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1
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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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2
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Kim HS, Kim Y, Lee HS. Clinicopathologic Characteristics of Trop Family Proteins (Trop-2 and EpCAM) in Gastric Carcinoma. J Gastric Cancer 2024; 24:391-405. [PMID: 39375055 PMCID: PMC11471318 DOI: 10.5230/jgc.2024.24.e32] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2024] [Revised: 07/17/2024] [Accepted: 07/18/2024] [Indexed: 10/09/2024] Open
Abstract
PURPOSE Trop family proteins, including epithelial cell adhesion molecule (EpCAM) and Trop-2, have garnered attention as potential therapeutic and diagnostic targets for various malignancies. This study aimed to elucidate the clinicopathological significance of these proteins in gastric carcinoma (GC) and to reinforce their potential as biomarkers for patient stratification in targeted therapies. MATERIALS AND METHODS Immunohistochemical (IHC) analyses of EpCAM and Trop-2 were performed on GC and precancerous lesions, following rigorous orthogonal validation of the antibodies to ensure specificity and sensitivity. RESULTS Strong membranous staining (3+) for Trop-2 was observed in 49.3% of the GC cases, whereas EpCAM was strongly expressed in almost all cases (93.2%), indicating its widespread expression in GC. A high Trop-2 expression level, characterized by an elevated H-score, was significantly associated with intestinal type by Lauren classification, gastric mucin type, presence of lymph node metastasis, human epidermal growth factor receptor 2-positivity, and Epstein-Barr virus (EBV)-positivity. Patients with a high Trop-2 expression level exhibited poorer survival outcomes on univariate and multivariate analyses. High EpCAM expression levels were prevalent in differentiated histologic type, microsatellite instability-high, and EBV-negative cancer, and were correlated with high densities of CD3 and CD8 T cells and elevated combined positive score for programmed death-ligand 1. CONCLUSIONS These results highlight the differential expression of Trop-2 and EpCAM and their prognostic implications in GC. The use of meticulously validated antibodies ensured the reliability of our IHC data, thereby offering a robust foundation for future therapeutic strategies targeting Trop family members in GC.
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Affiliation(s)
- Hye Sung Kim
- Department of Pathology, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Younghoon Kim
- Department of Pathology, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Hye Seung Lee
- Department of Pathology, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
- Department of Pathology, Seoul National University Hospital, Seoul, Korea.
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Shimozaki K, Fukuoka S, Ooki A, Yamaguchi K. HER2-low gastric cancer: is the subgroup targetable? ESMO Open 2024; 9:103679. [PMID: 39178538 PMCID: PMC11386020 DOI: 10.1016/j.esmoop.2024.103679] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2024] [Revised: 07/20/2024] [Accepted: 07/22/2024] [Indexed: 08/26/2024] Open
Abstract
Therapeutic developments in the targeting of human epidermal growth factor receptor 2 (HER2)-expressing gastric cancer have followed the dramatic success of HER2-expressing breast cancer treatment, which has facilitated the expansion of indications for anti-HER2 agents to include not only conventional HER2-positive breast cancer, but also HER2-low and HER2-ultralow subgroups. The targetability of HER2-low gastric cancer, however, has yet to be established. Hence, further studies are needed to comprehensively understand the clinicopathological features, specific gene alterations, and distinct tumor immune microenvironment of HER2-low gastric cancer and compare them with those for HER2-positive or -negative gastric cancer. Antibody-drug conjugates for HER2 play an important role in making HER2-low gastric cancer targetable. In this context, a deeper understanding of the novel anti-HER2 agents, including antibody-drug conjugates, bispecific T-cell engager antibodies, and a combination of these agents, as well as new forms of immunomodulatory agents are also required. Redefining and re-categorizing HER2 status through not only immunohistochemistry/fluorescence in situ hybridization but also evaluating ERRB2 copy number gain or protein overexpression levels measured using DNA or RNA sequencing might be helpful for identifying populations with HER2-expressing tumors who would ideally benefit from anti-HER2 treatment. The current paper reviewed recent clinical trials, focusing particularly on HER2-low gastric cancer together with basic/translational findings, and discuss perspectives on further therapeutic development in the treatment of this distinct subgroup.
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Affiliation(s)
- K Shimozaki
- Department of Gastroenterological Chemotherapy, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo; Keio Cancer Center, Keio University School of Medicine, Tokyo, Japan
| | - S Fukuoka
- Department of Gastroenterological Chemotherapy, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo
| | - A Ooki
- Department of Gastroenterological Chemotherapy, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo.
| | - K Yamaguchi
- Department of Gastroenterological Chemotherapy, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo
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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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5
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Wang D, Hao S, He H, Zhang J, You G, Wu X, Zhang R, Meng X, Cui X, Bai J, Fu S, Yu J. Contribution of PGAP3 co-amplified and co-overexpressed with ERBB2 at 17q12 involved poor prognosis in gastric cancer. J Cell Mol Med 2023; 27:2424-2436. [PMID: 37386793 PMCID: PMC10424286 DOI: 10.1111/jcmm.17828] [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: 03/10/2023] [Revised: 06/10/2023] [Accepted: 06/19/2023] [Indexed: 07/01/2023] Open
Abstract
The locus at 17q12 erb-b2 receptor tyrosine kinase 2 (ERBB2) has been heavily amplificated and overexpressed in gastric cancer (GC), but it remains to be elucidated about the clinical significance of the co-amplification and co-overexpression of PGAP3 gene located around ERBB2 in GC. The profile of PGAP3 and ERBB2 in four GC cell lines and tissue microarrays containing 418 primary GC tissues was assessed to investigate the co-overexpression and clinical significance of the co-amplified genes, and to evaluate the impact of the co-amplified genes on the malignancy of GC. Co-amplification of PGAP3 and ERBB2 accompanied with co-overexpression was observed in a haploid chromosome 17 of NCI-N87 cells with double minutes (DMs). PGAP3 and ERBB2 were overexpressed and positively correlated in 418 GC patients. Co-overexpression of the PGAP3 and ERBB2 was correlated with T stage, TNM stage, tumour size, intestinal histological type and poor survival proportion in 141 GC patients. In vitro, knockdown of the endogenous PGAP3 or ERBB2 decreased cell proliferation and invasion, increased G1 phase accumulation and induced apoptosis in NCI-N87 cells. Furthermore, combined silencing of PGAP3 and ERBB2 showed an additive effect on resisting proliferation of NCI-N87 cells compared with targeting ERBB2 or PGAP3 alone. Taken together, the co-overexpression of PGAP3 and ERBB2 may be crucial due to its significant correlation with clinicopathological factors of GC. Haploid gain of PGAP3 co-amplified with ERBB2 is sufficient to facilitate the malignancy and progression of GC cells in a synergistic way.
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Affiliation(s)
- Dong Wang
- Scientific Research CentreThe Second Affiliated Hospital of Harbin Medical UniversityHarbinChina
| | - Siyu Hao
- Scientific Research CentreThe Second Affiliated Hospital of Harbin Medical UniversityHarbinChina
| | - Hongjie He
- Scientific Research CentreThe Second Affiliated Hospital of Harbin Medical UniversityHarbinChina
| | - Jian Zhang
- Scientific Research CentreThe Second Affiliated Hospital of Harbin Medical UniversityHarbinChina
| | - Ge You
- Scientific Research CentreThe Second Affiliated Hospital of Harbin Medical UniversityHarbinChina
| | - Xin Wu
- Scientific Research CentreThe Second Affiliated Hospital of Harbin Medical UniversityHarbinChina
| | - Rui Zhang
- Scientific Research CentreThe Second Affiliated Hospital of Harbin Medical UniversityHarbinChina
| | - Xiangning Meng
- Key Laboratory of Preservation of Human Genetic Resources and Disease Control in China (Harbin Medical University)Ministry of EducationHarbinChina
| | - Xiaobo Cui
- Key Laboratory of Preservation of Human Genetic Resources and Disease Control in China (Harbin Medical University)Ministry of EducationHarbinChina
| | - Jing Bai
- Key Laboratory of Preservation of Human Genetic Resources and Disease Control in China (Harbin Medical University)Ministry of EducationHarbinChina
| | - Songbin Fu
- Key Laboratory of Preservation of Human Genetic Resources and Disease Control in China (Harbin Medical University)Ministry of EducationHarbinChina
| | - Jingcui Yu
- Scientific Research CentreThe Second Affiliated Hospital of Harbin Medical UniversityHarbinChina
- Key Laboratory of Preservation of Human Genetic Resources and Disease Control in China (Harbin Medical University)Ministry of EducationHarbinChina
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6
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Businello G, Angerilli V, Lonardi S, Bergamo F, Valmasoni M, Farinati F, Savarino E, Spolverato G, Fassan M. Current molecular biomarkers evaluation in gastric/gastroesophageal junction adenocarcinoma: pathologist does matter. Updates Surg 2023; 75:291-303. [PMID: 35834132 PMCID: PMC9852175 DOI: 10.1007/s13304-022-01330-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Accepted: 07/05/2022] [Indexed: 01/24/2023]
Abstract
The comprehensive molecular characterization of gastric and gastroesophageal junction adenocarcinomas has led to the improvement of targeted and more effective treatments. As a result, several biomarkers have been introduced into clinical practice and the implementation of innovative diagnostic tools is under study. Such assessments are mainly based on the evaluation of limited biopsy material in clinical practice. In this setting, the pathologist represents a key player in the selection of patients facilitating precision medicine approaches.
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Affiliation(s)
| | | | - Sara Lonardi
- Veneto Institute of Oncology, Istituto Di Ricovero E Cura a Carattere Scientifico (IRCCS), Padua, Italy
| | - Francesca Bergamo
- Veneto Institute of Oncology, Istituto Di Ricovero E Cura a Carattere Scientifico (IRCCS), Padua, Italy
| | - Michele Valmasoni
- Department of Surgery, Oncology and Gastroenterology (DISCOG), University of Padua, Padua, Italy
| | - Fabio Farinati
- Department of Surgery, Oncology and Gastroenterology (DISCOG), University of Padua, Padua, Italy
| | - Edoardo Savarino
- Department of Surgery, Oncology and Gastroenterology (DISCOG), University of Padua, Padua, Italy
| | - Gaya Spolverato
- Department of Surgery, Oncology and Gastroenterology (DISCOG), University of Padua, Padua, Italy
| | - Matteo Fassan
- Department of Medicine (DIMED), University of Padua, Padua, Italy.
- Veneto Institute of Oncology, Istituto Di Ricovero E Cura a Carattere Scientifico (IRCCS), Padua, Italy.
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7
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Park YS, Kook MC, Kim BH, Lee HS, Kang DW, Gu MJ, Shin OR, Choi Y, Lee W, Kim H, Song IH, Kim KM, Kim HS, Kang G, Park DY, Jin SY, Kim JM, Choi YJ, Chang HK, Ahn S, Chang MS, Han SH, Kwak Y, Seo AN, Lee SH, Cho MY. A Standardized Pathology Report for Gastric Cancer: 2nd Edition. J Gastric Cancer 2023; 23:107-145. [PMID: 36750994 PMCID: PMC9911618 DOI: 10.5230/jgc.2023.23.e7] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Revised: 12/22/2022] [Accepted: 12/23/2022] [Indexed: 01/27/2023] Open
Abstract
The first edition of 'A Standardized Pathology Report for Gastric Cancer' was initiated by the Gastrointestinal Pathology Study Group of the Korean Society of Pathologists and published 17 years ago. Since then, significant advances have been made in the pathologic diagnosis, molecular genetics, and management of gastric cancer (GC). To reflect those changes, a committee for publishing a second edition of the report was formed within the Gastrointestinal Pathology Study Group of the Korean Society of Pathologists. This second edition consists of two parts: standard data elements and conditional data elements. The standard data elements contain the basic pathologic findings and items necessary to predict the prognosis of GC patients, and they are adequate for routine surgical pathology service. Other diagnostic and prognostic factors relevant to adjuvant therapy, including molecular biomarkers, are classified as conditional data elements to allow each pathologist to selectively choose items appropriate to the environment in their institution. We trust that the standardized pathology report will be helpful for GC diagnosis and facilitate large-scale multidisciplinary collaborative studies.
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Affiliation(s)
- Young Soo Park
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | | | - Baek-Hui Kim
- Department of Pathology, Korea University Guro Hospital, Seoul, Korea
| | - Hye Seung Lee
- Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Dong-Wook Kang
- Department of Pathology, Chungnam National University Sejong Hospital, Chungnam National University School of Medicine, Sejong, Korea
| | - Mi-Jin Gu
- Department of Pathology, Yeungnam University College of Medicine, Daegu, Korea
| | - Ok Ran Shin
- Department of Hospital Pathology, Uijeongbu St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Uijeongbu, Korea
| | - Younghee Choi
- Department of Pathology, Hallym University Dongtan Sacred Heart Hospital, Hwaseong, Korea
| | - Wonae Lee
- Department of Pathology, Dankook University College of Medicine, Cheonan, Korea
| | - Hyunki Kim
- Department of Pathology, Yonsei University College of Medicine, Seoul, Korea
| | - In Hye Song
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Kyoung-Mee Kim
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Hee Sung Kim
- Department of Pathology, Chung-Ang University Hospital, Chung-Ang University College of Medicine, Seoul, Korea
| | - Guhyun Kang
- LabGenomics Clinical Laboratories, Seongnam, Korea
| | | | - So-Young Jin
- Department of Pathology, Soonchunhyang University Seoul Hospital, Seoul, Korea
| | - Joon Mee Kim
- Department of Pathology, Inha University School of Medicine, Incheon, Korea
| | - Yoon Jung Choi
- Department of Pathology, Yongin Severance Hospital, Yonsei University College of Medicine, Yongin, Korea
| | - Hee Kyung Chang
- Department of Pathology, Kosin University Gospel Hospital, Kosin University College of Medicine, Busan, Korea
| | - Soomin Ahn
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Mee Soo Chang
- Department of Pathology, Seoul National University Boramae Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Song-Hee Han
- Department of Pathology, Dong-A University College of Medicine, Busan, Korea
| | - Yoonjin Kwak
- Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - An Na Seo
- Department of Pathology, School of Medicine, Kyungpook National University, Kyungpook National University Chilgok Hospital, Daegu, Korea
| | - Sung Hak Lee
- Department of Hospital Pathology, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.
| | - Mee-Yon Cho
- Department of Pathology, Wonju Severance Christian Hospital, Yonsei University Wonju College of Medicine, Wonju, Korea.
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8
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Park YS, Kook MC, Kim BH, Lee HS, Kang DW, Gu MJ, Shin OR, Choi Y, Lee W, Kim H, Song IH, Kim KM, Kim HS, Kang G, Park DY, Jin SY, Kim JM, Choi YJ, Chang HK, Ahn S, Chang MS, Han SH, Kwak Y, Seo AN, Lee SH, Cho MY. A standardized pathology report for gastric cancer: 2nd edition. J Pathol Transl Med 2023; 57:1-27. [PMID: 36647283 PMCID: PMC9846007 DOI: 10.4132/jptm.2022.12.23] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Revised: 12/22/2022] [Accepted: 12/23/2022] [Indexed: 01/18/2023] Open
Abstract
The first edition of 'A Standardized Pathology Report for Gastric Cancer' was initiated by the Gastrointestinal Pathology Study Group of the Korean Society of Pathologists and published 17 years ago. Since then, significant advances have been made in the pathologic diagnosis, molecular genetics, and management of gastric cancer (GC). To reflect those changes, a committee for publishing a second edition of the report was formed within the Gastrointestinal Pathology Study Group of the Korean Society of Pathologists. This second edition consists of two parts: standard data elements and conditional data elements. The standard data elements contain the basic pathologic findings and items necessary to predict the prognosis of GC patients, and they are adequate for routine surgical pathology service. Other diagnostic and prognostic factors relevant to adjuvant therapy, including molecular biomarkers, are classified as conditional data elements to allow each pathologist to selectively choose items appropriate to the environment in their institution. We trust that the standardized pathology report will be helpful for GC diagnosis and facilitate large-scale multidisciplinary collaborative studies.
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Affiliation(s)
- Young Soo Park
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | | | - Baek-hui Kim
- Department of Pathology, Korea University Guro Hospital, Seoul, Korea
| | - Hye Seung Lee
- Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Dong-Wook Kang
- Department of Pathology, Chungnam National University Sejong Hospital, Chungnam National University School of Medicine, Sejong, Korea
| | - Mi-Jin Gu
- Department of Pathology, Yeungnam University College of Medicine, Daegu, Korea
| | - Ok Ran Shin
- Department of Hospital Pathology, Uijeongbu St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Uijeongbu, Korea
| | - Younghee Choi
- Department of Pathology, Hallym University Dongtan Sacred Heart Hospital, Hwaseong, Korea
| | - Wonae Lee
- Department of Pathology, Dankook University College of Medicine, Cheonan, Korea
| | - Hyunki Kim
- Department of Pathology, Yonsei University College of Medicine, Seoul, Korea
| | - In Hye Song
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Kyoung-Mee Kim
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Hee Sung Kim
- Department of Pathology, Chung-Ang University Hospital, Chung-Ang University College of Medicine, Seoul, Korea
| | - Guhyun Kang
- LabGenomics Clinical Laboratories, Seongnam, Korea
| | | | - So-Young Jin
- Department of Pathology, Soonchunhyang University Seoul Hospital, Seoul, Korea
| | - Joon Mee Kim
- Department of Pathology, Inha University School of Medicine, Incheon, Korea
| | - Yoon Jung Choi
- Department of Pathology, Yongin Severance Hospital, Yonsei University College of Medicine, Yongin, Korea
| | - Hee Kyung Chang
- Department of Pathology, Kosin University Gospel Hospital, Kosin University College of Medicine, Busan, Korea
| | - Soomin Ahn
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Mee Soo Chang
- Department of Pathology, Seoul National University Boramae Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Song-Hee Han
- Department of Pathology, Dong-A University College of Medicine, Busan, Korea
| | - Yoonjin Kwak
- Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - An Na Seo
- Department of Pathology, School of Medicine, Kyungpook National University, Kyungpook National University Chilgok Hospital, Daegu, Korea
| | - Sung Hak Lee
- Department of Hospital Pathology, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Mee-Yon Cho
- Department of Pathology, Wonju Severance Christian Hospital, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - The Gastrointestinal Pathology Study Group of the Korean Society of Pathologists
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
- Center for Gastric Cancer, National Cancer Center, Goyang, Korea
- Department of Pathology, Korea University Guro Hospital, Seoul, Korea
- Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
- Department of Pathology, Chungnam National University Sejong Hospital, Chungnam National University School of Medicine, Sejong, Korea
- Department of Pathology, Yeungnam University College of Medicine, Daegu, Korea
- Department of Hospital Pathology, Uijeongbu St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Uijeongbu, Korea
- Department of Pathology, Hallym University Dongtan Sacred Heart Hospital, Hwaseong, Korea
- Department of Pathology, Dankook University College of Medicine, Cheonan, Korea
- Department of Pathology, Yonsei University College of Medicine, Seoul, Korea
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
- Department of Pathology, Chung-Ang University Hospital, Chung-Ang University College of Medicine, Seoul, Korea
- LabGenomics Clinical Laboratories, Seongnam, Korea
- St. Maria Pathology Laboratory, Busan, Korea
- Department of Pathology, Soonchunhyang University Seoul Hospital, Seoul, Korea
- Department of Pathology, Inha University School of Medicine, Incheon, Korea
- Department of Pathology, Yongin Severance Hospital, Yonsei University College of Medicine, Yongin, Korea
- Department of Pathology, Kosin University Gospel Hospital, Kosin University College of Medicine, Busan, Korea
- Department of Pathology, Seoul National University Boramae Hospital, Seoul National University College of Medicine, Seoul, Korea
- Department of Pathology, Dong-A University College of Medicine, Busan, Korea
- Department of Pathology, School of Medicine, Kyungpook National University, Kyungpook National University Chilgok Hospital, Daegu, Korea
- Department of Hospital Pathology, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
- Department of Pathology, Wonju Severance Christian Hospital, Yonsei University Wonju College of Medicine, Wonju, Korea
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9
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Coutzac C, Funk-Debleds P, Cattey-Javouhey A, Desseigne F, Guibert P, Marolleau P, Rochefort P, de la Fouchardière C. Targeting HER2 in metastatic gastroesophageal adenocarcinomas: What is new? Bull Cancer 2022; 110:552-559. [PMID: 36229267 DOI: 10.1016/j.bulcan.2022.08.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Revised: 08/19/2022] [Accepted: 08/27/2022] [Indexed: 11/07/2022]
Abstract
Gastric and esophageal adenocarcinomas represent a biologically heterogeneous disease. The identification, in early eighties, of human epidermal growth factor receptor 2 (HER2) overexpression, being present in 12 to 20% of the cases, marked a major milestone in the efforts of unraveling the molecular complexity of this disease. This led to the development of anti-HER2-therapies, trastuzumab being the first to demonstrate, in combination with cisplatin and 5FU/capecitabine chemotherapy, an improvement in response rate and survival in the first-line setting of patients with metastatic, HER2-positive gastroesophageal adenocarcinomas. Afterwards, during a decade, several studies have tried new strategies either to block HER2 pathway differently or to combine different anti-HER2, without efficacy. Everything changed with studies demonstrating additive effect between anti-HER2 and immune checkpoint inhibitors and leading to phase III clinical trials combining anti-HER2 and anti-PD-L1/PD1 therapies. Pembrolizumab, a PD-1 inhibitor, was recently granted by FDA an accelerated approval, in patients with HER2-positive gastro-oesophageal adenocarcinomas, in combination with trastuzumab and platinum-based chemotherapy following meaningful improvement in overall response rate over standard treatment. Progression-free and overall-survival results are still awaited to change our first-line standard treatment. Furthermore, new HER2 inhibitors have been developed, blocking HER2-mediated pathway signaling via different mechanisms from pan-HER inhibition to anti-HER2 antibody drug conjugates with promising results in pretreated patients. Trastuzumab-deruxtecan has in particular showed interesting results in pretreated patients. We present here a review of the recent data and perspectives in HER2-positive metastatic gastroesophageal adenocarcinomas.
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10
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Abstract
Gastric cancer (GC) is one of the most common lethal malignant neoplasms worldwide, with limited treatment options for both locally advanced and/or metastatic conditions, resulting in a dismal prognosis. Although the widely used morphological classifications may be helpful for endoscopic or surgical treatment choices, they are still insufficient to guide precise and/or personalized therapy for individual patients. Recent advances in genomic technology and high-throughput analysis may improve the understanding of molecular pathways associated with GC pathogenesis and aid in the classification of GC at the molecular level. Advances in next-generation sequencing have enabled the identification of several genetic alterations through single experiments. Thus, understanding the driver alterations involved in gastric carcinogenesis has become increasingly important because it can aid in the discovery of potential biomarkers and therapeutic targets. In this article, we review the molecular classifications of GC, focusing on The Cancer Genome Atlas (TCGA) classification. We further describe the currently available biomarker-targeted therapies and potential biomarker-guided therapies. This review will help clinicians by providing an inclusive understanding of the molecular pathology of GC and may assist in selecting the best treatment approaches for patients with GC.
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Affiliation(s)
- Moonsik Kim
- Department of Pathology, School of Medicine, Kyungpook National University, Kyungpook National University Chilgok Hospital, Daegu, Korea
| | - An Na Seo
- Department of Pathology, School of Medicine, Kyungpook National University, Kyungpook National University Chilgok Hospital, Daegu, Korea.
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11
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Stein SM, Snider J, Ali SM, Miksad RA, Alexander BM, Castellanos E, Schrock AB, Madison R, Swaminathan A, Venstrom JM, McCusker M. Real-world association of HER2/ ERBB2 concordance with trastuzumab clinical benefit in advanced esophagogastric cancer. Future Oncol 2021; 17:4101-4114. [PMID: 34463133 DOI: 10.2217/fon-2021-0203] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023] Open
Abstract
Aim: To assess concordance between HER2 status measured by traditional methods and ERBB2 amplification measured by next-generation sequencing and its association with first-line trastuzumab clinical benefit in patients with advanced esophagogastric cancer. Methods: Retrospective analysis of HER2/ERBB2 concordance using a deidentified USA-based clinicogenomic database. Clinical outcomes were assessed for patients with HER2+ advanced esophagogastric cancer who received first-line trastuzumab. Results: Overall HER2/ERBB2 concordance was 87.5%. Among patients who received first-line trastuzumab, concordant HER2/ERBB2 was associated with longer time to treatment discontinuation (adjusted hazard ratio [aHR]: 0.63; 95% CI: 0.43-0.90) and overall survival (aHR: 0.51; 95% CI: 0.33-0.79). ERBB2 copy number ≥25 (median) was associated with longer time to treatment discontinuation (aHR: 0.56; 95% CI: 0.35-0.88) and overall survival (aHR: 0.52; 95% CI: 0.30-0.91). Conclusion: HER2/ERBB2 concordance and higher ERBB2 copy number predicted clinical benefit from trastuzumab.
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Affiliation(s)
- Stacey M Stein
- Section of Medical Oncology, Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06510, USA
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12
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Pucher PH, Allum WH, Bateman AC, Green M, Maynard N, Novelli M, Petty R, Underwood TJ, Gossage J. Consensus recommendations for the standardized histopathological evaluation and reporting after radical oesophago-gastrectomy (HERO consensus). Dis Esophagus 2021; 34:doab033. [PMID: 33969411 DOI: 10.1093/dote/doab033] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 04/12/2021] [Accepted: 04/20/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND Variation in the approach, radicality, and quality of gastroesophageal surgery impacts patient outcomes. Pathological outcomes such as lymph node yield are routinely used as surrogate markers of surgical quality, but are subject to significant variations in histopathological evaluation and reporting. A multi-society consensus group was convened to develop evidence-based recommendations for the standardized assessment of gastroesophageal cancer specimens. METHODS A consensus group comprised of surgeons, pathologists, and oncologists was convened on behalf of the Association of Upper Gastrointestinal Surgery of Great Britain & Ireland. Literature was reviewed for 17 key questions. Draft recommendations were voted upon via an anonymous Delphi process. Consensus was considered achieved where >70% of participants were in agreement. RESULTS Consensus was achieved on 18 statements for all 17 questions. Twelve strong recommendations regarding preparation and assessment of lymph nodes, margins, and reporting methods were made. Importantly, there was 100% agreement that the all specimens should be reported using the Royal College of Pathologists Guidelines as the minimum acceptable dataset. In addition, two weak recommendations regarding method and duration of specimen fixation were made. Four topics lacked sufficient evidence and no recommendation was made. CONCLUSIONS These consensus recommendations provide explicit guidance for gastroesophageal cancer specimen preparation and assessment, to provide maximum benefit for patient care and standardize reporting to allow benchmarking and improvement of surgical quality.
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Affiliation(s)
- Philip H Pucher
- Department of General Surgery, Guys and St Thomas' Hospital NHS Foundation Trust, London, UK
- Department of General Surgery, Portsmouth University Hospital NHS Trust, Portsmouth, UK
| | - William H Allum
- Department of Academic Surgery, The Royal Marsden Hospital NHS Foundation Trust, London, UK
| | - Adrian C Bateman
- Department of Cellular Pathology, University Hospital Southampton NHS Foundation Trust, Southampton, UK
| | - Michael Green
- Department of General Surgery, Guys and St Thomas' Hospital NHS Foundation Trust, London, UK
| | - Nick Maynard
- Department of General Surgery, Oxford University Hospital NHS Foundation Trust, Oxford, UK
| | - Marco Novelli
- Department of Histopathology, University College London Hospitals NHS Foundation Trust, London, UK
| | - Russell Petty
- Department of Medical Oncology, Division of Molecular and Clinical Medicine, Ninewells Hospital and Medical School, Dundee, UK
| | - Timothy J Underwood
- Royal College of Surgeons of England and Association of Upper Gastrointestinal Surgery of GB&I (AUGIS) Surgical Specialty Lead for Oesophageal Cancer, UK
- School of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, UK
| | - James Gossage
- Department of General Surgery, Guys and St Thomas' Hospital NHS Foundation Trust, London, UK
- Oesophagogastric Cancer Lead, AUGIS, UK
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13
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Biomarker-targeted therapies for advanced-stage gastric and gastro-oesophageal junction cancers: an emerging paradigm. Nat Rev Clin Oncol 2021; 18:473-487. [PMID: 33790428 DOI: 10.1038/s41571-021-00492-2] [Citation(s) in RCA: 156] [Impact Index Per Article: 39.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/22/2021] [Indexed: 02/02/2023]
Abstract
Advances in cancer biology and sequencing technology have enabled the selection of targeted and more effective treatments for individual patients with various types of solid tumour. However, only three molecular biomarkers have thus far been demonstrated to predict a response to targeted therapies in patients with gastric and/or gastro-oesophageal junction (G/GEJ) cancers: HER2 positivity for trastuzumab and trastuzumab deruxtecan, and microsatellite instability (MSI) status and PD-L1 expression for pembrolizumab. Despite this lack of clinically relevant biomarkers, distinct molecular subtypes of G/GEJ cancers have been identified and have informed the development of novel agents, including receptor tyrosine kinase inhibitors and monoclonal antibodies, several of which are currently being tested in ongoing trials. Many of these trials include biomarker stratification, and some include analysis of circulating tumour DNA (ctDNA), which both enables the noninvasive assessment of biomarker expression and provides an indication of the contributions of intratumoural heterogeneity to response and resistance. The results of these studies might help to optimize the selection of patients to receive targeted therapies, thus facilitating precision medicine approaches for patients with G/GEJ cancers. In this Review, we describe the current evidence supporting the use of targeted therapies in patients with G/GEJ cancers and provide guidance on future research directions.
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Catanese S, Lordick F. Targeted and immunotherapy in the era of personalised gastric cancer treatment. Best Pract Res Clin Gastroenterol 2021; 50-51:101738. [PMID: 33975679 DOI: 10.1016/j.bpg.2021.101738] [Citation(s) in RCA: 16] [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: 11/27/2020] [Revised: 02/16/2021] [Accepted: 02/19/2021] [Indexed: 02/07/2023]
Abstract
Gastric cancer is a major cause of cancer-related morbidity and mortality worldwide. Advances in targeted medical treatment were scarce in the past and challenged by the marked spatial and temporal biological heterogeneity of gastric cancer. Recent molecular profiling studies have increased our understanding of genetic and epigenetic drivers, leading to better patient selection for drug development. Beyond that, immune-related biomarkers were identified, paving the way for future effective immunotherapy. We systematically reviewed articles from PubMed of the past 10 years, and abstracts from annual meetings of ESMO, ASCO and AACR to summarise the current knowledge about targeted and immunotherapy and outline pathways to future personalised therapy of gastric cancer.
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Affiliation(s)
- Silvia Catanese
- Unit of Medical Oncology, Department of Oncology, University of Pisa, Pisa, Italy
| | - Florian Lordick
- Department of Oncology, Gastroenterology, Hepatology, Pulmonology, and Infectious Diseases, University Cancer Centre Leipzig (UCCL), Leipzig University Medical Centre, Leipzig, Germany.
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Liu Z, Shi M, Li X, Song S, Liu N, Du H, Ye J, Li H, Zhang Z, Zhang L. HER2 copy number as predictor of disease-free survival in HER2-positive resectable gastric adenocarcinoma. J Cancer Res Clin Oncol 2021; 147:1315-1324. [PMID: 33543328 PMCID: PMC8021510 DOI: 10.1007/s00432-021-03522-9] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2020] [Accepted: 01/10/2021] [Indexed: 01/28/2023]
Abstract
Purpose The identification of HER2 overexpression in a subset of gastric adenocarcinoma (GA) patients represents a significant step forward in unveiling the molecular complexity of this disease. The predictive and prognostic value of HER2 amplification in advanced HER2 inhibitor-treated GA patients has been investigated. However, its predictive value in resectable patients remains elusive. Methods We enrolled 98 treatment-naïve resectable Chinese GA patients with HER2 overexpression assessed using IHC. Capture-based targeted sequencing using a panel consisting of 41 gastrointestinal cancer-related genes was performed on tumor tissues. Furthermore, we also investigated the correlation between HER2 copy number (CN) and survival outcomes. Results Of the 98 HER2-overexpressed patients, 90 had HER2 CN amplification assessed using next-generation sequencing, achieving 92% concordance. The most commonly seen concurrent mutations were occurring in TP53, EGFR and PIK3CA. We found HER2 CN as a continuous variable was an independent predictor associated with DFS (p = 0.029). Our study revealed HER2 CN-high patients showed a trend of intestinal-type GA predominant (p = 0.075) and older age (p = 0.07). The median HER2 CN was 15.34, which was used to divide the cohort into CN-high and CN-low groups. Patients with high HER2 CN had a significantly shorter DFS than patients with low HER2 CN (p = 0.002). Furthermore, HER2 CN as a categorical variable was also an independent predictor associated with DFS in patients. Conclusion We elucidated the mutation spectrum of HER2-positive resectable Chinese GA patients and the association between HER2 CN and DFS. Our work revealed HER2 CN as an independent risk factor predicted unfavorable prognosis in HER2-positive GA patients and allowed us to further stratify HER2-positive resectable GA patients for disease management.
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Affiliation(s)
- Zimin Liu
- Oncology Department, The Affiliated Hospital of Qingdao University, Qingdao, 266000, China.
| | - Mingpeng Shi
- Operating Room of Neurosurgery, The Affiliated Hospital of Qingdao University, Qingdao, 266000, China
| | - Xiaoxiao Li
- Oncology Department, The Affiliated Hospital of Qingdao University, Qingdao, 266000, China
| | - Shanai Song
- Oncology Department, The Affiliated Hospital of Qingdao University, Qingdao, 266000, China
| | - Ning Liu
- Oncology Department, The Affiliated Hospital of Qingdao University, Qingdao, 266000, China
| | - Haiwei Du
- Burning Rock Biotech, Guangzhou, China
| | - Junyi Ye
- Burning Rock Biotech, Guangzhou, China
| | - Haiyan Li
- Burning Rock Biotech, Guangzhou, China
| | | | - Lu Zhang
- Burning Rock Biotech, Guangzhou, China
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16
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Lengyel CG, Habeeb B, Khan SZ, El Bairi K, Altuna SC, Hussain S, Mazher SA, Trapani D, Petrillo A. Role of Her-2 in Gastrointestinal Tumours beyond Gastric Cancer: A Tool for Precision Medicine. GASTROINTESTINAL DISORDERS 2020; 3:1-22. [DOI: 10.3390/gidisord3010001] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Gastrointestinal (GI) tumors account for a quarter of all the cancer burden and a third of the global cancer-related mortality. Among them, some cancers retain a dismal prognosis; therefore, newer and innovative therapies are urgently needed in priority disease areas of high-unmet medical need. In this context, HER2 could be a relevant prognostic and predictive biomarker acting as a target for specific drugs. However, if the role of HER2 has been object of investigation for several years in gastric cancer, it is not well established in other GI malignancies. The aim of this narrative review was to portray the current landscape of the potential role of HER2 as a predictive biomarker for GI tumors beyond gastric cancer. In colon cancer, the benefit from anti-HER2 therapies is less clear than in gastric neoplasms for the lack of controlled studies. Pancreatic, biliary tract adenocarcinomas and hepatocarcinoma may derive a less clear clinical benefit by using anti-HER2 agents in HER2 positive tumors. Overall, the results are promising and seem to suggest that the integration of multiple modalities of therapies can optimize the cancer care. However, further prospective trials are needed to validate the use of personalized targeted therapies in this field.
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Affiliation(s)
- Csongor G. Lengyel
- Head and Neck Surgery, National Institute of Oncology, 1122 Budapest, Hungary
| | - Baker Habeeb
- Medical Oncology Department, Shaqlawa Teaching Hospital, Erbil 44001, Iraq
| | - Shah Z. Khan
- Department of Clinical Oncology, BINOR Cancer Hospital, Bannu 28100, Pakistan
| | | | | | - Sadaqat Hussain
- Northwest Cancer Center, Western Health and Social Care Trust, Altnagelvin Hospital, Londonderry BT47 6SB, UK
| | - Syed Ayub Mazher
- UT Southwestern Clements University Hospital, Dallas, TX 75390, USA
| | - Dario Trapani
- European Institute of Oncology, IRCCS, 20141 Milan, Italy
| | - Angelica Petrillo
- Medical Oncology Unit, Ospedale del Mare, 80147 Naples, Italy
- Division of Medical Oncology, Department of Precision Medicine, School of Medicine, University of Study of Campania “L.Vanvitelli”, 81100 Caserta, Italy
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Gülten G, Yilmaz B, Demirkan NÇ. Comparing human epidermal growth factor receptor 2 amplification and expression using immunohistochemistry and silver in situ hybridisation in gastric carcinoma and lymph node metastasis. Oncol Lett 2020; 20:1897-1905. [PMID: 32724433 PMCID: PMC7377164 DOI: 10.3892/ol.2020.11731] [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: 10/31/2019] [Accepted: 05/13/2020] [Indexed: 12/24/2022] Open
Abstract
Detecting the amplification and expression of human epidermal growth factor receptor (HER2) is important for planning trastuzumab treatment for patients with gastric carcinoma. The present study aimed to analyse HER2 amplification and expression in primary gastric adenocarcinoma tumours and metastatic lymph nodes using microarray methods, and to assess the potential contribution of these methods to treatment planning. In total, 60 patients with lymph node metastasis were included in the present study. Microarray blocks were obtained from the tissue blocks of primary tumours and metastatic lymph nodes. HER2 expression and amplification were investigated using immunohistochemical and silver in situ hybridisation (SISH) methods, respectively. Following immunohistochemical evaluation of HER2 in primary tumours, the sensitivity and specificity of the microarray method relative to the single block method were 69 and 100%, respectively. For HER2 detection in microarray block sections from primary tumours, the sensitivity and specificity of the SISH method relative to immunohistochemistry were 56 and 100%, respectively. When using SISH in microarray blocked sections, there was a high degree of concordance (98% concordance rate) between HER2 amplification in the primary tumour and the metastatic lymph node. Furthermore, the sensitivity and specificity of metastatic lymph node results relative to those of the primary tumour were 100 and 98%, respectively. Overall, the single block method was more reliable compared with the microarray method for planning treatment. When microarray blocking was used, a large number of samples must be tested to ensure reliable results. The immunohistochemical method is recommended as the first step as SISH alone increases the risk of false-negative results. Assessing HER2 amplification for treatment planning would be beneficial for primary tumours, as well as metastatic lymph nodes.
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Affiliation(s)
- Gülsün Gülten
- Department of Pathology, Şanlıurfa Training and Research Hospital, 63250 Şanlıurfa, Turkey
| | - Bayram Yilmaz
- Department of Pathology, Hitit University Erol Olçok Training and Research Hospital, 19040 Çorum, Turkey
| | - Neşe Çalli Demirkan
- Department of Pathology, Faculty of Medicine, Pamukkale University, 20160 Denizli, Turkey
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Hirose S, Moriwaki T, Yamaura M, Suganuma D, Tajima H, Sato M, Enami C, Yamada T, Yamamoto Y, Sakamoto N, Hyodo I. A case of advanced gastric cancer showing HER2 positivity after chemotherapy. Int Cancer Conf J 2020; 9:112-115. [PMID: 32582513 PMCID: PMC7297895 DOI: 10.1007/s13691-020-00412-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2019] [Accepted: 03/19/2020] [Indexed: 01/14/2023] Open
Abstract
A 63-year-old man had advanced poorly differentiated gastric adenocarcinoma with para-aortic lymph node metastases. No HER2 expression was observed in four endoscopic biopsies from the primary tumor. Tumors shrunk after S-1 with cisplatin treatment, and he underwent simple gastrectomy due to stenosis. Interestingly, HER2 diffusely overexpressed in the resected surgical specimen. His disease was stable with trastuzumab-containing therapy for 6.4 months. This case may suggest a selection of HER2-positive cells that were insensitive to the chemotherapy, and further study is needed for the change of intratumoral HER2 heterogeneity after chemotherapy.
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Affiliation(s)
- Suguru Hirose
- Division of Gastroenterology, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575 Japan
| | - Toshikazu Moriwaki
- Division of Gastroenterology, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575 Japan
| | - Masamichi Yamaura
- Division of Gastroenterology, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575 Japan
| | - Daisuke Suganuma
- Division of Gastroenterology, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575 Japan
| | - Hiroki Tajima
- Division of Gastroenterology, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575 Japan
| | - Masashi Sato
- Division of Gastroenterology, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575 Japan
| | - Chiaki Enami
- Division of Gastroenterology, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575 Japan
| | - Takeshi Yamada
- Division of Gastroenterology, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575 Japan
| | - Yoshiyuki Yamamoto
- Division of Gastroenterology, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575 Japan
| | - Noriaki Sakamoto
- Department of Pathology, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki Japan
| | - Ichinosuke Hyodo
- Division of Gastroenterology, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575 Japan
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García P, Bizama C, Rosa L, Espinoza JA, Weber H, Cerda-Infante J, Sánchez M, Montecinos VP, Lorenzo-Bermejo J, Boekstegers F, Dávila-López M, Alfaro F, Leiva-Acevedo C, Parra Z, Romero D, Kato S, Leal P, Lagos M, Roa JC. Functional and genomic characterization of three novel cell lines derived from a metastatic gallbladder cancer tumor. Biol Res 2020; 53:13. [PMID: 32293552 PMCID: PMC7158131 DOI: 10.1186/s40659-020-00282-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Accepted: 04/06/2020] [Indexed: 12/19/2022] Open
Abstract
Background Gallbladder cancer (GBC) is the most common tumor of the biliary tract. The incidence of GBC shows a large geographic variability, being particularly frequent in Native American populations. In Chile, GBC represents the second cause of cancer-related death among women. We describe here the establishment of three novel cell lines derived from the ascitic fluid of a Chilean GBC patient, who presented 46% European, 36% Mapuche, 12% Aymara and 6% African ancestry. Results After immunocytochemical staining of the primary cell culture, we isolated and comprehensively characterized three independent clones (PUC-GBC1, PUC-GBC2 and PUC-GBC3) by short tandem repeat DNA profiling and RNA sequencing as well as karyotype, doubling time, chemosensitivity, in vitro migration capability and in vivo tumorigenicity assay. Primary culture cells showed high expression of CK7, CK19, CA 19-9, MUC1 and MUC16, and negative expression of mesothelial markers. The three isolated clones displayed an epithelial phenotype and an abnormal structure and number of chromosomes. RNA sequencing confirmed the increased expression of cytokeratin and mucin genes, and also of TP53 and ERBB2 with some differences among the three cells lines, and revealed a novel exonic mutation in NF1. The PUC-GBC3 clone was the most aggressive according to histopathological features and the tumorigenic capacity in NSG mice. Conclusions The first cell lines established from a Chilean GBC patient represent a new model for studying GBC in patients of Native American descent.
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Affiliation(s)
- Patricia García
- Department of Pathology, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Carolina Bizama
- Department of Pathology, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Lorena Rosa
- Department of Pathology, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.,Applied Molecular and Cellular Biology PhD Program, Universidad de La Frontera, Temuco, Chile
| | - Jaime A Espinoza
- Science for Life Laboratory, Division of Genome Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
| | - Helga Weber
- Center of Excellence in Translational Medicine (CEMT) and Scientific and Technological Bioresource Nucleus (BIOREN), Universidad de La Frontera, Temuco, Chile
| | - Javier Cerda-Infante
- Department of Hematology Oncology; Cellular and Molecular Biology, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Marianela Sánchez
- Department of Hematology Oncology, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Viviana P Montecinos
- Department of Hematology Oncology, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Justo Lorenzo-Bermejo
- Statistical Genetics Research Group, Institute of Medical Biometry and Informatics, University of Heidelberg, Heidelberg, Germany
| | - Felix Boekstegers
- Statistical Genetics Research Group, Institute of Medical Biometry and Informatics, University of Heidelberg, Heidelberg, Germany
| | - Marcela Dávila-López
- Bioinformatics Core Facility, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Francisca Alfaro
- Department of Pathology, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Claudia Leiva-Acevedo
- Department of Pathology, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Zasha Parra
- Cytogenetics Laboratory, Complejo Asistencial Dr. Sótero del Río, Santiago, Chile
| | - Diego Romero
- Department of Pathology, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Sumie Kato
- Division of Obstetrics and Gynecology, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Pamela Leal
- Center of Excellence in Translational Medicine (CEMT) and Scientific and Technological Bioresource Nucleus (BIOREN), Universidad de La Frontera, Temuco, Chile
| | - Marcela Lagos
- Department of Clinical Laboratory, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Juan Carlos Roa
- Department of Pathology, Faculty of Medicine, Millennium Institute of Immunology and Immunotherapy, Pontificia Universidad Católica de Chile, Santiago, Chile.
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Ieni A, Cardia R, Pizzimenti C, Zeppa P, Tuccari G. HER2 Heterogeneity in Personalized Therapy of Gastro-Oesophageal Malignancies: An Overview by Different Methodologies. J Pers Med 2020; 10:jpm10010010. [PMID: 32098203 PMCID: PMC7151629 DOI: 10.3390/jpm10010010] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2019] [Revised: 02/06/2020] [Accepted: 02/12/2020] [Indexed: 12/15/2022] Open
Abstract
Human epidermal growth factor receptor-2 (HER2)-expression gastro-oesophageal adenocarcinomas (GEA) gained interest as an important target for therapy with trastuzumab. In the current review, we focused the current knowledge on HER2 status in dysplastic and neoplastic gastric conditions, analyzing the methodological procedures to identify HER2 expression/amplification, as well as the proposed scoring recommendations. One of the most relevant questions to evaluate the useful impact of HER2 status on therapeutic choice in GEAs is represented by the significant heterogeneity of HER2 protein and gene expression that may affect the targeted treatment selection. Future development of biotechnology will continue to evolve in order to offer more powerful detection systems for the assessment of HER2 status. Finally, liquid biopsy as well as mutation/amplification of several additional genes may furnish an early detection of secondary HER2 resistance mechanisms in GEAs with a better monitoring of the treatment response.
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Affiliation(s)
- Antonio Ieni
- Department of Human Pathology in Adult and Developmental Age “Gaetano Barresi”, Section of Pathology, University of Messina, 98125 Messina, Italy; (R.C.); (C.P.); (G.T.)
- Correspondence: ; Tel.: +39-90-221-2536; Fax: +39-90-292-8150
| | - Roberta Cardia
- Department of Human Pathology in Adult and Developmental Age “Gaetano Barresi”, Section of Pathology, University of Messina, 98125 Messina, Italy; (R.C.); (C.P.); (G.T.)
| | - Cristina Pizzimenti
- Department of Human Pathology in Adult and Developmental Age “Gaetano Barresi”, Section of Pathology, University of Messina, 98125 Messina, Italy; (R.C.); (C.P.); (G.T.)
| | - Pio Zeppa
- Department of Medicine and Surgery, University of Salerno, 84131 Salerno, Italy;
| | - Giovanni Tuccari
- Department of Human Pathology in Adult and Developmental Age “Gaetano Barresi”, Section of Pathology, University of Messina, 98125 Messina, Italy; (R.C.); (C.P.); (G.T.)
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21
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Hotta K, Yanai H, Ohashi K, Ninomiya K, Nakashima H, Kayatani H, Takata M, Kiura K. Pilot evaluation of a HER2 testing in non-small-cell lung cancer. J Clin Pathol 2019; 73:353-357. [PMID: 31796633 DOI: 10.1136/jclinpath-2019-206204] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2019] [Revised: 11/06/2019] [Accepted: 11/08/2019] [Indexed: 11/03/2022]
Abstract
AIMS HER2-positivity pattern in the specimens of immunohistochemistry (IHC) and fluorescence in situ hybridisation (FISH) has been hardly reported in non-small-cell lung cancer (NSCLC). METHODS We evaluated the characteristics of HER2-positivity pattern in formalin-fixed paraffin-embedded samples using IHC and FISH in 15 patients enrolled in a larger prospective cohort study to survey a HER2-positive NSCLC. RESULTS As for the immunostaining pattern, most specimens (79%) demonstrated incomplete or mixed-typed membranous immunoreactivity with heterogeneity, resembling that observed in gastric cancer rather than breast cancer. Concordance between IHC-positivity and FISH-positivity was 87.5% according to the criteria for breast cancer scoring system. On application of the gastric cancer scoring system to the examined tumours, the IHC score increased in the seven (43.8%) specimens, and the concordance between IHC positivity and FISH positivity rose to 93.8%. CONCLUSIONS In our pilot series, the pattern of IHC reactivity closely resembled that observed in gastric cancer rather than breast cancer. TRIAL REGISTRATION NUMBER 000017003.
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Affiliation(s)
- Katsuyuki Hotta
- Department of Respiratory Medicine, Okayama University Hospital, Okayama, Japan .,Center of Innovative Clinical Medicine, Okayama University Hospital, Okayama, Japan
| | - Hiroyuki Yanai
- Department of Pathology, Okayama University Hospital, Okayama, Japan
| | - Kadoaki Ohashi
- Department of Respiratory Medicine, Okayama University Hospital, Okayama, Japan
| | - Kiichiro Ninomiya
- Department of Respiratory Medicine, Okayama University Hospital, Okayama, Japan
| | - Hiromi Nakashima
- Department of Respiratory Medicine, Okayama University Hospital, Okayama, Japan
| | - Hiroe Kayatani
- Department of Respiratory Medicine, Okayama University Hospital, Okayama, Japan
| | - Minoru Takata
- Laboratory of DNA Damage Signaling, Department of Late Effects Studies, Radiation Biology Center, Graduate School Biostudies, Kyoto University, Kyoto, Japan
| | - Katsuyuki Kiura
- Department of Respiratory Medicine, Okayama University Hospital, Okayama, Japan
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22
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Jung DH, Bae YJ, Kim JH, Shin YK, Jeung HC. HER2 Regulates Cancer Stem Cell Activities via the Wnt Signaling Pathway in Gastric Cancer Cells. Oncology 2019; 97:311-318. [PMID: 31550723 DOI: 10.1159/000502845] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2019] [Accepted: 08/19/2019] [Indexed: 12/24/2022]
Abstract
INTRODUCTION Human epidermal growth factor 2 (HER2) gene overexpression in breast carcinoma cell lines has been shown to drive mammary carcinogenesis and tumor growth and invasion through its effects on mammary stem cells. OBJECTIVE Therefore, we investigated the mechanism by which HER2 regulates cancer stem cell (CSC) activity in gastric cancer cells. METHODS HER2 was transfected into MKN28 gastric cancer cells, and its role in regulating CSC activity was determined by characterizing the HER2-overexpressing cells. RESULTS The sphere formation assay revealed that the sphere sizes and frequency of sphere formation were significantly greater for the HER2-overexpressing cells than for the MKN28 control cells. The CSC markers Oct-4 and BMI1 were more highly expressed in the HER2-overexpressing cells, as were the EMT markers. This was accompanied by a significant enhancement in cellular invasion of the Matrigel and migration. The E-cadherin level was significantly downregulated, and the mesenchymal marker Snail upregulated, in the HER2-transfected cells. HER2 overexpression activated the well-characterized CSC-associated Wnt/β-catenin signaling pathway, as shown by the luciferase assay. After treatment of these cells with the Wnt signal inhibitor PRI-724, the BMI1 and Oct-4 levels were decreased for 24 h and Snail was also downregulated. Immunofluorescence staining revealed the significant restoration of E-cadherin levels in the HER2-transfected cells after PRI-724 treatment. CONCLUSIONS These results established a role for HER2 in regulating gastric CSC activity, with Wnt/β-catenin signaling being mediated via a HER2-dependent pathway. In summary, HER2-overexpressing gastric cancer cells exhibited increased stemness and invasiveness and were regulated by Wnt/β-catenin signaling.
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Affiliation(s)
- Da Hyun Jung
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Yoo Jin Bae
- Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Jie-Hyun Kim
- Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea,
| | - You Keun Shin
- Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Hei-Cheul Jeung
- Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
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23
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Evaluation of Intratumoral and Intertumoral Heterogeneity of MET Protein Expression in Gastric Cancer. Appl Immunohistochem Mol Morphol 2019; 26:445-453. [PMID: 28968267 DOI: 10.1097/pai.0000000000000448] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Tumor heterogeneity of a target molecule could contribute to failure of the targeted therapy. We investigated the heterogeneity of MET expression within same primary gastric cancer (GC) and between primary and corresponding secondary GC lesions using immunohistochemistry (IHC). Intratumoral heterogeneity was defined as discordant MET status among 3 tissue microarray cores (3 different areas of same tumor). IHC 3+ was considered positive for MET overexpression. MET overexpression was observed in 2.7% (50/1869) of all examined cores and 5.3% (33/623) of primary GCs. When we compared MET IHC results between 3 cores from each tumor, intratumoral heterogeneity was identified (65.0% in total 623 cases; 84.4% in 480 cases with any staining intensity; 84.9% in 251 cases with moderate to strong intensity; 90.9% in 33 cases with strong intensity). Of 33 MET-overexpressed GCs, the average proportion of strongly stained area was 19.6% in the whole sections. Of 269 cases with primary GC and regional lymph node metastasis, 17 (6.3%) showed MET positivity in which 9 (52.9%) were discordant (negative conversion). In 123 cases with primary and corresponding local recurrent/distant metastatic GC, 3 (2.4%) showed MET positivity in which 2 (66.7%) were discordant (positive conversion). In the survival analysis, MET IHC 3+ in lymph node metastases was an independent negative prognostic factor for overall survival. We found that MET overexpression is uncommon and highly heterogeneous in GC. This severe heterogeneity of MET status should be considered in tissue sampling and development of biomarkers for anti-MET therapy.
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24
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Serra O, Galán M, Ginesta MM, Calvo M, Sala N, Salazar R. Comparison and applicability of molecular classifications for gastric cancer. Cancer Treat Rev 2019; 77:29-34. [PMID: 31195213 DOI: 10.1016/j.ctrv.2019.05.005] [Citation(s) in RCA: 54] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2019] [Revised: 05/20/2019] [Accepted: 05/21/2019] [Indexed: 02/06/2023]
Abstract
Gastric Cancer (GC) is a complex and heterogeneous disease, which represents a global health concern. Despite advances in prevention, diagnosis, and therapy, GC is still a leading cause of cancer-related death. Over the last decade, several clinical trials have tested novel agents for advanced GC with mostly disappointing results. Heterogeneity, the absence of molecular selection in clinical trials and powerless predictive biomarkers may be potential explanations. Different molecular classification proposals for GC based on the genetic, epigenetic, and molecular signatures have been published. Molecular characterization of GC may offer new tools for more effective therapeutic strategies, such as the development of therapies for specifically well-defined sets of patients as well as the use of new clinical trial designs, which will ultimately lead to an improvement of medical management of this disease. However, the possibilities of implementation of GC molecular classifications on daily practice and their therapeutic implications remain challenging to date. In this review, we will describe and compare these GC molecular classifications, focusing on their main characteristics as the basis for their potential therapeutic implications and strategies for their clinical application. Key Message: A better understanding of gastric cancer molecular characteristics may lead to further improvements in treatment and outcomes for patients with the disease.
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Affiliation(s)
- O Serra
- Department of Medical Oncology, Catalan Institute of Oncology (ICO), Hospital Duran y Reynals, Hospitalet de Llobregat, Barcelona, Spain; Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL) - University of Barcelona, Hospital Duran y Reynals, Hospitalet de Llobregat, Barcelona, Spain; Gastroesophageal Tumors Functional Unit (UTEG), Catalan Institute of Oncology (ICO) - Hospital Universitari de Bellvitge (HUB), Hospitalet de Llobregat, Barcelona, Spain.
| | - M Galán
- Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL) - University of Barcelona, Hospital Duran y Reynals, Hospitalet de Llobregat, Barcelona, Spain; Gastroesophageal Tumors Functional Unit (UTEG), Catalan Institute of Oncology (ICO) - Hospital Universitari de Bellvitge (HUB), Hospitalet de Llobregat, Barcelona, Spain
| | - M M Ginesta
- Translational Research Laboratory, Catalan Insitute of Oncology (ICO), Hospital Duran y Reynals, Hospitalet de Llobregat, Barcelona, Spain; Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL) - University of Barcelona, Hospital Duran y Reynals, Hospitalet de Llobregat, Barcelona, Spain; CIBERONC Centro de Investigación Biomédica en Red Cáncer, Spain
| | - M Calvo
- Department of Medical Oncology, Catalan Institute of Oncology (ICO), Hospital Duran y Reynals, Hospitalet de Llobregat, Barcelona, Spain; Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL) - University of Barcelona, Hospital Duran y Reynals, Hospitalet de Llobregat, Barcelona, Spain; Gastroesophageal Tumors Functional Unit (UTEG), Catalan Institute of Oncology (ICO) - Hospital Universitari de Bellvitge (HUB), Hospitalet de Llobregat, Barcelona, Spain
| | - N Sala
- Unit of Nutrition and Cancer, Cancer Epidemiology Research Program and Translational Research Laboratory, Catalan Institute of Oncology (ICO) - Bellvitge Biomedical Research Institute (IDIBELL), Hospitalet de Llobregat, Barcelona, Spain
| | - R Salazar
- Department of Medical Oncology, Catalan Institute of Oncology (ICO), Hospital Duran y Reynals, Hospitalet de Llobregat, Barcelona, Spain; Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL) - University of Barcelona, Hospital Duran y Reynals, Hospitalet de Llobregat, Barcelona, Spain; CIBERONC Centro de Investigación Biomédica en Red Cáncer, Spain
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25
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Huber AR, Buscaglia B, Koltz BR, Henry J, McMahon L, Guo J, Hicks DG, Whitney-Miller CL. Impact of Specimen Type and Specimen Number on HER2 Status in Gastroesophageal Junction and Gastric Adenocarcinoma. Am J Clin Pathol 2019; 151:461-468. [PMID: 30624589 DOI: 10.1093/ajcp/aqy166] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
OBJECTIVES Human epidermal growth factor receptor 2 (HER2) is expressed in some gastric and gastroesophageal junction adenocarcinomas. There were two goals: assess the impact of specimen type on HER2 status and evaluate HER2 concordance with multiple specimens. METHODS All cases were evaluated by immunohistochemistry (IHC) for HER2 and interpreted using established criteria. Fluorescence in situ hybridization (FISH) was performed on a subset. RESULTS Of 460 specimens, 83.9% were IHC negative, 5.4% were equivocal, and 10.7% were IHC positive. Of those with FISH testing, 78.5% were FISH negative, and 21.5% were FISH positive. IHC-FISH concordance for biopsy specimens, resections, and metastases was 82%, 84%, and 86%, respectively. With one vs two vs three or more specimens, the HER2-positive rate increased from 10.5% to 18.1% to 24.1%, respectively. CONCLUSIONS HER2 testing may be performed on biopsy specimens with a relatively high concordance rate with resection specimens, and if multiple samples are analyzed from a single patient, the HER2-positive rate increases over twofold.
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Affiliation(s)
- Aaron R Huber
- Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY
| | - Brandon Buscaglia
- Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY
| | - Brooke R Koltz
- Department of Pathology, University of Toledo, Toledo, OH
| | - Jill Henry
- Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY
| | - Loralee McMahon
- Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY
| | - James Guo
- Northwestern University, Feinberg School of Medicine, Chicago, IL
| | - David G Hicks
- Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY
| | - Christa L Whitney-Miller
- Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY
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26
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Oono Y, Kuwata T, Takashima K, Shinmura K, Hori K, Yoda Y, Ikematsu H, Shitara K, Kinoshita T, Yano T. Human epidermal growth factor receptor 2-, epidermal growth factor receptor-, and mesenchymal epithelial transition factor-positive sites of gastric cancer using surgical samples. Gastric Cancer 2019; 22:335-343. [PMID: 29951752 DOI: 10.1007/s10120-018-0853-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2018] [Accepted: 06/24/2018] [Indexed: 01/04/2023]
Abstract
BACKGROUND Receptor tyrosine kinases (RTKs) play critical roles in gastric cancer (GC) progression and are potential targets for novel molecular-targeted agents or photo-immunotherapies. During patient selection, targeted biopsy is the first step. However, heterogeneous expression of RTKs based on the macroscopic appearance in GC has not been extensively addressed. Accordingly, in this study, we evaluated differences in RTK expression associated with macroscopic appearance in GC. METHODS In total, 375 consecutive patients who had undergone gastrectomy at the National Cancer Center Hospital East and who had histologically proven adenocarcinoma, available archived tumor sample, and no history of chemotherapy were enrolled in this study. For these cases, tissue microarray (TMA) samples were examined using immunohistochemistry (IHC). Based on the results of IHC, cases were selected for detailed examination. We re-evaluated IHC scores in more than three tumor blocks per case and comparatively evaluated differences in IHC expression in RTKs between the mucosal portion (MuP) and invasive portion (InP). RESULTS Human epidermal growth factor receptor 2 (HER2)-, epidermal growth factor receptor (EGFR)-, and mesenchymal epithelial transition factor (c-MET)-positive rates were 6, 9, and 20%, respectively. Twenty-two cases were then analyzed to assess differences in IHC expression levels in the same lesion. Concordance rates of positive staining of HER2, EGFR, and MET between MuP and whole tumor were 100, 40, and 56% and those with InP were 46, 100, and 56%. CONCLUSIONS To avoid underestimating expression status, biopsies must be taken from MuP for HER2, InP for EGFR, and both proportions for c-MET.
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Affiliation(s)
- Yasuhiro Oono
- Department of Gastroenterology and Endoscopy, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.
| | - Takeshi Kuwata
- Department of Pathology and Clinical Laboratories, National Cancer Center Hospital East, Kashiwa, Japan
| | - Kenji Takashima
- Department of Gastroenterology and Endoscopy, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
| | - Kensuke Shinmura
- Department of Gastroenterology and Endoscopy, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
| | - Keisuke Hori
- Department of Gastroenterology and Endoscopy, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
| | - Yusuke Yoda
- Department of Gastroenterology and Endoscopy, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
| | - Hiroaki Ikematsu
- Department of Gastroenterology and Endoscopy, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
| | - Kohei Shitara
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Takahiro Kinoshita
- Gastric Surgery Division, National Cancer Center Hospital East, Kashiwa, Japan
| | - Tomonori Yano
- Department of Gastroenterology and Endoscopy, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
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27
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Luan L, Ge X, Xu C, Liu Y, Ji Y, Hou Y. Immunostaining by dual tumor tissue paraffin blocks increases the sensitivity of c-Met detection in gastric cancer. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2018; 11:5063-5071. [PMID: 31949583 PMCID: PMC6962921] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 07/24/2018] [Accepted: 08/25/2018] [Indexed: 06/10/2023]
Abstract
BACKGROUND Gastric cancer (GC) is the second most frequent cause of cancer deaths worldwide. c-Met, a receptor tyrosine kinase, transduces signals from extracellular growth factors. c-Met-targeted therapeutics hold a great potential in treating gastric and related cancers, and a precise evaluation of c-Met expression is a prerequisite for subsequent treatment. METHODS We compared the sensitivity between one and two paraffin blocks in evaluating c-Met expression in GC subjects by immunohistochemistry (IHC). A total of 365 GC patients were divided into cohort 1 (n = 206) for the one tumor tissue paraffin block test and cohort 2 (n = 159) for the dual tumor tissue paraffin block test. In the dual blocks group, we investigated the results from two different paraffin blocks, then we used the higher one as the final score. RESULTS Inconsistent c-Met expression in the dual paraffin blocks group occurred in 29 (18.2%) cases. The pooled data in cohort 1 and cohort 2 indicate that when using results from dual paraffin blocks, the c-Met positive (3+) rate of GC testing could be promoted. CONCLUSION In GC, using dual tumor tissue paraffin blocks instead of one tumor tissue paraffin block is an efficient, economical and practical method of minimizing the false-negative rate of c-Met status assessment by IHC.
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Affiliation(s)
- Lijuan Luan
- Department of Pathology, Zhongshan Hospital, Fudan University Shanghai, China
| | - Xiaowen Ge
- Department of Pathology, Zhongshan Hospital, Fudan University Shanghai, China
| | - Chen Xu
- Department of Pathology, Zhongshan Hospital, Fudan University Shanghai, China
| | - Yalan Liu
- Department of Pathology, Zhongshan Hospital, Fudan University Shanghai, China
| | - Yuan Ji
- Department of Pathology, Zhongshan Hospital, Fudan University Shanghai, China
| | - Yingyong Hou
- Department of Pathology, Zhongshan Hospital, Fudan University Shanghai, China
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28
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Zhou R, Yuan P, Zhang L, Shen S, Li Z, Wang Y. Using digital PCR to detect HER2 amplification in breast and gastric cancer patients. ACTA ACUST UNITED AC 2018. [DOI: 10.1016/j.flm.2018.11.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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Flynn M, Young K, Cunningham D, Starling N. The evolving immunotherapeutic landscape in advanced oesophagogastric cancer. Ther Adv Med Oncol 2018; 10:1758835918786228. [PMID: 30034550 PMCID: PMC6048671 DOI: 10.1177/1758835918786228] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2018] [Accepted: 05/25/2018] [Indexed: 12/13/2022] Open
Abstract
Improvements in median overall survival in the advanced oesophagogastric (OG) setting have plateaued, underlining the need for improved therapeutic approaches in this patient population. Immunotherapeutics are inducing unexpected durable responses in an expanding list of advanced disease indications. Although OG cancers have traditionally been considered to be more challenging to treat with immunotherapy than some other malignancies because of their variable tumour mutational burden and relative scarcity of infiltrating T cells, immune checkpoint inhibitor (ICPI) trials conducted over the last few years suggest there is an important role for these treatments. ICPI efficacy may be demonstrated in specific molecular subtypes of OG cancer. This review outlines the improvements in defining predictive biomarkers of responsiveness to ICPIs. Increasingly, identification of an expanding list of ICPI resistance mechanisms will drive biomarker-directed research. In addition, the specific rationale to combine ICPIs with chemotherapies, radiotherapies, targeted therapies and other novel immunotherapeutic drugs will be discussed.
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Affiliation(s)
- Michael Flynn
- Department of Medicine, Royal Marsden Hospital,
London, UK
| | - Kate Young
- Department of Medicine, Royal Marsden Hospital,
London, UK
| | | | - Naureen Starling
- Department of Medicine, Royal Marsden Hospital,
203 Fulham Road, Chelsea, London SW3 6JJ, UK
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30
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Xu S, Yu Y, Rong J, Hu D, Zhang L, Fu S, Yang H, Fan J, Yang L, Wu J. Expression of BRCA1 and ERCC1 as predictive clinical outcome after radiochemotherapy in patients with locoregionally moderate-advanced nasopharyngeal carcinoma. Oncotarget 2018; 8:31355-31367. [PMID: 28404895 PMCID: PMC5458213 DOI: 10.18632/oncotarget.15565] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2016] [Accepted: 01/26/2017] [Indexed: 01/18/2023] Open
Abstract
In this study, we examined ERCC1 and BRCA1 expression and clinical outcome of 201 phase-III-IV nasopharyngeal carcinoma patients who were treated with cisplatin-based induced chemotherapy and concurrent radiochemotherapy. The chemotherapy response rate of BRCA1– and BRCA1+ patients was 73.6% and 55.8%, respectively. In addition, the chemotherapy response rate of ERCC1– and ERCC1+ patients was 76.9% and 56.6%, respectively. In patients’ tissues, ERCC1 expression associated with BRCA1 expression. The chemotherapy response rate of BRCA1– and ERCC1– patients was (82.1%) and higher than that of other groups (range 52.4-73.1%). The radiochemotherapy response rate of BRCA1– and ERCC1– patients was higher than that BRCA1+ and ERCC1+ patients. BRCA1– and ERCC1– patients showed higher 3-year overall survival, failure-free survival, locoregional failure-free survival and distant failure-free survival compared to BRCA1+ or ERCC1+ patients. Moreover, the 3-year overall survival, failure-free survival and distant failure-free survival of the BRCA1– and ERCC1– group were higher than that of other groups. TNM stage, ERCC1 expression and the correlation between BRCA1 and ERCC1 expression seemed significant overall survival factors. In conclusion, in nasopharyngeal carcinoma patients, ERCC1 and BRCA1 may be a predictor of response to platinum-based chemotherapy and concurrent radiochemotherapy.
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Affiliation(s)
- Shan Xu
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, P. R. China
| | - Yanxin Yu
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, P. R. China
| | - Jinfeng Rong
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, P. R. China
| | - Defeng Hu
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, P. R. China
| | - LiJun Zhang
- Department of Otolaryngology Head and Neck Surgery, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, P. R. China
| | - Shaozhi Fu
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, P. R. China
| | - Hongru Yang
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, P. R. China
| | - Juan Fan
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, P. R. China
| | - Linglin Yang
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, P. R. China
| | - Jingbo Wu
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, P. R. China
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Detection of HER2 Amplification in Circulating Tumor Cells of HER2-Negative Gastric Cancer Patients. Target Oncol 2018; 12:341-351. [PMID: 28508152 DOI: 10.1007/s11523-017-0493-6] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
A key to the successful use of targeted cancer therapy is the ability to preselect patients who are likely to benefit from the treatment according to molecular markers. Assessment for predicting therapy response is mostly done using tumor biopsies. However, these might not truly represent all of the patient's malignant cells because of tumor heterogeneity and/or clonal evolution during disease progression. One potential strategy that can complement primary tumor biopsy is the analysis of circulating tumor cells (CTCs). In this study, we analyzed CTCs of patients with gastric cancer (GC) to find those who were likely to benefit from trastuzumab therapies. We developed an imaging-based method that enabled CTC identification simultaneously with evaluation of HER2 gene amplification (the 3D-IF-FISH method). Then we performed a study enrolling 101 GC patients in whom we analyzed CTCs by both 3D-IF-FISH and an FDA-approved CellSearch system. As compared with the CellSearch system, 3D-IF-FISH methods identified a higher number of patients whose primary tumors were HER2- but who had HER2+ CTCs, suggesting that the 3D-IF-FISH method is effective in preselecting patients for trastuzumab therapies. To demonstrate this, we performed an exploratory clinical study to evaluate the clinical benefits of trastuzumab treatment for advanced GC patients (n = 15) whose primary tumors were HER2-, but whose CTCs showed HER2 amplification. An interim evaluation after the first stage showed that these preselected patients had response rates comparable to those reported in the trastuzumab-plus-chemotherapy arm of the ToGA study. The present study offers a new, non-invasive strategy to select patients who are likely to benefit from trastuzumab-based therapies, despite their primary biopsy being HER2-negative. (UMIN ID: UMIN000008622).
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32
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Clinicopathological features and endoscopic findings of HER2-positive gastric cancer. Surg Endosc 2018; 32:3964-3971. [PMID: 29500656 DOI: 10.1007/s00464-018-6138-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2017] [Accepted: 02/23/2018] [Indexed: 12/18/2022]
Abstract
BACKGROUND Human epidermal growth factor receptor 2 (HER2) expression in gastric cancer is highly heterogeneous. Therefore, it is important to take endoscopic samples from appropriate tumor sites. METHODS Between January 2008 and April 2015, patients with gastric or gastroesophageal junction cancer with histologically confirmed adenocarcinoma were included. Surgical samples or endoscopic biopsy samples were examined for HER2 using immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). Tissues were considered to be HER2 positive when either assessment revealed either an IHC score of 3+ or an IHC score of 2+ accompanied by a positive FISH result. Endoscopic findings were retrieved in all cases where available, and we examined the portion from which a biopsy was obtained. RESULTS Out of the 612 patients included in the study, 104 (17%) were HER2 positive. The proportion of HER2-positive gastric tumors with differentiated (vs. undifferentiated) histology was significantly higher (29 vs. 6%, respectively; p < 0.001). The HER2-positive rate of papillary adenocarcinomas (vs. tubular) was particularly high (62%, 8/13; p = 0.023). The proportion of HER2-positive gastric tumors of Borrmann classification 0 or 1 was significantly higher than that of tumors of classified as 2, 3, or 4 (45 vs. 16%, respectively; p < 0.001). The HER2-positive rates per biopsy specimen from the superficial spreading portion, ulcer mound, ulcer bed, and mass portion were 100, 91, 45, and 100%, respectively. CONCLUSIONS HER2-positive gastric cancer tends to be associated with a differentiated histology, particularly papillary adenocarcinoma, and a Borrmann classification of 0 or 1 tumors. Based on these endoscopic findings, it is important to recognize the superficial spreading portion and the mass portion of gastric malignancies.
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Ammannagari N, Atasoy A. Current status of immunotherapy and immune biomarkers in gastro-esophageal cancers. J Gastrointest Oncol 2018; 9:196-207. [PMID: 29564185 DOI: 10.21037/jgo.2017.06.12] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Gastroesophageal (GE) cancers continue to be a significant cause of mortality globally. Despite therapeutic advances in oncology, the prognosis of advanced GE cancer remains exceedingly poor. Immunotherapy has caused a major paradigm shift in the field of oncology. Not all patients benefit from these agents and several studies are trying to identify predictive and prognostic biomarkers to better inform and guide treatment decisions. The potential role of immunotherapy in GE cancers is emerging. These cancer types are molecularly and immunologically heterogeneous, and this heterogeneity influences the tumor microenvironment posing a significant challenge to studying biomarkers of response to immunotherapy. Here in this article, we discuss the need for new therapeutic approaches in GE cancers, review the emerging data on the activity of checkpoint inhibitors and the role of biomarkers in this setting.
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Affiliation(s)
| | - Ajlan Atasoy
- Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA
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Prognostic implications of HER2 heterogeneity in gastric cancer. Oncotarget 2018; 9:9262-9272. [PMID: 29507688 PMCID: PMC5823644 DOI: 10.18632/oncotarget.24265] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2017] [Accepted: 01/09/2018] [Indexed: 12/12/2022] Open
Abstract
The prognostic implications of human epidermal growth receptor 2 (HER2) heterogeneity in gastric cancer (GC) are not well established. Therefore, the aim of the present study was to determine to the effect of HER2 status on the prognosis of GC patients. We retrieved data on 248 pathologically-confirmed, consecutive patients with primary adenocarcinoma of the stomach or gastro-esophageal junction who underwent surgical resection at Kurume University Medical Center between July 2000 and December 2012. HER2 status was classified as HER2 positive or negative and HER2 heterogeneity or homogeneity. The endpoint was overall survival (OS), which was compared using the generalized Wilcoxon test. HER2 status was positive in 36 patients (14.5%) and negative in 212 patients (85.5%). Among the 36 HER2 positive patients, 25 patients (69.4%) had HER2 heterogeneity and the remaining 11 patients (30.6%) had HER2 homogeneity. Among the 141 patients with stage III or IV disease, the prognosis of the HER2 homogeneity group was significantly worse than that of the HER2 heterogeneity group (p = 0.019; median OS 193 and 831 days, respectively). The prognosis was not significantly different between the HER2 positive group and the HER2 negative group (p = 0.84; median OS 552 and 556 days, respectively). The present study was conducted with small samples, however, the results of the study suggest that HER2 homogeneity but not HER2 positivity may represent a prognostic indicator in GC.
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Baraniskin A, Van Laethem JL, Wyrwicz L, Guller U, Wasan HS, Matysiak-Budnik T, Gruenberger T, Ducreux M, Carneiro F, Van Cutsem E, Seufferlein T, Schmiegel W. Clinical relevance of molecular diagnostics in gastrointestinal (GI) cancer: European Society of Digestive Oncology (ESDO) expert discussion and recommendations from the 17th European Society for Medical Oncology (ESMO)/World Congress on Gastrointestinal Cancer, Barcelona. Eur J Cancer 2017; 86:305-317. [DOI: 10.1016/j.ejca.2017.09.021] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2017] [Accepted: 09/12/2017] [Indexed: 02/06/2023]
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Will molecular target agents enable the multidisciplinary treatment in stage IV gastric cancer? Eur J Surg Oncol 2017; 43:1835-1845. [PMID: 28888797 DOI: 10.1016/j.ejso.2017.08.006] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2017] [Revised: 08/02/2017] [Accepted: 08/10/2017] [Indexed: 02/06/2023] Open
Abstract
A detailed molecular characterization of gastric cancer has been revealed by global initiatives and a number of new molecular agents are under investigation. Currently only trastuzumab, a monoclonal antibody for human epidermal growth factor receptor 2 (HER2), is clinically used for HER2 positive advanced gastric cancer patients and ramucirumab, a monoclonal antibody directed against the extracellular ligand-binding domain of vascular endothelial growth factor receptor (VEGFR)2, can be used in second line. However, despite the progress in gastric cancer treatment, the prognosis of stage IV gastric cancer patients remains dismal. To achieve a remarkable improvement in the prognosis of patients, a multidisciplinary treatment approach with the help of effective molecular target agents should be considered. So far the role of multidisciplinary treatment for stage IV gastric cancer is still uncertain due to limited available data and absence of long-lasting tumor control with systemic therapy. Herein, an overview of the latest developments of molecular targeted agents for gastric cancer in advanced stages, in the perioperative setting and in oligometastatic disease is provided. The possibility of a multidisciplinary strategy using molecular target agents and surgery for stage IV gastric cancer is also assessed.
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High-throughput Protein and mRNA Expression-based Classification of Gastric Cancers Can Identify Clinically Distinct Subtypes, Concordant With Recent Molecular Classifications. Am J Surg Pathol 2017; 41:106-115. [PMID: 27819872 DOI: 10.1097/pas.0000000000000756] [Citation(s) in RCA: 76] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Gastric cancers have recently been classified into several types on the basis of molecular characterization, and the new taxonomy has shown to have clinical relevance. However, the technology required for thorough molecular classification is complicated and expensive, currently preventing widespread use. We aimed to reproduce the results of molecular classification using only simple techniques, that is, immunohistochemical analysis and in situ hybridization. We classified a cohort of 349 successive gastric adenocarcinomas into 5 subtypes, on the basis of protein or mRNA expression of MLH1, E-cadherin, p53, and Epstein-Barr virus. We observed that the subtypes presented distinct clinicopathologic characteristics and corresponded to the molecular classifications previously reported. Epstein-Barr virus -positive tumors were more common in male individuals and in the body of the stomach. Microsatellite-unstable (MSI) tumors, which showed aberrant MLH1 expression, were correlated with increased age and intestinal histology. Both types showed better overall survival than the other types. Gastric cancers with reduced expression of E-cadherin, corresponding to the epithelial to mesenchymal transition or genome stable subtypes, showed the poorest overall survival, with a high prevalence of poorly cohesive carcinoma (ie, diffuse type, of the Lauren classification system). In conclusion, we were able to reproduce a previously reported molecular classification of gastric cancers using immunohistochemical analysis and in situ hybridization. We verified the effectiveness and applicability of this method, which shows promise for use in a clinical setting in the foreseeable future.
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Creemers A, Ter Veer E, de Waal L, Lodder P, Hooijer GKJ, van Grieken NCT, Bijlsma MF, Meijer SL, van Oijen MGH, van Laarhoven HWM. Discordance in HER2 Status in Gastro-esophageal Adenocarcinomas: A Systematic Review and Meta-analysis. Sci Rep 2017; 7:3135. [PMID: 28600510 PMCID: PMC5466678 DOI: 10.1038/s41598-017-03304-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2017] [Accepted: 04/26/2017] [Indexed: 02/06/2023] Open
Abstract
Trastuzumab combined with chemotherapy is standard of care for HER2 positive advanced gastro-esophageal cancers. The reported prevalence of HER2 discordance between primary tumors and corresponding metastases varies, hampering uniform patient selection for HER2 targeted therapy. This meta-analysis explores the influence of HER2 assessment methods on this discordance and investigates the prevalence of HER2 discordance in gastro-esophageal adenocarcinomas. PubMed, Embase and Cochrane databases were searched until January 2016. Differences in discordance rate between strict and broad(er) definitions of HER2 status were assessed using random-effect pair-wise meta-analysis. Random-effect single-arm meta-analyses were performed to assess HER2 discordance and the prevalence of positive and negative conversion. A significantly lower discordance rate in HER2 status between primary tumors and corresponding metastases was observed using a strict vs. broad definition of HER2 status (RR = 0.58, 95%CI 0.41-0.82), with a pooled discordance rate of 6.2% and 12.2%, respectively. Using the strict definition of HER2 assessment pooled overall discordance was 7% (95%CI 5-10%). The lowest discordance rates between primary tumors and corresponding metastasis are observed when using a strict method of HER2 positivity. Treatment outcomes of different studies will be better comparable if selection of eligible patients for HER2 targeted therapy is based on this strict definition.
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Affiliation(s)
- A Creemers
- Cancer Center Amsterdam, Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, AMC, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
- Cancer Center Amsterdam, Department of Medical Oncology, AMC, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
| | - E Ter Veer
- Cancer Center Amsterdam, Department of Medical Oncology, AMC, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands
| | - L de Waal
- Cancer Center Amsterdam, Department of Medical Oncology, AMC, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands
| | - P Lodder
- Department of Methodology and Statistics/Department of Medical and Clinical Psychology, Tilburg University, Warandelaan 2, 5037 AB, Tilburg, The Netherlands
| | - G K J Hooijer
- Department of Pathology, AMC, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands
| | - N C T van Grieken
- Department of Pathology, VUMC, De Boelenlaan 1117, 1081 HV, Amsterdam, The Netherlands
| | - M F Bijlsma
- Cancer Center Amsterdam, Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, AMC, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands
| | - S L Meijer
- Department of Pathology, AMC, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands
| | - M G H van Oijen
- Cancer Center Amsterdam, Department of Medical Oncology, AMC, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands
| | - H W M van Laarhoven
- Cancer Center Amsterdam, Department of Medical Oncology, AMC, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands
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Paulik R, Micsik T, Kiszler G, Kaszál P, Székely J, Paulik N, Várhalmi E, Prémusz V, Krenács T, Molnár B. An optimized image analysis algorithm for detecting nuclear signals in digital whole slides for histopathology. Cytometry A 2017; 91:595-608. [PMID: 28472544 DOI: 10.1002/cyto.a.23124] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2016] [Revised: 03/08/2017] [Accepted: 03/28/2017] [Indexed: 11/11/2022]
Affiliation(s)
| | - Tamás Micsik
- 1st Department of Pathology and Experimental Cancer Research; Semmelweis University; Budapest Hungary
| | | | | | | | | | | | | | - Tibor Krenács
- 1st Department of Pathology and Experimental Cancer Research; Semmelweis University; Budapest Hungary
| | - Béla Molnár
- Clinical Gastroenterology Research Unit; Hungarian Academy of Sciences; Budapest Hungary
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Bartley AN, Washington MK, Colasacco C, Ventura CB, Ismaila N, Benson AB, Carrato A, Gulley ML, Jain D, Kakar S, Mackay HJ, Streutker C, Tang L, Troxell M, Ajani JA. HER2 Testing and Clinical Decision Making in Gastroesophageal Adenocarcinoma: Guideline From the College of American Pathologists, American Society for Clinical Pathology, and the American Society of Clinical Oncology. J Clin Oncol 2017; 35:446-464. [PMID: 28129524 DOI: 10.1200/jco.2016.69.4836] [Citation(s) in RCA: 267] [Impact Index Per Article: 33.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Context ERBB2 (erb-b2 receptor tyrosine kinase 2 or HER2) is currently the only biomarker established for selection of a specific therapy for patients with advanced gastroesophageal adenocarcinoma (GEA). However, there are no comprehensive guidelines for the assessment of HER2 in patients with GEA. Objectives To establish an evidence-based guideline for HER2 testing in patients with GEA, formalize the algorithms for methods to improve the accuracy of HER2 testing while addressing which patients and tumor specimens are appropriate, and to provide guidance on clinical decision making. Design The College of American Pathologists (CAP), American Society for Clinical Pathology (ASCP), and the American Society of Clinical Oncology (ASCO) convened an Expert Panel to conduct a systematic review of the literature to develop an evidence-based guideline with recommendations for optimal HER2 testing in patients with GEA. Results The Panel is proposing 11 recommendations with strong agreement from the open comment participants. Recommendations The Panel recommends that tumor specimen(s) from all patients with advanced GEA, who are candidates for HER2-targeted therapy, should be assessed for HER2 status before the initiation of HER2-targeted therapy. Clinicians should offer combination chemotherapy and an HER2-targeted agent as initial therapy for all patients with HER2-positive advanced GEA. For pathologists, guidance is provided for morphologic selection of neoplastic tissue, testing algorithms, scoring methods, interpretation and reporting of results, and laboratory quality assurance. Conclusion This guideline provides specific recommendations for assessment of HER2 in patients with advanced GEA while addressing pertinent technical issues and clinical implications of the results.
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Affiliation(s)
- Angela N Bartley
- Angela N. Bartley, St Joseph Mercy Hospital, Ann Arbor, MI; Mary Kay Washington, Vanderbilt University Medical Center, Nashville, TN; Carol Colasacco and Christina B. Ventura, College of American Pathologists, Northfield; Al B. Benson III, Northwestern University, Chicago, IL; Nofisat Ismaila, American Society of Clinical Oncology, Alexandria, VA; Alfredo Carrato, Ramón y Cajal University Hospital, Madrid, Spain; Margaret L. Gulley, University of North Carolina, Chapel Hill, NC; Dhanpat Jain, Yale University School of Medicine, New Haven, CT; Sanjay Kakar, University of California, San Francisco, CA; Helen J. Mackay, Princess Margaret Cancer Centre; Catherine Streutker, St Michael's Hospital, University of Toronto, Toronto, Canada; Laura Tang, Memorial Sloan Kettering Cancer Center, New York, NY; Megan Troxell, Stanford University Medical Center, Stanford, CA; and Jaffer A. Ajani, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Mary Kay Washington
- Angela N. Bartley, St Joseph Mercy Hospital, Ann Arbor, MI; Mary Kay Washington, Vanderbilt University Medical Center, Nashville, TN; Carol Colasacco and Christina B. Ventura, College of American Pathologists, Northfield; Al B. Benson III, Northwestern University, Chicago, IL; Nofisat Ismaila, American Society of Clinical Oncology, Alexandria, VA; Alfredo Carrato, Ramón y Cajal University Hospital, Madrid, Spain; Margaret L. Gulley, University of North Carolina, Chapel Hill, NC; Dhanpat Jain, Yale University School of Medicine, New Haven, CT; Sanjay Kakar, University of California, San Francisco, CA; Helen J. Mackay, Princess Margaret Cancer Centre; Catherine Streutker, St Michael's Hospital, University of Toronto, Toronto, Canada; Laura Tang, Memorial Sloan Kettering Cancer Center, New York, NY; Megan Troxell, Stanford University Medical Center, Stanford, CA; and Jaffer A. Ajani, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Carol Colasacco
- Angela N. Bartley, St Joseph Mercy Hospital, Ann Arbor, MI; Mary Kay Washington, Vanderbilt University Medical Center, Nashville, TN; Carol Colasacco and Christina B. Ventura, College of American Pathologists, Northfield; Al B. Benson III, Northwestern University, Chicago, IL; Nofisat Ismaila, American Society of Clinical Oncology, Alexandria, VA; Alfredo Carrato, Ramón y Cajal University Hospital, Madrid, Spain; Margaret L. Gulley, University of North Carolina, Chapel Hill, NC; Dhanpat Jain, Yale University School of Medicine, New Haven, CT; Sanjay Kakar, University of California, San Francisco, CA; Helen J. Mackay, Princess Margaret Cancer Centre; Catherine Streutker, St Michael's Hospital, University of Toronto, Toronto, Canada; Laura Tang, Memorial Sloan Kettering Cancer Center, New York, NY; Megan Troxell, Stanford University Medical Center, Stanford, CA; and Jaffer A. Ajani, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Christina B Ventura
- Angela N. Bartley, St Joseph Mercy Hospital, Ann Arbor, MI; Mary Kay Washington, Vanderbilt University Medical Center, Nashville, TN; Carol Colasacco and Christina B. Ventura, College of American Pathologists, Northfield; Al B. Benson III, Northwestern University, Chicago, IL; Nofisat Ismaila, American Society of Clinical Oncology, Alexandria, VA; Alfredo Carrato, Ramón y Cajal University Hospital, Madrid, Spain; Margaret L. Gulley, University of North Carolina, Chapel Hill, NC; Dhanpat Jain, Yale University School of Medicine, New Haven, CT; Sanjay Kakar, University of California, San Francisco, CA; Helen J. Mackay, Princess Margaret Cancer Centre; Catherine Streutker, St Michael's Hospital, University of Toronto, Toronto, Canada; Laura Tang, Memorial Sloan Kettering Cancer Center, New York, NY; Megan Troxell, Stanford University Medical Center, Stanford, CA; and Jaffer A. Ajani, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Nofisat Ismaila
- Angela N. Bartley, St Joseph Mercy Hospital, Ann Arbor, MI; Mary Kay Washington, Vanderbilt University Medical Center, Nashville, TN; Carol Colasacco and Christina B. Ventura, College of American Pathologists, Northfield; Al B. Benson III, Northwestern University, Chicago, IL; Nofisat Ismaila, American Society of Clinical Oncology, Alexandria, VA; Alfredo Carrato, Ramón y Cajal University Hospital, Madrid, Spain; Margaret L. Gulley, University of North Carolina, Chapel Hill, NC; Dhanpat Jain, Yale University School of Medicine, New Haven, CT; Sanjay Kakar, University of California, San Francisco, CA; Helen J. Mackay, Princess Margaret Cancer Centre; Catherine Streutker, St Michael's Hospital, University of Toronto, Toronto, Canada; Laura Tang, Memorial Sloan Kettering Cancer Center, New York, NY; Megan Troxell, Stanford University Medical Center, Stanford, CA; and Jaffer A. Ajani, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Al B Benson
- Angela N. Bartley, St Joseph Mercy Hospital, Ann Arbor, MI; Mary Kay Washington, Vanderbilt University Medical Center, Nashville, TN; Carol Colasacco and Christina B. Ventura, College of American Pathologists, Northfield; Al B. Benson III, Northwestern University, Chicago, IL; Nofisat Ismaila, American Society of Clinical Oncology, Alexandria, VA; Alfredo Carrato, Ramón y Cajal University Hospital, Madrid, Spain; Margaret L. Gulley, University of North Carolina, Chapel Hill, NC; Dhanpat Jain, Yale University School of Medicine, New Haven, CT; Sanjay Kakar, University of California, San Francisco, CA; Helen J. Mackay, Princess Margaret Cancer Centre; Catherine Streutker, St Michael's Hospital, University of Toronto, Toronto, Canada; Laura Tang, Memorial Sloan Kettering Cancer Center, New York, NY; Megan Troxell, Stanford University Medical Center, Stanford, CA; and Jaffer A. Ajani, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Alfredo Carrato
- Angela N. Bartley, St Joseph Mercy Hospital, Ann Arbor, MI; Mary Kay Washington, Vanderbilt University Medical Center, Nashville, TN; Carol Colasacco and Christina B. Ventura, College of American Pathologists, Northfield; Al B. Benson III, Northwestern University, Chicago, IL; Nofisat Ismaila, American Society of Clinical Oncology, Alexandria, VA; Alfredo Carrato, Ramón y Cajal University Hospital, Madrid, Spain; Margaret L. Gulley, University of North Carolina, Chapel Hill, NC; Dhanpat Jain, Yale University School of Medicine, New Haven, CT; Sanjay Kakar, University of California, San Francisco, CA; Helen J. Mackay, Princess Margaret Cancer Centre; Catherine Streutker, St Michael's Hospital, University of Toronto, Toronto, Canada; Laura Tang, Memorial Sloan Kettering Cancer Center, New York, NY; Megan Troxell, Stanford University Medical Center, Stanford, CA; and Jaffer A. Ajani, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Margaret L Gulley
- Angela N. Bartley, St Joseph Mercy Hospital, Ann Arbor, MI; Mary Kay Washington, Vanderbilt University Medical Center, Nashville, TN; Carol Colasacco and Christina B. Ventura, College of American Pathologists, Northfield; Al B. Benson III, Northwestern University, Chicago, IL; Nofisat Ismaila, American Society of Clinical Oncology, Alexandria, VA; Alfredo Carrato, Ramón y Cajal University Hospital, Madrid, Spain; Margaret L. Gulley, University of North Carolina, Chapel Hill, NC; Dhanpat Jain, Yale University School of Medicine, New Haven, CT; Sanjay Kakar, University of California, San Francisco, CA; Helen J. Mackay, Princess Margaret Cancer Centre; Catherine Streutker, St Michael's Hospital, University of Toronto, Toronto, Canada; Laura Tang, Memorial Sloan Kettering Cancer Center, New York, NY; Megan Troxell, Stanford University Medical Center, Stanford, CA; and Jaffer A. Ajani, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Dhanpat Jain
- Angela N. Bartley, St Joseph Mercy Hospital, Ann Arbor, MI; Mary Kay Washington, Vanderbilt University Medical Center, Nashville, TN; Carol Colasacco and Christina B. Ventura, College of American Pathologists, Northfield; Al B. Benson III, Northwestern University, Chicago, IL; Nofisat Ismaila, American Society of Clinical Oncology, Alexandria, VA; Alfredo Carrato, Ramón y Cajal University Hospital, Madrid, Spain; Margaret L. Gulley, University of North Carolina, Chapel Hill, NC; Dhanpat Jain, Yale University School of Medicine, New Haven, CT; Sanjay Kakar, University of California, San Francisco, CA; Helen J. Mackay, Princess Margaret Cancer Centre; Catherine Streutker, St Michael's Hospital, University of Toronto, Toronto, Canada; Laura Tang, Memorial Sloan Kettering Cancer Center, New York, NY; Megan Troxell, Stanford University Medical Center, Stanford, CA; and Jaffer A. Ajani, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Sanjay Kakar
- Angela N. Bartley, St Joseph Mercy Hospital, Ann Arbor, MI; Mary Kay Washington, Vanderbilt University Medical Center, Nashville, TN; Carol Colasacco and Christina B. Ventura, College of American Pathologists, Northfield; Al B. Benson III, Northwestern University, Chicago, IL; Nofisat Ismaila, American Society of Clinical Oncology, Alexandria, VA; Alfredo Carrato, Ramón y Cajal University Hospital, Madrid, Spain; Margaret L. Gulley, University of North Carolina, Chapel Hill, NC; Dhanpat Jain, Yale University School of Medicine, New Haven, CT; Sanjay Kakar, University of California, San Francisco, CA; Helen J. Mackay, Princess Margaret Cancer Centre; Catherine Streutker, St Michael's Hospital, University of Toronto, Toronto, Canada; Laura Tang, Memorial Sloan Kettering Cancer Center, New York, NY; Megan Troxell, Stanford University Medical Center, Stanford, CA; and Jaffer A. Ajani, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Helen J Mackay
- Angela N. Bartley, St Joseph Mercy Hospital, Ann Arbor, MI; Mary Kay Washington, Vanderbilt University Medical Center, Nashville, TN; Carol Colasacco and Christina B. Ventura, College of American Pathologists, Northfield; Al B. Benson III, Northwestern University, Chicago, IL; Nofisat Ismaila, American Society of Clinical Oncology, Alexandria, VA; Alfredo Carrato, Ramón y Cajal University Hospital, Madrid, Spain; Margaret L. Gulley, University of North Carolina, Chapel Hill, NC; Dhanpat Jain, Yale University School of Medicine, New Haven, CT; Sanjay Kakar, University of California, San Francisco, CA; Helen J. Mackay, Princess Margaret Cancer Centre; Catherine Streutker, St Michael's Hospital, University of Toronto, Toronto, Canada; Laura Tang, Memorial Sloan Kettering Cancer Center, New York, NY; Megan Troxell, Stanford University Medical Center, Stanford, CA; and Jaffer A. Ajani, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Catherine Streutker
- Angela N. Bartley, St Joseph Mercy Hospital, Ann Arbor, MI; Mary Kay Washington, Vanderbilt University Medical Center, Nashville, TN; Carol Colasacco and Christina B. Ventura, College of American Pathologists, Northfield; Al B. Benson III, Northwestern University, Chicago, IL; Nofisat Ismaila, American Society of Clinical Oncology, Alexandria, VA; Alfredo Carrato, Ramón y Cajal University Hospital, Madrid, Spain; Margaret L. Gulley, University of North Carolina, Chapel Hill, NC; Dhanpat Jain, Yale University School of Medicine, New Haven, CT; Sanjay Kakar, University of California, San Francisco, CA; Helen J. Mackay, Princess Margaret Cancer Centre; Catherine Streutker, St Michael's Hospital, University of Toronto, Toronto, Canada; Laura Tang, Memorial Sloan Kettering Cancer Center, New York, NY; Megan Troxell, Stanford University Medical Center, Stanford, CA; and Jaffer A. Ajani, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Laura Tang
- Angela N. Bartley, St Joseph Mercy Hospital, Ann Arbor, MI; Mary Kay Washington, Vanderbilt University Medical Center, Nashville, TN; Carol Colasacco and Christina B. Ventura, College of American Pathologists, Northfield; Al B. Benson III, Northwestern University, Chicago, IL; Nofisat Ismaila, American Society of Clinical Oncology, Alexandria, VA; Alfredo Carrato, Ramón y Cajal University Hospital, Madrid, Spain; Margaret L. Gulley, University of North Carolina, Chapel Hill, NC; Dhanpat Jain, Yale University School of Medicine, New Haven, CT; Sanjay Kakar, University of California, San Francisco, CA; Helen J. Mackay, Princess Margaret Cancer Centre; Catherine Streutker, St Michael's Hospital, University of Toronto, Toronto, Canada; Laura Tang, Memorial Sloan Kettering Cancer Center, New York, NY; Megan Troxell, Stanford University Medical Center, Stanford, CA; and Jaffer A. Ajani, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Megan Troxell
- Angela N. Bartley, St Joseph Mercy Hospital, Ann Arbor, MI; Mary Kay Washington, Vanderbilt University Medical Center, Nashville, TN; Carol Colasacco and Christina B. Ventura, College of American Pathologists, Northfield; Al B. Benson III, Northwestern University, Chicago, IL; Nofisat Ismaila, American Society of Clinical Oncology, Alexandria, VA; Alfredo Carrato, Ramón y Cajal University Hospital, Madrid, Spain; Margaret L. Gulley, University of North Carolina, Chapel Hill, NC; Dhanpat Jain, Yale University School of Medicine, New Haven, CT; Sanjay Kakar, University of California, San Francisco, CA; Helen J. Mackay, Princess Margaret Cancer Centre; Catherine Streutker, St Michael's Hospital, University of Toronto, Toronto, Canada; Laura Tang, Memorial Sloan Kettering Cancer Center, New York, NY; Megan Troxell, Stanford University Medical Center, Stanford, CA; and Jaffer A. Ajani, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Jaffer A Ajani
- Angela N. Bartley, St Joseph Mercy Hospital, Ann Arbor, MI; Mary Kay Washington, Vanderbilt University Medical Center, Nashville, TN; Carol Colasacco and Christina B. Ventura, College of American Pathologists, Northfield; Al B. Benson III, Northwestern University, Chicago, IL; Nofisat Ismaila, American Society of Clinical Oncology, Alexandria, VA; Alfredo Carrato, Ramón y Cajal University Hospital, Madrid, Spain; Margaret L. Gulley, University of North Carolina, Chapel Hill, NC; Dhanpat Jain, Yale University School of Medicine, New Haven, CT; Sanjay Kakar, University of California, San Francisco, CA; Helen J. Mackay, Princess Margaret Cancer Centre; Catherine Streutker, St Michael's Hospital, University of Toronto, Toronto, Canada; Laura Tang, Memorial Sloan Kettering Cancer Center, New York, NY; Megan Troxell, Stanford University Medical Center, Stanford, CA; and Jaffer A. Ajani, The University of Texas MD Anderson Cancer Center, Houston, TX
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Ross DS, Zehir A, Cheng DT, Benayed R, Nafa K, Hechtman JF, Janjigian YY, Weigelt B, Razavi P, Hyman DM, Baselga J, Berger MF, Ladanyi M, Arcila ME. Next-Generation Assessment of Human Epidermal Growth Factor Receptor 2 (ERBB2) Amplification Status: Clinical Validation in the Context of a Hybrid Capture-Based, Comprehensive Solid Tumor Genomic Profiling Assay. J Mol Diagn 2016; 19:244-254. [PMID: 28027945 DOI: 10.1016/j.jmoldx.2016.09.010] [Citation(s) in RCA: 88] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2016] [Revised: 08/02/2016] [Accepted: 09/27/2016] [Indexed: 12/31/2022] Open
Abstract
Establishing ERBB2 [human epidermal growth factor receptor 2 (HER2)] amplification status in breast and gastric carcinomas is essential to treatment selection. Immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) constitute the current standard for assessment. With further advancements in genomic medicine, new clinically relevant biomarkers are rapidly emerging and options for targeted therapy are increasing in patients with advanced disease, driving the need for comprehensive molecular profiling. Next-generation sequencing (NGS) is an attractive approach for up-front comprehensive assessment, including ERBB2 status, but the concordance with traditional methods of HER2 assessment is not well established. The Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) assay, a hybrid capture-based NGS assay interrogating the coding regions of 410 cancer-related genes, was performed on manually macrodissected unstained sections from formalin-fixed, paraffin-embedded breast (n = 213) and gastroesophageal (n = 39) tumors submitted for clinical mutation profiling. ERBB2 status was assessed using a custom bioinformatics pipeline, and NGS results were compared to IHC and FISH. NGS ERBB2 amplification calls had an overall concordance of 98.4% (248/252) with the combined IHC/FISH results in this validation set. Discrepancies occurred in the context of low tumor content and HER2 heterogeneity. ERBB2 amplification status can be reliably determined by hybridization capture-based NGS methods, allowing efficient concurrent testing for other potentially actionable genomic alterations, particularly in limited material.
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Affiliation(s)
- Dara S Ross
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
| | - Ahmet Zehir
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Donavan T Cheng
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Ryma Benayed
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Khedoudja Nafa
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Jaclyn F Hechtman
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Yelena Y Janjigian
- Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Britta Weigelt
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Pedram Razavi
- Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | - David M Hyman
- Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | - José Baselga
- Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Michael F Berger
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Marc Ladanyi
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Maria E Arcila
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York
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Bartley AN, Washington MK, Ventura CB, Ismaila N, Colasacco C, Benson AB, Carrato A, Gulley ML, Jain D, Kakar S, Mackay HJ, Streutker C, Tang L, Troxell M, Ajani JA. HER2 Testing and Clinical Decision Making in Gastroesophageal Adenocarcinoma: Guideline From the College of American Pathologists, American Society for Clinical Pathology, and American Society of Clinical Oncology. Arch Pathol Lab Med 2016; 140:1345-1363. [PMID: 27841667 DOI: 10.5858/arpa.2016-0331-cp] [Citation(s) in RCA: 105] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
CONTEXT - ERBB2 (erb-b2 receptor tyrosine kinase 2 or HER2) is currently the only biomarker established for selection of a specific therapy for patients with advanced gastroesophageal adenocarcinoma (GEA). However, there are no comprehensive guidelines for the assessment of HER2 in patients with GEA. OBJECTIVES - To establish an evidence-based guideline for HER2 testing in patients with GEA, to formalize the algorithms for methods to improve the accuracy of HER2 testing while addressing which patients and tumor specimens are appropriate, and to provide guidance on clinical decision making. DESIGN - The College of American Pathologists, American Society for Clinical Pathology, and American Society of Clinical Oncology convened an expert panel to conduct a systematic review of the literature to develop an evidence-based guideline with recommendations for optimal HER2 testing in patients with GEA. RESULTS - The panel is proposing 11 recommendations with strong agreement from the open-comment participants. RECOMMENDATIONS - The panel recommends that tumor specimen(s) from all patients with advanced GEA, who are candidates for HER2-targeted therapy, should be assessed for HER2 status before the initiation of HER2-targeted therapy. Clinicians should offer combination chemotherapy and a HER2-targeted agent as initial therapy for all patients with HER2-positive advanced GEA. For pathologists, guidance is provided for morphologic selection of neoplastic tissue, testing algorithms, scoring methods, interpretation and reporting of results, and laboratory quality assurance. CONCLUSIONS - This guideline provides specific recommendations for assessment of HER2 in patients with advanced GEA while addressing pertinent technical issues and clinical implications of the results.
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Affiliation(s)
- Angela N Bartley
- From the Department of Pathology, St. Joseph Mercy Hospital, Ann Arbor, Michigan (Dr Bartley); the Department of Pathology, Vanderbilt University Medical Center, Nashville, Tennessee (Dr Washington); Surveys (Ms Ventura) and Governance (Ms Colasacco), College of American Pathologists, Northfield, Illinois; Quality and Guidelines Department, American Society of Clinical Oncology, Alexandria, Virginia (Dr Ismaila); the Division of Hematology/Oncology, Northwestern University, Chicago, Illinois (Dr Benson); Medical Oncology Department, Ramon y Cajal University Hospital, Madrid, Spain (Dr Carrato); the Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill (Dr Gulley); the Department of Pathology, Yale University School of Medicine, New Haven, Connecticut (Dr Jain); the Department of Pathology and Laboratory Medicine, UCSF, San Francisco, California (Dr Kakar); the Division of Medical Oncology and Hematology, University of Toronto/Sunnybrook Odette Cancer Centre, Toronto, Ontario, Canada (Dr Mackay); the Department of Laboratory Medicine, St. Michael's Hospital, Toronto, Ontario, Canada (Dr Streutker); the Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York (Dr Tang); the Department of Pathology, Stanford University Medical Center, Stanford, California (Dr Troxell); and the Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston (Dr Ajani)
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Bartley AN, Washington MK, Ventura CB, Ismaila N, Colasacco C, Benson AB, Carrato A, Gulley ML, Jain D, Kakar S, Mackay HJ, Streutker C, Tang L, Troxell M, Ajani JA. HER2 Testing and Clinical Decision Making in Gastroesophageal Adenocarcinoma: Guideline From the College of American Pathologists, American Society for Clinical Pathology, and American Society of Clinical Oncology. Am J Clin Pathol 2016; 146:647-669. [PMID: 28077399 PMCID: PMC6272805 DOI: 10.1093/ajcp/aqw206] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
CONTEXT ERBB2 (erb-b2 receptor tyrosine kinase 2 or HER2) is currently the only biomarker established for selection of a specific therapy for patients with advanced gastroesophageal adenocarcinoma (GEA). However, there are no comprehensive guidelines for the assessment of HER2 in patients with GEA. OBJECTIVES To establish an evidence-based guideline for HER2 testing in patients with GEA, to formalize the algorithms for methods to improve the accuracy of HER2 testing while addressing which patients and tumor specimens are appropriate, and to provide guidance on clinical decision making. DESIGN The College of American Pathologists, American Society for Clinical Pathology, and American Society of Clinical Oncology convened an expert panel to conduct a systematic review of the literature to develop an evidence-based guideline with recommendations for optimal HER2 testing in patients with GEA. RESULTS The panel is proposing 11 recommendations with strong agreement from the open-comment participants. RECOMMENDATIONS The panel recommends that tumor specimen(s) from all patients with advanced GEA, who are candidates for HER2-targeted therapy, should be assessed for HER2 status before the initiation of HER2-targeted therapy. Clinicians should offer combination chemotherapy and a HER2-targeted agent as initial therapy for all patients with HER2-positive advanced GEA. For pathologists, guidance is provided for morphologic selection of neoplastic tissue, testing algorithms, scoring methods, interpretation and reporting of results, and laboratory quality assurance. CONCLUSIONS This guideline provides specific recommendations for assessment of HER2 in patients with advanced GEA while addressing pertinent technical issues and clinical implications of the results.
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Affiliation(s)
- Angela N Bartley
- From the Department of Pathology, St Joseph Mercy Hospital, Ann Arbor, MI
| | - Mary Kay Washington
- Department of Pathology, Vanderbilt University Medical Center, Nashville, TN
| | | | - Nofisat Ismaila
- Quality and Guidelines Department, American Society of Clinical Oncology, Alexandria, VA
| | - Carol Colasacco
- Surveys and Governance, College of American Pathologists, Northfield, IL
| | - Al B Benson
- Division of Hematology/Oncology, Northwestern University, Chicago, IL
| | - Alfredo Carrato
- Medical Oncology Department, Ramon y Cajal University Hospital, Madrid, Spain
| | - Margaret L Gulley
- Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill
| | - Dhanpat Jain
- Department of Pathology, Yale University School of Medicine, New Haven, CT
| | - Sanjay Kakar
- Department of Pathology and Laboratory Medicine, UCSF, San Francisco, CA
| | - Helen J Mackay
- Division of Medical Oncology and Hematology, University of Toronto/Sunnybrook Odette Cancer Centre, Toronto, Canada
| | | | - Laura Tang
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Megan Troxell
- Department of Pathology, Stanford University Medical Center, Stanford, CA
| | - Jaffer A Ajani
- Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston
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Davidson M, Starling N. Trastuzumab in the management of gastroesophageal cancer: patient selection and perspectives. Onco Targets Ther 2016; 9:7235-7245. [PMID: 27932891 PMCID: PMC5135398 DOI: 10.2147/ott.s100643] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023] Open
Abstract
The addition of trastuzumab to the treatment of a subset of patients with advanced gastric and gastroesophageal junction cancers showing HER2 positivity has been shown to confer clinical benefit; however, questions remain over the optimal methods for defining and selecting such patients. This review provides an overview of current standards for assessing HER2 positivity, the evolving treatment landscape for HER2-positive gastric and esophageal cancers and the challenges and potential future directions in optimal patient selection for HER2-targeted therapy.
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Affiliation(s)
- Michael Davidson
- Department of Gastrointestinal Oncology, The Royal Marsden Hospital NHS Foundation Trust, London, UK
| | - Naureen Starling
- Department of Gastrointestinal Oncology, The Royal Marsden Hospital NHS Foundation Trust, London, UK
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Choi Y, Ko YS, Park J, Choi Y, Kim Y, Pyo JS, Jang BG, Hwang DH, Kim WH, Lee BL. HER2-induced metastasis is mediated by AKT/JNK/EMT signaling pathway in gastric cancer. World J Gastroenterol 2016; 22:9141-9153. [PMID: 27895401 PMCID: PMC5107595 DOI: 10.3748/wjg.v22.i41.9141] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2016] [Revised: 08/12/2016] [Accepted: 09/12/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To investigated the relationships between HER2, c-Jun N-terminal kinase (JNK) and protein kinase B (AKT) with respect to metastatic potential of HER2-positive gastric cancer (GC) cells.
METHODS Immunohistochemistry was performed on tissue array slides containing 423 human GC specimens. Using HER2-positve GC cell lines SNU-216 and NCI-N87, HER2 expression was silenced by RNA interference, and the activations of JNK and AKT were suppressed by SP600125 and LY294002, respectively. Transwell assay, Western blot, semi-quantitative reverse transcription-polymerase chain reaction and immunofluorescence staining were used in cell culture experiments.
RESULTS In GC specimens, HER2, JNK, and AKT activations were positively correlated with each other. In vitro analysis revealed a positive regulatory feedback loop between HER2 and JNK in GC cell lines and the role of JNK as a downstream effector of AKT in the HER2/AKT signaling pathway. JNK inhibition suppressed migratory capacity through reversing EMT and dual inhibition of JNK and AKT induced a more profound effect on cancer cell motility.
CONCLUSION HER2, JNK and AKT in human GC specimens are positively associated with each other. JNK and AKT, downstream effectors of HER2, co-operatively contribute to the metastatic potential of HER2-positive GC cells. Thus, targeting of these two molecules in combination with HER2 downregulation may be a good approach to combat HER2-positive GC.
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Madani SH, Rahmati A, Sadeghi E, Khazaei S, Sadeghi M, Payandeh M, Amirifard N. Survey of Her2-neu Expression and its Correlation with Histology of Gastric Carcinoma and Gastroesophageal Junction Adenocarcinoma. Asian Pac J Cancer Prev 2016; 16:7755-8. [PMID: 26625793 DOI: 10.7314/apjcp.2015.16.17.7755] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND There is increasing evidence that HER2-neu is an important biomarker in gastric carcinomas (GC) and gastroesophageal junction (GEJ) adenocarcinomas. The aim of this study was to evaluate HER2-neu expression and also some clinicopathological features of these neoplasms. MATERIALS AND METHODS We selected 211 paraffin-embedded blocks, 193 GC and 18 GEJ. Then 4 micron sections were prepared for staining with hematoxylin and eosin and also for IHC (Her2-neu). The Chi-square test was used for significance between expression of HER2-neu and clinicopathological parameters. RESULTS In patients with advanced cancer of GC and GEJ, HER2-neu overexpression was more associated with the intestinal cancer subtype. CONCLUSIONS This could be a guide to new complementary therapy for affected patients.
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Affiliation(s)
- Seyed-Hamid Madani
- Molecular Pathology Research Center, Imam Reza Hospital, Kermanshah University of Medical Sciences, Kermanshah, Iran E-mail :
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Goode EF, Smyth EC. Immunotherapy for Gastroesophageal Cancer. J Clin Med 2016; 5:jcm5100084. [PMID: 27669318 PMCID: PMC5086586 DOI: 10.3390/jcm5100084] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2016] [Revised: 09/07/2016] [Accepted: 09/14/2016] [Indexed: 12/29/2022] Open
Abstract
Survival for patients with advanced oesophageal and stomach cancer is poor; together these cancers are responsible for more than a million deaths per year globally. As chemotherapy and targeted therapies such as trastuzumab and ramucirumab result in modest improvements in survival but not long-term cure for such patients, development of alternative treatment approaches is warranted. Novel immunotherapy drugs such as checkpoint inhibitors have been paradigm changing in melanoma, non-small cell lung cancer and urothelial cancers. In this review, we assess the early evidence for efficacy of immunotherapy in patients with gastroesophageal cancer in addition to considering biomarkers associated with response to these treatments. Early results of Anti- Programmed Cell Death Protein-1 (anti-PD-1), anti-PD-L1 and anti-Cytotoxic T-lymphocyte assosciated protein-4 (anti-CTLA4) trials are examined, and we conclude with a discussion on the future direction for immunotherapy for gastroesophageal cancer patients.
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Affiliation(s)
- Emily F Goode
- The Royal Marsden Hospital, NHS Foundation Trust, London SW3 6JJ, UK.
| | - Elizabeth C Smyth
- The Royal Marsden Hospital, NHS Foundation Trust, London SW3 6JJ, UK.
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Concordance of HER2 expression in paired primary and metastatic sites of gastric and gastro-oesophageal junction cancers. Pathology 2016; 47:641-6. [PMID: 26517644 DOI: 10.1097/pat.0000000000000323] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
HER2 is amplified/overexpressed in a subset of gastric and gastro-oesophageal junction cancers. Addition of anti-HER2 therapy has been shown to provide survival benefit in this setting. However, there are limited data assessing the concordance of HER2 status between primary and metastatic sites.A total of 113 samples from 43 paired primary and metastatic tumours were tested for HER2 status, by immunohistochemistry (IHC) for protein expression and silver in situ hybridisation (SISH) for gene amplification.Primary sites tested included endoscopic biopsies (n = 30) and resections (n = 24). Metastatic samples included lymph nodes (n = 29), peritoneal effusions (n = 21) and miscellaneous sites (n = 9). The overall HER2+ rate was 11%. Of 41 (95%; 95% CI 88.5-100%) concordant cases, 38 were HER2- and three were HER2+. There were two (5%) discordant cases, one of which showed heterogeneity of HER2 expression.This series confirms a high concordance rate of 95%, supporting that testing of primary tumours and metastases is equally valid and providing clinical rationale for the addition of anti-HER2 therapy in HER2+ disseminated disease.
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Baniak N, Senger JL, Ahmed S, Kanthan SC, Kanthan R. Gastric biomarkers: a global review. World J Surg Oncol 2016; 14:212. [PMID: 27514667 PMCID: PMC4982433 DOI: 10.1186/s12957-016-0969-3] [Citation(s) in RCA: 74] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2016] [Accepted: 08/02/2016] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Gastric cancer is an aggressive disease with a poor 5-year survival and large global burden of disease. The disease is biologically and genetically heterogeneous with a poorly understood carcinogenesis at the molecular level. Despite the many prognostic, predictive, and therapeutic biomarkers investigated to date, gastric cancer continues to be detected at an advanced stage with resultant poor clinical outcomes. MAIN BODY This is a global review of gastric biomarkers with an emphasis on HER2, E-cadherin, fibroblast growth factor receptor, mammalian target of rapamycin, and hepatocyte growth factor receptor as well as sections on microRNAs, long noncoding RNAs, matrix metalloproteinases, PD-L1, TP53, and microsatellite instability. CONCLUSION A deeper understanding of the pathogenesis and biological features of gastric cancer, including the identification and characterization of diagnostic, prognostic, predictive, and therapeutic biomarkers, hopefully will provide improved clinical outcomes.
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Affiliation(s)
- Nick Baniak
- Department of Pathology and Laboratory Medicine, University of Saskatchewan, 103 Hospital Drive, Saskatoon, SK S7N 0W8 Canada
| | - Jenna-Lynn Senger
- Department of Surgery, University of Alberta, 116 St & 85 Ave, Edmonton, T6G 2R3, T6G 2B7 AB Canada
| | - Shahid Ahmed
- Division of Medical Oncology, University of Saskatchewan, 103 Hospital Drive, Saskatoon, SK S7N 0W8 Canada
| | - S. C. Kanthan
- Department of General Surgery, University of Saskatchewan, 103 Hospital Drive, Saskatoon, SK S7N 0W8 Canada
| | - Rani Kanthan
- Department of General Surgery, University of Saskatchewan, 103 Hospital Drive, Saskatoon, SK S7N 0W8 Canada
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Grillo F, Fassan M, Sarocchi F, Fiocca R, Mastracci L. HER2 heterogeneity in gastric/gastroesophageal cancers: From benchside to practice. World J Gastroenterol 2016; 22:5879-5887. [PMID: 27468182 PMCID: PMC4948273 DOI: 10.3748/wjg.v22.i26.5879] [Citation(s) in RCA: 87] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2016] [Revised: 05/13/2016] [Accepted: 05/23/2016] [Indexed: 02/06/2023] Open
Abstract
HER2 is overexpressed in approximately 10%-20% of gastric and gastroesophageal junction carcinomas. In these types of cancer, accurate assessment of HER2 status is mandatory, for selecting patients who may benefit from targeted therapies with anti-HER2 drugs such as Trastuzumab. This manuscript focuses on HER2 in gastric carcinogenesis, on optimal evaluation of HER2 and on the possible causes which may contribute to inaccurate HER2 evaluation. Similarly to breast cancer HER2 evaluation, standardization of HER2 testing in gastric cancer is necessary in diagnostic practice. The three principle aspects which require consideration are: (1) the choice of sample with regards to cancer morphology - intestinal vs diffuse areas; (2) the choice of scoring criteria - use of HER2 scoring criteria specific for gastric cancer; and (3) the choice of HER2 evaluation methods - use of an algorithm in which both immunohistochemistry and in situ hybridization play a role. Problematic issues include: (1) pre-analytic variables with particular emphasis on fixation; (2) recommended methodology for HER2 assessment (immunohistochemistry vs in situ hybridization); (3) HER2 heterogeneity both within the primary tumor and between primary tumor and metastases; (4) reliability of biopsies in HER 2 evaluation; and (5) quantity of sample (FFPE blocks from surgical specimens or endoscopic biopsies) necessary for an adequate assessment.
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