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He WZ, Yang YZ, Yin CX, Xian XY, Gu JM, Yi JH, Xue J, Zhao Y, Wang F, Hu WM, Xia LP. Evolution of HER2-low expression from primary to paired metastatic gastric cancer lesions. NPJ Precis Oncol 2025; 9:108. [PMID: 40234621 PMCID: PMC12000306 DOI: 10.1038/s41698-025-00881-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2024] [Accepted: 03/15/2025] [Indexed: 04/17/2025] Open
Abstract
HER2-low expression has recently gained considerable attention as an actionable biomarker in gastric cancer. However, changes in HER2-low expression between primary and metastatic gastric cancers remain inadequately explored. This study included consecutive patients diagnosed with metastatic gastric cancer with both primary and metastatic tumors, between January 2014 and December 2023. HER2 status was evaluated in both primary and matched metastatic tumors. A total of 332 patients were enrolled, with HER2-negative, HER2-low, and HER2-positive statuses were observed in 226, 81, and 25 primary tumors, respectively, and in 175, 104, and 53 metastatic tumors, respectively. Among the 226 patients with HER2-negative primary tumors, 74 and 23 developed HER2-low and HER2-positive metastatic tumors, respectively. Conversion from HER2-negative primary to HER2-low metastatic gastric cancer was associated with metachronous and non-peritoneal metastasis. Overall, re-biopsy to evaluate HER2 status may be necessary, potentially broadening the patient population eligible for targeted HER2 therapy.
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Affiliation(s)
- Wen-Zhuo He
- Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, PR China
| | - Yuan-Zhong Yang
- Department of Pathology, Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, PR China
| | - Chen-Xi Yin
- Department of Intensive Care Unit, Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, PR China
| | - Xin-Yi Xian
- Department of Pathology, Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, PR China
| | - Jia-Mei Gu
- Department of Molecular Diagnostics, Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, PR China
| | - Jia-Hong Yi
- Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, PR China
| | - Ju Xue
- Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, PR China
| | - Yue Zhao
- Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, PR China
| | - Fang Wang
- Department of Molecular Diagnostics, Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, PR China.
| | - Wan-Ming Hu
- Department of Pathology, Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, PR China.
| | - Liang-Ping Xia
- Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, PR China.
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2
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He WZ, Yang YZ, Yin CX, Xian XY, Gu JM, Yi JH, Xue J, Zhao Y, Wang F, Hu WM, Xia LP. Evolution of HER2-low expression from primary to paired metastatic gastric cancer lesions. NPJ Precis Oncol 2025; 9:108. [DOI: 40234621 10.1038/s41698-025-00881-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2024] [Accepted: 03/15/2025] [Indexed: 05/20/2025] Open
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3
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He L, Liu B, Wang Z, Han Q, Chen H. Evolving Landscape of HER2-Targeted Therapies for Gastric Cancer Patients. Curr Treat Options Oncol 2025; 26:260-277. [PMID: 40056280 DOI: 10.1007/s11864-025-01300-0] [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] [Accepted: 02/06/2025] [Indexed: 03/10/2025]
Abstract
OPINION STATEMENT Gastric cancer (GC) is a deadly disease worldwide, and trastuzumab in combination with chemotherapy has been the standard first-line treatment for HER2-positive GC following the TOGA trial. Besides adjuvant therapy, HER2-directed therapy is widely used as neoadjuvant or translational therapy, and survival benefit even surgical opportunities is seen in these patients. However, resistance is not rare in recent years, and the second-line treatment for trastuzumab beyond progression has received widespread attention in GC. Moreover, current evidence cannot recommend trastuzumab for patients with IHC1+ HER2 low expression GC yet. Researchers are currently investigating whether GC patients with low HER2 expression could also benefit from HER2-directed therapies. In addition to using HER2 as a target for targeted therapy, HER2-mediated targeted delivery of cytotoxic drugs and targeted immunity have made important contributions to overcoming trastuzumab resistance in recent trials. HER2/neu-derived peptide epitopes vaccination and HER2-specific chimeric antigen receptor (CAR) therapy focus on reestablishing anti-tumor immunity in different ways and show significant anti-tumor activity. Other antibodies that target different regions of the HER2 receptor or block key downstream pathways such as AKT or PI3K also offer potential anti-tumor activity against HER2. HER2 use in GC will not be hampered by resistance or low expression and will play a bigger role. We review the current efforts to enable GC patients with trastuzumab-resistant and HER2 low-expressing accessible to HER2 targeted therapy and present our consideration for future HER2 in GC.
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Affiliation(s)
- Lijuan He
- Lanzhou University Second Hospital, Lanzhou, 730030, China
- Department of Surgical Oncology, Lanzhou University Second Hospital, Lanzhou, 730030, China
| | - Ben Liu
- Lanzhou University Second Hospital, Lanzhou, 730030, China
- Department of Surgical Oncology, Lanzhou University Second Hospital, Lanzhou, 730030, China
| | - Zhuanfang Wang
- Lanzhou University Second Hospital, Lanzhou, 730030, China
- Department of Surgical Oncology, Lanzhou University Second Hospital, Lanzhou, 730030, China
| | - Qinying Han
- Lanzhou University Second Hospital, Lanzhou, 730030, China
- Department of Surgical Oncology, Lanzhou University Second Hospital, Lanzhou, 730030, China
| | - Hao Chen
- Lanzhou University Second Hospital, Lanzhou, 730030, China.
- Department of Surgical Oncology, Lanzhou University Second Hospital, Lanzhou, 730030, China.
- Gansu Provincial Key Laboratory of Environmental Oncology, Lanzhou, 730030, China.
- Humanized animal model laboratory, Lanzhou University Second Hospital, Lanzhou, 730030, China.
- Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201620, China.
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4
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Rajadurai P, Ravindran S, Lee BR, Md Pauzi SH, Chiew SF, Teoh KH, S Raja Gopal N, Md Yusof M, Yip CH. Consensus Guidelines on Human Epidermal Growth Factor Receptor 2 (HER2)-Low Testing in Breast Cancer in Malaysia. Cancers (Basel) 2024; 16:2325. [PMID: 39001387 PMCID: PMC11240573 DOI: 10.3390/cancers16132325] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Revised: 06/18/2024] [Accepted: 06/22/2024] [Indexed: 07/16/2024] Open
Abstract
Breast cancer is one of the most common cancers in Malaysia. Recently, a new nomenclature was introduced for breast cancers with human epidermal growth factor receptor 2 (HER2) immunohistochemistry (IHC) 1+, or 2+ with negative in situ hybridization (ISH), i.e., HER2-low breast cancer. In current clinical practice, these breast cancers are reported as HER2-negative. Clinical trials have shown that HER2-low breast cancer benefits from targeted therapy with anti-HER2 antibody-drug conjugates. Unfortunately, various challenges and obstacles are faced by local pathologists in HER2 testing, which may jeopardize the standard of care for patients with HER2-low breast cancer. This consensus guideline aims to elucidate standard practices pertaining to HER2 testing and HER2-low interpretation in Malaysia. Topics discussed among a panel of local experts include tissue sampling and handling, assay and antibody selection, result interpretation and reporting, and quality assurance. Practice recommendations made in this consensus guideline reflect current international guidelines and, where appropriate, adapted to the Malaysian landscape.
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Affiliation(s)
- Pathmanathan Rajadurai
- Subang Jaya Medical Centre, Subang Jaya 47500, Malaysia
- Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Petaling Jaya 47500, Malaysia
- Department of Pathology, University of Malaya Medical Centre, Lembah Pantai, Kuala Lumpur 59100, Malaysia
| | - Sarala Ravindran
- Premier Integrated Labs, Pantai Hospital Kuala Lumpur, Kuala Lumpur 59100, Malaysia
| | | | - Suria Hayati Md Pauzi
- Department of Pathology, Faculty of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Kuala Lumpur 56000, Malaysia
| | - Seow Fan Chiew
- Department of Pathology, University of Malaya Medical Centre, Lembah Pantai, Kuala Lumpur 59100, Malaysia
| | - Kean Hooi Teoh
- Sunway Medical Centre, Bandar Sunway, Subang Jaya 47500, Malaysia
| | | | | | - Cheng Har Yip
- Subang Jaya Medical Centre, Subang Jaya 47500, Malaysia
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5
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Kumarasinghe MP, Houghton D, Allanson BM, Price TJ. What Therapeutic Biomarkers in Gastro-Esophageal Junction and Gastric Cancer Should a Pathologist Know About? Surg Pathol Clin 2023; 16:659-672. [PMID: 37863558 DOI: 10.1016/j.path.2023.05.004] [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: 10/22/2023]
Abstract
Malignancies of upper gastrointestinal tract are aggressive, and most locally advanced unresectable and metastatic cancers are managed by a combination of surgery and neoadjuvant/adjuvant chemotherapy and radiotherapy. Current therapeutic recommendations include targeted therapies based on biomarker expression of an individual tumor. All G/gastro-esophageal junction (GEJ) cancers should be tested for HER2 status as a reflex test at the time of diagnosis. Currently, testing for PDL 1 and mismatch repair protein status is optional. HER2 testing is restricted to adenocarcinomas only and endoscopic biopsies, resections, or cellblocks. Facilities should be available for performing validated immunohistochemical stains and in-situ hybridization techniques, and importantly, pathologists should be experienced with preanalytical and analytical issues and scoring criteria. Genomic profiling via next-generation sequencing (NGS) is another strategy that assess numerous mutations and other molecular events simultaneously, including HER2 amplification, MSS status, tumor mutation burden, and neurotrophic tropomyosin-receptor kinases gene fusions.
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Affiliation(s)
- Marian Priyanthi Kumarasinghe
- Anatomical Pathology, PathWest, QEII Medical Centre, School of Pathology and Laboratory Medicine, UWA and Curtin Medical School, J Block, Hospital Avenue, Nedlands, Western Australia 6009, Australia.
| | - Daniel Houghton
- Department of Anatomical Pathology, PathWest, QEII Medical Centre, J Block, Hospital Avenue, Nedlands, Western Australia 6009, Australia
| | - Benjamin Michael Allanson
- Department of Anatomical Pathology, PathWest, QEII Medical Centre, J Block, Hospital Avenue, Nedlands, Western Australia 6009, Australia
| | - Timothy J Price
- Department Medical Oncology, The Queen Elizabeth Hospital and University of Adelaide, Adelaide, South Australia, Australia
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Nakamura M, Watanabe A, Yoshizawa A, Iwasaki S, Nomura A, Matsumura M, Murai T, Itaya K, Koike Y, Izumi T, Endo A, Kato S, Ono Y, Ohshima T, Okazaki N, Nakagawa S, Ishii Y, Fukasawa Y, Yokota I, Tsuji T, Nishikawa S. The risk of weekend biopsy: Impact of specimen source and fixation status on HER2 assessment in the treatment of advanced gastric cancer (The HER_WEEKEND study). Pathol Int 2023; 73:509-519. [PMID: 37589434 PMCID: PMC11551806 DOI: 10.1111/pin.13367] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2023] [Revised: 07/24/2023] [Accepted: 07/30/2023] [Indexed: 08/18/2023]
Abstract
Accurate evaluation of human epidermal growth factor receptor type 2 (HER2) expression is crucial for determining chemotherapy regimens in gastric cancer. However, formalin fixation status has been identified as an important factor affecting HER2 assessment reliability. This retrospective cohort study aimed to investigate the correlation between sample collection day (weekday vs. weekend) and source (biopsy vs. surgical specimens) in assessing HER2 expression in patients with unresectable advanced/recurrent gastric cancer. Data were collected from gastric cancer patients who received chemotherapy at a single public hospital in Japan from 2008 to 2021. The analysis included 177 patients (109 men, 68 women) with a median age of 68.0 (21-88) years, and the primary outcome was the HER2 positivity rate. The overall HER2 positivity rate was 18.1%, with higher rates on weekdays (20.0%) compared to weekends (12.8%). Biopsies had higher positivity rates on weekdays (23.9%) but lower rates on weekends (11.1%) than surgical specimens. Significant differences were observed in formalin fixation times between weekdays and weekends for both biopsies and surgical samples. The study findings suggest that longer formalin fixation times on weekends may lead to underestimating HER2 expression, particularly in biopsies. Therefore, it is crucial to be cautious of excessive formalin fixation when collecting samples, especially during weekend biopsies.
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Affiliation(s)
- Michio Nakamura
- Department of GastroenterologySapporo City General HospitalSapporoJapan
| | - Ayako Watanabe
- Department of Clinical LaboratoriesSapporo City General HospitalSapporoJapan
| | - Aki Yoshizawa
- Department of Clinical LaboratoriesSapporo City General HospitalSapporoJapan
| | - Sari Iwasaki
- Department of PathologySapporo City General HospitalSapporoJapan
| | - Asako Nomura
- Department of GastroenterologySapporo City General HospitalSapporoJapan
| | - Mariko Matsumura
- Department of GastroenterologySapporo City General HospitalSapporoJapan
| | - Taichi Murai
- Department of GastroenterologySapporo City General HospitalSapporoJapan
| | - Kazufumi Itaya
- Department of GastroenterologySapporo City General HospitalSapporoJapan
| | - Yuta Koike
- Department of GastroenterologySapporo City General HospitalSapporoJapan
| | - Takaaki Izumi
- Department of GastroenterologySapporo City General HospitalSapporoJapan
| | - Ayana Endo
- Department of GastroenterologySapporo City General HospitalSapporoJapan
| | - Shin Kato
- Department of GastroenterologySapporo City General HospitalSapporoJapan
| | - Yuji Ono
- Department of GastroenterologySapporo City General HospitalSapporoJapan
| | | | - Nanase Okazaki
- Department of PathologySapporo City General HospitalSapporoJapan
| | - Shimpei Nakagawa
- Department of PathologySapporo City General HospitalSapporoJapan
| | - Yasushi Ishii
- Department of PathologySapporo City General HospitalSapporoJapan
| | | | - Isao Yokota
- Department of Biostatistics, Graduate School of MedicineHokkaido UniversitySapporoJapan
| | - Takahiro Tsuji
- Department of PathologySapporo City General HospitalSapporoJapan
| | - Shuji Nishikawa
- Department of GastroenterologySapporo City General HospitalSapporoJapan
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7
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Lawson NL, Scorer PW, Williams GH, Vandenberghe ME, Ratcliffe MJ, Barker C. Impact of Decalcification, Cold Ischemia, and Deglycosylation on Performance of Programmed Cell Death Ligand-1 Antibodies With Different Binding Epitopes: Comparison of 7 Clones. Mod Pathol 2023; 36:100220. [PMID: 37230414 DOI: 10.1016/j.modpat.2023.100220] [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: 01/09/2023] [Revised: 05/04/2023] [Accepted: 05/10/2023] [Indexed: 05/27/2023]
Abstract
Programmed cell death ligand-1 (PD-L1) expression levels in patients' tumors have demonstrated clinical utility across many cancer types and are used to determine treatment eligibility. Several independently developed PD-L1 immunohistochemical (IHC) predictive assays are commercially available and have demonstrated different levels of staining between assays, generating interest in understanding the similarities and differences between assays. Previously, we identified epitopes in the internal and external domains of PD-L1, bound by antibodies in routine clinical use (SP263, SP142, 22C3, and 28-8). Variance in performance of assays utilizing these antibodies, observed following exposure to preanalytical factors such as decalcification, cold ischemia, and duration of fixation, encouraged additional investigation of antibody-binding sites, to understand whether binding site structures/conformations contribute to differential PD-L1 IHC assay staining. We proceeded to further investigate the epitopes on PD-L1 bound by these antibodies, alongside the major clones utilized in laboratory-developed tests (E1L3N, QR1, and 73-10). Characterization of QR1 and 73-10 clones demonstrated that both bind the PD-L1 C-terminal internal domain, similar to SP263/SP142. Our results also demonstrate that under suboptimal decalcification or fixation conditions, the performance of internal domain antibodies is less detrimentally affected than that of external domain antibodies 22C3/28-8. Furthermore, we show that the binding sites of external domain antibodies are susceptible to deglycosylation and conformational structural changes, which directly result in IHC staining reduction or loss. The binding sites of internal domain antibodies were unaffected by deglycosylation or conformational structural change. This study demonstrates that the location and conformation of binding sites, recognized by antibodies employed in PD-L1 diagnostic assays, differ significantly and exhibit differing degrees of robustness. These findings should reinforce the need for vigilance when performing clinical testing with different PD-L1 IHC assays, particularly in the control of cold ischemia and the selection of fixation and decalcification conditions.
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Affiliation(s)
- Nicola L Lawson
- Precision Medicine and Biosamples, Oncology R&D, AstraZeneca, Cambridge, United Kingdom; Biologics Engineering, Oncology R&D, AstraZeneca, Cambridge, United Kingdom.
| | - Paul W Scorer
- Precision Medicine and Biosamples, Oncology R&D, AstraZeneca, Cambridge, United Kingdom
| | | | - Michel E Vandenberghe
- Precision Medicine and Biosamples, Oncology R&D, AstraZeneca, Cambridge, United Kingdom
| | - Marianne J Ratcliffe
- Precision Medicine and Biosamples, Oncology R&D, AstraZeneca, Cambridge, United Kingdom
| | - Craig Barker
- Precision Medicine and Biosamples, Oncology R&D, AstraZeneca, Cambridge, United Kingdom
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8
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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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9
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Ngaiza A, Vuhahula E, Yahaya J, Ndayisaba MC, Kawishe GJ, Grenert JP, Zhang L, Van Loon K, Ng DL. Evaluation of Human Epidermal Growth Factor Receptor 2 Expression in Gastric and Gastroesophageal Cancers in Tanzania. Arch Pathol Lab Med 2022; 146:1523-1529. [PMID: 35344993 PMCID: PMC9515243 DOI: 10.5858/arpa.2021-0394-oa] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/28/2021] [Indexed: 11/06/2022]
Abstract
CONTEXT.— The incidence of human epidermal growth factor receptor 2 (HER2) positivity in gastric cancers differs widely across various populations and is unknown in many low-resource settings. OBJECTIVE.— To evaluate the rates of HER2 positivity in gastric and gastroesophageal adenocarcinoma at a national referral hospital in East Africa. We also assessed the association between HER2 overexpression and patient clinicopathologic characteristics. DESIGN.— A retrospective review of cases diagnosed as either gastric or gastroesophageal adenocarcinoma between 2013 and 2017 was performed at Muhimbili National Hospital in Dar es Salaam, Tanzania. Of 1205 specimens meeting inclusion criteria, stratified random sampling was conducted to select 150 cases for HER2 immunohistochemistry and clinicopathologic analysis. RESULTS.— The median age of patients was 56.5 years, with 65.3% (98 of 150) of the cohort composed of male patients, and 34.7% (52 of 150) of female patients. HER2 overexpression was identified in 6.0% (9 of 150) of cases. Approximately half of the tumors (51.3%; 77 of 150) were intestinal-type gastric adenocarcinoma, and 36.0% (54 of 150) were moderately differentiated. Intestinal-type (P = .01) and well-differentiated tumors (P = .001) were associated with HER2 overexpression. CONCLUSIONS.— HER2 overexpression was primarily seen in intestinal-type and well-differentiated tumors. Therefore, prioritizing HER2 testing for patients with intestinal-type, well-differentiated, or moderately differentiated gastric and gastroesophageal adenocarcinomas may be appropriate in Tanzania in efforts to allocate testing for patients who are most likely to benefit from trastuzumab therapy.
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Affiliation(s)
- Advera Ngaiza
- From the Department of Pathology, Muhimbili National Hospital, Dar es Salaam, Tanzania (Ngaiza, Vuhahula)
| | - Edda Vuhahula
- From the Department of Pathology, Muhimbili National Hospital, Dar es Salaam, Tanzania (Ngaiza, Vuhahula)
- The Department of Pathology, Muhimbili University of Health and Allied Sciences, Dar es Salaam, Tanzania (Vuhahula)
| | - James Yahaya
- The Department of Histopathology and Morbid Anatomy, University of Dodoma, Dodoma, Tanzania (Yahaya)
| | - Marie Claire Ndayisaba
- The Department of Pathology, University Teaching Hospital of Kigali, Kigali, Rwanda (Ndayisaba)
| | - Gerald J Kawishe
- The Department of Molecular Biology and Biotechnology, University of Dar es Salaam, Dar es Salaam, Tanzania (Kawishe)
| | - James P Grenert
- The Department of Pathology (Grenert, Ng), University of California, San Francisco
| | - Li Zhang
- The Department of Epidemiology and Biostatistics (Zhang), University of California, San Francisco
- The Division of Hematology/Oncology, Department of Medicine (Zhang, Van Loon), University of California, San Francisco
- The Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco (Ng, Zhang, Van Loon)
| | - Katherine Van Loon
- The Division of Hematology/Oncology, Department of Medicine (Zhang, Van Loon), University of California, San Francisco
- The Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco (Ng, Zhang, Van Loon)
| | - Dianna L Ng
- The Department of Pathology (Grenert, Ng), University of California, San Francisco
- The Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco (Ng, Zhang, Van Loon)
- Ng is currently affiliated with the Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York
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10
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Juarez I, Toro-Fernandez JF, Vaquero-Yuste C, Molina-Alejandre M, Lasa I, Gomez R, Lopez A, Martin-Villa JM, Gutierrez A. A Reliable and Standardizable Differential PCR and qPCR Methodology Assesses HER2 Gene Amplification in Gastric Cancer. BIOLOGY 2021; 10:516. [PMID: 34200787 PMCID: PMC8230392 DOI: 10.3390/biology10060516] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Revised: 05/28/2021] [Accepted: 06/03/2021] [Indexed: 11/16/2022]
Abstract
We have applied two PCR techniques, differential PCR (diffPCR) and qPCR for the identification of HER2 gene amplifications in genomic DNA of tumor and distal gastric samples from patients with gastric cancer. The diffPCR technique consists of the simultaneous amplification of the HER2 gene and a housekeeping gene by conventional PCR and the densitometric analysis of the bands obtained. We established a cut-off point based on the mean and standard deviation analyzing the DNA of 30 gastric tissues from patients undergoing non-cancer gastrectomy. diffPCR and qPCR yielded consistent results. HER2-overexpression was detected in 25% of patients and was further confirmed by immunohistochemistry and immunofluorescence. The approaches herein described may serve as complementary and reliable methods to assess HER2 amplification.
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Affiliation(s)
- Ignacio Juarez
- Department of Immunology, Ophthalmology and ENT, Facultad de Medicina, Universidad Complutense de Madrid (UCM), 28040 Madrid, Spain; (I.J.); (J.F.T.-F.); (C.V.-Y.); (M.M.-A.)
- Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), 28007 Madrid, Spain
| | - Juan Francisco Toro-Fernandez
- Department of Immunology, Ophthalmology and ENT, Facultad de Medicina, Universidad Complutense de Madrid (UCM), 28040 Madrid, Spain; (I.J.); (J.F.T.-F.); (C.V.-Y.); (M.M.-A.)
| | - Christian Vaquero-Yuste
- Department of Immunology, Ophthalmology and ENT, Facultad de Medicina, Universidad Complutense de Madrid (UCM), 28040 Madrid, Spain; (I.J.); (J.F.T.-F.); (C.V.-Y.); (M.M.-A.)
| | - Marta Molina-Alejandre
- Department of Immunology, Ophthalmology and ENT, Facultad de Medicina, Universidad Complutense de Madrid (UCM), 28040 Madrid, Spain; (I.J.); (J.F.T.-F.); (C.V.-Y.); (M.M.-A.)
| | - Inmaculada Lasa
- Hospital Universitario Príncipe de Asturias, 28006 Madrid, Spain; (I.L.); (R.G.); (A.L.); (A.G.)
| | - Remedios Gomez
- Hospital Universitario Príncipe de Asturias, 28006 Madrid, Spain; (I.L.); (R.G.); (A.L.); (A.G.)
| | - Adela Lopez
- Hospital Universitario Príncipe de Asturias, 28006 Madrid, Spain; (I.L.); (R.G.); (A.L.); (A.G.)
| | - Jose Manuel Martin-Villa
- Department of Immunology, Ophthalmology and ENT, Facultad de Medicina, Universidad Complutense de Madrid (UCM), 28040 Madrid, Spain; (I.J.); (J.F.T.-F.); (C.V.-Y.); (M.M.-A.)
- Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), 28007 Madrid, Spain
| | - Alberto Gutierrez
- Hospital Universitario Príncipe de Asturias, 28006 Madrid, Spain; (I.L.); (R.G.); (A.L.); (A.G.)
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11
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Ireka Y, Agustina H, Aziz A, Hernowo BS, Suryanti S. Comparison of Fixation Methods for Preservation Cytology Specimens of Cell Block Preparation Using 10% Neutral Buffer Formalin and 96% Alcohol Fixation in E-cadherin and Ki-67 Immunohistochemical Examination. Open Access Maced J Med Sci 2019; 7:3139-3144. [PMID: 31949505 PMCID: PMC6953932 DOI: 10.3889/oamjms.2019.452] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2019] [Revised: 08/19/2019] [Accepted: 08/20/2019] [Indexed: 11/17/2022] Open
Abstract
BACKGROUND: Cytological and molecular examinations are among the most important examinations in cancer diagnosis. 96% alcohol is a fixative solution commonly used by clinicians for cytological samples because of its accessibility and affordability. Cellblock preparation from cytology specimen may increase morphology detail and may be used for further biomarker analysis. E-cadherin is an adhesion protein expressed in the cell membrane of most carcinoma. Ki67 is a protein expressed in nuclei of malignant cells that used as a proliferation marker. AIM: This study was designed to investigate the effect of fixation duration in 96% alcohol on protein preservation for immunohistochemistry (IHC) evaluation compared to 10% neutral buffered formalin (NBF) as the gold standard. METHODS: Twenty-five fine-needle aspiration biopsy (FNAB) specimen diagnosed as carcinoma were fixed in 10% NBF and 96% alcohol for 1 hour, 6 hours, 24 hours, 48 hours and 72 hours. Cell blocks preparation were made from those 6 groups of specimens. E-cadherin and Ki67 IHC were done to cell blocks section and evaluated. The data were statistically analysed using the Friedman test with p-value < 0.05 of a significant level. RESULTS: There were significant differences between E-cadherin and Ki67 expression in cell block preparation from 96% alcohol-fixed cytology specimen for 1 hour, 6 hours, 24 hours, 48 hours and 72 hours to 10% NBF (p = 0.0001). CONCLUSION: The result indicated that 96% alcohol is not suitable as a fixative solution for cell block preparation in E-cadherin and Ki-67 IHC examination.
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Affiliation(s)
- Yuke Ireka
- Department of Pathology Anatomy, Faculty of Medicine, Padjadjaran University, RSUP Dr Hasan Sadikin, Bandung, Indonesia.,Oncology and Stem Cell Working Group, Faculty of Medicine, Padjadjaran University, Bandung, Indonesia
| | - Hasrayati Agustina
- Department of Pathology Anatomy, Faculty of Medicine, Padjadjaran University, RSUP Dr Hasan Sadikin, Bandung, Indonesia.,Oncology and Stem Cell Working Group, Faculty of Medicine, Padjadjaran University, Bandung, Indonesia
| | - Afiati Aziz
- Department of Pathology Anatomy, Faculty of Medicine, Padjadjaran University, RSUP Dr Hasan Sadikin, Bandung, Indonesia.,Oncology and Stem Cell Working Group, Faculty of Medicine, Padjadjaran University, Bandung, Indonesia
| | - Bethy S Hernowo
- Department of Pathology Anatomy, Faculty of Medicine, Padjadjaran University, RSUP Dr Hasan Sadikin, Bandung, Indonesia.,Oncology and Stem Cell Working Group, Faculty of Medicine, Padjadjaran University, Bandung, Indonesia
| | - Sri Suryanti
- Department of Pathology Anatomy, Faculty of Medicine, Padjadjaran University, RSUP Dr Hasan Sadikin, Bandung, Indonesia.,Oncology and Stem Cell Working Group, Faculty of Medicine, Padjadjaran University, Bandung, Indonesia
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12
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Subasinghe D, Acott N, Kumarasinghe MP. A survival guide to HER2 testing in gastric/gastroesophageal junction carcinoma. Gastrointest Endosc 2019; 90:44-54. [PMID: 30928424 DOI: 10.1016/j.gie.2019.03.022] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2018] [Accepted: 03/14/2019] [Indexed: 02/06/2023]
Abstract
Human epidermal growth factor receptor 2 (HER2) status determines gastric/gastroesophageal junction (GEJ) adenocarcinomas that benefit from targeted therapy; hence, HER2 testing has become a routine practice. Accurate HER2 testing is fundamental to select eligible patients who will benefit from HER2-targeted treatment. The reported HER2-positive rate in gastric/GEJ cancers ranges from 4.4% to 53.4%, and HER2-positive tumors are considered to have more-aggressive biologic behavior and tumor recurrence. Main modalities of HER2 testing in clinical practice include immunohistochemistry (IHC) for protein expression and in situ hybridization (ISH) for gene amplification. Many technical pitfalls affect the accuracy of HER2 result. Additionally, several issues in HER2 testing are related to the tumor biology, sample selection, interpretation of IHC and ISH results, and confirming HER2 status. Therefore, gastric/GEJ adenocarcinoma-specific HER2 testing protocols have been developed and standardized to minimize the impact of these preanalytical and analytical factors and to enhance reproducibility of HER2 testing results. This review provides up-to-date practical guidance to clinicians on accurate HER2 testing and interpretation of results in gastric/GEJ adenocarcinoma.
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Affiliation(s)
- Duminda Subasinghe
- Department of Surgery, Faculty of Medicine, University of Colombo, Colombo, Sri Lanka; Digestive Disease Unit, Aintree University Hospital, NHS Foundation Trust, Liverpool, UK; Pathwest Laboratory Medicine, Perth and University of Western Australia, Perth, Australia
| | - Nathan Acott
- Pathwest Laboratory Medicine, Perth and University of Western Australia, Perth, Australia
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13
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Kai K, Yoda Y, Kawaguchi A, Minesaki A, Iwasaki H, Aishima S, Noshiro H. Formalin fixation on HER-2 and PD-L1 expression in gastric cancer: A pilot analysis using the same surgical specimens with different fixation times. World J Clin Cases 2019; 7:419-430. [PMID: 30842953 PMCID: PMC6397813 DOI: 10.12998/wjcc.v7.i4.419] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2018] [Revised: 12/24/2018] [Accepted: 12/29/2018] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND The needs for human epidermal growth factor receptor 2 (HER-2) and/or programmed death-ligand 1 (PD-L1) evaluations in gastric cancer are dramatically increasing. Although the importance of standardization of sample fixation has been widely recognized, most of the evidence regarding the fixation duration or type of fixing solution are based on breast cancer. AIM To investigate the real effects of fixation conditions on HER-2 testing or PD-L1 testing for gastric cancer using gastrectomy specimens. METHODS Thirty-two patients who underwent gastrectomy for gastric cancer were enrolled. Their resected specimens were each divided into four pieces and fixed in four strictly controlled different durations (6 h, 24 h, and 48 h, and 1 wk) by 10% formalin (n = 22) or 10% neutral buffered formalin (NBF) (n = 10). Immunohistochemistry (IHC) of HER-2 and PD-1 was performed, and a pathology examination was conducted. In the HER-2-immunoreactive cases, all four specimens were subjected to dual-color in situ hybridization (DISH). Five cases were assessed as HER-2-positive by IHC and DISH. We used the cut-off values of 1%, 10%, and 50% to assess the IHC findings of PD-L1. RESULTS No significant difference was observed in comparisons between the shorter fixation period groups (6 h, 24 h, and 48 h) and the prolonged fixation period (1 wk) group in the HER-2 and PD-L1 analyses. Although no significant difference was observed between 10% formalin and 10% NBF within 1 wk of fixation, the superiority of 10% NBF was confirmed in a long-term (> 3 mo) fixation in both the HER-2 and PD-L1 analyses. CONCLUSION In this small-numbered pilot study, prolonged fixation within 1 wk showed no inferiority in HER-2 or PD-L1 testing. However, a large-numbered prospective study is needed to obtain conclusive results.
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Affiliation(s)
- Keita Kai
- Department of Pathology, Saga University Hospital, Saga 849-8501, Japan
| | - Yukie Yoda
- Department of Surgery, Saga University Faculty of Medicine, Saga 849-8501, Japan
| | - Atsushi Kawaguchi
- Center for Comprehensive Community Medicine, Saga University Faculty of Medicine, Saga 849-8501, Japan
| | - Akimichi Minesaki
- Department of Pathology and Microbiology, Saga University Faculty of Medicine, Saga 849-8501, Japan
- Department of Otolaryngology - Head and Neck Surgery, Saga University Faculty of Medicine, Saga 849-8501, Japan
| | - Hironori Iwasaki
- Department of Surgery, Saga University Faculty of Medicine, Saga 849-8501, Japan
| | - Shinichi Aishima
- Department of Pathology, Saga University Hospital, Saga 849-8501, Japan
- Department of Pathology and Microbiology, Saga University Faculty of Medicine, Saga 849-8501, Japan
| | - Hirokazu Noshiro
- Department of Surgery, Saga University Faculty of Medicine, Saga 849-8501, Japan
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14
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Yamashita-Kashima Y, Yoshimura Y, Fujimura T, Shu S, Yanagisawa M, Yorozu K, Furugaki K, Higuchi R, Shoda J, Harada N. Molecular targeting of HER2-overexpressing biliary tract cancer cells with trastuzumab emtansine, an antibody–cytotoxic drug conjugate. Cancer Chemother Pharmacol 2019; 83:659-671. [DOI: 10.1007/s00280-019-03768-8] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2018] [Accepted: 01/05/2019] [Indexed: 12/24/2022]
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15
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Saeki H, Oki E, Kashiwada T, Arigami T, Makiyama A, Iwatsuki M, Narita Y, Satake H, Matsuda Y, Sonoda H, Shimokawa M, Maehara Y. Re-evaluation of HER2 status in patients with HER2-positive advanced or recurrent gastric cancer refractory to trastuzumab (KSCC1604). Eur J Cancer 2018; 105:41-49. [PMID: 30391779 DOI: 10.1016/j.ejca.2018.09.024] [Citation(s) in RCA: 64] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2018] [Revised: 09/12/2018] [Accepted: 09/22/2018] [Indexed: 12/31/2022]
Abstract
BACKGROUND Anti-HER2 therapy has not demonstrated a survival advantage in the second-line setting of patients with HER2-positive gastric cancer. We conducted this study to assess changes in HER2 status and to identify possible biomarkers for acquired resistance after the use of trastuzumab as the first-line therapy. PATIENTS AND METHODS Patients with advanced or recurrent HER2-positive gastric adenocarcinoma who were diagnosed with progressive disease after the first-line trastuzumab-based therapy and developed pathologically confirmed adenocarcinoma within 3 months after completion of trastuzumab-based therapy were enrolled in this study. We collected re-biopsied samples from the HER2-positive patients who had developed resistance to trastuzumab and re-evaluated their HER2 status. Amplification of EGFR and c-met, as well as PIK3CA mutation, were comparatively analysed when samples were available. RESULTS Among 33 eligible patients, loss of HER2 was identified in 20 patients (60.6%) with refractory disease. Immunohistochemistry showed that the rate of HER2 overexpression was greatly reduced after therapy (pre-HER2 3+: 24 [72.7%] vs. post-HER2 3+: 13 [39.4%]). We found that the use of fixatives other than 10% neutral buffered formalin significantly reduced the HER2-positive rate. EGFR amplification, c-met amplification and PIK3CA mutation before and after trastuzumab-based therapy were observed in 10.3% and 3.8%, 17.9% and 4.2% and 4.0% and 4.2% of cases, respectively. CONCLUSION Re-evaluation of HER2 status is needed to determine the appropriate use of anti-HER2-targeted therapy after disease progression. Our results also highlight the importance of formalin fixation conditions for HER2 testing.
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Affiliation(s)
- Hiroshi Saeki
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Japan
| | - Eiji Oki
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Japan.
| | - Tomomi Kashiwada
- Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Japan
| | - Takaaki Arigami
- Department of Digestive Surgery, Breast and Thyroid Surgery, Kagoshima University Graduate School of Medical and Dental Sciences, Japan
| | - Akitaka Makiyama
- Department of Hematology/Oncology, Japan Community Healthcare Organization Kyushu Hospital, Japan
| | - Masaaki Iwatsuki
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Japan
| | - Yukiya Narita
- Department of Clinical Oncology, Aichi Cancer Center Hospital, Japan
| | - Hironaga Satake
- Department of Medical Oncology, Kobe City Medical Center General Hospital, Japan
| | - Yoshiko Matsuda
- Division of Gastrointestinal Surgery, Department of Surgery, Graduate School of Medicine, Kobe University, Japan
| | - Hideto Sonoda
- Department of Surgery, Imari Arita Kyoritsu Hospital, Japan
| | - Mototsugu Shimokawa
- Clinical Research Institute, Cancer Biostatistics Laboratory, National Kyushu Cancer Center, Fukuoka, Japan
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16
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Shu S, Iimori M, Nakanishi R, Jogo T, Saeki H, Oki E, Maehara Y. Changes in HER2 Expression and Amplification Status Following Preoperative Chemotherapy for Gastric Cancer. In Vivo 2018; 32:1491-1498. [PMID: 30348707 PMCID: PMC6365720 DOI: 10.21873/invivo.11405] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2018] [Revised: 09/11/2018] [Accepted: 09/13/2018] [Indexed: 12/16/2022]
Abstract
BACKGROUND It is essential to establish a strategy for second-line treatment for human epidermal growth factor receptor 2 (HER2)-positive gastric cancer; however, HER2 expression status after chemotherapy treatment is not routinely determined. MATERIALS AND METHODS We analyzed 25 cases of gastric cancer that received preoperative chemotherapy and selected the six pre-treatment samples that were HER2-positive. Pre- and post-treatment tumor samples were examined for HER2 expression, and for HER2, epidermal growth factor receptor (EGFR), and hepatocyte growth factor receptor (MET) gene amplification. RESULTS Three patients had been treated with trastuzumab plus chemotherapy, and three patients with cytotoxic chemotherapy alone. Only one case that had an initial HER2 score of 3+ and had received trastuzumab plus chemotherapy remained HER2-positive after treatment. Decrease or loss of HER2 expression and amplification was observed in the other five patients. Amplification of EGFR or MET was not observed in any pre- or post-treatment specimens. CONCLUSION Our data suggest that trastuzumab plus chemotherapy or chemotherapy alone may induce loss of HER2 positivity.
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Affiliation(s)
- Sei Shu
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Kyushu University, Fukuoka, Japan
- Product Research Department, Medical Affairs Division, Chugai Pharmaceutical Co., Ltd., Kamakura, Japan
| | - Makoto Iimori
- Department of Molecular Cancer Biology, Graduate School of Pharmaceutical Sciences, Kyushu University, Kyushu University, Fukuoka, Japan
| | - Ryota Nakanishi
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Kyushu University, Fukuoka, Japan
| | - Tomoko Jogo
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Kyushu University, Fukuoka, Japan
| | - Hiroshi Saeki
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Kyushu University, Fukuoka, Japan
| | - Eiji Oki
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Kyushu University, Fukuoka, Japan
| | - Yoshihiko Maehara
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Kyushu University, Fukuoka, Japan
- Kyushu Central Hospital of the Mutual Aid Association of Public School Teachers, Fukuoka, Japan
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17
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Wong NACS, Amary F, Butler R, Byers R, Gonzalez D, Haynes HR, Ilyas M, Salto-Tellez M, Taniere P. HER2 testing of gastro-oesophageal adenocarcinoma: a commentary and guidance document from the Association of Clinical Pathologists Molecular Pathology and Diagnostics Committee. J Clin Pathol 2018; 71:388-394. [PMID: 29439009 DOI: 10.1136/jclinpath-2017-204943] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2017] [Revised: 01/12/2018] [Accepted: 01/15/2018] [Indexed: 01/29/2023]
Abstract
The use of biologics targeted to the human epidermal growth factor receptor 2 (HER2) protein is the latest addition to the armamentarium used to fight advanced gastric or gastro-oesophageal junction adenocarcinoma. The decision to treat with the biologic trastuzumab is completely dependent on HER2 testing of tumour tissue. In 2017, the College of American Pathologists, American Society for Clinical Pathology and the American Society of Clinical Oncology jointly published guidelines for HER2 testing and clinical decision making in gastro-oesophageal adenocarcinoma. The Association of Clinical Pathologists Molecular Pathology and Diagnostics Committee has issued the following document as a commentary of these guidelines and, in parallel, to provide guidance on HER2 testing in National Health Service pathology departments within the UK. This guidance covers issues related to case selection, preanalytical aspects, analysis and interpretation of such HER2 testing.
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Affiliation(s)
| | - Fernanda Amary
- Department of Cellular and Molecular Pathology, Royal National Orthopaedic Hospital, Stanmore, UK
| | - Rachel Butler
- All Wales Genetics Laboratory, University Hospital of Wales, Cardiff, UK
| | - Richard Byers
- Department of Histopathology, Central Manchester University Hospitals NHS Trust, Manchester, UK
| | - David Gonzalez
- Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, UK
| | - Harry R Haynes
- Department of Cellular Pathology, University of Bristol and Southmead Hospital, Bristol, UK
| | - Mohammad Ilyas
- Division of Cancer and Stem Cells and Nottingham Molecular Pathology Node, Queen's Medical Centre, Nottingham, UK
| | - Manuel Salto-Tellez
- Northern Ireland - Molecular Pathology Laboratory, Queen's University, Belfast, UK
| | - Philippe Taniere
- Department of Cellular Pathology, Queen Elizabeth Hospital, Birmingham, UK
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18
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Seo KW, Jeon T, Kim S, Kim SS, Kim K, Suh BJ, Hwang S, Choi S, Ryu S, Min JS, Lee YJ, Jee YS, Chae H, Yang DH, Lee SH. Epidemiologic Study of Human Epidermal Growth Factor Receptor 2 Expression in Advanced/Metastatic Gastric Cancer: an Assessment of Human Epidermal Growth Factor Receptor 2 Status in Tumor Tissue Samples of Gastric and Gastro-Esophageal Junction Cancer. J Gastric Cancer 2017; 17:52-62. [PMID: 28337363 PMCID: PMC5362834 DOI: 10.5230/jgc.2017.17.e6] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2016] [Revised: 12/29/2016] [Accepted: 01/09/2017] [Indexed: 01/04/2023] Open
Abstract
Purpose The Trastuzumab for gastric cancer (GC) trial identified human epidermal growth factor receptor 2 (HER2) as a predictor of successful treatment with trastuzumab (HER2 receptor targeting agent) among patients with advanced/metastatic GC. To date, the prevalence of HER2 overexpression in the Korean population is unknown. The present study aimed to assess the incidence of HER2 positivity among GC and gastroesophageal (GE) junction cancer samples and the relationship between HER2 overexpression and clinicopathological characteristics in Korean patients. Materials and Methods Tumor samples collected from 1,695 patients with histologically proven GC or GE junction enrolled at 14 different hospitals in Korea were examined. After gathering clinicopathological data of all patients, HER2 status was assessed by immunohistochemistry (IHC) at each hospital, and IHC 2+ cases were subjected to silver-enhanced in situ hybridization at 3 central laboratories. Results A total of 182 specimens tested positive for HER2, whereas 1,505 tested negative. Therefore, the overall HER2-positive rate in this study was 10.8% (95% confidence interval=9.3%–12.3%). The HER2-positive rate was higher among intestinal-type cases (17.6%) than among other types, and was higher among patients older than 70 years and 50 years of age, compared to other age groups. Conclusions Our evaluation of the HER2 positivity rate (10.8%) among Korean patients with GC and GE junction indicated the necessity of epidemiological data when conducting studies related to HER2 expression in GC and GE junction.
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Affiliation(s)
- Kyung Won Seo
- Department of Surgery, Kosin University College of Medicine, Busan, Korea
| | - Taeyong Jeon
- Pusan National University Hospital, Busan, Korea
| | - Sewon Kim
- Yeungnam University Medical Center, Daegu, Korea
| | | | - Kwanghee Kim
- Inje University Busan Paik Hospital, Busan, Korea
| | - Byoung-Jo Suh
- Inje University Haeundae Paik Hospital, Busan, Korea
| | - Sunhwi Hwang
- Pusan National University Yangsan Hospital, Yangsan, Korea
| | - SeongHee Choi
- Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon, Korea
| | - Seungwan Ryu
- Keimyung University Dongsan Medical Center, Daegu, Korea
| | - Jae Seok Min
- Dongnam Institute of Radiological and Medical Sciences, Busan, Korea
| | | | | | | | - Doo Hyun Yang
- Chonbuk National University Medical School, Jeonju, Korea
| | - Sang Ho Lee
- Department of Surgery, Kosin University College of Medicine, Busan, Korea
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19
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A new method for real-time evaluation of pepsin digestion of paraffin-embedded tissue sections, prior to fluorescence in situ hybridisation. Virchows Arch 2017; 470:567-573. [DOI: 10.1007/s00428-017-2097-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2016] [Revised: 01/28/2017] [Accepted: 02/16/2017] [Indexed: 01/02/2023]
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20
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Bartley AN, Washington MK, Ventura CB, Ismaila N, Colasacco C, Benson AB, Carrato A, Gulley ML, Jain D, Kakar S, Mackay HJ, Streutker C, Tang L, Troxell M, Ajani JA. HER2 Testing and Clinical Decision Making in Gastroesophageal Adenocarcinoma: Guideline From the College of American Pathologists, American Society for Clinical Pathology, and American Society of Clinical Oncology. Arch Pathol Lab Med 2016; 140:1345-1363. [PMID: 27841667 DOI: 10.5858/arpa.2016-0331-cp] [Citation(s) in RCA: 123] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
CONTEXT - ERBB2 (erb-b2 receptor tyrosine kinase 2 or HER2) is currently the only biomarker established for selection of a specific therapy for patients with advanced gastroesophageal adenocarcinoma (GEA). However, there are no comprehensive guidelines for the assessment of HER2 in patients with GEA. OBJECTIVES - To establish an evidence-based guideline for HER2 testing in patients with GEA, to formalize the algorithms for methods to improve the accuracy of HER2 testing while addressing which patients and tumor specimens are appropriate, and to provide guidance on clinical decision making. DESIGN - The College of American Pathologists, American Society for Clinical Pathology, and American Society of Clinical Oncology convened an expert panel to conduct a systematic review of the literature to develop an evidence-based guideline with recommendations for optimal HER2 testing in patients with GEA. RESULTS - The panel is proposing 11 recommendations with strong agreement from the open-comment participants. RECOMMENDATIONS - The panel recommends that tumor specimen(s) from all patients with advanced GEA, who are candidates for HER2-targeted therapy, should be assessed for HER2 status before the initiation of HER2-targeted therapy. Clinicians should offer combination chemotherapy and a HER2-targeted agent as initial therapy for all patients with HER2-positive advanced GEA. For pathologists, guidance is provided for morphologic selection of neoplastic tissue, testing algorithms, scoring methods, interpretation and reporting of results, and laboratory quality assurance. CONCLUSIONS - This guideline provides specific recommendations for assessment of HER2 in patients with advanced GEA while addressing pertinent technical issues and clinical implications of the results.
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Affiliation(s)
- Angela N Bartley
- From the Department of Pathology, St. Joseph Mercy Hospital, Ann Arbor, Michigan (Dr Bartley); the Department of Pathology, Vanderbilt University Medical Center, Nashville, Tennessee (Dr Washington); Surveys (Ms Ventura) and Governance (Ms Colasacco), College of American Pathologists, Northfield, Illinois; Quality and Guidelines Department, American Society of Clinical Oncology, Alexandria, Virginia (Dr Ismaila); the Division of Hematology/Oncology, Northwestern University, Chicago, Illinois (Dr Benson); Medical Oncology Department, Ramon y Cajal University Hospital, Madrid, Spain (Dr Carrato); the Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill (Dr Gulley); the Department of Pathology, Yale University School of Medicine, New Haven, Connecticut (Dr Jain); the Department of Pathology and Laboratory Medicine, UCSF, San Francisco, California (Dr Kakar); the Division of Medical Oncology and Hematology, University of Toronto/Sunnybrook Odette Cancer Centre, Toronto, Ontario, Canada (Dr Mackay); the Department of Laboratory Medicine, St. Michael's Hospital, Toronto, Ontario, Canada (Dr Streutker); the Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York (Dr Tang); the Department of Pathology, Stanford University Medical Center, Stanford, California (Dr Troxell); and the Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston (Dr Ajani)
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21
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Bartley AN, Washington MK, Ventura CB, Ismaila N, Colasacco C, Benson AB, Carrato A, Gulley ML, Jain D, Kakar S, Mackay HJ, Streutker C, Tang L, Troxell M, Ajani JA. HER2 Testing and Clinical Decision Making in Gastroesophageal Adenocarcinoma: Guideline From the College of American Pathologists, American Society for Clinical Pathology, and American Society of Clinical Oncology. Am J Clin Pathol 2016; 146:647-669. [PMID: 28077399 PMCID: PMC6272805 DOI: 10.1093/ajcp/aqw206] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
CONTEXT ERBB2 (erb-b2 receptor tyrosine kinase 2 or HER2) is currently the only biomarker established for selection of a specific therapy for patients with advanced gastroesophageal adenocarcinoma (GEA). However, there are no comprehensive guidelines for the assessment of HER2 in patients with GEA. OBJECTIVES To establish an evidence-based guideline for HER2 testing in patients with GEA, to formalize the algorithms for methods to improve the accuracy of HER2 testing while addressing which patients and tumor specimens are appropriate, and to provide guidance on clinical decision making. DESIGN The College of American Pathologists, American Society for Clinical Pathology, and American Society of Clinical Oncology convened an expert panel to conduct a systematic review of the literature to develop an evidence-based guideline with recommendations for optimal HER2 testing in patients with GEA. RESULTS The panel is proposing 11 recommendations with strong agreement from the open-comment participants. RECOMMENDATIONS The panel recommends that tumor specimen(s) from all patients with advanced GEA, who are candidates for HER2-targeted therapy, should be assessed for HER2 status before the initiation of HER2-targeted therapy. Clinicians should offer combination chemotherapy and a HER2-targeted agent as initial therapy for all patients with HER2-positive advanced GEA. For pathologists, guidance is provided for morphologic selection of neoplastic tissue, testing algorithms, scoring methods, interpretation and reporting of results, and laboratory quality assurance. CONCLUSIONS This guideline provides specific recommendations for assessment of HER2 in patients with advanced GEA while addressing pertinent technical issues and clinical implications of the results.
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Affiliation(s)
- Angela N Bartley
- From the Department of Pathology, St Joseph Mercy Hospital, Ann Arbor, MI
| | - Mary Kay Washington
- Department of Pathology, Vanderbilt University Medical Center, Nashville, TN
| | | | - Nofisat Ismaila
- Quality and Guidelines Department, American Society of Clinical Oncology, Alexandria, VA
| | - Carol Colasacco
- Surveys and Governance, College of American Pathologists, Northfield, IL
| | - Al B Benson
- Division of Hematology/Oncology, Northwestern University, Chicago, IL
| | - Alfredo Carrato
- Medical Oncology Department, Ramon y Cajal University Hospital, Madrid, Spain
| | - Margaret L Gulley
- Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill
| | - Dhanpat Jain
- Department of Pathology, Yale University School of Medicine, New Haven, CT
| | - Sanjay Kakar
- Department of Pathology and Laboratory Medicine, UCSF, San Francisco, CA
| | - Helen J Mackay
- Division of Medical Oncology and Hematology, University of Toronto/Sunnybrook Odette Cancer Centre, Toronto, Canada
| | | | - Laura Tang
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Megan Troxell
- Department of Pathology, Stanford University Medical Center, Stanford, CA
| | - Jaffer A Ajani
- Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston
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Grillo F, Fassan M, Sarocchi F, Fiocca R, Mastracci L. HER2 heterogeneity in gastric/gastroesophageal cancers: From benchside to practice. World J Gastroenterol 2016; 22:5879-5887. [PMID: 27468182 PMCID: PMC4948273 DOI: 10.3748/wjg.v22.i26.5879] [Citation(s) in RCA: 82] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2016] [Revised: 05/13/2016] [Accepted: 05/21/2016] [Indexed: 02/06/2023] Open
Abstract
HER2 is overexpressed in approximately 10%-20% of gastric and gastroesophageal junction carcinomas. In these types of cancer, accurate assessment of HER2 status is mandatory, for selecting patients who may benefit from targeted therapies with anti-HER2 drugs such as Trastuzumab. This manuscript focuses on HER2 in gastric carcinogenesis, on optimal evaluation of HER2 and on the possible causes which may contribute to inaccurate HER2 evaluation. Similarly to breast cancer HER2 evaluation, standardization of HER2 testing in gastric cancer is necessary in diagnostic practice. The three principle aspects which require consideration are: (1) the choice of sample with regards to cancer morphology - intestinal vs diffuse areas; (2) the choice of scoring criteria - use of HER2 scoring criteria specific for gastric cancer; and (3) the choice of HER2 evaluation methods - use of an algorithm in which both immunohistochemistry and in situ hybridization play a role. Problematic issues include: (1) pre-analytic variables with particular emphasis on fixation; (2) recommended methodology for HER2 assessment (immunohistochemistry vs in situ hybridization); (3) HER2 heterogeneity both within the primary tumor and between primary tumor and metastases; (4) reliability of biopsies in HER 2 evaluation; and (5) quantity of sample (FFPE blocks from surgical specimens or endoscopic biopsies) necessary for an adequate assessment.
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Lilo MT, Allison D, Wang Y, Ao M, Gabrielson E, Geddes S, Zhang H, Askin F, Li QK. Expression of P40 and P63 in lung cancers using fine needle aspiration cases. Understanding clinical pitfalls and limitations. J Am Soc Cytopathol 2016; 5:123-132. [PMID: 27699149 PMCID: PMC5044754 DOI: 10.1016/j.jasc.2015.07.002] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/06/2023]
Abstract
BACKGROUND Fine-needle aspiration (FNA) biopsy of lung lesions is a highly accurate method for diagnosing and staging of lung cancers, particularly in patients with advanced cancer. Although, the majority of FNA cases of non-small cell lung carcinoma (NSCLC) can be subclassified by hematoxylin and eosin (H&E) sections, immunohistochemical (IHC) markers are usually necessary for difficult cases. Our previous study has shown that both P40 and P63 demonstrate differential sensitivity and specificity in the subclassification of squamous cell carcinoma (SqCC) using tumor tissue microarrays (TMA). In the present study, we further evaluated the utility of P40 and P63 and the potential pitfalls and limitations associated with the usefulness of these stains in FNA cases. METHODS By a computer search of pathology archives, 144 FNA biopsies with diagnoses of lung cancers and P40/P63 stains were identified, including 50 adenocarcinomas (ADCs), 56 SqCCs, 8 small cell lung carcinomas (SCLCs), and 12 cases of poorly differentiated carcinoma (PD CA). Ten benign FNA lung lesions and 8 other malignant neoplasms were also included as controls. Nuclear staining patterns of P40 and P63 were scored semi-quantitatively as 0 (negative), 1 (<10%, weak and focal), or 2 (>10%, strong and diffuse). RESULTS In lung SqCCs, P40 and P63 were positive in 77.3% and 89.5% cases, respectively. In ADCs, P40 was weakly and focally positive in 6.1% cases, and P63 was variably positive in 62.8% cases. In SCLCs, P40 and P63 were focally positive in 12.5% and 50% cases. In PD CAs, no P40 or P63 immunoreactivity was detected. In the group of other neoplasms (n=8) both P40 and P63 were positive in the case of metastatic non-seminomatous germ cell tumor (NSGCT) (n=1), and P63 was positive in the case of metastatic Merkel cell carcinoma (n=1). The sensitivity and specificity of P40 and P63 were 76.9%/93.3%, and 90.2%/50.7% in the lung SqCC. CONCLUSIONS P63 has a better sensitivity, and P40 has a better specificity for SqCC. A positive staining pattern with both markers was also found in certain non-SqCC cases. Recognizing limitations of these markers are particularly important in FNA cases.
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Affiliation(s)
- Mohammed T. Lilo
- The Department of Pathology, the Johns Hopkins Medical Institutions, Baltimore, MD 21224
| | - Derek Allison
- The Department of Pathology, the Johns Hopkins Medical Institutions, Baltimore, MD 21224
| | - Yuting Wang
- The Department of Chemistry, Magdalen College, University of Oxford, OX1 4AU, United Kingdom
| | - MingHui Ao
- The Department of Pathology, the Johns Hopkins Medical Institutions, Baltimore, MD 21224
| | - Edward Gabrielson
- The Department of Pathology, the Johns Hopkins Medical Institutions, Baltimore, MD 21224
| | - Susan Geddes
- The Department of Pathology, the Johns Hopkins Medical Institutions, Baltimore, MD 21224
| | - Hui Zhang
- The Department of Pathology, the Johns Hopkins Medical Institutions, Baltimore, MD 21224
| | - Frederic Askin
- The Department of Pathology, the Johns Hopkins Medical Institutions, Baltimore, MD 21224
| | - Qing Kay Li
- The Department of Pathology, the Johns Hopkins Medical Institutions, Baltimore, MD 21224
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Heterogeneity of anaplastic lymphoma kinase gene rearrangement in non-small-cell lung carcinomas: a comparative study between small biopsy and excision samples. J Thorac Oncol 2016; 10:800-805. [PMID: 25898958 DOI: 10.1097/jto.0000000000000507] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
INTRODUCTION The standard diagnostic method for echinoderm microtubule-associated protein-like 4-anaplastic lymphoma receptor tyrosine kinase translocation is fluorescence in situ hybridization (FISH). Recently, immunohistochemistry (IHC) has been reported as a potential method in screening for anaplastic lymphoma kinase (ALK)-positive non-small-cell lung carcinomas (NSCLC), whereas several authors have reported a discordance between FISH and IHC results. We investigated the heterogeneity of ALK gene rearrangement in excision specimens by FISH and also examined whether the FISH score of ALK gene rearrangement corresponded in excision and biopsy samples from the same patient. METHODS Twenty ALK IHC-positive patients including six patients treated with crizotinib therapy were evaluated for the presence of ALK FISH. For evaluation of heterogeneity of ALK gene rearrangement in excision specimens, we defined six to 10 observation areas in each case, and the number of ALK FISH positive observation areas (≥15% rearrangement detected) was investigated. ALK FISH score in small biopsy samples was classified as positive (≥15% rearrangement detected), equivocal (5-14% rearrangement detected), or negative (<4% rearrangement detected). RESULTS Of a total of 64 tumor observation areas from nine excision specimens, 50 areas were positive for ALK gene rearrangement (81.8%). In the comparison of excision and small biopsy samples, all excision specimens were ALK FISH-positive (100%; 6 of 6), whereas only three of the small biopsy samples in these patients were positive (50%; 3 of 6), two were equivocal (33%; 2 of 6), and one was negative (17%; 1 of 6). The two equivocal patients received crizotinib and showed a response. CONCLUSION ALK gene rearrangement heterogeneity was observed in NSCLC specimens by FISH. Our findings suggested that IHC-positive/FISH-equivocal cases should not be considered true "false-negatives" when a small biopsy sample was used for ALK analysis.
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Kawahara A, Taira T, Abe H, Takase Y, Kurita T, Sadashima E, Hattori S, Imamura I, Matsumoto S, Fujisaki H, Sueyoshi K, Akiba J, Kage M. Diagnostic utility of phosphorylated signal transducer and activator of transcription 5 immunostaining in the diagnosis of mammary analogue secretory carcinoma of the salivary gland: A comparative study of salivary gland cancers. Cancer Cytopathol 2015; 123:603-11. [DOI: 10.1002/cncy.21594] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2015] [Revised: 06/23/2015] [Accepted: 07/09/2015] [Indexed: 01/11/2023]
Affiliation(s)
- Akihiko Kawahara
- Department of Diagnostic Pathology; Kurume University Hospital; Kurume Japan
| | - Tomoki Taira
- Department of Diagnostic Pathology; Kurume University Hospital; Kurume Japan
| | - Hideyuki Abe
- Department of Diagnostic Pathology; Kurume University Hospital; Kurume Japan
| | - Yorihiko Takase
- Department of Diagnostic Pathology; Kurume University Hospital; Kurume Japan
| | - Takashi Kurita
- Head and Neck Surgery, Department of Otolaryngology; Kurume University School of Medicine; Kurume Japan
| | - Eiji Sadashima
- Biostatistics Center; Kurume University; Kurume Japan
- Shin-Koga Hospital; Kurume Japan
| | | | | | - Shinji Matsumoto
- Department of Pathology; Fukuoka University Hospital and School of Medicine; Fukuoka Japan
| | | | | | - Jun Akiba
- Department of Pathology; Kurume University School of Medicine; Kurume Japan
| | - Masayoshi Kage
- Department of Diagnostic Pathology; Kurume University Hospital; Kurume Japan
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Peng Z, Zou J, Zhang X, Yang Y, Gao J, Li Y, Li Y, Shen L. HER2 discordance between paired primary gastric cancer and metastasis: a meta-analysis. Chin J Cancer Res 2015; 27:163-71. [PMID: 25937778 DOI: 10.3978/j.issn.1000-9604.2014.12.09] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2014] [Accepted: 11/10/2014] [Indexed: 12/27/2022] Open
Abstract
BACKGROUND A number of studies have examined human epidermal growth factor receptor 2 (HER2) status in primary gastric cancer (GC) and associated metastasis, some showed their great concordance in HER2 expression, but others demonstrated notable discordance. There is still little consensus on HER2 discordance, therefore, a systematic review and meta-analysis was conducted to assess the status on HER2 discordance between primary GC and its paired metastasis. METHODS PubMed, EMBASE, ASCO and The Cochrane Library were searched for studies that explored the concordance between primary tumor and metastasis in patients with GC up to 10 March, 2014. Data of discordance of HER2 between primary GC and corresponding metastasis were extracted from the publications and random-effects models were used to estimate pooled discordance proportions. RESULTS Eighteen articles including 1,867 patients were included for the meta-analysis in accordance with the selection criteria. Pooled discordance proportions were 7% [95% confidence interval (CI): 5-10%] for HER2 status. Pooled proportions of tumors shifting from positive to negative and from negative to positive were 17% (95% CI: 7-29%) and 4% (95% CI: 2-6%) respectively. No publication bias was found in the meta-analysis. CONCLUSIONS The discordance of HER2 status is not rare in primary and metastatic GC through our meta-analysis. Prospective studies are needed to testify the clinical significance of the discordance of HER2 status.
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Affiliation(s)
- Zhi Peng
- 1 Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing 100142, China ; 2 Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & School of Basic Medicine Peking Union Medical College, Beijing 100730, China
| | - Jianling Zou
- 1 Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing 100142, China ; 2 Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & School of Basic Medicine Peking Union Medical College, Beijing 100730, China
| | - Xiaotian Zhang
- 1 Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing 100142, China ; 2 Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & School of Basic Medicine Peking Union Medical College, Beijing 100730, China
| | - Yehong Yang
- 1 Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing 100142, China ; 2 Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & School of Basic Medicine Peking Union Medical College, Beijing 100730, China
| | - Jing Gao
- 1 Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing 100142, China ; 2 Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & School of Basic Medicine Peking Union Medical College, Beijing 100730, China
| | - Yilin Li
- 1 Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing 100142, China ; 2 Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & School of Basic Medicine Peking Union Medical College, Beijing 100730, China
| | - Yanyan Li
- 1 Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing 100142, China ; 2 Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & School of Basic Medicine Peking Union Medical College, Beijing 100730, China
| | - Lin Shen
- 1 Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing 100142, China ; 2 Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & School of Basic Medicine Peking Union Medical College, Beijing 100730, China
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Photoimmunotherapy of gastric cancer peritoneal carcinomatosis in a mouse model. PLoS One 2014; 9:e113276. [PMID: 25401794 PMCID: PMC4234664 DOI: 10.1371/journal.pone.0113276] [Citation(s) in RCA: 58] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2014] [Accepted: 10/21/2014] [Indexed: 12/28/2022] Open
Abstract
Photoimmunotherapy (PIT) is a new cancer treatment that combines the specificity of antibodies for targeting tumors with the toxicity induced by photosensitizers after exposure to near infrared (NIR) light. We performed PIT in a model of disseminated gastric cancer peritoneal carcinomatosis and monitored efficacy with in vivo GFP fluorescence imaging. In vitro and in vivo experiments were conducted with a HER2-expressing, GFP-expressing, gastric cancer cell line (N87-GFP). A conjugate comprised of a photosensitizer, IR-700, conjugated to trastuzumab (tra-IR700), followed by NIR light was used for PIT. In vitro PIT was evaluated by measuring cytotoxicity with dead staining and a decrease in GFP fluorescence. In vivo PIT was evaluated in a disseminated peritoneal carcinomatosis model and a flank xenograft using tumor volume measurements and GFP fluorescence intensity. In vivo anti-tumor effects of PIT were confirmed by significant reductions in tumor volume (at day 15, p<0.0001 vs. control) and GFP fluorescence intensity (flank model: at day 3, PIT treated vs. control p<0.01 and peritoneal disseminated model: at day 3 PIT treated vs. control, p<0.05). Cytotoxic effects in vitro were shown to be dependent on the light dose and caused necrotic cell rupture leading to GFP release and a decrease in fluorescence intensity in vitro. Thus, loss of GFP fluorescence served as a useful biomarker of cell necrosis after PIT.
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