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Theocharopoulos C, Ziogas IA, Mungo B, Gogas H, Ziogas DC, Kontis E. HER2-targeted therapies: Unraveling their role in biliary tract cancers. Crit Rev Oncol Hematol 2025; 208:104655. [PMID: 39923923 DOI: 10.1016/j.critrevonc.2025.104655] [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: 11/21/2024] [Revised: 01/31/2025] [Accepted: 02/05/2025] [Indexed: 02/11/2025] Open
Abstract
Biliary tract cancers (BTCs) constitute a heterogeneous group of malignancies with rising incidence and limited therapeutic options in advanced stages, leading to increased overall mortality. Extensive genomic profiling has identified key oncogenic drivers in BTCs that represent promising therapeutic targets and could change the treatment paradigm. Evidence suggests improved survival outcomes for patients with actionable molecular alterations who received matched targeted therapies. Human epidermal growth factor receptor 2 (HER2) is a receptor tyrosine kinase and proto-oncogene that has been extensively studied as a prognostic biomarker and a therapeutic target in multiple solid organ malignancies. Recent clinical trials on the combination of trastuzumab with tucatinib, FOLFOX, or pertuzumab for previously treated, HER2-positive, advanced BTCs have shown improved outcomes compared to current second-line therapies. Early evidence from observational studies on trastuzumab-containing regimens as first-line suggests promising efficacy. Furthermore, the recent tumor-agnostic approval of trastuzumab deruxtecan for HER2-positive solid tumors has formally introduced HER2-directed agents in the BTC therapeutic arsenal. This review aims to summarize the rapidly evolving landscape of HER2-directed agents for BTCs, highlighting current evidence of survival benefit. Beginning with a concise presentation of the structural and functional aspects of HER2, we detail the frequency and prognostic significance of HER2 alterations in BTCs and discuss all available preclinical and clinical data on anti-HER2 agents tested for BTCs.
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Affiliation(s)
| | - Ioannis A Ziogas
- Department of Surgery, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
| | - Benedetto Mungo
- Department of Surgery, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
| | - Helen Gogas
- First Department of Internal Medicine, Laikon General Hospital, School of Medicine, National Kapodistrian University of Athens, Athens 11527, Greece.
| | - Dimitrios C Ziogas
- First Department of Internal Medicine, Laikon General Hospital, School of Medicine, National Kapodistrian University of Athens, Athens 11527, Greece.
| | - Elissaios Kontis
- Department of Surgery, Metaxa Cancer Hospital, Piraeus 18537, Greece.
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2
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van Dijk D, Vermij L, León-Castillo A, Powell M, Jobsen J, Leary A, Bowes D, Mileshkin L, Genestie C, Jürgenliemk-Schulz I, de Kroon C, Post C, de Boer S, Nooij L, Kroep J, Creutzberg C, Smit V, Horeweg N, Bosse T, Westermann A. Clinical and Molecular Characteristics of High-Risk, Recurrent, or Metastatic Endometrial Cancer That Is Human Epidermal Growth Factor Receptor 2-Low. J Clin Oncol 2025; 43:443-452. [PMID: 39374474 DOI: 10.1200/jco.23.02768] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2023] [Revised: 06/10/2024] [Accepted: 08/25/2024] [Indexed: 10/09/2024] Open
Abstract
PURPOSE Recent success of human epidermal growth factor receptor 2 (HER2)-targeted antibody-drug-conjugate trastuzumab-deruxtecan in HER2-low and HER2-positive tumors has sparked interest in examining the HER2 status of tumors not traditionally associated with HER2 amplification. Despite the increasing number of systemic treatment options, patients with advanced endometrial cancer (EC) still face a poor prognosis. This study evaluates HER2-low status in over 800 EC, correlating HER2 with both molecular and clinical features. METHODS HER2 status was determined by immunohistochemistry (IHC) and dual in situ hybridization (DISH) on four studies of previously classified high-risk EC (PORTEC-3 and Medical Spectrum Twente cohort), recurrent or metastatic EC (DOMEC), and a primary stage IV cohort. EC was classified as HER2-negative (IHC 0), HER2-low (IHC 1+/2+ without amplification), or HER2-positive (IHC 3+ or DISH-confirmed amplification). Survival analysis was performed using the Kaplan-Meier method. Cox proportional hazards models assessed the independence of any prognostic impact of HER2 status. RESULTS HER2 status was determined in 806 EC: 74.8% were HER2-negative, 17.2% HER2-low, and 7.9% HER2-positive. HER2-low was found across all molecular classes and histotypes. The highest rates of HER2-low and HER2-positive tumors were in recurrent or metastatic EC (35.6% and 15.6%), followed by primary stage IV EC (29.9% and 12.4%) and high-risk EC (14.2% and 6.8%). HER2 status had no independent prognostic value. CONCLUSION A quarter of high-risk, metastatic, or recurrent EC exhibited HER2 overexpression. The presence of HER2 overexpression in all clinical and molecular categories highlights the need for broad testing and offers treatment options for a wide range of patients.
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Affiliation(s)
- Dione van Dijk
- Department of Medical Oncology, Amsterdam University Medical Centers, Amsterdam, the Netherlands
| | - Lisa Vermij
- Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands
| | - Alicia León-Castillo
- Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands
| | - Melanie Powell
- Department of Clinical Oncology, Barts Health NHS Trust, London, United Kingdom
| | - Jan Jobsen
- Department of Radiation Oncology, Medisch Spectrum Twente, Enschede, the Netherlands
| | - Alexandra Leary
- Department of Medical Oncology, Gustave Roussy, Villejuif, France
| | - David Bowes
- Department of Radiation Oncology, Dalhousie University, Halifax, Canada
| | - Linda Mileshkin
- Division of Cancer Medicine, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
| | | | - Ina Jürgenliemk-Schulz
- Department of Radiation Oncology, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Cor de Kroon
- Department of Gynaecology, Leiden University Medical Center, Leiden, the Netherlands
| | - Cathelijne Post
- Department of Radiation Oncology, Leiden University Medical Center, Leiden, the Netherlands
| | - Stephanie de Boer
- Department of Radiation Oncology, Leiden University Medical Center, Leiden, the Netherlands
| | - Linda Nooij
- Department of Gynaecology, Leiden University Medical Center, Leiden, the Netherlands
| | - Judith Kroep
- Department of Medical Oncology, Leiden University Medical Center, Leiden, the Netherlands
| | - Carien Creutzberg
- Department of Radiation Oncology, Leiden University Medical Center, Leiden, the Netherlands
| | - Vincent Smit
- Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands
| | - Nanda Horeweg
- Department of Radiation Oncology, Leiden University Medical Center, Leiden, the Netherlands
| | - Tjalling Bosse
- Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands
| | - Anneke Westermann
- Department of Medical Oncology, Amsterdam University Medical Centers, Amsterdam, the Netherlands
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3
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Cammarota A, Woodford R, Smyth EC. Targeting HER2 in Gastroesophageal Cancer: A New Appetite for an Old Plight. Drugs 2025:10.1007/s40265-024-02132-2. [PMID: 39843758 DOI: 10.1007/s40265-024-02132-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/21/2024] [Indexed: 01/24/2025]
Abstract
The incidence of gastroesophageal cancers is rising, driven, in part, by an increasing burden of risk factors of obesity and gastroesophageal reflux. Despite efforts to address these risk factors, and a growing interest in methods of population screening, the bulk of these tumours are unresectable at diagnosis. In this setting, effective systemic treatments are paramount to improve survival and quality of life. Early and accurate identification of oncogenic drivers, such as human epidermal growth factor receptor 2 (HER2), present in 5-30% of gastroesophageal adenocarcinomas (GEAs), is integral to guide choice of therapies due to the clear predictive implications that arise from overexpression of this receptor. After trastuzumab, the first anti-HER2 agent with approved use in HER2-positive GEA, the addition of pembrolizumab to first-line trastuzumab-chemotherapy and trastuzumab deruxtecan in the refractory space have more recently changed practice. Yet, the response to these agents has been vastly different across patients with HER2-positive disease, underpinning the need for reliable biomarkers of response. Emergent data have suggested that levels of HER2 expression on tissue or liquid biopsies may predict response to first-generation HER2 therapies while HER2 heterogeneity, receptor changes, co-occurring molecular alterations and oncogenic genomic and metabolic reprogramming may be implicated in resistance. A robust knowledge of the mechanisms of resistance and response to HER2-directed therapies is necessary to inform novel strategies of HER2-targeting and guide choice combinations with other biomarker-directed therapies, to improve outcomes from a new generation of clinical trials in HER2-positive GEA. Understanding and close examination of previous failures in this space form an important part of this assessment, as does correlative biomarker and translational work pertaining to the role of HER2 and dynamic changes that result through treatment exposure. In this review, we aim to provide an overview of strategies for HER2 targeting, summarising both the successes and disappointments in this therapeutic landscape and discuss existing challenges and future perspectives on development in this highly morbid tumour type.
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Affiliation(s)
- Antonella Cammarota
- Sarah Cannon Research Institute UK, 93 Harley St, London, UK
- Department of Medical Sciences, Humanitas University, Via Rita Levi Montalcini, Pieve Emanuele, Milan, Italy
| | - Rachel Woodford
- Sarah Cannon Research Institute UK, 93 Harley St, London, UK
- National Health and Medical Research Council Clinical Trials Centre (NHMRC CTC), University of Sydney, Parramatta Road, Camperdown, Australia
| | - Elizabeth C Smyth
- Oxford NIHR Biomedical Research Centre, Churchill Hospital, Oxford, UK.
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Lee HS. Spatial and Temporal Tumor Heterogeneity in Gastric Cancer: Discordance of Predictive Biomarkers. J Gastric Cancer 2025; 25:192-209. [PMID: 39822175 PMCID: PMC11739643 DOI: 10.5230/jgc.2025.25.e3] [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: 11/13/2024] [Accepted: 12/09/2024] [Indexed: 01/19/2025] Open
Abstract
Gastric cancer (GC) is a highly heterogeneous disease that varies in both histological presentation and genetic characteristics. Recent advances in the treatment of metastatic and unresectable GC have made several biomarker tests essential for patient management. Predictive biomarkers such as human epidermal growth factor receptor 2 (HER2), programmed death-ligand 1 (PD-L1), mismatch-repair (MMR) proteins, claudin 18.2, and fibroblast growth factor receptor 2b (FGFR2b) are commonly evaluated using immunohistochemistry. However, the expression levels of these biomarkers may vary across different tumor areas, and the accuracy of biomarker diagnosis can be affected by sample quantity, sample location, and collection method. Therefore, tumor heterogeneity presents substantial challenges for accurate biomarker-based diagnosis and prediction of therapeutic responses. Tumor heterogeneity can be categorized into spatial heterogeneity, which refers to variations within the primary tumor (intra-tumoral) or between primary and metastatic sites, and temporal heterogeneity, which encompasses changes over time. This review addresses the tumor heterogeneity in predictive biomarker expression in GC, focusing on HER2, PD-L1, MMR, the Epstein-Barr virus, claudin 18.2, and FGFR2b.
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Affiliation(s)
- Hye Seung Lee
- Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea.
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5
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Yang M, Lin W, Huang J, Mannucci A, Luo H. Novel immunotherapeutic approaches in gastric cancer. PRECISION CLINICAL MEDICINE 2024; 7:pbae020. [PMID: 39397869 PMCID: PMC11467695 DOI: 10.1093/pcmedi/pbae020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Revised: 09/08/2024] [Accepted: 09/08/2024] [Indexed: 10/15/2024] Open
Abstract
Gastric cancer is a malignant tumor that ranks third in cancer-related deaths worldwide. Early-stage gastric cancer can often be effectively managed through surgical resection. However, the majority of cases are diagnosed in advanced stages, where outcomes with conventional radiotherapy and chemotherapy remain unsatisfactory. Immunotherapy offers a novel approach to treating molecularly heterogeneous gastric cancer by modifying the immunosuppressive tumor microenvironment. Immune checkpoint inhibitors and adoptive cell therapy are regarded as promising modalities in cancer immunotherapy. Food and Drug Administration-approved programmed death-receptor inhibitors, such as pembrolizumab, in combination with chemotherapy, have significantly extended overall survival in gastric cancer patients and is recommended as a first-line treatment. Despite challenges in solid tumor applications, adoptive cell therapy has demonstrated efficacy against various targets in gastric cancer treatment. Among these approaches, chimeric antigen receptor-T cell therapy research is the most widely explored and chimeric antigen receptor-T cell therapy targeting claudin18.2 has shown acceptable safety and robust anti-tumor capabilities. However, these advancements primarily remain in preclinical stages and further investigation should be made to promote their clinical application. This review summarizes the latest research on immune checkpoint inhibitors and adoptive cell therapy and their limitations, as well as the role of nanoparticles in enhancing immunotherapy.
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Affiliation(s)
- Meng Yang
- Department of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
- Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou 510060, China
| | - Wuhao Lin
- Department of Molecular Diagnostics, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
| | - Jiaqian Huang
- Department of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
- Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou 510060, China
| | - Alessandro Mannucci
- Gastroenterology and Gastrointestinal Emndoscopy Unit, IRCCS San Raffaele Hospital, Vita-Salute San Raffaele University, Milan 20132, Italy
- Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute of City of Hope; Monrovia, CA 91016, USA
| | - Huiyan Luo
- Department of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
- Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou 510060, China
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6
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Lu H, Xu Z, Shao L, Li P, Xia Y. High infiltration of immune cells with lower immune activity mediated the heterogeneity of gastric adenocarcinoma and promoted metastasis. Heliyon 2024; 10:e37092. [PMID: 39319155 PMCID: PMC11419928 DOI: 10.1016/j.heliyon.2024.e37092] [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: 05/23/2024] [Revised: 07/21/2024] [Accepted: 08/27/2024] [Indexed: 09/26/2024] Open
Abstract
Background Gastric adenocarcinoma (GA) is a heterogeneous malignancy with high invasion and metastasis. We aimed to explore the metastatic characteristics of GA using single-cell RNA-sequencing (scRNA-seq) analysis. Methods The scRNA-seq dataset was downloaded from the GEO database and the "Seurat" package was used to perform the scRNA-seq analysis. The CellMarker2.0 database provided gene markers. Subsequently, differentially expressed genes (DEGs) were identified using the FindMarkers function and subjected to enrichment analysis with the "ClusterProlifer". "GseaVis" package was used for visualizing the gene levels. Finally, the SCENIC analysis was performed for identifying key regulons. The expression level and functionality of the key genes were verified by quantitative real-time PCR (qRT-PCR), wound healing and transwell assays. Results A total of 7697 cells were divided into 8 cell subsets, in which the Cytotoxic NK/T cells, Myeloid cells and Myofibroblasts had higher proportion in the metastatic tissues. Further screening of DEGs and enrichment analysis revealed that in the metastatic tissues, NK cells, monocytes and inflammatory fibroblasts with low immune levels contributed to GA metastasis. In addition, this study identified a series of key immune-related regulons that mediated the lower immune activity of immune cells. Further in vitro experiment verified that CXCL8 was a key factor mediating the proliferation and migration of GA cells. Conclusion The scRNA-seq analysis showed that high infiltration of immune cells with lower immune activity mediated heterogeneity to contribute to GA metastasis.
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Affiliation(s)
- Hongpeng Lu
- Department of Gastroenterology, The First Affiliated Hospital of Ningbo University, Ningbo, 315010, China
| | - Zhihui Xu
- Department of Gastroenterology, Ninghai County Second Hospital, Ningbo, 315600, China
| | - Lihong Shao
- Department of Gastroenterology, The First Affiliated Hospital of Ningbo University, Ningbo, 315010, China
| | - Peifei Li
- Department of Gastroenterology, The First Affiliated Hospital of Ningbo University, Ningbo, 315010, China
| | - Yonghong Xia
- Department of Gastroenterology, Ninghai County Second Hospital, Ningbo, 315600, China
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7
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Mo C, Sterpi M, Jeon H, Bteich F. Resistance to Anti-HER2 Therapies in Gastrointestinal Malignancies. Cancers (Basel) 2024; 16:2854. [PMID: 39199625 PMCID: PMC11352490 DOI: 10.3390/cancers16162854] [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: 06/21/2024] [Revised: 08/13/2024] [Accepted: 08/14/2024] [Indexed: 09/01/2024] Open
Abstract
Human epidermal growth factor 2 (HER2) is a tyrosine kinase receptor that interacts with multiple signaling pathways related to cellular growth and proliferation. Overexpression or amplification of HER2 is linked to various malignancies, and there have been decades of research dedicated to targeting HER2. Despite the landmark ToGA trial, progress in HER2-positive gastrointestinal malignancies has been hampered by drug resistance. This review examines current HER2 expression patterns and therapies for gastroesophageal, colorectal, biliary tract, and small bowel cancers, while dissecting potential resistance mechanisms that limit treatment effectiveness.
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Affiliation(s)
- Christiana Mo
- Department of Medical Oncology, Albert Einstein College of Medicine, Bronx, NY 10461, USA; (C.M.); (M.S.); (H.J.)
- Department of Medical Oncology, Montefiore Medical Center, Bronx, NY 10467, USA
| | - Michelle Sterpi
- Department of Medical Oncology, Albert Einstein College of Medicine, Bronx, NY 10461, USA; (C.M.); (M.S.); (H.J.)
- Department of Medical Oncology, Montefiore Medical Center, Bronx, NY 10467, USA
| | - Hyein Jeon
- Department of Medical Oncology, Albert Einstein College of Medicine, Bronx, NY 10461, USA; (C.M.); (M.S.); (H.J.)
- Department of Medical Oncology, Montefiore Medical Center, Bronx, NY 10467, USA
| | - Fernand Bteich
- Department of Medical Oncology, Albert Einstein College of Medicine, Bronx, NY 10461, USA; (C.M.); (M.S.); (H.J.)
- Department of Medical Oncology, Montefiore Medical Center, Bronx, NY 10467, USA
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8
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Singh H, Lowder KE, Kapner K, Kelly RJ, Zheng H, McCleary NJ, Abrams TA, Chan JA, Regan EM, Klempner SJ, Hannigan AM, Remland J, Brais LK, Andrews E, Yurgelun M, Cleary JM, Rubinson DA, Ritterhouse LL, Maron G, Aguirre AJ, Meyerhardt JA, Gardecki E, Lennerz JK, Wolpin BM, Enzinger PC. Clinical outcomes and ctDNA correlates for CAPOX BETR: a phase II trial of capecitabine, oxaliplatin, bevacizumab, trastuzumab in previously untreated advanced HER2+ gastroesophageal adenocarcinoma. Nat Commun 2024; 15:6833. [PMID: 39122726 PMCID: PMC11316091 DOI: 10.1038/s41467-024-51271-3] [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: 08/05/2024] [Indexed: 08/12/2024] Open
Abstract
Preclinical studies suggest that simultaneous HER2/VEGF blockade may have cooperative effects in gastroesophageal adenocarcinomas. In a single-arm investigator initiated clinical trial for patients with untreated advanced HER2+ gastroesophageal adenocarcinoma, bevacizumab was added to standard of care capecitabine, oxaliplatin, and trastuzumab in 36 patients (NCT01191697). Primary endpoint was objective response rate and secondary endpoints included safety, duration of response, progression free survival, and overall survival. The study met its primary endpoint with an objective response rate of 81% (95% CI 65-92%). Median progression free and overall survival were 14.0 (95% CI, 11.3-36.4) and 23.2 months (95% CI, 16.6-36.4), respectively. The median duration of response was 14.9 months. The regimen was well tolerated without unexpected or severe toxicities. In post-hoc ctDNA analysis, baseline ctDNA features were prognostic: Higher tumor fraction and alternative MAPK drivers portended worse outcomes. ctDNA at resistance identified oncogenic mutations and these were detectable 2-8 cycles prior to radiographic progression. Capecitabine, oxaliplatin, trastuzumab and bevacizumab shows robust clinical activity in HER2+ gastroesophageal adenocarcinoma. Combination of VEGF inhibitors with chemoimmunotherapy and anti-PD1 regimens is warranted.
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Affiliation(s)
- Harshabad Singh
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
- Harvard Medical School, Boston, MA, USA.
| | - Kristen E Lowder
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Kevin Kapner
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Ronan J Kelly
- Johns Hopkins Hospital & School of Medicine, Baltimore, MD, USA
- Charles A. Sammons Cancer Center at Baylor University Medical Center, Dallas, TX, USA
| | - Hui Zheng
- Harvard Medical School, Boston, MA, USA
- Massachusetts General Hospital, Boston, MA, USA
| | - Nadine Jackson McCleary
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Thomas A Abrams
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Jennifer A Chan
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Eileen M Regan
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Samuel J Klempner
- Harvard Medical School, Boston, MA, USA
- Massachusetts General Hospital, Boston, MA, USA
| | - Alison M Hannigan
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Joshua Remland
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Lauren K Brais
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Elizabeth Andrews
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Matthew Yurgelun
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - James M Cleary
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Douglas A Rubinson
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Lauren L Ritterhouse
- Harvard Medical School, Boston, MA, USA
- Center for Integrated Diagnostics, Department of Pathology, Massachusetts General Hospital, Boston, MA, USA
| | - Garrett Maron
- Center for Integrated Diagnostics, Department of Pathology, Massachusetts General Hospital, Boston, MA, USA
| | - Andrew J Aguirre
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
- The Broad Institute of Harvard and MIT, Cambridge, MA, USA
| | - Jeffrey A Meyerhardt
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Emma Gardecki
- Harvard Medical School, Boston, MA, USA
- Center for Integrated Diagnostics, Department of Pathology, Massachusetts General Hospital, Boston, MA, USA
| | - Jochen K Lennerz
- Harvard Medical School, Boston, MA, USA
- Center for Integrated Diagnostics, Department of Pathology, Massachusetts General Hospital, Boston, MA, USA
| | - Brian M Wolpin
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Peter C Enzinger
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
- Harvard Medical School, Boston, MA, USA.
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Eissler N, Altena R, Alhuseinalkhudhur A, Bragina O, Feldwisch J, Wuerth G, Loftenius A, Brun N, Axelsson R, Tolmachev V, Sörensen J, Frejd FY. Affibody PET Imaging of HER2-Expressing Cancers as a Key to Guide HER2-Targeted Therapy. Biomedicines 2024; 12:1088. [PMID: 38791050 PMCID: PMC11118066 DOI: 10.3390/biomedicines12051088] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2024] [Revised: 04/27/2024] [Accepted: 05/08/2024] [Indexed: 05/26/2024] Open
Abstract
Human epidermal growth factor receptor 2 (HER2) is a major prognostic and predictive marker overexpressed in 15-20% of breast cancers. The diagnostic reference standard for selecting patients for HER2-targeted therapy is based on the analysis of tumor biopsies. Previously patients were defined as HER2-positive or -negative; however, with the approval of novel treatment options, specifically the antibody-drug conjugate trastuzumab deruxtecan, many breast cancer patients with tumors expressing low levels of HER2 have become eligible for HER2-targeted therapy. Such patients will need to be reliably identified by suitable diagnostic methods. Biopsy-based diagnostics are invasive, and repeat biopsies are not always feasible. They cannot visualize the heterogeneity of HER2 expression, leading to a substantial number of misdiagnosed patients. An alternative and highly accurate diagnostic method is molecular imaging with radiotracers. In the case of HER2, various studies demonstrate the clinical utility and feasibility of such approaches. Radiotracers based on Affibody® molecules, small, engineered affinity proteins with a size of ~6.5 kDa, are clinically validated molecules with favorable characteristics for imaging. In this article, we summarize the HER2-targeted therapeutic landscape, describe our experience with imaging diagnostics for HER2, and review the currently available clinical data on HER2-Affibody-based molecular imaging as a novel diagnostic tool in breast cancer and beyond.
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Affiliation(s)
| | - Renske Altena
- Department of Oncology-Pathology, Karolinska Institutet, 17164 Solna, Sweden
- Medical Unit Breast, Endocrine Tumors and Sarcoma, Theme Cancer, Karolinska Comprehensive Cancer Center, Karolinska University Hospital, 17164 Solna, Sweden
- Medical Radiation Physics and Nuclear Medicine, Functional Unit of Nuclear Medicine, Karolinska University Hospital, 14157 Huddinge, Sweden
| | - Ali Alhuseinalkhudhur
- Nuclear Medicine and PET, Department of Surgical Sciences, Uppsala University, 75310 Uppsala, Sweden
- Department of Immunology, Genetics and Pathology, Uppsala University, 75310 Uppsala, Sweden
| | - Olga Bragina
- Department of Nuclear Therapy and Diagnostic, Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, 634055 Tomsk, Russia
- Research Centrum for Oncotheranostics, Research School of Chemistry and Applied Biomedical Sciences, Tomsk Polytechnic University, 634050 Tomsk, Russia
| | | | | | | | | | - Rimma Axelsson
- Medical Radiation Physics and Nuclear Medicine, Functional Unit of Nuclear Medicine, Karolinska University Hospital, 14157 Huddinge, Sweden
- Department of Molecular Medicine and Surgery, Karolinska Institutet, 14152 Stockholm, Sweden
| | - Vladimir Tolmachev
- Department of Immunology, Genetics and Pathology, Uppsala University, 75310 Uppsala, Sweden
| | - Jens Sörensen
- Nuclear Medicine and PET, Department of Surgical Sciences, Uppsala University, 75310 Uppsala, Sweden
| | - Fredrik Y. Frejd
- Affibody AB, 17165 Solna, Sweden
- Department of Immunology, Genetics and Pathology, Uppsala University, 75310 Uppsala, Sweden
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Tanei T, Seno S, Sota Y, Hatano T, Kitahara Y, Abe K, Masunaga N, Tsukabe M, Yoshinami T, Miyake T, Shimoda M, Matsuda H, Shimazu K. High HER2 Intratumoral Heterogeneity Is a Predictive Factor for Poor Prognosis in Early-Stage and Locally Advanced HER2-Positive Breast Cancer. Cancers (Basel) 2024; 16:1062. [PMID: 38473420 DOI: 10.3390/cancers16051062] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Revised: 02/20/2024] [Accepted: 02/26/2024] [Indexed: 03/14/2024] Open
Abstract
PURPOSE Breast cancer tumors frequently have intratumoral heterogeneity (ITH). Tumors with high ITH cause therapeutic resistance and have human epidermal growth factor receptor 2 (HER2) heterogeneity in response to HER2-targeted therapies. This study aimed to investigate whether high HER2 heterogeneity levels were clinically related to a poor prognosis for HER2-targeted adjuvant therapy resistance in primary breast cancers. METHODS This study included patients with primary breast cancer (n = 251) treated with adjuvant HER2-targeted therapies. HER2 heterogeneity was manifested by the shape of HER2 fluorescence in situ hybridization amplification (FISH) distributed histograms with the HER2 gene copy number within a tumor sample. Each tumor was classified into a biphasic grade graph (high heterogeneity [HH]) group or a monophasic grade graph (low heterogeneity [LH]) group based on heterogeneity. Both groups were evaluated for disease-free survival (DFS) and overall survival (OS) for a median of ten years of annual follow-up. RESULTS Of 251 patients with HER2-positive breast cancer, 46 (18.3%) and 205 (81.7%) were classified into the HH and LH groups, respectively. The HH group had more distant metastases and a poorer prognosis than the LH group (DFS: p < 0.001 (HH:63% vs. LH:91% at 10 years) and for the OS: p = 0.012 (HH:78% vs. LH:95% at 10 years). CONCLUSIONS High HER2 heterogeneity is a poor prognostic factor in patients with HER2-positive breast cancer. A novel approach to heterogeneity, which is manifested by the shape of HER2 FISH distributions, might be clinically useful in the prognosis prediction of patients after HER2 adjuvant therapy.
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Affiliation(s)
- Tomonori Tanei
- Department of Breast and Endocrine Surgery, Graduate School of Medicine, Osaka University, 2-2-E10 Yamadaoka, Suita 565-0871, Osaka, Japan
| | - Shigeto Seno
- Department of Bioinformatic Engineering, Graduate School of Information Science and Technology, Osaka University, 1-5 Yamadaoka, Suita 565-0871, Osaka, Japan
| | - Yoshiaki Sota
- Department of Breast and Endocrine Surgery, Graduate School of Medicine, Osaka University, 2-2-E10 Yamadaoka, Suita 565-0871, Osaka, Japan
| | - Takaaki Hatano
- Department of Breast and Endocrine Surgery, Graduate School of Medicine, Osaka University, 2-2-E10 Yamadaoka, Suita 565-0871, Osaka, Japan
| | - Yuri Kitahara
- Department of Breast and Endocrine Surgery, Graduate School of Medicine, Osaka University, 2-2-E10 Yamadaoka, Suita 565-0871, Osaka, Japan
| | - Kaori Abe
- Department of Breast and Endocrine Surgery, Graduate School of Medicine, Osaka University, 2-2-E10 Yamadaoka, Suita 565-0871, Osaka, Japan
| | - Nanae Masunaga
- Department of Breast and Endocrine Surgery, Graduate School of Medicine, Osaka University, 2-2-E10 Yamadaoka, Suita 565-0871, Osaka, Japan
| | - Masami Tsukabe
- Department of Breast and Endocrine Surgery, Graduate School of Medicine, Osaka University, 2-2-E10 Yamadaoka, Suita 565-0871, Osaka, Japan
| | - Tetsuhiro Yoshinami
- Department of Breast and Endocrine Surgery, Graduate School of Medicine, Osaka University, 2-2-E10 Yamadaoka, Suita 565-0871, Osaka, Japan
| | - Tomohiro Miyake
- Department of Breast and Endocrine Surgery, Graduate School of Medicine, Osaka University, 2-2-E10 Yamadaoka, Suita 565-0871, Osaka, Japan
| | - Masafumi Shimoda
- Department of Breast and Endocrine Surgery, Graduate School of Medicine, Osaka University, 2-2-E10 Yamadaoka, Suita 565-0871, Osaka, Japan
| | - Hideo Matsuda
- Department of Bioinformatic Engineering, Graduate School of Information Science and Technology, Osaka University, 1-5 Yamadaoka, Suita 565-0871, Osaka, Japan
| | - Kenzo Shimazu
- Department of Breast and Endocrine Surgery, Graduate School of Medicine, Osaka University, 2-2-E10 Yamadaoka, Suita 565-0871, Osaka, Japan
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Angerilli V, Ghelardi F, Nappo F, Grillo F, Parente P, Lonardi S, Luchini C, Pietrantonio F, Ugolini C, Vanoli A, Fassan M. Claudin-18.2 testing and its impact in the therapeutic management of patients with gastric and gastroesophageal adenocarcinomas: A literature review with expert opinion. Pathol Res Pract 2024; 254:155145. [PMID: 38277741 DOI: 10.1016/j.prp.2024.155145] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2023] [Revised: 01/10/2024] [Accepted: 01/16/2024] [Indexed: 01/28/2024]
Abstract
Claudin-18.2 (CLDN18.2) is a member of the tight junction protein family and is a highly selective biomarker with frequent abnormal expression during the occurrence and development of various primary malignant tumors, including gastric cancer (GC) and esophago-gastric junction adenocarcinomas (EGJA). For these reasons, CLDN18.2 has been investigated as a therapeutic target for GC/EGJA malignancies. Recently, zolbetuximab has been proposed as a new standard of care for patients with CLDN18.2-positive, HER2-negative, locally advanced and metastatic GC/EGJA. The use of CLDN18 IHC assays to select patients who might benefit from anti-CLDN18.2 therapy is currently entering clinical practice. In this setting, pathologists play a central role in therapeutic decision-making. Accurate biomarker assessment is essential to ensure the best therapeutic option for patients. In the present review, we provide a comprehensive overview of available evidence on CLDN18.2 testing and its impact on the therapeutic management of patients with GC/EGJA, as well as some practical suggestions for CLDN18.2 staining interpretation and potential pitfalls in the real-world setting.
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Affiliation(s)
- Valentina Angerilli
- Department of Medicine (DIMED), Surgical Pathology & Cytopathology Unit, University of Padua, Padua, Italy
| | - Filippo Ghelardi
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Floriana Nappo
- Medical Oncology 1, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy
| | - Federica Grillo
- IRCCS Ospedale Policlinico San Martino, Genoa, Italy; Anatomic Pathology, Department of Surgical Sciences and Integrated Diagnostics (DISC), University of Genova, Italy.
| | - Paola Parente
- Unit of Pathology, Fondazione IRCCS Ospedale Casa Sollievo della Sofferenza, San Giovanni Rotondo, FG, Italy.
| | - Sara Lonardi
- Medical Oncology 3, Istituto Oncologico Veneto IOV-IRCCS, Padua, Italy
| | - Claudio Luchini
- Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy
| | - Filippo Pietrantonio
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Clara Ugolini
- Department of Surgical, Medical, Molecular Pathology and Critical Area, University of Pisa, Pisa, Italy
| | - Alessandro Vanoli
- Anatomic Pathology Unit, Department of Molecular Medicine, University of Pavia and Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Matteo Fassan
- Department of Medicine (DIMED), Surgical Pathology & Cytopathology Unit, University of Padua, Padua, Italy; Veneto Institute of Oncology (IOV-IRCCS), Padua, Italy
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12
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Tsimafeyeu I, Raskin G. Challenges of FGFR2 Testing in Gastric Cancer. Oncol Rev 2023; 17:11790. [PMID: 38155920 PMCID: PMC10752926 DOI: 10.3389/or.2023.11790] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Accepted: 11/29/2023] [Indexed: 12/30/2023] Open
Affiliation(s)
- Ilya Tsimafeyeu
- Bureau for Cancer Research, New York Office, New York, NY, United States
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13
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Angerilli V, Parente P, Campora M, Ugolini C, Battista S, Cassoni P, Gambella A, Cavallin F, De Lisi G, Vanoli A, Grillo F, Mastracci L, Fassan M. HER2-low in gastro-oesophageal adenocarcinoma: a real-world pathological perspective. J Clin Pathol 2023; 76:815-821. [PMID: 37055161 DOI: 10.1136/jcp-2023-208767] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Accepted: 04/03/2023] [Indexed: 04/15/2023]
Abstract
AIMS In the DESTINY-Gastric01 trial, a novel HER2-targeted antibody-drug conjugate trastuzumab deruxtecan proved to be effective in HER2-low gastro-oesophageal adenocarcinomas. The aim of our study is to investigate the clinicopathological and molecular features of HER2-low gastric/gastro-oesophageal junction cancers in the real-world setting of a large multi-Institutional series. METHODS We retrospectively evaluated 1210 formalin-fixed paraffin-embedded samples of gastro-oesophageal adenocarcinomas which were analysed by immunohistochemistry for HER2 protein expression in 8 Italian surgical pathology units from January 2018 to June 2022. We assessed the prevalence of HER2-low (ie, HER2 1+ and HER2 2+ without amplification) and its correlation with clinical and histopathological features, other biomarkers' status, including mismatch repair/microsatellite instability status, Epstein-Barr encoding region (EBER) and PD-L1 Combined Positive Score. RESULTS HER2 status could be assessed in 1189/1210 cases, including 710 HER2 0 cases, 217 HER2 1+, 120 not amplified HER2 2+, 41 amplified HER2 2+ and 101 HER2 3+. The estimated prevalence of HER2-low was 28.3% (95% CI 25.8% to 31.0%) overall, and was higher in biopsy specimens (34.9%, 95% CI 31.2% to 38.8%) compared with surgical resection specimens (21.0%, 95% CI 17.7% to 24.6%) (p<0.0001). Moreover, HER2-low prevalence ranged from 19.1% to 40.6% among centres (p=0.0005). CONCLUSIONS This work shows how the expansion of the HER2 spectrum might raise problems in reproducibility, especially in biopsy specimens, decreasing interlaboratory and interobserver concordance. If controlled trials confirm the promising activity of novel anti-HER2 agents in HER2-low gastro-oesophageal cancers, a shift in the interpretation of HER2 status may need to be pursued.
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Affiliation(s)
- Valentina Angerilli
- Department of Medicine (DIMED), Surgical Pathology Unit, University of Padua, Padova, Italy
| | - Paola Parente
- Unit of Pathology, Fondazione IRCCS Ospedale Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
| | - Michela Campora
- Department of Laboratory Medicine, Pathology Unit, Public Healthcare Trust of the Autonomous Province of Trento, Santa Chiara Hospital, Trento, Italy
| | - Clara Ugolini
- Department of Surgical, Medical, Molecular Pathology and Critical Area, University of Pisa, Pisa, Italy
| | - Serena Battista
- Department of Pathology, Santa Maria della Misericordia Hospital, Udine, Italy
| | - Paola Cassoni
- Department of Medical Sciences, Pathology Unit, University of Turin, Torino, Italy
| | - Alessandro Gambella
- Department of Medical Sciences, Pathology Unit, University of Turin, Torino, Italy
| | | | - Giuseppe De Lisi
- IRCCS San Matteo Hospital, Pavia, Italy
- Anatomic Pathology Unit, Department of Molecular Medicine, University of Pavia, Pavia, Italy
| | - Alessandro Vanoli
- IRCCS San Matteo Hospital, Pavia, Italy
- Anatomic Pathology Unit, Department of Molecular Medicine, University of Pavia, Pavia, Italy
| | - Federica Grillo
- IRCCS Ospedale Policlinico San Martino, Genova, Italy
- Anatomic Pathology, Department of Surgical Sciences and Integrated Diagnostics (DISC), Univeristy of Genova, Genova, Italy
| | - Luca Mastracci
- IRCCS Ospedale Policlinico San Martino, Genova, Italy
- Anatomic Pathology, Department of Surgical Sciences and Integrated Diagnostics (DISC), Univeristy of Genova, Genova, Italy
| | - Matteo Fassan
- Department of Medicine (DIMED), Surgical Pathology Unit, University of Padua, Padova, Italy
- Veneto Institute of Oncology IOV - IRCCS, Padua, Italy
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14
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Shen S, Ma W, Brown D, Da Cruz Paula A, Zhou Q, Iaosonos A, Tessier-Cloutier B, Ross DS, Troso-Sandoval T, Reis-Filho JS, Abu-Rustum N, Zhang Y, Ellenson LH, Weigelt B, Makker V, Chui MH. HER2 Genetic Intratumor Heterogeneity Is Associated With Resistance to Trastuzumab and Trastuzumab Emtansine Therapy in Recurrent High-Grade Endometrial Cancer. Mod Pathol 2023; 36:100299. [PMID: 37558129 PMCID: PMC10841308 DOI: 10.1016/j.modpat.2023.100299] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2023] [Revised: 07/11/2023] [Accepted: 07/31/2023] [Indexed: 08/11/2023]
Abstract
Anti-HER2 targeted therapies have recently demonstrated clinical activity in the treatment of high-grade endometrial carcinomas (ECs), particularly serous carcinomas with HER2 amplification and/or overexpression. Intratumor heterogeneity of HER2 amplification or HER2 genetic intratumor heterogeneity (G-ITH) has been associated with resistance to anti-HER2 therapies in breast and gastroesophageal cancers; however, its clinical relevance in EC is unknown. To characterize HER2 G-ITH in EC, archival specimens from a clinically annotated cohort of 57 ECs treated with trastuzumab or trasutuzmab emtansine in the recurrent (n = 38) or adjuvant (n = 19) setting were subjected to central pathology review, HER2 assessment by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH), and next-generation sequencing. HER2 G-ITH, defined as HER2 amplification in 5% to 50% of tumor cells examined by FISH, was identified in 36% (19/53) of ECs and was associated with lower HER2 copy number and levels of protein expression. HER2 IHC revealed spatially distinct areas of strong expression juxtaposed with areas of low/absent expression in tumors with the "cluster" pattern of G-ITH, whereas the "mosaic" pattern was typically associated with a diffuse admixture of cells with variable levels of HER2 expression. HER2 G-ITH was frequently observed in cases with IHC/FISH or FISH/next-generation sequencing discrepancies and/or with an equivocal/negative FISH result (9/13, 69%). Although the objective response rate to anti-HER2 therapy in recurrent ECs was 52% (13/25) for tumors lacking HER2 G-ITH, none (0%, 0/10) of the patients with HER2 G-ITH achieved a complete or partial response (P = .005). HER2 G-ITH was significantly associated with worse progression-free survival (hazard ratio, 2.88; 95% CI, 1.33-6.27; P = .005) but not overall survival. HER2 IHC score, HER2/CEP17 ratio, HER2 copy number, histologic subtype, and other genetic alterations, including PIK3CA hotspot mutations, were not significantly associated with therapeutic response or survival outcomes. Treatment responses were not restricted to serous carcinomas, supporting consideration of anti-HER2 therapy in patients with HER2-positive high-grade ECs of non-serous histology. Our results demonstrate that HER2 G-ITH is an important determinant of response to trastuzumab and trastuzumab emtansine in EC, providing a rationale for the development of novel therapeutic strategies to target HER2-nonamplified resistant tumor subpopulations, such as HER2 antibody-drug conjugates with bystander effects.
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Affiliation(s)
- Sherry Shen
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Weining Ma
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - David Brown
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Arnaud Da Cruz Paula
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Qin Zhou
- Department of Biostatistics and Epidemiology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Alexia Iaosonos
- Department of Biostatistics and Epidemiology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Basile Tessier-Cloutier
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Dara S Ross
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | | | - Jorge S Reis-Filho
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Nadeem Abu-Rustum
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Yanming Zhang
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Lora H Ellenson
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Britta Weigelt
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Vicky Makker
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | - M Herman Chui
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
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15
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Brown EL, Shmuel S, Mandleywala K, Panikar SS, Berry NK, Rao Y, Zidel A, Lewis JS, Pereira PMR. Immuno-PET Detects Antibody-Drug Potency on Coadministration with Statins. J Nucl Med 2023; 64:1638-1646. [PMID: 37385676 PMCID: PMC10586480 DOI: 10.2967/jnumed.122.265172] [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: 11/16/2022] [Revised: 05/12/2023] [Indexed: 07/01/2023] Open
Abstract
The human epidermal growth factor receptor 2 (HER2)-targeting trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd) are antibody-drug conjugates (ADC) clinically used to treat HER2-positive breast cancer, with the latter receiving clinical approval in 2021 for HER2-positive gastric cancer. Lovastatin, a cholesterol-lowering drug, temporally elevates cell-surface HER2 in ways that enhance HER2-ADC binding and internalization. Methods: In an NCIN87 gastric xenograft model and a gastric patient-derived xenograft model, we used the 89Zr-labeled or 64Cu-labeled anti-HER2 antibody trastuzumab to investigate the dosing regimen of ADC therapy with and without coadministration of lovastatin. We compared the ADC efficacy of a multiple-dose ADC regime, which replicates the clinical dose regimen standard, with a single-dose regime. Results: T-DM1/lovastatin treatment inhibited tumor growth, regardless of multiple- or single-dose T-DM1 administration. Coadministration of lovastatin with T-DM1 or T-DXd as a single dose enhanced tumor growth inhibition, which was accompanied by a decrease in signal on HER2-targeted immuno-PET and a decrease in HER2-mediated signaling at the cellular level. DNA damage signaling was increased on ADC treatment in vitro. Conclusion: Our data from a gastric cancer xenograft show the utility of HER2-targeted immuno-PET to inform the tumor response to ADC therapies in combination with modulators of cell-surface target availability. Our studies also demonstrate that statins enhance ADC efficacy in both a cell-line and a patient-derived xenograft model in ways that enable a single-dose administration of the ADC.
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Affiliation(s)
- Emma L Brown
- Department of Radiology, Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri
| | - Shayla Shmuel
- Department of Radiology, Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri
| | - Komal Mandleywala
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Sandeep Surendra Panikar
- Department of Radiology, Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri
| | - Na-Keysha Berry
- Department of Radiology, Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri
| | - Yi Rao
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Abbey Zidel
- Department of Radiology, Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri
- Department of Biology, Washington University School of Medicine, St. Louis, Missouri
| | - Jason S Lewis
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York
- Department of Pharmacology, Weill Cornell Medical College, New York, New York
- Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, New York
- Department of Radiology, Weill Cornell Medical College, New York, New York; and
- Radiochemistry and Molecular Imaging Probes Core, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Patrícia M R Pereira
- Department of Radiology, Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri;
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16
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Radford M, Abushukair H, Hentzen S, Cavalcante L, Saeed A. Targeted and Immunotherapy Approaches in HER2-Positive Gastric and Gastroesophageal Junction Adenocarcinoma: A New Era. JOURNAL OF IMMUNOTHERAPY AND PRECISION ONCOLOGY 2023; 6:150-157. [PMID: 37637236 PMCID: PMC10448730 DOI: 10.36401/jipo-22-36] [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: 12/14/2022] [Revised: 03/28/2023] [Accepted: 05/05/2023] [Indexed: 08/29/2023]
Abstract
HER2-targeted therapy with the HER2 monoclonal antibody trastuzumab has achieved impressive outcomes in the first-line settings of patients with advanced gastric and gastroesophageal junction (GEJ) adenocarcinoma overexpressing HER2. However, considering that a substantial proportion of those patients eventually relapses, as well as the relatively limited performance of those agents in second-line settings, a deeper understanding of resistance mechanisms is needed for enhanced guidance for patients' therapeutic selection in the second-line setting and beyond. In this review, we highlight trastuzumab's (HER2-targeting agent) performance in patients with gastric or GEJ cancer, with insight into mechanisms of resistance. We also discuss the new integration of PD-1 inhibitor pembrolizumab into the trastuzumab for gastric cancer frontline regimen, the latest addition of trastuzumab deruxtecan to the treatment armamentarium, and the potential of pipeline HER2-targeting approaches and combinations in patients with gastric or GEJ adenocarcinoma.
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Affiliation(s)
- Maluki Radford
- Department of Medicine, Division of Medical Oncology, Kansas University Medical Center, Kansas City, KS, USA
| | - Hassan Abushukair
- Department of Medicine, Jordan University of Science and Technology, Irbid, Jordan
| | - Stijn Hentzen
- Department of Medicine, Division of Medical Oncology, Kansas University Medical Center, Kansas City, KS, USA
| | - Ludimila Cavalcante
- Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA, USA
| | - Anwaar Saeed
- Department of Medicine, Division of Hematology and Oncology, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA
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17
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Parente P, Grillo F, Vanoli A, Mastracci L, Fassan M. A charming molecular profile in the wrong tissue: the pathologist in the era of molecular diagnostics in the gastrointestinal tract. Expert Rev Mol Diagn 2023; 23:1045-1047. [PMID: 37997281 DOI: 10.1080/14737159.2023.2288267] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2023] [Accepted: 11/22/2023] [Indexed: 11/25/2023]
Affiliation(s)
- Paola Parente
- Unit of Pathology, Fondazione IRCCS Ospedale Casa Sollievo Della Sofferenza, San Giovanni Rotondo, FG, Italy
| | - Federica Grillo
- Anatomic Pathology, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
- Anatomic Pathology, Department of Surgical Sciences and Integrated Diagnostics (DISC), University of Genova, Genoa, Italy
| | - Alessandro Vanoli
- Anatomic Pathology Unit, Department of Molecular Medicine, University of Pavia, Pavia, Italy
- Anatomic Pathology Unit, IRCCS San Matteo Hospital, Pavia, Italy
| | - Luca Mastracci
- Anatomic Pathology, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
- Anatomic Pathology, Department of Surgical Sciences and Integrated Diagnostics (DISC), University of Genova, Genoa, Italy
| | - Matteo Fassan
- Surgical Pathology Unit, Department of Medicine (DIMED), University Hospital of Padua, Padua, Italy
- Unit of Pathology, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy
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18
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Albin J, Fahrig L, Siemanowski J, Rehkaemper J, Gebauer F, Zander T, Buettner R, Bruns CJ, Schroeder W, Alakus H, Hieggelke L, Quaas A. FGFR2-amplified tumor clones are markedly heterogeneously distributed in carcinomas of the upper gastrointestinal tract. J Cancer Res Clin Oncol 2023; 149:5289-5300. [PMID: 36416959 PMCID: PMC10349760 DOI: 10.1007/s00432-022-04460-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Accepted: 11/01/2022] [Indexed: 11/24/2022]
Abstract
BACKGROUND FGFR2 is a therapy-relevant target in tumors of the upper gastrointestinal tract (GIT), and clinical trials are currently underway to test the efficacy of FGFR2 inhibitors. Tumor heterogeneity is one of the relevant causes of treatment failure. Almost nothing is known about the heterogeneous distribution of FGFR2-amplified clones in adenocarcinomas of the upper GIT. PATIENTS AND METHODS To assess FGFR2 gene copy number alteration and intratumoral heterogeneity of upper GIT adenocarcinomas, we analyzed 893 patient-derived formalin-fixed paraffin-embedded tumor specimens, including primary operated and neoadjuvant-treated tumors (462 gastric carcinomas and 429 esophageal adenocarcinomas) as well as complementary lymph node and distant metastasis by fluorescence in situ hybridization. RESULTS Twenty-six gastric tumors (5.6%) and 21 esophageal adenocarcinomas (4.9%) showed FGFR2 amplification. Overall, 93% of gastric carcinomas and 83% of esophageal carcinomas showed heterogeneous amplification. FGFR2 amplification was found in different histological growth patterns, including intestinal and diffuse type according to the Lauren classification. In the primary gastric carcinoma group, FGFR2 amplification was associated with poor prognosis (p = 0.005). CONCLUSION Homogeneous FGFR2 amplification in tumors of the upper GIT is the exception. This has highly relevant implications in the nature of FGFR2 diagnostics (sufficient tumor cell number, determination of amplification at metastasis versus primary tumor, etc.) and on the response probability of appropriate inhibitors. It is relevant that the often poorly treatable and aggressive subtype of diffuse carcinomas (poorly cohesive carcinomas) also shows FGFR2 amplification and that an individualized therapy option with FGFR2 inhibitors could be an option in this group.
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Affiliation(s)
- Jan Albin
- Institute of Pathology, University Hospital Cologne, Kerpener Street 62, 50937, Cologne, Germany
| | - Luca Fahrig
- Department of General, Visceral and Cancer Surgery, University Hospital Cologne, Cologne, Germany
| | - Janna Siemanowski
- Institute of Pathology, University Hospital Cologne, Kerpener Street 62, 50937, Cologne, Germany
| | - Jan Rehkaemper
- Institute of Pathology, University Hospital Cologne, Kerpener Street 62, 50937, Cologne, Germany
| | - Florian Gebauer
- Department of General, Visceral and Cancer Surgery, University Hospital Cologne, Cologne, Germany
| | - Thomas Zander
- Department of Internal Medicine I, University Hospital Cologne, Cologne, Germany
| | - Reinhard Buettner
- Institute of Pathology, University Hospital Cologne, Kerpener Street 62, 50937, Cologne, Germany
| | | | - Wolfgang Schroeder
- Department of General, Visceral and Cancer Surgery, University Hospital Cologne, Cologne, Germany
| | - Hakan Alakus
- Department of General, Visceral and Cancer Surgery, University Hospital Cologne, Cologne, Germany
| | - Lena Hieggelke
- Institute of Pathology, University Hospital Cologne, Kerpener Street 62, 50937, Cologne, Germany
| | - Alexander Quaas
- Institute of Pathology, University Hospital Cologne, Kerpener Street 62, 50937, Cologne, Germany.
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19
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Constantin A, Constantin R, Achim F, Socea B, Predescu D. Pregnancy and Gastric Cancer: A Narrative Review. Diagnostics (Basel) 2023; 13:diagnostics13111909. [PMID: 37296761 DOI: 10.3390/diagnostics13111909] [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: 02/27/2023] [Revised: 05/22/2023] [Accepted: 05/26/2023] [Indexed: 06/12/2023] Open
Abstract
Cases of digestive cancers diagnosed during pregnancy are rare. The increasing prevalence of pregnancy in women aged 30-39 years (and not exceptionally 40-49 years) could explain the frequent co-occurrence of cancers and pregnancy. The diagnosis of digestive cancers in pregnancy is difficult due to the overlap between neoplasm symptomatology and the clinical picture of pregnancy. A paraclinical evaluation may also be difficult depending on the trimester of the pregnancy. Diagnosis is also delayed by practitioners' hesitation to use invasive investigations (imaging, endoscopy, etc.) due to fetal safety concerns. Therefore, digestive cancers are often diagnosed during pregnancy in advanced stages, where complications such as occlusions, perforations, and cachexia have already arisen. In this review, we highlight the epidemiology, clinical aspects, paraclinical evaluation, and particularities of the diagnosis and treatment of gastric cancer during pregnancy.
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Affiliation(s)
- Adrian Constantin
- Department of Esophageal and General Surgery, Sf. Maria Clinical Hospital Bucharest, 011192 Bucharest, Romania
- Faculty of Medicine, Carol Davila University of Medicine and Pharmacy Bucharest, 050474 Bucharest, Romania
| | - Roxana Constantin
- Department of Obstetrics and Gynecology, Sanador Hospital, 010991 Bucharest, Romania
| | - Florin Achim
- Department of Esophageal and General Surgery, Sf. Maria Clinical Hospital Bucharest, 011192 Bucharest, Romania
- Faculty of Medicine, Carol Davila University of Medicine and Pharmacy Bucharest, 050474 Bucharest, Romania
| | - Bogdan Socea
- Faculty of Medicine, Carol Davila University of Medicine and Pharmacy Bucharest, 050474 Bucharest, Romania
- Department of Surgery, Sf. Pantelimon Emergency Clinical Hospital, 021659 Bucharest, Romania
| | - Dragos Predescu
- Department of Esophageal and General Surgery, Sf. Maria Clinical Hospital Bucharest, 011192 Bucharest, Romania
- Faculty of Medicine, Carol Davila University of Medicine and Pharmacy Bucharest, 050474 Bucharest, Romania
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20
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Rao Y, Samuels Z, Carter LM, Monette S, Panikar S, Pereira P, Lewis J. Statins enhance the efficacy of HER2-targeting radioligand therapy in drug-resistant gastric cancers. Proc Natl Acad Sci U S A 2023; 120:e2220413120. [PMID: 36972439 PMCID: PMC10083538 DOI: 10.1073/pnas.2220413120] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Accepted: 03/03/2023] [Indexed: 03/29/2023] Open
Abstract
Human epidermal growth factor receptor 2 (HER2) is overexpressed in various cancer types. HER2-targeting trastuzumab plus chemotherapy is used as first-line therapy for HER2-positive recurrent or primary metastatic gastric cancer, but intrinsic and acquired trastuzumab resistance inevitably develop over time. To overcome gastric cancer resistance to HER2-targeted therapies, we have conjugated trastuzumab with a beta-emitting therapeutic isotope, lutetium-177, to deliver radiation locally to gastric tumors with minimal toxicity. Because trastuzumab-based targeted radioligand therapy (RLT) requires only the extramembrane domain binding of membrane-bound HER2 receptors, HER2-targeting RLT can bypass any resistance mechanisms that occur downstream of HER2 binding. Leveraging our previous discoveries that statins, a class of cholesterol-lowering drugs, can enhance the cell surface-bound HER2 to achieve effective drug delivery in tumors, we proposed that the combination of statins and [177Lu]Lu-trastuzumab-based RLT can enhance the therapeutic efficacy of HER2-targeted RLT in drug-resistant gastric cancers. We demonstrate that lovastatin elevates cell surface HER2 levels and increases the tumor-absorbed radiation dose of [177Lu]Lu-DOTA-trastuzumab. Furthermore, lovastatin-modulated [177Lu]Lu-DOTA-trastuzumab RLT durably inhibits tumor growth and prolongs overall survival in mice bearing NCI-N87 gastric tumors and HER2-positive patient-derived xenografts (PDXs) of known clinical resistance to trastuzumab therapy. Statins also exhibit a radioprotective effect, reducing radiotoxicity in a mice cohort given the combination of statins and [177Lu]Lu-DOTA-trastuzumab. Since statins are commonly prescribed to patients, our results strongly support the feasibility of clinical studies that combine lovastatin with HER2-targeted RLT in HER2-postive patients and trastuzumab-resistant HER2-positive patients.
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Affiliation(s)
- Yi Rao
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY10065
| | - Zachary Samuels
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY10065
| | - Lukas M. Carter
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY10065
| | - Sebastien Monette
- Laboratory of Comparative Pathology, Memorial Sloan Kettering Cancer Center, The Rockefeller University, Weill Cornell Medicine, New York, NY10065
| | - Sandeep Surendra Panikar
- Department of Radiology, Washington University School of Medicine in St. Louis, St. Louis, MO63110
| | - Patricia M. R. Pereira
- Department of Radiology, Washington University School of Medicine in St. Louis, St. Louis, MO63110
| | - Jason S. Lewis
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY10065
- Department of Pharmacology, Weill Cornell Medicine, New York, NY10021
- Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY10065
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21
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Yang J, Shi Z, Zhang X, Liu Q, Cui X, Li L, Liu B, Wei J. Real-world clinical outcomes of the combination of anti-PD-1 antibody, trastuzumab, and chemotherapy for HER2-positive gastric/gastroesophageal junction cancer. Cancer Med 2023; 12:9517-9526. [PMID: 36912199 PMCID: PMC10166915 DOI: 10.1002/cam4.5722] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Revised: 01/18/2023] [Accepted: 02/08/2023] [Indexed: 03/14/2023] Open
Abstract
BACKGROUND Previous clinical trials indicated the addition of anti-PD-1 antibody remarkably improved the efficacy of trastuzumab and chemotherapy in patients with HER2-positive gastric/gastroesophageal junction (GEJ) cancer. However, no real-world experiences have been reported yet. METHODS We retrospectively analyzed 1212 patients with gastric/GEJ cancer treated at Nanjing Drum Tower Hospital between 2019 and 2022. Among 138 patients with HER2-positive gastric/GEJ cancer, 47 patients receiving at least two doses of the combination regimen with anti-PD-1 antibody, trastuzumab, and chemotherapy were recruited in the study population, and 38 out of 47 patients with measurable disease were included in the efficacy population. Progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and toxicity profiles were reported. RESULTS In the study population, 37 (78.7%) received the study therapy as a first-line treatment. In the efficacy population, the ORR and DCR were 76.3% and 94.7%, respectively. The overall median PFS was 9.1 months (95% confidence interval [CI] 6.3-11.9 months). For the first-line treatment, the mPFS was 10 months, and 7 months for the second-line. Among 14 patients who failed the study treatment, three (21.4%) developed brain metastasis as the first failure site. No significant association was found between PFS and the expression of PD-L1. 22.2% of patients developed grade 3 treatment-related adverse events (TRAEs). No treatment-related grade ≥4 adverse events or deaths occurred. CONCLUSION This real-world study validated the combination regimen's high efficacy and good tolerance in patients with HER2-positive gastric/GEJ cancer. An increased incidence of brain metastasis was observed in patients who failed this regimen.
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Affiliation(s)
- Ju Yang
- The Comprehensive Cancer Centre of Drum Tower HospitalMedical School of Nanjing University and Clinical Cancer Institute of Nanjing UniversityNanjingChina
| | - Zhan Shi
- The Comprehensive Cancer Centre of Drum Tower HospitalMedical School of Nanjing University and Clinical Cancer Institute of Nanjing UniversityNanjingChina
| | - Xin Zhang
- The Comprehensive Cancer Centre of Drum Tower HospitalMedical School of Nanjing University and Clinical Cancer Institute of Nanjing UniversityNanjingChina
| | - Qin Liu
- The Comprehensive Cancer Centre of Drum Tower HospitalMedical School of Nanjing University and Clinical Cancer Institute of Nanjing UniversityNanjingChina
| | - Xiaobin Cui
- The Department of Pathology of Drum Tower HospitalMedical School of Nanjing UniversityNanjingChina
| | - Lin Li
- The Department of Pathology of Drum Tower HospitalMedical School of Nanjing UniversityNanjingChina
| | - Baorui Liu
- The Comprehensive Cancer Centre of Drum Tower HospitalMedical School of Nanjing University and Clinical Cancer Institute of Nanjing UniversityNanjingChina
| | - Jia Wei
- The Comprehensive Cancer Centre of Drum Tower HospitalMedical School of Nanjing University and Clinical Cancer Institute of Nanjing UniversityNanjingChina
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22
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Subasinghe D, Acott N, Mahesh PKB, Sivaganesh S, Munasinghe S, Kumarasinghe MP, Samarasekera DN, Lokuhetty MDS. Human epidermal growth factor receptor-2 gene expression positivity determined by silver in situ hybridization/immunohistochemistry methods and associated factors in a cohort of Sri Lankan patients with gastric adenocarcinoma: a prospective study. J Int Med Res 2023; 51:3000605231154403. [PMID: 36814374 PMCID: PMC9950620 DOI: 10.1177/03000605231154403] [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] [Indexed: 02/24/2023] Open
Abstract
OBJECTIVE Positive human epidermal growth factor 2 (HER2) expression and its predictive clinicopathological features remain unclear in Sri Lankan gastric cancer (GC) patients. Here, we aimed to determine GC HER2 status predictors by analyzing associations between clinicopathological features and HER2 expression using immunohistochemistry (IHC) and silver in situ hybridization (SISH). METHODS During this 4-year prospective study, clinicopathological data were collected from participants in the National Hospital of Sri Lanka. HER2 IHC and SISH were performed using commercial reagents. Using chi-square tests, associations of HER2-IHC/SISH with clinicopathological features were analyzed. RESULTS Overall, 145 GC patients were included, 69 had gastrectomies and 76 had biopsies. Positive HER2 expression by IHC was associated with age <60 years, high T stage (assessed pathologically in resections and radiologically in biopsies), high nuclear grade, tumor necrosis, mitosis >5/high-power field, with additional perineural invasion and lymphovascular invasion in resections. These features, excluding lymphovascular invasion but including male sex, were associated with HER2 expression by SISH. CONCLUSIONS Age <60 years, high nuclear grade, tumor necrosis, and perineural invasion are associated factors of HER2 status. These could be used to triage GC patients for HER2 status testing in limited resource settings where IHC/SISH analysis is costly.
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Affiliation(s)
- Duminda Subasinghe
- Department of Surgery, Faculty of Medicine, University of
Colombo, University Surgical Unit, The National Hospital of Sri Lanka, Colombo,
Sri Lanka,PathWest Laboratory Medicine, Perth, & School of Pathology
and Laboratory Medicine, University of Western Australia, Perth, Australia,Duminda Subasinghe, Department of Surgery,
Faculty of Medicine, University of Colombo, University Surgical Unit, The
National Hospital of Sri Lanka, Colombo 00800, Sri Lanka.
| | - Nathan Acott
- PathWest Laboratory Medicine, Perth, & School of Pathology
and Laboratory Medicine, University of Western Australia, Perth, Australia
| | | | - Sivasuriya Sivaganesh
- Department of Surgery, Faculty of Medicine, University of
Colombo, University Surgical Unit, The National Hospital of Sri Lanka, Colombo,
Sri Lanka
| | - Sithum Munasinghe
- Translational Health Research Institute, Western Sydney
University, Campbelltown Campus, Campbelltown, New South Wales, Australia
| | - Mariyan Priyanthi Kumarasinghe
- PathWest Laboratory Medicine, Perth, & School of Pathology
and Laboratory Medicine, University of Western Australia, Perth, Australia
| | - Dharmabandu Nandaveva Samarasekera
- Department of Surgery, Faculty of Medicine, University of
Colombo, University Surgical Unit, The National Hospital of Sri Lanka, Colombo,
Sri Lanka
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23
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Locke D, Hoyt CC. Companion diagnostic requirements for spatial biology using multiplex immunofluorescence and multispectral imaging. Front Mol Biosci 2023; 10:1051491. [PMID: 36845550 PMCID: PMC9948403 DOI: 10.3389/fmolb.2023.1051491] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Accepted: 01/16/2023] [Indexed: 02/11/2023] Open
Abstract
Immunohistochemistry has long been held as the gold standard for understanding the expression patterns of therapeutically relevant proteins to identify prognostic and predictive biomarkers. Patient selection for targeted therapy in oncology has successfully relied upon standard microscopy-based methodologies, such as single-marker brightfield chromogenic immunohistochemistry. As promising as these results are, the analysis of one protein, with few exceptions, no longer provides enough information to draw effective conclusions about the probability of treatment response. More multifaceted scientific queries have driven the development of high-throughput and high-order technologies to interrogate biomarker expression patterns and spatial interactions between cell phenotypes in the tumor microenvironment. Such multi-parameter data analysis has been historically reserved for technologies that lack the spatial context that is provided by immunohistochemistry. Over the past decade, technical developments in multiplex fluorescence immunohistochemistry and discoveries made with improving image data analysis platforms have highlighted the importance of spatial relationships between certain biomarkers in understanding a patient's likelihood to respond to, typically, immune checkpoint inhibitors. At the same time, personalized medicine has instigated changes in both clinical trial design and its conduct in a push to make drug development and cancer treatment more efficient, precise, and economical. Precision medicine in immuno-oncology is being steered by data-driven approaches to gain insight into the tumor and its dynamic interaction with the immune system. This is particularly necessary given the rapid growth in the number of trials involving more than one immune checkpoint drug, and/or using those in combination with conventional cancer treatments. As multiplex methods, like immunofluorescence, push the boundaries of immunohistochemistry, it becomes critical to understand the foundation of this technology and how it can be deployed for use as a regulated test to identify the prospect of response from mono- and combination therapies. To that end, this work will focus on: 1) the scientific, clinical, and economic requirements for developing clinical multiplex immunofluorescence assays; 2) the attributes of the Akoya Phenoptics workflow to support predictive tests, including design principles, verification, and validation needs; 3) regulatory, safety and quality considerations; 4) application of multiplex immunohistochemistry through lab-developed-tests and regulated in vitro diagnostic devices.
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Affiliation(s)
- Darren Locke
- Clinical Assay Development, Akoya Biosciences, Marlborough, MA, United States,*Correspondence: Darren Locke,
| | - Clifford C. Hoyt
- Translational and Scientific Affairs, Akoya Biosciences, Marlborough, MA, United States
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24
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Weidemann S, Gorbokon N, Lennartz M, Hube-Magg C, Fraune C, Bernreuther C, Clauditz TS, Jacobsen F, Jansen K, Schmalfeldt B, Wölber L, Paluchowski P, Berkes E, Heilenkötter U, Sauter G, Uhlig R, Wilczak W, Steurer S, Simon R, Krech T, Marx A, Burandt E, Lebok P. High Homogeneity of Mesothelin Expression in Primary and Metastatic Ovarian Cancer. Appl Immunohistochem Mol Morphol 2023; 31:77-83. [PMID: 36728364 PMCID: PMC9928564 DOI: 10.1097/pai.0000000000001097] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Accepted: 11/22/2022] [Indexed: 02/03/2023]
Abstract
To study the extent of heterogeneity of mesothelin overexpression in primary ovarian cancers and their peritoneal and lymph node metastases, a tissue microarray (TMA) was constructed from multiple sites of 220 ovarian cancers and analyzed by immunohistochemistry. One tissue core each was taken from up to 18 different tumor blocks per cancer, resulting in a total of 2460 tissue spots from 423 tumor sites (188 primary cancers, 162 peritoneal carcinosis, and 73 lymph node metastases). Positive mesothelin expression was found in 2041 of the 2342 (87%) arrayed tissue spots and in 372 of the 392 (95%) tumor sites that were interpretable for mesothelin immunohistochemistry. Intratumoral heterogeneity was found in 23% of 168 primary cancer sites interpretable for mesothelin and decreased to 12% in 154 peritoneal carcinosis and to 6% in 71 lymph node metastases ( P <0.0001). Heterogeneity between the primary tumor and matched peritoneal carcinosis was found in 16% of 102 cancers with interpretable mesothelin results. In these cancers, the mesothelin status switched from positive in the primary tumor to negative in the peritoneal carcinosis (3 cancers) in or vice versa (2 cancers), or a mixture of positive and negative peritoneal carcinoses was found (11 cancers). No such switch was seen between the mesothelin-interpretable primary tumors and their nodal metastases of 59 cancers, and only 1 mesothelin-positive tumor had a mixture of positive and negative lymph node metastases. In conclusion, mesothelin expression is frequent and highly homogeneous in ovarian cancer.
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Affiliation(s)
- Sören Weidemann
- Institute of Pathology, University Medical Center Hamburg-Eppendorf
| | - Natalia Gorbokon
- Institute of Pathology, University Medical Center Hamburg-Eppendorf
| | | | | | - Christoph Fraune
- Institute of Pathology, University Medical Center Hamburg-Eppendorf
| | | | - Till S. Clauditz
- Institute of Pathology, University Medical Center Hamburg-Eppendorf
| | - Frank Jacobsen
- Institute of Pathology, University Medical Center Hamburg-Eppendorf
| | - Kristina Jansen
- General, Visceral and Thoracic Surgery Department and Clinic
| | | | - Linn Wölber
- Department of Gynecology, University Medical Center Hamburg-Eppendorf
| | | | - Enikö Berkes
- Department of Gynecology, Regio Clinic Itzehoe, Itzehoe
| | | | - Guido Sauter
- Institute of Pathology, University Medical Center Hamburg-Eppendorf
| | - Ria Uhlig
- Institute of Pathology, University Medical Center Hamburg-Eppendorf
| | - Waldemar Wilczak
- Institute of Pathology, University Medical Center Hamburg-Eppendorf
| | - Stefan Steurer
- Institute of Pathology, University Medical Center Hamburg-Eppendorf
| | - Ronald Simon
- Institute of Pathology, University Medical Center Hamburg-Eppendorf
| | - Till Krech
- Institute of Pathology, University Medical Center Hamburg-Eppendorf
- Clinical Center Osnabrueck, Institute of Pathology, Osnabrueck
| | - Andreas Marx
- Institute of Pathology, University Medical Center Hamburg-Eppendorf
- Department of Pathology, Academic Hospital Fuerth, Fuerth, Germany
| | - Eike Burandt
- Institute of Pathology, University Medical Center Hamburg-Eppendorf
| | - Patrick Lebok
- Institute of Pathology, University Medical Center Hamburg-Eppendorf
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25
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Li Q, Lv M, Lv L, Cao N, Zhao A, Chen J, Tang X, Luo R, Yu S, Zhou Y, Cui Y, Guo W, Liu T. Identifying HER2 from serum-derived exosomes in advanced gastric cancer as a promising biomarker for assessing tissue HER2 status and predicting the efficacy of trastuzumab-based therapy. Cancer Med 2023; 12:4110-4124. [PMID: 36208025 PMCID: PMC9972160 DOI: 10.1002/cam4.5269] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Revised: 08/15/2022] [Accepted: 08/24/2022] [Indexed: 11/09/2022] Open
Abstract
PURPOSE This study aimed to evaluate the clinical relevance of exosomal HER2 (Exo HER2) level in assessing the tissue HER2 status and predicting the efficacy of trastuzumab treatment. METHODS In this prospective study, patients with advanced gastric cancer (AGC) from three hospitals between August 2016 to November 2020 were enrolled. The Exo HER2 level was detected by enzyme-linked immunosorbent assay. Receiver operating characteristic curve (ROC) was drawn referring to the HER2 tissue status to assess the diagnostic value of Exo HER2. Cox proportional hazards regression and logistic regression were used to evaluate the association between Exo HER2 and progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) in patients who received trastuzumab-based first-line therapy. RESULTS In this study, 242 patients with advanced or metastatic gastric adenocarcinoma were registered. Of these, 238 AGC patients were eligible for evaluating serum-derived exosome HER2 diagnostic value, including 114 HER2-positive. Finally, 64 were eligible for efficacy analysis. The area under the ROC curve was 0.746. The optimal cutoff value for diagnosing tissue HER2-positive status was 729.95 ng/ml, with a sensitivity of 66.7% and a specificity of 74.2%. In 64 patients treated with trastuzumab, higher baseline Exo HER2 level indicated better prognosis. 844 ng/ml and 723 ng/ml were the right cutoffs for distinguishing the population with superior PFS (hazard ratio [HR] = 0.41, P = 0.017) and OS (HR = 0.30, P < 0.001), respectively. CONCLUSION Serum exosomal HER2 level might serve as an effective biomarker for assessing tissue HER2 status in AGC and screening the potential patients who might benefit from anti-HER2 therapy.
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Affiliation(s)
- Qian Li
- Department of Medical Oncology, Zhongshan HospitalFudan UniversityShanghaiChina
| | - Minzhi Lv
- Department of Biostatistics, Zhongshan HospitalFudan UniversityShanghaiChina
| | - Lihua Lv
- Departments of Laboratory Medicine, Zhongshan HospitalFudan UniversityShanghaiChina
| | - Nida Cao
- Oncology Department ILonghua Hospital Shanghai University of Traditional Chinese MedicineShanghaiChina
| | - Aiguang Zhao
- Oncology Department ILonghua Hospital Shanghai University of Traditional Chinese MedicineShanghaiChina
| | - Jiayan Chen
- Department of Medical OncologyHuadong HospitalShanghaiChina
| | - Xi Tang
- Department of Medical OncologyHuadong HospitalShanghaiChina
| | - Rongkui Luo
- Department of Pathology, Zhongshan HospitalFudan UniversityShanghaiChina
| | - Shan Yu
- Department of Medical Oncology, Zhongshan HospitalFudan UniversityShanghaiChina
| | - Yan Zhou
- Departments of Laboratory Medicine, Zhongshan HospitalFudan UniversityShanghaiChina
| | - Yuehong Cui
- Department of Medical Oncology, Zhongshan HospitalFudan UniversityShanghaiChina
| | - Wei Guo
- Department of Medical Oncology, Zhongshan HospitalFudan UniversityShanghaiChina
- Department of Laboratory Medicine, Xiamen Branch, Zhongshan HospitalFudan UniversityXiamenChina
| | - Tianshu Liu
- Department of Medical Oncology, Zhongshan HospitalFudan UniversityShanghaiChina
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26
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Yang T, Xu R, You J, Li F, Yan B, Cheng JN. Prognostic and clinical significance of HER-2 low expression in early-stage gastric cancer. BMC Cancer 2022; 22:1168. [DOI: 10.1186/s12885-022-10262-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2022] [Accepted: 10/31/2022] [Indexed: 11/15/2022] Open
Abstract
Abstract
Introduction
Gastric cancer is the most fifth common tumor worldwide. Human epidermal growth factor receptor 2 (HER2) overexpression is associated with poor prognosis and clinical characteristics in gastric cancer. Nevertheless, the biology of HER2-low expression has not reported in gastric cancer.
Materials and methods
A total of 157 patients with early-stage gastric cancer were retrospectively analyzed. The associations between HER-2 low expression and clinical characteristics were analyzed by Chi-square test. And the prognostic value of HER-2 low expression and clinical characteristics in disease-free survival (DFS) and overall survival (OS) were analyzed by univariate and multivariate Cox regression analysis.
Results
Of 157 patients with early-stage gastric cancer, 31.8% had HER2-low tumors and 50.3% had HER2-negative tumors. HER2-low expression was associated with age, histological differentiation, tumor location and Ki-67 index. However, HER2-low expression was not associated with DFS or OS in early-stage gastric cancer.
Conclusion
HER2-low expression might result in distinct biology, but it was not an independent prognostic factor of DFS or OS in early-stage gastric cancer.
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27
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Gordon A, Johnston E, Lau DK, Starling N. Targeting FGFR2 Positive Gastroesophageal Cancer: Current and Clinical Developments. Onco Targets Ther 2022; 15:1183-1196. [PMID: 36238135 PMCID: PMC9553429 DOI: 10.2147/ott.s282718] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Accepted: 08/29/2022] [Indexed: 11/06/2022] Open
Abstract
Despite recent advances in the systemic treatment of gastroesophageal cancers, prognosis remains poor. Comprehensive molecular analyses have characterized the genomic landscape of gastroesophageal cancer that has established therapeutic targets such as human epidermal growth factor receptor 2 (HER2), vascular endothelial growth factor receptor (VEGFR) and programmed death ligand 1 (PD-L1). The aberrant fibroblast growth factor receptor 2 (FGFR2) pathway is attractive for targetable therapy with FGFR inhibition based on preclinical data showing a pivotal role in the progression of gastric cancer (GC). FGFR2 amplification is the most common FGFR2 gene aberration in gastroesophageal cancer, and most associated with diffuse GC, which is often linked to poorer prognostic outcomes. There has been considerable progress with drug development focused on FGFR inhibition. At present, there is no approved FGFR inhibitor for FGFR2 positive gastroesophageal cancer. A selective FGFR2b monoclonal antibody bemarituzumab is currently being investigated in the first phase III randomized trial for patients with first line advanced GC, which may change the treatment paradigm for FGFR2b positive GC. The role of FGFR signalling, specifically FGFR2, is less established in oesophageal squamous cell cancer (ESCC) with a paucity of evidence for clinical benefit in these patients. Precision medicine is part of the wider approach in gastrointestinal cancers; however, it can be challenging due to heterogeneity and here circulating tumour DNA (ctDNA) for patient selection may have future clinical utility. In our review, we outline the FGFR pathway and focus on the developments and challenges of targeting FGFR2 driven gastroesophageal cancers.
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Affiliation(s)
- Anderley Gordon
- Gastrointestinal and Lymphoma Unit, Royal Marsden NHS Foundation, London, UK
| | - Edwina Johnston
- Gastrointestinal and Lymphoma Unit, Royal Marsden NHS Foundation, London, UK
| | - David K Lau
- Gastrointestinal and Lymphoma Unit, Royal Marsden NHS Foundation, London, UK
| | - Naureen Starling
- Gastrointestinal and Lymphoma Unit, Royal Marsden NHS Foundation, London, UK,Correspondence: Naureen Starling, Gastrointestinal and Lymphoma Unit, The Royal Marsden Hospital, Downs Road, Sutton, Surrey, SM2 5PT, United Kingdom, Tel +44 2086426011, Email
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28
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Liu ZH, Zhu BW, Shi M, Qu YR, He XJ, Yuan HL, Ma J, Li W, Zhao DD, Liu ZC, Wang BM, Wang CY, Tao HQ, Ma TH. Profiling of gene fusion involving targetable genes in Chinese gastric cancer. World J Gastrointest Oncol 2022; 14:1528-1539. [PMID: 36160735 PMCID: PMC9412921 DOI: 10.4251/wjgo.v14.i8.1528] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Revised: 06/14/2022] [Accepted: 07/19/2022] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Approximately half of all new cases of gastric cancer (GC) and related deaths occur in China. More than 80% of patients with GC are diagnosed at an advanced stage, which results in poor prognosis. Although HER2-directed therapy and immune checkpoint inhibitors have been somewhat successful, new drugs are still needed for the treatment of GC. Notably, several gene fusion-targeted drugs have been approved by the United States Food and Drug Administration for solid tumors, including GC, such as larotrectinib for NTRK fusion-positive cancers and zenocutuzumab for NRG1 fusion-positive cancers. However, gene fusions involving targetable genes have not been well characterized in Chinese patients with GC.
AIM To identify the profile of fusions involving targetable genes in Chinese patients with GC using clinical specimens and determine the distribution of patients with gene fusion variants among the molecular subtypes of GC.
METHODS We retrospectively analyzed gene fusion events in tumor tissue samples from 954 Chinese patients with GC. Clinicopathological characteristics were obtained from their medical records. Genetic alterations, such as single nucleotide variants, indels, amplifications, and gene fusions, were identified using a targeted sequencing panel containing 825 genes. Fusions were validated by fluorescence in situ hybridization (FISH) using break-apart probes. The microsatellite instability (MSI) status was evaluated using MSIsensor from the targeted sequencing panel data. Tumor mutational burden (TMB) was calculated using the total number of nonsynonymous mutations divided by the total genomic targeted region. Chi-square analysis was used to determine the enrichment of gene fusions associated with the molecular subtypes of GC.
RESULTS We found that 1.68% (16/954) of patients harbored 20 fusion events involving targetable genes. RARA fusions (n = 5) were the most common, followed by FGFR2, BRAF, MET, FGFR3, RET, ALK, EGFR, NTRK2, and NRG1 fusions. Two of the RARA fusions, EML4-ALK (E6:E20) and EGFR-SEPTIN14 (E7:E10), have been identified in other tumors but not in GC. Surprisingly, 18 gene fusion events were previously not reported in any cancer types. Twelve of the eighteen novel gene fusions included complete exons encoding functional domains of targetable genes, such as the tyrosine kinase domain of receptor tyrosine kinases and the DNA- and ligand-binding domains of RARA. Consistent with the results of detection using the targeted sequencing fusion panel, the results of FISH (fluorescence in situ hybridization) confirmed the rearrangement of FGFR2 and BRAF in tumors from patients 04 and 09, respectively. Genetic analysis indicated that the fusion genes were significantly enriched in patients with ERBB2 amplification (P = 0.02); however, there were no significant differences between fusion-positive and fusion-negative patients in age, sex, MSI status, and TMB.
CONCLUSION We characterized the landscape of fusions involving targetable genes in a Chinese GC cohort and found that 1.68% of patients with GC harbor potential targetable gene fusions, which were enriched in patients with ERBB2 amplification. Gene fusion detection may provide a potential treatment strategy for patients with GC with disease progression following standard therapy.
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Affiliation(s)
- Zhen-Hua Liu
- Department of Medical Oncology, Fujian Medical University, Fuzhou 350001, Fujian Province, China
| | - Bo-Wen Zhu
- Medical Center, Genetron Health (Beijing) Technology, Co. Ltd., Beijing 102200, China
| | - Min Shi
- Medical Center, Genetron Health (Beijing) Technology, Co. Ltd., Beijing 102200, China
| | - Yu-Rong Qu
- Medical Center, Genetron Health (Beijing) Technology, Co. Ltd., Beijing 102200, China
| | - Xun-Jun He
- Department of Genetics and Genomic Medicine, Zhejiang Provincial People’s Hospital, Hangzhou 310000, Zhejiang Province, China
- Key Laboratory of Gastroenterology of Zhejiang Province, Zhejiang Provincial People’s Hospital, Hangzhou 310000, Zhejiang Province, China
| | - Hong-Ling Yuan
- Medical Center, Genetron Health (Beijing) Technology, Co. Ltd., Beijing 102200, China
| | - Jie Ma
- Department of Pathology, Zhejiang Provincial People's Hospital, Hangzhou 310000, Zhejiang Province, China
| | - Wei Li
- Medical Center, Genetron Health (Beijing) Technology, Co. Ltd., Beijing 102200, China
| | - Dan-Dan Zhao
- Medical Center, Genetron Health (Beijing) Technology, Co. Ltd., Beijing 102200, China
| | - Zheng-Chuang Liu
- Key Laboratory of Gastroenterology of Zhejiang Province, Zhejiang Provincial People’s Hospital, Hangzhou 310000, Zhejiang Province, China
- Department of Gastroenterology of Zhejiang Province, Zhejiang Provincial People’s Hospital, Hangzhou 310000, Zhejiang Province, China
| | - Bao-Ming Wang
- Medical Center, Genetron Health (Beijing) Technology, Co. Ltd., Beijing 102200, China
| | - Chun-Yang Wang
- Medical Center, Genetron Health (Beijing) Technology, Co. Ltd., Beijing 102200, China
| | - Hou-Quan Tao
- Key Laboratory of Gastroenterology of Zhejiang Province, Zhejiang Provincial People’s Hospital, Hangzhou 310000, Zhejiang Province, China
- Department of Gastroenterology of Zhejiang Province, Zhejiang Provincial People’s Hospital, Hangzhou 310000, Zhejiang Province, China
| | - Tong-Hui Ma
- Department of Translational Medicine, Genetron Health (Beijing) Technology, Co. Ltd., Beijing 102200, China
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Myer NM, Shitara K, Chung HC, Lordick F, Kelly RJ, Szabo Z, Cao ZA, Leong S, Ilson DH, Weichert W. Evolution of predictive and prognostic biomarkers in the treatment of advanced gastric cancer. J Cancer Res Clin Oncol 2022; 148:2023-2043. [PMID: 35551464 PMCID: PMC11110882 DOI: 10.1007/s00432-021-03902-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Accepted: 12/24/2021] [Indexed: 12/30/2022]
Abstract
Despite new therapeutic options, advanced gastric cancer remains associated with a poor prognosis compared with other cancers. Recent gains in the treatment of gastric cancer were accompanied by the identification of novel biomarkers associated with various cellular pathways and corresponding diagnostic technologies. It is expected that the standardization of clinical workflow and technological refinements in biomarker assessment will support greater personalization and further improve treatment outcomes. In this article, we review the current state of prognostic and predictive biomarkers in gastric cancer.
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Affiliation(s)
- Nicole M Myer
- Merck & Co., Inc., 90 E. Scott Avenue, Rahway, NJ, 07065, USA.
| | - Kohei Shitara
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Chiba, Japan
| | - Hyun C Chung
- Division of Medical Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea
| | - Florian Lordick
- Medical Department (Oncology, Gastroenterology, Hepatology, Pulmonology, and Infectious Diseases), University Cancer Center Leipzig (UCCL), Leipzig University Medical Center, Leipzig, Germany
| | - Ronan J Kelly
- Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, TX, USA
| | - Zsolt Szabo
- Merck & Co., Inc., Ringstrasse 27 Kriens, LUZERN, 6010, Switzerland
| | - Z Alexander Cao
- Merck & Co., Inc., 90 E. Scott Avenue, Rahway, NJ, 07065, USA
| | - Stephen Leong
- Merck & Co., Inc., 351 N Sumneytown Pike, North Wales, PA, 19454, USA
| | - David H Ilson
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Wilko Weichert
- Institute of Pathology, School of Medicine, Technical University of Munich, Munich, Germany
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Xu C, Sun M, Jin M, Li Z, Qin R, Ren G, Sun W, Chen L, Luan L, Liu Y, Jiang D, Chen L, Luo R, Hou Y. Dual block HER2 assessment increased HER2 immunohistochemistry positive rate in resected specimens of gastric cancer: a prospective multicenter clinical trial from China. Diagn Pathol 2022; 17:54. [PMID: 35765007 PMCID: PMC9238183 DOI: 10.1186/s13000-022-01230-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Accepted: 05/18/2022] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
Former single center studies indicated that HER2 assessment with two primary tumor blocks (dual block HER2 assessment) could be an efficient and practical approach to overcome the adverse impact of heterogeneity and acquire a HER2 positive rate in gastric cancer (GC). This multicenter prospective clinical trial (NCT 02843412) was launched to verify its value and generality.
Methods
A total of 3806 participants with primary GCs have been enrolled from 8 hospitals in China. Two primary tumor blocks were selected and recorded as block 1 and block 2 after histological evaluation. An HER2 (4B5) rabbit monoclonal antibody was used for the immunohistochemistry (IHC) analysis.
Results
In total patients, HER2 IHC positive (3+) rate with dual block assessment (9.4%) was higher than that with single block assessment (block 1: 7.8%, block 2: 7.8%) (P < 0.001). Compared with single-block assessment, dual-block assessment increased the positive rate by approximate 20%. Similarly, HER2 equivocal (2+) rate was increased in dual block assessment (25.8%), which was higher than that in single block assessment (block 1: 20.3%, block 2: 20.9%) (P < 0.001). Conversely, dual block assessment demonstrated a lower HER2 negative (0/1+) rate (64.8%) than single block assessment (block1: 71.9%, block 2: 71.3%) (P < 0.001). These findings were also confirmed in individual hospitals.
Conclusions
Dual block HER2 assessment effectively increased HER2 IHC positive rate in resected specimens of GC. We recommended dual block HER2 assessment be promoted in routine clinical practice in GC.
Trial registration
ClinicalTrials.gov, NCT 02843412. Registered 1 July 2016 - Retrospectively registered.
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Liu R, Wang X, Ji Z, Deng T, Li HL, Zhang YH, Yang YC, Ge SH, Zhang L, Bai M, Ning T, Ba Y. Toripalimab combined with targeted therapy and chemotherapy achieves pathologic complete response in gastric carcinoma: A case report. World J Clin Cases 2022; 10:6184-6191. [PMID: 35949814 PMCID: PMC9254214 DOI: 10.12998/wjcc.v10.i18.6184] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Revised: 02/28/2022] [Accepted: 04/22/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Neoadjuvant or perioperative chemotherapy combined with surgery can reduce postoperative recurrence and improve the long-term survival rate of patients with locally advanced resectable gastric carcinoma. Nivolumab combined with chemotherapy has been recommended by the National Comprehensive Cancer Network guidelines as a first-line therapy for advanced gastric carcinoma/ adenocarcinoma of the gastroesophageal junction and serves as the basis for immunotherapy combined with chemotherapy to become a neoadjuvant therapy. Herein, we report a case in which pathologic complete response was achieved by neoadjuvant administration of toripalimab, Herceptin, and docetaxel, oxaliplatin, calcium folinate, and fluorouracil (FLOT) chemotherapy followed by surgery for human epidermal growth factor receptor 2 (HER2)- and programmed death-ligand 1 (PD-L1)-positive locally advanced gastric carcinoma. We hope that this case will shed some light on neoadjuvant therapy for gastric carcinoma.
CASE SUMMARY The patient was diagnosed with locally advanced adenocarcinoma of the cardia. Immunohistochemistry of the baseline tissues suggested that the tissues were HER2- (fluorescent in situ hybridization) and PD-L1-positive (combined positive score = 1). The patient underwent surgery following a four-cycle neoadjuvant therapy comprising Herceptin, toripalimab, and FLOT chemotherapy. The postoperative pathological findings showed mild atypical hyperplasia of the local glands with chronic mucosal inflammation (proximal stomach), no clear residual tumor (tumor regression grade 0), no regional lymph node metastasis, and negative upper and lower cut ends. The levels of tumor markers were reduced to normal levels after re-examination. With good postoperative recovery, the four-cycle preoperative chemotherapy was continued at the same dosage as that previously administered. After the treatment, the patient was monitored every 3 mo with a follow-up of 12 mo (4 times). As of February 27, 2022, he was in a good condition without disease progression. The clinical trial registration number is E2019401.
CONCLUSION There are many ongoing studies on neoadjuvant immunotherapy combined with chemotherapy or radiotherapy; however, most of these studies are phase II studies with small cohorts. According to the results of some current studies, these combined regimens have shown promising results in terms of efficacy and safety. However, the clinical efficacy and safety of the neoadjuvant therapies used in these combined regimens need to be confirmed by additional prospective phase III clinical trials, and further exploration of molecular markers for effective populations is required.
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Affiliation(s)
- Rui Liu
- National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300000, China
| | - Xia Wang
- National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300000, China
| | - Zhi Ji
- National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300000, China
| | - Ting Deng
- National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300000, China
| | - Hong-Li Li
- National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300000, China
| | - Yan-Hui Zhang
- National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300000, China
| | - Yu-Chong Yang
- National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300000, China
| | - Shao-Hua Ge
- National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300000, China
| | - Le Zhang
- National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300000, China
| | - Ming Bai
- National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300000, China
| | - Tao Ning
- National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300000, China
| | - Yi Ba
- National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300000, China
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Mohamed AA, Lau DK, Chau I. HER2 targeted therapy in colorectal cancer: New horizons. Cancer Treat Rev 2022; 105:102363. [DOI: 10.1016/j.ctrv.2022.102363] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Revised: 02/18/2022] [Accepted: 02/19/2022] [Indexed: 12/18/2022]
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Zhao H, Huang C, Lin M, Zhou M, Huang C. Dynamic detection of HER2 of circulating tumor cells in patients with gastric carcinoma and its clinical application. Mol Med Rep 2022; 25:187. [PMID: 35348186 DOI: 10.3892/mmr.2022.12703] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Accepted: 12/09/2021] [Indexed: 11/06/2022] Open
Abstract
The aim of the present study was to construct and characterize human epidermal growth factor receptor 2 (HER2) lipid magnetic ball (H‑LMB) for separating circulating tumor cells (CTCs) in patients with gastric carcinoma (GC) and to compare the result of separated CTC counts with that of next‑generation sequencing (NGS) for single‑gene analysis to verify the consistency for evaluating the association between the detection results and the progress of clinical treatment, so as to facilitate early diagnosis and dynamic monitoring of GC. A lipid magnetic ball (LMB), coated with Fe3O4 nanoparticles, was synthesized by microemulsion technique and an anti‑HER2 antibody was conjugated to the surface of LMB to form H‑LMB, followed by the characterization of the prepared H‑LMB. The detection of capture efficiency of LMBs in GC cells was tested by MTT and expression of HER2 mRNA was determined by reverse transcription‑quantitative PCR. The positive detection rate of HER2 was verified by HER2‑fluorescence in situ hybridization (FISH) test on the separated CTCs from GC. Further verification was performed based on the consistency between the result of separated CTCs and that of single‑gene NGS assay of HER2, associated with the determination of clinical consistency. The constructed H‑LMB exhibited good stability and specificity. The mutation rate of HER2 by the FISH test was 14% in the blood samples of 50 patients with GC and was 14% by NGS assay. The mutation rate of HER2 was 12% in H‑LMB and the positive detection rate was 85.7% compared with the results of the FISH test, indicating consistency with the clinical diagnosis and pathological examination results. In conclusion, the anti‑HER2 antibody‑modified LMB can separate CTCs with HER2 abnormal expression, which exhibits an application potential in GC diagnosis and treatment and is of great clinical significance for the diagnosis and evaluation of its therapeutic effect on GC.
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Affiliation(s)
- Hongjian Zhao
- Department of General Surgery, Zhabei District Central Hospital of Shanghai, Shanghai 200070, P.R. China
| | - Chunyan Huang
- Department of Anesthesia, Zhabei District Central Hospital of Shanghai, Shanghai 200070, P.R. China
| | - Mei Lin
- Department of Anesthesia, The People's Hospital of Suzhou New District, Suzhou, Jiangsu 215163, P.R. China
| | - Mingqing Zhou
- Department of General Surgery, Zhabei District Central Hospital of Shanghai, Shanghai 200070, P.R. China
| | - Chunjin Huang
- Department of General Surgery, Huadong Hospital Affiliated to Fudan University, Shanghai 200040, P.R. China
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Faghfuri E, Shadbad MA, Faghfouri AH, Soozangar N. Cellular immunotherapy in gastric cancer: adoptive cell therapy and dendritic cell-based vaccination. Immunotherapy 2022; 14:475-488. [PMID: 35232264 DOI: 10.2217/imt-2021-0285] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Gastric cancer (GC) is one of the most frequently diagnosed malignancies. Recent studies have highlighted cellular immunotherapy (CI) as a promising approach for treating this disease. Among the CI-based approaches, adoptive cell therapy and dendritic cell-based vaccination are commonly studied in preclinical and clinical trials. Here we review the current evidence on the potentiality of CI in treating GC, the targets for adoptive cell therapy, ongoing clinical trials, constraints and the future outlook. The results suggest that there is a need to identify novel biomarkers that predict which GC patients will most likely respond to these approaches. Also, CI plus chemotherapy or immune checkpoint inhibitors can improve the survival of patients with late-stage GC. Therefore, this approach can be promising for treating these patients.
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Affiliation(s)
- Elnaz Faghfuri
- Digestive Disease Research Center, Ardabil University of Medical Sciences, Ardabil, Iran
| | | | | | - Narges Soozangar
- Digestive Disease Research Center, Ardabil University of Medical Sciences, Ardabil, Iran
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35
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Staudt RE, Carlson RD, Snook AE. Targeting gastrointestinal cancers with chimeric antigen receptor (CAR)-T cell therapy. Cancer Biol Ther 2022; 23:127-133. [PMID: 35129050 PMCID: PMC8820794 DOI: 10.1080/15384047.2022.2033057] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
The immune system is capable of remarkably potent and specific efficacy against infectious diseases. For decades, investigators sought to leverage those characteristics to create immune-based therapies (immunotherapy) that might be far more effective and less toxic than conventional chemotherapy and radiation therapy for cancer. Those studies revealed many factors and mechanisms underlying the success or failure of cancer immunotherapy, leading to synthetic biology approaches, including CAR-T cell therapy. In this approach, patient T cells are genetically modified to express a chimeric antigen receptor (CAR) that converts T cells of any specificity into tumor-specific T cells that can be expanded to large numbers and readministered to the patient to eliminate cancer cells, including bulky metastatic disease. This approach has been most successful against hematologic cancers, resulting in five FDA approvals to date. Here, we discuss some of the most promising attempts to apply this technology to cancers of the gastrointestinal tract.
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Affiliation(s)
- Ross E Staudt
- Department of Pharmacology & Experimental Therapeutics, Thomas Jefferson University, Philadelphia, PA, USA
| | - Robert D Carlson
- Department of Pharmacology & Experimental Therapeutics, Thomas Jefferson University, Philadelphia, PA, USA
| | - Adam E Snook
- Department of Pharmacology & Experimental Therapeutics, Thomas Jefferson University, Philadelphia, PA, USA
- Department of Microbiology & Immunology, Thomas Jefferson University, Philadelphia, PA, USA
- Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA
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36
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Prospective analysis of the expression status of FGFR2 and HER2 in colorectal and gastric cancer populations: DS-Screen Study. Int J Colorectal Dis 2022; 37:1393-1402. [PMID: 35585358 PMCID: PMC9167213 DOI: 10.1007/s00384-022-04162-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/17/2022] [Indexed: 02/04/2023]
Abstract
PURPOSE Fibroblast growth factor receptor 2 (FGFR2) and human epidermal growth factor receptor 2 (HER2) proteins are both molecular targets for cancer therapy. The objective of this study was to evaluate the expression status of FGFR2 and HER2 in patients with gastric cancer (GC) or colorectal cancer (CRC). METHODS Archived tumor tissue samples from patients with histologically-confirmed GC or CRC suitable for chemotherapy were analyzed for FGFR2 and HER2 expression using immunohistochemistry and fluorescence in situ hybridization (HER2 in CRC only). RESULTS A total of 176 GC patients and 389 CRC patients were enrolled. Among patients with GC, 25.6% were FGFR2-positive and 26.1% were HER2-positive. Among patients with CRC, 2.9% were FGFR2-positive and 16.2% were HER2-positive. No clear relationship was found between FGFR2 and HER2 status in either GC or CRC. In GC, FGFR2 and HER2 statuses did not differ between different primary cancer locations, whereas there were some differences between histological types. Based on FGFR2- and/or HER2-positive status, 117 patients were identified as potentially suitable for inclusion in clinical trials of therapeutic agents targeting the relevant protein (GC = 45, CRC = 72; FGFR = 56, HER2 = 62), of whom 7 were eventually enrolled into such clinical trials. CONCLUSIONS This study indicated the prevalence of FGFR2 and HER2 in GC and CRC in the Japanese population. The screening performed in this study could be useful for identifying eligible patients for future clinical trials of agents targeting these proteins. TRIAL REGISTRATION Clinical trial registration Japic CTI No.: JapicCTI-163380. https://www. CLINICALTRIALS jp/cti-user/trial/ShowDirect.jsp?directLink=RNlzx1PPCuT.PrVNPxPRwA .
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37
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Shah MA, Cunningham D, Metges JP, Van Cutsem E, Wainberg Z, Elboudwarej E, Lin KW, Turner S, Zavodovskaya M, Inzunza D, Liu J, Patterson SD, Zhou J, He J, Thai D, Bhargava P, Brachmann CB, Cantenacci DVT. Randomized, open-label, phase 2 study of andecaliximab plus nivolumab versus nivolumab alone in advanced gastric cancer identifies biomarkers associated with survival. J Immunother Cancer 2021; 9:jitc-2021-003580. [PMID: 34893523 PMCID: PMC8666898 DOI: 10.1136/jitc-2021-003580] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/05/2021] [Indexed: 12/13/2022] Open
Abstract
Background Matrix metalloproteinase-9 (MMP9) selectively cleaves extracellular matrix proteins contributing to tumor growth and an immunosuppressive microenvironment. This study evaluated andecaliximab (ADX), an inhibitor of MMP9, in combination with nivolumab (NIVO), for the treatment of advanced gastric cancer. Methods Phase 2, open-label, randomized multicenter study evaluating the efficacy, safety, and pharmacodynamics of ADX+NIVO versus NIVO in patients with pretreated metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma. The primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and adverse events (AEs). We explored the correlation of efficacy outcomes with biomarkers. Results 144 patients were randomized; 141 were treated: 81% white, 69% male, median age was 61 years in the ADX+NIVO group and 62 years in the NIVO-alone group. The ORR was 10% (95% CI 4 to 19) in the ADX+NIVO group and 7% (95% CI 2 to 16) in the NIVO-alone group (OR: 1.5 (95% CI 0.4 to 6.1; p=0.8)). There was no response or survival benefit associated with adding ADX. AE rates were comparable in both treatment groups; the most common AEs were fatigue, decreased appetite, nausea, and vomiting. Programmed cell death ligand 1, interferon-γ (IFN), and intratumoral CD8+ cell density were not associated with treatment response or survival. The gene signature most correlated with shorter survival was the epithelial-to-mesenchymal gene signature; high transforming growth factor (TGF)-β fibrosis score was negatively associated with OS (p=0.036). Gene expression analysis of baseline tumors comparing long-(1+ years) and short-term (<1 year) survivors showed that GRB7 was associated with survival beyond 1 year. Human epidermal growth factor receptor 2 (HER2)-positive disease was associated with significantly longer survival (p=0.0077). Median tumor mutation burden (TMB) was 2.01; patients with TMB ≥median had longer survival (p=0.0025) and improved PFS (p=0.016). Based on a model accounting for TMB, TGF-β fibrosis, and HER2, TMB was the main driver of survival in this patient population. Conclusion Combination of ADX+NIVO had a favorable safety profile but did not improve efficacy compared with NIVO alone in patients with pretreated metastatic gastric or GEJ adenocarcinoma. HER2 positivity, higher TMB or GRB7, and lower TGF-β were associated with improved outcomes. Trial registration number NCT02864381 or GS-US-296–-2013.
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Affiliation(s)
- Manish A Shah
- Medicine, Weill Cornell Medicine, New York, New York, USA .,Medicine, NewYork-Presbyterian Hospital/Weill Cornell Medical Center, New York, New York, USA
| | - David Cunningham
- Gastrointestinal and Lymphoma Unit, The Royal Marsden NHS Foundation Trust, Sutton and London Hospital, Sutton, UK
| | | | - Eric Van Cutsem
- Division Head of Digestive Oncology, University Hospitals Leuven and KU Leuven, Leuven, Belgium
| | - Zev Wainberg
- Gastrointestinal Medical Oncology, University of California Los Angeles School of Medicine, Los Angeles, California, USA
| | | | - Kai-Wen Lin
- Gilead Sciences, Inc, Foster City, California, USA
| | - Scott Turner
- Gilead Sciences, Inc, Foster City, California, USA
| | | | | | - Jinfeng Liu
- Gilead Sciences, Inc, Foster City, California, USA
| | | | - Jingzhu Zhou
- Gilead Sciences, Inc, Foster City, California, USA
| | - Jing He
- Gilead Sciences, Inc, Foster City, California, USA
| | - Dung Thai
- Gilead Sciences, Inc, Foster City, California, USA
| | | | | | - Daniel V T Cantenacci
- Biological Sciences Division, University of Chicago Medical Center, Chicago, Illinois, USA
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Rosenbaum MW, Gonzalez RS. Immunohistochemistry as predictive and prognostic markers for gastrointestinal malignancies. Semin Diagn Pathol 2021; 39:48-57. [PMID: 34740486 DOI: 10.1053/j.semdp.2021.10.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Accepted: 10/28/2021] [Indexed: 11/11/2022]
Abstract
Biomarkers play a key role in the comprehensive pathologic evaluation of gastrointestinal malignancies. These biomarkers can be predictive, indicating whether a tumor is likely to respond to a particular therapy, or prognostic, providing information about the likely course and outcome of a disease. This review article will discuss available immunohistochemical stains for assessing these markers, including staining rationale, scoring criteria, associated systemic therapies, and pictorial examples. PD-L1, HER2, and mismatch repair status can be evaluated via immunohistochemistry for esophageal, gastric, and colorectal carcinomas. Biomarkers currently play a more limited role in evaluation of pancreatic and small bowel malignancies. Immunohistochemistry can also be used to evaluate biomarker status in gastrointestinal stromal tumors, gastrointestinal malignancies with NTRK gene fusions, and undifferentiated carcinomas with switch-sucrose non-fermentable complex abnormalities.
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Affiliation(s)
- Matthew W Rosenbaum
- Department of Pathology, Beth Israel Deaconess Medical Center, United States
| | - Raul S Gonzalez
- Department of Pathology, Beth Israel Deaconess Medical Center, United States.
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Pellino A, Brignola S, Riello E, Niero M, Murgioni S, Guido M, Nappo F, Businello G, Sbaraglia M, Bergamo F, Spolverato G, Pucciarelli S, Merigliano S, Pilati P, Cavallin F, Realdon S, Farinati F, Dei Tos AP, Zagonel V, Lonardi S, Loupakis F, Fassan M. Association of CLDN18 Protein Expression with Clinicopathological Features and Prognosis in Advanced Gastric and Gastroesophageal Junction Adenocarcinomas. J Pers Med 2021; 11:1095. [PMID: 34834447 PMCID: PMC8624955 DOI: 10.3390/jpm11111095] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Revised: 10/11/2021] [Accepted: 10/22/2021] [Indexed: 12/16/2022] Open
Abstract
The tight junction protein claudin-18 (CLDN18), is often expressed in various cancer types including gastric (GC) and gastroesophageal adenocarcinomas (GECs). In the last years, the isoform CLDN18.2 emerged as a potential drug target in metastatic GCs, leading to the development of monoclonal antibodies against this protein. CLDN18.2 is the dominant isoform of CLDN18 in normal gastric and gastric cancer tissues. In this work, we evaluated the immunohistochemical (IHC) profile of CLDN18 and its correlation with clinical and histopathological features including p53, E-cadherin, MSH2, MSH6, MLH1, PMS2, HER2, EBER and PD-L1 combined positive score, in a large real-world and mono-institutional series of advanced GCs (n = 280) and GECs (n = 70). The association of IHC results with survival outcomes was also investigated. High membranous CLDN18 expression (2+ and 3+ intensity ≥75%) was found in 117/350 (33.4%) samples analyzed. CLDN18 expression correlated with age <70 (p = 0.0035), positive EBV status (p = 0.002), high stage (III, IV) at diagnosis (p = 0.003), peritoneal involvement (p < 0.001) and lower incidence of liver metastases (p = 0.013). CLDN18 did not correlate with overall survival. The predictive value of response of CLDN18 to targeted agents is under investigation in several clinical trials and further studies will be needed to select patients who could benefit from these therapies.
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Affiliation(s)
- Antonio Pellino
- Oncology Unit 1, Department of Oncology, Veneto Institute of Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), 35128 Padua, Italy; (A.P.); (S.M.); (F.N.); (F.B.); (V.Z.); (F.L.)
| | - Stefano Brignola
- Surgical Pathology Unit, Department of Medicine (DIMED), University of Padua, 35122 Padua, Italy; (S.B.); (E.R.); (M.G.); (G.B.); (M.S.); (A.P.D.T.)
- Department of Pathology, Azienda ULSS 2 Marca Trevigiana, 31100 Treviso, Italy;
| | - Erika Riello
- Surgical Pathology Unit, Department of Medicine (DIMED), University of Padua, 35122 Padua, Italy; (S.B.); (E.R.); (M.G.); (G.B.); (M.S.); (A.P.D.T.)
| | - Monia Niero
- Department of Pathology, Azienda ULSS 2 Marca Trevigiana, 31100 Treviso, Italy;
| | - Sabina Murgioni
- Oncology Unit 1, Department of Oncology, Veneto Institute of Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), 35128 Padua, Italy; (A.P.); (S.M.); (F.N.); (F.B.); (V.Z.); (F.L.)
| | - Maria Guido
- Surgical Pathology Unit, Department of Medicine (DIMED), University of Padua, 35122 Padua, Italy; (S.B.); (E.R.); (M.G.); (G.B.); (M.S.); (A.P.D.T.)
- Department of Pathology, Azienda ULSS 2 Marca Trevigiana, 31100 Treviso, Italy;
| | - Floriana Nappo
- Oncology Unit 1, Department of Oncology, Veneto Institute of Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), 35128 Padua, Italy; (A.P.); (S.M.); (F.N.); (F.B.); (V.Z.); (F.L.)
| | - Gianluca Businello
- Surgical Pathology Unit, Department of Medicine (DIMED), University of Padua, 35122 Padua, Italy; (S.B.); (E.R.); (M.G.); (G.B.); (M.S.); (A.P.D.T.)
| | - Marta Sbaraglia
- Surgical Pathology Unit, Department of Medicine (DIMED), University of Padua, 35122 Padua, Italy; (S.B.); (E.R.); (M.G.); (G.B.); (M.S.); (A.P.D.T.)
| | - Francesca Bergamo
- Oncology Unit 1, Department of Oncology, Veneto Institute of Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), 35128 Padua, Italy; (A.P.); (S.M.); (F.N.); (F.B.); (V.Z.); (F.L.)
| | - Gaya Spolverato
- 1st Surgery Unit, Department of Surgical, Oncological, and Gastroenterological Sciences (DISCOG), University of Padua, 35122 Padua, Italy; (G.S.); (S.P.)
| | - Salvatore Pucciarelli
- 1st Surgery Unit, Department of Surgical, Oncological, and Gastroenterological Sciences (DISCOG), University of Padua, 35122 Padua, Italy; (G.S.); (S.P.)
| | - Stefano Merigliano
- 3rd Surgery Unit, Department of Surgical, Oncological and Gastroenterological Sciences, University of Padua, 35122 Padua, Italy;
| | - Pierluigi Pilati
- Surgery Unit, Veneto Institute of Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), 31033 Castelfranco Veneto, Italy;
| | | | - Stefano Realdon
- Gastroenterology Unit, Veneto Institute of Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), 35128 Padua, Italy;
| | - Fabio Farinati
- Gastroenterology Unit, Department of Surgical, Oncological, and Gastroenterological Sciences (DISCOG), University of Padua, 35122 Padua, Italy;
| | - Angelo Paolo Dei Tos
- Surgical Pathology Unit, Department of Medicine (DIMED), University of Padua, 35122 Padua, Italy; (S.B.); (E.R.); (M.G.); (G.B.); (M.S.); (A.P.D.T.)
| | - Vittorina Zagonel
- Oncology Unit 1, Department of Oncology, Veneto Institute of Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), 35128 Padua, Italy; (A.P.); (S.M.); (F.N.); (F.B.); (V.Z.); (F.L.)
| | - Sara Lonardi
- Oncology Unit 3, Department of Oncology, Veneto Institute of Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), 35128 Padua, Italy;
| | - Fotios Loupakis
- Oncology Unit 1, Department of Oncology, Veneto Institute of Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), 35128 Padua, Italy; (A.P.); (S.M.); (F.N.); (F.B.); (V.Z.); (F.L.)
| | - Matteo Fassan
- Surgical Pathology Unit, Department of Medicine (DIMED), University of Padua, 35122 Padua, Italy; (S.B.); (E.R.); (M.G.); (G.B.); (M.S.); (A.P.D.T.)
- Veneto Institute of Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), 35128 Padua, Italy
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Liu Y, Chen L, Jiang D, Luan L, Huang J, Hou Y, Xu C. HER2 promotes epithelial-mesenchymal transition through regulating osteopontin in gastric cancer. Pathol Res Pract 2021; 227:153643. [PMID: 34634565 DOI: 10.1016/j.prp.2021.153643] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2021] [Revised: 09/24/2021] [Accepted: 09/30/2021] [Indexed: 01/07/2023]
Abstract
AIMS HER2 and osteopontin (OPN) are both important biomarkers in gastric cancer (GC). The relationships between them remain to be revealed. The purpose of this study is to explore the role of OPN in epithelial-mesenchymal transition (EMT) in HER2 positive GCs. METHODS Nanostring analysis was used to compare the mRNA levels of 730 cancer related genes between paired HER2 3+ and non-3+ areas in GC patients. Immunohistochemistry (IHC) staining was performed to analyze the expression levels of OPN, as well as EMT markers including E-cad, N-cad, twist and vimentin in both areas. To further verify the role of OPN in EMT, the expression levels of OPN and EMT markers, tumor invasion/migration were analyzed after down-regulating HER2 and OPN in GC cell lines MKN-45 and N-87. RESULTS Nanostring analysis identified 8 differential expression genes between HER2 3+ and non-3+ areas. Among them, the expression level of OPN was positively correlated with that of HER2. In GC specimens, OPN showed higher expression level in HER2 3+ areas where higher E-cad expression levels and lower N-cad and twist levels were also found. After knocking down OPN and HER2 by siRNA, both cell lines show decreased invasion/migration abilities, along with the down-regulation of the EMT phenotype, supporting by the decrease of E-cad, and the increase of N-cad and twist at both mRNA and protein levels. In addition, HER2 knock-down lead to a dramatic decrease of OPN expression. CONCLUSIONS These findings indicate that HER2 may promote EMT via the regulation of OPN in GCs.
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Affiliation(s)
- Yalan Liu
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China; Department of Pathology, School of Basic Medical Sciences & Zhongshan Hospital, Fudan University, Shanghai, China
| | - Lingli Chen
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China; Department of Pathology, School of Basic Medical Sciences & Zhongshan Hospital, Fudan University, Shanghai, China
| | - Dongxian Jiang
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China; Department of Pathology, School of Basic Medical Sciences & Zhongshan Hospital, Fudan University, Shanghai, China
| | - Lijuan Luan
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China; Department of Pathology, School of Basic Medical Sciences & Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jie Huang
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China; Department of Pathology, School of Basic Medical Sciences & Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yingyong Hou
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China; Department of Pathology, School of Basic Medical Sciences & Zhongshan Hospital, Fudan University, Shanghai, China.
| | - Chen Xu
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China; Department of Pathology, School of Basic Medical Sciences & Zhongshan Hospital, Fudan University, Shanghai, China.
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Ishii T, Shitara K. Trastuzumab deruxtecan and other HER2-targeting agents for the treatment of HER2-positive gastric cancer. Expert Rev Anticancer Ther 2021; 21:1193-1201. [PMID: 34543577 DOI: 10.1080/14737140.2021.1982698] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
INTRODUCTION Although various new drugs have been developed, the prognosis of therapeutic advances for metastatic gastric cancer is insufficient. Trastuzumab deruxtecan (T-DXd), a new human epidermal growth factor receptor 2 (HER2)-targeting antibody-drug conjugate (ADC), has demonstrated promising results in clinical trials. AREAS COVERED In this article, we review the history of anti-HER2 ADCs and focus on the efficacy and safety of T-DXd and describe the development of new anti-HER2 drugs. EXPERT OPINION So far, no other anti-HER2 ADCs have demonstrated efficacy in patients with HER2-positive advanced gastric cancer with two or more previous lines of chemotherapy, including trastuzumab. However, a new drug, T-DXd, has shown a significantly higher objective response rate and a longer overall survival and, thus, was approved in Japan. In the future, new anti-HER2 drugs and/or treatment strategies including T-DXd along with cytotoxic chemotherapy or immune checkpoint inhibitors will be developed.
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Affiliation(s)
- Takahiro Ishii
- Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Kohei Shitara
- Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan.,Department of Experimental Therapeutics, National Cancer Center Hospital East, Kashiwa, Japan
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Li H, Zhang X, Xu Z, Li L, Liu W, Dai Z, Zhao Z, Xiao L, Li H, Hu C. Preclinical evaluation of MRG002, a novel HER2-targeting antibody-drug conjugate with potent antitumor activity against HER2-positive solid tumors. Antib Ther 2021; 4:175-184. [PMID: 34532642 DOI: 10.1093/abt/tbab017] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Revised: 08/18/2021] [Accepted: 08/19/2021] [Indexed: 12/30/2022] Open
Abstract
Background ERBB2 is a proto-oncogene of multiple cancers including breast and gastric cancers with HER2 protein overexpression or gene amplification and has been proven clinically as a valid target for these cancers. HER2-targeting agents such as Herceptin®, Kadcyla® and ENHERTU® have been approved by the FDA for the treatment of breast cancer, but these drugs still face the challenge of acquired resistance and/or severe adverse reactions in clinical use. Therefore, there is significant unmet medical need for developing new agents that are more effective and safer for patients with advanced HER2-positive solid tumors including breast and gastric cancers. Methods We report here the making of MRG002, a novel HER2-targeted antibody drug conjugate (ADC), and preclinical characterization including pharmacology, pharmacodynamics and toxicology and discuss its potential as a novel agent for treating patients with HER2-positive solid tumors. Results MRG002 exhibited similar antigen binding affinity but much reduced antibody-dependent cellular cytotoxicity (ADCC) activity compared to trastuzumab. In addition to potent in vitro cytotoxicity, MRG002 showed tumor regression in both high- and medium-to-low HER2 expressing in vivo xenograft models. Furthermore, MRG002 showed enhanced antitumor activity when used in combination with an anti-PD-1 antibody. Main findings from toxicology studies are related to the payload and are consistent with literature report of other ADCs with monomethyl auristatinE. Conclusion MRG002 has demonstrated a favorable toxicity profile and potent antitumor activities in the breast and gastric PDX models with varying levels of HER2 expression, and/or resistance to trastuzumab or T-DM1. A phase I clinical study of MRG002 in patients with HER2-positive solid tumors is ongoing (CTR20181778).
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Affiliation(s)
- Hu Li
- Research and Development, Shanghai Miracogen, Suite 4E, Bldg. 3, No. 1238 Zhangjiang Road, Pudong District, Shanghai 201203, China
| | - Xiao Zhang
- Research and Development, Shanghai Miracogen, Suite 4E, Bldg. 3, No. 1238 Zhangjiang Road, Pudong District, Shanghai 201203, China
| | - Zhenyi Xu
- Research and Development, Shanghai Miracogen, Suite 4E, Bldg. 3, No. 1238 Zhangjiang Road, Pudong District, Shanghai 201203, China
| | - Lingrui Li
- Research and Development, Shanghai Miracogen, Suite 4E, Bldg. 3, No. 1238 Zhangjiang Road, Pudong District, Shanghai 201203, China
| | - Wenchao Liu
- Research and Development, Shanghai Miracogen, Suite 4E, Bldg. 3, No. 1238 Zhangjiang Road, Pudong District, Shanghai 201203, China
| | - Zhenyu Dai
- Research and Development, Shanghai Miracogen, Suite 4E, Bldg. 3, No. 1238 Zhangjiang Road, Pudong District, Shanghai 201203, China
| | - Zhongrun Zhao
- Research and Development, Shanghai Miracogen, Suite 4E, Bldg. 3, No. 1238 Zhangjiang Road, Pudong District, Shanghai 201203, China
| | - Lili Xiao
- Research and Development, Shanghai Miracogen, Suite 4E, Bldg. 3, No. 1238 Zhangjiang Road, Pudong District, Shanghai 201203, China
| | - Hongfeng Li
- Research and Development, Shanghai Miracogen, Suite 4E, Bldg. 3, No. 1238 Zhangjiang Road, Pudong District, Shanghai 201203, China
| | - Chaohong Hu
- Research and Development, Shanghai Miracogen, Suite 4E, Bldg. 3, No. 1238 Zhangjiang Road, Pudong District, Shanghai 201203, China
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Grillo F, Mastracci L, Saragoni L, Vanoli A, Limarzi F, Gullo I, Ferro J, Paudice M, Parente P, Fassan M. Neoplastic and pre-neoplastic lesions of the oesophagus and gastro-oesophageal junction. Pathologica 2021; 112:138-152. [PMID: 33179618 PMCID: PMC7931575 DOI: 10.32074/1591-951x-164] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Accepted: 06/29/2020] [Indexed: 12/12/2022] Open
Abstract
Oesophageal and gastro-oesophageal junction (GOJ) neoplasms, and their predisposing conditions, may be encountered by the practicing pathologist both as biopsy samples and as surgical specimens in daily practice. Changes in incidence of oesophageal squamous cell carcinomas (such as a decrease in western countries) and in oesophageal and GOJ adenocarcinomas (such as a sharp increase in western countries) are being reported globally. New modes of treatment have changed our histologic reports as specific aspects must be detailed such as in post endoscopic resections or with regards to post neo-adjuvant therapy tumour regression grades. The main aim of this overview is therefore to provide an up-to-date, easily available and clear diagnostic approach to neoplastic and pre-neoplastic conditions of the oesophagus and GOJ, based on the most recent available guidelines and literature.
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Affiliation(s)
- Federica Grillo
- Anatomic Pathology Unit, Department of Surgical Sciences and Integrated Diagnostics (DICS), University of Genova, Italy.,Ospedale Policlinico San Martino, IRCCS for Oncology and Neuroscience, Genova, Italy
| | - Luca Mastracci
- Anatomic Pathology Unit, Department of Surgical Sciences and Integrated Diagnostics (DICS), University of Genova, Italy.,Ospedale Policlinico San Martino, IRCCS for Oncology and Neuroscience, Genova, Italy
| | - Luca Saragoni
- UO Anatomia Patologica, Ospedale G.B. Morgagni-L. Pierantoni, Forlì, Italy
| | - Alessandro Vanoli
- Anatomic Pathology Unit, Department of Molecular Medicine, University of Pavia and Fondazione IRCCS San Matteo Hospital, Pavia, Italy
| | - Francesco Limarzi
- Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST/IRCCS), Meldola (FC), Italy
| | - Irene Gullo
- Department of Pathology, Centro Hospitalar Universitário de São João (CHUSJ) & Department of Pathology, Faculty of Medicine of the University of Porto (FMUP), Porto, Portugal and Instituto de Investigação e Inovação em Saúde (i3S) & Institute of Molecular Pathology and Immunology of the University of Porto (Ipatimup), Porto, Portugal
| | - Jacopo Ferro
- Anatomic Pathology Unit, Department of Surgical Sciences and Integrated Diagnostics (DICS), University of Genova, Italy
| | - Michele Paudice
- Anatomic Pathology Unit, Department of Surgical Sciences and Integrated Diagnostics (DICS), University of Genova, Italy
| | - Paola Parente
- Unit of Pathology, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo (FG), Italy
| | - Matteo Fassan
- Surgical Pathology Unit, Department of Medicine (DIMED), University of Padua, Italy
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Fassan M, Scarpa A, Remo A, De Maglio G, Troncone G, Marchetti A, Doglioni C, Ingravallo G, Perrone G, Parente P, Luchini C, Mastracci L. Current prognostic and predictive biomarkers for gastrointestinal tumors in clinical practice. Pathologica 2021; 112:248-259. [PMID: 33179625 PMCID: PMC7931577 DOI: 10.32074/1591-951x-158] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Accepted: 06/24/2020] [Indexed: 12/12/2022] Open
Abstract
The pathologist emerged in the personalized medicine era as a central actor in the definition of the most adequate diagnostic and therapeutic algorithms. In the last decade, gastrointestinal oncology has seen a significantly increased clinical request for the integration of novel prognostic and predictive biomarkers in histopathological reports. This request couples with the significant contraction of invasive sampling of the disease, thus conferring to the pathologist the role of governor for both proper pathologic characterization and customized processing of the biospecimens. This overview will focus on the most commonly adopted immunohistochemical and molecular biomarkers in the routine clinical characterization of gastrointestinal neoplasms referring to the most recent published recommendations, guidelines and expert opinions.
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Affiliation(s)
- Matteo Fassan
- Surgical Pathology Unit, Department of Medicine (DIMED), University of Padua, Italy
| | - Aldo Scarpa
- ARC-NET Research Centre, University of Verona, Italy.,Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy
| | - Andrea Remo
- Pathology Unit, Service Department, ULSS9 "Scaligera", Verona, Italy
| | | | - Giancarlo Troncone
- Department of Public Health, Federico II University Medical School Naples, Italy
| | - Antonio Marchetti
- Center of Predictive Molecular Medicine, Center for Excellence on Aging and Translational Medicine, University of Chieti-Pescara, Italy
| | - Claudio Doglioni
- Vita e Salute University, Milan, Italy.,Pathology Unit, Pancreas Translational and Clinical Research Center, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Giuseppe Ingravallo
- Department of Emergency and Organ Transplantation, Section of Pathological Anatomy, University of Bari Aldo Moro, Bari, Italy
| | - Giuseppe Perrone
- Department of Pathology, Campus Bio-Medico University, Rome, Italy
| | - Paola Parente
- Pathology Unit, Fondazione IRCCS Ospedale Casa Sollievo della Sofferenza, San Giovanni Rotondo (FG), Italy
| | - Claudio Luchini
- Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy
| | - Luca Mastracci
- Anatomic Pathology, San Martino IRCCS Hospital,, Genova, Italy.,Anatomic Pathology, Department of Surgical Sciences and Integrated Diagnostics (DISC), University of Genova, Genova, Italy
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Chen MH, Lu SN, Chen CH, Lin PC, Jiang JK, D’yachkova Y, Lukanowski M, Cheng R, Chen LT. How May Ramucirumab Help Improve Treatment Outcome for Patients with Gastrointestinal Cancers? Cancers (Basel) 2021; 13:3536. [PMID: 34298750 PMCID: PMC8306041 DOI: 10.3390/cancers13143536] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 05/24/2021] [Accepted: 07/09/2021] [Indexed: 12/24/2022] Open
Abstract
GI cancers are characterized by high recurrence rates and a dismal prognosis and there is an urgent need for new therapeutic approaches. This is a narrative review designed to provide a summary of the efficacy as measured by overall survival, progression free survival, and safety data from phase 3 randomized controlled GI clinical trials of ramucirumab including those from important pre-specified patient subgroups and evidence from real clinical practice worldwide. Quality of life (QOL) is discussed where data are available. Our aim was to summarize the efficacy and safety of ramucirumab in the treatment of GI cancers using these existing published data with a view to demonstrating how ramucirumab may help improve treatment outcome for patients with GI cancers. The data indicate that ramucirumab is efficacious, safe, and tolerable across the intent-to-treat patient populations as a whole and across several pre-specified subgroups, even those whose disease is traditionally more difficult to treat. Furthermore, survival outcomes observed in real-world clinical practice demonstrate similar data from phase 3 clinical trials even in patients with complications, suggesting that the benefits of ramucirumab translate in actual clinical practice.
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Affiliation(s)
- Ming-Huang Chen
- Taipei Veterans General Hospital, Taipei 11217, Taiwan; (M.-H.C.); (J.-K.J.)
| | - Sheng-Nan Lu
- Kaohsiung Chang Gung Memorial Hospital, Kaohsiung City 83301, Taiwan;
| | - Chien-Hung Chen
- Department of Internal Medicine, National Taiwan University Hospital, Douliu 64041, Taiwan;
| | - Peng-Chan Lin
- National Cheng Kung University Hospital, National Cheng Kung University, Tainan 70403, Taiwan;
| | - Jeng-Kai Jiang
- Taipei Veterans General Hospital, Taipei 11217, Taiwan; (M.-H.C.); (J.-K.J.)
| | | | - Mariusz Lukanowski
- Global Medical Affairs, Eli Lilly Denmark, Hovedstaden, 2730 Herlev, Denmark;
| | - Rebecca Cheng
- Eli Lilly and Company (Taiwan) Inc., Taipe City 10543, Taiwan;
| | - Li-Tzong Chen
- National Cheng Kung University Hospital, National Cheng Kung University, Tainan 70403, Taiwan;
- National Institute of Cancer Research, National Health Research Institutes, Tainan 70456, Taiwan
- Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung City 80756, Taiwan
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Salani F, Ugolini C, Catanese S, Cacciato Insilla A, Fornaro L, Campani D, Vasile E, Fontanini G, Masi G, Vivaldi C. In Reply. Oncologist 2021; 26:e1895-e1896. [PMID: 34176190 DOI: 10.1002/onco.13886] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Accepted: 06/18/2021] [Indexed: 11/10/2022] Open
Affiliation(s)
- Francesca Salani
- Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy
| | - Clara Ugolini
- Department of Surgical, Medical and Molecular Pathology and Critical Care Medicine, University of Pisa, Pisa, Italy
| | - Silvia Catanese
- Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy
| | - Andrea Cacciato Insilla
- Department of Surgical, Medical and Molecular Pathology and Critical Care Medicine, University of Pisa, Pisa, Italy
| | - Lorenzo Fornaro
- Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy
| | - Daniela Campani
- Department of Surgical, Medical and Molecular Pathology and Critical Care Medicine, University of Pisa, Pisa, Italy
| | - Enrico Vasile
- Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy
| | - Gabriella Fontanini
- Department of Surgical, Medical and Molecular Pathology and Critical Care Medicine, University of Pisa, Pisa, Italy
| | - Gianluca Masi
- Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy.,Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
| | - Caterina Vivaldi
- Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy.,Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
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Gonzalez RS, Raza A, Propst R, Adeyi O, Bateman J, Sopha SC, Shaw J, Auerbach A. Recent Advances in Digestive Tract Tumors: Updates From the 5th Edition of the World Health Organization "Blue Book". Arch Pathol Lab Med 2021; 145:607-626. [PMID: 32886739 DOI: 10.5858/arpa.2020-0047-ra] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/12/2020] [Indexed: 11/06/2022]
Abstract
CONTEXT.— The World Health Organization Classification of Tumours: Digestive System Tumors, 5th edition, was published in 2019 and shows several impactful changes as compared with the 4th edition published in 2010. Changes include a revised nomenclature of serrated lesions and revamping the classification of neuroendocrine neoplasms. Appendiceal goblet cell adenocarcinoma is heavily revised, and intrahepatic cholangiocarcinoma is split into 2 subtypes. New subtypes of colorectal carcinoma and hepatocellular carcinoma are described. Precursor lesions are emphasized with their own entries, and both dysplastic and invasive lesions are generally recommended to be graded using a 2-tier system. Hematolymphoid tumors, mesenchymal tumors, and genetic tumor syndromes each have their own sections in the 5th edition. New hematolymphoid lesions include monomorphic epitheliotropic intestinal T-cell lymphoma; duodenal-type follicular lymphoma; intestinal T-cell lymphoma, not otherwise specified; and indolent T-cell lymphoproliferative disorder of the gastrointestinal tract. This paper will provide an in-depth look at the changes in the 5th edition as compared with the 4th edition. OBJECTIVE.— To provide a comprehensive, in-depth update on the World Health Organization classification of digestive tumors, including changes to nomenclature, updated diagnostic criteria, and newly described entities. DATA SOURCES.— The 5th edition of the World Health Organization Classification of Tumours: Digestive System Tumours, as well as the 4th edition. CONCLUSIONS.— The World Health Organization has made many key changes in its newest update on tumors of the digestive system. Pathologists should be aware of these changes and incorporate them into their practice as able or necessary.
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Affiliation(s)
- Raul S Gonzalez
- The Department of Pathology, Beth Israel Deaconess Medical Center, Boston, Massachusetts (Gonzalez)
| | - Anwar Raza
- The Department of Pathology and Human Anatomy, Loma Linda University, Loma Linda, California (Raza, Propst)
| | - Robert Propst
- The Department of Pathology and Human Anatomy, Loma Linda University, Loma Linda, California (Raza, Propst)
| | - Oyedele Adeyi
- The Department of Pathology, University of Minnesota, Minneapolis (Adeyi, Bateman)
| | - Justin Bateman
- The Department of Pathology, University of Minnesota, Minneapolis (Adeyi, Bateman)
| | - Sabrina C Sopha
- The Department of Pathology, University of Maryland Baltimore Washington Medical Center, Glen Burnie (Sopha)
| | - Janet Shaw
- The Joint Pathology Center, Silver Spring, Maryland (Shaw, Auerbach)
| | - Aaron Auerbach
- The Joint Pathology Center, Silver Spring, Maryland (Shaw, Auerbach)
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Mishima S, Shitara K. Trastuzumab deruxtecan for the treatment of HER2-positive gastric cancer. Expert Opin Biol Ther 2021; 21:825-830. [PMID: 33798395 DOI: 10.1080/14712598.2021.1912007] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
Introduction: Trastuzumab deruxtecan (T-DXd) is a novel human epidermal growth factor receptor 2 (HER2)-targeted antibody-drug conjugate with a humanized anti-HER2 antibody, cleavable peptide-based linker, and topoisomerase I inhibitor payload. The phase II trial DESTINY-Gastric01 has demonstrated that T-DXd exhibits antitumor activity in patients with HER2-positive advanced gastric cancer (AGC) who had received at least two previous therapies, including trastuzumab.Area covered: T-DXd was approved for previously treated HER2-positive AGC in Japan. The US Food and Drug Administration also approved on 15 January 2021. In this article, we review the development of T-DXd, its pharmacology, and its safety profile in patients with HER2-positive AGC.Expert opinion: T-DXd has demonstrated a significantly higher objective response rate and a longer overall survival in HER2-positive AGC patients with two or more previous lines of systemic chemotherapy, including trastuzumab. Safety profile was acceptable. Currently, there are several ongoing clinical trials of T-DXd in combination with cytotoxic chemotherapy or an immune checkpoint inhibitor.
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Affiliation(s)
- Saori Mishima
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Kohei Shitara
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
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Washington MK, Goldberg RM, Chang GJ, Limburg P, Lam AK, Salto-Tellez M, Arends MJ, Nagtegaal ID, Klimstra DS, Rugge M, Schirmacher P, Lazar AJ, Odze RD, Carneiro F, Fukayama M, Cree IA. Diagnosis of digestive system tumours. Int J Cancer 2021; 148:1040-1050. [PMID: 32674220 DOI: 10.1002/ijc.33210] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2020] [Revised: 06/09/2020] [Accepted: 06/11/2020] [Indexed: 12/12/2022]
Abstract
The WHO Classification of Tumours provides the international standards for the classification and diagnosis of tumours. It enables direct comparisons to be made between different countries. In the new fifth edition, the series has gone digital with the launch of a website as well as a series of books, known widely as the WHO Blue Books. The first volume to be produced is on the classification of Digestive System tumours, replacing the successful 2010 version. It has been rewritten and updated accordingly. This article summarises the major diagnostic innovations that have occurred over the last decade and that have now been incorporated in the classification. As an example, it incorporates the recently proposed classification of neuroendocrine tumours, based on the recognition that neuroendocrine tumours and carcinomas differ substantially in the genetic abnormalities that drive their growth, findings relevant to treatment selection and outcome prediction. Several themes have emerged during the production process. One is the importance of the progression from hyperplasia to dysplasia to carcinoma in the evolution of the malignant process. Advances in imaging techniques and endoscopy have resulted in enhanced access to precancerous lesions in the gastrointestinal and biliary tract, necessitating both changes in classification schema and clinical practice. Diagnosis of tumours is no longer the sole purview of pathologists, and some patients now receive treatment before tissue is obtained, based on clinical, radiological and liquid biopsy results. This makes the classification relevant to many disciplines involved in the care of patients with tumours of the digestive system.
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Affiliation(s)
| | - Richard M Goldberg
- West Virginia University Cancer Institute and the Mary Babb Randolph Cancer Center, Morgantown, West Virginia, USA
| | - George J Chang
- Department of Surgical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA
| | - Paul Limburg
- Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Alfred K Lam
- Pathology, School of Medicine, Gold Coast campus, Griffith University, Gold Coast, Queensland, Australia
| | - Manuel Salto-Tellez
- Queen's Precision Medicine Centre of Excellence, Queen's University Belfast, Belfast Health & Social Care Trust, Belfast, UK
| | - Mark J Arends
- Cancer Research UK Edinburgh Centre, MRC Institute of Genetics & Molecular Medicine, The University of Edinburgh, Western General Hospital, Edinburgh, UK
| | - Iris D Nagtegaal
- Department of Pathology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - David S Klimstra
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | | | | | - Alexander J Lazar
- Departments of Pathology, Genomic Medicine, and Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | | | | | - Masashi Fukayama
- Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Ian A Cree
- WHO Classification of Tumours Group, International Agency for Research on Cancer (IARC), World Health Organization, Lyon, France
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Tarantino P, Mazzarella L, Marra A, Trapani D, Curigliano G. The evolving paradigm of biomarker actionability: Histology-agnosticism as a spectrum, rather than a binary quality. Cancer Treat Rev 2021; 94:102169. [PMID: 33652262 DOI: 10.1016/j.ctrv.2021.102169] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Revised: 02/02/2021] [Accepted: 02/05/2021] [Indexed: 02/06/2023]
Abstract
Precision medicine is progressively revolutionizing oncology, through the identification of biomarkers predictive of treatment response in cancer patients. For three of such biomarkers, namely NTRK-fusions, microsatellite instability and high tumor mutational burden, drugs have been approved by regulatory agencies regardless of tumor histology, realizing the paradigm of histology-agnostic actionability. Several additional biomarkers are being studied in a histology-agnostic manner, and may in the future expand this list. However, most available evidence suggest that histology-agnosticism may be the extreme of a continuous spectrum of actionability, rather than a binary quality. The present review recapitulates such evidence, highlighting opportunities and challenges posed by the emergence of the spectrum of biomarker actionability in the context of a prevalently histology-based oncology.
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Affiliation(s)
- Paolo Tarantino
- European Institute of Oncology IRCCS, Milan, Italy; University of Milan, Milan, Italy
| | | | - Antonio Marra
- European Institute of Oncology IRCCS, Milan, Italy; University of Milan, Milan, Italy
| | | | - Giuseppe Curigliano
- European Institute of Oncology IRCCS, Milan, Italy; University of Milan, Milan, Italy.
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