy of 30-min maintenance infusions of trastuzumab in advanced gastric cancer positive for human epidermal growth factor receptor 2 (HER2). METHODS This was a retrospective study conducted across five Korean hospitals in patients with HER2-positive gastric or gastroesophageal junction adenocarcinoma treated with first-line, 3-weekly trastuzumab plus chemotherapy. The first dose of trastuzumab (8 mg/kg) was administered as a 90-min infusion, with all subsequent maintenance infusions (6 mg/kg) given over 30 min. The primary aim was to investigate infusion-related reactions and cardiac events with 30-min infusions of trastuzumab. Objective response rate, progression-free survival, and overall survival were secondary endpoints. RESULTS The study included 128 patients (efficacy population), of whom 123 received both induction and maintenance infusions and formed the safety population. The median age was 63 years; 80% were presenting for the first time with metastatic disease, and 94% were treated with trastuzumab plus capecitabine/cisplatin. Infusion-related reactions were observed in 32 of 123 patients (26%). There were no cardiac events. The most frequent adverse events were anorexia and nausea, followed by vomiting, fatigue, mucositis, sensory neuropathy, and hand-foot syndrome. Most events were grade 1-2 and were manageable. No patient discontinued study treatment due to adverse events. The objective response rate was 63%, and included 6 complete responses. CONCLUSIONS Trastuzumab 30-min maintenance infusions were well tolerated with a good safety profile, and resulted in sustained efficacy in patients with HER2-positive advanced gastric cancer.
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Affiliation(s)
- Sung Yong Oh
- Department of Internal Medicine, Dong-A University College of Medicine, Busan, Republic of Korea
| | - Suee Lee
- Department of Internal Medicine, Dong-A University College of Medicine, Busan, Republic of Korea
| | - Seok Jae Huh
- Department of Internal Medicine, Dong-A University College of Medicine, Busan, Republic of Korea
| | - Jeeyun Lee
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Seung Tae Kim
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Se Hoon Park
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Ho Yeong Lim
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Won Ki Kang
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Byung Woog Kang
- Department of Oncology/Hematology, Kyungpook National University Medical Center, Kyungpook National University School of Medicine, 807 Hoguk-ro, Buk-gu, Daegu, 41404, Republic of Korea
| | - Jong Gwang Kim
- Department of Oncology/Hematology, Kyungpook National University Medical Center, Kyungpook National University School of Medicine, 807 Hoguk-ro, Buk-gu, Daegu, 41404, Republic of Korea.
| | - Hyo Jin Lee
- Division of Hematology-Oncology, Department of Internal Medicine, Chungnam National University College of Medicine, Daejeon, Republic of Korea
| | - Jung Hoon Kim
- Division of Hematology/Oncology, Department of Internal Medicine, School of Medicine, Gyeongsang National University, Jinju, Republic of Korea
| | - Jung Hun Kang
- Division of Hematology/Oncology, Department of Internal Medicine, School of Medicine, Gyeongsang National University, Jinju, Republic of Korea
| | - HoUng Kim
- CELLTRION Healthcare Co. Ltd, Incheon, Republic of Korea
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Jung S, Anusha JR, Park S, Yu KH, Raj CJ, Kim BC. HER2 inhibition efficiency of 6-amino-2-methyl-2-phenethyl-2H-benzopyran and feasibility of the 64Cu-labeled benzopyran derivative in cancer diagnosis. NEW J CHEM 2019. [DOI: 10.1039/c9nj02893e] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
The benzopyran derivative 6-amino-2-methyl-2-phenethyl-2H-benzopyran inhibits the overexpression of the protein HER2, and the 64Cu-labeled compound is promising for cancer diagnosis and treatment.
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Affiliation(s)
- Soonjae Jung
- Division of Applied RI
- Korea Institute of Radiological & Medical Sciences
- Seoul-01812
- Republic of Korea
| | - J. R. Anusha
- Department of Chemistry
- Dongguk University
- Seoul-04620
- Republic of Korea
- Department of Advanced Zoology and Biotechnology
| | - Seungil Park
- Department of Chemistry
- Dongguk University
- Seoul-04620
- Republic of Korea
| | - Kook Hyun Yu
- Department of Chemistry
- Dongguk University
- Seoul-04620
- Republic of Korea
| | - C. Justin Raj
- Department of Chemistry
- Dongguk University
- Seoul-04620
- Republic of Korea
| | - Byung Chul Kim
- Department of Printed Electronics Engineering
- Sunchon National University
- 255, Jungang-ro
- Suncheon-si
- Republic of Korea
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Fahad Ullah M. Breast Cancer: Current Perspectives on the Disease Status. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1152:51-64. [PMID: 31456179 DOI: 10.1007/978-3-030-20301-6_4] [Citation(s) in RCA: 338] [Impact Index Per Article: 56.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Breast cancer is the most frequently diagnosed cancer in women and ranks second among causes for cancer related death in women. Evidence in literature has shown that the past and ongoing research has an enormous implication in improving the clinical outcome in breast cancer. This has been attributed to the progress made in the realm of screening, diagnosis and therapeutic strategies engaged in breast cancer management. However, poor prognosis in TNBC and drug resistance presents major inhibitions which are also current challenges for containing the disease. Similarly, a focal point of concern is the rising rate of breast cancer incidence and mortality among the population of under developed world. In this chapter, an overview of the current practices for the diagnosis and treatment of breast cancer and associated impediments has been provided.
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Affiliation(s)
- Mohammad Fahad Ullah
- Prince Fahd Research Chair, Department of Medical Laboratory Technology, Faculty of Applied Medical Science, University of Tabuk, Tabuk-71491, Saudi Arabia.
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Quartino AL, Li H, Kirschbrown WP, Mangat R, Wada DR, Garg A, Jin JY, Lum B. Population pharmacokinetic and covariate analyses of intravenous trastuzumab (Herceptin ®), a HER2-targeted monoclonal antibody, in patients with a variety of solid tumors. Cancer Chemother Pharmacol 2018; 83:329-340. [PMID: 30467591 PMCID: PMC6394489 DOI: 10.1007/s00280-018-3728-z] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2018] [Accepted: 11/08/2018] [Indexed: 12/18/2022]
Abstract
PURPOSE The aim of the study was to characterize the population pharmacokinetics (PK) of the intravenous formulation of trastuzumab, assess the impact of patient and pathological covariates on trastuzumab PK, and perform simulations to support dosing recommendations in special situations. METHODS Serum trastuzumab concentrations were obtained from 1582 patients with metastatic breast cancer (MBC), early breast cancer (EBC), advanced gastric cancer (AGC), or other tumor types/healthy volunteers in 18 phase I, II, and III trials and analyzed by nonlinear mixed-effects modeling. RESULTS A two-compartment model with parallel linear and nonlinear elimination best described the data. During treatment, linear clearance (CL) dominated, resulting in a total CL of 0.173-0.337 L/day, which is similar to other IgG1 monoclonal antibodies. Covariates influencing CL were baseline body weight, aspartate aminotransferase, albumin, gastric cancer, and the presence of liver metastases. MBC and EBC had similar PK parameters, while CL was higher in AGC. Simulations indicated that at least 95% of patients with BC reach concentrations < 1 µg/mL (~ 97% washout) by 7 months. A dose delay in BC or AGC patients of > 1 week would take approximately 6 weeks to get back within steady-state exposure range. CONCLUSIONS Trastuzumab PK for the intravenous formulation was well-described across cancer types, disease status, and regimens. No dose adjustment is required for any of the identified patient covariates. A 7-month serum washout period for trastuzumab is recommended. A reloading dose is required if a maintenance dose is missed by > 1 week.
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Affiliation(s)
- Angelica L Quartino
- Genentech, Inc., 1 DNA Way, Mail Stop 463A, South San Francisco, CA, 94080, USA.
| | - Hanbin Li
- Certara, L.P., 845 Oak Grove Ave, Menlo Park, CA, 94025, USA
| | | | - Ranvir Mangat
- Genentech, Inc., 1 DNA Way, Mail Stop 463A, South San Francisco, CA, 94080, USA.,Insight Rx, 233 Stanyan Street, San Francisco, CA, 94118, USA
| | - D Russell Wada
- Certara, L.P., 845 Oak Grove Ave, Menlo Park, CA, 94025, USA
| | - Amit Garg
- Genentech, Inc., 1 DNA Way, Mail Stop 463A, South San Francisco, CA, 94080, USA
| | - Jin Y Jin
- Genentech, Inc., 1 DNA Way, Mail Stop 463A, South San Francisco, CA, 94080, USA
| | - Bert Lum
- Genentech, Inc., 1 DNA Way, Mail Stop 463A, South San Francisco, CA, 94080, USA
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Phase I trial of afatinib and 3-weekly trastuzumab with optimal anti-diarrheal management in patients with HER2-positive metastatic cancer. Cancer Chemother Pharmacol 2018; 82:979-986. [PMID: 30350178 PMCID: PMC6267664 DOI: 10.1007/s00280-018-3689-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2018] [Accepted: 09/17/2018] [Indexed: 12/30/2022]
Abstract
Background Trastuzumab is the mainstay of therapy for patients with HER2-positive breast and gastric cancer but resistance frequently occurs. Afatinib, an irreversible oral ErbB family blocker, shows clinical activity in trastuzumab-refractory HER2-positive metastatic breast cancer. Materials and methods This phase I study used a modified 3 + 3 dose escalation design to determine the maximum tolerated dose (MTD) of oral once-daily afatinib in combination with 3-weekly intravenous trastuzumab (8 mg/kg week 1; 6 mg/kg 3-weekly thereafter) for patients with confirmed advanced or metastatic HER2-positive cancer. Results Of the 13 patients treated, 6 received daily afatinib 20 mg and 7 received 30 mg. One patient who received afatinib 30 mg developed a tumor lysis syndrome and was not evaluable for dose-limiting toxicity (DLT). Two of the six remaining patients receiving afatinib 30 mg and 1 of the 6 patients receiving afatinib 20 mg experienced DLTs (all CTCAE ≥ grade 2 diarrhea despite optimal management) in the first treatment cycle. The most common drug-related adverse events were diarrhea (n = 13, 100%), asthenia (n = 8, 61.5%), rash (n = 7, 53.8%) and paronychia (n = 5, 38.5%). No pharmacokinetic interaction was observed. One patient (7.7%) had an objective response (20 mg afatinib cohort). Nine patients (69.2%) experienced clinical benefit. Conclusions Despite optimal management of diarrhea including treatment of grade I symptoms, it was not possible to treat the patients above a dose of 20 mg of afatinib daily in combination with 3-weekly trastuzumab. The MTD of afatinib in combination with the recommended 3-weekly dose of trastuzumab was 20 mg daily.
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Iwabuchi E, Miki Y, Kanai A, Miyashita M, Kijima G, Hirakawa H, Suzuki T, Ishida T, Sasano H. The interaction between carcinoembryonic antigen-related cell adhesion molecule 6 and human epidermal growth factor receptor 2 is associated with therapeutic efficacy of trastuzumab in breast cancer. J Pathol 2018; 246:379-389. [PMID: 30058236 DOI: 10.1002/path.5148] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2018] [Revised: 07/10/2018] [Accepted: 07/26/2018] [Indexed: 12/12/2022]
Abstract
Human epidermal growth factor receptor 2 (HER2) is a target of the HER2 inhibitor trastuzumab, which has been administered to HER2-positive breast cancer patients. However, the therapeutic effects of HER2 inhibitor monotherapy are not always clinically effective as compared with cotreatment with chemotherapy. Therefore, it has become pivotal to predict the therapeutic efficacy of trastuzumab monotherapy prior to administration. Recently, carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) has been reported to be a HER2-related factor. The aim of the present study was to explore the therapeutic mechanism of trastuzumab, including the relevance of CEACAM6 expression. CEACAM6/HER2-double-positive human breast carcinoma cell lines BT-474, HCC-1419 and MDA-MB-361 were used in this study. CEACAM6 knockdown decreased the inhibitory effects of trastuzumab in the trastuzumab-sensitive BT-474 and HCC-1419 cells, but not in the trastuzumab-resistant MDA-MB-361 cells. We examined the interaction between CEACAM6 and HER2 by using a proximity ligation assay (PLA). The interaction was detected in BT-474 and HCC-1419 cells, but not in MDA-MB-361 cells, and was significantly associated with in vitro trastuzumab therapeutic sensitivity. We further analysed the status of CEACAM6 and HER2 and their interaction in archival pathology specimens, also using PLA. The interaction was detected only in CEACAM6/HER2-double-positive breast cancer cases, and their PLA score was significantly associated with the efficacy of trastuzumab treatment. Therefore, evaluation of the CEACAM6-HER2 interaction could serve as a marker to predict the efficacy of trastuzumab monotherapy in breast cancer patients. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Affiliation(s)
- Erina Iwabuchi
- Department of Pathology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Yasuhiro Miki
- Department of Disaster Obstetrics and Gynaecology, International Research Institute of Disaster Science (IRIDes), Tohoku University, Sendai, Japan
| | - Ayako Kanai
- Department of Breast and Endocrine Surgical Oncology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Minoru Miyashita
- Department of Breast and Endocrine Surgical Oncology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | | | | | - Takashi Suzuki
- Department of Pathology and Histotechnology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Takanori Ishida
- Department of Breast and Endocrine Surgical Oncology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Hironobu Sasano
- Department of Pathology, Tohoku University Graduate School of Medicine, Sendai, Japan
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Shen Y, Fujii T, Ueno NT, Tripathy D, Fu N, Zhou H, Ning J, Xiao L. Comparative efficacy of adjuvant trastuzumab-containing chemotherapies for patients with early HER2-positive primary breast cancer: a network meta-analysis. Breast Cancer Res Treat 2018; 173:1-9. [PMID: 30242579 DOI: 10.1007/s10549-018-4969-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2018] [Accepted: 09/15/2018] [Indexed: 12/27/2022]
Abstract
BACKGROUND Trastuzumab (H) with chemotherapy benefits patients with HER2+ breast cancer (BC); however, we lack head-to-head pairwise assessment of survival or cardiotoxicity for specific combinations. We sought to identify optimal combinations. METHODS We searched PubMed, updated October 2017, using keywords "Breast Neoplasms/drug therapy," "Trastuzumab," and "Clinical Trial" and searched Cochrane Library. Our search included randomized trials of adjuvant H plus chemotherapy for early-stage HER2+ BC, and excluding trials of neoadjuvant therapy or without data to obtain hazard ratios (HRs) for outcomes. Following PRISMA guidelines, one investigator did initial search; two others independently confirmed and extracted information; and consensus with another investigator resolved disagreements. Before gathering data, we set outcomes of overall survival (OS), event-free survival (EFS), and severe cardiac adverse events (SCAEs). Analyzing 6 trials and 13,621 patients, we made direct and indirect comparisons using network meta-analysis on HR for OS or EFS and on odds ratio (OR) for SCAE; ranked therapy was done based on outcomes using p scores. RESULTS Compared with anthracycline-cyclophosphamide with taxane (ACT), ACT with concurrent H (ACT+H) showed best OS (HR 0.63, 95% confidence interval [CI] 0.55, 0.72), followed by taxane and carboplatin (TC) with concurrent H (TC+H) (HR 0.77, 95% CI 0.59, 1) and ACT with sequential H (ACT-H) (HR 0.85, 95% CI 0.68, 1.05). Pairwise comparisons showed statistically significant OS benefit for ACT+H over others; similar results for EFS. TC+H showed statistically significant lower SCAE risk compared to ACT+H (OR 0.13, 95% CI 0.03, 0.61). CONCLUSIONS Concurrent H with ACT or TC showed most clinical benefit for early-stage HER2+ BC; TC+H had lowest cardiotoxicity.
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Affiliation(s)
- Y Shen
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, 1400 Pressler St, Unit 1411, Houston, TX, 77030, USA.
| | - T Fujii
- Section of Translational Breast Cancer, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, 77030, USA
| | - N T Ueno
- Section of Translational Breast Cancer, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, 77030, USA
| | - D Tripathy
- Section of Translational Breast Cancer, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, 77030, USA
| | - N Fu
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, 1400 Pressler St, Unit 1411, Houston, TX, 77030, USA
| | - H Zhou
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, 1400 Pressler St, Unit 1411, Houston, TX, 77030, USA
| | - J Ning
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, 1400 Pressler St, Unit 1411, Houston, TX, 77030, USA
| | - L Xiao
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, 1400 Pressler St, Unit 1411, Houston, TX, 77030, USA
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Liu W, Bennett AL, Ning W, Tan HY, Berwanger JD, Zeng X, Bruening ML. Monoclonal Antibody Capture and Analysis Using Porous Membranes Containing Immobilized Peptide Mimotopes. Anal Chem 2018; 90:12161-12167. [DOI: 10.1021/acs.analchem.8b03183] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Affiliation(s)
| | - Austin L. Bennett
- Department of Chemistry, Michigan State University, East Lansing, Michigan 48824, United States
| | - Wenjing Ning
- Department of Chemistry, Michigan State University, East Lansing, Michigan 48824, United States
| | | | | | - Xiangqun Zeng
- Department of Chemistry, Oakland University, Rochester, Michigan 48309, United States
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Reijers JAA, Dane MJC, van Zonneveld AJ, Burggraaf J, Moerland M. Potential Influence of Endothelial Adsorption on the Delayed Time to Maximum Concentration of Biopharmaceuticals. Eur J Drug Metab Pharmacokinet 2018; 43:103-113. [PMID: 28795390 PMCID: PMC5794845 DOI: 10.1007/s13318-017-0430-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Background and objectives Maximum plasma concentration of biopharmaceuticals sometimes occurs long after completion of intravenous infusion. The objective of this research was to study the hypothetical adsorption of biopharmaceuticals to endothelium and infusion material, which may theoretically explain this phenomenon. Methods Infusion procedures were mimicked in an artificial vessel covered with a confluent monolayer of endothelial cells. Three monoclonal antibodies (MAbs) and C1 inhibitor were studied. Results Adsorption of MAbs to endothelium was observed followed by release when the vessel was subsequently perfused with buffer. Adsorption to infusion material also occurred to various degrees and in a seemingly random fashion, with a loss of up to 15% during a single flush of the line, but release from the line was not seen. Conclusions Our results indicate that adsorption of biopharmaceuticals to endothelium can occur. This observation can explain the increase in plasma concentration after completion of intravenous administration.
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Affiliation(s)
- Joannes A A Reijers
- Centre for Human Drug Research (CHDR), Zernikedreef 8, 2333 CL, Leiden, The Netherlands. .,Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands.
| | - Martijn J C Dane
- Department of Internal Medicine (Nephrology) and the Einthoven Laboratory of Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands
| | - Anton Jan van Zonneveld
- Department of Internal Medicine (Nephrology) and the Einthoven Laboratory of Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands
| | - Jacobus Burggraaf
- Centre for Human Drug Research (CHDR), Zernikedreef 8, 2333 CL, Leiden, The Netherlands
| | - Matthijs Moerland
- Centre for Human Drug Research (CHDR), Zernikedreef 8, 2333 CL, Leiden, The Netherlands
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