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Bach Y, Sharma D, Aoyama H, Ma LX, Barron CC, Wang X, Akhtar S, Yang Y, St Bernard A, McLaughlin R, Megid TBC, Farooq AR, Chen EX, Jang RWJ, Elimova E. Ramucirumab and paclitaxel in second or greater lines of therapy in patients with HER2-positive gastroesophageal cancer: a single center study. Oncologist 2025; 30:oyaf037. [PMID: 40152313 PMCID: PMC11950916 DOI: 10.1093/oncolo/oyaf037] [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: 10/24/2024] [Accepted: 02/04/2025] [Indexed: 03/29/2025] Open
Abstract
BACKGROUND Human epidermal growth factor receptor 2 (HER2) overexpression is present in approximately 20-25 of patients with advanced gastroesophageal adenocarcinoma (GEA). Upon progression on 1st line therapy, ramucirumab and paclitaxel (rampac) is given in ≥2 line setting regardless of HER2 status. We aim to assess whether ramucirumab is associated with better survival in HER2 positive(+) pts compared to those with HER2(-) disease. METHODS We reviewed all consecutive adult patients with metastatic/unresectable GEA who were treated with rampac for ≥2nd line therapy at Princess Margaret Cancer Centre from 2010 to 2021. Progression free survival (PFS) and overall survival (OS) were defined as time from starting rampac to progression or death and estimated using the Kaplan-Meier method. RESULTS There were 126 patients who received rampac following progression of 1st line chemotherapy, 96(76%) were male. The age at time of presentation and starting rampac was 59.0 ± 10.3 years and 59.9 ± 10.3 years, respectively. At the time of diagnosis, 32(25%) patients were HER2+. The majority of patients (n = 99;78%) received rampac in the 2L line setting compared to 28(22%) patients who received it in the 3rd/4th line setting. The median PFS and OS for HER2 + pts were 3.6 months and 9.4 months, respectively, which were similar to HER2- patients (median PFS = 3.6 months; median OS = 8.2 months). There was no statistically significant association between HER2 positivity and PFS (adjusted hazards ratio (HR) = 0.76, 95% confidence interval (CI) 0.48-1.22, P = .26), nor OS (adjusted HR = 0.88, 95% CI, 0.55-1.41, P = .59). CONCLUSION Rampac remains a valid treatment option for patients who are unable to participate in trials or do not have access to further HER2-directed therapy beyond first line.
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Affiliation(s)
- Yvonne Bach
- Princess Margaret Cancer Centre, 700 University Avenue, Toronto, ON, Canada M5G 1X6
| | - Divya Sharma
- Princess Margaret Cancer Centre, 700 University Avenue, Toronto, ON, Canada M5G 1X6
| | - Hiroko Aoyama
- Princess Margaret Cancer Centre, 700 University Avenue, Toronto, ON, Canada M5G 1X6
| | - Lucy X Ma
- Princess Margaret Cancer Centre, 700 University Avenue, Toronto, ON, Canada M5G 1X6
| | - Carly C Barron
- Princess Margaret Cancer Centre, 700 University Avenue, Toronto, ON, Canada M5G 1X6
| | - Xin Wang
- Princess Margaret Cancer Centre, 700 University Avenue, Toronto, ON, Canada M5G 1X6
| | - Sokaina Akhtar
- Princess Margaret Cancer Centre, 700 University Avenue, Toronto, ON, Canada M5G 1X6
| | - Yahan Yang
- Princess Margaret Cancer Centre, 700 University Avenue, Toronto, ON, Canada M5G 1X6
| | - Alana St Bernard
- Princess Margaret Cancer Centre, 700 University Avenue, Toronto, ON, Canada M5G 1X6
| | - Ronan McLaughlin
- Princess Margaret Cancer Centre, 700 University Avenue, Toronto, ON, Canada M5G 1X6
| | - Thais B C Megid
- Princess Margaret Cancer Centre, 700 University Avenue, Toronto, ON, Canada M5G 1X6
| | - Abdul R Farooq
- Princess Margaret Cancer Centre, 700 University Avenue, Toronto, ON, Canada M5G 1X6
| | - Eric X Chen
- Princess Margaret Cancer Centre, 700 University Avenue, Toronto, ON, Canada M5G 1X6
| | - Raymond W J Jang
- Princess Margaret Cancer Centre, 700 University Avenue, Toronto, ON, Canada M5G 1X6
| | - Elena Elimova
- Princess Margaret Cancer Centre, 700 University Avenue, Toronto, ON, Canada M5G 1X6
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Narita Y, Mizuno T, Ishizuka Y, Sakakida T, Masuishi T, Taniguchi H, Kadowaki S, Honda K, Ando M, Tajika M, Takahari D, Muro K. Clinicopathological and prognostic significance of HER2-low expression in advanced gastric cancer: a retrospective observational study. Oncologist 2024:oyae328. [PMID: 39673418 DOI: 10.1093/oncolo/oyae328] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2024] [Accepted: 10/30/2024] [Indexed: 12/16/2024] Open
Abstract
PURPOSE Human epidermal growth factor receptor 2 (HER2) status is a critical biomarker in advanced gastric cancer (AGC). While the role of HER2-positive tumors in guiding targeted therapies is well-established, the clinical implications of HER2-low expression, defined as immunohistochemistry (IHC) 1+ or IHC 2+/in situ hybridization-negative (ISH-negative), remain undetermined. The aim of this study was to investigate the prognostic significance and clinicopathological features of HER2-low AGC. PATIENTS AND METHODS This retrospective analysis involved patients with AGC treated with first-line fluoropyrimidine and platinum-based chemotherapy from 2011 to 2020. Patients were categorized into HER2-zero (HER2 IHC 0), HER2-low (IHC 1+ or 2+/ISH-negative), and HER2-positive (IHC 2+/ISH-positive or 3+) groups. RESULTS Among 548 patients analyzed, 33.0%, 45.1%, and 21.8% were classified as HER2-zero, HER2-low, and HER2-positive, respectively. The proportions of male patients, intestinal-type histology, esophagogastric junction/cardia involvement, metastatic disease status, ≥2 metastatic sites, liver metastasis, lymph node metastasis, and high serum carcinoembryonic antigen levels were gradually elevated in the HER2-zero, HER2-low, and HER2-positive groups. Overall survival (median) was 13.8, 13.6, and 23.0 months, respectively, with a non-significant trend favoring HER2-positive over HER2-low (adjusted hazard ratio: 0.80; P = .0672). A delayed separation of Kaplan-Meier curves for overall survival between the HER2-zero and HER2-low groups was observed, without reaching statistical significance (adjusted hazard ratio: 1.12; P = .2568). CONCLUSION Patients with HER2-low status exhibited intermediate and specific clinicopathological features within the HER2-negative category. In terms of prognosis, HER2-low patients showed a worsening trend compared with HER2-positive patients. This evidence implies that HER2-low status represents a distinct clinical subset, bridging the gap between the HER2-zero and HER2-positive profiles.
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Affiliation(s)
- Yukiya Narita
- Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya 484-8681, Japan
| | - Taro Mizuno
- Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya 484-8681, Japan
| | - Yasunobu Ishizuka
- Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya 484-8681, Japan
| | - Tomoki Sakakida
- Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya 484-8681, Japan
| | - Toshiki Masuishi
- Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya 484-8681, Japan
| | - Hiroya Taniguchi
- Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya 484-8681, Japan
| | - Shigenori Kadowaki
- Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya 484-8681, Japan
| | - Kazunori Honda
- Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya 484-8681, Japan
| | - Masashi Ando
- Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya 484-8681, Japan
| | - Masahiro Tajika
- Department of Endoscopy, Aichi Cancer Center Hospital, Nagoya, 484-8681, Japan
| | - Daisuke Takahari
- Department of Medical Oncology, Graduate School of Medicine, Gunma University, Maebashi 371-5811, Japan
| | - Kei Muro
- Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya 484-8681, Japan
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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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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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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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Moradi L, Tajik F, Saeednejad Zanjani L, Panahi M, Gheytanchi E, Biabanaki ZS, Kazemi-Sefat GE, Hashemi F, Dehghan Manshadi M, Madjd Z. Clinical significance of CD166 and HER-2 in different types of gastric cancer. Clin Transl Oncol 2024; 26:664-681. [PMID: 37537510 DOI: 10.1007/s12094-023-03297-0] [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: 05/08/2023] [Accepted: 07/24/2023] [Indexed: 08/05/2023]
Abstract
INTRODUCTION Cluster of differentiation 166 (CD166), a cancer stem cell (CSC) marker, and human epidermal growth factor receptor 2 (HER-2) are expressed in a diversity of malignancies and is associated with tumor progression. Although studies regarding the importance of CSC markers and HER-2 in gastric cancer (GC) have rapidly developed, their clinicopathological, prognosis, and diagnosis value still remain unsatisfying in GC. Therefore, the present study aims to investigate the clinical, prognostic, and diagnostic significance of CD166 and HER-2 in different histological types of GC. MATERIALS AND METHODS Bioinformatic analysis was applied to determine the clinical importance of CD166 and HER-2 expression based on their tissue localization in primary GC tumors and the normal adjacent samples. The expression patterns, clinical significance, prognosis, and diagnosis value of CD166 and HER-2 proteins in tissue microarrays (TMAs) of 206 GC samples, including Signet Ring Cell (SRC) and intestinal types and also 28 adjacent normal tissues were evaluated using immunohistochemistry (IHC). RESULTS The results indicated that the expression of CD166 (membranous and cytoplasmic) and HER-2 were significantly up-regulated in tumor cells compared to adjacent normal tissues (P = 0.010, P < 0.001, and P = 0.011, respectively). A statistically significant association was detected between a high level of membranous expression of CD166 and lymphovascular invasion (P = 0.006); We also observed a statistically significant association between high cytoplasmic expression of CD166 protein and more invasion of the subserosa (P = 0.040) in the SRC type. In contrast, there was no correlation between the expression of HER-2 and clinicopathologic characteristics. Both CD166 and HER-2 showed reasonable accuracy and high specificity as diagnostic markers. CONCLUSION Our results confirmed that increased membranous and cytoplasmic expression of CD166 showed clinical significance in the SRC type and is associated with the progression of the disease and more aggressive tumor behaviors. These findings can be used to assist in designating subgroups of patients that require different follow-up strategies, and also, they might be utilized as the prognostic or diagnostic biomarkers in these types of GC for prospective clinical application.
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Affiliation(s)
- Leila Moradi
- Department of Pathology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Fatemeh Tajik
- Oncopathology Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Leili Saeednejad Zanjani
- Oncopathology Research Center, Iran University of Medical Sciences, Tehran, Iran
- Department of Pathology and Genomic Medicine, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA
| | - Mahshid Panahi
- Department of Pathology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Elmira Gheytanchi
- Oncopathology Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Zahra Sadat Biabanaki
- Faculty of Biological Sciences, Department of Genetics, Tarbiat Modares University, Tehran, Iran
| | - Golnaz Ensieh Kazemi-Sefat
- Faculty of Advanced Technologies in Medicine, Department of Molecular Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Farideh Hashemi
- Oncopathology Research Center, Iran University of Medical Sciences, Tehran, Iran
- Faculty of Advanced Technologies in Medicine, Department of Molecular Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Masoumeh Dehghan Manshadi
- Oncopathology Research Center, Iran University of Medical Sciences, Tehran, Iran
- Faculty of Advanced Technologies in Medicine, Department of Molecular Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Zahra Madjd
- Department of Pathology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
- Oncopathology Research Center, Iran University of Medical Sciences, Tehran, Iran.
- Faculty of Advanced Technologies in Medicine, Department of Molecular Medicine, Iran University of Medical Sciences, Tehran, Iran.
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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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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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Yanagimoto Y, Imamura H, Adachi S, Odagiri K, Kawase T, Yamashita M, Takeyama H, Suzuki Y, Ikenaga M, Shimizu J, Tomita N, Dono K. The effect of specimen processing time on HER2 expression in gastric cancer and esophagogastric junction cancer: a single-center retrospective observational study. BMC Cancer 2023; 23:645. [PMID: 37434116 PMCID: PMC10334514 DOI: 10.1186/s12885-023-11148-y] [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: 03/29/2023] [Accepted: 07/04/2023] [Indexed: 07/13/2023] Open
Abstract
BACKGROUND Recent developments in the field of companion diagnosis and molecular-targeting therapeutic agents have helped in developing treatments targeting human epidermal growth factor receptor 2 (HER2) in gastric cancer (GC) and esophagogastric junction cancer (EGJC), and the importance of accurate diagnosis of HER2 expression is increasing. However, the HER2-positivity rate significantly differs among reports in GC and EGJC, and factors that affect HER2-positivity require elucidation. METHODS The present study retrospectively examined factors related to HER2-positivity in a single institution, including age, sex, body mass index, the American Society of Anesthesiologists physical status, tumor information, and surgery information, including time to specimen processing. RESULTS Our study included 165 patients tested for HER2 using GC and EGJC surgery specimens among the 1,320 patients who underwent gastrectomy from January 2007 to June 2022. In total, 35 (21.2%) and 130 (78.8%) patients were HER2-positive and -negative, respectively. Multivariate analysis revealed that intestinal type (odds ratio [OR]: 3.41, 95% confidence interval [CI]: 1.44-8.09, p = 0.005), pM1 (OR: 3.99, 95% CI: 1.51-10.55, p = 0.005), and time to specimen processing of < 120 min (OR: 2.65, 95% CI: 1.01-6.98, p = 0.049) were independent factors that affected HER2-positivity. CONCLUSIONS The outcomes of the present study indicated that intestinal type, pM, and time to specimen processing are important factors affecting HER2-positive rates in GC and EGJC. Therefore, the risk of false-negative HER2 results may be reduced by decreasing the time required to process the resected specimen. Additionally, accurate diagnosis of HER2 expression may increase the opportunity to administer molecular-targeted drugs that can expect therapeutic effects to patients appropriately. TRAIL REGISTRATION Retrospectively registered.
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Affiliation(s)
- Yoshitomo Yanagimoto
- Department of Surgery, Toyonaka Municipal Hospital, 4-14-1 Shimahara-Cho, Toyonaka, Osaka, 560-8565, Japan.
| | - Hiroshi Imamura
- Department of Surgery, Toyonaka Municipal Hospital, 4-14-1 Shimahara-Cho, Toyonaka, Osaka, 560-8565, Japan
| | - Shiro Adachi
- Department Diagnostic Pathology, Toyonaka Municipal Hospital, 4-14-1 Shimahara-Cho, Toyonaka, Osaka, 560-8565, Japan
| | - Kazuki Odagiri
- Department of Surgery, Toyonaka Municipal Hospital, 4-14-1 Shimahara-Cho, Toyonaka, Osaka, 560-8565, Japan
| | - Tomono Kawase
- Department of Surgery, Toyonaka Municipal Hospital, 4-14-1 Shimahara-Cho, Toyonaka, Osaka, 560-8565, Japan
| | - Masafumi Yamashita
- Department of Surgery, Toyonaka Municipal Hospital, 4-14-1 Shimahara-Cho, Toyonaka, Osaka, 560-8565, Japan
| | - Hiroshi Takeyama
- Department of Surgery, Toyonaka Municipal Hospital, 4-14-1 Shimahara-Cho, Toyonaka, Osaka, 560-8565, Japan
| | - Yozo Suzuki
- Department of Surgery, Toyonaka Municipal Hospital, 4-14-1 Shimahara-Cho, Toyonaka, Osaka, 560-8565, Japan
| | - Masakazu Ikenaga
- Department of Surgery, Toyonaka Municipal Hospital, 4-14-1 Shimahara-Cho, Toyonaka, Osaka, 560-8565, Japan
| | - Junzo Shimizu
- Department of Surgery, Toyonaka Municipal Hospital, 4-14-1 Shimahara-Cho, Toyonaka, Osaka, 560-8565, Japan
| | - Naohiro Tomita
- Department of Surgery, Toyonaka Municipal Hospital, 4-14-1 Shimahara-Cho, Toyonaka, Osaka, 560-8565, Japan
| | - Keizo Dono
- Department of Surgery, Toyonaka Municipal Hospital, 4-14-1 Shimahara-Cho, Toyonaka, Osaka, 560-8565, Japan
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Shimizu H, Kochi M, Fujii M, Watabe M, Matsuno Y, Kawai T, Suda H, Tanino T, Nakanishi Y, Masuda S, Okamura Y. Human epidermal growth factor 2 overexpressed alpha-fetoprotein-producing-gastric cancer. Discov Oncol 2023; 14:111. [PMID: 37354221 DOI: 10.1007/s12672-023-00731-1] [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: 03/29/2023] [Accepted: 06/16/2023] [Indexed: 06/26/2023] Open
Abstract
PURPOSE This study aimed to elucidate the clinicopathological characteristics of α-fetoprotein (AFP)-producing gastric carcinoma (AFP-GC) with human epidermal growth factor receptor (HER)2 overexpression to extend the treatment strategy for AFP-GC. METHODS We analyzed 41 patients with AFP-GC who underwent surgical resection or chemotherapy from 1989 to 2019, and who had over 20ng/mL of serum AFP or positive immunohistochemical AFP expression. HER2 expression status was investigated by immunohistochemistry (IHC) for all patients and by fluorescence in situ hybridization (FISH) for cases with an IHC score of 2+. AFP-GC with an IHC score of 3 + or 2 + and FISH positivity was defined as HER2 overexpressed AFP-GC. The correlation between HER2 status and clinicopathological characteristics and prognosis in AFP-GC was analyzed. RESULTS HER2 overexpression was detected in 17.1% of AFP-GC patients. The prognosis of the patients with HER2 overexpressed AFP-GC was not significantly different compared to HER2 non-overexpressed AFP-GC. HER2 overexpressed AFP-GC consisted of heterogeneous histology with a higher proportion of mixed-type tumors (p = 0.002). The clinical outcome of AFP-GC with mixed-type of histology tended to be better than other intestinal or diffuse types (p = 0.05). CONCLUSION HER2 overexpressed AFP-GC consisted of a mixed type of histology, which showed a better prognosis. The results presented that HER2 status in AFP-GC is one of the molecular candidates to improve the prognosis.
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Affiliation(s)
- Hiroko Shimizu
- Division of Digestive Surgery, Department of Surgery, Nihon University School of Medicine, Tokyo, Japan
| | - Mitsugu Kochi
- Division of Digestive Surgery, Department of Surgery, Nihon University School of Medicine, Tokyo, Japan
| | - Masashi Fujii
- Japan Clinical Cancer Research Organization, Tokyo, Japan
| | - Megumu Watabe
- Division of Digestive Surgery, Department of Surgery, Nihon University School of Medicine, Tokyo, Japan
| | - Yoritaka Matsuno
- Division of Digestive Surgery, Department of Surgery, Nihon University School of Medicine, Tokyo, Japan
| | - Takaharu Kawai
- Division of Digestive Surgery, Department of Surgery, Nihon University School of Medicine, Tokyo, Japan
| | - Hiroshi Suda
- Division of Digestive Surgery, Department of Surgery, Nihon University School of Medicine, Tokyo, Japan
| | - Tomoyuki Tanino
- Division of Oncologic Pathology, Department of Pathology and Microbiology, Nihon University School of Medicine, Tokyo, Japan
| | - Yoko Nakanishi
- Division of Oncologic Pathology, Department of Pathology and Microbiology, Nihon University School of Medicine, Tokyo, Japan.
- Division of Oncologic Pathology, Department of Pathology and Microbiology, Nihon University School of Medicine, 30-1 Ohyaguchi-Kamicho, Itabashi-ku, Tokyo, 173-8610, Japan.
| | - Shinobu Masuda
- Division of Oncologic Pathology, Department of Pathology and Microbiology, Nihon University School of Medicine, Tokyo, Japan
| | - Yukiyasu Okamura
- Division of Digestive Surgery, Department of Surgery, Nihon University School of Medicine, Tokyo, Japan
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11
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Jain P, Wadhwa N, Diwaker P, Joshi MK, Mishra K. Alteration in key oncoprotein expression in gastric adenocarcinoma - An immunohistochemical study. J Cancer Res Ther 2023; 19:S0. [PMID: 37147954 DOI: 10.4103/jcrt.jcrt_760_21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/07/2023]
Abstract
Objective This study was conducted to evaluate the frequency and clinicopathologic correlates of human epidermal growth factor receptor 2 (HER-2)/neu and betacatenin (BC) oncoproteins in gastric adenocarcinoma and to seek correlation if any between their expression status. Materials and Methods This cross-sectional analytical immunohistochemistry (IHC) study was performed on 50 cases of gastric adenocarcinoma. HER-2/neu immunoexpression was scored as per criteria by Ruschoff et al. as positive (3+), equivocal (2+), and negative (1+, 0). Aberrant BC expression was categorized as nuclear, cytoplasmic, and reduced membranous immunoexpression. Protein expression results of both oncoproteins were correlated with conventional clinicopathological parameters. Correlation between immunoexpression profiles of both proteins was also analyzed. P <0.05 was considered statistically significant. Results HER-2/neu positivity (2 + and 3+) was seen in 94% of the cases; almost 60% had strong (3+) expression. All cases showed aberrant BC immunoexpression (any pattern) except 2 cases that revealed negative expression (a form of aberrant immunoexpression) and were removed from analysis due to a very small number. The pattern of BC expression was as follows: nuclear expression (38%), cytoplasmic expression (82%), reduced membranous expression (96%), no staining (4%) cases. HER-2/neu expression correlated with age. No significant correlation was found between any of the 2 oncoprotein immunoexpression and other clinicopathological parameters (P > 0.05). Concordance between protein expression of HER-2/neu and BC was seen in >93% cases, however, the correlation was not significant. Conclusion HER-2/neu and BC oncoprotein expression are frequently dysregulated in gastric adenocarcinomas. The significance of pathways involving HER-2/neu and BC in gastric carcinogenesis should be explored.
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Affiliation(s)
- Pragya Jain
- Department of Pathology, University College of Medical Sciences and Guru Teg Bahadur Hospital, New Delhi, India
| | - Neelam Wadhwa
- Department of Pathology, University College of Medical Sciences and Guru Teg Bahadur Hospital, New Delhi, India
| | - Preeti Diwaker
- Department of Pathology, University College of Medical Sciences and Guru Teg Bahadur Hospital, New Delhi, India
| | - Mohit Kumar Joshi
- Department of Surgical Disciplines, All India Institute of Medical Sciences, New Delhi, India
| | - Kiran Mishra
- Department of Pathology, University College of Medical Sciences and Guru Teg Bahadur Hospital, New Delhi, India
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12
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Zhao J, Han Z, Xu C, Li L, Pei H, Song Y, Wang Z, Tang B. Separation and single-cell analysis for free gastric cancer cells in ascites and peritoneal lavages based on microfluidic chips. EBioMedicine 2023; 90:104522. [PMID: 36933411 PMCID: PMC10034419 DOI: 10.1016/j.ebiom.2023.104522] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Revised: 02/13/2023] [Accepted: 02/28/2023] [Indexed: 03/18/2023] Open
Abstract
BACKGROUNDS Detecting free cancer cells from ascites and peritoneal lavages is crucial for diagnosing gastric cancer (GC). However, traditional methods are limited for early-stage diagnosis due to their low sensitivity. METHODS A label-free, rapid, and high-throughput technique was developed for separating cancer cells from ascites and peritoneal lavages using an integrated microfluidic device, taking advantage of dean flow fractionation and deterministic lateral displacement. Afterward, separated cells were analyzed using a microfluidic single-cell trapping array chip (SCTA-chip). In situ immunofluorescence for EpCAM, YAP-1, HER-2, CD45 molecular expressions, and Wright-Giemsa staining were performed for cells in SCTA-chips. At last, YAP1 and HER-2 expression in tissues was analyzed by immunohistochemistry. FINDINGS Through integrated microfluidic device, cancer cells were successfully separated from simulated peritoneal lavages containing 1/10,000 cancer cells with recovery rate of 84.8% and purity of 72.4%. Afterward, cancer cells were isolated from 12 patients' ascites samples. Cytological examinations showed cancer cells were efficiently enriched with background cells excluded. Afterwards, separated cells from ascites were analyzed by SCTA-chips, and recognized as cancer cells through EpCAM+/CD45- expression and Wright-Giemsa staining. Interestingly, 8 out of 12 ascites samples showed HER-2+ cancer cells. At last, the results through a serial expression analysis showed that YAP1 and HER-2 have discordant expression during metastasis. INTERPRETATION Microfluidic Chips developed in our study could not only rapidly detect label-free free GC cells in ascites and peritoneal lavages with high-throughput, they could also analyze ascites cancer cells at the single-cell level, improving peritoneal metastasis diagnosis and investigation of therapeutic targets. FUNDING This research was supported by National Natural Science Foundation of China (22134004, U1908207, 91859111); Natural Science Foundation of Shandong Province of China (ZR2019JQ06); Taishan Scholars Program of Shandong Province tsqn (201909077); Local Science and Technology Development Fund Guided by the Central Government (YDZX20203700002568); Applied Basic Research Program of Liaoning Province (2022020284-JH2/1013).
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Affiliation(s)
- Junhua Zhao
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, 155 N. Nanjing Street, Shenyang, Liaoning, 110001, PR China; Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, No.77, Puhe Road, Shenyang, Liaoning, 110001, PR China; Institute of Health Sciences, China Medical University, No.77, Puhe Road, Shenyang, Liaoning, 110001, PR China
| | - Zhaojun Han
- College of Chemistry, Chemical Engineering and Materials Science, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong, Institute of Molecular and Nano Science, Shandong Normal University, Jinan, 250014, PR China
| | - Chang Xu
- College of Chemistry, Chemical Engineering and Materials Science, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong, Institute of Molecular and Nano Science, Shandong Normal University, Jinan, 250014, PR China
| | - Lu Li
- College of Chemistry, Chemical Engineering and Materials Science, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong, Institute of Molecular and Nano Science, Shandong Normal University, Jinan, 250014, PR China.
| | - Haimeng Pei
- College of Chemistry, Chemical Engineering and Materials Science, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong, Institute of Molecular and Nano Science, Shandong Normal University, Jinan, 250014, PR China
| | - Yongxi Song
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, 155 N. Nanjing Street, Shenyang, Liaoning, 110001, PR China; Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, No.77, Puhe Road, Shenyang, Liaoning, 110001, PR China; Institute of Health Sciences, China Medical University, No.77, Puhe Road, Shenyang, Liaoning, 110001, PR China.
| | - Zhenning Wang
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, 155 N. Nanjing Street, Shenyang, Liaoning, 110001, PR China; Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, No.77, Puhe Road, Shenyang, Liaoning, 110001, PR China; Institute of Health Sciences, China Medical University, No.77, Puhe Road, Shenyang, Liaoning, 110001, PR China.
| | - Bo Tang
- College of Chemistry, Chemical Engineering and Materials Science, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong, Institute of Molecular and Nano Science, Shandong Normal University, Jinan, 250014, PR China.
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13
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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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14
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Yang T, Xu R, You J, Li F, Yan B, Cheng JN. Prognostic and clinical significance of HER-2 low expression in early-stage gastric cancer. BMC Cancer 2022; 22:1168. [DOI: 10.1186/s12885-022-10262-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2022] [Accepted: 10/31/2022] [Indexed: 11/15/2022] Open
Abstract
Abstract
Introduction
Gastric cancer is the most fifth common tumor worldwide. Human epidermal growth factor receptor 2 (HER2) overexpression is associated with poor prognosis and clinical characteristics in gastric cancer. Nevertheless, the biology of HER2-low expression has not reported in gastric cancer.
Materials and methods
A total of 157 patients with early-stage gastric cancer were retrospectively analyzed. The associations between HER-2 low expression and clinical characteristics were analyzed by Chi-square test. And the prognostic value of HER-2 low expression and clinical characteristics in disease-free survival (DFS) and overall survival (OS) were analyzed by univariate and multivariate Cox regression analysis.
Results
Of 157 patients with early-stage gastric cancer, 31.8% had HER2-low tumors and 50.3% had HER2-negative tumors. HER2-low expression was associated with age, histological differentiation, tumor location and Ki-67 index. However, HER2-low expression was not associated with DFS or OS in early-stage gastric cancer.
Conclusion
HER2-low expression might result in distinct biology, but it was not an independent prognostic factor of DFS or OS in early-stage gastric cancer.
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15
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Chen N, Li CL, Peng YF, Yao YF. Long-term follow-up of HER2 overexpression in patients with rectal cancer after preoperative radiotherapy: A prospective cohort study. World J Gastrointest Oncol 2022; 14:2048-2060. [PMID: 36310698 DOI: 10.4251/wjgo.v14.i] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Revised: 05/17/2022] [Accepted: 08/24/2022] [Indexed: 01/21/2025] Open
Abstract
BACKGROUND The role of HER2 overexpression in rectal cancer is controversial. AIM To assess the role of HER2 overexpression in the long-term prognosis of rectal cancer. METHODS Data from patients with locally advanced rectal cancer who underwent total mesorectal excision after short-course radiotherapy at Beijing Cancer Hospital between May 2002 and October 2005 were collected. A total of 151 tissue samples of rectal cancer were obtained using rigid proctoscopy before neoadjuvant radiotherapy, followed by immunohistochemistry and fluorescence in situ hybridisation to determine the patients' HER2 expression status. Univariate and multivariate analyses of the associations between the clinicopathological factors and HER2 status were performed. Survival was estimated and compared using the Kaplan-Meier method based on HER2 expression status, and the differences between groups were verified using the log-rank test. RESULTS A total of 151 patients were enrolled in this study. A total of 27 (17.9%) patients were ultimately confirmed to be HER2-positive. The follow-up duration ranged from 9 mo to 210 mo, with a median of 134 mo. Distant metastasis and local recurrence occurred in 60 (39.7%) and 24 (15.9%) patients, respectively. HER2 positivity was significantly associated with the pre-treatment lymph node stage (pre-N) (P = 0.040), while there were no differences between HER2 status and age, sex, preoperative CEA levels (pre-CEA), T stage, and lympho-vascular invasion. In terms of prognosis, HER2 overexpression was correlated with distant metastasis (P = 0.002) rather than local recurrence (P > 0.05). The multivariate analysis demonstrated that elevated pre-CEA [P = 0.002, odds ratio (OR) = 3.277, 97.5% confidence interval (CI): 1.543-7.163], post N(+) (P = 0.022, OR = 2.437, 97.5%CI: 1.143-5.308) and HER2(+) (P = 0.003, OR = 4.222, 97.5%CI: 1.667-11.409) were risk factors for distant metastasis. The survival analysis showed that there were significant differences between rectal cancer patients in terms of disease-free survival (DFS) [hazard ratio: 1.69 (95%CI: 0.91-3.14); P = 0.048] and overall survival (OS) [1.95 (1.05-3.63); P = 0.0077]. CONCLUSION HER2 overexpression is a potential biomarker for predicting lymph node metastasis and distant metastasis, which are associated with worse long-term DFS and OS in rectal cancer patients with locally advanced disease.
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Affiliation(s)
- Nan Chen
- Department of Gastrointestinal Surgery, Ward III, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing 100142, China.
| | - Chang-Long Li
- Department of Gastrointestinal Surgery, Ward III, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Yi-Fan Peng
- Department of Gastrointestinal Surgery, Ward III, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Yun-Feng Yao
- Department of Gastrointestinal Surgery, Ward III, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing 100142, China
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16
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Chen N, Li CL, Peng YF, Yao YF. Long-term follow-up of HER2 overexpression in patients with rectal cancer after preoperative radiotherapy: A prospective cohort study. World J Gastrointest Oncol 2022; 14:2048-2060. [PMID: 36310698 PMCID: PMC9611427 DOI: 10.4251/wjgo.v14.i10.2048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Revised: 05/17/2022] [Accepted: 08/25/2022] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND The role of HER2 overexpression in rectal cancer is controversial.
AIM To assess the role of HER2 overexpression in the long-term prognosis of rectal cancer.
METHODS Data from patients with locally advanced rectal cancer who underwent total mesorectal excision after short-course radiotherapy at Beijing Cancer Hospital between May 2002 and October 2005 were collected. A total of 151 tissue samples of rectal cancer were obtained using rigid proctoscopy before neoadjuvant radiotherapy, followed by immunohistochemistry and fluorescence in situ hybridisation to determine the patients’ HER2 expression status. Univariate and multivariate analyses of the associations between the clinicopathological factors and HER2 status were performed. Survival was estimated and compared using the Kaplan-Meier method based on HER2 expression status, and the differences between groups were verified using the log-rank test.
RESULTS A total of 151 patients were enrolled in this study. A total of 27 (17.9%) patients were ultimately confirmed to be HER2-positive. The follow-up duration ranged from 9 mo to 210 mo, with a median of 134 mo. Distant metastasis and local recurrence occurred in 60 (39.7%) and 24 (15.9%) patients, respectively. HER2 positivity was significantly associated with the pre-treatment lymph node stage (pre-N) (P = 0.040), while there were no differences between HER2 status and age, sex, preoperative CEA levels (pre-CEA), T stage, and lympho-vascular invasion. In terms of prognosis, HER2 overexpression was correlated with distant metastasis (P = 0.002) rather than local recurrence (P > 0.05). The multivariate analysis demonstrated that elevated pre-CEA [P = 0.002, odds ratio (OR) = 3.277, 97.5% confidence interval (CI): 1.543-7.163], post N(+) (P = 0.022, OR = 2.437, 97.5%CI: 1.143-5.308) and HER2(+) (P = 0.003, OR = 4.222, 97.5%CI: 1.667-11.409) were risk factors for distant metastasis. The survival analysis showed that there were significant differences between rectal cancer patients in terms of disease-free survival (DFS) [hazard ratio: 1.69 (95%CI: 0.91-3.14); P = 0.048] and overall survival (OS) [1.95 (1.05-3.63); P = 0.0077].
CONCLUSION HER2 overexpression is a potential biomarker for predicting lymph node metastasis and distant metastasis, which are associated with worse long-term DFS and OS in rectal cancer patients with locally advanced disease.
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Affiliation(s)
- Nan Chen
- Department of Gastrointestinal Surgery, Ward III, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Chang-Long Li
- Department of Gastrointestinal Surgery, Ward III, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Yi-Fan Peng
- Department of Gastrointestinal Surgery, Ward III, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Yun-Feng Yao
- Department of Gastrointestinal Surgery, Ward III, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing 100142, China
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Cann C, Ciombor KK. Systemic therapy for gastric cancer: Perioperative strategies and beyond. J Surg Oncol 2022; 125:1151-1160. [PMID: 35230696 DOI: 10.1002/jso.26834] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Accepted: 02/16/2022] [Indexed: 12/23/2022]
Abstract
Each year, gastric cancer claims the lives of hundreds of thousands of patients worldwide. Despite surgical resection, the risk of residual disease, micrometastatic disease, and disease recurrence remain elevated. Herein, we review systemic therapy strategies in the neoadjuvant, adjuvant, and metastatic settings, including novel uses of immunotherapy, targeted therapies and cytotoxic chemotherapies, for the treatment of gastric cancer.
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Affiliation(s)
- Christopher Cann
- Division of Hematology/Oncology, Department of Internal Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Kristen K Ciombor
- Division of Hematology/Oncology, Department of Internal Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
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Abstract
Trimodality therapy, or the use of concurrent chemoradiation followed by surgery, is the cornerstone of contemporary management of esophageal cancer. This article discusses the landmark trials and most current data to understand the concepts, applications, and outcomes from trimodality therapy in locally advanced esophageal cancer.
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Affiliation(s)
- Ammara A Watkins
- Division of Thoracic Surgery and Interventional Pulmonology, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, 185 Pilgrim Road, Boston, MA 02215, USA
| | - Jessica A Zerillo
- Division of Medical Oncology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Shapiro 9, Boston, MA 02215, USA
| | - Michael S Kent
- Division of Thoracic Surgery and Interventional Pulmonology, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, 185 Pilgrim Road, Boston, MA 02215, USA.
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19
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Kim TH, Do Cho H, Choi YW, Lee HW, Kang SY, Jeong GS, Choi JH, Ahn MS, Sheen SS. Trastuzumab-based palliative chemotherapy for HER2-positive gastric cancer: a single-center real-world data. BMC Cancer 2021; 21:325. [PMID: 33771119 PMCID: PMC7995795 DOI: 10.1186/s12885-021-08058-2] [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: 01/27/2021] [Accepted: 03/15/2021] [Indexed: 12/12/2022] Open
Abstract
Background Since the results of the ToGA trial were published, trastuzumab-based chemotherapy has been used as the standard first-line treatment for HER2-positive recurrent or primary metastatic gastric cancer (RPMGC). However, the real-world data has been rarely reported. Therefore, we investigated the outcomes of trastuzumab-based chemotherapy in a single center. Methods This study analyzed the real-world data of 47 patients with HER2-positive RPMGC treated with trastuzumab-based chemotherapy in a single institution. Results With the median follow-up duration of 18.8 months in survivors, the median overall survival (OS) and progression-free survival were 12.8 and 6.9 months, respectively, and the overall response rate was 64%. Eastern Cooperative Oncology Group performance status 2 and massive amount of ascites were independent poor prognostic factors for OS, while surgical resection before or after chemotherapy was associated with favorable OS, in multivariate analysis. In addition, 5 patients who underwent conversion surgery after chemotherapy demonstrated an encouraging median OS of 30.8 months, all with R0 resection. Conclusions Trastuzumab-based chemotherapy in patients with HER2-positive RPMGC in the real world demonstrated outcomes almost comparable to those of the ToGA trial. Moreover, conversion surgery can be actively considered in fit patients with a favorable response after trastuzumab-based chemotherapy.
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Affiliation(s)
- Tae-Hwan Kim
- Department of Hematology-Oncology, Ajou University School of Medicine, 164, World cup-ro, Yeongtong-gu, Suwon, 443-380, South Korea
| | - Hun Do Cho
- Department of Hematology-Oncology, Ajou University School of Medicine, 164, World cup-ro, Yeongtong-gu, Suwon, 443-380, South Korea
| | - Yong Won Choi
- Department of Hematology-Oncology, Ajou University School of Medicine, 164, World cup-ro, Yeongtong-gu, Suwon, 443-380, South Korea
| | - Hyun Woo Lee
- Department of Hematology-Oncology, Ajou University School of Medicine, 164, World cup-ro, Yeongtong-gu, Suwon, 443-380, South Korea
| | - Seok Yun Kang
- Department of Hematology-Oncology, Ajou University School of Medicine, 164, World cup-ro, Yeongtong-gu, Suwon, 443-380, South Korea
| | - Geum Sook Jeong
- Department of Hematology-Oncology, Ajou University School of Medicine, 164, World cup-ro, Yeongtong-gu, Suwon, 443-380, South Korea
| | - Jin-Hyuk Choi
- Department of Hematology-Oncology, Ajou University School of Medicine, 164, World cup-ro, Yeongtong-gu, Suwon, 443-380, South Korea.
| | - Mi Sun Ahn
- Department of Hematology-Oncology, Ajou University School of Medicine, 164, World cup-ro, Yeongtong-gu, Suwon, 443-380, South Korea.
| | - Seung-Soo Sheen
- Department of Pulmonology and Critical Care Medicine, Ajou University School of Medicine, 164, World cup-ro, Yeongtong-gu, Suwon, 443-380, South Korea
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20
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Sentani K, Imai T, Kobayashi G, Hayashi T, Sasaki N, Oue N, Yasui W. Histological diversity and molecular characteristics in gastric cancer: relation of cancer stem cell-related molecules and receptor tyrosine kinase molecules to mixed histological type and more histological patterns. Gastric Cancer 2021; 24:368-381. [PMID: 33118117 DOI: 10.1007/s10120-020-01133-w] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2020] [Accepted: 09/28/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND Gastric cancers (GCs) are still one of the leading causes of cancer-related mortality. The histological and molecular features of GC may differ widely from area to area within the same tumor. Intratumoral heterogeneity has been considered a major obstacle to an efficient diagnosis and successful molecular treatment. METHODS We selected and reevaluated 842 GC cases and analyzed the relationship between numbers or composites of histological patterns within tumors, and clinicopathological parameters in mucosal and invasive areas. In addition, we searched for the GC-associated molecules or molecular subtypes marking histological diversities. RESULTS GC cases with more histological numbers or mixed types in invasive areas showed significantly higher T grade and staging, whereas those in mucosal areas did not show any significant associations. GCs with histological diversities showed poorer prognosis and characteristically expressed cancer stem cell-related molecules (CD44, CD133 or ALDH1) and receptor tyrosine kinase molecules (HER2, EGFR or c-MET) as well as Helicobacter pylori infection. Expressions of CD44, HER2, c-MET, laminin 5·2 or retained E-cadherin in mucosal areas were predictive of more histological numbers and mixed types in invasive areas. In addition, the chromosomal instability subtype of GC showed significant associations with more histological numbers and mixed histological type, whereas the genomic stability subtype of GC showed a significant relationship with pure type. CONCLUSIONS We displayed the relationship between histological diversity and molecular features in GC, and we hope that the present data can contribute to the early diagnosis and prevention, and effective treatment of GC.
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Affiliation(s)
- Kazuhiro Sentani
- Department of Molecular Pathology, Graduate School of Biomedical and Health Sciences, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.
| | - Takeharu Imai
- Department of Molecular Pathology, Graduate School of Biomedical and Health Sciences, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Go Kobayashi
- Department of Molecular Pathology, Graduate School of Biomedical and Health Sciences, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Tetsutaro Hayashi
- Department of Molecular Pathology, Graduate School of Biomedical and Health Sciences, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Naomi Sasaki
- Department of Pathology, Kure-Kyosai Hospital, Federation of National Public Service Personnel Mutual Aid Associations, Hiroshima, Japan
| | - Naohide Oue
- Department of Molecular Pathology, Graduate School of Biomedical and Health Sciences, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Wataru Yasui
- Department of Molecular Pathology, Graduate School of Biomedical and Health Sciences, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
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21
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Re VD, Brisotto G, Repetto O, De Zorzi M, Caggiari L, Zanussi S, Alessandrini L, Canzonieri V, Miolo G, Puglisi F, Belluco C, Steffan A, Cannizzaro R. Overview of Epstein-Barr-Virus-Associated Gastric Cancer Correlated with Prognostic Classification and Development of Therapeutic Options. Int J Mol Sci 2020; 21:E9400. [PMID: 33321820 PMCID: PMC7764600 DOI: 10.3390/ijms21249400] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Revised: 12/07/2020] [Accepted: 12/08/2020] [Indexed: 02/08/2023] Open
Abstract
Gastric cancer (GC) is a deadly disease with poor prognosis that is characterized by heterogeneity. New classifications based on histologic features, genotypes, and molecular phenotypes, for example, the Cancer Genome Atlas subtypes and those by the Asian Cancer Research Group, help understand the carcinogenic differences in GC and have led to the identification of an Epstein-Barr virus (EBV)-related GC subtype (EBVaGC), providing new indications for tailored treatment and prognostic factors. This article provides a review of the features of EBVaGC and an update on the latest insights from EBV-related research with a particular focus on the strict interaction between EBV infection and the gastric tumor environment, including the host immune response. This information may help increase our knowledge of EBVaGC pathogenesis and the mechanisms that sustain the immune response of patients since this mechanism has been demonstrated to offer a survival advantage in a proportion of patients with GC.
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Affiliation(s)
- Valli De Re
- Immunopathology and Cancer Biomarkers, Department of Translational Research, Bioproteomic Facility, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33077 Aviano, Italy; (G.B.); (O.R.); (M.D.Z.); (L.C.); (S.Z.); (A.S.)
| | - Giulia Brisotto
- Immunopathology and Cancer Biomarkers, Department of Translational Research, Bioproteomic Facility, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33077 Aviano, Italy; (G.B.); (O.R.); (M.D.Z.); (L.C.); (S.Z.); (A.S.)
| | - Ombretta Repetto
- Immunopathology and Cancer Biomarkers, Department of Translational Research, Bioproteomic Facility, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33077 Aviano, Italy; (G.B.); (O.R.); (M.D.Z.); (L.C.); (S.Z.); (A.S.)
| | - Mariangela De Zorzi
- Immunopathology and Cancer Biomarkers, Department of Translational Research, Bioproteomic Facility, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33077 Aviano, Italy; (G.B.); (O.R.); (M.D.Z.); (L.C.); (S.Z.); (A.S.)
| | - Laura Caggiari
- Immunopathology and Cancer Biomarkers, Department of Translational Research, Bioproteomic Facility, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33077 Aviano, Italy; (G.B.); (O.R.); (M.D.Z.); (L.C.); (S.Z.); (A.S.)
| | - Stefania Zanussi
- Immunopathology and Cancer Biomarkers, Department of Translational Research, Bioproteomic Facility, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33077 Aviano, Italy; (G.B.); (O.R.); (M.D.Z.); (L.C.); (S.Z.); (A.S.)
| | - Lara Alessandrini
- Pathology, Department of Medicine DIMED, University of Padova, 61-35121 Padova, Italy;
| | - Vincenzo Canzonieri
- Surgical and Health Sciences, Department of Medical, University of Trieste Medical School, 34100 Trieste, Italy;
- Pathology, Department of Translational Research, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33081 Aviano, Italy
| | - Gianmaria Miolo
- Medical Oncology and Cancer Prevention, Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33081 Aviano, Italy; (G.M.); (F.P.)
| | - Fabio Puglisi
- Medical Oncology and Cancer Prevention, Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33081 Aviano, Italy; (G.M.); (F.P.)
- Department of Medicine, University of Udine, 33100 Udine, Italy
| | - Claudio Belluco
- Surgical Oncology, Department of Surgery, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33081 Aviano, Italy;
| | - Agostino Steffan
- Immunopathology and Cancer Biomarkers, Department of Translational Research, Bioproteomic Facility, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33077 Aviano, Italy; (G.B.); (O.R.); (M.D.Z.); (L.C.); (S.Z.); (A.S.)
| | - Renato Cannizzaro
- Gastroenterology, Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33081 Aviano, Italy;
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22
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Heidarpour M, Taheri M, Akhavan A, Goli P, Kefayat A. Investigation of HER-2 Expression an Its Correlation with Clinicopathological Parameters and Overall Survival of Esophageal Squamous Cell Carcinoma Patients. IRANIAN JOURNAL OF PATHOLOGY 2020; 15:274-281. [PMID: 32944039 PMCID: PMC7477677 DOI: 10.30699/ijp.2020.113829.2235] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Accepted: 04/22/2020] [Indexed: 12/18/2022]
Abstract
Background & Objective: Human epidermal growth factor receptor 2 (HER-2) exhibits a vast range of expression in esophageal squamous cell carcinoma (ESCC) patients as a biomarker. This paper aimed to investigate HER-2 expression and clinicopathological parameters of esophageal SCC. Methods: HER-2 expression was assessed in 102 ESCC patients by immunohistochemistry. The HER-2 staining intensity , according to the Gastric HER2 Biomarker1.0.0.1 version of the college of American pathologists (CAP) protocol for gastric and gastroesophageal junction cancers, was graded as 0 (no reactivity in any of the cancer cells’ membranes); 1+ (pale or hardly noticeable reactivity in the membrane of cancer cells’ cluster [≥ 5 neoplastic cells] regardless of the positive cancer cells’ percentage); 2+ (weak-to-moderate complete, basolateral, or lateral membranous reactivity regardless of the positive cancer cells’ percentage); and 3+ ( strong complete, basolateral, or lateral reactivity in the membrane of the cancer cell cluster regardless of the positive cancer cells’ percentage).In this regard, 3+ scored samples were considered as positive. If HER-2 expression was scored 2+, an additional fluorescence in situ hybridization (FISH) was performed. Fisher's exact test was employed for investigating the correlation of HER-2 expression status with patients’ clinicopathological characteristics (including age, gender, tumor location, stage, grade, infiltration level, venous invasion, lymphatic invasion, and tumor recurrence). Kaplan-Meier analysis was done for the patients’ survival assessments. Results: Five patients (~5%) were HER-2 positive and no significant association was observed between HER-2 expression and clinicopathological properties. In addition, HER-2 expression status exhibited no significant association with the patients’ overall survival (P=0.9299). Conclusion: HER-2 is not a suitable prognostic biomarker for Iranian ESCC patients.
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Affiliation(s)
- Mitra Heidarpour
- Department of Pathology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mehran Taheri
- Department of Pathology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Ali Akhavan
- Department of Radiation Oncology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Parvin Goli
- Department of Immunology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Amirhosein Kefayat
- Department of Oncology, Cancer Prevention Research Center, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
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23
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Chrzanowska NM, Kowalewski J, Lewandowska MA. Use of Fluorescence In Situ Hybridization (FISH) in Diagnosis and Tailored Therapies in Solid Tumors. Molecules 2020; 25:molecules25081864. [PMID: 32316657 PMCID: PMC7221545 DOI: 10.3390/molecules25081864] [Citation(s) in RCA: 51] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2020] [Revised: 04/05/2020] [Accepted: 04/10/2020] [Indexed: 11/16/2022] Open
Abstract
Fluorescence in situ hybridization (FISH) is a standard technique used in routine diagnostics of genetic aberrations. Thanks to simple FISH procedure is possible to recognize tumor-specific abnormality. Its applications are limited to designed probe type. Gene rearrangements e.g., ALK, ROS1 reflecting numerous translocational partners, deletions of critical regions e.g., 1p and 19q, gene fusions e.g., COL1A1-PDGFB, genomic imbalances e.g., 6p, 6q, 11q and amplifications e.g., HER2 are targets in personalized oncology. Confirmation of genetic marker is frequently a direct indication to start specific, targeted treatment. In other cases, detected aberration helps pathologists to better distinguish soft tissue sarcomas, or to state a final diagnosis. Our main goal is to show that applying FISH to formalin-fixed paraffin-embedded tissue sample (FFPE) enables assessing genomic status in the population of cells deriving from a primary tumor or metastasis. Although many more sophisticated techniques are available, like Real-Time PCR or new generation sequencing, FISH remains a commonly used method in many genetic laboratories.
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Affiliation(s)
- Natalia Magdalena Chrzanowska
- Molecular Oncology and Genetics Department, Innovative Medical Forum, The F. Lukaszczyk Oncology Center, 85-796 Bydgoszcz, Poland;
| | - Janusz Kowalewski
- Department of Thoracic Surgery and Tumors, Ludwik Rydygier Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, 85-067 Torun, Poland;
| | - Marzena Anna Lewandowska
- Molecular Oncology and Genetics Department, Innovative Medical Forum, The F. Lukaszczyk Oncology Center, 85-796 Bydgoszcz, Poland;
- Department of Thoracic Surgery and Tumors, Ludwik Rydygier Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, 85-067 Torun, Poland;
- Correspondence: ; Tel.: +48-52-3743030
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24
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Local and Central Evaluation of HER2 Positivity and Clinical Outcome in Advanced Gastric and Gastroesophageal Cancer-Results from the AGMT GASTRIC-5 Registry. J Clin Med 2020; 9:jcm9040935. [PMID: 32235305 PMCID: PMC7230156 DOI: 10.3390/jcm9040935] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2020] [Revised: 03/24/2020] [Accepted: 03/26/2020] [Indexed: 01/21/2023] Open
Abstract
Trastuzumab in combination with a platinum and fluorouracil is the treatment of choice for patients with advanced human epidermal growth factor receptor 2 (HER2) positive gastric cancer and gastroesophageal junction (GEJ) cancer. Pathological assessment of the HER2 status in gastric/GEJ cancer, however, still remains difficult. However, it is a crucial prerequisite for optimal treatment. The GASTRIC-5 registry was designed as an observational, multi-center research initiative comparing local and central HER2 testing. HER2 status was assessed by immunohistochemistry (IHC) and in equivocal cases (IHC score 2+) by additional in-situ hybridization. Between May 2011 and August 2018, tumor samples of 183 patients were tested in local and central pathology laboratories, respectively. Central testing revealed HER2 positivity in 38 samples (21%). Discordant HER2 results were found in 12% (22 out of 183) with locally HER2 positive/centrally HER2 negative results (9%, 17 out of 183), exceeding locally HER2 negative/centrally HER2 positive results (3%, 5 out of 183). Centrally confirmed HER2 positive patients receiving trastuzumab-based palliative first-line therapy showed a longer median overall survival compared to centrally HER2 positive patients not receiving trastuzumab (17.7 months (95% CI: 10,870–24,530) vs. 6.9 months (95% CI: 3.980–9.820), p = 0.016). The findings of the GASTRIC-5 registry corroborate the challenge of HER2 testing in gastric/GEJ cancer and highlight the necessity for central quality control to optimize individual treatment options. Centrally HER2 positive patients not receiving trastuzumab had the worst outcome in a Western real-world gastric/GEJ cancer cohort.
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25
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Genc AZ, Koseoglu RD, Arici A, Demir O. HER-2/neu gene analysis on endoscopic biopsy samples and gastric resection materials in gastric carcinomas. RUSSIAN OPEN MEDICAL JOURNAL 2019; 8. [DOI: 10.15275/rusomj.2019.0410] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/30/2023] Open
Abstract
Objective ― HER-2/neu assay in gastric cancers is routinely evaluated by immunohistochemistry and fluorescent in situ hybridization methods because the monoclonal antibody trastuzumab developed against HER-2/neu give rise to significant improving on the survival. In the HER-2/neu evaluation, some problems related to the sampling process, analysis method, tumor biology and heterogeinity are encountered. Our aim in the present study was to analyze these evaluation problems on endoscopic biopsy samples and resection materials of our cases with gastric carcinoma. Material and Methods ― The study included 109 gastric cancer cases. The analyses were realized on the resection materials of the 109 cases and the endoscopic mucosa biopsies of 43 out of these 109 cases. Immunohistochemistry was applied on mucosa biopsies and, tumor sections of resections, while fluorescent in situ hybridization was performed on tumor sections of resections (21 cases). The assays results were compared with each other and clinicopathological parameters. Results ― Our rate of HER-2/neu positivity (IHC3+ and IHC2+/FISH+ cases) was 6.42%. The compatibility rate between the rates of overexpression and amplification in resections was 90.5% while the compatibility ratio between the overexpression rates of mucosa samples and resections was 95.4%. The false negativity rate on mucosa biopsies was detected as 4.65%. HER-2/neu status was not correlated with unfavorable clinicopatological features. Conclusion ― Our gene positivity rate was near the lower limit of the range reported in the literature. Our compatibility rate between the results of immunohistochemistry and fluorescent in situ hybridization was over 90%. However our false negativity rate in mucosa biopsy analysis was low according to the literature. In order to preclude false negativity arising from tumor heterogeinity, we think that immunohistochemistry should be applied on the whole section.
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26
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Liu F, Ren C, Jin Y, Xi S, He C, Wang F, Wang Z, Xu RH, Wang F. Assessment of two different HER2 scoring systems and clinical relevance for colorectal cancer. Virchows Arch 2019; 476:391-398. [PMID: 31720832 PMCID: PMC7085476 DOI: 10.1007/s00428-019-02668-9] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2019] [Revised: 08/28/2019] [Accepted: 09/10/2019] [Indexed: 12/24/2022]
Abstract
Although the positivity of human epidermal growth factor receptor 2 (HER2) is low in colorectal cancer (CRC), anti-HER2 is becoming a new target therapy in metastatic colorectal cancer (mCRC). However, assessment of the HER2 scoring system was still not established in CRC. The purpose of our study was to evaluate HER2 status and its correlation with clinicopathological characteristics and survival according to the HER2 diagnostic criteria for gastroesophageal adenocarcinoma (GEA criteria) and the HERACLES diagnostic criteria (HERACLES criteria) in a large cohort of Chinese CRC patients. The HER2 positivity was 2.9% (43/1490) and 2.6% (39/1490) in CRCs based on the GEA criteria and the HERACLES criteria, and 3.7% (9/243) in mCRC according to both criteria. HER2 status was associated with primary tumor location (P = 0.037), regional lymph node metastasis (P = 0.035), and TNM stage (P = 0.022) in CRCs based on the HERACLES criteria. No such association was found based on the GEA criteria. Furthermore, HER2 positive only presented in patients with RAS gene wild type (P = 0.001). Significant difference was only observed between the HER2-positive and HER2-negative groups in terms of disease-free survival for stage II-III CRCs (P = 0.048) according to the HERACLES criteria, but not based on the GEA criteria. Our findings suggest that the frequency of HER2 overexpression or amplification was low in Chinese CRC patients, and provide a rationale for further evaluation of HER2 in CRC based on the HERACLES criteria and the HER2 diagnostic criteria for gastroesophageal adenocarcinoma.
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Affiliation(s)
- Furong Liu
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, 651 Dongfeng Road East, Guangzhou, 510060, People's Republic of China.,Department of Medical Oncology, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, People's Republic of China
| | - Chao Ren
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, 651 Dongfeng Road East, Guangzhou, 510060, People's Republic of China.,Department of Medical Oncology, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, People's Republic of China
| | - Ying Jin
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, 651 Dongfeng Road East, Guangzhou, 510060, People's Republic of China.,Department of Medical Oncology, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, People's Republic of China
| | - Shaoyan Xi
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, 651 Dongfeng Road East, Guangzhou, 510060, People's Republic of China.,Department of Pathology, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, People's Republic of China
| | - Caiyun He
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, 651 Dongfeng Road East, Guangzhou, 510060, People's Republic of China.,Department of Molecular Diagnostics, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, People's Republic of China
| | - Fang Wang
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, 651 Dongfeng Road East, Guangzhou, 510060, People's Republic of China.,Department of Molecular Diagnostics, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, People's Republic of China
| | - Zixian Wang
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, 651 Dongfeng Road East, Guangzhou, 510060, People's Republic of China.,Department of Medical Oncology, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, People's Republic of China
| | - Rui-Hua Xu
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, 651 Dongfeng Road East, Guangzhou, 510060, People's Republic of China.,Department of Medical Oncology, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, People's Republic of China
| | - Feng Wang
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, 651 Dongfeng Road East, Guangzhou, 510060, People's Republic of China. .,Department of Medical Oncology, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, People's Republic of China.
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27
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Zhu W, Ma L, Qian J, Xu J, Xu T, Pang L, Zhou H, Shu Y, Zhou J. The molecular mechanism and clinical significance of LDHA in HER2-mediated progression of gastric cancer. Am J Transl Res 2018; 10:2055-2067. [PMID: 30093943 PMCID: PMC6079134] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2018] [Accepted: 06/08/2018] [Indexed: 06/08/2023]
Abstract
OBJECTIVE The use of human epidermal growth factor receptor-2 (HER2) as a biomarker for gastric cancer (GC) has greatly helped some patients receive benefit from HER2-targeted therapy. However, the correlation between HER2 and other biochemical markers is unclear. The aim of this study was to examine the relationship between HER2 and lactate dehydrogenase A (LDHA) in GC tissues and GC cells. METHODS The correlation between clinicopathological features and HER2 was analyzed in 179 cases of GC. The expression of HER2 and LDHA was examined by immunohistochemical staining in 12 pairs of GC tissues and by western blotting in seven pairs of fresh GC tissues and adjacent normal tissues. Wound healing, transwell migration assay, quantitative real-time reverse-transcription polymerase chain reaction (RT-PCR), and LDH activity assays were performed with GC cells. RESULTS HER2 expression and serum LDH levels were closely correlated (P = 0.027) in 179 GC patient cases. Immunohistochemical staining demonstrated a positive correlation between HER2 and LDHA in 12 pairs of GC tissues (P = 0.0308). Knocking down LDHA suppressed cell migration and invasion in GC cells. In addition, HER2 positively regulated hypoxia-inducible factor-1α (HIF-1α) and LDHA. Furthermore, the expressions of HER2, HIF-1α, and LDHA were consistent in 5/7 pairs of fresh GC tissues and adjacent normal tissues as well as in GC cell lines. CONCLUSIONS The HER2-HIF-1α-LDHA axis may serve as the basis for new methods and strategies for the treatment of GC.
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Affiliation(s)
- Weiyou Zhu
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical UniversityNanjing 210029, People’s Republic of China
- Cancer Center, The Affiliated Jiangsu Shengze Hospital of Nanjing Medical UniversitySuzhou 215228, People’s Republic of China
| | - Ling Ma
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical UniversityNanjing 210029, People’s Republic of China
| | - Jing Qian
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical UniversityNanjing 210029, People’s Republic of China
| | - Jin Xu
- Department of Molecular Cell Biology and Toxicology, Cancer Center, School of Public Health, Nanjing Medical University101 Longmian Avenue, Nanjing 211166, Jiangsu Province, People’s Republic of China
| | - Tongpeng Xu
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical UniversityNanjing 210029, People’s Republic of China
| | - Lijun Pang
- Cancer Center, The Affiliated Jiangsu Shengze Hospital of Nanjing Medical UniversitySuzhou 215228, People’s Republic of China
| | - Hong Zhou
- Cancer Center, The Affiliated Jiangsu Shengze Hospital of Nanjing Medical UniversitySuzhou 215228, People’s Republic of China
| | - Yongqian Shu
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical UniversityNanjing 210029, People’s Republic of China
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University101 Longmian Avenue, Nanjing 211166, People’s Republic of China
| | - Jianwei Zhou
- Department of Molecular Cell Biology and Toxicology, Cancer Center, School of Public Health, Nanjing Medical University101 Longmian Avenue, Nanjing 211166, Jiangsu Province, People’s Republic of China
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University101 Longmian Avenue, Nanjing 211166, People’s Republic of China
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28
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Battaglin F, Naseem M, Puccini A, Lenz HJ. Molecular biomarkers in gastro-esophageal cancer: recent developments, current trends and future directions. Cancer Cell Int 2018; 18:99. [PMID: 30008616 PMCID: PMC6042434 DOI: 10.1186/s12935-018-0594-z] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2018] [Accepted: 06/28/2018] [Indexed: 12/12/2022] Open
Abstract
Gastro-esophageal adenocarcinomas (GEA) represent a severe global health burden and despite improvements in the multimodality treatment of these malignancies the prognosis of patients remains poor. HER2 overexpression/amplification has been the first predictive biomarker approved in clinical practice to guide patient selection for targeted treatment with trastuzumab in advanced gastric and gastro-esophageal junction cancers. More recently, immunotherapy has been approved for the treatment of GEA and PD-L1 expression is now a biomarker required for the administration of pembrolizumab in these diseases. Significant progress has been made in recent years in dissecting the genomic makeup of GEA in order to identify distinct molecular subtypes linked to distinct patterns of molecular alterations. GEA have been found to be highly heterogeneous malignances, representing a challenge for biomarkers discovery and targeted treatment development. The current review focuses on an overview of established and novel promising biomarkers in GEA, covering recent molecular classifications from TCGA and ACRG. Main elements of molecular heterogeneity are discussed, as well as emerging mechanisms of primary and secondary resistance to HER2 targeted treatment and recent biomarker-driven trials. Future perspectives on the role of epigenetics, miRNA/lncRNA and liquid biopsy, and patient-derived xenograft models as a new platform for molecular-targeted drug discovery in GEA are presented. Our knowledge on the genomic landscape of GEA continues to evolve, uncovering the high heterogeneity and deep complexity of these tumors. The availability of new technologies and the identification of promising novel biomarker will be critical to optimize targeted treatment development in a setting where therapeutic options are currently lacking. Nevertheless, clinical validation of novel biomarkers and treatment strategies still represents an issue.
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Affiliation(s)
- Francesca Battaglin
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, 1441 Eastlake Avenue, Suite 5410, Los Angeles, CA 90033 USA
- Medical Oncology Unit 1, Clinical and Experimental Oncology Department, Veneto Institute of Oncology IOV-IRCCS, 35128 Padua, Italy
| | - Madiha Naseem
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, 1441 Eastlake Avenue, Suite 5410, Los Angeles, CA 90033 USA
| | - Alberto Puccini
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, 1441 Eastlake Avenue, Suite 5410, Los Angeles, CA 90033 USA
- Oncologia Medica 1, Ospedale Policlinico San Martino, 16132 Genoa, Italy
| | - Heinz-Josef Lenz
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, 1441 Eastlake Avenue, Suite 5410, Los Angeles, CA 90033 USA
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29
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Petrelli F, Ghidini M, Barni S, Steccanella F, Sgroi G, Passalacqua R, Tomasello G. Prognostic Role of Primary Tumor Location in Non-Metastatic Gastric Cancer: A Systematic Review and Meta-Analysis of 50 Studies. Ann Surg Oncol 2017; 24:2655-2668. [DOI: 10.1245/s10434-017-5832-4] [Citation(s) in RCA: 50] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/30/2023]
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30
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Kumarasinghe MP, Morey A, Bilous M, Farshid G, Francis G, Lampe G, McCue G, Von Neumann-Cosel V, Fox SB. HER2 testing in advanced gastric and gastro-oesophageal cancer: analysis of an Australia-wide testing program. Pathology 2017; 49:575-581. [PMID: 28823752 DOI: 10.1016/j.pathol.2017.05.009] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2017] [Revised: 05/15/2017] [Accepted: 05/21/2017] [Indexed: 01/29/2023]
Abstract
This Australian human epidermal growth factor receptor 2 (HER2) testing program aimed to analyse >800 cases tested in a coordinated setting to further evaluate the criteria to establish HER2 status in advanced gastric and gastro-oesophageal junction (GOJ) cancer. Heterogeneity, and minimum number of biopsy fragments for reliable HER2 assessment were also examined in a subset of samples. Five laboratories tested 891 samples referred to determine HER2 status for potential anti-HER2 treatment. Cancer site, specimen type (endoscopic biopsy/resection/metastases), immunohistochemistry (IHC) score, HER2 gene and CEP17 copy number (CN) and HER2:CEP17 ratios were recorded. Samples were derived from stomach (53.1%), GOJ (28.2%) or metastases (18.5%). IHC for HER2 and dual probe HER2:CEP17 in situ hybridisation (ISH) were performed in parallel. A stringent definition (SD) of HER2 positivity was used (IHC2+/3+ plus CN>6 and ratio>2) and compared with other published criteria. HER2 positive rate was 13.9% (114/820) by SD, and 12.9-16.0% using other definitions. There was higher concordance between IHC and HER2 CN by ISH than with ratio. The HER2 positive rate was significantly higher in GOJ samples than others (p = 0.03) and in endoscopic biopsies than resections (p = 0.047). In a subset of 98 positive cases, 39 (39.8%) showed heterogeneity, and in 282 endoscopic biopsies positivity rate plateaued at five tumour fragments, suggesting this is the minimum number of biopsies that should be examined.
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Affiliation(s)
- M Priyanthi Kumarasinghe
- PathWest, QEII Medical Centre and School of Pathology & Laboratory Medicine, University of Western Australia, Perth, WA, Australia.
| | | | - Michael Bilous
- Australian Clinical Labs, Norwest Private Hospital, Bella Vista, NSW, Australia
| | - Gelareh Farshid
- Discipline of Medicine, Adelaide University and Directorate of Surgical Pathology, SA Pathology, Adelaide, SA, Australia
| | | | - Guy Lampe
- Pathology Queensland, Brisbane, Qld, Australia
| | | | | | - Stephen B Fox
- Peter MacCallum Cancer Centre and the Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Vic, Australia
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Abstract
Inhibitor of kappa B kinase epsilon (IKKε) and TANK-binding kinase 1 (TBK1) are non-canonical IKKs. IKKε and TBK1 share the kinase domain and are similar in their ability to activate the nuclear factor-kappa B signaling pathway. IKKε and TBK1 are overexpressed through multiple mechanisms in various human cancers. However, the expression of IKKε and TBK1 in gastric cancer and their role in prognosis have not been studied. To investigate overexpression of the IKKε and TBK1 proteins in gastric cancer and their relationship with clinicopathologic factors, we performed immunohistochemical staining using a tissue microarray. Tissue microarray samples were obtained from 1,107 gastric cancer patients who underwent R0 gastrectomy with extensive lymph node dissection and adjuvant chemotherapy. We identified expression of IKKε in 150 (13.6%) and TBK1 in 38 (3.4%) gastric cancers. Furthermore, co-expression of IKKε and TBK1 was identified in 1.5% of cases. Co-expression of IKKε and TBK1 was associated with differentiated intestinal histology and earlier T stage. In a multivariate binary logistic regression model, intestinal histologic type by Lauren classification and early AJCC stage were significant predictors for expression of IKKε and TBK1 proteins in gastric cancer. Changes in IKKε and TBK1 expression may be involved in the development of intestinal-type gastric cancer. The overexpression of IKKε and TBK1 should be considered in selected patients with intestinal-type gastric cancer. In conclusion, this is the first large-scale study investigating the relationships between expression of IKKε and TBK1 and clinicopathologic features of gastric cancer. The role of IKKε and TBK1 in intestinal-type gastric cancer pathogenesis should be elucidated by further investigation.
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Wang Y, He L, Cheng Y. An independent survival prognostic role for human epidermal growth factor receptor 2 in gastric cancer: evidence from a meta-analysis. Clin Transl Oncol 2017; 20:212-220. [DOI: 10.1007/s12094-017-1711-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2017] [Accepted: 06/23/2017] [Indexed: 12/16/2022]
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De Souza K, Atabani S, Madhusudan S. Precision medicine in gastric cancer: where are we now? EXPERT REVIEW OF PRECISION MEDICINE AND DRUG DEVELOPMENT 2017. [DOI: 10.1080/23808993.2017.1357431] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Affiliation(s)
- Karen De Souza
- Department of Oncology, Nottingham University Hospitals, Nottingham, UK
| | - Suha Atabani
- Department of Oncology, Nottingham University Hospitals, Nottingham, UK
| | - Srinivasan Madhusudan
- Department of Oncology, Nottingham University Hospitals, Nottingham, UK
- Translational Oncology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham, UK
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Narita Y, Kadowaki S, Masuishi T, Taniguchi H, Takahari D, Ura T, Ando M, Tajika M, Niwa Y, Eto T, Hara H, Asayama M, Yamaguchi K, Yatabe Y, Muro K. Correlation between human epidermal growth factor receptor 2 expression level and efficacy of trastuzumab beyond progression in metastatic gastric cancer. Oncol Lett 2017; 14:2545-2551. [PMID: 28781693 DOI: 10.3892/ol.2017.6409] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2016] [Accepted: 01/06/2017] [Indexed: 11/05/2022] Open
Abstract
There is currently no clinical data regarding the efficacy of trastuzumab treatment for the progression of human epidermal growth factor receptor 2 (HER2)-positive advanced gastric cancer (AGC) occurring during trastuzumab-based chemotherapy. The aim of this study was to retrospectively examine the clinical benefits of trastuzumab for HER2-positive AGC patients who progressed during first-line trastuzumab-based chemotherapy. Among the 108 patients treated with trastuzumab combined with fluoropyrimidine and cisplatin as first-line therapy, 46 HER2-positive AGC patients who received cytotoxic agents with or without trastuzumab subsequent to disease progression were included. Of these, the efficacy and safety outcomes of 26 patients who continued trastuzumab were compared with those of the 20 patients who discontinued trastuzumab. No difference in response rate (18.2 vs. 15.8%, P=1.00) was observed between the two groups. Progression-free survival (PFS) time was numerically longer in the chemotherapy combination with trastuzumab group than in the chemotherapy combination without trastuzumab group (median, 4.0 vs. 2.3 months), with no significance [hazard ratio (HR), 0.63; P=0.14]. In the subset analysis, continuation of trastuzumab significantly improved PFS time in selected subgroups of patients with tumors exhibiting HER2 expression scores of 3+ (HR, 0.41; P=0.04), intestinal-type histology (HR, 0.32; P<0.01), and a first PFS time of >6 months (HR, 0.44; P=0.04). The survival times for the trastuzumab beyond progression (TBP) and non-TBP groups were similar (HR, 1.06; P=0.88), with equivalent overall survival times in the subgroups with immunohistochemistry scores of 3+ (HR, 0.97; P=0.94), intestinal-type histology (HR, 0.53; P=0.19), and a first PFS time of >6 months (HR, 0.62; P=0.31). There were no differences in the incidence rates of toxicity, including cardiac dysfunction, between the two groups. The study results suggest that selected HER2-positive AGC patients may benefit from trastuzumab continuation during first progression, and further prospective studies are warranted.
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Affiliation(s)
- Yukiya Narita
- Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Aichi 464-8681, Japan
| | - Shigenori Kadowaki
- Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Aichi 464-8681, Japan
| | - Toshiki Masuishi
- Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Aichi 464-8681, Japan
| | - Hiroya Taniguchi
- Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Aichi 464-8681, Japan
| | - Daisuke Takahari
- Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Aichi 464-8681, Japan
| | - Takashi Ura
- Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Aichi 464-8681, Japan
| | - Masashi Ando
- Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Aichi 464-8681, Japan
| | - Masahiro Tajika
- Department of Endoscopy, Aichi Cancer Center Hospital, Nagoya, Aichi 464-8681, Japan
| | - Yasumasa Niwa
- Department of Endoscopy, Aichi Cancer Center Hospital, Nagoya, Aichi 464-8681, Japan
| | - Tetsuya Eto
- Department of Gastroenterology, Tsuchiura Kyodo General Hospital, Tsuchiura, Ibaraki 300-0028, Japan
| | - Hiroki Hara
- Department of Gastroenterology, Saitama Cancer Center Hospital, Saitama 362-0806, Japan
| | - Masako Asayama
- Department of Gastroenterology, Saitama Cancer Center Hospital, Saitama 362-0806, Japan
| | - Kensei Yamaguchi
- Department of Gastroenterology, Saitama Cancer Center Hospital, Saitama 362-0806, Japan
| | - Yasushi Yatabe
- Department of Pathology and Molecular Diagnostics, Aichi Cancer Center Hospital, Nagoya, Aichi 464-8681, Japan
| | - Kei Muro
- Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Aichi 464-8681, Japan
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Phan DAT, Nguyen VT, Hua TNH, Ngo QD, Doan TPT, Nguyen ST, Thai AT, Nguyen VT. HER2 Status and Its Heterogeneity in Gastric Carcinoma of Vietnamese Patient. J Pathol Transl Med 2017. [PMID: 28625044 PMCID: PMC5525041 DOI: 10.4132/jptm.2017.04.24] [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] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Background Human epidermal growth factor receptor 2 (HER2) is related to the pathogenesis and poor outcome of numerous types of carcinomas, including gastric carcinoma. Gastric cancer patients with HER2 positivity have become potential candidates for targeted therapy with trastuzumab. Methods We investigated 208 gastric cancer specimens using immunohistochemistry (IHC), fluorescence in situ hybridization and dual in situ hybridization (ISH). We also investigated the concordance between IHC and ISH. The correlation between HER2 status and various clinicopathological findings was also investigated. Results In total, 15.9% (33/208) and 24.5% (51/208) of gastric cancers showed HER2 gene amplification and protein overexpression, respectively. A high level of concordance between ISH and IHC analyses (91.3%, κ = 0.76) was found. A significant correlation between HER2 status and intestinal-type (p < .05) and differentiated carcinomas (p < .05) was also noted. The HER2 heterogeneity was high in gastric cancers; we found 68.8% phenotypic heterogeneity and 57.6% genotypic heterogeneity. Heterogeneity in HER2 protein expression and gene amplification showed a close association with diffuse histologic type and IHC 2+. Conclusions HER2 protein overexpression and gene amplification were detected in 24.5% and 15.9% of gastric cancer specimens, respectively. Intestinal-type showed a higher level of HER2 protein overexpression and gene amplification than diffuse type. HER2 status also showed a significant relationship with well- and moderately-differentiated carcinomas. The ratio of phenotypic and genotypic heterogeneity of HER2 was high in gastric carcinomas and was associated with HER2 IHC 2+ and diffuse histologic type.
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Affiliation(s)
- Dang Anh Thu Phan
- Department of Pathology, University of Medicine and Pharmacy Ho Chi Minh City, Ho Chi Minh City, Vietnam
| | - Vu Thien Nguyen
- Department of Pathology, University of Medicine and Pharmacy Ho Chi Minh City, Ho Chi Minh City, Vietnam
| | - Thi Ngoc Ha Hua
- Department of Pathology, University of Medicine and Pharmacy Ho Chi Minh City, Ho Chi Minh City, Vietnam
| | - Quoc Dat Ngo
- Department of Pathology, University of Medicine and Pharmacy Ho Chi Minh City, Ho Chi Minh City, Vietnam
| | - Thi Phuong Thao Doan
- Department of Pathology, University of Medicine and Pharmacy Ho Chi Minh City, Ho Chi Minh City, Vietnam
| | - Sao Trung Nguyen
- Department of Pathology, University of Medicine and Pharmacy Ho Chi Minh City, Ho Chi Minh City, Vietnam
| | - Anh Tu Thai
- Department of Pathology, Ho Chi Minh City Oncology Hospital, Ho Chi Minh City, Vietnam
| | - Van Thanh Nguyen
- Department of Pathology, Ho Chi Minh City Oncology Hospital, Ho Chi Minh City, Vietnam
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Zeichner SB, Goldstein DA, Kohn C, Flowers CR. Cost-effectiveness of precision medicine in gastrointestinal stromal tumor and gastric adenocarcinoma. J Gastrointest Oncol 2017; 8:513-523. [PMID: 28736638 DOI: 10.21037/jgo.2016.04.03] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Over the past 20 years, with the incorporation of genetic sequencing and improved understanding regarding the mechanisms of cancer growth/metastasis, novel targets and their associated treatments have emerged in oncology and are now regularly incorporated into the clinical care of patients in the US. Novel, more tumor-specific, non-chemotherapy agents, including agents that are commonly used in the treatment of patients with gastric adenocarcinoma (GA) and gastrointestinal stromal tumor (GIST), fall under a broader treatment strategy, termed "precision medicine". While diagnostic testing and associated treatments in metastatic GA (mGA) are costly and may produce marginal benefit, those associated with GIST, despite being costly, produce significant improvements in patient outcomes. Despite the significant difference in impact, the agents associated with these cancers have similar acquisition costs. In this paper, we will review the current literature regarding cost and cost-effectiveness associated with precision medicine diagnosis and treatment strategies for GA and GIST.
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Affiliation(s)
- Simon B Zeichner
- Winship Cancer Institute at Emory University, Division of Hematology & Oncology, Atlanta, GA 30322, USA
| | - Daniel A Goldstein
- Davidoff Cancer Center, Rabin Medical Center, Petah Tikva 4941492, Israel
| | - Christine Kohn
- University of Saint Joseph School of Pharmacy, Hartford Hospital Evidence-based Practice Center, Hartford, CT 06103, USA
| | - Christopher R Flowers
- Winship Cancer Institute at Emory University, Division of Hematology & Oncology, Atlanta, GA 30322, USA
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Panarese I, De Vita F, Ronchi A, Romano M, Alfano R, Di Martino N, Zito Marino F, Ferraraccio F, Franco R. Predictive biomarkers along gastric cancer pathogenetic pathways. Expert Rev Anticancer Ther 2017; 17:417-425. [PMID: 28277834 DOI: 10.1080/14737140.2017.1301207] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
INTRODUCTION Gastric cancer is the second leading cause of cancer all over the world. Unfortunately, several gastric cancers are diagnosed in an advanced stage and chemotherapy and/or target therapies remain the only options to treat patients. Areas covered: Herein we evaluate the new molecular proposal of gastric cancer classification, offering the possibility to recognize different pathogenetic mechanisms and molecular biomarkers potentially useful for target therapies. Expert commentary: The possibility of introducing new specific tests for identification of molecular biomarkers critical for targeted therapies response represents the new frontier in the selection of gastric cancer patients to improve their survival. Besides HER2, already used in clinical settings as a target biomarker for biological therapy in gastric cancer patients with tissue cancer cells overexpressing HER2, other promising target biomarkers which are deregulated in gastric cancer, such as MET and FGFR, could be identified in tissue and then used for therapeutic purposes. In addition immunotherapy represents the most promising possibility of advanced gastric cancer treatment. In particular, as in other solid tumors, PD-1/PDL1 pathway has emerged in several clinical trials as an interesting therapeutic target.
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Affiliation(s)
- Iacopo Panarese
- a Pathology Unit, Department of Mental and Physical Health and Preventive Medicine , Università della Campania 'Luigi Vanvitelli,' , Naples , Italy
| | - Ferdinando De Vita
- b Division of Medical Oncology, Department of Internal and Experimental Medicine 'F. Magrassi' , Università della Campania 'Luigi Vanvitelli,' , Naples , Italy
| | - Andrea Ronchi
- a Pathology Unit, Department of Mental and Physical Health and Preventive Medicine , Università della Campania 'Luigi Vanvitelli,' , Naples , Italy
| | - Marco Romano
- c Division of Hepatogastroenterology, Department of Clinical and Experimental Medicine , Università della Campania 'Luigi Vanvitelli,' , Naples , Italy
| | - Roberto Alfano
- d General Surgery Unit, Department of Anesthesiology , Surgery and Emergency, Università della Campania 'Luigi Vanvitelli,' , Naples , Italy
| | - Natale Di Martino
- e Department of Internal Medicine , Surgical, Neurological Metabolic Disease and Geriatric Medicine, Università della Campania 'Luigi Vanvitelli,' , Naples , Italy
| | - Federica Zito Marino
- a Pathology Unit, Department of Mental and Physical Health and Preventive Medicine , Università della Campania 'Luigi Vanvitelli,' , Naples , Italy.,f Pathology Unit, Istituto dei tumori 'Fondazione G. Pascale'
| | - Francesca Ferraraccio
- a Pathology Unit, Department of Mental and Physical Health and Preventive Medicine , Università della Campania 'Luigi Vanvitelli,' , Naples , Italy
| | - Renato Franco
- a Pathology Unit, Department of Mental and Physical Health and Preventive Medicine , Università della Campania 'Luigi Vanvitelli,' , Naples , Italy
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Lordick F, Al-Batran SE, Dietel M, Gaiser T, Hofheinz RD, Kirchner T, Kreipe HH, Lorenzen S, Möhler M, Quaas A, Röcken C, Rüschoff J, Tannapfel A, Thuss-Patience P, Baretton G. HER2 testing in gastric cancer: results of a German expert meeting. J Cancer Res Clin Oncol 2017; 143:835-841. [PMID: 28285403 PMCID: PMC5384945 DOI: 10.1007/s00432-017-2374-x] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2017] [Accepted: 02/12/2017] [Indexed: 12/12/2022]
Abstract
Valid HER2 testing is essential for optimal therapy of patients with HER2-positive gastric cancer and the correct use of first-line chemotherapy. While testing for HER2 status in breast cancer is routinely performed, this is not the case for HER2 testing in gastric cancer and it is usually only performed on clinician request. An interdisciplinary German expert group (pathologists and clinicians) took the challenges of HER2 testing in gastric cancer as an opportunity to address essential aspects and questions for the practical use of HER2 testing in this indication. The recommendations made in this manuscript reflect the consensus of all participants and reflect their opinions and long-term experience in this field.
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Affiliation(s)
- Florian Lordick
- Universitätsklinikum Leipzig, Universitäres Krebszentrum (UCCL), Liebigstraße 20, 04103, Leipzig, Germany.
| | | | - Manfred Dietel
- Institut für Pathologie, Charité Universitätsmedizin Berlin Campus Mitte, Berlin, Germany
| | - Timo Gaiser
- Pathologisches Institut der Universitätsmedizin Mannheim, Mannheim, Germany
| | | | - Thomas Kirchner
- Pathologisches Institut der Ludwig-Maximilians-Universität München, Munich, Germany
| | - Hans H Kreipe
- Institut für Pathologie, Medizinische Hochschule Hannover, Hanover, Germany
| | - Sylvie Lorenzen
- Medizinische Klinik des Klinikums rechts der Isar, Munich, Germany
| | - Markus Möhler
- Medizinische Klinik und Poliklinik, Universitätsmedizin Mainz, Mainz, Germany
| | | | - Christoph Röcken
- Institut für Pathologie Christian-Albrechts-Universität, Kiel, Germany
| | - Josef Rüschoff
- Institut für Pathologie Nordhessen u. Targos GmbH, Kassel, Germany
| | - Andrea Tannapfel
- Georgius Agricola Stiftung Ruhr, Institut für Pathologie der Ruhr-Universität Bochum am Berufsgenossenschaftlichen Universitätsklinikum, Bochum, Germany
| | | | - Gustavo Baretton
- Institut für Pathologie, Universitätsklinikum Carl Gustav Carus, Dresden, Germany
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Apicella M, Corso S, Giordano S. Targeted therapies for gastric cancer: failures and hopes from clinical trials. Oncotarget 2017; 8:57654-57669. [PMID: 28915702 PMCID: PMC5593674 DOI: 10.18632/oncotarget.14825] [Citation(s) in RCA: 98] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2016] [Accepted: 01/17/2017] [Indexed: 12/25/2022] Open
Abstract
Gastric cancer is the third leading cause of cancer mortality worldwide. As surgery is the only curative treatment strategy and conventional chemotherapy has shown limited efficacy -with a median overall survival of 10 months- new treatments are urgently needed. Trastuzumab and Ramucirumab (targeting HER2 and VEGFR2, respectively) are the only targeted therapies approved so far. Indeed, most Phase III clinical trials evaluating molecular drugs in gastric cancer failed. This review will retrace the relevant clinical trials with molecular therapies performed in gastric cancer patients, discussing the possible reasons for their failure and indicating new perspective for a real improvement of the treatment of this disease.
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Affiliation(s)
- Maria Apicella
- Department of Oncology, University of Torino, Candiolo Cancer Institute-FPO, IRCCS, Candiolo, Torino, Italy
| | - Simona Corso
- Department of Oncology, University of Torino, Candiolo Cancer Institute-FPO, IRCCS, Candiolo, Torino, Italy
| | - Silvia Giordano
- Department of Oncology, University of Torino, Candiolo Cancer Institute-FPO, IRCCS, Candiolo, Torino, Italy
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40
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Baniak N, Senger JL, Ahmed S, Kanthan SC, Kanthan R. Gastric biomarkers: a global review. World J Surg Oncol 2016; 14:212. [PMID: 27514667 PMCID: PMC4982433 DOI: 10.1186/s12957-016-0969-3] [Citation(s) in RCA: 74] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2016] [Accepted: 08/02/2016] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Gastric cancer is an aggressive disease with a poor 5-year survival and large global burden of disease. The disease is biologically and genetically heterogeneous with a poorly understood carcinogenesis at the molecular level. Despite the many prognostic, predictive, and therapeutic biomarkers investigated to date, gastric cancer continues to be detected at an advanced stage with resultant poor clinical outcomes. MAIN BODY This is a global review of gastric biomarkers with an emphasis on HER2, E-cadherin, fibroblast growth factor receptor, mammalian target of rapamycin, and hepatocyte growth factor receptor as well as sections on microRNAs, long noncoding RNAs, matrix metalloproteinases, PD-L1, TP53, and microsatellite instability. CONCLUSION A deeper understanding of the pathogenesis and biological features of gastric cancer, including the identification and characterization of diagnostic, prognostic, predictive, and therapeutic biomarkers, hopefully will provide improved clinical outcomes.
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Affiliation(s)
- Nick Baniak
- Department of Pathology and Laboratory Medicine, University of Saskatchewan, 103 Hospital Drive, Saskatoon, SK S7N 0W8 Canada
| | - Jenna-Lynn Senger
- Department of Surgery, University of Alberta, 116 St & 85 Ave, Edmonton, T6G 2R3, T6G 2B7 AB Canada
| | - Shahid Ahmed
- Division of Medical Oncology, University of Saskatchewan, 103 Hospital Drive, Saskatoon, SK S7N 0W8 Canada
| | - S. C. Kanthan
- Department of General Surgery, University of Saskatchewan, 103 Hospital Drive, Saskatoon, SK S7N 0W8 Canada
| | - Rani Kanthan
- Department of General Surgery, University of Saskatchewan, 103 Hospital Drive, Saskatoon, SK S7N 0W8 Canada
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Riquelme I, Saavedra K, Espinoza JA, Weber H, García P, Nervi B, Garrido M, Corvalán AH, Roa JC, Bizama C. Molecular classification of gastric cancer: Towards a pathway-driven targeted therapy. Oncotarget 2016; 6:24750-79. [PMID: 26267324 PMCID: PMC4694793 DOI: 10.18632/oncotarget.4990] [Citation(s) in RCA: 102] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2015] [Accepted: 07/17/2015] [Indexed: 02/07/2023] Open
Abstract
Gastric cancer (GC) is the third leading cause of cancer mortality worldwide. Although surgical resection is a potentially curative approach for localized cases of GC, most cases of GC are diagnosed in an advanced, non-curable stage and the response to traditional chemotherapy is limited. Fortunately, recent advances in our understanding of the molecular mechanisms that mediate GC hold great promise for the development of more effective treatment strategies. In this review, an overview of the morphological classification, current treatment approaches, and molecular alterations that have been characterized for GC are provided. In particular, the most recent molecular classification of GC and alterations identified in relevant signaling pathways, including ErbB, VEGF, PI3K/AKT/mTOR, and HGF/MET signaling pathways, are described, as well as inhibitors of these pathways. An overview of the completed and active clinical trials related to these signaling pathways are also summarized. Finally, insights regarding emerging stem cell pathways are described, and may provide additional novel markers for the development of therapeutic agents against GC. The development of more effective agents and the identification of biomarkers that can be used for the diagnosis, prognosis, and individualized therapy for GC patients, have the potential to improve the efficacy, safety, and cost-effectiveness for GC treatments.
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Affiliation(s)
- Ismael Riquelme
- Department of Pathology, School of Medicine, Universidad de La Frontera, CEGIN-BIOREN, Temuco, Chile
| | - Kathleen Saavedra
- Department of Pathology, School of Medicine, Universidad de La Frontera, CEGIN-BIOREN, Temuco, Chile
| | - Jaime A Espinoza
- Department of Pathology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.,UC-Center for Investigational Oncology (CITO), Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Helga Weber
- Department of Pathology, School of Medicine, Universidad de La Frontera, CEGIN-BIOREN, Temuco, Chile
| | - Patricia García
- Department of Pathology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.,UC-Center for Investigational Oncology (CITO), Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Bruno Nervi
- UC-Center for Investigational Oncology (CITO), Pontificia Universidad Católica de Chile, Santiago, Chile.,Department of Hematology Oncology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.,Millennium Institute on Immunology and Immunotherapy, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Marcelo Garrido
- UC-Center for Investigational Oncology (CITO), Pontificia Universidad Católica de Chile, Santiago, Chile.,Department of Hematology Oncology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Alejandro H Corvalán
- UC-Center for Investigational Oncology (CITO), Pontificia Universidad Católica de Chile, Santiago, Chile.,Department of Hematology Oncology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.,Advanced Center for Chronic Diseases (ACCDIS), Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Juan Carlos Roa
- Department of Pathology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.,UC-Center for Investigational Oncology (CITO), Pontificia Universidad Católica de Chile, Santiago, Chile.,Advanced Center for Chronic Diseases (ACCDIS), Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Carolina Bizama
- Department of Pathology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.,UC-Center for Investigational Oncology (CITO), Pontificia Universidad Católica de Chile, Santiago, Chile
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Grillo F, Fassan M, Sarocchi F, Fiocca R, Mastracci L. HER2 heterogeneity in gastric/gastroesophageal cancers: From benchside to practice. World J Gastroenterol 2016; 22:5879-5887. [PMID: 27468182 PMCID: PMC4948273 DOI: 10.3748/wjg.v22.i26.5879] [Citation(s) in RCA: 87] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2016] [Revised: 05/13/2016] [Accepted: 05/23/2016] [Indexed: 02/06/2023] Open
Abstract
HER2 is overexpressed in approximately 10%-20% of gastric and gastroesophageal junction carcinomas. In these types of cancer, accurate assessment of HER2 status is mandatory, for selecting patients who may benefit from targeted therapies with anti-HER2 drugs such as Trastuzumab. This manuscript focuses on HER2 in gastric carcinogenesis, on optimal evaluation of HER2 and on the possible causes which may contribute to inaccurate HER2 evaluation. Similarly to breast cancer HER2 evaluation, standardization of HER2 testing in gastric cancer is necessary in diagnostic practice. The three principle aspects which require consideration are: (1) the choice of sample with regards to cancer morphology - intestinal vs diffuse areas; (2) the choice of scoring criteria - use of HER2 scoring criteria specific for gastric cancer; and (3) the choice of HER2 evaluation methods - use of an algorithm in which both immunohistochemistry and in situ hybridization play a role. Problematic issues include: (1) pre-analytic variables with particular emphasis on fixation; (2) recommended methodology for HER2 assessment (immunohistochemistry vs in situ hybridization); (3) HER2 heterogeneity both within the primary tumor and between primary tumor and metastases; (4) reliability of biopsies in HER 2 evaluation; and (5) quantity of sample (FFPE blocks from surgical specimens or endoscopic biopsies) necessary for an adequate assessment.
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Baretton G, Dietel M, Gaiser T, Kirchner T, Kreipe HH, Quaas A, Röcken C, Rüschoff J, Tannapfel A, Lordick F, Al-Batran S, Hofheinz R, Lorenzen S, Moehler M, Thuss-Patience P. HER2-Testung beim Magenkarzinom. DER PATHOLOGE 2016; 37:361-6. [DOI: 10.1007/s00292-016-0179-3] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
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Concordance rate between HER2 immunohistochemistry and in situ hybridization in gastric carcinoma: systematic review and meta-analysis. Int J Biol Markers 2016; 31:e1-10. [PMID: 26349670 DOI: 10.5301/jbm.5000171] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/24/2015] [Indexed: 12/17/2022]
Abstract
PURPOSE The aim of this study was to investigate the diagnostic accuracy of HER2 immunohistochemistry (IHC) in gastric carcinoma (GC) through a systematic review, meta-analysis and diagnostic test accuracy review. METHOD The current study included 12,679 GC cases and 181 subsets in 45 eligible studies. We performed concordance analysis between HER2 IHC and in situ hybridization (ISH) in GC. Diagnostic test accuracy was analyzed and the area under the curve (AUC) on the summary receiver operating characteristic (SROC) curve was calculated. RESULTS HER2 amplification rates were 3.0%, 31.8%, and 93.0% in the IHC score 0/1+, 2+, and 3+ groups, respectively. The concordance rates between IHC and ISH were 0.969 (95% confidence interval [CI] 0.962-0.975), 0.393 (95% CI 0.331-0.458) and 0.915 (95% CI 0.882-0.939) in the HER2 IHC score 0/1+, 2+, and 3+ groups, respectively. For all the HER2 IHC score groups, the positive rates were higher in the silver ISH (SISH) subgroup than in the fluorescence ISH (FISH) and chromogenic ISH (CISH) subgroups. In diagnostic test accuracy review, the pooled sensitivity and specificity were 0.86 (95% CI 0.84-0.87) and 0.91 (95% CI 0.90-0.91). The AUC on SROC curve was 0.958. However, there was no significant difference in the values of AUC between the ISH methods. CONCLUSIONS Our results showed that HER2 IHC was well concordant with ISH in HER2 IHC score 0/1+ or 3+. Although this meta-analysis showed higher diagnostic accuracy of HER2 IHC, more detailed criteria for HER2 IHC score 2+ cases will be required to predict HER2 status.
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Liu X, Xu P, Qiu H, Liu J, Chen S, Xu D, Li W, Zhan Y, Li Y, Chen Y, Zhou Z, Sun X. Clinical utility of HER2 assessed by immunohistochemistry in patients undergoing curative resection for gastric cancer. Onco Targets Ther 2016; 9:949-58. [PMID: 27013889 PMCID: PMC4777257 DOI: 10.2147/ott.s100979] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Purpose We sought to determine whether human epidermal growth factor receptor 2 (HER2) and vascular endothelial growth factor (VEGF) expression were independent prognostic factors for gastric cancer (GC). Patients and methods A total of 678 consecutive patients with GC undergoing curative surgery between October 2010 and December 2012 had resected tissue examined for HER2 and VEGF expression using immunohistochemistry. Immunohistochemical expression of HER2 was analyzed using the DAKO-HercepTest™ and scored according to published reports. VEGF expression was calculated by multiplying the score for the percentage of positive cells by the intensity score. We defined positive expression as a score of 1+, 2+, or 3+, and a score of 0 was defined as negative expression. We compared these results to clinicopathological characteristics, including overall survival (OS). Results Multivariate analysis revealed that HER2 expression was independently associated with shorter OS (hazard ratio [HR], 1.55; 95% confidence interval [CI], 1.10–2.18; P=0.01) and with higher tumor–nodes–metastasis stage (HR, 3.88; 95% CI, 2.67–5.64; P<0.001) in patients with GC. VEGF expression was not associated with OS (HR, 1.25; 95% CI, 0.86–1.82; P=0.24). HER2 expression was still identified as an independent prognostic factor in Stage II–III patients treated with surgery and adjuvant chemotherapy (P=0.004) but not in patients who received surgery alone (P=0.61). Among patients with Stage III GC, those without HER2 expression survived longer with adjuvant chemotherapy (median 43.9 vs 32.2 months, respectively; P=0.04), whereas those with HER2 expression did not (median 37.1 vs 33.9 months, respectively; P=0.67). Conclusion HER2 expression is independently associated with OS in GC, especially in patients who are at higher risk and receive adjuvant chemotherapy after curative resection. HER2 expression may have important clinical utility in directing adjuvant treatment for Stage III GC patients.
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Affiliation(s)
- Xuechao Liu
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China; Department of Gastric and Pancreatic Surgery, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China; Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China
| | - Pengfei Xu
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China; Department of Thoracic Surgery, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China; Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China
| | - Haibo Qiu
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China; Department of Gastric and Pancreatic Surgery, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China; Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China
| | - Jianjun Liu
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China; Department of Gastric and Pancreatic Surgery, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China
| | - Shangxiang Chen
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China; Department of Gastric and Pancreatic Surgery, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China
| | - Dazhi Xu
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China; Department of Gastric and Pancreatic Surgery, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China
| | - Wei Li
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China; Department of Gastric and Pancreatic Surgery, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China
| | - Youqing Zhan
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China; Department of Gastric and Pancreatic Surgery, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China
| | - Yuanfang Li
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China; Department of Gastric and Pancreatic Surgery, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China
| | - Yingbo Chen
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China; Department of Gastric and Pancreatic Surgery, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China
| | - Zhiwei Zhou
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China; Department of Gastric and Pancreatic Surgery, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China
| | - Xiaowei Sun
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China; Department of Gastric and Pancreatic Surgery, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China
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Kanayama K, Imai H, Yoneda M, Hirokawa YS, Shiraishi T. Significant intratumoral heterogeneity of human epidermal growth factor receptor 2 status in gastric cancer: A comparative study of immunohistochemistry, FISH, and dual-color in situ hybridization. Cancer Sci 2016; 107:536-42. [PMID: 26752196 PMCID: PMC4832862 DOI: 10.1111/cas.12886] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2015] [Revised: 01/04/2016] [Accepted: 01/07/2016] [Indexed: 01/14/2023] Open
Abstract
The assessment of human epidermal growth factor receptor 2 (HER2) status is crucial for selecting patients with gastric cancer who may benefit from HER2‐targeted therapy. Accurate assessment using biopsy specimens is important for patients with advanced‐stage cancer. Intratumoral heterogeneity of HER2, however, is a major challenge in HER2 testing. Here, we aimed to examine whether assessment of HER2 status could be accurately carried out with currently used methods, namely, immunohistochemistry (IHC), FISH, and dual‐color in situ hybridization (DISH). Human epidermal growth factor receptor 2 status was evaluated in 108 biopsy tissues from patients with gastric adenocarcinoma and 70 matched surgical specimens by IHC, FISH, and DISH; HER2 amplification was detected in 11 (10.2%) out of 108 biopsy specimens. The IHC and FISH results were well correlated, and FISH and DISH results were consistent for all cases. The overall concordance rate of HER2 status between biopsy tissues and surgical specimens was 91.4%. All six discordant cases were false negative on biopsy; of these cases, five showed HER2 heterogeneity on surgical resection. Assessment of the HER2 status of biopsy tissues could predict the status of the whole tumor; however, a proportion of these cases may be discordant because of intratumoral heterogeneity. This study demonstrated that HER2 assessment in biopsy tissues may predict the HER2 status of the whole tumor by IHC, FISH, and DISH. However, some cases of discordance may occur because of intratumoral HER2 heterogeneity in gastric cancers. In cases of intratumoral heterogeneity, more accurate HER2 assessment can be achieved by analysis of whole sections and by using a combination of IHC and DISH, if possible.
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Affiliation(s)
- Kazuki Kanayama
- Department of Oncologic Pathology, Mie University Graduate School of Medicine, Tsu, Japan
| | - Hiroshi Imai
- Department of Oncologic Pathology, Mie University Graduate School of Medicine, Tsu, Japan
| | - Misao Yoneda
- Department of Clinical Nutrition, Suzuka University of Medical Science, Suzuka, Japan
| | - Yoshifumi S Hirokawa
- Department of Oncologic Pathology, Mie University Graduate School of Medicine, Tsu, Japan
| | - Taizo Shiraishi
- Department of Oncologic Pathology, Mie University Graduate School of Medicine, Tsu, Japan
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Tomasello G, Ghidini M, Liguigli W, Ratti M, Toppo L, Passalacqua R. Targeted therapies in gastric cancer treatment: where we are and where we are going. Invest New Drugs 2016; 34:378-93. [PMID: 26873643 DOI: 10.1007/s10637-016-0330-2] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2015] [Accepted: 02/09/2016] [Indexed: 12/12/2022]
Abstract
Gastric cancer (GC) is one of the most common malignancies and a major cause of cancer-related deaths worldwide. Its incidence has significantly declined over the last few decades, probably due to the identification of specific etiologic agents such as Helicobacter pylori and other dietary and environmental risk factors. Nevertheless, most of the cases are unfortunately diagnosed at an advanced stage justifying median overall survival rates frequently not exceeding one year. Palliative combination chemotherapy usually represented by a platinum-based doublet is the mainstay of treatment in the metastatic setting. Adding a third drug such as an anthracycline or a taxane has been shown to improve response rate and provide limited survival benefits in fit selected patients. Unlike other tumors, the introduction of molecularly targeted drugs in the medical armamentarium for GC is relatively recent with trastuzumab and ultimately ramucirumab constituting the only agents approved to date. Recent advances in the understanding of GC biology have led to the development of novel targeted therapies holding the promise to further improve treatment outcomes. The aim of this paper is to review the main available data coming from clinical trials of targeted drugs and to describe some of the most interesting molecules in clinical development in GC. These include drugs targeting EGFR, angiogenesis, c-MET, FGFR2, mTOR and immune checkpoints.
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Affiliation(s)
- Gianluca Tomasello
- Oncology Division, Azienda Socio Sanitaria Territoriale di Cremona, Ospedale di Cremona, Viale Concordia 1, 26100, Cremona, Italy.
| | - Michele Ghidini
- Oncology Division, Azienda Socio Sanitaria Territoriale di Cremona, Ospedale di Cremona, Viale Concordia 1, 26100, Cremona, Italy
| | - Wanda Liguigli
- Oncology Division, Azienda Socio Sanitaria Territoriale di Cremona, Ospedale di Cremona, Viale Concordia 1, 26100, Cremona, Italy
| | - Margherita Ratti
- Oncology Division, Azienda Socio Sanitaria Territoriale di Cremona, Ospedale di Cremona, Viale Concordia 1, 26100, Cremona, Italy
| | - Laura Toppo
- Oncology Division, Azienda Socio Sanitaria Territoriale di Cremona, Ospedale di Cremona, Viale Concordia 1, 26100, Cremona, Italy
| | - Rodolfo Passalacqua
- Oncology Division, Azienda Socio Sanitaria Territoriale di Cremona, Ospedale di Cremona, Viale Concordia 1, 26100, Cremona, Italy
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Lee SY, Oh SC. Changing strategies for target therapy in gastric cancer. World J Gastroenterol 2016; 22:1179-89. [PMID: 26811656 PMCID: PMC4716029 DOI: 10.3748/wjg.v22.i3.1179] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2015] [Revised: 09/08/2015] [Accepted: 11/13/2015] [Indexed: 02/06/2023] Open
Abstract
In spite of a worldwide decrease in the incidence of gastric cancer, this malignancy still remains one of the leading causes of cancer mortality. Great efforts have been made to improve treatment outcomes in patients with metastatic gastric cancer, and the introduction of trastuzumab has greatly improved the overall survival. The trastuzumab treatment took its first step in opening the era of molecular targeted therapy, however several issues still need to be resolved to increase the efficacy of targeted therapy. Firstly, many patients with metastatic gastric cancer who receive trastuzumab in combination with chemotherapeutic agents develop resistance to the targeted therapy. Secondly, many clinical trials testing novel molecular targeted agents with demonstrated efficacy in other malignancies have failed to show benefit in patients with metastatic gastric cancer, suggesting the importance of the selection of appropriate indications according to molecular characteristics in application of targeted agents. Herein, we review the molecular targeted agents currently approved and in use, and clinical trials in patients with metastatic gastric cancer, and demonstrate the limitations and future direction in treatment of advanced gastric cancer.
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De Carli DM, Rocha MPD, Antunes LCM, Fagundes RB. Immunohistochemical expression of HER2 in adenocarcinoma of the stomach. ARQUIVOS DE GASTROENTEROLOGIA 2016; 52:152-5. [PMID: 26039836 DOI: 10.1590/s0004-28032015000200015] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Received: 07/18/2014] [Accepted: 07/21/2014] [Indexed: 01/26/2023]
Abstract
BACKGROUND Worldwide, gastric cancer is the fourth cancer in incidence and the second most common cause of cancer death. Gastric cancer is asymptomatic in the early stages and very often diagnosed at advanced stages, determining a dismal prognosis. Expression of the HER2 gene has been identified in about 20% of gastric cancer cases, and its hyper-expression is associated with poor prognosis. OBJECTIVE To investigate HER2 immunohistochemical expression in gastric adenocarcinoma and its relationship to the histological type and anatomic location. METHODS A cross-sectional retrospective study analyzed the immunohistochemical expression of HER2 in a sample of 48 specimens of gastric cancer. Immunohistochemical analysis were performed using avidin-biotin-peroxidase method with C-erb B2 (clone EP1045Y), as a primary antibody (Biocare Medical, USA). Standardized gastric adenocarcinoma's HER2 expression criteria has been used in the analysis of samples. RESULTS There were seven cases with reactivity for HER2. Five were of intestinal-type while two cases were of mixed-type in which the expression occurred in the intestinal component. It was identified a significant association of HER2 expression in the intestinal subtype of gastric adenocarcinoma (P=0.003). Regarding the anatomical site, HER2 was positive in only one (16.6%) of the six proximal cases and six (14.28%) of the 42 distal cases (P=0.88). CONCLUSION HER2 immunoexpression was identified in 14.6% of the samples, and the expression was significantly associated to Lauren's intestinal subtype.
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Affiliation(s)
- Diego Michelon De Carli
- Hospital Universitário de Santa Maria, Departamento de Clínica Médica, Universidade Federal de Santa Maria, Santa Maria, RS, Brasil
| | - Marta Pires da Rocha
- Hospital Universitário de Santa Maria, Departamento de Clínica Médica, Universidade Federal de Santa Maria, Santa Maria, RS, Brasil
| | - Luis Carlos Moreira Antunes
- Hospital Universitário de Santa Maria, Departamento de Clínica Médica, Universidade Federal de Santa Maria, Santa Maria, RS, Brasil
| | - Renato Borges Fagundes
- Hospital Universitário de Santa Maria, Departamento de Clínica Médica, Universidade Federal de Santa Maria, Santa Maria, RS, Brasil
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Clinicopathological factors associated with HER2 status in gastric cancer: results from a prospective multicenter observational cohort study in a Japanese population (JFMC44-1101). Gastric Cancer 2016; 19:839-51. [PMID: 26265390 PMCID: PMC4906061 DOI: 10.1007/s10120-015-0518-8] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2015] [Accepted: 07/10/2015] [Indexed: 02/07/2023]
Abstract
BACKGROUND Human epidermal growth factor (HER) 2 positivity and its association with clinicopathological factors remain unclear in Japanese gastric cancer (GC) patients. We performed a prospective, multicenter, observational cohort study to evaluate HER2 protein expression and gene amplification in Japanese metastatic and recurrent GC patients, and explored its correlations with clinicopathological features. METHODS HER2 protein expression and gene amplification were centrally assessed in formalin-fixed, paraffin-embedded GC tissue by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). Patient information was collected, and associations between clinicopathological factors and HER2 positivity (IHC score 3+ and/or FISH positive) and low HER2 expression (IHC score 0/FISH positive or IHC score 1+/FISH positive) were examined. RESULTS From September 2011 to June 2012, 1461 patients were registered across 157 sites, and the HER2 status of 1427 patients was evaluated. The rate of HER2 positivity was 21.2 %, whereas the rate of high HER2 expression (IHC score 2+/FISH positive or IHC score 3+) was 15.6 % and that of low HER2 expression was 7.0 %. Multiple logistic regression analysis identified intestinal type, absence of peritoneal metastasis, and hepatic metastasis as significant independent factors related to HER2 positivity. The intestinal type was confirmed to be the GC subtype predominantly associated with lower HER2 expression. Sampling conditions including number of biopsy samples, formalin concentration, and formalin-fixation time did not significantly affect HER2 positivity. CONCLUSIONS HER2 expression in Japanese patients was comparable to that in other populations examined. Intestinal type was an independent factor related to HER2 positivity and low HER2 expression.
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