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1
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Beauchamp L, Indulkar S, Erak E, Salimian M, Matoso A. Tissue-Based Biomarkers Important for Prognostication and Management of Genitourinary Tumors, Including Surrogate Markers of Genomic Alterations. Surg Pathol Clin 2025; 18:175-189. [PMID: 39890303 DOI: 10.1016/j.path.2024.10.002] [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] [Indexed: 02/03/2025]
Abstract
A better understanding of the molecular alterations that underlie urologic malignancies and advances in targeted therapies has impacted classification, prognostication, and treatment. In bladder tumors, these advances include the development of antibody-drug conjugates targeting nectin-4 and Trop-2, as well as human epidermal growth factor receptor 2 and immunotherapy. In prostate cancer, assessment of the percentage of Gleason pattern 4, presence of cribriform glands, and molecular alterations, including PTEN and mismatch repair protein loss, have become standard for clinical care. In renal malignancies, alterations in TSC1/2, mammalian target of rapamycin, anaplastic lymphoma kinase, and other genes impact classification and therapeutic decisions.
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Affiliation(s)
- Leonie Beauchamp
- Departments of Pathology, The Johns Hopkins Medical Institutions, Baltimore, MD 21231, USA
| | - Shreeya Indulkar
- Departments of Pathology, The Johns Hopkins Medical Institutions, Baltimore, MD 21231, USA
| | - Eric Erak
- Departments of Pathology, The Johns Hopkins Medical Institutions, Baltimore, MD 21231, USA
| | - Mohammad Salimian
- Departments of Pathology, The Johns Hopkins Medical Institutions, Baltimore, MD 21231, USA
| | - Andres Matoso
- Departments of Pathology, The Johns Hopkins Medical Institutions, Baltimore, MD 21231, USA; Department of Urology, The Johns Hopkins Medical Institutions, Baltimore, MD 21231, USA; Department of Oncology, The Johns Hopkins Medical Institutions, Baltimore, MD 21231, USA.
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2
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Abe H, Kuwata T, Kushima R, Ushiku T. Nationwide survey on HER2 and PD-L1 testing practices in gastric cancer across Japan. Gastric Cancer 2025; 28:294-300. [PMID: 39656340 PMCID: PMC11842516 DOI: 10.1007/s10120-024-01571-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2024] [Accepted: 11/24/2024] [Indexed: 02/21/2025]
Abstract
BACKGROUND Since HER2 and PD-L1 testing are key to selecting drugs for first-line treatments in advanced gastric cancer, evaluating differences in these tests among institutions is necessary to standardize treatment. METHODS A questionnaire survey was conducted targeting institutions certified by the Japanese Gastric Cancer Association. RESULTS Responses were obtained from 155 institutions. Most institutions performed HER2 testing in-house, while PD-L1 tests were largely outsourced. HER2 scores and PD-L1 CPS rates showed greater variability across institutions than anticipated. In the pre-analytic phase, 10% neutral buffered formalin was commonly used, with fixation practices generally following guidelines. Overall, the impact of fixation-related factors was limited, but in surgical specimens, longer fixation was associated with a higher proportion of score 0/1+ and a lower proportion of score 3+. When examining HER2 scores by institution, if a particular score had a high (or low) frequency in biopsy, the same trend was also seen in surgical specimens. CONCLUSIONS These findings suggest that not only factors related to specimen preparation, but also biases in evaluation criteria among pathologists may contribute to the significant variability among institutions. Standardization of pre- and post-analytic phases, coupled with appropriate training, is essential to achieve consistent gastric cancer therapy.
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Affiliation(s)
- Hiroyuki Abe
- Japanese Gastric Cancer Association, Kyoto, Japan
- Department of Pathology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
| | - Takeshi Kuwata
- Japanese Gastric Cancer Association, Kyoto, Japan
- Department of Genetic Medicine and Services, National Cancer Center Hospital East, Kashiwa, Japan
| | - Ryoji Kushima
- Japanese Gastric Cancer Association, Kyoto, Japan
- Department of Pathology, Shiga University of Medical Science, Otsu, Japan
| | - Tetsuo Ushiku
- Japanese Gastric Cancer Association, Kyoto, Japan.
- Department of Pathology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.
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Jang D, Hwa C, Kim S, Oh J, Shin S, Lee S, Kim J, Lee SE, Yang Y, Kim D, Lee S, Jung HR, Oh Y, Kim K, Lee HS, An J, Cho S. RNA N 6-Methyladenosine-Binding Protein YTHDFs Redundantly Attenuate Cancer Immunity by Downregulating IFN-γ Signaling in Gastric Cancer. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2410806. [PMID: 39587835 PMCID: PMC11744580 DOI: 10.1002/advs.202410806] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/05/2024] [Revised: 10/31/2024] [Indexed: 11/27/2024]
Abstract
Immunotherapy holds potential as a treatment for gastric cancer (GC), though immune checkpoint inhibitor (ICI) resistance remains an obstacle. One resistance mechanism involves defects in interferon-γ (IFN-γ) signaling, in which IFN-γ is linked to improved responsiveness to ICIs. Herein, the roles of RNA N6-methyladenosine (m6A) modifications in regulation of IFN-γ signaling and the responsiveness to ICIs are unveiled. The m6A-binding protein YTH N6-methyladenosine RNA-binding protein F1 (YTHDF1) is overexpressed in GC tissues, correlating with the suppression of cancer immunity and poorer survival rates. YTHDF1 overexpression impaired the responsiveness to IFN-γ in GC cells, and knockdown studies indicated the redundant effects of YTHDF2 and YTHDF3 with YTHDF1 in IFN-γ responsiveness. RNA immunoprecipitation sequencing revealed YTHDFs directly target interferon regulatory factor 1 (IRF1) mRNA, a master regulator of IFN-γ signaling, leading to reduced RNA stability and consequent downregulation of IFN-γ signaling. Furthermore, in mouse syngeneic tumor models, Ythdf1 depletion in cancer cells resulted in reduced tumor growth and increased tumor-infiltrating lymphocytes, which are attributed to the augmentation of IFN-γ signaling. Collectively, these findings highlight how YTHDFs modulate cancer immunity by influencing IFN-γ signaling through IRF1 regulation, suggesting their viability as therapeutic targets in cancer immunotherapy.
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Affiliation(s)
- Dongjun Jang
- Department of Biomedical SciencesSeoul National University College of MedicineSeoul03080South Korea
| | - Chanwoong Hwa
- L‐HOPE Program for Community‐Based Total Learning Health SystemsKorea UniversitySeoul02841South Korea
- Department of Integrated Biomedical and Life ScienceKorea UniversitySeoul02841South Korea
| | - Seoyeon Kim
- L‐HOPE Program for Community‐Based Total Learning Health SystemsKorea UniversitySeoul02841South Korea
- Department of Integrated Biomedical and Life ScienceKorea UniversitySeoul02841South Korea
| | - Jaeik Oh
- Department of Translational MedicineSeoul National University College of MedicineSeoul03080South Korea
| | - Seungjae Shin
- Department of Biomedical SciencesSeoul National University College of MedicineSeoul03080South Korea
| | - Soo‐Jin Lee
- Department of Biomedical SciencesSeoul National University College of MedicineSeoul03080South Korea
| | - Jiwon Kim
- Department of Biomedical SciencesSeoul National University College of MedicineSeoul03080South Korea
| | - Sang Eun Lee
- Department of Biomedical SciencesSeoul National University College of MedicineSeoul03080South Korea
| | - Yoojin Yang
- Department of Biomedical SciencesSeoul National University College of MedicineSeoul03080South Korea
| | - Dohee Kim
- Department of Biomedical SciencesSeoul National University College of MedicineSeoul03080South Korea
| | - Seoho Lee
- Department of Biomedical SciencesSeoul National University College of MedicineSeoul03080South Korea
| | - Hae Rim Jung
- Medical Research Center, Genomic Medicine InstituteSeoul National University College of MedicineSeoul03080South Korea
| | - Yumi Oh
- Medical Research Center, Genomic Medicine InstituteSeoul National University College of MedicineSeoul03080South Korea
| | - Kyunggon Kim
- Department of Biomedical SciencesUniversity of Ulsan College of MedicineSeoul05505South Korea
| | - Hye Seung Lee
- Department of PathologySeoul National University College of MedicineSeoul03080South Korea
- Cancer Research InstituteSeoul National UniversitySeoul03080South Korea
| | - Joon‐Yong An
- L‐HOPE Program for Community‐Based Total Learning Health SystemsKorea UniversitySeoul02841South Korea
- Department of Integrated Biomedical and Life ScienceKorea UniversitySeoul02841South Korea
- School of Biosystem and Biomedical ScienceCollege of Health ScienceKorea UniversitySeoul02841South Korea
| | - Sung‐Yup Cho
- Department of Biomedical SciencesSeoul National University College of MedicineSeoul03080South Korea
- Department of Translational MedicineSeoul National University College of MedicineSeoul03080South Korea
- Medical Research Center, Genomic Medicine InstituteSeoul National University College of MedicineSeoul03080South Korea
- Cancer Research InstituteSeoul National UniversitySeoul03080South Korea
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Kahiye M, Yahaya J, Kalungi S, Nalwoga H. HER2 immunohistochemical expression and its association with clinicopathological features of gastric adenocarcinoma in Uganda. Turk J Surg 2024; 40:328-335. [PMID: 39980649 PMCID: PMC11831991 DOI: 10.47717/turkjsurg.2024.6501] [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: 06/28/2024] [Accepted: 12/04/2024] [Indexed: 02/22/2025]
Abstract
Objectives Despite the remarkable improvement in gastric adenocarcinoma treatment modalities, the prognosis of gastric adenocarcinoma remains poor. The purpose of this study was to determine the prevalence of HER2 immunohistochemical expression and its association with clinicopathological features of patients with gastric adenocarcinoma. Material and Methods This was a cross-sectional study which was conducted at the department of pathology. A total of 86 formalin fixed paraffin embedded tissue blocks of the patients who were confirmed histologically with gastric adenocarcinoma from January 2009 to December 2019 were included in the analysis. Laboratory requisition form and patients' files were used to extract the clinical and pathological data of the cases. Immunohistochemistry to assess HER2 overexpression was done using monoclonal (SP3 clone) rabbit anti-HER2/neu (Thermo Fisher Scientific-USA). Chi-square statistical test was used to determine the association of the clinicopathological characteristics with HER2 expression. P <0.05 was considered statistically significant. Results Mean age of the patients included in the study was 58.5 ± 14.3 years, and over half 54.7% (n= 47) of the patients were males. Poorly cohesive non-signet ring types contributed most (47.7%) (n= 41) of the cases, and diffuse/mixed histological subtypes were more prevalent (57%) (n= 49) subtypes. Poorly differentiated cases accounted for the majority (66.3%) (n= 57) of the cases. The prevalence of HER2 immunohistochemical expression was 8.1% (n= 7). None of the clinicopathological characteristics were associated with HER2 expression. Conclusion This study has shown almost every one in 10 patients with gastric adenocarcinoma may express HER2 when using immunohistochemistry test. However, the HER2 in this study was not associated with age, sex, tumor location, the nature of biopsy, histological subtypes, and tumor grade.
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Affiliation(s)
- Mohamed Kahiye
- Department of Pathology, Sahan Pathology Laboratories, Mogadishu, Somalia
| | - James Yahaya
- Department of Pathology, Soroti University Faculty of Medicine, Soroti, Uganda
| | - Sam Kalungi
- Department of Pathology, Mulago National Referral Hospital, Kampala, Uganda
| | - Hawa Nalwoga
- Department of Pathology, Makerere College of Health Sciences, Kampala, Uganda
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Rehman ZU, Ahmad Fauzi MF, Wan Ahmad WSHM, Abas FS, Cheah PL, Chiew SF, Looi LM. Computational approach for counting of SISH amplification signals for HER2 status assessment. PeerJ Comput Sci 2024; 10:e2373. [PMID: 39650490 PMCID: PMC11623010 DOI: 10.7717/peerj-cs.2373] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2024] [Accepted: 09/09/2024] [Indexed: 12/11/2024]
Abstract
The human epidermal growth factor receptor 2 (HER2) gene is a critical biomarker for determining amplification status and targeting clinical therapies in breast cancer treatment. This study introduces a computer-aided method that automatically measures and scores HER2 gene status from invasive tissue regions of breast cancer using whole slide images (WSI) through silver in situ hybridization (SISH) staining. Image processing and deep learning techniques are employed to isolate untruncated and non-overlapping single nuclei from cancer regions. The Stardist deep learning model is fine-tuned on our HER2-SISH data to identify nuclei regions, followed by post-processing based on identified HER2 and CEP17 signals. Conventional thresholding techniques are used to segment HER2 and CEP17 signals. HER2 amplification status is determined by calculating the HER2-to-CEP17 signal ratio, in accordance with ASCO/CAP 2018 standards. The proposed method significantly reduces the effort and time required for quantification. Experimental results demonstrate a 0.91% correlation coefficient between pathologists manual enumeration and the proposed automatic SISH quantification approach. A one-sided paired t-test confirmed that the differences between the outcomes of the proposed method and the reference standard are statistically insignificant, with p-values exceeding 0.05. This study illustrates how deep learning can effectively automate HER2 status determination, demonstrating improvements over current manual methods and offering a robust, reproducible alternative for clinical practice.
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Affiliation(s)
- Zaka Ur Rehman
- Faculty of Engineering, Multimedia University, Cyberjaya, Selangor, Malaysia
| | | | - Wan Siti Halimatul Munirah Wan Ahmad
- Faculty of Engineering, Multimedia University, Cyberjaya, Selangor, Malaysia
- Institute for Research, Development and Innovation, International Medical University, Bukit Jalil, Kuala Lumpur, Malaysia
| | - Fazly Salleh Abas
- Faculty of Engineering and Technology, Multimedia University, Ayer Keroh, Malacca, Malaysia
| | - Phaik Leng Cheah
- Department of Pathology, University Malaya Medical Center, Kuala Lumpur, Malaysia
| | - Seow Fan Chiew
- Department of Pathology, University Malaya Medical Center, Kuala Lumpur, Malaysia
| | - Lai-Meng Looi
- Department of Pathology, University Malaya Medical Center, Kuala Lumpur, Malaysia
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6
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Kővári B, Carneiro F, Lauwers GY. Epithelial tumours of the stomach. MORSON AND DAWSON'S GASTROINTESTINAL PATHOLOGY 2024:227-286. [DOI: 10.1002/9781119423195.ch13] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Sekmek S, Karahan I, Ucar G, Ceylan F, Bayram D, Seven I, Bölek H, Ürün Y, Yücel KB, Yazici O, Kadioglu A, Karacin C, Canaslan K, Atag E, Demirer S, Erdem GU, Ergun Y, Atak M, Koksal B, Kiran MM, Turkay DO, Civelek B, Yalcin B, Uncu D. Effect of HER2/CEP17 ratio on survival in metastatic HER2-positive gastric cancer, multicenter study. Clin Transl Oncol 2024; 26:1878-1885. [PMID: 38451412 DOI: 10.1007/s12094-024-03410-x] [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: 01/24/2024] [Accepted: 02/12/2024] [Indexed: 03/08/2024]
Abstract
AIM HER2-positive metastatic gastric cancer is still a highly fatal disease despite advances. We aimed to investigate the relationship between HER2/CEP17 ratio and survival in patients with HER2-positive metastatic gastric cancer. METHODS A total of 99 patients from 8 different centers in Turkey were included in the study. Patients with HER2-positive metastatic gastric cancer and whose HER2/CEP17 ratio was examined were included in the study. Patients were divided into two groups according to HER2/CEP17 values, and survival analysis was performed. RESULTS The median age was 64 (24-83) years. There were 74 (74.8%) male and 25 (25.2%) female patients. OS in the high HER2/CEP17 ratio group was 21.97 months (95% CI: 16.36-27.58), and in the low ratio group was 16.17 months (95% CI: 10.95-21.38) (p = 0.015). OS was 17.7 months (95% CI: 7.02-28.37) in the high HER2 gene copy number group and 10.13 months (5.55-14.71) in the group with low copy number (p = 0.03). PFS was 10.94 months (95% CI: 7.55-14.33) in the group with high HER2 gene copy number and 7.56 months (4.62-10.49) in the low copy number group (p = 0.06). CONCLUSION Patients with both high HER2 gene amplification and high HER2/CEP17 ratio had better OS. The PFS of the group with high HER2 gene amplification was also better. To our knowledge, this is the first study in the literature showing that the HER2/CEP17 ratio affects survival in patients with metastatic gastric cancer.
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Affiliation(s)
- Serhat Sekmek
- Department of Medical Oncology, Ankara City Hospital, Ankara, Turkey.
| | - Irfan Karahan
- Department of Medical Oncology, Ankara City Hospital, Ankara, Turkey
| | - Gokhan Ucar
- Department of Medical Oncology, Ankara City Hospital, Ankara, Turkey
| | - Furkan Ceylan
- Department of Medical Oncology, Ankara City Hospital, Ankara, Turkey
| | - Dogan Bayram
- Department of Medical Oncology, Ankara City Hospital, Ankara, Turkey
| | - Ismet Seven
- Department of Medical Oncology, Ankara City Hospital, Ankara, Turkey
| | - Hatice Bölek
- Department of Medical Oncology, Ankara University, Ankara, Turkey
| | - Yüksel Ürün
- Department of Medical Oncology, Ankara University, Ankara, Turkey
| | | | - Ozan Yazici
- Department of Medical Oncology, Gazi University, Ankara, Turkey
| | - Ahmet Kadioglu
- Department of Medical Oncology, UHS Dr Abdurrahman Yurtaslan Ankara Oncology Training and Research Hospital, Ankara, Turkey
| | - Cengiz Karacin
- Department of Medical Oncology, UHS Dr Abdurrahman Yurtaslan Ankara Oncology Training and Research Hospital, Ankara, Turkey
| | - Kubra Canaslan
- Department of Medical Oncology, Dokuz Eylul University, Izmir, Turkey
| | - Elif Atag
- Department of Medical Oncology, Dokuz Eylul University, Izmir, Turkey
| | - Serhat Demirer
- Department of Medical Oncology, İstanbul Basaksehir Cam and Sakura City Hospital, Istanbul, Turkey
| | - Gokmen Umut Erdem
- Department of Medical Oncology, İstanbul Basaksehir Cam and Sakura City Hospital, Istanbul, Turkey
| | - Yakup Ergun
- Department of Medical Oncology, Antalya City Hospital, Antalya, Turkey
| | - Mehmetcan Atak
- Department of Medical Oncology, Ankara Etlik City Hospital, Ankara, Turkey
| | - Baris Koksal
- Department of Medical Oncology, Hacettepe University, Ankara, Turkey
| | | | | | - Burak Civelek
- Department of Medical Oncology, Ankara City Hospital, Ankara, Turkey
| | - Bulent Yalcin
- Department of Medical Oncology, Ankara City Hospital, Ankara, Turkey
| | - Dogan Uncu
- Department of Medical Oncology, Ankara City Hospital, Ankara, Turkey
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8
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Zhang H, Finkelman BS, Ettel MG, Velez MJ, Turner BM, Hicks DG. HER2 evaluation for clinical decision making in human solid tumours: pearls and pitfalls. Histopathology 2024; 85:3-19. [PMID: 38443321 DOI: 10.1111/his.15170] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2023] [Revised: 01/23/2024] [Accepted: 02/17/2024] [Indexed: 03/07/2024]
Abstract
The significant clinical benefits of human epidermal growth factor receptor 2 (HER2)-targeted therapeutic agents have revolutionized the clinical treatment landscape in a variety of human solid tumours. Accordingly, accurate evaluation of HER2 status in these different tumour types is critical for clinical decision making to select appropriate patients who may benefit from life-saving HER2-targeted therapies. HER2 biomarker scoring criteria is different in different organ systems, and close adherence to the corresponding HER2 biomarker testing guidelines and their updates, if available, is essential for accurate evaluation. In addition, knowing the unusual patterns of HER2 expression is also important to avoid inaccurate evaluation. In this review, we discuss the key considerations when evaluating HER2 status in solid tumours for clinical decision making, including tissue handling and preparation for HER2 biomarker testing, as well as pathologist's readout of HER2 testing results in breast carcinomas, gastroesophageal adenocarcinomas, colorectal adenocarcinomas, gynaecologic carcinomas, and non-small cell lung carcinomas.
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Affiliation(s)
- Huina Zhang
- Department of Pathology, University of Rochester Medical Center, Rochester, NY, USA
| | - Brian S Finkelman
- Department of Pathology, University of Rochester Medical Center, Rochester, NY, USA
| | - Mark G Ettel
- Department of Pathology, University of Rochester Medical Center, Rochester, NY, USA
| | - Moises J Velez
- Department of Pathology, University of Rochester Medical Center, Rochester, NY, USA
| | - Bradley M Turner
- Department of Pathology, University of Rochester Medical Center, Rochester, NY, USA
| | - David G Hicks
- Department of Pathology, University of Rochester Medical Center, Rochester, NY, USA
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Andronic M, Scripcariu DV, Palaghia MM, Trofin AM, Bejan V, Scripcariu V. Clinical Pathological and Immunohistochemical Correlations in Gastric Cancer. Diagnostics (Basel) 2024; 14:1367. [PMID: 39001256 PMCID: PMC11241519 DOI: 10.3390/diagnostics14131367] [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: 05/03/2024] [Revised: 06/13/2024] [Accepted: 06/26/2024] [Indexed: 07/16/2024] Open
Abstract
Due to its high aggressiveness and polyclonal tumor state, stomach cancer is considered a severe health problem. In this study, we analyzed Her2 and Ki67 in correlation with patient data for the possibility of prognostic factors. The study included 48 cases of gastric tumors that had been surgically treated in a period of five years. The percentage was statistically significant for intestinal-type adenocarcinomas located in the medio-gastric region (p = 0.05); in the diffuse subtype, there were no Her2 positive samples, and in the mixed subtype only one out of three samples was Her2 positive. Our results confirm the existing data, and we can conclude that this link can be considered a prognostic factor in the progression and treatment effectiveness.
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Affiliation(s)
- Mihaela Andronic
- First Surgical Clinic, Saint Spiridon Clinical Hospital, 700111 Iași, Romania
| | - Dragoș-Viorel Scripcariu
- Surgery Department, Regional Institute of Oncology Iași, 700483 Iasi, Romania (V.S.)
- Faculty of Medicine, University of Medicine and Farmacy “Grigore. T. Popa” Iasi, 700115 Iasi, Romania;
| | - Mădălina Maria Palaghia
- First Surgical Clinic, Saint Spiridon Clinical Hospital, 700111 Iași, Romania
- Faculty of Medicine, University of Medicine and Farmacy “Grigore. T. Popa” Iasi, 700115 Iasi, Romania;
| | - Ana-Maria Trofin
- Faculty of Medicine, University of Medicine and Farmacy “Grigore. T. Popa” Iasi, 700115 Iasi, Romania;
- Second Surgical Clinic, Saint Spiridon Clinical Hospital, 700111 Iași, Romania
| | - Valentin Bejan
- First Surgical Clinic, Saint Spiridon Clinical Hospital, 700111 Iași, Romania
- Faculty of Medicine, University of Medicine and Farmacy “Grigore. T. Popa” Iasi, 700115 Iasi, Romania;
| | - Viorel Scripcariu
- Surgery Department, Regional Institute of Oncology Iași, 700483 Iasi, Romania (V.S.)
- Faculty of Medicine, University of Medicine and Farmacy “Grigore. T. Popa” Iasi, 700115 Iasi, Romania;
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10
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Speel EJM, Dafni U, Thunnissen E, Hendrik Rüschoff J, O'Brien C, Kowalski J, Kerr KM, Bubendorf L, Sansano I, Joseph L, Kriegsmann M, Navarro A, Monkhorst K, Bille Madsen L, Hernandez Losa J, Biernat W, Stenzinger A, Rüland A, Hillen LM, Marti N, Molina-Vila MA, Dellaporta T, Kammler R, Peters S, Stahel RA, Finn SP, Radonic T. ROS1 fusions in resected stage I-III adenocarcinoma: Results from the European Thoracic Oncology Platform Lungscape project. Lung Cancer 2024; 194:107860. [PMID: 39002492 DOI: 10.1016/j.lungcan.2024.107860] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2024] [Revised: 06/10/2024] [Accepted: 06/21/2024] [Indexed: 07/15/2024]
Abstract
BACKGROUND ROS1 fusion is a relatively low prevalence (0.6-2.0%) but targetable driver in lung adenocarcinoma (LUAD). Robust and low-cost tests, such as immunohistochemistry (IHC), are desirable to screen for patients potentially harboring this fusion. The aim was to investigate the prevalence of ROS1 fusions in a clinically annotated European stage I-III LUAD cohort using IHC screening with the in vitro diagnostics (IVD)-marked clone SP384, followed by confirmatory molecular analysis in pre-defined subsets. METHODS Resected LUADs constructed in tissue microarrays, were immunostained for ROS1 expression using SP384 clone in a ready-to-use kit and Ventana immunostainers. After external quality control, analysis was performed by trained pathologists. Staining intensity of at least 2+ (any percentage of tumor cells) was considered IHC positive (ROS1 IHC + ). Subsequently, ROS1 IHC + cases were 1:1:1 matched with IHC0 and IHC1 + cases and subjected to orthogonal ROS1 FISH and RNA-based testing. RESULTS The prevalence of positive ROS1 expression (ROS1 IHC + ), defined as IHC 2+/3+, was 4 % (35 of 866 LUADs). Twenty-eight ROS1 IHC + cases were analyzed by FISH/RNA-based testing, with only two harboring a confirmed ROS1 gene fusion, corresponding to a lower limit for the prevalence of ROS1 gene fusion of 0.23 %. They represent a 7 % probability of identifying a fusion among ROS1 IHC + cases. Both confirmed cases were among the only four with sufficient material and H-score ≥ 200, leading to a 50 % probability of identifying a ROS1 gene fusion in cases with an H-score considered strongly positive. All matched ROS1 IHC- (IHC0 and IHC1 + ) cases were also found negative by FISH/RNA-based testing, leading to a 100 % probability of lack of ROS1 fusion for ROS1 IHC- cases. CONCLUSIONS The prevalence of ROS1 fusion in an LUAD stage I-III European cohort was relatively low. ROS1 IHC using SP384 clone is useful for exclusion of ROS1 gene fusion negative cases.
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Affiliation(s)
- Ernst-Jan M Speel
- Department of Pathology, GROW-School for Oncology and Reproduction, Maastricht University Medical Center, MUMC+ Maastricht, Netherlands & Department of Pathology, Erasmus Medical Center, Rotterdam, Netherlands
| | - Urania Dafni
- ETOP IBCSG Partners Foundation, ETOP Statistical Center, Frontier Science Foundation-Hellas & National and Kapodistrian University of Athens, Athens, Greece
| | - Erik Thunnissen
- Department of Pathology, Amsterdam University Medical Centre, location VUmc, Cancer Center Amsterdam, Amsterdam, Netherlands
| | | | - Cathal O'Brien
- Department of Histopathology, St James's Hospital and Trinity College, Dublin, Ireland
| | - Jacek Kowalski
- Pathomorphology Department, Medical University of Gdansk, Gdansk, Poland
| | - Keith M Kerr
- Department of Pathology, Aberdeen Royal Infirmary - NHS Grampian, Aberdeen, United Kingdom
| | - Lukas Bubendorf
- Institute of Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland
| | - Irene Sansano
- Department of Pathology, Vall d'Hebron University Hospital, Barcelona, Spain
| | - Leena Joseph
- Department of Pathology, Lung Cancer Group Manchester, Manchester, United Kingdom
| | - Mark Kriegsmann
- Department of Histopathology, University Hospital Heidelberg, Germany
| | - Atilio Navarro
- Department of Pathology, Hospital General Universitario de Valencia, Valencia, Spain
| | - Kim Monkhorst
- Pathology Department, NKI-AVL - Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Amsterdam, Netherlands
| | | | | | - Wojciech Biernat
- Pathomorphology Department, Medical University of Gdansk, Gdansk, Poland
| | | | - Andrea Rüland
- Department of Pathology, GROW-School for Oncology and Reproduction, Maastricht University Medical Center, MUMC+ Maastricht, Netherlands & Department of Pathology, Erasmus Medical Center, Rotterdam, Netherlands
| | - Lisa M Hillen
- Department of Pathology, GROW-School for Oncology and Reproduction, Maastricht University Medical Center, MUMC+ Maastricht, Netherlands & Department of Pathology, Erasmus Medical Center, Rotterdam, Netherlands
| | - Nesa Marti
- Translational Research Coordination, ETOP IBCSG Partners Foundation, Bern, Switzerland
| | - Miguel A Molina-Vila
- Laboratory of Oncology, Pangaea Oncology, Dexeus University Hospital, Barcelona, Spain
| | - Tereza Dellaporta
- ETOP Statistical Center, Frontier Science Foundation-Hellas, Athens, Greece
| | - Roswitha Kammler
- Translational Research Coordination, ETOP IBCSG Partners Foundation, Bern, Switzerland
| | - Solange Peters
- Oncology Department, CHUV - Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
| | - Rolf A Stahel
- President, ETOP IBCSG Partners Foundation, Bern, Switzerland.
| | - Stephen P Finn
- Department of Histopathology, St James's Hospital and Trinity College, Dublin, Ireland
| | - Teodora Radonic
- Department of Pathology, Amsterdam University Medical Centre, location VUmc, Cancer Center Amsterdam, Amsterdam, Netherlands
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11
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Scheck MK, Hofheinz RD, Lorenzen S. HER2-Positive Gastric Cancer and Antibody Treatment: State of the Art and Future Developments. Cancers (Basel) 2024; 16:1336. [PMID: 38611014 PMCID: PMC11010911 DOI: 10.3390/cancers16071336] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2024] [Revised: 03/22/2024] [Accepted: 03/25/2024] [Indexed: 04/14/2024] Open
Abstract
Despite a decreasing incidence in Western countries, gastric cancer is among the most common cancer subtypes globally and is associated with one of the highest tumor-related mortality rates. Biomarkers play an increasing role in the treatment against gastric cancer. HER2 was one of the first biomarkers that found its way into clinical practice. Since the ToGA trial, trastuzumab has been part of first-line palliative chemotherapy in metastatic or unresectable gastric cancer. HER2-targeting agents, such as the tyrosine kinase inhibitor lapatinib, the antibody drug conjugate (ADC) trastuzumab-emtansine or dual HER2 inhibition (pertuzumab and trastuzumab), have been investigated in the second-line setting but led to negative study results. More recently, the ADC trastuzumab-deruxtecan was authorized after the failure of trastuzumab-based treatment. However, further improvements in HER2-directed therapy are required as resistance mechanisms and HER2 heterogeneity limit the existing treatment options. This review aims to give an overview of the current standard-of-care HER2-directed therapy in gastric cancer, as well as its challenges and future developments.
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Affiliation(s)
- Magdalena K. Scheck
- Klinik und Poliklinik für Innere Medizin III, Klinikum rechts der Isar der TU München, 81675 Munich, Germany;
| | - Ralf D. Hofheinz
- Mannheim Cancer Center, Universitätsklinikum Mannheim, 68167 Mannheim, Germany;
| | - Sylvie Lorenzen
- Klinik und Poliklinik für Innere Medizin III, Klinikum rechts der Isar der TU München, 81675 Munich, Germany;
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12
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Eren OC, Mericoz CA, Bozkurtlar E, Bulutay P, Baygul A, Kulac I. Novel ALK immunohistochemistry assay (clone OTI1A4, Dako) is a sensitive, reliable marker for identifying ALK rearrangements in lung adenocarcinomas: A validation study. Am J Clin Pathol 2024; 161:71-82. [PMID: 37681660 PMCID: PMC10765139 DOI: 10.1093/ajcp/aqad111] [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: 06/24/2023] [Accepted: 08/04/2023] [Indexed: 09/09/2023] Open
Abstract
OBJECTIVES We present the first study validating the recent Dako ALK assay (clone OTI1A4, in vitro diagnostic) for detecting ALK rearrangements in lung adenocarcinoma. METHODS Lung adenocarcinoma cases between 2011 and 2023 were retrospectively collected to create a cohort of 203 samples. Cases were stained with Dako ALK OTI1A4 and Ventana ALK D5F3 and reviewed by 3 pathologists independently. Correlation between assays, including their sensitivity and specificity, was evaluated. RESULTS The cohort (n = 203) consisted of resections, core needle biopsies, and cell blocks. Agreement between Dako ALK OTI1A4 and Ventana ALK D5F3 assays was "almost perfect," with κ = 0.89. The sensitivity and specificity of the Dako ALK OTI1A4 assay were 93.3% and 96%, respectively, in a subgroup of 55 molecularly confirmed cases (n = 30 with and n = 25 without ALK rearrangement). CONCLUSIONS Immunohistochemistry-based assays provide a valid and reasonably priced alternative, especially in settings where molecular confirmatory tests are neither offered nor accessible. Given high interassay and molecular concordance, we propose that the novel Dako OTI1A4 assay can be reliably used to identify cases with ALK rearrangement.
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Affiliation(s)
- Ozgur Can Eren
- Department of Pathology, Koç University School of Medicine, Istanbul, Turkey
- Department of Immunology, Graduate School of Health Sciences, Koç University, Istanbul, Turkey
- Koç University IsBank Research Center for Infectious Diseases, Istanbul, Turkey
| | - Cisel Aydin Mericoz
- Department of Pathology, Koç University School of Medicine, Istanbul, Turkey
| | - Emine Bozkurtlar
- Department of Pathology, Marmara University School of Medicine, Istanbul, Turkey
| | - Pinar Bulutay
- Department of Pathology, Koç University School of Medicine, Istanbul, Turkey
| | - Arzu Baygul
- Department of Biostatistics, Koç University School of Medicine, Istanbul, Turkey
| | - Ibrahim Kulac
- Department of Pathology, Koç University School of Medicine, Istanbul, Turkey
- Research Center for Translational Medicine, Koç University, Istanbul, Turkey
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13
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Estephan F, Lap CJ, Banagan J, Antonio M, Liu S, Diao G, Rozalen AZ, Rajendran R, Krasnow S, Subrahmanyam R, Nava VE, Jain M. The prevalence and clinical significance of HER2 expression in prostate adenocarcinoma. Ann Diagn Pathol 2023; 67:152219. [PMID: 38622987 DOI: 10.1016/j.anndiagpath.2023.152219] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2023] [Revised: 10/17/2023] [Accepted: 10/18/2023] [Indexed: 04/17/2024]
Abstract
AIMS Abnormalities in HER2 are well-established oncogenic drivers and are approved therapeutic targets in various malignancies. Prior studies evaluating HER2 expression in prostate cancer (PCa) have yielded variable results. Most of these studies used immunohistochemistry scoring systems based on breast cancer data. The goal of this study was to determine the prevalence and clinical significance of HER2 expression using a scoring system that better reflects the HER2 staining pattern observed in PCa. METHODS We randomly selected similar numbers of localized low risk (AJCC stage I), locally advanced (AJCC stages II & III), and metastatic (AJCC stage IV) PCa patients treated at the DC VA Medical Center between 2000 and 2022. Among them, we included patients who had sufficient PCa tissue samples and clinical information required for this analysis. Two experienced pathologists independently scored HER2 expression (Ventana Pathway anti-HER2) according to a modified gastric cancer HER2 scoring system. RESULTS Out of the 231 patients included, 85 % self-identified as Black. 58.9 % of patients expressed HER2 (1+: 35.5 %; 2+: 18.2 %; 3+: 5.2 %). Validity of the results was confirmed using the HercepTest antibody. Higher HER2 expression was associated with a higher Gleason Score/Grade Group and advanced disease. CONCLUSIONS Our findings support the adverse prognostic impact on HER2 in PCa. We propose the use of a modified scoring system to evaluate HER2 expression in PCa. The observed high prevalence of HER2 expression supports the consideration of novel HER2-targeted therapies addressing even low levels of HER2 expression in future PCa trials.
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Affiliation(s)
- Fayez Estephan
- The George Washington University School of Medicine and Health Sciences, Washington, DC, USA; The Edward P. Evans Precision Oncology Center of Excellence, Washington DC VA Medical Center, Washington, DC, USA
| | - Coen J Lap
- The George Washington University School of Medicine and Health Sciences, Washington, DC, USA; The Edward P. Evans Precision Oncology Center of Excellence, Washington DC VA Medical Center, Washington, DC, USA
| | - Jeff Banagan
- Institute for Clinical Research, Washington, DC, USA
| | | | - Shanshan Liu
- Department of Biostatistics and Bioinformatics, Milken Institute School of Public Health, Washington, DC, USA
| | - Guoqing Diao
- Department of Biostatistics and Bioinformatics, Milken Institute School of Public Health, Washington, DC, USA
| | - Alexandra Zara Rozalen
- The Edward P. Evans Precision Oncology Center of Excellence, Washington DC VA Medical Center, Washington, DC, USA
| | | | - Steven Krasnow
- The Edward P. Evans Precision Oncology Center of Excellence, Washington DC VA Medical Center, Washington, DC, USA
| | - Ramesh Subrahmanyam
- The Edward P. Evans Precision Oncology Center of Excellence, Washington DC VA Medical Center, Washington, DC, USA
| | - Victor E Nava
- The George Washington University School of Medicine and Health Sciences, Washington, DC, USA; The Edward P. Evans Precision Oncology Center of Excellence, Washington DC VA Medical Center, Washington, DC, USA
| | - Maneesh Jain
- The George Washington University School of Medicine and Health Sciences, Washington, DC, USA; The Edward P. Evans Precision Oncology Center of Excellence, Washington DC VA Medical Center, Washington, DC, USA.
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14
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Hechtman JF. Her2 low (but not negative): the newest biomarker on the block for gastro-oesophageal adenocarcinoma. J Clin Pathol 2023; 76:813-814. [PMID: 37679032 DOI: 10.1136/jcp-2023-209088] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2023] [Accepted: 08/23/2023] [Indexed: 09/09/2023]
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15
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Taieb J, Bennouna J, Penault-Llorca F, Basile D, Samalin E, Zaanan A. Treatment of gastric adenocarcinoma: A rapidly evolving landscape. Eur J Cancer 2023; 195:113370. [PMID: 37948843 DOI: 10.1016/j.ejca.2023.113370] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Revised: 09/11/2023] [Accepted: 09/26/2023] [Indexed: 11/12/2023]
Abstract
Gastric adenocarcinoma (GC) and gastroesophageal junction adenocarcinoma represent frequent and severe diseases whose management has radically changed over the last 10 years. With the advent of second- and third-line standard therapies for metastatic GC patients in the 2010s, the molecular dismemberment of the disease and positive trials with immunotherapy and targeted agents will mark the 2020s. New treatment options have emerged in the neoadjuvant, adjuvant, and metastatic setting. In addition to improved multimodal treatment in operable patients, new subgroups have emerged depending on molecular alterations (HER2, Microsatellite instability) or expression of specific proteins in the tumour (PDL1, Claudin 18.2) making immunohistochemistry central in profiling the tumour for an optimal individualised management. The aim of this review is to describe the current standards of management of early and late stage GC and the molecular markers needed today to optimally manage our patients together with future perspectives on this disease.
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Affiliation(s)
- Julien Taieb
- Department of Gastroenterology and Digestive Oncology, Hôpital Européen Georges Pompidou, AP-HP, Paris, France; Institut du Cancer Paris CARPEM, Université Paris Cité, Paris, Hôpital Européen Georges Pompidou, Department of Tumor and Cancer Genomic Medicine, Paris, France.
| | - Jaafar Bennouna
- Department of Medical Oncology, Hopital Foch, Suresnes, France
| | | | - Debora Basile
- Department of Medical Oncology, San Giovanni di Dio Hospital, Crotone, Italy
| | - Emmanuelle Samalin
- Department of Medical Oncology, Institut du Cancer de Montpellier, Univ. Montpellier (ICM), Montpellier, France
| | - Aziz Zaanan
- Department of Gastroenterology and Digestive Oncology, Hôpital Européen Georges Pompidou, AP-HP, Paris, France; Institut du Cancer Paris CARPEM, Université Paris Cité, Paris, Hôpital Européen Georges Pompidou, Department of Tumor and Cancer Genomic Medicine, Paris, France
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16
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Skórzewska M, Gęca K, Polkowski WP. A Clinical Viewpoint on the Use of Targeted Therapy in Advanced Gastric Cancer. Cancers (Basel) 2023; 15:5490. [PMID: 38001751 PMCID: PMC10670421 DOI: 10.3390/cancers15225490] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2023] [Revised: 11/05/2023] [Accepted: 11/17/2023] [Indexed: 11/26/2023] Open
Abstract
The development of therapies for advanced gastric cancer (GC) has made significant progress over the past few years. The identification of new molecules and molecular targets is expanding our understanding of the disease's intricate nature. The end of the classical oncology era, which relied on well-studied chemotherapeutic agents, is giving rise to novel and unexplored challenges, which will cause a significant transformation of the current oncological knowledge in the next few years. The integration of established clinically effective regimens in additional studies will be crucial in managing these innovative aspects of GC. This study aims to present an in-depth and comprehensive review of the clinical advancements in targeted therapy and immunotherapy for advanced GC.
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17
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Schirizzi A, Arshadi A, Tolomeo D, Schirosi L, Valentini AM, De Leonardis G, Refolo MG, Donghia R, Storlazzi CT, Zito A, Ricci AD, Vallarelli S, Ostuni C, Bencivenga M, De Manzoni G, Messa C, Armentano R, Giannelli G, Lotesoriere C, D’Alessandro R. VEGFA Status as a Predictive Marker of Therapy Outcome in Metastatic Gastric Cancer Patients Following Ramucirumab-Based Treatment. Biomedicines 2023; 11:2721. [PMID: 37893095 PMCID: PMC10603940 DOI: 10.3390/biomedicines11102721] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2023] [Revised: 10/03/2023] [Accepted: 10/05/2023] [Indexed: 10/29/2023] Open
Abstract
Metastatic gastric cancer (mGC) often has a poor prognosis and may benefit from a few targeted therapies. Ramucirumab-based anti-angiogenic therapy targeting the VEGFR2 represents a milestone in the second-line treatment of mGC. Several studies on different cancers are focusing on the major VEGFR2 ligand status, meaning VEGFA gene copy number and protein overexpression, as a prognostic marker and predictor of response to anti-angiogenic therapy. Following this insight, our study aims to examine the role of VEGFA status as a predictive biomarker for the outcome of second-line therapy with Ramucirumab and paclitaxel in mGC patients. To this purpose, the copy number of the VEGFA gene, by fluorescence in situ hybridization experiments, and its expression in tumor tissue as well as the density of micro-vessels, by immunohistochemistry experiments, were assessed in samples derived from mGC patients. This analysis found that amplification of VEGFA concomitantly with VEGFA overexpression and overexpression of VEGFA with micro-vessels density are more represented in patients showing disease control during treatment with Ramucirumab. In addition, in the analyzed series, it was found that amplification was not always associated with overexpression of VEGFA, but overexpression of VEGFA correlates with high micro-vessel density. In conclusion, overexpression of VEGFA could emerge as a potential biomarker to predict the response to anti-angiogenic therapy.
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Affiliation(s)
- Annalisa Schirizzi
- Laboratory of Experimental Oncology, National Institute of Gastroenterology, IRCCS “S. de Bellis” Research Hospital, 70013 Castellana Grotte, Italy; (A.S.); (G.D.L.); (C.M.)
| | - Aram Arshadi
- Department of Biosciences, Biotechnology and Environment, University of Bari Aldo Moro, 70125 Bari, Italy; (A.A.); (D.T.); (C.T.S.)
| | - Doron Tolomeo
- Department of Biosciences, Biotechnology and Environment, University of Bari Aldo Moro, 70125 Bari, Italy; (A.A.); (D.T.); (C.T.S.)
| | - Laura Schirosi
- Pathology Department, IRCCS Istituto Tumori “Giovanni Paolo II”, 70124 Bari, Italy; (L.S.); (A.Z.)
| | - Anna Maria Valentini
- Histopathology Unit, National Institute of Gastroenterology, IRCCS “S. de Bellis” Research Hospital, 70013 Castellana Grotte, Italy; (A.M.V.); (R.A.)
| | - Giampiero De Leonardis
- Laboratory of Experimental Oncology, National Institute of Gastroenterology, IRCCS “S. de Bellis” Research Hospital, 70013 Castellana Grotte, Italy; (A.S.); (G.D.L.); (C.M.)
| | - Maria Grazia Refolo
- Clinical Pathology Unit, National Institute of Gastroenterology, IRCCS “S. de Bellis” Research Hospital, 70013 Castellana Grotte, Italy;
| | - Rossella Donghia
- Data Science Unit, National Institute of Gastroenterology, IRCCS “S. de Bellis” Research Hospital, 70013 Castellana Grotte, Italy;
| | - Clelia Tiziana Storlazzi
- Department of Biosciences, Biotechnology and Environment, University of Bari Aldo Moro, 70125 Bari, Italy; (A.A.); (D.T.); (C.T.S.)
| | - Alfredo Zito
- Pathology Department, IRCCS Istituto Tumori “Giovanni Paolo II”, 70124 Bari, Italy; (L.S.); (A.Z.)
| | - Angela Dalia Ricci
- Medical Oncology Unit, National Institute of Gastroenterology, IRCCS “S. de Bellis” Research Hospital, 70013 Castellana Grotte, Italy; (A.D.R.); (S.V.); (C.O.)
| | - Simona Vallarelli
- Medical Oncology Unit, National Institute of Gastroenterology, IRCCS “S. de Bellis” Research Hospital, 70013 Castellana Grotte, Italy; (A.D.R.); (S.V.); (C.O.)
| | - Carmela Ostuni
- Medical Oncology Unit, National Institute of Gastroenterology, IRCCS “S. de Bellis” Research Hospital, 70013 Castellana Grotte, Italy; (A.D.R.); (S.V.); (C.O.)
| | - Maria Bencivenga
- General and Upper GI Surgery Division, University of Verona, 37126 Verona, Italy; (M.B.); (G.D.M.)
| | - Giovanni De Manzoni
- General and Upper GI Surgery Division, University of Verona, 37126 Verona, Italy; (M.B.); (G.D.M.)
| | - Caterina Messa
- Laboratory of Experimental Oncology, National Institute of Gastroenterology, IRCCS “S. de Bellis” Research Hospital, 70013 Castellana Grotte, Italy; (A.S.); (G.D.L.); (C.M.)
| | - Raffaele Armentano
- Histopathology Unit, National Institute of Gastroenterology, IRCCS “S. de Bellis” Research Hospital, 70013 Castellana Grotte, Italy; (A.M.V.); (R.A.)
| | - Gianluigi Giannelli
- Scientific Direction, National Institute of Gastroenterology, IRCCS “S. de Bellis” Research Hospital, 70013 Castellana Grotte, Italy;
| | - Claudio Lotesoriere
- Medical Oncology Unit, National Institute of Gastroenterology, IRCCS “S. de Bellis” Research Hospital, 70013 Castellana Grotte, Italy; (A.D.R.); (S.V.); (C.O.)
| | - Rosalba D’Alessandro
- Laboratory of Experimental Oncology, National Institute of Gastroenterology, IRCCS “S. de Bellis” Research Hospital, 70013 Castellana Grotte, Italy; (A.S.); (G.D.L.); (C.M.)
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18
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ABOOD RAFIDA, ALOMAR SAAD, ALHAROON SAWSANS. A study of human epidermal growth factor receptor 2 overexpression by immunohistochemistry in patients with gastric adenocarcinoma. J Public Health Afr 2023; 14:2721. [PMID: 37859935 PMCID: PMC10583233 DOI: 10.4081/jphia.2023.2721] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2023] Open
Abstract
Gastric cancer is one of the leading causes of cancer-related deaths across the world and in the Middle East. Human epidermal growth factor receptor 2 (HER2) overexpression has been observed in gastric cancers. Trastuzumab, a recombinant monoclonal antibody targeting HER2 protein, is being used for treatment of metastatic gastric cancer. To study the frequency and association of HER2 overexpression with age, gender, histopathological subtype and grade of differentiation in patients with gastric adenocarcinoma from Basra, Iraq. This cross-sectional single-center study collected demographic (age, gender), histopathological (histological subtype, grade of differentiation) and immunohistochemical (HER2 overexpression status) data from 100 consenting adult patients (male: 56) with histopathologically confirmed gastric adenocarcinoma from samples obtained through endoscopy or surgery. HER2 overexpression (ToGA score 3+) was observed in 6/100 (6%) of patients, with another 6 showing 'equivocal' HER2 expression (2+). Out of 20 patients with moderately differentiated gastric cancer, 4 (20%) showed HER2 overexpression (p=0.008). Other factors considered (age, gender, histological subtype) did not show statistically significant correlation with HER2 overexpression. More females showed HER2 overexpression than males (4 vs. 2), and more patients with intestinal type gastric cancer showed HER2 overexpression than diffuse gastric cancer (5 vs. 1), but the difference was not statistically significant in both variables. HER2 overexpression was 6% in this population; statistically significant correlation was found with histological grade. Statistically non-significant correlations were observed between HER2 overexpression and gender, age, and histological subtype.
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Affiliation(s)
- RAFID A. ABOOD
- Basra College of Medicine
- Basra Oncology and Hematology Center
| | - SAAD ALOMAR
- Basra College of Medicine
- Depatment of Pathology, Al Sadar Teaching Hospital, Iraq
| | - SAWSAN S. ALHAROON
- Basra College of Medicine
- Depatment of Pathology, Al Sadar Teaching Hospital, Iraq
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19
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Selves J, Brunac AC. L’essentiel sur la biopsie gastrique tumorale. Cas no 6. Ann Pathol 2023; 43:394-399. [PMID: 37657987 DOI: 10.1016/j.annpat.2023.06.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Accepted: 06/16/2023] [Indexed: 09/03/2023]
Affiliation(s)
- Janick Selves
- Département d'anatomie et cytologie pathologiques, Institut universitaire du cancer Toulouse, 1, avenue Irène-Joliot-Curie, 31059 Toulouse cedex 9, France.
| | - Anne-Cécile Brunac
- Département d'anatomie et cytologie pathologiques, Institut universitaire du cancer Toulouse, 1, avenue Irène-Joliot-Curie, 31059 Toulouse cedex 9, France
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20
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Xu B, Chen H, Zhang J, Cong Y, Ning L, Chen L, Zhang Y, Zhang Y, Song Z, Meng Y, He L, Liao WL, Lu Y, Zhao F. A comparative study of gastric adenocarcinoma HER2 IHC phenotype and mass spectrometry-based quantification. Front Oncol 2023; 13:1152895. [PMID: 37350943 PMCID: PMC10283037 DOI: 10.3389/fonc.2023.1152895] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2023] [Accepted: 04/10/2023] [Indexed: 06/24/2023] Open
Abstract
Introduction Gastric cancer is a highly heterogeneous malignant tumor of the digestive system. Anti-HER2 treatment can inhibit downstream signaling pathways and improve clinical treatment and outcomes in patients with HER2 protein overexpression. Currently, two standard methods for evaluating HER2 expression status are immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). However, these low-throughput assays often produce discordant or equivocal results. Methods In this study, we presented a new HER2 protein detection method based on mass spectrometry selected reaction monitoring (MS-SRM) and validated the method. We conducted a retrospective study on 118 formalin-fixed paraffin-embedded (FFPE) tissues from patients with advanced gastric adenocarcinoma in northern China, and we compared the MS-SRM results with those from IHC and correlated them with FISH. Results We established and validated the upper and lower detection limits (300-700 amol/μg) for abnormal HER2 protein expression in advanced gastric cancer. We also found that, among samples with mixed Lauren subtypes, those with a high level of HER2 expression had typical intestinal type features in pathology. Discussion This study demonstrated that the MS-SRM method can overcome the limitations and deficiencies of IHC, directly quantify the expression of HER2 protein in tumor cells and be used as a supplement to IHC. It has the potential to be used as a companion diagnosis for new drugs used to treat advanced gastric cancer. Large-scale clinical validation is required.
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Affiliation(s)
- Bin Xu
- Pathology Department, Fushun Central Hospital, Fushun, Liaoning, China
| | - Hui Chen
- Stomatology Department, Fushun Central Hospital, Fushun, Liaoning, China
| | - Jingjing Zhang
- Technology Department, Tianjin Yunjian Medical Laboratory Co. Ltd., Tianjin, China
| | - Yanghai Cong
- Technology Department, Tianjin Yunjian Medical Laboratory Co. Ltd., Tianjin, China
| | - Li Ning
- Medical Oncology, Fushun Central Hospital, Fushun, Liaoning, China
| | - Limin Chen
- Technology Department, Tianjin Yunjian Medical Laboratory Co. Ltd., Tianjin, China
| | - Yushi Zhang
- Technology Department, Tianjin Yunjian Medical Laboratory Co. Ltd., Tianjin, China
| | - Yong Zhang
- Pathology Department, Liaoning Cancer Hospital & Institute, Shenyang, Liaoning, China
| | - Zhanchun Song
- Circulation Department, Fushun Central Hospital, Fushun, Liaoning, China
| | - Yuan Meng
- Pathology Department, Fushun Central Hospital, Fushun, Liaoning, China
| | - Lianqi He
- Circulation Department, Fushun Central Hospital, Fushun, Liaoning, China
| | - Wei-li Liao
- Research and Development Department, mProbe Inc., Palo Alto, CA, United States
| | - Ying Lu
- Laboratory Medicine, Fushun Central Hospital, Fushun, Liaoning, China
| | - Fengyi Zhao
- Technology Department, Tianjin Yunjian Medical Laboratory Co. Ltd., Tianjin, China
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21
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Pawluczuk E, Łukaszewicz-Zając M, Mroczko B. The Comprehensive Analysis of Specific Proteins as Novel Biomarkers Involved in the Diagnosis and Progression of Gastric Cancer. Int J Mol Sci 2023; 24:ijms24108833. [PMID: 37240178 DOI: 10.3390/ijms24108833] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Revised: 05/12/2023] [Accepted: 05/14/2023] [Indexed: 05/28/2023] Open
Abstract
Gastric cancer (GC) cases are predicted to rise by 2040 to approximately 1.8 million cases, while GC-caused deaths to 1.3 million yearly worldwide. To change this prognosis, there is a need to improve the diagnosis of GC patients because this deadly malignancy is usually detected at an advanced stage. Therefore, new biomarkers of early GC are sorely needed. In the present paper, we summarized and referred to a number of original pieces of research concerning the clinical significance of specific proteins as potential biomarkers for GC in comparison to well-established tumor markers for this malignancy. It has been proved that selected chemokines and their specific receptors, vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR), specific proteins such as interleukin 6 (IL-6) and C-reactive protein (CRP), matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs), a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS), as well as DNA- and RNA-based biomarkers, and c-MET (tyrosine-protein kinase Met) play a role in the pathogenesis of GC. Based on the recent scientific literature, our review indicates that presented specific proteins are potential biomarkers in the diagnosis and progression of GC as well as might be used as prognostic factors of GC patients' survival.
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Affiliation(s)
- Elżbieta Pawluczuk
- Department of Neurodegeneration Diagnostics, Medical University of Bialystok, 15-269 Bialystok, Poland
| | - Marta Łukaszewicz-Zając
- Department of Biochemical Diagnostics, Medical University of Bialystok, Waszyngtona 15a, 15-269 Bialystok, Poland
| | - Barbara Mroczko
- Department of Neurodegeneration Diagnostics, Medical University of Bialystok, 15-269 Bialystok, Poland
- Department of Biochemical Diagnostics, Medical University of Bialystok, Waszyngtona 15a, 15-269 Bialystok, Poland
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Feng W, Inoue R, Kuwata T, Niikura N, Fujii S, Kumaki N, Honda K, Xu LA, Goetz A, Gaule P, Cogswell J, Rimm DL, McGee R. Assessment of the Impact of Alternative Fixatives on HER2 Detection in Breast Cancer and Gastric Cancer Tumor Specimens. Appl Immunohistochem Mol Morphol 2023; 31:339-345. [PMID: 37093713 PMCID: PMC10155692 DOI: 10.1097/pai.0000000000001126] [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: 10/12/2022] [Accepted: 03/22/2023] [Indexed: 04/25/2023]
Abstract
The type of fixative used for preserving tumor specimens can significantly impact the performance of the immunohistochemistry and in situ hybridization assays used for assessing human epidermal growth factor receptor 2 (HER2) status. This study reports the prevalence of the use of alternative fixatives other than the guideline-recommended 10% neutral buffered formalin (NBF) during HER2 testing in a real-world setting. The effects of alternative fixatives [20% NBF and 10% unbuffered formalin (UBF) fixatives] on HER2 testing of breast cancer (BC) and gastric cancer (GC) cell lines and tissues are also assessed. Overall, 117,636 tumor samples received at a central laboratory from >8000 clinical trial sites across 60 countries were reviewed to determine the prevalence of alternative fixative usage. To investigate the impact of alternative fixatives, 27 cell lines (21 BC and 6 GC) and 76 tumor tissue samples (50 BC and 26 GC) were fixed in 10% NBF, 20% NBF, or 10% UBF, and evaluated for HER2 status by immunohistochemistry and in situ hybridization. Real-world data showed that 9195 (7.8%) tumor samples were preserved using an alternative fixative. In cell lines, overall percentage agreement, negative percentage agreement, and positive percentage agreement among the 3 fixatives were 100%. In tumor tissues, the agreement among 10% NBF, 20% NBF, and 10% UBF ranged between 94.7% and 96.6% for negative percentage agreement and 90.9% for overall percentage agreement compared with a range of 58.3% to 66.7% for positive percentage agreement. These results suggest that alternative fixatives may have the potential to convert HER2 status in tissues from positive to negative.
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Affiliation(s)
- Wenqin Feng
- Clinical Biomarkers and Translational Sciences
| | - Ryotaku Inoue
- Translational Science Department I, Daiichi Sankyo, Tokyo
| | - Takeshi Kuwata
- Department of Genetic Medicine and Services, National Cancer Center Hospital East
| | | | - Satoshi Fujii
- Department of Pathology, Yokohama City University Graduate School of Medicine, Kanazawa-ku, Yokohama, Japan and Division of Pathology, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Chiba
| | - Nobue Kumaki
- Department of Breast Oncology, Tokai University
- Deparment of Pathology, Tokai University, School of Medicine, Ishehara, Kanagawa, Japan
| | - Kokichi Honda
- Translational Science Department I, Daiichi Sankyo, Tokyo
| | - Li-An Xu
- Hematology Early Oncology Development and Precision Medicine Biostatistics and Data Management, Daiichi Sankyo, Inc., Basking Ridge, NJ
| | - Aaron Goetz
- Global Anatomic Pathology/Histology, Labcorp Drug Development, Indianapolis, IN
| | - Patricia Gaule
- Department of Pathology, Yale University School of Medicine, New Haven, CT
| | | | - David L. Rimm
- Department of Pathology, Yale University School of Medicine, New Haven, CT
| | - Robert McGee
- Global Anatomic Pathology/Histology, Labcorp Drug Development, Indianapolis, IN
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23
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Yang L, Liu S, He W, Xiong Z, Xia L. Characterisation of tumor microenvironment and prevalence of CD274/PD-L1 genetic alterations difference in colorectal Cancer. BMC Cancer 2023; 23:221. [PMID: 36894899 PMCID: PMC9996909 DOI: 10.1186/s12885-023-10610-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Accepted: 02/06/2023] [Indexed: 03/11/2023] Open
Abstract
BACKGROUND Large-scale genomic alterations, especially CD274/PD-L1 gene amplification, have great impact on anti-PD-1 efficacy on cancers such as Hodgkin's lymphoma. However, the prevalence of PD-L1 genetic alterations in colorectal cancer (CRC) and its correlation with the tumor immune microenvironment and clinical implications remain unknown. MATERIALS AND METHODS PD-L1 genetic alterations were evaluated in 324 patients with newly diagnosed CRC including 160 mismatch repair-deficient (dMMR) patients and 164 mismatch repair-proficient (pMMR) patients using fluorescence in situ hybridization (FISH) method. The correlation between PD-L1 and the expression of the common immune markers was analyzed. RESULTS Totally 33 (10.2%) patients were identified with aberrant PD-L1 genetic alternations including deletion (2.2%), polysomy (4.9%), and amplification (3.1%); They had more aggressive features such as advanced stage (P = 0.02), shorter overall survival (OS) (P < 0.001) than patients with disomy. The aberrations correlated with positive lymph node (PLN) (p = 0.001), PD-L1 expression by immunohistochemistry (IHC) in tumor cells (TCs) or tumor-infiltrated immunocytes (ICs) (both p < 0.001), and pMMR (p = 0.029). When dMMR and pMMR were analyzed independently, the correlations of aberrant PD-L1 genetic alterations with PD-1 expression (p = 0.016), CD4 + T cells (p = 0.032), CD8 T + cells (p = 0.032) and CD68 + cells (p = 0.04) were only found in dMMR cohort. CONCLUSIONS The prevalence of PD-L1 genetic alterations was relatively low in CRC, but the aberrations usually correlate with aggressive nature. The correlation between PD-L1 genetic alterations and tumor immune features was only observed in dMMR CRC.
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Affiliation(s)
- Lin Yang
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, 1838 Baiyun Avenue North, Guangzhou, 510515, China
| | - Shousheng Liu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Centre for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 Dongfeng Road east, Guangzhou, 510060, China.,Department of General Medicine, Sun Yat-sen University Cancer Center, 651 Dongfeng Road east, Guangzhou, 510060, China
| | - Wenzhuo He
- State Key Laboratory of Oncology in South China, Collaborative Innovation Centre for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 Dongfeng Road east, Guangzhou, 510060, China.,Department of General Medicine, Sun Yat-sen University Cancer Center, 651 Dongfeng Road east, Guangzhou, 510060, China
| | - Zhenchong Xiong
- State Key Laboratory of Oncology in South China, Collaborative Innovation Centre for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 Dongfeng Road east, Guangzhou, 510060, China. .,Department of Breast Oncology, Sun Yat-sen University Cancer Center, 651 Dongfeng Road east, Guangzhou, 510060, China.
| | - Liangping Xia
- State Key Laboratory of Oncology in South China, Collaborative Innovation Centre for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 Dongfeng Road east, Guangzhou, 510060, China. .,Department of General Medicine, Sun Yat-sen University Cancer Center, 651 Dongfeng Road east, Guangzhou, 510060, China.
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24
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[Targeting HER2 in colorectal cancer]. Bull Cancer 2023; 110:402-411. [PMID: 36870811 DOI: 10.1016/j.bulcan.2023.01.013] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Revised: 01/10/2023] [Accepted: 01/12/2023] [Indexed: 03/06/2023]
Abstract
Among the molecular subgroups of interest in metastatic colorectal cancer (mCRC), innovations are underway for tumors with overexpression of HER2 (Human Epidermal Growth Factor Receptor 2). Overexpression of the HER2 protein concerns 2 to 5% of CRC at any stage mainly located in the distal colon and rectum. Diagnosis is based on immunohistochemistry, in situ hybridization with appropriate criteria for colorectal localization, and molecular biology (NGS: next-generation sequencing). Overexpression of HER2 is a predictive factor for resistance to treatments targeting EGFR which are indicated in the case where the tumor is wild-type RAS. It seems to be associated with a poor prognosis of mCRC with a higher risk of brain metastasis. Regarding treatments targeting HER2, no randomized controlled phase III has been published to date. However, several combinations have been evaluated in phase II with clinically meaningful objective response rates: trastuzumab-deruxtecan (45%), trastuzumab-tucatinib (46%), trastuzumab-pyrotinib (45%), trastuzumab-pertuzumab (30%) ou trastuzumab-lapatinib (30%). In this literature review, we present here the current state of knowledge on the diagnostic methods of HER2 overexpression in CRC, the main clinical, molecular and prognostic characteristics, and the efficacy results of the different therapeutic combinations for the patients with HER2 overexpressed mCRC. This justifies, despite the lack of marketing authorization in France and in Europe for agents targeting HER2 in CRC, the systematic evaluation of the HER2 status, as recommended in particular by the NCCN (National Comprehensive Cancer Network).
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25
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Kolbe K, Haffner I, Schierle K, Maier D, Geier B, Luber B, Bläker H, Wittekind C, Lordick F. Deviating HER2 test results in gastric cancer: analysis from the prospective multicenter VARIANZ study. J Cancer Res Clin Oncol 2023; 149:1319-1329. [PMID: 36030286 PMCID: PMC9984518 DOI: 10.1007/s00432-022-04208-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2022] [Accepted: 07/12/2022] [Indexed: 11/09/2022]
Abstract
PURPOSE The prospective multicenter VARIANZ study aimed to identify resistance biomarkers for HER2-targeted treatment in advanced gastric and esophago-gastric junction cancer (GC, EGJC). HER2 test deviations were found in 90 (22.3%) of 404 cases (central versus local testing) and were associated with negative impact on survival for trastuzumab-treated patients. Here, we investigated methodological and biological variables that may promote deviating HER2 test results. METHODS We analyzed HER2 testing procedures and participation in quality assurance programs of 105 participating local pathology laboratories. Furthermore, tumor localization and histological subtypes were compared between patients with centrally confirmed (central HER2 + /local HER2 + , n = 68) and unconfirmed HER2 status (central HER2 -/local HER2 + , n = 68). RESULTS For central HER2 testing, concordance between in situ hybridization (ISH) and immunohistochemistry (IHC) was 98.3%, with IHC sensitivity of 93.3% (84 IHC + of 90 ISH +), specificity of 99.5% (389 IHC- of 391 ISH-), and a positive diagnosis rate of 97.7%. Central confirmation of the local HER2 IHC scores were seen for the majority of locally HER2- IHC 0/1 (172/178; 96.6%), but less frequently for locally IHC3 + (57/124; 46.0%) cases. Deviation rate was not associated with IHC antibody platform used in the local pathology institute neither with participation in quality-assuring tests. Regarding tumor characteristics, deviating test results were more frequently found in GC vs. EGJC (69.1% vs. 39.7%; p = 0.001) and in Laurén diffuse vs. intestinal subtype (23.5% vs. 5.9%, p = 0.004). CONCLUSION Tumor localization and histological subtype have an impact on HER2 test deviation rates. Assessment of HER2 remains challenging for GC and EGJC.
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Affiliation(s)
- Katharina Kolbe
- Department of Oncology, Gastroenterology, Hepatology, Pulmonology and Infectious Disease, Leipzig University Medical Center, University Cancer Center Leipzig (UCCL), Leipzig, Germany
| | - Ivonne Haffner
- Department of Oncology, Gastroenterology, Hepatology, Pulmonology and Infectious Disease, Leipzig University Medical Center, University Cancer Center Leipzig (UCCL), Leipzig, Germany.
| | - Katrin Schierle
- Institute of Pathology, Heilbronn SLK-Kliniken GmbH, Heilbronn, Germany
| | | | | | - Birgit Luber
- Institute of Pathology, Technische Universität München, Munich, Germany
| | - Hendrik Bläker
- Department of Pathology, Leipzig University Medical Center, Leipzig, Germany
| | - Christian Wittekind
- Department of Pathology, Leipzig University Medical Center, Leipzig, Germany
| | - Florian Lordick
- Department of Oncology, Gastroenterology, Hepatology, Pulmonology and Infectious Disease, Leipzig University Medical Center, University Cancer Center Leipzig (UCCL), Leipzig, Germany
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26
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Shimozaki K, Shinozaki E, Yamamoto N, Imamura Y, Osumi H, Nakayama I, Wakatsuki T, Ooki A, Takahari D, Ogura M, Chin K, Watanabe M, Yamaguchi K. KRAS mutation as a predictor of insufficient trastuzumab efficacy and poor prognosis in HER2-positive advanced gastric cancer. J Cancer Res Clin Oncol 2023; 149:1273-1283. [PMID: 35438321 DOI: 10.1007/s00432-022-03966-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Accepted: 02/21/2022] [Indexed: 10/18/2022]
Abstract
PURPOSE Although RAS and PIK3CA mutations have been associated with resistance to anti-EGFR antibody in colorectal cancer or trastuzumab in breast cancer, their implications for trastuzumab resistance in HER2-positive advanced gastric cancer (AGC) remains unclear. We aimed to assess the relationship between trastuzumab efficacy and mutation status in the HER family signaling pathway. METHODS This study retrospectively evaluated patients with HER2-positive AGC who received first-line trastuzumab-containing chemotherapy between March 2011 and November 2015. Multiplex genotyping, including KRAS, NRAS, PIK3CA, and BRAF, was then performed using the Luminex Assay, after which KRAS amplification was measured using quantitative real-time reverse transcription-polymerase chain reaction. Thereafter, the association between genetic alterations and clinical outcomes were evaluated. RESULTS KRAS mutation (MT) was detected in 6 of 77 patients (7.8%), whereas KRAS amplification was found in 15 of 67 patients (22%). No mutations in NRAS, PIK3CA, or BRAF were identified. The KRAS MT group showed significantly worse response rates (16.7% vs. 66.2%, P = 0.016), progression-free survival [median, 4.8 vs. 11.6 months; hazard ratio (HR), 3.95; 95% CI, 1.60-9.76; P = 0.0029], and overall survival (11.5 vs. 23.6 months; HR, 3.80; 95% CI, 1.56-9.28; P = 0.033) compared to the KRAS wild-type group. KRAS amplification had no effect on clinical outcomes. CONCLUSION KRAS mutation was an independent prognostic factor for poor survival and might predict insufficient trastuzumab efficacy, whereas KRAS amplification showed no prognostic significance during trastuzumab treatment. Further investigations are warranted to confirm the predictive value of KRAS status in HER2-positive AGC.
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Affiliation(s)
- Keitaro Shimozaki
- Department of Gastrointestinal Oncology, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Ariake 3-8-3, Koto-ku, Tokyo, Japan.,Department of Gastroenterology and Hepatology, Division of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Eiji Shinozaki
- Department of Gastrointestinal Oncology, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Ariake 3-8-3, Koto-ku, Tokyo, Japan.
| | - Noriko Yamamoto
- Department of Pathology, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Yu Imamura
- Department of Gastroenterological Surgery, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Hiroki Osumi
- Department of Gastrointestinal Oncology, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Ariake 3-8-3, Koto-ku, Tokyo, Japan
| | - Izuma Nakayama
- Department of Gastrointestinal Oncology, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Ariake 3-8-3, Koto-ku, Tokyo, Japan
| | - Takeru Wakatsuki
- Department of Gastrointestinal Oncology, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Ariake 3-8-3, Koto-ku, Tokyo, Japan
| | - Akira Ooki
- Department of Gastrointestinal Oncology, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Ariake 3-8-3, Koto-ku, Tokyo, Japan
| | - Daisuke Takahari
- Department of Gastrointestinal Oncology, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Ariake 3-8-3, Koto-ku, Tokyo, Japan
| | - Mariko Ogura
- Department of Gastrointestinal Oncology, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Ariake 3-8-3, Koto-ku, Tokyo, Japan
| | - Keisho Chin
- Department of Gastrointestinal Oncology, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Ariake 3-8-3, Koto-ku, Tokyo, Japan
| | - Masayuki Watanabe
- Department of Gastroenterological Surgery, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Kensei Yamaguchi
- Department of Gastrointestinal Oncology, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Ariake 3-8-3, Koto-ku, Tokyo, Japan
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27
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Wu S, Yue M, Zhang J, Li X, Li Z, Zhang H, Wang X, Han X, Cai L, Shang J, Jia Z, Wang X, Li J, Liu Y. The Role of Artificial Intelligence in Accurate Interpretation of HER2 Immunohistochemical Scores 0 and 1+ in Breast Cancer. Mod Pathol 2023; 36:100054. [PMID: 36788100 DOI: 10.1016/j.modpat.2022.100054] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Revised: 10/28/2022] [Accepted: 11/20/2022] [Indexed: 01/11/2023]
Abstract
The new human epidermal growth factor receptor (HER)2-targeting antibody-drug conjugate offers the opportunity to treat patients with HER2-low breast cancer. Distinguishing HER2 immunohistochemical (IHC) scores of 0 and 1+ is not only critical but also challenging owing to HER2 heterogeneity and variability of observers. In this study, we aimed to increase the interpretation accuracy and consistency of HER2 IHC 0 and 1+ evaluation through assistance from an artificial intelligence (AI) algorithm. In addition, we examined the value of our AI algorithm in evaluating HER2 IHC scores in tumors with heterogeneity. AI-assisted interpretation consisted of AI algorithms and an augmenting reality module with a microscope. Fifteen pathologists (5 junior, 5 midlevel, and 5 senior) participated in this multi-institutional 2-round ring study that included 246 infiltrating duct carcinoma cases that were not otherwise specified. In round 1, pathologists analyzed 246 HER2 IHC slides by microscope without AI assistance. After a 2-week washout period, the pathologists read the same slides with AI algorithm assistance and rendered the definitive results by adjusting to the AI algorithm. The accuracy of interpretation accuracy with AI assistance (0.93 vs 0.80), thereby the evaluation precision of HER2 0 and the recall of HER2 1+. In addition, the AI algorithm improved the total consistency (intraclass correlation coefficient = 0.542-0.812), especially in HER2 1+ cases. In cases with heterogeneity, accuracy improved significantly (0.68 to 0.89) and to a similar level as in cases without heterogeneity (accuracy, 0.97). Both accuracy and consistency improved more for junior pathologists than those for the midlevel and senior pathologists. To the best of our knowledge, this is the first study to show that the accuracy and consistency of HER2 IHC 0 and 1+ evaluation and the accuracy of HER2 IHC evaluation in breast cancers with heterogeneity can be significantly improved using AI-assisted interpretation.
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Affiliation(s)
- Si Wu
- Department of Pathology, the Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Meng Yue
- Department of Pathology, the Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Jun Zhang
- Tencent AI Lab, Nanshan District, Tencent Binhai Building, Shenzhen, Guangdong, China
| | - Xiaoxian Li
- Department of Pathology and Laboratory Medicine, The Emory University School of Medicine, Atlanta, Georgia
| | - Zaibo Li
- Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, Ohio
| | - Huina Zhang
- Department of Pathology, University of Rochester Medical Center, Rochester, New York
| | - Xinran Wang
- Department of Pathology, the Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Xiao Han
- Tencent AI Lab, Nanshan District, Tencent Binhai Building, Shenzhen, Guangdong, China
| | - Lijing Cai
- Department of Pathology, the Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Jiuyan Shang
- Department of Pathology, the Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Zhanli Jia
- Department of Pathology, the Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Xiaoxiao Wang
- Department of Pathology, the Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Jinze Li
- Department of Pathology, the Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Yueping Liu
- Department of Pathology, the Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China.
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28
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Subasinghe D, Acott N, Mahesh PKB, Sivaganesh S, Munasinghe S, Kumarasinghe MP, Samarasekera DN, Lokuhetty MDS. Human epidermal growth factor receptor-2 gene expression positivity determined by silver in situ hybridization/immunohistochemistry methods and associated factors in a cohort of Sri Lankan patients with gastric adenocarcinoma: a prospective study. J Int Med Res 2023; 51:3000605231154403. [PMID: 36814374 PMCID: PMC9950620 DOI: 10.1177/03000605231154403] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/24/2023] Open
Abstract
OBJECTIVE Positive human epidermal growth factor 2 (HER2) expression and its predictive clinicopathological features remain unclear in Sri Lankan gastric cancer (GC) patients. Here, we aimed to determine GC HER2 status predictors by analyzing associations between clinicopathological features and HER2 expression using immunohistochemistry (IHC) and silver in situ hybridization (SISH). METHODS During this 4-year prospective study, clinicopathological data were collected from participants in the National Hospital of Sri Lanka. HER2 IHC and SISH were performed using commercial reagents. Using chi-square tests, associations of HER2-IHC/SISH with clinicopathological features were analyzed. RESULTS Overall, 145 GC patients were included, 69 had gastrectomies and 76 had biopsies. Positive HER2 expression by IHC was associated with age <60 years, high T stage (assessed pathologically in resections and radiologically in biopsies), high nuclear grade, tumor necrosis, mitosis >5/high-power field, with additional perineural invasion and lymphovascular invasion in resections. These features, excluding lymphovascular invasion but including male sex, were associated with HER2 expression by SISH. CONCLUSIONS Age <60 years, high nuclear grade, tumor necrosis, and perineural invasion are associated factors of HER2 status. These could be used to triage GC patients for HER2 status testing in limited resource settings where IHC/SISH analysis is costly.
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Affiliation(s)
- Duminda Subasinghe
- Department of Surgery, Faculty of Medicine, University of
Colombo, University Surgical Unit, The National Hospital of Sri Lanka, Colombo,
Sri Lanka,PathWest Laboratory Medicine, Perth, & School of Pathology
and Laboratory Medicine, University of Western Australia, Perth, Australia,Duminda Subasinghe, Department of Surgery,
Faculty of Medicine, University of Colombo, University Surgical Unit, The
National Hospital of Sri Lanka, Colombo 00800, Sri Lanka.
| | - Nathan Acott
- PathWest Laboratory Medicine, Perth, & School of Pathology
and Laboratory Medicine, University of Western Australia, Perth, Australia
| | | | - Sivasuriya Sivaganesh
- Department of Surgery, Faculty of Medicine, University of
Colombo, University Surgical Unit, The National Hospital of Sri Lanka, Colombo,
Sri Lanka
| | - Sithum Munasinghe
- Translational Health Research Institute, Western Sydney
University, Campbelltown Campus, Campbelltown, New South Wales, Australia
| | - Mariyan Priyanthi Kumarasinghe
- PathWest Laboratory Medicine, Perth, & School of Pathology
and Laboratory Medicine, University of Western Australia, Perth, Australia
| | - Dharmabandu Nandaveva Samarasekera
- Department of Surgery, Faculty of Medicine, University of
Colombo, University Surgical Unit, The National Hospital of Sri Lanka, Colombo,
Sri Lanka
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29
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Li Q, Lv M, Lv L, Cao N, Zhao A, Chen J, Tang X, Luo R, Yu S, Zhou Y, Cui Y, Guo W, Liu T. Identifying HER2 from serum-derived exosomes in advanced gastric cancer as a promising biomarker for assessing tissue HER2 status and predicting the efficacy of trastuzumab-based therapy. Cancer Med 2023; 12:4110-4124. [PMID: 36208025 PMCID: PMC9972160 DOI: 10.1002/cam4.5269] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Revised: 08/15/2022] [Accepted: 08/24/2022] [Indexed: 11/09/2022] Open
Abstract
PURPOSE This study aimed to evaluate the clinical relevance of exosomal HER2 (Exo HER2) level in assessing the tissue HER2 status and predicting the efficacy of trastuzumab treatment. METHODS In this prospective study, patients with advanced gastric cancer (AGC) from three hospitals between August 2016 to November 2020 were enrolled. The Exo HER2 level was detected by enzyme-linked immunosorbent assay. Receiver operating characteristic curve (ROC) was drawn referring to the HER2 tissue status to assess the diagnostic value of Exo HER2. Cox proportional hazards regression and logistic regression were used to evaluate the association between Exo HER2 and progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) in patients who received trastuzumab-based first-line therapy. RESULTS In this study, 242 patients with advanced or metastatic gastric adenocarcinoma were registered. Of these, 238 AGC patients were eligible for evaluating serum-derived exosome HER2 diagnostic value, including 114 HER2-positive. Finally, 64 were eligible for efficacy analysis. The area under the ROC curve was 0.746. The optimal cutoff value for diagnosing tissue HER2-positive status was 729.95 ng/ml, with a sensitivity of 66.7% and a specificity of 74.2%. In 64 patients treated with trastuzumab, higher baseline Exo HER2 level indicated better prognosis. 844 ng/ml and 723 ng/ml were the right cutoffs for distinguishing the population with superior PFS (hazard ratio [HR] = 0.41, P = 0.017) and OS (HR = 0.30, P < 0.001), respectively. CONCLUSION Serum exosomal HER2 level might serve as an effective biomarker for assessing tissue HER2 status in AGC and screening the potential patients who might benefit from anti-HER2 therapy.
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Affiliation(s)
- Qian Li
- Department of Medical Oncology, Zhongshan HospitalFudan UniversityShanghaiChina
| | - Minzhi Lv
- Department of Biostatistics, Zhongshan HospitalFudan UniversityShanghaiChina
| | - Lihua Lv
- Departments of Laboratory Medicine, Zhongshan HospitalFudan UniversityShanghaiChina
| | - Nida Cao
- Oncology Department ILonghua Hospital Shanghai University of Traditional Chinese MedicineShanghaiChina
| | - Aiguang Zhao
- Oncology Department ILonghua Hospital Shanghai University of Traditional Chinese MedicineShanghaiChina
| | - Jiayan Chen
- Department of Medical OncologyHuadong HospitalShanghaiChina
| | - Xi Tang
- Department of Medical OncologyHuadong HospitalShanghaiChina
| | - Rongkui Luo
- Department of Pathology, Zhongshan HospitalFudan UniversityShanghaiChina
| | - Shan Yu
- Department of Medical Oncology, Zhongshan HospitalFudan UniversityShanghaiChina
| | - Yan Zhou
- Departments of Laboratory Medicine, Zhongshan HospitalFudan UniversityShanghaiChina
| | - Yuehong Cui
- Department of Medical Oncology, Zhongshan HospitalFudan UniversityShanghaiChina
| | - Wei Guo
- Department of Medical Oncology, Zhongshan HospitalFudan UniversityShanghaiChina
- Department of Laboratory Medicine, Xiamen Branch, Zhongshan HospitalFudan UniversityXiamenChina
| | - Tianshu Liu
- Department of Medical Oncology, Zhongshan HospitalFudan UniversityShanghaiChina
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30
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Noh JH, Shin JY, Lee JH, Park YS, Lee IS, Kim GH, Na HK, Ahn JY, Jung KW, Kim DH, Choi KD, Song HJ, Lee GH, Jung HY. Clinical Significance of Epstein-Barr Virus and Helicobacter pylori Infection in Gastric Carcinoma. Gut Liver 2023; 17:69-77. [PMID: 35611669 PMCID: PMC9840931 DOI: 10.5009/gnl210593] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Revised: 03/11/2022] [Accepted: 04/01/2022] [Indexed: 02/01/2023] Open
Abstract
Background/Aims Epstein-Barr virus (EBV) and Helicobacter pylori (HP) coinfection may synergistically induce severe inflammatory responses in the stomach tissue, increasing the risk of developing gastric cancer. We aimed to analyze the effect of EBV and HP coinfection on the clinicopathologic features and prognosis of gastric cancer, as well as to evaluate the role of EBV infection in non-gastric carcinoma with lymphoid stroma (non-GCLS). Methods Overall, 956 patients who underwent surgery for gastric cancer between September 2014 and August 2015 were eligible and divided into groups, according to GCLS morphology, EBV infection, and HP infection. Clinicopathologic characteristics and oncologic outcomes were analyzed retrospectively. Results EBV and HP coinfection was significantly associated with male sex, proximal location, GCLS morphology, and equivocal p53 expression (p<0.001). Multivariate analysis revealed that EBV infection alone (hazard ratio [HR], 0.362; 95% CI, 0.131 to 0.996; p=0.049) and lower third location (HR, 0.624; 95% CI, 0.413 to 0.943; p=0.025) were inversely correlated with overall survival. During median follow-up period of 72 months, overall survival rate was not significantly different between the EBV and HP coinfection group and others (97.6% vs 86.8%; log-rank p=0.144). In non-GCLS patients (n=920), overall survival rate was not significantly different between the EBV infection group and others (96.9% vs 86.4%; log-rank p=0.126). Conclusions EBV and HP coinfection is not an independent prognostic factor for gastric cancer. EBV infection status, regardless of HP infection, affects the clinicopathologic features of all types of gastric cancer. However, it does not lead to a significant difference in overall survival of non-GCLS patients.
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Affiliation(s)
- Jin Hee Noh
- Departments of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Jun Young Shin
- Departments of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Jeong Hoon Lee
- Departments of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea,Corresponding AuthorJeong Hoon Lee, ORCIDhttps://orcid.org/0000-0002-0778-7585, E-mail
| | - Young Soo Park
- Departments of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea,Young Soo Park, ORCIDhttps://orcid.org/0000-0001-5389-4245, E-mail
| | - In-Seob Lee
- Departments of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Ga Hee Kim
- Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul, Korea
| | - Hee Kyong Na
- Departments of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Ji Yong Ahn
- Departments of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Kee Wook Jung
- Departments of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Do Hoon Kim
- Departments of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Kee Don Choi
- Departments of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Ho June Song
- Departments of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Gin Hyug Lee
- Departments of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Hwoon-Yong Jung
- Departments of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
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Czogalla B, Dötzer K, Sigrüner N, von Koch FE, Brambs CE, Anthuber S, Frangini S, Burges A, Werner J, Mahner S, Mayer B. Combined Expression of HGFR with Her2/neu, EGFR, IGF1R, Mucin-1 and Integrin α2β1 Is Associated with Aggressive Epithelial Ovarian Cancer. Biomedicines 2022; 10:2694. [PMID: 36359213 PMCID: PMC9687566 DOI: 10.3390/biomedicines10112694] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Revised: 10/15/2022] [Accepted: 10/21/2022] [Indexed: 09/10/2023] Open
Abstract
Hepatocyte growth factor receptor (HGFR), also known as c-mesenchymal-epithelial transition factor (c-MET), plays a crucial role in the carcinogenesis of epithelial ovarian cancer (EOC). In contrast, the mechanisms contributing to aberrant expression of HGFR in EOC are not fully understood. In the present study, the expression of HGFR with its prognostic and predictive role was evaluated immunohistochemically in a cohort of 42 primary ovarian cancer patients. Furthermore, we analyzed the dual expression of HGFR and other druggable biomarkers. In the multivariate Cox regression analysis, high HGFR expression was identified as an independent prognostic factor for a shorter progression-free survival (PFS) (hazard ratio (HR) 2.99, 95% confidence interval (CI95%) 1.01-8.91, p = 0.049) and overall survival (OS) (HR 5.77, CI95% 1.56-21.34, p = 0.009). In addition, the combined expression of HGFR, human epidermal growth factor receptor 2 (Her2/neu), epithelial growth factor receptor (EGFR), insulin-like growth factor 1 (IGF1R), Mucin-1 and Integrin α2β1 further significantly impaired PFS, platinum-free interval (PFI) and OS. Protein co-expression analyses were confirmed by transcriptomic data in a large, independent cohort of patients. In conclusion, new biomarker-directed treatment targets were identified to fight poor prognosis of primary EOC.
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Affiliation(s)
- Bastian Czogalla
- Department of Obstetrics and Gynecology, University Hospital, Ludwig-Maximilians-University Munich, Marchioninistraße 15, 81377 Munich, Germany
- German Cancer Consortium (DKTK), Partner Site Munich, Pettenkoferstraße 8a, 80336 Munich, Germany
| | - Katharina Dötzer
- Department of General, Visceral and Transplant Surgery, University Hospital, Ludwig-Maximilians-University Munich, Marchioninistraße 15, 81377 Munich, Germany
| | - Nicole Sigrüner
- Department of General, Visceral and Transplant Surgery, University Hospital, Ludwig-Maximilians-University Munich, Marchioninistraße 15, 81377 Munich, Germany
| | - Franz Edler von Koch
- Gynecology and Obstetrics Clinic, Klinikum Dritter Orden, Menzinger Straße 44, 80638 Munich, Germany
| | - Christine E. Brambs
- Department of Obstetrics and Gynecology, Klinikum Rechts der Isar, Technical University Munich, Ismaninger Straße 22, 81675 Munich, Germany
| | - Sabine Anthuber
- Department of Obstetrics and Gynecology, Starnberg Hospital, Oßwaldstraße 1, 82319 Starnberg, Germany
| | - Sergio Frangini
- Department of Obstetrics and Gynecology, Munich Clinic Harlaching, Sanatoriumsplatz 2, 81545 Munich, Germany
| | - Alexander Burges
- Department of Obstetrics and Gynecology, University Hospital, Ludwig-Maximilians-University Munich, Marchioninistraße 15, 81377 Munich, Germany
- German Cancer Consortium (DKTK), Partner Site Munich, Pettenkoferstraße 8a, 80336 Munich, Germany
| | - Jens Werner
- German Cancer Consortium (DKTK), Partner Site Munich, Pettenkoferstraße 8a, 80336 Munich, Germany
- Department of General, Visceral and Transplant Surgery, University Hospital, Ludwig-Maximilians-University Munich, Marchioninistraße 15, 81377 Munich, Germany
| | - Sven Mahner
- Department of Obstetrics and Gynecology, University Hospital, Ludwig-Maximilians-University Munich, Marchioninistraße 15, 81377 Munich, Germany
- German Cancer Consortium (DKTK), Partner Site Munich, Pettenkoferstraße 8a, 80336 Munich, Germany
| | - Barbara Mayer
- German Cancer Consortium (DKTK), Partner Site Munich, Pettenkoferstraße 8a, 80336 Munich, Germany
- Department of General, Visceral and Transplant Surgery, University Hospital, Ludwig-Maximilians-University Munich, Marchioninistraße 15, 81377 Munich, Germany
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Scherrer E, Kang A, Bloudek LM, Koshkin VS. HER2 expression in urothelial carcinoma, a systematic literature review. Front Oncol 2022; 12:1011885. [PMID: 36338710 PMCID: PMC9635895 DOI: 10.3389/fonc.2022.1011885] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Accepted: 09/30/2022] [Indexed: 11/30/2022] Open
Abstract
Background Urothelial carcinoma (UC) is a common malignancy with significant associated mortality. Recent clinical trials suggest an emerging role for HER2-targeted therapy. Testing for HER2 expression in UC is not part of current routine clinical practice. In consequence, the prevalence of HER2 expression in UC is not well defined. Methods A systematic literature review (SLR) was conducted to characterize HER2 expression in both locally advanced unresectable or metastatic (LA/mUC) and earlier stage UC, classified as HER2+, HER2-low, HER2-. HER2+ was defined as an immunohistochemistry (IHC) score of 3+ or IHC 2+ and ISH/FISH+. HER2-low was defined as an IHC score of 2+ and ISH/FISH- or IHC 1+. HER2- was defined as an IHC score of 0. Weighted averages were calculated to generate an estimate of the population prevalence. Results A total of 88 studies were identified, with 45, 30, and 13 studies investigating LA/mUC, earlier stage UC, and mixed stage/unspecified, respectively. The most common assays used were Dako HercepTest and Ventana Pathway anti-HER2/neu (4B5) for IHC to assess HER2 protein expression; Abbott PathVysion HER-2 DNA Probe Kit, FoundationOne CDx, and Guardant360 CDx for assessing HER2 gene amplification. The most frequently cited scoring guidelines were ASCO/CAP guidelines for breast cancer and gastric cancer, though most studies defined their own criteria for HER2 expression. Using the pre-specified definition, HER2+ prevalence ranged from 6.7% to 37.5% with a weighted average of 13.0% in LA/mUC. Only 1 study presented data that could be classified as HER2+ based on pre-specified criteria in earlier stage UC patients, and this study represented a likely outlier, at 76.0%. Conclusion The results from this SLR help to shed light on HER2 expression in UC, a potentially clinically relevant biomarker-driven subpopulation for emerging HER2-directed regimens. Results of this SLR illuminate the variability in how HER2+ status expression levels are being assessed and how HER2+ is defined. Consensus on standardized HER2 testing and scoring criteria is paramount to better understand the clinical relevance in patients with UC.
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Affiliation(s)
| | | | | | - Vadim S. Koshkin
- Helen Diller Family Cancer Center, University of California San Francisco, San Francisco, CA, United States
- *Correspondence: Vadim S. Koshkin,
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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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Lee JY, Park MJ. The Role of Serum CD26 in the Diagnosis of Gastric Cancer. Int J Gen Med 2022; 15:7179-7187. [PMID: 36118182 PMCID: PMC9481300 DOI: 10.2147/ijgm.s378620] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Accepted: 09/07/2022] [Indexed: 11/23/2022] Open
Abstract
Purpose The value of serum cluster of differentiation 26 (CD26) in gastric cancer remains unknown. We investigated serum CD26 as a non-invasive serological marker for the diagnosis of gastric cancer and its relationship with serum human epidermal growth factor receptor-2 (HER2) levels. Patients and Methods We enrolled 393 gastric cancer patients treated with endoscopic resection or surgery, and 90 healthy controls. HER2 positivity in tissue was evaluated by immunohistochemistry staining, and the serum CD26 and HER2 levels were measured using an enzyme-linked immunosorbent assay. Results Serum CD26 levels were significantly lower in gastric cancer patients than in healthy controls (582.2 ± 254.3 vs 862.7 ± 410.6 ng/mL, P<0.001). Serum CD26 levels were significantly lower in advanced gastric cancer compared to early gastric cancer (642.2 ± 333.9 vs 503.4 ± 332.7 ng/mL, P<0.001), and tended to decrease with gastric cancer progression. To diagnose gastric cancer, the optimal cut-off value of serum CD26 was 762.7 ng/mL with 75.6% sensitivity and 64.4% specificity. Serum CD26 levels were weakly correlated with serum HER2 levels (rs=0.363, P<0.001). However, no difference in serum CD26 levels was observed between tissue HER2-negative and HER2-positive gastric cancer groups (586.2 ± 362.1 vs 579.6 ± 264.8 ng/mL, P=0.898). Conclusion CD26 is a useful non-invasive serological marker for gastric cancer diagnosis; however, its levels do not correlate with HER2 status.
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Affiliation(s)
- Ju Yup Lee
- Department of Internal Medicine, Keimyung University School of Medicine, Daegu, South Korea
- Institute for Cancer Research, Keimyung University, Daegu, South Korea
| | - Mae-Ja Park
- Department of Anatomy, School of Medicine, Kyungpook National University, Daegu, South Korea
- Correspondence: Mae-Ja Park, Department of Anatomy, School of Medicine, Kyungpook National University, Daegu, South Korea, Tel/Fax +82-53-420-4802, Email
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Bang K, Cheon J, Park YS, Kim HD, Ryu MH, Park Y, Moon M, Lee H, Kang YK. Association between HER2 heterogeneity and clinical outcomes of HER2-positive gastric cancer patients treated with trastuzumab. Gastric Cancer 2022; 25:794-803. [PMID: 35524883 DOI: 10.1007/s10120-022-01298-6] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Accepted: 04/04/2022] [Indexed: 02/07/2023]
Abstract
BACKGROUND The GASTHER1 study showed that re-evaluation of HER2 status rescued 8% of HER2-positive gastric cancer (GC) patients with initially HER2-negative GC. Since rescued HER2 positivity represents HER2 heterogeneity, we aimed to investigate this in a larger cohort with longer follow-up duration. METHODS Data of 153 HER2-positive advanced GC patients who received first-line trastuzumab-based chemotherapy were analyzed. Repeat endoscopic biopsy was performed in patients with initially HER2-negative GC. Survival outcomes were analyzed according to the immunohistochemistry (IHC) score (IHC 2+ /in situ hybridization [ISH] + vs IHC 3+), HER2 status (initially vs rescued HER2 positive), and H-score. RESULTS IHC 2+ /ISH + patients showed worse progression-free survival (PFS) and overall survival (OS) than those with IHC 3+ (p < 0.05). Rescued HER2-positive patients showed worse PFS and OS than initially HER2-positive patients (p < 0.05). Although survival outcomes were comparable according to HER2 status in IHC 2+ /ISH + patients, initially HER2-positive patients showed more favorable PFS and OS than rescued HER2-positive patients (p < 0.05) among those with IHC 3+ . Among the subgroups determined by HER2 status and IHC score, the initially IHC 3+ subgroup had the highest H-score. The low H-score group (H-score ≤ 210) had significantly worse survival outcomes than the high H-score group (H-score > 210) (p < 0.05). An H-score of ≤ 210 was independently associated with shorter OS (HR = 1.54, 95% CI 1.02-2.31, p = 0.04). CONCLUSIONS Rescued HER2-positive patients showed worse clinical outcomes than initially HER2-positive patients, especially those with IHC 3+ . This finding highlights the impact of HER2 heterogeneity, which can be quantified indirectly as an H-score.
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Affiliation(s)
- Kyunghye Bang
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, South Korea
| | - Jaekyung Cheon
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, South Korea
- Department of Medical Oncology, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, South Korea
| | - Young Soo Park
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Hyung-Don Kim
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, South Korea
| | - Min-Hee Ryu
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, South Korea
| | - Yangsoon Park
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Meesun Moon
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, South Korea
| | - Hyungeun Lee
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, South Korea
| | - Yoon-Koo Kang
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, South Korea.
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Xu C, Sun M, Jin M, Li Z, Qin R, Ren G, Sun W, Chen L, Luan L, Liu Y, Jiang D, Chen L, Luo R, Hou Y. Dual block HER2 assessment increased HER2 immunohistochemistry positive rate in resected specimens of gastric cancer: a prospective multicenter clinical trial from China. Diagn Pathol 2022; 17:54. [PMID: 35765007 PMCID: PMC9238183 DOI: 10.1186/s13000-022-01230-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Accepted: 05/18/2022] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
Former single center studies indicated that HER2 assessment with two primary tumor blocks (dual block HER2 assessment) could be an efficient and practical approach to overcome the adverse impact of heterogeneity and acquire a HER2 positive rate in gastric cancer (GC). This multicenter prospective clinical trial (NCT 02843412) was launched to verify its value and generality.
Methods
A total of 3806 participants with primary GCs have been enrolled from 8 hospitals in China. Two primary tumor blocks were selected and recorded as block 1 and block 2 after histological evaluation. An HER2 (4B5) rabbit monoclonal antibody was used for the immunohistochemistry (IHC) analysis.
Results
In total patients, HER2 IHC positive (3+) rate with dual block assessment (9.4%) was higher than that with single block assessment (block 1: 7.8%, block 2: 7.8%) (P < 0.001). Compared with single-block assessment, dual-block assessment increased the positive rate by approximate 20%. Similarly, HER2 equivocal (2+) rate was increased in dual block assessment (25.8%), which was higher than that in single block assessment (block 1: 20.3%, block 2: 20.9%) (P < 0.001). Conversely, dual block assessment demonstrated a lower HER2 negative (0/1+) rate (64.8%) than single block assessment (block1: 71.9%, block 2: 71.3%) (P < 0.001). These findings were also confirmed in individual hospitals.
Conclusions
Dual block HER2 assessment effectively increased HER2 IHC positive rate in resected specimens of GC. We recommended dual block HER2 assessment be promoted in routine clinical practice in GC.
Trial registration
ClinicalTrials.gov, NCT 02843412. Registered 1 July 2016 - Retrospectively registered.
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Hoffmann OI, Regenauer M, Czogalla B, Brambs C, Burges A, Mayer B. Interpatient Heterogeneity in Drug Response and Protein Biomarker Expression of Recurrent Ovarian Cancer. Cancers (Basel) 2022; 14:cancers14092279. [PMID: 35565408 PMCID: PMC9103312 DOI: 10.3390/cancers14092279] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2022] [Revised: 04/24/2022] [Accepted: 04/29/2022] [Indexed: 12/10/2022] Open
Abstract
Recurrent ovarian-cancer patients face low 5-year survival rates despite chemotherapy. A variety of guideline-recommended second-line therapies are available, but they frequently result in trial-and-error treatment. Alterations and adjustments are common in the treatment of recurrent ovarian cancer. The drug response of 30 lesions obtained from 22 relapsed ovarian cancer patients to different chemotherapeutic and molecular agents was analyzed with the patient-derived ovarian-cancer spheroid model. The profile of druggable biomarkers was immunohistochemically assessed. The second-line combination therapy of carboplatin with gemcitabine was significantly superior to the combination of carboplatin with PEGylated liposomal doxorubicin (p < 0.0001) or paclitaxel (p = 0.0007). Except for treosulfan, all nonplatinum treatments tested showed a lesser effect on tumor spheroids compared to that of platinum-based therapies. Treosulfan showed the highest efficacy of all nonplatinum agents, with significant advantage over vinorelbine (p < 0.0001) and topotecan (p < 0.0001), the next best agents. The comparative testing of a variety of treatment options in the ovarian-cancer spheroid model resulted in the identification of more effective regimens for 30% of patients compared to guideline-recommended therapies. Recurrent cancers obtained from different patients revealed profound interpatient heterogeneity in the expression pattern of druggable protein biomarkers. In contrast, different lesions obtained from the same patient revealed a similar drug response and biomarker expression profile. Biological heterogeneity observed in recurrent ovarian cancers might explain the strong differences in the clinical drug response of these patients. Preclinical drug testing and biomarker profiling in the ovarian-cancer spheroid model might help in optimizing treatment management for individual patients.
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Affiliation(s)
| | - Manuel Regenauer
- Department of General, Visceral and Transplant Surgery, Ludwig-Maximilians-University Munich, Marchioninistraße 15, 81377 Munich, Germany;
| | - Bastian Czogalla
- Department of Obstetrics and Gynecology, Klinikum der Universität München, Ludwig-Maximilians-University Munich, Marchioninistraße 15, 81377 Munich, Germany; (B.C.); (A.B.)
| | - Christine Brambs
- Department of Obstetrics and Gynecology, Klinikum Rechts der Isar, Technical University Munich, Ismaninger Straße 22, 81675 Munich, Germany;
| | - Alexander Burges
- Department of Obstetrics and Gynecology, Klinikum der Universität München, Ludwig-Maximilians-University Munich, Marchioninistraße 15, 81377 Munich, Germany; (B.C.); (A.B.)
| | - Barbara Mayer
- SpheroTec GmbH, Am Klopferspitz 19, 82152 Martinsried, Germany;
- Department of General, Visceral and Transplant Surgery, Ludwig-Maximilians-University Munich, Marchioninistraße 15, 81377 Munich, Germany;
- German Cancer Consortium (DKTK), Partner Site Munich, Pettenkoferstraße 8a, 80336 Munich, Germany
- Correspondence: ; Tel.: +49-89-4400-76438
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High Dual Expression of the Biomarkers CD44v6/α2β1 and CD44v6/PD-L1 Indicate Early Recurrence after Colorectal Hepatic Metastasectomy. Cancers (Basel) 2022; 14:cancers14081939. [PMID: 35454846 PMCID: PMC9027562 DOI: 10.3390/cancers14081939] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Revised: 03/28/2022] [Accepted: 04/07/2022] [Indexed: 11/17/2022] Open
Abstract
Considering the biology of CRC, distant metastases might support the identification of high-risk patients for early recurrence and targeted therapy. Expression of a panel of druggable, metastasis-related biomarkers was immunohistochemically analyzed in 53 liver (LM) and 15 lung metastases (LuM) and correlated with survival. Differential expression between LM and LuM was observed for the growth factor receptors IGF1R (LuM 92.3% vs. LM 75.8%, p = 0.013), EGFR (LuM 68% vs. LM 41.5%, p = 0.004), the cell adhesion molecules CD44v6 (LuM 55.7% vs. LM 34.9%, p = 0.019) and α2β1 (LuM 88.3% vs. LM 58.5%, p = 0.001) and the check point molecule PD-L1 (LuM 6.1% vs. LM 3.3%, p = 0.005). Contrary, expression of HGFR, Hsp90, Muc1, Her2/neu, ERα and PR was comparable in LuM and LM. In the LM cohort (n = 52), a high CD44v6 expression was identified as an independent factor of poor prognosis (PFS: HR 2.37, 95% CI 1.18-4.78, p = 0.016). High co-expression of CD44v6/α2β1 (HR 4.14, 95% CI 1.65-10.38, p = 0.002) and CD44v6/PD-L1 (HR 2.88, 95% CI 1.21-6.85, p = 0.017) indicated early recurrence after hepatectomy, in a substantial number of patients (CD44v6/α2β1: 11 (21.15%) patients; CD44v6/PD-L1: 12 (23.1%) patients). Dual expression of druggable protein biomarkers may refine prognostic prediction and stratify high-risk patients for new therapeutic concepts, depending on the metastatic location.
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Paschold L, Binder M. Circulating Tumor DNA in Gastric and Gastroesophageal Junction Cancer. Curr Oncol 2022; 29:1430-1441. [PMID: 35323320 PMCID: PMC8947276 DOI: 10.3390/curroncol29030120] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Revised: 02/15/2022] [Accepted: 02/20/2022] [Indexed: 12/21/2022] Open
Abstract
Tumor cells shed DNA into the plasma. “Liquid biopsy” analysis of mutations or other genomic alterations in circulating cell-free DNA (cfDNA) may provide us with a tool to detect minimal residual cancer, comprehensively profile the genomic tumor landscape in search of druggable targets, and monitor cancers non-invasively over time for treatment failure or emerging treatment-resistant tumor subclones. While liquid biopsies have not yet entered routine clinical management in patients with gastric and gastroesophageal junction cancers, this group of diseases may benefit from such advanced diagnostic tools due to their pronounced genetic spatiotemporal heterogeneity and limitations in imaging sensitivity. Moreover, as the armamentarium of targeted treatment approaches and immunotherapies expands, cfDNA analyses may reveal their utility not only as a biomarker of response but also for precision monitoring. In this review, we discuss the different applications of cfDNA analyses in patients with gastric and gastroesophageal junction cancer and the technical challenges that such liquid biopsies have yet to overcome.
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Affiliation(s)
| | - Mascha Binder
- Correspondence: ; Tel.: +49-345-557-4972; Fax: +49-345-557-2950
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Ajani JA, D'Amico TA, Bentrem DJ, Chao J, Cooke D, Corvera C, Das P, Enzinger PC, Enzler T, Fanta P, Farjah F, Gerdes H, Gibson MK, Hochwald S, Hofstetter WL, Ilson DH, Keswani RN, Kim S, Kleinberg LR, Klempner SJ, Lacy J, Ly QP, Matkowskyj KA, McNamara M, Mulcahy MF, Outlaw D, Park H, Perry KA, Pimiento J, Poultsides GA, Reznik S, Roses RE, Strong VE, Su S, Wang HL, Wiesner G, Willett CG, Yakoub D, Yoon H, McMillian N, Pluchino LA. Gastric Cancer, Version 2.2022, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 2022; 20:167-192. [PMID: 35130500 DOI: 10.6004/jnccn.2022.0008] [Citation(s) in RCA: 832] [Impact Index Per Article: 277.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Gastric cancer is the third leading cause of cancer-related deaths worldwide. Over 95% of gastric cancers are adenocarcinomas, which are typically classified based on anatomic location and histologic type. Gastric cancer generally carries a poor prognosis because it is often diagnosed at an advanced stage. Systemic therapy can provide palliation, improved survival, and enhanced quality of life in patients with locally advanced or metastatic disease. The implementation of biomarker testing, especially analysis of HER2 status, microsatellite instability (MSI) status, and the expression of programmed death-ligand 1 (PD-L1), has had a significant impact on clinical practice and patient care. Targeted therapies including trastuzumab, nivolumab, and pembrolizumab have produced encouraging results in clinical trials for the treatment of patients with locally advanced or metastatic disease. Palliative management, which may include systemic therapy, chemoradiation, and/or best supportive care, is recommended for all patients with unresectable or metastatic cancer. Multidisciplinary team management is essential for all patients with localized gastric cancer. This selection from the NCCN Guidelines for Gastric Cancer focuses on the management of unresectable locally advanced, recurrent, or metastatic disease.
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Affiliation(s)
| | | | - David J Bentrem
- Robert H. Lurie Comprehensive Cancer Center of Northwestern University
| | | | | | | | - Prajnan Das
- The University of Texas MD Anderson Cancer Center
| | - Peter C Enzinger
- Dana-Farber/Brigham and Women's Cancer Center
- Massachusetts General Hospital Cancer Center
| | | | | | - Farhood Farjah
- Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance
| | | | | | | | | | | | - Rajesh N Keswani
- Robert H. Lurie Comprehensive Cancer Center of Northwestern University
| | | | | | - Samuel J Klempner
- Dana-Farber/Brigham and Women's Cancer Center
- Massachusetts General Hospital Cancer Center
| | - Jill Lacy
- Yale Cancer Center/Smilow Cancer Hospital
| | | | | | - Michael McNamara
- Case Comprehensive Cancer Center/University Hospitals Seidman Cancer Center and Cleveland Clinic Taussig Cancer Institute
| | - Mary F Mulcahy
- Robert H. Lurie Comprehensive Cancer Center of Northwestern University
| | | | - Haeseong Park
- Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine
| | - Kyle A Perry
- The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute
| | | | | | - Scott Reznik
- UT Southwestern Simmons Comprehensive Cancer Center
| | - Robert E Roses
- Abramson Cancer Center at the University of Pennsylvania
| | | | | | | | | | | | - Danny Yakoub
- St. Jude Children's Research Hospital/The University of Tennessee Health Science Center
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Mei Y, Wang S, Feng T, Yan M, Yuan F, Zhu Z, Li T, Zhu Z. Nomograms Involving HER2 for Predicting Lymph Node Metastasis in Early Gastric Cancer. Front Cell Dev Biol 2022; 9:781824. [PMID: 35004681 PMCID: PMC8740268 DOI: 10.3389/fcell.2021.781824] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Accepted: 12/07/2021] [Indexed: 01/19/2023] Open
Abstract
Objective: We aimed to establish a nomogram for predicting lymph node metastasis in early gastric cancer (EGC) involving human epidermal growth factor receptor 2 (HER2). Methods: We collected clinicopathological data of patients with EGC who underwent radical gastrectomy and D2 lymphadenectomy at Ruijin Hospital, Shanghai Jiao Tong University School of Medicine between January 2012 and August 2018. Univariate and multivariate logistic regression analysis were used to examine the relationship between lymph node metastasis and clinicopathological features. A nomogram was constructed based on a multivariate prediction model. Internal validation from the training set was performed using receiver operating characteristic (ROC) and calibration plots to evaluate discrimination and calibration, respectively. External validation from the validation set was utilized to examine the external validity of the prediction model using the ROC plot. A decision curve analysis was used to evaluate the benefit of the treatment. Results: Among 1,212 patients with EGC, 210 (17.32%) presented with lymph node metastasis. Multivariable analysis showed that age, tumor size, submucosal invasion, histological subtype, and HER2 positivity were independent risk factors for lymph node metastasis in EGC. The area under the ROC curve of the model was 0.760 (95% CI: 0.719–0.800) in the training set (n = 794) and 0.771 (95% CI: 0.714–0.828) in the validation set (n = 418). A predictive nomogram was constructed based on a multivariable prediction model. The decision curve showed that using the prediction model to guide treatment had a higher net benefit than using endoscopic submucosal dissection (ESD) absolute criteria over a range of threshold probabilities. Conclusion: A clinical prediction model and an effective nomogram with an integrated HER2 status were used to predict EGC lymph node metastasis with better accuracy and clinical performance.
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Affiliation(s)
- Yu Mei
- Department of General Surgery, Gastrointestinal Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Shuo Wang
- State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Tienan Feng
- Clinical Research Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Min Yan
- Department of General Surgery, Gastrointestinal Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Fei Yuan
- Department of Pathology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhenggang Zhu
- Department of General Surgery, Gastrointestinal Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Tian Li
- School of Basic Medicine, Fourth Military Medical University, Xi'an, China
| | - Zhenglun Zhu
- Department of General Surgery, Gastrointestinal Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Alsina M, Diez M, Tabernero J. Emerging biological drugs for the treatment of gastroesophageal adenocarcinoma. Expert Opin Emerg Drugs 2021; 26:385-400. [PMID: 34814781 DOI: 10.1080/14728214.2021.2010705] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
INTRODUCTION Gastric cancer (GC) and gastroesophageal junction cancer (GOJC) patients have a poor prognosis with a 5-year relative survival rate of 6% in the metastatic setting. Despite the well-characterized molecular features, patients have been historically considered for treatment with universal and undistinguishing chemotherapies and targeted agents, except for the HER2-positive population and some immunological approaches. AREAS COVERED In this review, we discuss the intrinsic characteristics of GC/GOJC from an epidemiological, molecular, and clinical perspective with an exhaustive evaluation of the reported and ongoing phase II/III clinical trials with targeted therapies. EXPERT OPINION The absence of robust biomarkers, the difficulties in measuring it due to the well-recognized molecular heterogeneity, and in part nonoptimistic clinical trial designs have been a major cause of frequent failure. Current efforts should focus on proper recognition of the distinctive molecular and clinical features of each GC/GOJC patient. Sequencing both tumor tissue DNA and ctDNA could identify targetable alterations, including rare alterations, thus allowing GC/GOJC patients for a precision medicine benefit.
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Affiliation(s)
- Maria Alsina
- Gastrointestinal and Endocrine Tumors Group, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain.,Medical Oncology Department, Hospital Universitario de Navarra (HUN), Pamplona, Spain
| | - Marc Diez
- Gastrointestinal and Endocrine Tumors Group, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
| | - Josep Tabernero
- Gastrointestinal and Endocrine Tumors Group, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
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Franchet C, Djerroudi L, Maran-Gonzalez A, Abramovici O, Antoine M, Becette V, Berghian A, Blanc-Fournier C, Brabencova E, Charafe-Jauffret E, Chenard MP, Dauplat MM, Delrée P, Duprez-Paumier R, Fleury C, Ghnassia JP, Haudebourg J, Leroux A, MacGrogan G, Mathieu MC, Michenet P, Penault-Llorca F, Poulet B, Robin YM, Roger P, Russ E, Tixier L, Treilleux I, Valent A, Verriele V, Vincent-Salomon A, Arnould L, Lacroix-Triki M. [2021 update of the GEFPICS' recommendations for HER2 status assessment in invasive breast cancer in France]. Ann Pathol 2021; 41:507-520. [PMID: 34393014 DOI: 10.1016/j.annpat.2021.07.014] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Revised: 07/01/2021] [Accepted: 07/11/2021] [Indexed: 12/15/2022]
Abstract
The last international guidelines on HER2 determination in breast cancer have been updated in 2018 by the American Society of Clinical Oncology and College of American Pathologists, on the basis of a twenty-year practice and results of numerous clinical trials. Moreover, the emerging HER2-low concept for 1+ and 2+ non amplified breast cancers lead to refine French practices for HER2 status assessment. The GEFPICS group, composed of expert pathologists, herein presents the latest French recommendations for HER2 status evaluation in breast cancer, taking into account the ASCO/CAP guidelines and introducing the HER2-low concept. In the era of personalized medicine, HER2 status assessment remains one of the most important biomarkers in breast cancer and its quality guaranties the optimal patients' care. French pathologists' commitment in theranostic biomarker quality is more than ever required to provide the most efficient cares in oncology.
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Affiliation(s)
- Camille Franchet
- Groupe d'étude des facteurs pronostiques immunohistochimiques dans le cancer du sein, Unicancer, 101, rue de Tolbiac, 75654 Paris cedex 13, France.
| | - Lounes Djerroudi
- Groupe d'étude des facteurs pronostiques immunohistochimiques dans le cancer du sein, Unicancer, 101, rue de Tolbiac, 75654 Paris cedex 13, France
| | - Aurélie Maran-Gonzalez
- Groupe d'étude des facteurs pronostiques immunohistochimiques dans le cancer du sein, Unicancer, 101, rue de Tolbiac, 75654 Paris cedex 13, France
| | - Olivia Abramovici
- Groupe d'étude des facteurs pronostiques immunohistochimiques dans le cancer du sein, Unicancer, 101, rue de Tolbiac, 75654 Paris cedex 13, France
| | - Martine Antoine
- Groupe d'étude des facteurs pronostiques immunohistochimiques dans le cancer du sein, Unicancer, 101, rue de Tolbiac, 75654 Paris cedex 13, France
| | - Véronique Becette
- Groupe d'étude des facteurs pronostiques immunohistochimiques dans le cancer du sein, Unicancer, 101, rue de Tolbiac, 75654 Paris cedex 13, France
| | - Anca Berghian
- Groupe d'étude des facteurs pronostiques immunohistochimiques dans le cancer du sein, Unicancer, 101, rue de Tolbiac, 75654 Paris cedex 13, France
| | - Cécile Blanc-Fournier
- Groupe d'étude des facteurs pronostiques immunohistochimiques dans le cancer du sein, Unicancer, 101, rue de Tolbiac, 75654 Paris cedex 13, France
| | - Eva Brabencova
- Groupe d'étude des facteurs pronostiques immunohistochimiques dans le cancer du sein, Unicancer, 101, rue de Tolbiac, 75654 Paris cedex 13, France
| | - Emmanuelle Charafe-Jauffret
- Groupe d'étude des facteurs pronostiques immunohistochimiques dans le cancer du sein, Unicancer, 101, rue de Tolbiac, 75654 Paris cedex 13, France
| | - Marie-Pierre Chenard
- Groupe d'étude des facteurs pronostiques immunohistochimiques dans le cancer du sein, Unicancer, 101, rue de Tolbiac, 75654 Paris cedex 13, France
| | - Marie-Mélanie Dauplat
- Groupe d'étude des facteurs pronostiques immunohistochimiques dans le cancer du sein, Unicancer, 101, rue de Tolbiac, 75654 Paris cedex 13, France
| | - Paul Delrée
- Groupe d'étude des facteurs pronostiques immunohistochimiques dans le cancer du sein, Unicancer, 101, rue de Tolbiac, 75654 Paris cedex 13, France
| | - Raphaëlle Duprez-Paumier
- Groupe d'étude des facteurs pronostiques immunohistochimiques dans le cancer du sein, Unicancer, 101, rue de Tolbiac, 75654 Paris cedex 13, France
| | - Clémence Fleury
- Groupe d'étude des facteurs pronostiques immunohistochimiques dans le cancer du sein, Unicancer, 101, rue de Tolbiac, 75654 Paris cedex 13, France
| | - Jean-Pierre Ghnassia
- Groupe d'étude des facteurs pronostiques immunohistochimiques dans le cancer du sein, Unicancer, 101, rue de Tolbiac, 75654 Paris cedex 13, France
| | - Juliette Haudebourg
- Groupe d'étude des facteurs pronostiques immunohistochimiques dans le cancer du sein, Unicancer, 101, rue de Tolbiac, 75654 Paris cedex 13, France
| | - Agnès Leroux
- Groupe d'étude des facteurs pronostiques immunohistochimiques dans le cancer du sein, Unicancer, 101, rue de Tolbiac, 75654 Paris cedex 13, France
| | - Gaëtan MacGrogan
- Groupe d'étude des facteurs pronostiques immunohistochimiques dans le cancer du sein, Unicancer, 101, rue de Tolbiac, 75654 Paris cedex 13, France
| | - Marie-Christine Mathieu
- Groupe d'étude des facteurs pronostiques immunohistochimiques dans le cancer du sein, Unicancer, 101, rue de Tolbiac, 75654 Paris cedex 13, France
| | - Patrick Michenet
- Groupe d'étude des facteurs pronostiques immunohistochimiques dans le cancer du sein, Unicancer, 101, rue de Tolbiac, 75654 Paris cedex 13, France
| | - Frédérique Penault-Llorca
- Groupe d'étude des facteurs pronostiques immunohistochimiques dans le cancer du sein, Unicancer, 101, rue de Tolbiac, 75654 Paris cedex 13, France
| | - Bruno Poulet
- Groupe d'étude des facteurs pronostiques immunohistochimiques dans le cancer du sein, Unicancer, 101, rue de Tolbiac, 75654 Paris cedex 13, France
| | - Yves Marie Robin
- Groupe d'étude des facteurs pronostiques immunohistochimiques dans le cancer du sein, Unicancer, 101, rue de Tolbiac, 75654 Paris cedex 13, France
| | - Pascal Roger
- Groupe d'étude des facteurs pronostiques immunohistochimiques dans le cancer du sein, Unicancer, 101, rue de Tolbiac, 75654 Paris cedex 13, France
| | - Elisabeth Russ
- Groupe d'étude des facteurs pronostiques immunohistochimiques dans le cancer du sein, Unicancer, 101, rue de Tolbiac, 75654 Paris cedex 13, France
| | - Lucie Tixier
- Groupe d'étude des facteurs pronostiques immunohistochimiques dans le cancer du sein, Unicancer, 101, rue de Tolbiac, 75654 Paris cedex 13, France
| | - Isabelle Treilleux
- Groupe d'étude des facteurs pronostiques immunohistochimiques dans le cancer du sein, Unicancer, 101, rue de Tolbiac, 75654 Paris cedex 13, France
| | - Alexander Valent
- Groupe d'étude des facteurs pronostiques immunohistochimiques dans le cancer du sein, Unicancer, 101, rue de Tolbiac, 75654 Paris cedex 13, France
| | - Véronique Verriele
- Groupe d'étude des facteurs pronostiques immunohistochimiques dans le cancer du sein, Unicancer, 101, rue de Tolbiac, 75654 Paris cedex 13, France
| | - Anne Vincent-Salomon
- Groupe d'étude des facteurs pronostiques immunohistochimiques dans le cancer du sein, Unicancer, 101, rue de Tolbiac, 75654 Paris cedex 13, France
| | - Laurent Arnould
- Groupe d'étude des facteurs pronostiques immunohistochimiques dans le cancer du sein, Unicancer, 101, rue de Tolbiac, 75654 Paris cedex 13, France
| | - Magali Lacroix-Triki
- Groupe d'étude des facteurs pronostiques immunohistochimiques dans le cancer du sein, Unicancer, 101, rue de Tolbiac, 75654 Paris cedex 13, France
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Rosenbaum MW, Gonzalez RS. Immunohistochemistry as predictive and prognostic markers for gastrointestinal malignancies. Semin Diagn Pathol 2021; 39:48-57. [PMID: 34740486 DOI: 10.1053/j.semdp.2021.10.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Accepted: 10/28/2021] [Indexed: 11/11/2022]
Abstract
Biomarkers play a key role in the comprehensive pathologic evaluation of gastrointestinal malignancies. These biomarkers can be predictive, indicating whether a tumor is likely to respond to a particular therapy, or prognostic, providing information about the likely course and outcome of a disease. This review article will discuss available immunohistochemical stains for assessing these markers, including staining rationale, scoring criteria, associated systemic therapies, and pictorial examples. PD-L1, HER2, and mismatch repair status can be evaluated via immunohistochemistry for esophageal, gastric, and colorectal carcinomas. Biomarkers currently play a more limited role in evaluation of pancreatic and small bowel malignancies. Immunohistochemistry can also be used to evaluate biomarker status in gastrointestinal stromal tumors, gastrointestinal malignancies with NTRK gene fusions, and undifferentiated carcinomas with switch-sucrose non-fermentable complex abnormalities.
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Affiliation(s)
- Matthew W Rosenbaum
- Department of Pathology, Beth Israel Deaconess Medical Center, United States
| | - Raul S Gonzalez
- Department of Pathology, Beth Israel Deaconess Medical Center, United States.
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Liu Y, Chen L, Jiang D, Luan L, Huang J, Hou Y, Xu C. HER2 promotes epithelial-mesenchymal transition through regulating osteopontin in gastric cancer. Pathol Res Pract 2021; 227:153643. [PMID: 34634565 DOI: 10.1016/j.prp.2021.153643] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2021] [Revised: 09/24/2021] [Accepted: 09/30/2021] [Indexed: 01/07/2023]
Abstract
AIMS HER2 and osteopontin (OPN) are both important biomarkers in gastric cancer (GC). The relationships between them remain to be revealed. The purpose of this study is to explore the role of OPN in epithelial-mesenchymal transition (EMT) in HER2 positive GCs. METHODS Nanostring analysis was used to compare the mRNA levels of 730 cancer related genes between paired HER2 3+ and non-3+ areas in GC patients. Immunohistochemistry (IHC) staining was performed to analyze the expression levels of OPN, as well as EMT markers including E-cad, N-cad, twist and vimentin in both areas. To further verify the role of OPN in EMT, the expression levels of OPN and EMT markers, tumor invasion/migration were analyzed after down-regulating HER2 and OPN in GC cell lines MKN-45 and N-87. RESULTS Nanostring analysis identified 8 differential expression genes between HER2 3+ and non-3+ areas. Among them, the expression level of OPN was positively correlated with that of HER2. In GC specimens, OPN showed higher expression level in HER2 3+ areas where higher E-cad expression levels and lower N-cad and twist levels were also found. After knocking down OPN and HER2 by siRNA, both cell lines show decreased invasion/migration abilities, along with the down-regulation of the EMT phenotype, supporting by the decrease of E-cad, and the increase of N-cad and twist at both mRNA and protein levels. In addition, HER2 knock-down lead to a dramatic decrease of OPN expression. CONCLUSIONS These findings indicate that HER2 may promote EMT via the regulation of OPN in GCs.
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Affiliation(s)
- Yalan Liu
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China; Department of Pathology, School of Basic Medical Sciences & Zhongshan Hospital, Fudan University, Shanghai, China
| | - Lingli Chen
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China; Department of Pathology, School of Basic Medical Sciences & Zhongshan Hospital, Fudan University, Shanghai, China
| | - Dongxian Jiang
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China; Department of Pathology, School of Basic Medical Sciences & Zhongshan Hospital, Fudan University, Shanghai, China
| | - Lijuan Luan
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China; Department of Pathology, School of Basic Medical Sciences & Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jie Huang
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China; Department of Pathology, School of Basic Medical Sciences & Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yingyong Hou
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China; Department of Pathology, School of Basic Medical Sciences & Zhongshan Hospital, Fudan University, Shanghai, China.
| | - Chen Xu
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China; Department of Pathology, School of Basic Medical Sciences & Zhongshan Hospital, Fudan University, Shanghai, China.
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Liao H, Tian T, Sheng Y, Peng Z, Li Z, Wang J, Li Y, Zhang C, Gao J. The Significance of MET Expression and Strategies of Targeting MET Treatment in Advanced Gastric Cancer. Front Oncol 2021; 11:719217. [PMID: 34557411 PMCID: PMC8453156 DOI: 10.3389/fonc.2021.719217] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Accepted: 08/20/2021] [Indexed: 11/18/2022] Open
Abstract
Background Accurate assessment of predictive biomarker expression is critical in patient selection in clinical trials or clinical practice. However, changes in biomarker expression may occur after treatment. The aim of the present study was to evaluate the effects of chemotherapy on MET expression in gastric cancer (GC). Methods MET expression was examined immunohistochemically before and after treatment in 122 patients with unresectable or recurrent GC, and was evaluated according to H-score or the scoring criteria used in the MetMAb trial. MET gene amplification was assessed by chromogenic in situ hybridization (CISH). The antitumor effect of MET targeted therapy was investigated in human gastric cancer cells in vitro and in vivo, and the underlying molecular mechanisms were analyzed by western blot. Results MET expression was associated with Lauren classification as well as tumor differentiation by either scoring system. MET amplification was not associated with clinical characteristics. Of the 71 patients who had paired pre- and post-treatment tumor tissues, 28 patients (39%) were initially positive for MET expression, and 43 (61%) were negative. Twenty-five patients (35%) showed significant changes in MET expression after treatment (P=0.007). Additionally, there was a concomitant overexpression of MET and HER2 in a subset of GC patients. MET inhibitor volitinib could significantly inhibit cell proliferation and xenograft growth in vitro and in vivo in MKN45 cells with MET and phosphorylated MET (pMET) high expressions via suppressing downstream PI3K/Akt and MAPK signaling pathways. Furthermore, combination therapy targeting both MET and HER2 demonstrated a synergistic antitumor activity. Conclusions MET expression is altered post chemotherapy and MET status should be evaluated in real-time. Both MET and pMET expressions might need to be considered for patients suitable for volitinib treatment.
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Affiliation(s)
- Haiyan Liao
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, China
| | - Tiantian Tian
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing, China.,Department of Oncology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China
| | - Yuling Sheng
- School of Medicine, The Southern University of Science and Technology, Shenzhen, China
| | - Zhi Peng
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing, China
| | - Zhongwu Li
- Department of Pathology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing, China
| | - Jingyuan Wang
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing, China
| | - Yanyan Li
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing, China
| | - Cheng Zhang
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing, China
| | - Jing Gao
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, China
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Grillo F, Mastracci L, Saragoni L, Vanoli A, Limarzi F, Gullo I, Ferro J, Paudice M, Parente P, Fassan M. Neoplastic and pre-neoplastic lesions of the oesophagus and gastro-oesophageal junction. Pathologica 2021; 112:138-152. [PMID: 33179618 PMCID: PMC7931575 DOI: 10.32074/1591-951x-164] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Accepted: 06/29/2020] [Indexed: 12/12/2022] Open
Abstract
Oesophageal and gastro-oesophageal junction (GOJ) neoplasms, and their predisposing conditions, may be encountered by the practicing pathologist both as biopsy samples and as surgical specimens in daily practice. Changes in incidence of oesophageal squamous cell carcinomas (such as a decrease in western countries) and in oesophageal and GOJ adenocarcinomas (such as a sharp increase in western countries) are being reported globally. New modes of treatment have changed our histologic reports as specific aspects must be detailed such as in post endoscopic resections or with regards to post neo-adjuvant therapy tumour regression grades. The main aim of this overview is therefore to provide an up-to-date, easily available and clear diagnostic approach to neoplastic and pre-neoplastic conditions of the oesophagus and GOJ, based on the most recent available guidelines and literature.
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Affiliation(s)
- Federica Grillo
- Anatomic Pathology Unit, Department of Surgical Sciences and Integrated Diagnostics (DICS), University of Genova, Italy.,Ospedale Policlinico San Martino, IRCCS for Oncology and Neuroscience, Genova, Italy
| | - Luca Mastracci
- Anatomic Pathology Unit, Department of Surgical Sciences and Integrated Diagnostics (DICS), University of Genova, Italy.,Ospedale Policlinico San Martino, IRCCS for Oncology and Neuroscience, Genova, Italy
| | - Luca Saragoni
- UO Anatomia Patologica, Ospedale G.B. Morgagni-L. Pierantoni, Forlì, Italy
| | - Alessandro Vanoli
- Anatomic Pathology Unit, Department of Molecular Medicine, University of Pavia and Fondazione IRCCS San Matteo Hospital, Pavia, Italy
| | - Francesco Limarzi
- Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST/IRCCS), Meldola (FC), Italy
| | - Irene Gullo
- Department of Pathology, Centro Hospitalar Universitário de São João (CHUSJ) & Department of Pathology, Faculty of Medicine of the University of Porto (FMUP), Porto, Portugal and Instituto de Investigação e Inovação em Saúde (i3S) & Institute of Molecular Pathology and Immunology of the University of Porto (Ipatimup), Porto, Portugal
| | - Jacopo Ferro
- Anatomic Pathology Unit, Department of Surgical Sciences and Integrated Diagnostics (DICS), University of Genova, Italy
| | - Michele Paudice
- Anatomic Pathology Unit, Department of Surgical Sciences and Integrated Diagnostics (DICS), University of Genova, Italy
| | - Paola Parente
- Unit of Pathology, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo (FG), Italy
| | - Matteo Fassan
- Surgical Pathology Unit, Department of Medicine (DIMED), University of Padua, Italy
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48
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Grieb BC, Agarwal R. HER2-Directed Therapy in Advanced Gastric and Gastroesophageal Adenocarcinoma: Triumphs and Troubles. Curr Treat Options Oncol 2021; 22:88. [PMID: 34424404 PMCID: PMC8436174 DOI: 10.1007/s11864-021-00884-7] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/23/2021] [Indexed: 01/22/2023]
Abstract
OPINION STATEMENT Gastric and gastroesophageal junction (GEJ) cancers represent the third leading cause of malignancy-associated death worldwide. Approximately 15-20% of these adenocarcinomas overexpress the human epidermal growth factor receptor 2 (HER2), a pro-proliferative receptor tyrosine kinase that has been therapeutically exploited in other disease contexts. The landmark ToGA trial demonstrated that trastuzumab, an anti-HER2 antibody, could improve overall survival for patients with HER2 overexpressing advanced gastric and GEJ adenocarcinomas. In the ensuing decade, great effort has been made to refine and expand this therapeutic strategy through a variety of avenues including optimization of chemotherapy backbones, identifying potential synergy with immune checkpoint inhibition, deployment of alternative HER2-targeted antibodies, use of small molecule inhibitors, and development of HER2-directed antibody drug conjugates. While the results of these efforts have had variable success, they have led to a greater understanding of the mechanisms of both primary and acquired resistance to HER2-directed therapies, laying the groundwork for future investigations. Recently, KEYNOTE-811 and DESTINY-Gastric01 have led to the FDA approvals of pembrolizumab in combination with trastuzumab and chemotherapy in the 1st-line advanced setting and trastuzumab deruxtecan (fam-trastuzumab deruxtecan-nxki) in the 2nd-line setting, respectively. Herein, we review these significant works as well as discuss the ongoing investigations they have inspired, which aim to find and utilize additional means for targeting HER2 in gastric and GEJ cancers.
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Affiliation(s)
- Brian C Grieb
- Division of Hematology/Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
- Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, USA
| | - Rajiv Agarwal
- Division of Hematology/Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
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Jenniskens JCA, Offermans K, Samarska I, Fazzi GE, Simons CCJM, Smits KM, Schouten LJ, Weijenberg MP, van den Brandt PA, Grabsch HI. Validity and Reproducibility of Immunohistochemical Scoring by Trained Non-Pathologists on Tissue Microarrays. Cancer Epidemiol Biomarkers Prev 2021; 30:1867-1874. [PMID: 34272264 DOI: 10.1158/1055-9965.epi-21-0295] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Revised: 05/04/2021] [Accepted: 07/12/2021] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND Scoring of immunohistochemistry (IHC) staining is often done by non-pathologists, especially in large-scale tissue microarray (TMA)-based studies. Studies on the validity and reproducibility of scoring results from non-pathologists are limited. Therefore, our main aim was to assess interobserver agreement between trained non-pathologists and an experienced histopathologist for three IHC markers with different subcellular localization (nucleus/membrane/cytoplasm). METHODS Three non-pathologists were trained in recognizing adenocarcinoma and IHC scoring by a senior histopathologist. Kappa statistics were used to analyze interobserver and intraobserver agreement for 6,249 TMA cores from a colorectal cancer series. RESULTS Interobserver agreement between non-pathologists (independently scored) and the histopathologist was "substantial" for nuclear and membranous IHC markers (κrange = 0.67-0.75 and κrange = 0.61-0.69, respectively), and "moderate" for the cytoplasmic IHC marker (κrange = 0.43-0.57). Scores of the three non-pathologists were also combined into a "combination score" (if at least two non-pathologists independently assigned the same score to a core, this was the combination score). This increased agreement with the pathologist (κnuclear = 0.74; κmembranous = 0.73; κcytopasmic = 0.57). Interobserver agreement between non-pathologists was "substantial" (κnuclear = 0.78; κmembranous = 0.72; κcytopasmic = 0.61). Intraobserver agreement of non-pathologists was "substantial" to "almost perfect" (κnuclear,range = 0.83-0.87; κmembranous,range = 0.75-0.82; κcytopasmic = 0.69). Overall, agreement was lowest for the cytoplasmic IHC marker. CONCLUSIONS This study shows that adequately trained non-pathologists are able to generate reproducible IHC scoring results, that are similar to those of an experienced histopathologist. A combination score of at least two non-pathologists yielded optimal results. IMPACT Non-pathologists can generate reproducible IHC results after appropriate training, making analyses of large-scale molecular pathological epidemiology studies feasible within an acceptable time frame.
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Affiliation(s)
- Josien C A Jenniskens
- Department of Epidemiology, GROW School for Oncology and Developmental Biology, Maastricht University Medical Center+, Maastricht, the Netherlands
| | - Kelly Offermans
- Department of Epidemiology, GROW School for Oncology and Developmental Biology, Maastricht University Medical Center+, Maastricht, the Netherlands
| | - Iryna Samarska
- Department of Pathology, GROW School for Oncology and Developmental Biology, Maastricht University Medical Center+, Maastricht, the Netherlands
| | - Gregorio E Fazzi
- Department of Pathology, GROW School for Oncology and Developmental Biology, Maastricht University Medical Center+, Maastricht, the Netherlands
| | - Colinda C J M Simons
- Department of Epidemiology, GROW School for Oncology and Developmental Biology, Maastricht University Medical Center+, Maastricht, the Netherlands
| | - Kim M Smits
- Department of Pathology, GROW School for Oncology and Developmental Biology, Maastricht University Medical Center+, Maastricht, the Netherlands
| | - Leo J Schouten
- Department of Epidemiology, GROW School for Oncology and Developmental Biology, Maastricht University Medical Center+, Maastricht, the Netherlands
| | - Matty P Weijenberg
- Department of Epidemiology, GROW School for Oncology and Developmental Biology, Maastricht University Medical Center+, Maastricht, the Netherlands
| | - Piet A van den Brandt
- Department of Epidemiology, GROW School for Oncology and Developmental Biology, Maastricht University Medical Center+, Maastricht, the Netherlands. .,Department of Epidemiology, Care and Public Health Research Institute (CAPHRI), Maastricht University Medical Center+, Maastricht, the Netherlands
| | - Heike I Grabsch
- Department of Pathology, GROW School for Oncology and Developmental Biology, Maastricht University Medical Center+, Maastricht, the Netherlands. .,Pathology and Data Analytics, Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, United Kingdom
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50
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Kahraman S, Yalcin S. Recent Advances in Systemic Treatments for HER-2 Positive Advanced Gastric Cancer. Onco Targets Ther 2021; 14:4149-4162. [PMID: 34285507 PMCID: PMC8286155 DOI: 10.2147/ott.s315252] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2021] [Accepted: 06/09/2021] [Indexed: 12/13/2022] Open
Abstract
Gastric cancer (GC) is the fifth most common cancer worldwide. Despite recent improvements in treatment quality and options, advanced gastric cancer remains one of the hardest to cure cancers, with a median overall survival (OS) of 10–12 months and a 5-year OS of approximately 5–20%. There is an unmet need for further efforts to palliate disease-related symptoms, improve quality of life, increase tumor response rate, and prolong progression free and overall survival while balancing the toxicities of therapy. The most common type of GC is adenocarcinoma, which demonstrates morphological, biological, and clinical heterogeneity. A plethora of genomic alterations and the activation of numerous molecular pathways including human epidermal growth receptor 2 (HER2), epidermal growth factor receptor (EGFR), fibroblast growth factor receptor-2 (FGFR2), mesenchymal epidermal transforming factor receptor (MET), and the phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) are responsible for the complex heterogeneity of GC. Efforts to validate the therapeutic effects of inhibiting some of these aberrantly expressed pathways have failed to lead to a clinically meaningful outcome apart from the overexpression/amplification of the HER2 gene, inhibition of which has had a significant impact on clinical practice. The only available biomarkers to guide the effective treatment of patients with advanced GC are HER2 overexpression, MSI/PD-L1 status, and FGFR alterations. Various anti-HER2 agents have been evaluated after the success of the ToGA trial, but none led to a significant enough clinical improvement to be considered a viable alternative for HER2-targeted therapy in advanced GC until the global Keynote-811 trial, which added pembrolizumab to trastuzumab in combination with chemotherapy. This combination demonstrated a survival advantage for the first time in the 11 years since ToGA. Trastuzumab deruxtecan (T-DXd) was also found to be effective in patients who had already received >2 previous lines of treatment. Despite these promising avenues, the optimal management of HER-2 positive GC still requires further development.
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Affiliation(s)
- Seda Kahraman
- Yıldırım Beyazıt University Faculty of Medicine, Department of Medical Oncology, Ankara, Turkey
| | - Suayib Yalcin
- Hacettepe University Institute of Cancer, Department of Medical Oncology, Ankara, Turkey
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