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Xu Q, Yin Z, Li Y, Zhu X, Lou H, Ni J. Prognostic value of HER2 expression in cervical adenocarcinoma: A retrospective cohort study. Oncol Lett 2025; 29:217. [PMID: 40093868 PMCID: PMC11907399 DOI: 10.3892/ol.2025.14963] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2024] [Accepted: 01/30/2025] [Indexed: 03/19/2025] Open
Abstract
Human epidermal growth factor receptor 2 (HER2) is an important therapeutic target in various types of cancer, although the prognostic value and therapeutic potential of HER2 in cervical adenocarcinoma are still underexplored. The present study aimed to examine the association between HER2 expression levels and prognosis in cervical adenocarcinoma, offering new insights into targeted therapies for HER2-expressing cervical adenocarcinoma. A total of 179 patients with cervical cancer who received surgery were included, and HER2 status in surgical specimens of the included patients were assessed using two classification methods: Immunohistochemistry (IHC) alone and traditional combined IHC/fluorescence in situ hybridization (FISH). IHC alone was used to categorize patients into the HER2 zero expression (IHC 0) and HER2 expression (IHC 1+, 2+ and 3+) groups, while traditional combined IHC/FISH classified the HER2 expression as negative (IHC 0 and 1+ or IHC 2+/FISH-) or positive (IHC 3+ or IHC 2+/FISH+). Kaplan-Meier survival analysis and log-rank tests were used to assess the patients' survival prognosis. A Cox proportional hazards regression model was used to identify independent prognostic factors. The HER2 expression rate was 44.1% (79/179) according to IHC alone, while 5.0% (9/179) were classified as HER2-positive according to the traditional method. HER2 expression was significantly associated with advanced International Federation of Gynecology and Obstetrics stages, higher rates of lymph node metastasis, vascular or perineural invasion, elevated cancer antigen 125 levels and increased recurrence rate (P<0.05). Moreover, HER2 expression was significantly associated with shorter progression-free survival (PFS) time [51.02±2.75 vs. 56.01±2.22 months; hazard ratio (HR), 0.559; 95% confidence interval (CI), 0.313-0.998; P=0.049]. Additionally, programmed death-ligand 1 expression levels were significantly higher in HER2-expressing patients who died (P=0.039). When HER2 status was assessed using the traditional combined IHC/FISH method, HER2 positivity was significantly associated with poorer PFS time (36.44±7.85 vs. 55.17±1.78 months; HR, 0.125; 95% CI, 0.03033-0.5156; P=0.004). In conclusion, classification of HER2 status in patients with cervical adenocarcinoma using IHC alone may provide a promising method for predicting patient outcomes and optimizing therapeutic strategies to improve treatment efficacy.
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Affiliation(s)
- Qing Xu
- The Second School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, P.R. China
- Department of Gynecological Oncology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, P.R. China
| | - Zhuomin Yin
- Department of Gynecological Oncology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, P.R. China
| | - Yueqi Li
- The Second School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, P.R. China
- Department of Gynecological Oncology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, P.R. China
| | - Xiu Zhu
- Department of Pathology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, P.R. China
| | - Hanmei Lou
- Department of Gynecological Oncology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, P.R. China
| | - Juan Ni
- Department of Gynecological Oncology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, P.R. China
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Wang X, Fan B, Liu S. Comprehensive treatment focusing on transarterial chemoembolization for postoperative liver metastasis in gastric cancer patients. Am J Transl Res 2024; 16:7330-7342. [PMID: 39822559 PMCID: PMC11733346 DOI: 10.62347/kwbt3893] [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: 09/13/2024] [Accepted: 11/11/2024] [Indexed: 01/19/2025]
Abstract
OBJECTIVE To investigate the clinical efficacy of comprehensive treatment focusing on transarterial chemoembolization (TACE) for postoperative liver metastasis in patients with gastric cancer and analyze the factors influencing prognosis. METHODS A retrospective study was conducted on 116 patients who developed liver metastasis after gastric cancer surgery and were admitted to Gansu Provincial Cancer Hospital between January 2018 and February 2020. The observation group, consisting of 62 patients, received TACE with fluorouracil (FU) + irinotecan (CPT-11) + oxaliplatin (OXA) and moderate lipiodol embolization. The control group, consisting of 54 patients, received systemic S-1 and Oxaliplatin regimen (SOX) alone. The clinical efficacy and incidence of adverse reactions were compared between the two groups. Liver function indicators, tumor markers, and immunoglobulin changes were analyzed in both groups. The 2-year survival rate of patients was analyzed using the Kaplan-Meier (K-M) curve. Lasso-Cox regression was used to identify independent prognostic factors affecting the 2-year survival rate. A Nomogram model was constructed to predict outcomes. RESULTS The overall clinical efficacy (P = 0.001) and objective response rate (ORR) (P = 0.001) were significantly lower in the control group compared to the observation group. No significant differences were found in ALT and AST changes between the two groups (P > 0.05). Post-treatment, CEA and CA19-9 levels were significantly lower, and IgG and IgM levels were significantly higher in the observation group (P < 0.001). There was no significant difference in the incidence of adverse reactions (P > 0.05). Lasso-Cox regression identified treatment plan, pathological differentiation, degree of liver metastasis, and pre-treatment CEA as independent prognostic factors for 2-year survival. Based on these, a Nomogram model was constructed. In the training group, the model had AUC values over 0.8 for 1- and 2-year survival rates, and in the validation group, the AUC was 0.765 and 0.687, respectively, indicating good predictive performance. CONCLUSION Compared to the conventional SOX regimen, comprehensive treatment focusing on TACE embolization for postoperative liver metastasis in gastric cancer is more effective and can improve survival rates.
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Affiliation(s)
- Xingdong Wang
- Department of Interventional Therapy, Gansu Provincial Cancer HospitalNo. 2 Xiaoxihu East Street, Qilihe District, Lanzhou 730050, Gansu, China
| | - Bin Fan
- Drug Research Institute, Gansu Province Academic Institute For Medical ResearchNo. 2 Xiaoxihu East Street, Qilihe District, Lanzhou 730050, Gansu, China
| | - Shuwen Liu
- Department of Gastric Tumor Surgery, Gansu Provincial Cancer HospitalNo. 2 Xiaoxihu East Street, Qilihe District, Lanzhou 730050, Gansu, China
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Wang Y, Ding G, Chu C, Cheng XD, Qin JJ. Genomic biology and therapeutic strategies of liver metastasis from gastric cancer. Crit Rev Oncol Hematol 2024; 202:104470. [PMID: 39111457 DOI: 10.1016/j.critrevonc.2024.104470] [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: 12/15/2023] [Revised: 07/30/2024] [Accepted: 08/02/2024] [Indexed: 08/12/2024] Open
Abstract
The liver is a frequent site of metastasis in advanced gastric cancer (GC). Despite significant advancements in diagnostic and therapeutic techniques, the overall survival rate for patients afflicted with gastric cancer liver metastasis (GCLM) remains dismally low. Precision oncology has made significant progress in identifying therapeutic targets and enhancing our understanding of metastasis mechanisms through genome sequencing and molecular characterization. Therefore, it is crucial to have a comprehensive understanding of the various molecular processes involved in GCLM and the fundamental principles of systemic therapy to develop new treatment approaches. This paper aims to review recent findings on the diagnosis, potential biomarkers, and therapies targeting the multiple molecular processes of GCLM, with the goal of improving treatment strategies for patients with GCLM.
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Affiliation(s)
- Yichao Wang
- College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou 313200, China; Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310022, China
| | - Guangyu Ding
- Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310022, China
| | - Chu Chu
- College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou 313200, China
| | - Xiang-Dong Cheng
- Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310022, China; Key Laboratory of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province, Hangzhou 310022, China.
| | - Jiang-Jiang Qin
- Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310022, China; Key Laboratory of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province, Hangzhou 310022, China; Key Laboratory for Molecular Medicine and Chinese Medicine Preparations, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310022, China.
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Lim SH, Kim MJ, Lee J, Lim HY, Kang WK, Kim ST. The Impact of Pembrolizumab as a Salvage Therapy Based on HER2 Expression in Advanced Gastric Cancer. Cancers (Basel) 2024; 16:2969. [PMID: 39272827 PMCID: PMC11393848 DOI: 10.3390/cancers16172969] [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: 06/22/2024] [Revised: 08/22/2024] [Accepted: 08/23/2024] [Indexed: 09/15/2024] Open
Abstract
Immune checkpoint inhibitors (ICIs) are used as salvage treatments for advanced gastric cancer (AGC) regardless of HER2 status. This study assessed the efficacy of ICIs based on HER2 expression in AGC patients who received pembrolizumab as salvage monotherapy at Samsung Medical Center from November 2017 to March 2023. HER2 status was determined via immunohistochemistry, and tumor response and survival outcomes were compared accordingly. Among the 113 patients analyzed, with a median age of 61 years and 64.6% being male, 12 patients (10.6%) were HER2-positive, and 101 patients (89.4%) were HER2-negative. Of 92 evaluable patients, none had a complete response. However, 50% of HER2-positive patients had a partial response, compared to 4.9% of HER2-negative patients (p < 0.001). The disease control rate was 70% in HER2-positive and 37.8% in HER2-negative patients (p = 0.086). Median progression-free survival was 5.53 months for HER2-positive patients versus 1.81 months for HER2-negative patients (p = 0.037). Pembrolizumab as a salvage chemotherapy for the treatment of AGC demonstrated superior effectiveness in HER2-positive patients compared with HER2-negative patients.
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Affiliation(s)
- Sung Hee Lim
- Division of Hematology-Oncology, Department of Internal Medicine, Samsung Medical Center, Seoul 06351, Republic of Korea
| | - Min Jung Kim
- Division of Hematology-Oncology, Department of Internal Medicine, Samsung Medical Center, Seoul 06351, Republic of Korea
| | - Jeeyun Lee
- Division of Hematology-Oncology, Department of Internal Medicine, Samsung Medical Center, Seoul 06351, Republic of Korea
| | - Ho Yeong Lim
- Division of Hematology-Oncology, Department of Internal Medicine, Samsung Medical Center, Seoul 06351, Republic of Korea
| | - Won Ki Kang
- Division of Hematology-Oncology, Department of Internal Medicine, Samsung Medical Center, Seoul 06351, Republic of Korea
| | - Seung Tae Kim
- Division of Hematology-Oncology, Department of Internal Medicine, Samsung Medical Center, Seoul 06351, Republic of Korea
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Nemtsova MV, Kuznetsova EB, Bure IV. Chromosomal Instability in Gastric Cancer: Role in Tumor Development, Progression, and Therapy. Int J Mol Sci 2023; 24:16961. [PMID: 38069284 PMCID: PMC10707305 DOI: 10.3390/ijms242316961] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2023] [Revised: 11/23/2023] [Accepted: 11/29/2023] [Indexed: 12/18/2023] Open
Abstract
According to the Cancer Genome Atlas (TCGA), gastric cancers are classified into four molecular subtypes: Epstein-Barr virus-positive (EBV+), tumors with microsatellite instability (MSI), tumors with chromosomal instability (CIN), and genomically stable (GS) tumors. However, the gastric cancer (GC) with chromosomal instability remains insufficiently described and does not have effective markers for molecular and histological verification and diagnosis. The CIN subtype of GC is characterized by chromosomal instability, which is manifested by an increased frequency of aneuploidies and/or structural chromosomal rearrangements in tumor cells. Structural rearrangements in the CIN subtype of GC are not accidental and are commonly detected in chromosomal loci, being abnormal because of specific structural organization. The causes of CIN are still being discussed; however, according to recent data, aberrations in the TP53 gene may cause CIN development or worsen its phenotype. Clinically, patients with the CIN subtype of GC demonstrate poor survival, but receive the maximum benefit from adjuvant chemotherapy. In the review, we consider the molecular mechanisms and possible causes of chromosomal instability in GC, the common rearrangements of chromosomal loci and their impact on the development and clinical course of the disease, as well as the driver genes, their functions, and perspectives on their targeting in the CIN subtype of GC.
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Affiliation(s)
- Marina V. Nemtsova
- Laboratory of Medical Genetics, I.M. Sechenov First Moscow State Medical University (Sechenov University), 119991 Moscow, Russia; (M.V.N.); (E.B.K.)
- Laboratory of Epigenetics, Research Centre for Medical Genetics, 115522 Moscow, Russia
| | - Ekaterina B. Kuznetsova
- Laboratory of Medical Genetics, I.M. Sechenov First Moscow State Medical University (Sechenov University), 119991 Moscow, Russia; (M.V.N.); (E.B.K.)
- Laboratory of Epigenetics, Research Centre for Medical Genetics, 115522 Moscow, Russia
| | - Irina V. Bure
- Laboratory of Medical Genetics, I.M. Sechenov First Moscow State Medical University (Sechenov University), 119991 Moscow, Russia; (M.V.N.); (E.B.K.)
- Russian Medical Academy of Continuous Professional Education, 125993 Moscow, Russia
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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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Falk Z, Bou Nasif M, Fallouh N. Ophthalmoplegia in a Her2+ and β-hCG+ Patient With Leptomeningeal Carcinomatosis Secondary to Gastric Adenocarcinoma. Cureus 2022; 14:e26658. [PMID: 35815304 PMCID: PMC9266915 DOI: 10.7759/cureus.26658] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/08/2022] [Indexed: 11/30/2022] Open
Abstract
Leptomeningeal carcinomatosis (LMC) is an uncommon and devastating late complication of metastatic malignancy that carries a poor prognosis, typically faring worse when secondary to solid tumors. Diagnosis of LMC can be challenging, especially if the underlying cancer is undiagnosed, as presenting symptoms can be nonspecific or involve focal deficits such as cranial nerve palsies. Typically, LMC can be recognized due to new central neurological findings with concomitant peripheral nerve involvement, but there has not been a case of LMC with isolated peripheral nerve findings to our knowledge. In this report, we present a case of LMC secondary to metastatic gastric adenocarcinoma in a patient whose only manifestation was cranial nerve palsies, and whose cancer was also found to be Her2+ and β-hCG positive, two markers not widely recognized in gastric cancer.
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Shi L, Wang Z, Wang L, Jia Y, Li J, Qin Y. A Prognostic Nomogram and Heat Map to Predict Survival in Stage II/III Gastric Cancer Patients After Curative Gastrectomy Followed by Adjuvant Chemotherapy. Cancer Manag Res 2022; 14:287-301. [PMID: 35115828 PMCID: PMC8800584 DOI: 10.2147/cmar.s348890] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Accepted: 01/12/2022] [Indexed: 02/01/2023] Open
Abstract
Purpose This study aimed to study the prognostic value of clinicopathological data, inflammation and nutritional indicators, and to design an effective prognostic nomogram and heat map to predict cancer-specific survival (CSS) and disease-free survival (DFS) of stage II/III GC patients who underwent curative gastrectomy with adjuvant chemotherapy. Patients and Methods We retrospectively analyzed the data of 611 patients with stage II/III GC after curative gastrectomy followed by adjuvant chemotherapy from 3 GC disease centers. Patients were divided into a training cohort (n = 503) and an external validation cohort (n = 108). Nomograms were established based on independent predictors identified by Cox regression analysis in the training cohort. The consistency index (C-index) and the calibration curve were used to evaluate the discriminative ability and accuracy of the nomogram. Heat maps were constructed with the prognostic factors and the corresponding survival probability. We further divided the patients into low-risk and high-risk groups based on the risk score of the nomogram. Results Through univariate and multivariate survival analysis, the independent risk factors common to CSS and DFS were identified. Then these predictors were incorporated into the nomograms, and the established nomograms used to predict CSS and DFS had high discriminative power in the training cohort. Meanwhile, the calibration curves of CSS and DFS probability also showed good agreement between the prediction based on the nomograms and the actual observation results. The above independent predictors were applied to establish heat maps. Compared with low-risk patients, the high-risk patients calculated according to the nomogram had a shorter survival time and a worse prognosis. Conclusion We established a nomogram and heat map, which could be used to assess the survival rate of stage II/III GC patients who underwent curative gastrectomy with adjuvant chemotherapy. These tools had high prognostic prediction accuracy and provided inspiration for clinical decision-making.
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Affiliation(s)
- Litong Shi
- Department of Oncology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People’s Republic of China
| | - Zehua Wang
- Department of Oncology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People’s Republic of China
| | - Lei Wang
- Department of Oncology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People’s Republic of China
| | - Yongxu Jia
- Department of Oncology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People’s Republic of China
| | - Jing Li
- Department of Oncology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People’s Republic of China
| | - Yanru Qin
- Department of Oncology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People’s Republic of China
- Correspondence: Yanru Qin, Department of Oncology, Zhengzhou University First Affiliated Hospital, No. 1 Jianshe East Road, Erqi District, Zhengzhou, 450052, Henan, People’s Republic of China, Tel +86 13676932999, Email
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Li HK, Morokoshi Y, Kodaira S, Kusumoto T, Minegishi K, Kanda H, Nagatsu K, Hasegawa S. Utility of 211At-Trastuzumab for the Treatment of Metastatic Gastric Cancer in the Liver: Evaluation of a Preclinical α-Radioimmunotherapy Approach in a Clinically Relevant Mouse Model. J Nucl Med 2021; 62:1468-1474. [PMID: 33547212 PMCID: PMC8724896 DOI: 10.2967/jnumed.120.249300] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Accepted: 01/13/2021] [Indexed: 02/06/2023] Open
Abstract
A liver metastasis from a primary gastric cancer (LMGC) is relatively common and results in an extremely poor prognosis due to a lack of effective therapeutics. We here demonstrate in a clinically relevant mouse model that an α-particle radioimmunotherapy approach with 211At-labeled trastuzumab has efficacy against LMGCs that are positive for human epidermal growth factor receptor 2 (HER2). Methods:211At was produced in a cyclotron via a 209Bi (α,2n) 211At reaction. 211At-trastuzumab was subsequently generated using a single-step labeling method. NCI-N87 cells (HER2-positive human gastric cancer cells) carrying a luciferase gene were intrasplenically transplanted into severe combined immunodeficiency mice to generate an HER2-positive LMGC model. A biodistribution study was then conducted through the intravenous injection of 211At-trastuzumab (1 MBq) into these LMGC xenograft mice. In parallel with this experimental therapy, phosphate-buffered saline, intact trastuzumab, or 211At-nonspecific human IgG (1 MBq) was injected into control groups. The therapeutic efficacy was evaluated by monitoring tumor changes by chemiluminescence imaging. Body weights, white blood cell counts, and serum markers of tissue damage were monitored at regular intervals. Microdosimetry using a CR-39 plastic detector was also performed. Results: The biodistribution analysis revealed an increased uptake of 211At-trastuzumab in the metastasized tumors that reached approximately 12% of the injected dose per gram of tissue (%ID/g) at 24 h. In contrast, its uptake to the surrounding liver was about 4 %ID/g. The LMGCs in the mouse model reduced dramatically at 1 wk after the single systemic injection of 211At-trastuzumab. No recurrences were observed in 6 of 8 mice treated with this single injection, and their survival time was significantly prolonged compared with the control groups, including the animals treated with 211At-nonspecific antibodies. No severe toxicities or abnormalities in terms of body weight, white blood cell number, liver function, or kidney parameters were observed in the 211At-trastuzumab group. Microdosimetric studies further revealed that 211At-trastuzumab had been delivered at an 11.5-fold higher dose to the LMGC lesions than to the normal liver. Conclusion: α-radioimmunotherapy with 211At-trastuzumab has considerable potential as an effective and safe therapeutic option for LMGC.
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Affiliation(s)
- Huizi Keiko Li
- Radiation and Cancer Biology Group, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan
| | - Yukie Morokoshi
- Radiation and Cancer Biology Group, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan
| | - Satoshi Kodaira
- Radiation Measurement Research Group, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan
| | - Tamon Kusumoto
- Radiation Measurement Research Group, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan
| | - Katsuyuki Minegishi
- Targetry and Target Chemistry Group, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan; and
| | - Hiroaki Kanda
- Department of Pathology, Saitama Cancer Center, Saitama, Japan
| | - Kotaro Nagatsu
- Targetry and Target Chemistry Group, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan; and
| | - Sumitaka Hasegawa
- Radiation and Cancer Biology Group, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan;
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Huang H, Wang Z, Li Y, Zhao Q, Niu Z. Amplification of the human epidermal growth factor receptor 2 ( HER2) gene is associated with a microsatellite stable status in Chinese gastric cancer patients. J Gastrointest Oncol 2021; 12:377-387. [PMID: 34012633 PMCID: PMC8107625 DOI: 10.21037/jgo-21-47] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Accepted: 04/04/2021] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Gastric cancer (GC) is one of the most common cancers worldwide. However, little is known about the combination of HER2 amplification and microsatellite instability (MSI) status in GC. This study aimed to analyze the correlation of HER2 amplification with microsatellite instability (MSI) status, clinical characteristics, and the tumor mutational burden (TMB) of patients. METHODS A total of 192 gastric cancer (GC) patients were enrolled in this cohort. To analyze genomic alterations (GAs), deep sequencing was performed on 450 target cancer genes. TMB was measured by an in-house algorithm. MSI status was inferred based on the MANTIS (Microsatellite Analysis for Normal-Tumor InStability) score. RESULTS The most frequently amplified genes in the GC patients included cyclin E1 (CCNE1), human epidermal growth factor receptor 2 (HER2), fibroblast growth factor receptor 2 (FGFR2), cyclin D1 (CCND1), fibroblast growth factor 19 (FGF19), fibroblast growth factor 3 (FGF3), and fibroblast growth factor 4 (FGF4). The frequency of HER2 amplification was 9.38% (18/192). HER2 amplification was higher in females than in males (14.52% vs. 6.92%, respectively, P=0.091), however, MSI was higher in males compared to females (7.69% vs. 4.84%, respectively, P=0.46). HER2 amplification was higher in metastatic loci compared to primary lesions (23.08% vs. 8.38%, respectively, P=0.079) and was lower in patients with high TMB (TMB-H) compared to those with low TMB (TMB-L) (4.0% vs. 11.35%, respectively, P=0.12). While the frequency of MSI in metastatic foci was higher than that in primary lesions (15.38% vs. 6.15%, respectively, P=0.48), MSI status was highly associated with TMB-H (20% vs. 0%, respectively, P=3.66×10-7). Furthermore, HER2 amplification was negatively correlated with MSI status in Chinese GC patients. CONCLUSIONS HER2 amplification was negatively correlated with TMB-H and MSI status, and MSI status was significantly associated with TMB-H in Chinese GC patients. These data suggested that HER2 amplification might be a negative indicator for GC immunotherapy.
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Affiliation(s)
- He Huang
- Department of Gastrointestinal Surgery, The First Hospital of Shanxi Medical University, Shanxi, China
| | - Zhengkun Wang
- Department of Gastrointestinal Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Yi Li
- Department of Gastrointestinal Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Qun Zhao
- Department of Gastrosurgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Zhaojian Niu
- Department of Gastrointestinal Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China
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11
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Ha GY, Yang SH, Kang HJ, Lee HL, Kim J, Kim YJ, Yu HJ, Lee JI, Jin SH. Comparison of survival outcomes according of patients with metastatic gastric cancer receiving trastuzumab with systemic chemotherapy. KOREAN JOURNAL OF CLINICAL ONCOLOGY 2020; 16:63-70. [PMID: 36945715 PMCID: PMC9942733 DOI: 10.14216/kjco.20011] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Revised: 11/11/2020] [Accepted: 11/18/2020] [Indexed: 11/07/2022]
Abstract
Purpose Currently, trastuzumab plus chemotherapy is the standard first-line therapy for human epidermal growth factor receptor 2 (HER2)-positive advanced or metastatic gastric cancer (mGC) or esophagogastric junction cancer. However, it is not clear whether the prognosis of HER2-positive mGC treated with trastuzumab plus chemotherapy is better than that of HER2-negative mGC treated with chemotherapy as the first-line therapy. Methods We performed a retrospective study comparing the prognosis of mGC according to first-line treatment with trastuzumab plus chemotherapy or chemotherapy only, at the Korea Cancer Center Hospital from 2011 to 2018. The Kaplan-Meier method and Cox proportional hazards model were used for univariate and multivariate survival analyses. Results The median overall survival of trastuzumab group was 26.1 months and that of chemotherapy group was 14.8 months (P=0.047). Trastuzumab group had a longer median progression-free survival than chemotherapy group (23.4 vs. 9.2 months, P=0.026). By univariate analysis, sex, age, World Health Organization (WHO) histology, HER2 status, primary tumor site, extent of disease, number of lesions, number of metastatic, measurability of disease, prior gastrectomy, and chemotherapy group are statistically significant. Using multivariate analysis, number of lesions, number of metastatic, prior gastrectomy, and trastuzumab group (hazard ratio, 0.594; 95% confidence interval, 0.384-0.921; P=0.020) were found to be independent prognostic factors of overall survival. Conclusion The result suggests prognosis of HER2-positive mGC treated by trastuzumab plus chemotherapy could be better than that of HER2-negative mGC treated by chemotherapy only. Well-designed prospective cohort studies are needed to confirm the results of this study. HER2 testing should be performed routinely in all patients newly diagnosed with mGC.
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Affiliation(s)
- Gi-Young Ha
- Department of Surgery, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul, Korea
| | - Sung-Hyun Yang
- Hemato-Oncology, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul, Korea
| | - Hye-Jin Kang
- Hemato-Oncology, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul, Korea
| | - Hyo-Lak Lee
- Hemato-Oncology, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul, Korea
| | - Jin Kim
- Gastroenterology, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul, Korea
| | - Yun-Ju Kim
- Gastroenterology, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul, Korea
| | - Hang-Jong Yu
- Department of Surgery, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul, Korea
| | - Jong-Inn Lee
- Department of Surgery, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul, Korea
| | - Sung-Ho Jin
- Department of Surgery, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul, Korea
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12
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Yu P, Zhang Y, Ye Z, Chen X, Huang L, Du Y, Cheng X. Treatment of Synchronous Liver Metastases from Gastric Cancer: A Single-Center Study. Cancer Manag Res 2020; 12:7905-7911. [PMID: 32904676 PMCID: PMC7457594 DOI: 10.2147/cmar.s261353] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Accepted: 08/13/2020] [Indexed: 12/28/2022] Open
Abstract
OBJECTIVE The therapeutic effects of surgical resection in gastric cancer with liver metastasis remain largely unclear. We sought to examine surgical resection combined with chemotherapy for survival benefit in cases of synchronous liver metastases from gastric cancer (LMGC), and to identify factors affecting patient prognosis. METHODS Patients diagnosed with synchronous LMGC between January 2010 and December 2015 were enrolled in this study. The effects of gastrectomy and metastasectomy combined with chemotherapy (surgical resection group) and palliative chemotherapy (palliative chemotherapy group) on survival were comparatively assessed. RESULTS Of the 132 included cases, 57 (43.2%) and 75 (56.8%) were treated with surgical resection/chemotherapy and palliative chemotherapy, respectively. Overall survival (OS) was markedly prolonged in the surgical resection group compared with the palliative chemotherapy group (33.6 vs 12.4 months, P<0.001). In patients who underwent surgical resection, R0 resection resulted in prolonged OS in comparison with the non-R0 resection subgroup (45.1 vs 13.5 months, P<0.001). Surgical resection (hazard ratio [HR]=0.453; 95% confidence interval [CI] 0.276-0.813; P=0.009) and solitary liver metastasis (HR=0.540; 95% CI 0.315-0.796; P =0.043) were independent predictors of OS. CONCLUSION Patients with synchronous LMGC might benefit from radical surgical resection combined with appropriate chemotherapy. Additional well-designed prospective studies are required to verify the above findings.
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Affiliation(s)
- Pengfei Yu
- Department of Gastric Surgery, Institute of Cancer Research and Basic Medical Sciences of Chinese Academy of Sciences, Cancer Hospital of University of Chinese Academy of Sciences, Zhejiang Cancer Hospital, Hangzhou310022, People’s Republic of China
| | - Yanqiang Zhang
- Department of Gastric Surgery, Institute of Cancer Research and Basic Medical Sciences of Chinese Academy of Sciences, Cancer Hospital of University of Chinese Academy of Sciences, Zhejiang Cancer Hospital, Hangzhou310022, People’s Republic of China
| | - Zeyao Ye
- Department of Gastric Surgery, Institute of Cancer Research and Basic Medical Sciences of Chinese Academy of Sciences, Cancer Hospital of University of Chinese Academy of Sciences, Zhejiang Cancer Hospital, Hangzhou310022, People’s Republic of China
| | - Xiangliu Chen
- Department of Gastric Surgery, Institute of Cancer Research and Basic Medical Sciences of Chinese Academy of Sciences, Cancer Hospital of University of Chinese Academy of Sciences, Zhejiang Cancer Hospital, Hangzhou310022, People’s Republic of China
| | - Ling Huang
- Department of Gastric Surgery, Institute of Cancer Research and Basic Medical Sciences of Chinese Academy of Sciences, Cancer Hospital of University of Chinese Academy of Sciences, Zhejiang Cancer Hospital, Hangzhou310022, People’s Republic of China
| | - Yian Du
- Department of Gastric Surgery, Institute of Cancer Research and Basic Medical Sciences of Chinese Academy of Sciences, Cancer Hospital of University of Chinese Academy of Sciences, Zhejiang Cancer Hospital, Hangzhou310022, People’s Republic of China
| | - Xiangdong Cheng
- Department of Gastric Surgery, Institute of Cancer Research and Basic Medical Sciences of Chinese Academy of Sciences, Cancer Hospital of University of Chinese Academy of Sciences, Zhejiang Cancer Hospital, Hangzhou310022, People’s Republic of China
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Arienti C, Pignatta S, Tesei A. Epidermal Growth Factor Receptor Family and its Role in Gastric Cancer. Front Oncol 2019; 9:1308. [PMID: 31850207 PMCID: PMC6901979 DOI: 10.3389/fonc.2019.01308] [Citation(s) in RCA: 86] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2019] [Accepted: 11/11/2019] [Indexed: 12/24/2022] Open
Abstract
Despite the gradual decrease in incidence, gastric cancer is still the third leading cause of cancer death worldwide. Although chemotherapy enhances overall survival and quality of life in advanced disease, the median overall survival is < 12 months. In recent years, the human epidermal growth factor receptor (ErbB) family has been extensively investigated in gastric cancer. The ErbB family is composed of four closely-related members: ErbB-1 (HER1 or epidermal growth factor receptor, EGFR), ErbB-2 (HER2), ErbB-3 (HER3), and ErbB-4 (HER4), all of which play a critical role in regulating cell growth, proliferation and migration of tumors. It is well known that gastric cancer overexpresses HER in a heterogeneous pattern, especially EGFR, and HER2. HER3 is another important member of the ErbB family that preferentially activates the phosphatidylinositol 3-kinase (PI3K) pathway. Furthermore, its heterodimerization with HER2 seems fundamental for steering HER2-overexpressing breast cancer tumor growth. Less is known about the impact of HER4 on gastric cancer. Improved survival from the use of trastuzumab has paved the way for ErbB receptor family-targeted treatments in gastric cancer. However, unlike trastuzumab, ErbB receptor-targeted drugs have not consistently maintained the encouraging results obtained in preclinical and early clinical trials. This may be attributable to the intrinsic heterogeneity of gastric cancer and/or to the lack of standardized test quality for established biomarkers used to evaluate these biological targets. This review presents an overview of the most recent clinical studies on agents targeting the ErbB family in gastric cancer.
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Affiliation(s)
| | | | - Anna Tesei
- Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
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14
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Fujiwara K, Tsuji AB, Sudo H, Sugyo A, Akiba H, Iwanari H, Kusano-Arai O, Tsumoto K, Momose T, Hamakubo T, Higashi T. 111In-labeled anti-cadherin17 antibody D2101 has potential as a noninvasive imaging probe for diagnosing gastric cancer and lymph-node metastasis. Ann Nucl Med 2019; 34:13-23. [PMID: 31605356 PMCID: PMC6970965 DOI: 10.1007/s12149-019-01408-y] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2019] [Accepted: 09/30/2019] [Indexed: 12/16/2022]
Abstract
OBJECTIVE Cadherin-17 (CDH17) is a transmembrane protein that mediates cell-cell adhesion and is frequently expressed in adenocarcinomas, including gastric cancer. CDH17 may be an effective diagnostic marker for the staging of gastric cancer. Here, we developed an 111In-labeled anti-CDH17 monoclonal antibody (Mab) as an imaging tracer and performed biodistribution and single-photon emission computed tomography (SPECT)/computed tomography (CT) imaging studies using mice with CDH17-positive gastric cancer xenografts. CDH17 expression in gastric cancer specimens was also analyzed. METHODS The cross-reactivity and affinity of our anti-CDH17 Mab D2101 was evaluated by surface plasmon resonance analysis and cell enzyme-linked immunosorbent assay, respectively. Biodistribution and SPECT/CT studies of 111In-labeled D2101 (111In-D2101) were performed. CDH17 expression in gastric cancer specimens was evaluated by immunohistochemistry. RESULTS Surface plasmon resonance analysis revealed that D2101 specifically recognizes human CDH17, but not murine CDH17. The affinity of D2101 slightly decreased as a result of the radiolabeling procedures. The biodistribution study revealed high uptake of 111In-D2101 in tumors (maximum, 39.2 ± 9.5% ID/g at 96 h postinjection), but low uptake in normal organs, including the stomach. Temporal SPECT/CT imaging with 111In-D2101 visualized tumors with a high degree of tumor-to-nontumor contrast. Immunohistochemical analysis revealed that, compared with HER2, which is a potential marker of N-stage, CDH17 had a higher frequency of positivity in specimens of primary and metastatic gastric cancer. CONCLUSION Our 111In-anti-CDH17 Mab D2101 depicted CDH17-positive gastric cancer xenografts in vivo and has the potential to be an imaging probe for the diagnosis of primary lesions and lymph-node metastasis in gastric cancer.
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Affiliation(s)
- Kentaro Fujiwara
- Department of Molecular Imaging and Theranostics, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology (QST-NIRS), 4-9-1 Anagawa, Inage, 263-8555, Chiba, Japan
| | - Atsushi B Tsuji
- Department of Molecular Imaging and Theranostics, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology (QST-NIRS), 4-9-1 Anagawa, Inage, 263-8555, Chiba, Japan.
| | - Hitomi Sudo
- Department of Molecular Imaging and Theranostics, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology (QST-NIRS), 4-9-1 Anagawa, Inage, 263-8555, Chiba, Japan
| | - Aya Sugyo
- Department of Molecular Imaging and Theranostics, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology (QST-NIRS), 4-9-1 Anagawa, Inage, 263-8555, Chiba, Japan
| | - Hiroki Akiba
- Laboratory of Pharmacokinetic Optimization, Center for Drug Design Research, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, Japan
| | - Hiroko Iwanari
- Department of Quantitative Biology and Medicine, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan
| | - Osamu Kusano-Arai
- Department of Quantitative Biology and Medicine, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan.,Institute of Immunology Co., Ltd., Tokyo, Japan
| | - Kouhei Tsumoto
- Department of Bioengineering, School of Engineering, The University of Tokyo, Tokyo, Japan
| | - Toshimitsu Momose
- Department of Radiology, Faculty of Medicine, International University of Health and Welfare, Chiba, Japan
| | - Takao Hamakubo
- Department of Quantitative Biology and Medicine, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan.,Department of Protein-Protein Interaction Research, Institute for Advanced Medical Sciences, Nippon Medical School, Tokyo, Japan
| | - Tatsuya Higashi
- Department of Molecular Imaging and Theranostics, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology (QST-NIRS), 4-9-1 Anagawa, Inage, 263-8555, Chiba, Japan
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15
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Wang Y, Zhang B, Gao G, Zhang Y, Xia Q. GEFT protein expression in digestive tract malignant tumors and its clinical significance. Oncol Lett 2019; 18:5577-5590. [PMID: 31620201 DOI: 10.3892/ol.2019.10915] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2019] [Accepted: 08/13/2019] [Indexed: 01/23/2023] Open
Abstract
Guanine nucleotide exchange factor T (GEFT), a member of the Rho guanine nucleotide exchange factor family, is expressed in a variety of tumors. In the present study, the expression and clinical significance of GEFT in malignant digestive tract tumors was assessed. Tumor and adjacent control samples from 180 patients were tested. Positive GEFT expression rates were 80, 83.33 and 86.67% in esophageal squamous carcinoma (ESCC), gastric carcinoma (GC) and colorectal cancer (CRC), respectively. GEFT expression was associated with diffuse type carcinoma according to the Lauren classification (χ2=12.525, P=0.002) and tumor-node-metastasis (TNM) stages III/IV (χ2=4.033, P=0.045) in GC, and with vessel carcinoma embolus (χ2=7.890, P=0.005) and lymph node metastasis (χ2=5.455, P=0.020) in CRC, but was not associated with other clinicopathological parameters. Patients with high levels of GEFT protein expression had a less favorable outcome compared with patients with low levels of GEFT expression in patients with CRC (χ2=3.876, P=0.049). However, a significant association was not found between GEFT expression and overall survival in patients with ESCC (χ2=0.040, P=0.842) or GC (χ2=0.501, P=0.479). The rate of human epidermal growth factor receptor 2 upregulation in patients with GC was 13.33% and it was associated with nerve invasion (χ2=4.005, P=0.045) and TNM stages III/IV (χ2=5.600, P=0.018). Mismatch repair protein (MMRP) defect was observed in six cases, and the KRAS mutation rate was 26.67% in patients with CRC. GEFT expression was significantly correlated with MMRP (r=-0.285, P=0.027) and KRAS mutation in patients with CRC (r=0.697, P<0.001). These findings revealed frequent GEFT upregulation in malignant digestive tract tumors, which may have promoted tumor development. GEFT expression in CRC may be associated with microsatellite instability and KRAS mutation status, suggesting that GEFT may be a potential therapeutic target for patients with CRC.
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Affiliation(s)
- Yuanyuan Wang
- Department of Pathology, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, Henan 450008, P.R. China
| | - Bing Zhang
- Department of Pathology, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, Henan 450008, P.R. China
| | - Ge Gao
- Department of Pathology, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, Henan 450008, P.R. China
| | - Yinping Zhang
- Department of Pathology, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, Henan 450008, P.R. China
| | - Qingxin Xia
- Department of Pathology, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, Henan 450008, P.R. China
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16
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Sakaguchi M, Shimoike N, Akagawa S, Kanaya S. Strategy for treatment of stage IV human epidermal growth factor 2-positive gastric cancer: a case report. J Med Case Rep 2019; 13:42. [PMID: 30791934 PMCID: PMC6385396 DOI: 10.1186/s13256-019-2001-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2018] [Accepted: 01/28/2019] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND The prognosis of stage IV gastric cancer and human epidermal growth factor 2 (HER2)-positive gastric cancer is poor, although new drugs and regimens have been developed. We report a case of a patient with stage IV HER2-positive gastric cancer treated successfully by conversion therapy and trastuzumab. CASE PRESENTATION The patient was a 73-year-old Japanese man diagnosed as L, type 3, circ, T4aNxCy1P1M1, stage IV (the Japanese classification of gastric carcinoma). The patient was treated with docetaxel, cisplatin, and TS-1 (DCS regimen). After two courses of the regimen, peritoneal dissemination disappeared, and peritoneal lavage cytology revealed no tumor cells in the abdominal cavity. Subsequently, he underwent laparoscopic distal gastrectomy with D1+. Pathological findings were ypT2(MP), ypN2(3/15), ypP0, ypCY0, M0, ypstage II. He received TS-1 as an adjuvant chemotherapy, but he had peritoneal recurrence. The original gastric cancer was HER2-positive. We therefore treated him with TS-1 with trastuzumab. This regimen was quite effective and achieved a complete response. After complete response, we switched the patient to trastuzumab monotherapy. He had no evidence of recurrence for 6 years, 3 months after surgery. CONCLUSION DCS regimen, R0 resection, and adjuvant chemotherapy with trastuzumab can be a powerful strategy for stage IV HER2-positive gastric cancer.
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Affiliation(s)
- Masazumi Sakaguchi
- Department of Surgery, Osaka Red Cross Hospital, 5-30 Fudegasakicho, Tennoji Ward, Osaka, 543-8555 Japan
| | - Norihiro Shimoike
- Department of Surgery, Osaka Red Cross Hospital, 5-30 Fudegasakicho, Tennoji Ward, Osaka, 543-8555 Japan
| | - Shin Akagawa
- Department of Surgery, Osaka Red Cross Hospital, 5-30 Fudegasakicho, Tennoji Ward, Osaka, 543-8555 Japan
| | - Seiichiro Kanaya
- Department of Surgery, Osaka Red Cross Hospital, 5-30 Fudegasakicho, Tennoji Ward, Osaka, 543-8555 Japan
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Rajadurai P, Fatt HK, Ching FY. Prevalence of HER2 Positivity and Its Clinicopathological Correlation in Locally Advanced/Metastatic Gastric Cancer Patients in Malaysia. J Gastrointest Cancer 2018; 49:150-157. [PMID: 28124769 PMCID: PMC5948243 DOI: 10.1007/s12029-017-9921-1] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Purpose Human epidermal growth factor receptor 2 (Erbb2/HER2) overexpression, which was previously detected in invasive breast cancer, has now been implicated in advanced gastric cancer (GC) and gastroesophageal junction cancer (GEC). A study was conducted to determine the rate of HER2 positivity in patients with locally advanced or metastatic GC and GEC in Malaysia and to assess the impact of various demographic and clinical parameters on HER2 positivity. Methods A total of 228 adult patients with GC or GEC were enrolled from Subang Jaya Medical Centre, Malaysia, for retrospective (210) and prospective study. All patients were subjected to the HER2 immunohistochemistry test using an FDA-approved, standardized test kit. Carcinomas scoring 2+ on immunohistochemistry were further tested with HER2 in situ hybridization (ISH) using an FDA-approved test kit. Results The overall rate of HER2 positivity in the population studied was 24.6% (n = 56). The rate was significantly higher in men than in women (29.6 vs. 16.3%; p = 0.024). HER2 overexpression was significantly more common in diffuse type than in intestinal type of tumors (39.8 vs. 14.9%; p < 0.001). In our study, out of 56 samples, 44 (78.6%) were considered for gene amplification testing, out of which 40 (90.1%) samples showed gene amplification. There was no statistically significant correlation between HER2 positivity and patient age, race, tumor location, tumor differentiation, and TNM staging. Conclusions HER2 overexpression was evident in nearly 25% of the Malaysian patients with locally advanced or metastatic gastric cancer. The overexpression correlated significantly with male gender and diffuse-type tumors. The majority of the IHC-positive tumors demonstrated c-erb2 gene amplification and this finding reached statistical significance.
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Affiliation(s)
- Pathmanathan Rajadurai
- Department of Pathology, Subang Jaya Medical Centre, Subang Jaya, Sunway Medical Centre, Monash University Malaysia, 1, Jalan SS 12/1A, 47500, Subang Jaya, Selangor, Malaysia.
| | - Ho Kean Fatt
- Mount Miriam Cancer Hospital, Tanjung Tokong, Penang, Malaysia
| | - Foo Yoke Ching
- Subang Jaya Medical Centre, Subang Jaya, Selangor, Malaysia
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Shimizu D, Kanda M, Kodera Y. Emerging evidence of the molecular landscape specific for hematogenous metastasis from gastric cancer. World J Gastrointest Oncol 2018; 10:124-136. [PMID: 29988904 PMCID: PMC6033711 DOI: 10.4251/wjgo.v10.i6.124] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2018] [Revised: 03/23/2018] [Accepted: 04/20/2018] [Indexed: 02/05/2023] Open
Abstract
Gastric cancer (GC) is one of the most frequently diagnosed cancers in the world. Most GC patients are diagnosed when the cancer is in an advanced stage, and consequently, some develop metastatic lesions that generally cause cancer-related death. Metastasis establishment is affected by various conditions, such as tumor location, hemodynamics and organotropism. While digestive cancers may share a primary site, certain cases develop hematogenous metastasis with the absence of peritoneal metastasis, and vice versa. Numerous studies have revealed the clinicopathological risk factors for hematogenous metastasis from GC, such as vascular invasion, advanced age, differentiation, Borrmann type 1 or 2 and expansive growth. Recently, molecular mechanisms that contribute to metastatic site determination have been elucidated by advanced molecular biological techniques. Investigating the molecules that specifically participate in metastasis establishment in distinct secondary organs will lead to the development of novel biomarkers for patient stratification according to their metastatic risk and strategies for preventing and treating distinct metastases. We reviewed articles related to the molecular landscape of hematogenous metastasis from GC.
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Affiliation(s)
- Dai Shimizu
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
| | - Mitsuro Kanda
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
| | - Yasuhiro Kodera
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
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HER-2 Protein Overexpression in Patients with Gastric and Oesophageal Adenocarcinoma at a Tertiary Care Facility in Ghana. ScientificWorldJournal 2018; 2018:1564150. [PMID: 29725274 PMCID: PMC5872623 DOI: 10.1155/2018/1564150] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2017] [Revised: 02/03/2018] [Accepted: 02/14/2018] [Indexed: 12/23/2022] Open
Abstract
The prognosis of gastric and oesophageal adenocarcinoma remains generally poor. However, mounting evidence suggests a positive role of human epidermal growth factor receptor-2 (HER-2) expression in the prognosis of patients with these cancers. In this work, the patterns of HER-2 protein expression were determined in patients with gastric or oesophageal adenocarcinoma. Retrospectively, we reviewed records of gastric and oesophageal biopsies received from 2008 to 2012 and their corresponding archived formalin-fixed paraffin-embedded tissue blocks selected for immunohistochemical analysis. The prevalence of gastric and oesophageal adenocarcinomas and their association with HER-2 protein overexpression were evaluated. Gastric adenocarcinoma made up 18.79% of the gastric biopsies reviewed, and majority of these cancers occurred in males. Regarding the tumour type, HER-2 overexpression was common in the intestinal subtype compared to the diffuse type. Although squamous cell carcinoma was observed to be the commonest (31%) tumour type in the oesophagus compared to adenocarcinoma (8.79%), HER-2 was overexpressed in 42.9% of oesophageal adenocarcinomas, like gastric adenocarcinoma (41.4%). There is a high prevalence of gastric and oesophageal adenocarcinoma, with significant overexpression of HER-2 in these tumours, a window of hope for the management of patients with these cancers.
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Shabbir A, Qureshi MA, Khalid AB, Mirza T, Shaikh A, Hasan SM. Gastric adenocarcinoma expressing human epidermal growth factor receptor in South Asian population. Saudi J Gastroenterol 2018; 24:289-293. [PMID: 29806596 PMCID: PMC6151997 DOI: 10.4103/sjg.sjg_23_18] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND/AIM Gastric cancer is the third leading cause of cancer mortality worldwide. Human epidermal growth factor (Her-2/neu) has shown strong therapeutic implication in breast cancer. Although the prevalence of Her-2/neu over-expression in gastric cancer has been reported across the world, it is still unknown from South Asia. The aim of this study is to evaluate Her-2/neu expression in gastric adenocarcinomas and to correlate with various clinicopathological variables. PATIENTS AND METHODS A total of 95 consecutive patients undergoing endoscopic biopsy or gastrectomy were recruited in this study. Clinicopathological parameters of all patients were recorded and hematoxylin and eosin (H and E) staining was performed. Over-expression of Her-2/neu was investigated by immunohistochemistry using α-Her-2 antibody. To quantify Her-2/neu over-expression, the Hofmann validation scoring system was used and further its association was seen with age, gender, histopathological type, grade, and stage of the tumor. Data were entered and analyzed using SPSS version 21. A P value of <0.05 was considered as significant. RESULTS Overall, 21 (22.1%) cases were positive for Her-2/neu overexpression from the total of 95 gastric adenocarcinomas. Her-2/neu was significantly expressed in low-grade gastric cancer (grade I = 50%, grade II = 34.5%, grade III = 14.5%; P = 0.030). Although there was insignificant difference between Her-2/neu over expression and other variables, Her-2/neu score 3+ was predominantly seen in females, age >60 years, Laurens intestinal type, and IIIC stage tumors. CONCLUSION Her-2/neu is over-expressed in a limited group of gastric cancer patients in our population and indicates a significant strong association with low grades of gastric cancer.
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Affiliation(s)
- Asma Shabbir
- Department of Pathology, Sindh Medical College, Jinnah Sindh Medical University, Karachi, Pakistan,Address for correspondence: Dr. Asma Shabbir, Department of Pathology, Sindh Medical College, Jinnah Sindh Medical University, Karachi, Pakistan. E-mail:
| | - Muhammad Asif Qureshi
- Department of Pathology, Dow International Medical College, Dow University of Health Sciences, Karachi, Pakistan
| | - Abdullah Bin Khalid
- Department of Pathology, Dow International Medical College, Dow University of Health Sciences, Karachi, Pakistan
| | - Talat Mirza
- Department of Pathology, Doctor. Ziauddin Hospital and University, Karachi, Pakistan
| | - Asma Shaikh
- Department of Pathology, Sindh Medical College, Jinnah Sindh Medical University, Karachi, Pakistan
| | - Syed Mehmood Hasan
- Department of Pathology, Sindh Medical College, Jinnah Sindh Medical University, Karachi, Pakistan
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21
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Caggiari L, Miolo G, Buonadonna A, Basile D, Santeufemia DA, Cossu A, Palmieri G, De Zorzi M, Fornasarig M, Alessandrini L, Canzonieri V, Lo Re G, Puglisi F, Steffan A, Cannizzaro R, De Re V. Characterizing Metastatic HER2-Positive Gastric Cancer at the CDH1 Haplotype. Int J Mol Sci 2017; 19:E47. [PMID: 29295527 PMCID: PMC5795997 DOI: 10.3390/ijms19010047] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2017] [Revised: 12/19/2017] [Accepted: 12/21/2017] [Indexed: 02/06/2023] Open
Abstract
The CDH1 gene, coding for the E-cadherin protein, is linked to gastric cancer (GC) susceptibility and tumor invasion. The human epidermal growth factor receptor 2 (HER2) is amplified and overexpressed in a portion of GC. HER2 is an established therapeutic target in metastatic GC (mGC). Trastuzumab, in combination with various chemotherapeutic agents, is a standard treatment for these tumors leading to outcome improvement. Unfortunately, the survival benefit is limited to a fraction of patients. The aim of this study was to improve knowledge of the HER2 and the E-cadherin alterations in the context of GC to characterize subtypes of patients that could better benefit from targeted therapy. An association between the P7-CDH1 haplotype, including two polymorphisms (rs16260A-rs1801552T) and a subset of HER2-positive mGC with better prognosis was observed. Results indicated the potential evaluation of CDH1 haplotypes in mGC to stratify patients that will benefit from trastuzumab-based treatments. Moreover, data may have implications to understanding the HER2 and the E-cadherin interactions in vivo and in response to treatments.
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Affiliation(s)
- Laura Caggiari
- Immunopathology and Cancer Biomarkers, IRCCS CRO National Cancer Institute, 33081 Aviano, Italy.
| | - Gianmaria Miolo
- Medical Oncology, IRCCS, CRO National Cancer Institute, 33081 Aviano, Italy.
| | - Angela Buonadonna
- Medical Oncology, IRCCS, CRO National Cancer Institute, 33081 Aviano, Italy.
| | - Debora Basile
- Medical Oncology, IRCCS, CRO National Cancer Institute, 33081 Aviano, Italy.
- Department of Medicine, School of Medical Oncology, University of Udine, 0432 Udine, Italy.
| | | | - Antonio Cossu
- Operative Unit of Pathology Department of Surgical, Microsurgical and Medical Sciences, University of Sassari, 07100 Sassari, Italy.
| | - Giuseppe Palmieri
- Institute of Biomolecular Chemistry, Cancer Genetics Unit, C.N.R., 07100 Sassari, Italy.
| | - Mariangela De Zorzi
- Immunopathology and Cancer Biomarkers, IRCCS CRO National Cancer Institute, 33081 Aviano, Italy.
| | - Mara Fornasarig
- Gastroenterology, IRCCS CRO National Cancer Institute, 33081 Aviano, Italy.
| | - Lara Alessandrini
- Pathology, IRCCS CRO National Cancer Institute, 33081 Aviano, Italy.
| | | | - Giovanni Lo Re
- Medical Oncology Department, Santa Maria degli Angeli Hospital, 33170 Pordenone, Italy.
| | - Fabio Puglisi
- Medical Oncology, IRCCS, CRO National Cancer Institute, 33081 Aviano, Italy.
- Department of Medicine, School of Medical Oncology, University of Udine, 0432 Udine, Italy.
| | - Agostino Steffan
- Immunopathology and Cancer Biomarkers, IRCCS CRO National Cancer Institute, 33081 Aviano, Italy.
| | - Renato Cannizzaro
- Gastroenterology, IRCCS CRO National Cancer Institute, 33081 Aviano, Italy.
| | - Valli De Re
- Immunopathology and Cancer Biomarkers, IRCCS CRO National Cancer Institute, 33081 Aviano, Italy.
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22
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Li Q, Li H, Jiang H, Feng Y, Cui Y, Wang Y, Ji Y, Yu Y, Li W, Xu C, Yu S, Zhuang R, Liu T. Predictive factors of trastuzumab-based chemotherapy in HER2 positive advanced gastric cancer: a single-center prospective observational study. Clin Transl Oncol 2017; 20:695-702. [DOI: 10.1007/s12094-017-1772-5] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2017] [Accepted: 10/13/2017] [Indexed: 12/20/2022]
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23
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Lei YY, Huang JY, Zhao QR, Jiang N, Xu HM, Wang ZN, Li HQ, Zhang SB, Sun Z. The clinicopathological parameters and prognostic significance of HER2 expression in gastric cancer patients: a meta-analysis of literature. World J Surg Oncol 2017; 15:68. [PMID: 28327158 PMCID: PMC5359900 DOI: 10.1186/s12957-017-1132-5] [Citation(s) in RCA: 76] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2016] [Accepted: 03/06/2017] [Indexed: 12/31/2022] Open
Abstract
Background Human epidermal growth factor receptor-2 (HER2) is regarded as an important and promising target in the treatment of HER2-positive breast cancers. However, the correlation of clinicopathological characteristics and prognostic significance of HER2 overexpression in gastric cancer patients remains unclear. Our aim was to clarify this issue. Methods Embase, PubMed, and the Cochrane Library were searched for relevant articles published up to May 2016. Outcomes of interest contained sex, age, tumor size, tumor site, tumor node metastasis (TNM) stage, distant metastasis, lymph node metastasis, Lauren’s classification, differentiation grade, lymphovascular invasion, neural invasion, and multivariate analysis data for overall survival. Results A total of 41 studies of 17,494 gastric cancer patients were identified with HER2 test. HER2 positive rate was 19.07% (95% CI = 9.16, 28.98). There existed statistical significance between HER2 overexpression and patients’ prognosis (RR = 1.47, 95% CI = 1.09, 1.98). Male patients (OR = 1.48, 95% CI = 1.34, 1.65), proximal tumors (OR = 1.25, 95% CI = 1.07, 1.47), intestinal-type tumors (OR = 3.37, 95% CI = 2.54, 4.47), advanced stage cancers (OR = 1.35, 95% CI = 1.10, 1.66), lymph node metastasis (OR = 1.26, 95% CI = 1.14, 1.41), well-differentiated cancers (OR = 1.79, 95% CI = 1.15, 2.76), and distant metastasis (OR = 1.91, 95% CI = 1.08, 3.38) were correlated with higher HER2 expression rates. However, no statistical differences existed in age, tumor size, lymphovascular invasion, or neural invasion. Subgroup analysis revealed that HER2 expression rates reported in articles from Asian (19.52%) countries were quantitatively higher than those from European (16.91%) areas. Results were consistent with those reports that define HER2 status according to trastuzumab for gastric cancer (ToGA) criteria. Conclusion This study showed that HER2 overexpression was associated with poor prognosis in gastric cancer patients. HER2 positive rates may be associated with sex, tumor site, TNM staging system, distant metastasis, lymph node metastasis, Lauren’s classification, and differentiation grade in gastric cancer patients. The HER2 expression rate in Asians may be higher than that in Europeans. This study offers a convenient way for doctors to select patients for relevant HER2 detection and following treatment. Electronic supplementary material The online version of this article (doi:10.1186/s12957-017-1132-5) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Yu-Ying Lei
- Department of Surgical Oncology, First Affiliated Hospital of China Medical University, 110001, Shenyang, Liaoning, China
| | - Jin-Yu Huang
- Department of Surgical Oncology, First Affiliated Hospital of China Medical University, 110001, Shenyang, Liaoning, China
| | - Qiong-Rui Zhao
- Department of Evidence Based Medicine, First Affiliated Hospital of China Medical University, 110001, Shenyang, Liaoning, China
| | - Nan Jiang
- International Education School, China Medical University, 110001, Shenyang, Liaoning, China
| | - Hui-Mian Xu
- Department of Surgical Oncology, First Affiliated Hospital of China Medical University, 110001, Shenyang, Liaoning, China
| | - Zhen-Ning Wang
- Department of Surgical Oncology, First Affiliated Hospital of China Medical University, 110001, Shenyang, Liaoning, China
| | - Hai-Qing Li
- Department of Surgical Oncology, First Affiliated Hospital of China Medical University, 110001, Shenyang, Liaoning, China
| | - Shi-Bo Zhang
- Department of Surgical Oncology, First Affiliated Hospital of China Medical University, 110001, Shenyang, Liaoning, China
| | - Zhe Sun
- Department of Surgical Oncology, First Affiliated Hospital of China Medical University, 110001, Shenyang, Liaoning, China.
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24
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Wang SC, Xu J, Qiu JF. Surgical treatment of gastric cancer liver metastasis: Focus on controversy. Shijie Huaren Xiaohua Zazhi 2016; 24:4450-4457. [DOI: 10.11569/wcjd.v24.i33.4450] [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] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer is the third most common malignancy in China, and the liver is the most common metastasis site which is responsible for poor prognosis in advanced gastric cancer. Gastric cancer liver metastasis (GCLM) has long been regarded as a systemic disease, and chemotherapy is still the main treatment, although the efficacy is unsatisfying. Recently, active surgical resection is reported to be practicable and beneficial in highly selected cases. In addition, either radiofrequency ablation or hepatic arterial infusion can be used for unresectable locally advanced tumors. Management of liver metastasis is the key to significantly improve the prognosis of patients. Further research is needed to establish individualized modalities for these particular patients. We herein discuss the surgical treatment of GCLM.
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25
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Celli R, Colunga M, Patel N, Djekidel M, Jain D. Metabolic Signature on 18F-FDG PET/CT, HER2 Status, and Survival in Gastric Adenocarcinomas. J Nucl Med Technol 2016; 44:234-238. [PMID: 27789750 DOI: 10.2967/jnmt.116.181479] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2016] [Accepted: 10/14/2016] [Indexed: 12/23/2022] Open
Abstract
The human epidermal growth factor 2 (HER2)-overexpressing (HER2-positive [HER2+]) gastric (GC) and gastroesophageal junction adenocarcinomas (GEJC) are felt to represent a more aggressive form of disease, which may correlate to increased metabolic activity. Whether tumor SUVmax measured by 18F-FDG PET/CT could be a preoperative parameter used to predict HER2 status of GC/GEJC is unknown. METHODS Pathology reports of HER2+ GC/GEJC biopsies and resections from 31 patients were reviewed and compared with HER2-negative (HER2-) cases distributed evenly over the same time period. We analyzed their SUVmax intensity and then compared the HER2 status and SUVmax parameters and their association with survival. RESULTS After matching for age and sex, there was no difference in SUVmax between HER2+ and HER2- cases (9.7 and 8.4, respectively; P = 0.6). No difference was seen between HER2+ and HER2- cases in tumor histology (81% and 57% intestinal type, respectively; P = 0.11), size (2.6 and 3.8 cm, respectively; P = 0.12), differentiation (47% and 68% poorly differentiated, respectively; P = 0.06), or presence of lymph node metastasis (60% and 40%, respectively; P = 0.3). Although there was no difference in survival demonstrated by HER2+ and HER2- cases, there was a significant difference in survival between SUVmax above (12.2 mo) and below (30 mo) the median SUVmax (6.6, P = 0.01). CONCLUSION Our study shows that SUVmax is not associated with HER2 status of GC/GEJC. Independent of HER2 overexpression, patients with a high SUVmax demonstrate a worse overall survival, suggesting that metabolic signature is a better predictor of biologic tumor aggressiveness than its histologic signature.
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Affiliation(s)
- Romulo Celli
- Department of Pathology, Yale School of Medicine, New Haven, Connecticut
| | | | - Natalie Patel
- Department of Pathology, Yale School of Medicine, New Haven, Connecticut
| | | | - Dhanpat Jain
- Department of Pathology, Yale School of Medicine, New Haven, Connecticut
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26
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Fanotto V, Ongaro E, Rihawi K, Avallone A, Silvestris N, Fornaro L, Vasile E, Antonuzzo L, Leone F, Rosati G, Giuliani F, Bordonaro R, Scartozzi M, Maglio GD, Negri FV, Fasola G, Aprile G. HER-2 inhibition in gastric and colorectal cancers: tangible achievements, novel acquisitions and future perspectives. Oncotarget 2016; 7:69060-69074. [PMID: 27542243 PMCID: PMC5356612 DOI: 10.18632/oncotarget.11264] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2015] [Accepted: 06/16/2016] [Indexed: 12/20/2022] Open
Abstract
HER-2 (ErbB-2, c-erbB2 or Her2/neu), a member of the HER-family, is directly involved in the pathogenesis and progression of several human cancers; as such, it is also often considered as a poor prognostic factor. Following the revolutionary impact of anti-HER-2 therapy in breast cancer patients, the role of HER-2 and its blockade has also been extensively evaluated in other tumor types, including gastric and colorectal adenocarcinoma. The aims of this review are to recall the important results achieved with the use of HER-2 inhibitors in both gastric and colorectal cancer, and to discuss on the updates available on the role of HER-2 as prognostic and predictive factor in these malignancies.
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Affiliation(s)
- Valentina Fanotto
- Department of Oncology, University and General Hospital, Udine, Italy
| | - Elena Ongaro
- Department of Oncology, University and General Hospital, Udine, Italy
| | - Karim Rihawi
- Department of Oncology, S.Orsola-Malpighi Hospital, Bologna, Italy
| | - Antonio Avallone
- Gastrointestinal Medical Oncology Unit, National Cancer Institute “Fondazione Giovanni Pascale”-IRCCS, Napoli, Italy
| | - Nicola Silvestris
- Department of Oncology, National CancerInstitute “Giovanni Paolo II”-IRCSS, Bari, Italy
| | - Lorenzo Fornaro
- Unit of Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy
| | - Enrico Vasile
- Unit of Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy
| | | | - Francesco Leone
- Department of Medical Oncology, University of Torino, Candiolo Cancer Institute-FPO-IRCCS, Torino, Italy
| | - Gerardo Rosati
- Medical Oncology Unit, San Carlo Hospital, Potenza, Italy
| | - Francesco Giuliani
- Department of Oncology, National CancerInstitute “Giovanni Paolo II”-IRCSS, Bari, Italy
| | | | - Mario Scartozzi
- Department of Oncology, University Hospital, Cagliari, Italy
| | | | | | - Gianpiero Fasola
- Department of Oncology, University and General Hospital, Udine, Italy
| | - Giuseppe Aprile
- Department of Oncology, University and General Hospital, Udine, Italy
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27
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Jiang H, Li Q, Yu S, Yu Y, Wang Y, Li W, Cui Y, Liu T. Impact of HER2 expression on outcome in gastric cancer patients with liver metastasis. Clin Transl Oncol 2016; 19:197-203. [PMID: 27324991 DOI: 10.1007/s12094-016-1523-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2016] [Accepted: 06/10/2016] [Indexed: 12/13/2022]
Abstract
PURPOSE We aim to investigate the correlation of HER2 expression with liver metastasis and the impact of HER2 status and trastuzumab therapy on the prognosis of gastric cancer with liver metastasis (GCLM) patients. METHODS This prospective observational study was carried out in Shanghai Zhongshan Hospital, Fudan University, from January 2012 to June 2015. HER2 status and baseline characteristics were collected from the patient record. GCLM patients were divided into three groups according to HER2 status and trastuzumab therapy. RESULTS A total of 290 patients were included, and94 patients were diagnosed with liver metastasis. The HER2 positivity was 37.2 % (35/94) in GCLM patients and 21 % (61/290) in the overall GC patients. Among 94 GCLM patients, 28 HER2-positive patients received trastuzumab-based therapy (group A), 7 HER2-positive patients received chemotherapy alone (group B) and the other 59 patients were HER2 negative (group C). The median progression-free survival (PFS) for groups A, B and C was 7.83, 6.30 and 5.33 months, respectively (P = 0.007). The median overall survival (OS) for groups A, B and C was 12.00, 10.47 and 8.67 months, respectively (P = 0.056). Further Cox analysis showed that there was no significant difference in OS (P = 0.917) and PFS (P = 0.456) between group B and C. CONCLUSIONS HER2 positivity was higher in GCLM patients. HER2 status itself was not an independent prognostic factor in GCLM patients. Trastuzumab-based therapy could significantly improve survival in HER2-positive GCLM patients.
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Affiliation(s)
- H Jiang
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Building 8, 180 Fenglin Road, Xuhui District, Shanghai, 200032, China
| | - Q Li
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Building 8, 180 Fenglin Road, Xuhui District, Shanghai, 200032, China
| | - S Yu
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Building 8, 180 Fenglin Road, Xuhui District, Shanghai, 200032, China
| | - Y Yu
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Building 8, 180 Fenglin Road, Xuhui District, Shanghai, 200032, China
| | - Y Wang
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Building 8, 180 Fenglin Road, Xuhui District, Shanghai, 200032, China
| | - W Li
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Building 8, 180 Fenglin Road, Xuhui District, Shanghai, 200032, China
| | - Y Cui
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Building 8, 180 Fenglin Road, Xuhui District, Shanghai, 200032, China
| | - T Liu
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Building 8, 180 Fenglin Road, Xuhui District, Shanghai, 200032, China.
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28
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Wada R, Hirabayashi K, Ohike N, Morii E. New guidelines for HER2 pathological diagnostics in gastric cancer. Pathol Int 2016; 66:57-62. [PMID: 26814046 DOI: 10.1111/pin.12390] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Affiliation(s)
- Ryo Wada
- Department of Pathology, Juntendo University Shizuoka Hospital, Shizuoka, Japan
| | - Kenichi Hirabayashi
- Department of Pathology, Tokai University School of Medicine, Kanagawa, Japan
| | - Nobuyuki Ohike
- Department of Pathology, Showa University Fujigaoka Hospital, Kanagawa, Japan
| | - Eiichi Morii
- Department of Pathology, Osaka University Graduate School of Medicine, Osaka, Japan
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29
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Clinical role of HER2 gene amplification and chromosome 17: a study on 154 IHC-equivocal cases of invasive breast carcinoma patients. Tumour Biol 2016; 37:8665-72. [PMID: 26738861 DOI: 10.1007/s13277-015-4657-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2014] [Accepted: 08/25/2014] [Indexed: 01/21/2023] Open
Abstract
Accurate evaluation of human epidermal growth factor receptor 2 (HER2) status is quite crucial for invasive breast tumor patients in order to select anti-HER2 therapy for effective clinical outcomes. Immunohistochemistry (IHC) assay is routinely used to evaluate the HER2 oncoprotein overexpression but is unable to explain the chromosomal and genetic alterations and has been considered as a hot issue in IHC-equivocal cases. We investigated these molecular aberrations in correlation with prognostic factors. A cohort of 154 IHC-equivocal (+2) cases was selected and retrospectively analyzed by dual-probe fluorescence in situ hybridization (FISH) assay by using locus-specific HER2 and centromere enumeration probes (CEP17) for the identification of HER2 proto-oncogene amplification and chromosomal copy number per cell, respectively. The data were analyzed by SPSS 16.0 version using chi-square test (p < 0.05). We identified 36 out of 154 cases (23.4 %) showing HER2 gene amplification (average HER2 gene copies per cell >4 or <4 with HER2/CEP17 ratio >2) in concordance with HER2 oncoprotein overexpression, and significant correlation was observed with prognostic parameters including histological type, tumor grade II to III, histology and pathological type, lymphatic invasion, ductal carcinoma in situ (DCIS), and estrogen-positive and progesterone-negative receptors. Of the 154 cases, 18 cases (11.7 %) showed polysomy 17 with CEP17 probe signals per cell ≥3 and 22 cases (14.3 %) presented monosomy 17 (CEP17 probe signals per cell ≤1). Our data indicate that the use of anti-HER2 therapy should not be suggested unless true evaluation of HER2 protein expression is made regarding gene amplification essentially in IHC-ambiguous invasive breast tumors.
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30
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Ieni A, Barresi V, Rigoli L, Caruso RA, Tuccari G. HER2 Status in Premalignant, Early, and Advanced Neoplastic Lesions of the Stomach. DISEASE MARKERS 2015; 2015:234851. [PMID: 26494937 PMCID: PMC4606090 DOI: 10.1155/2015/234851] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/05/2015] [Accepted: 07/30/2015] [Indexed: 02/06/2023]
Abstract
OBJECTIVES HER2 expression in gastric cancer (GC) has received attention as a potential target for therapy with Trastuzumab. We reviewed the current knowledge on HER2 status in premalignant gastric lesions and in early (EGC) and advanced (AGC) GC to discuss the possible pathogenetic and prognostic roles of HER2 overexpression in GC. RESULTS HER2 overexpression was documented in gastric low-grade (LG) and high-grade intraepithelial neoplasia (HG-IEN), with higher frequency in gastric type dysplasia. HER2 overexpression was significantly associated with disease recurrence and poor prognosis in EGC representing an independent risk factor for lymph node metastases. HER2 overexpression was more frequent in AGC characterized by high grade, advanced stage, and high Ki-67 labeling index. The discordance in HER2 status was evidenced between primitive GC and synchronous or metachronous metastases. CONCLUSIONS HER2 overexpression in premalignant gastric lesions suggests its potential involvement in the early steps of gastric carcinogenesis. The assessment of HER2 status in EGC may be helpful for the identification of patients who are at low risk for developing nodal metastases. Finally, the possible discordance in HER2 status between primary GC and its synchronous metastases support routine assessment of HER2 both in the primary GC and in its metastatic lesions.
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Affiliation(s)
- A. Ieni
- Department of Human Pathology “Gaetano Barresi”, Section of Anatomic Pathology, Azienda Ospedaliera Universitaria “Gaetano Martino, University of Messina,” Via Consolare Valeria 1, 98125 Messina, Italy
| | - V. Barresi
- Department of Human Pathology “Gaetano Barresi”, Section of Anatomic Pathology, Azienda Ospedaliera Universitaria “Gaetano Martino, University of Messina,” Via Consolare Valeria 1, 98125 Messina, Italy
| | - L. Rigoli
- Department of Pediatrics, Gynecology and Microbiology Sciences, Azienda Ospedaliera Universitaria “Gaetano Martino, University of Messina,” Via Consolare Valeria 1, 98125 Messina, Italy
| | - R. A. Caruso
- Department of Human Pathology “Gaetano Barresi”, Section of Anatomic Pathology, Azienda Ospedaliera Universitaria “Gaetano Martino, University of Messina,” Via Consolare Valeria 1, 98125 Messina, Italy
| | - G. Tuccari
- Department of Human Pathology “Gaetano Barresi”, Section of Anatomic Pathology, Azienda Ospedaliera Universitaria “Gaetano Martino, University of Messina,” Via Consolare Valeria 1, 98125 Messina, Italy
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31
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Baykara M, Benekli M, Ekinci O, Irkkan SC, Karaca H, Demirci U, Akinci MB, Unal OU, Dane F, Turkoz FP, Balakan O, Eser EP, Ozturk SC, Ozkan M, Oksuzoglu B, Sevinc A, Demir N, Harputluoglu H, Yalcin B, Coskun U, Uner A, Ozet A, Buyukberber S. Clinical Significance of HER2 Overexpression in Gastric and Gastroesophageal Junction Cancers. J Gastrointest Surg 2015; 19:1565-71. [PMID: 26179664 DOI: 10.1007/s11605-015-2888-y] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2014] [Accepted: 06/29/2015] [Indexed: 01/31/2023]
Abstract
BACKGROUND In this study, we investigated the rate of human epidermal growth factor receptor 2 (HER2) overexpression in gastric (GC) and gastroesophageal junction cancers (GEJCs) and the relationship with HER2 expression and clinical, pathological parameters and prognosis. METHODS Surgery or biopsy specimen of 598 (436 males, 162 females) patients with GC or GEJC was evaluated for the presence of HER2 overexpression by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) methods. RESULTS HER2 IHC scores were as follows: 418 (69.9%) IHC 0, 58 (9.7%) IHC 1+, 50 (8.4%) IHC 2+, 72 (12%) IHC 3+. Among 50 patients with IHC 2+, 18 (38.2%) were FISH positive, and 29 (61.7%) were FISH negative for HER2 amplification. Patients were regarded as HER2 positive in case of IHC 3+ disease or IHC 2+ disease with a positive FISH test result for HER2 amplification. In the primary analysis population, 90 (15%) were considered HER2 positive. HER2 positivity was higher in intestinal GC compared to diffuse GC (16.9 vs 6.6%, p = 0.014). HER2 positivity was significantly higher in well and moderately differentiated tumors than poorly differentiated tumors (p < 0.0001). HER2 positivity had no significant effect on median OS (23.2 vs 19.1 months, p = 0.44). But in the early stages (stages I and II), median OS of HER2-positive patients was shorter than HER2-negative patients (51.4 months vs not reach, p = 0.047). However, median OS was similar in patients with advanced stages (stages III and IV) HER2-positive and HER2-negative disease (16.2 vs 13.7 months, p = 0.72). CONCLUSIONS Rate of HER2 positivity is similar in Turkish patients with GC and GEJCs. HER2 positivity is associated with poor prognosis in patients with early-stage disease.
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Affiliation(s)
- Meltem Baykara
- Department of Medical Oncology, Sakarya University Training and Research Hospital, Sakarya, Turkey,
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Serum HER2 Is a Potential Surrogate for Tissue HER2 Status in Gastric Cancer: A Systematic Review and Meta-Analysis. PLoS One 2015; 10:e0136322. [PMID: 26292093 PMCID: PMC4546384 DOI: 10.1371/journal.pone.0136322] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2015] [Accepted: 08/02/2015] [Indexed: 02/07/2023] Open
Abstract
Determining the expression level of human epidermal growth factor receptor 2 (HER2) in tumor tissue is of great importance for personalized therapy in gastric cancer. Although several studies have investigated whether serum HER2 can serve as a surrogate for tissue HER2 status, results have been inconsistent. We therefore performed a meta-analysis of published clinical studies in an attempt to address this problem. PubMed, Embase, Web of Science, the Cochrane Library and Science Direct were queried for eligible studies that could provide sufficient data to construct 2 × 2 contingency tables. The quality of the studies included in the meta-analysis was assessed in accordance with the revised Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) criteria. The pooled sensitivity, specificity and diagnostic odds ratio (DOR) were calculated for the eligible studies. The summary receiver operating characteristic (SROC) curve was constructed and the area under the SROC (AUSROC) was used to evaluate overall diagnostic performance. Eight studies comprising a total of 1170 participants were included in our meta-analysis. The pooled sensitivity, specificity and DOR were 0.39 (95% CI: 0.21–0.61), 0.98 (95% CI: 0.87–1.00), and 27 (95% CI: 9–81), respectively. The AUSROC was 0.77 (95% CI: 0.73–0.80) and Deeks funnel plot suggested the absence of publication bias (p = 0.91). Meta-regression analysis indicated that threshold effect was the main source of heterogeneity. Assays for evaluating serum HER2 levels are highly specific and demonstrate moderate diagnostic performance for HER2 tissue status in gastric cancer.
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Oh SJ, Suh BJ. Metachronous Liver Metastasis Resulting from Early Gastric Carcinoma after Subtotal Gastrectomy Following Endoscopic Resection: A Case Report. J Gastric Cancer 2015; 15:139-42. [PMID: 26161288 PMCID: PMC4496441 DOI: 10.5230/jgc.2015.15.2.139] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2015] [Revised: 03/18/2015] [Accepted: 03/19/2015] [Indexed: 01/28/2023] Open
Abstract
Hepatic metastasis of early gastric cancer (EGC) following subtotal gastrectomy with lymphadenectomy is rare. We report the case of a 61-year-old male patient who was diagnosed with EGC that was initially treated using endoscopic submucosal dissection (ESD) and subsequently underwent laparoscopic subtotal gastrectomy. Histopathological examination of the patient's ESD specimen showed a moderately differentiated tubular adenocarcinoma invading the submucosa without lymphatic invasion. The deep margin of the specimen was positive for adenocarcinoma, and he subsequently underwent laparoscopic distal gastrectomy. The patient developed liver metastasis 15 months after the operation and then underwent liver resection. Histology of the resected specimen confirmed the diagnosis of two foci of metastatic adenocarcinoma originating from stomach cancer. Immunohistochemical analysis of the specimen demonstrated overexpression of human epidermal growth factor receptor 2. The patient was treated with trastuzumab in combination with chemotherapy consisting of capecitabine and cisplatin. Twenty-four months after the operation, the patient remained free of recurrence.
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Affiliation(s)
- Sung Jin Oh
- Department of Surgery, Haeundae Paik Hospital, Inje University College of Medicine, Busan, Korea
| | - Byoung Jo Suh
- Department of Surgery, Haeundae Paik Hospital, Inje University College of Medicine, Busan, Korea
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HER2/neu: an increasingly important therapeutic target. Part 2: Distribution of HER2/neu overexpression and gene amplification by organ, tumor site and histology. ACTA ACUST UNITED AC 2014. [DOI: 10.4155/cli.14.62] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
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Moorcraft SY, Chau I. Investigational therapies targeting the ErbB family in oesophagogastric cancer. Expert Opin Investig Drugs 2014; 23:1349-63. [PMID: 24949530 DOI: 10.1517/13543784.2014.930126] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
INTRODUCTION The prognosis for patients with oesophagogastric (OG) cancer remains poor, with a median survival of approximately 9 - 11 months for patients with metastatic disease. However, a more personalised approach to treatment, using drugs tailored to the molecular characteristics of patients' tumours, has the potential to improve patient outcomes. Drugs targeting the ErbB family of receptors have been developed, but these have had varying degrees of success in clinical practice. AREAS COVERED The authors provide an overview of the ErbB receptor family with regard to OG cancers. Furthermore, they evaluate the evidence from preclinical and clinical trials of therapeutics targeting this family, including monoclonal antibodies, tyrosine kinase inhibitors and novel agents. EXPERT OPINION Drugs targeting the ErbB family have been evaluated in OG cancer, with a notable success story in the case of trastuzumab, although there have been disappointing failures with anti-EGFR therapy. The response to targeted treatment remains variable and further biomarker research is essential to identify patients most likely to benefit from these therapies. The treatment of OG cancer remains challenging, but new anti-HER2 therapies and combination therapies hold promise for the future.
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Affiliation(s)
- Sing Yu Moorcraft
- The Royal Marsden NHS Foundation Trust, Gastrointestinal Unit, Department of Medicine , Sutton SM2 5PT , UK +44 020 8642 6011 ; +44 020 8643 9414 ;
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Yoshida H, Yamamoto N, Taniguchi H, Oda I, Katai H, Kushima R, Tsuda H. Comparison of HER2 status between surgically resected specimens and matched biopsy specimens of gastric intestinal-type adenocarcinoma. Virchows Arch 2014; 465:145-54. [PMID: 24889042 DOI: 10.1007/s00428-014-1597-3] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2013] [Revised: 04/29/2014] [Accepted: 05/22/2014] [Indexed: 12/20/2022]
Abstract
HER2 protein overexpression and gene amplification are important biomarkers for identifying gastric cancer patients who may respond to HER2-targeted therapy using trastuzumab. The aim of this study was to evaluate the concordance between HER2 protein expression and gene amplification in both surgically resected tumors and matched biopsy specimens of gastric cancer. Formalin-fixed, paraffin-embedded sections of 207 surgically resected tumors and 158 biopsy specimens from 207 cases of invasive intestinal-type gastric cancer were analyzed. Protein expression was assessed using immunohistochemistry and graded by the modified scoring criteria for gastric cancer. Gene amplification was evaluated by fluorescence in situ hybridization (FISH). HER2 overexpression was observed in 17 % of both surgically resected tumors (35/207) and biopsy specimens (26/158). HER2 gene amplification was detected in 31 % (61/200) of surgically resected tumors and 32 % (47/147) of biopsy specimens. Except for immunohistochemistry (IHC) equivocal (2+) cases, the concordance rates between IHC and FISH was 90.9 % in surgically resected tumors and 90.2 % in biopsy specimens. In IHC 2+ cases, the rate of HER2 gene amplification was 56 and 38 % in surgically resected tumors and biopsy specimens, respectively. IHC-FISH discordance was mainly due to intratumoral heterogeneity and low-level gene amplification. The concordance rate of IHC results between surgically resected specimens and the corresponding biopsy specimen was 57.0 % (κ = 0.224), and in discordant cases, HER2 positivity in biopsies and HER2 negativity in surgically resected tumors were most common. The concordance rate of FISH results between surgically resected tumors and biopsy specimens was 72.7 % (κ = 0.313). Polysomy 17 was detected in 5.5 and 7.5 % of surgically resected tumors and biopsy specimens and significantly correlated with IHC score, but polysomy 17 could explain one IHC score 3+ and FISH-negative tumor only. Although high concordance rates between HER2-protein expression and gene amplification were observed in both surgically resected tumors and biopsy specimens, the agreement levels were evaluated to be fair. Polysomy 17 was infrequent and seemed to have limited impact on gastric HER2 testing. Further investigations are required for an appropriate biopsy method to reduce false results of HER2 testing and to clarify the clinical significance of intratumoral heterogeneity in HER2 status.
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Affiliation(s)
- Hiroshi Yoshida
- Department of Pathology and Clinical Laboratories, National Cancer Center Hospital, Tokyo, Japan
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Qi W, Li X, Zhang Y, Yao R, Qiu W, Tang D, Liang J. Overexpression of Her-2 upregulates FoxM1 in gastric cancer. Int J Mol Med 2014; 33:1531-8. [PMID: 24715000 DOI: 10.3892/ijmm.2014.1732] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2013] [Accepted: 03/17/2014] [Indexed: 11/05/2022] Open
Abstract
The transcription factor, forkhead box protein M1 (FoxM1), and the tyrosine kinase receptor, human epidermal growth factor receptor-2 (Her-2), are aberrantly expressed in a number of human malignancies, and are closely associated with the development of cancer. However, their regulatory mechanisms and their involvement in tumor development have not been extensively investigated, particularly in gastric cancer. In the present study, we examined the expression levels of FoxM1 and Her-2 in samples from patients with gastric cancer, as well as gastric cancer cell lines. Their regulatory mechanisms and the connection between them were also explored. We found that FoxM1 and Her-2 expression was markedly higher in the gastric cancer samples, while a strong association was found between them at the mRNA and protein level. When we regulated the levels of Her-2 in the gastric cancer cell lines, the expression of FoxM1 changed accordingly. Following the transfection of Her-2 expression vectors into the gastric cell lines, the luciferase activity of the FoxM1 promoter positively increased along with the concentration of pcDNA3.1-Her-2. However, Her-2-siRNA inverted this variation, which was further confirmed by treatment with the Her-2 inhibitor, trastuzumab, revealing that Her-2 regulates FoxM1 expression at the promoter level in gastric cancer cells. Our results suggest that FoxM1 and Her-2 are important diagnostic markers for gastric cancer. FoxM1 may be a potential cellular target for therapeutic intervention, particularly in gastric cancers resistant to Her-2-targeted therapy.
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Affiliation(s)
- Weiwei Qi
- Department of Oncology, The Affiliated Hospital of Qingdao University Medical College, Qingdao, Shandong 266003, P.R. China
| | - Xiaoxiao Li
- Department of Oncology, The Affiliated Hospital of Qingdao University Medical College, Qingdao, Shandong 266003, P.R. China
| | - Yongchun Zhang
- Department of Oncology, The Affiliated Hospital of Qingdao University Medical College, Qingdao, Shandong 266003, P.R. China
| | - Ruyong Yao
- Central Laboratory, The Affiliated Hospital of Qingdao University Medical College, Qingdao, Shandong 266003, P.R. China
| | - Wensheng Qiu
- Department of Oncology, The Affiliated Hospital of Qingdao University Medical College, Qingdao, Shandong 266003, P.R. China
| | - Dongfang Tang
- Department of Thoracic Surgery, The Affiliated Hospital of Qingdao University Medical College, Qingdao, Shandong 266003, P.R. China
| | - Jun Liang
- Department of Oncology, The Affiliated Hospital of Qingdao University Medical College, Qingdao, Shandong 266003, P.R. China
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HER2 expression in primary gastric cancers and paired synchronous lymph node and liver metastases. A possible road to target HER2 with radionuclides. Tumour Biol 2014; 35:6319-26. [PMID: 24643685 DOI: 10.1007/s13277-014-1830-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2014] [Accepted: 03/05/2014] [Indexed: 12/14/2022] Open
Abstract
Resistance has been reported to human epidermal growth factor receptor 2 (HER2)-targeted therapy with the tyrosine kinase inhibitor lapatinib and the antibody trastuzumab in metastatic gastric cancer. An alternative or complement might be to target the extracellular domain of HER2 with therapy-effective radionuclides. The fraction of patients with HER2 expression in primary tumors and major metastatic sites, e.g., lymph nodes and liver, was analyzed to evaluate the potential for such therapy. Samples from primary tumors and lymph node and liver metastases were taken from each patient within a few hours, and to our knowledge, such sampling is unique. The number of analyzed cases was therefore limited, since patients that had received preoperative radiotherapy, chemotherapy, or HER2-targeted therapy were excluded. From a large number of considered patients, only 29 could be included for HER2 analysis. Intracellular mutations were not analyzed since they are assumed to have no or minor effect on the extracellular binding of molecules that deliver radionuclides. HER2 was positive in nearly 52 % of the primary tumors, and these expressed HER2 in corresponding lymph node and liver metastases in 93 and 100 % of the cases, respectively. Similar values for primary tumors and also good concordance with metastases have been indicated in the literature. Thus, relevant radionuclides and targeting molecules for nuclear medicine-based noninvasive, whole-body receptor analysis, dose planning, and therapy can be applied for many patients; see "Discussion" Hopefully, more patients can then be treated with curative instead of palliative intention.
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Liang JW, Zhang JJ, Zhang T, Zheng ZC. Clinicopathological and prognostic significance of HER2 overexpression in gastric cancer: a meta-analysis of the literature. Tumour Biol 2014; 35:4849-58. [PMID: 24449506 DOI: 10.1007/s13277-014-1636-3] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2013] [Accepted: 01/07/2014] [Indexed: 12/19/2022] Open
Abstract
Human epidermal growth factor receptor 2 (HER2) plays an important role in the aggressiveness and progression of gastric cancer. With the publication of trial results, we conducted a meta-analysis to investigate its prognostic significance for patients with gastric cancer. PubMed, Ovid, Web of Science, and Cochrane databases were searched. Statistical analysis was carried out by STATA version 12.0 software. The Newcastle-Ottawa scale was used to assess the quality of evidence. Fifteen studies involving 5,290 patients met the inclusion criteria. The results showed that HER2 overexpression was significantly associated with patients' overall survival (HR = 1.56, 95% confidence interval (CI) 1.05-2.07; Z = 6.03; P = 0.000). The results also suggested that HER2 overexpression was associated with Bormann type (odds ratio (OR) = 1.76, 95% CI 1.19-2.59; Z = 2.85; P = 0.004), tumor differentiation (OR = 3.14, 95% CI 1.91-5.17; Z = 4.49; P = 0.000), Lauren's classification (OR = 6.25, 95% CI 4.29-9.10; Z = 9.54; P = 0.000), lymph node metastasis (OR = 1.43, 95% CI 1.15-1.77; Z = 3.23; P = 0.001), venous invasion (OR = 1.69, 95% CI 1.15-2.48; Z = 2.67; P = 0.008), and lymphovascular invasion (OR = 1.57, 95% CI 1.21-2.04; Z = 3.4; P = 0.001). However, it had no correlation with tumor size, depth of invasion, and tumor stage. This study showed that HER2 overexpression had an unfavorable prognostic role for patients with gastric cancer. HER2-positive expression was associated with Bormann type, Lauren's classification, tumor differentiation, lymph node status, venous invasion, and lymphovascular invasion.
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Affiliation(s)
- Ji-wang Liang
- Department of Gastric Surgery, Liaoning Cancer Hospital and Institute, 44 Xiaoheyan Road, Dadong District, Shenyang, 110042, People's Republic of China,
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Mao BJ, Zhang ZM, Chen C, Wang D, Wang G. Significance and role of HER2 in targeted therapy of gastric cancer. Shijie Huaren Xiaohua Zazhi 2014; 22:31-38. [DOI: 10.11569/wcjd.v22.i1.31] [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] [Indexed: 02/06/2023] Open
Abstract
With the development of tumor molecular biology, the mechanisms responsible for metastasis and the proliferation and growth of tumor cells have become unmasking, which makes cancer treatment enter into a new era. HER2 is overexpressed or mutated in many kinds of tumors and have been associated with many malignant tumors, typically including advanced gastric and gastroesophageal junction cancer. The ToGA study is a milestone in the treatment of gastric cancer, which established the position of trastuzumab in the treatment of HER2-positive gastric cancer. In this review, we discuss the biological characteristics of HER2 and its role in the treatment of gastric cancer, the application prospects of trastuzumab in the treatment of gastric cancer, and the Chinese experts' consensus statement on targeted therapies for advanced gastric cancer. We also summarize the latest advances in basic and clinical research of HER2 positive gastric cancer. All in all, HER2 has nothing to do with the prognosis of gastric cancer. The combination of target-therapies may become a promising weapon for treatment of gastric cancer.
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Abstract
Human epidermal growth factor receptor 2 (HER2) is involved in the pathogenesis and poor outcomes of several types of cancer, including advanced gastric and gastroesophageal junction cancer. Molecular-targeted drugs, such as trastuzumab, which prolong overall survival and progression-free survival in HER2-positive breast cancer, may also be beneficial in patients with HER2-positive gastric cancer. Several studies have examined this possibility, such as the Trastuzumab for Gastric Cancer trial. In this context, the first part of this review provides an update on our knowledge of HER2 in breast and gastric cancer, including the detection and prognostic relevance of HER2 in gastric cancer. The second part of the review discusses the results of pivotal clinical trials that examined the potential for using trastuzumab to treat this disease. This section also summarizes the trials that have been conducted or that are underway to determine the optimal uses of trastuzumab in gastric cancer, including its use as monotherapy and continuation beyond disease progression. The final section discusses the future prospects of other anti-HER2 drugs, including lapatinib, trastuzumab emtansine, and pertuzumab, for the treatment of HER2-positive gastric cancer. The introduction of trastuzumab led to the establishment of a new disease entity, "HER2-positive gastric cancer," similar to HER2-positive breast cancer. It is expected that more anti-HER2 drugs will be developed and introduced into clinical practice to treat HER2-positive cancers, including gastric cancer.
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Kim JS, Young Park S. (18)F-FDG PET/CT of advanced gastric carcinoma and association of HER2 expression with standardized uptake value. ASIA OCEANIA JOURNAL OF NUCLEAR MEDICINE & BIOLOGY 2014; 2:12-8. [PMID: 27408854 PMCID: PMC4937706] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
OBJECTIVES Expression of HER2 in gastric carcinoma has direct prognostic and therapeutic implications in patient management. The aim of this study is to determine whether a relationship exists between standardized uptake value (SUV) and expression of HER2 in advanced gastric carcinoma. METHODS We analyzed the (18)F-FDG PET/CT results of 109 patients that underwent gastrectomy for advanced gastric carcinoma. The (18)F-FDG PET/CT imaging was requested at the initial staging before surgery. The examinations were evaluated semi-quantitatively, with calculation of maximum standardized uptake values (SUVmax). The clinicopathologic factors, including HER2 overexpression, were determined from tissue obtained from the primary tumor. Metabolic and clincopathologic parameters were correlated using a t-test, one way ANOVA and chi-square test. RESULTS Immunohistochemically, 26 patients (23.8%) showed HER2 overexpression. This overexpression was significantly associated with high SUV level (P=0.02). The SUV level was significantly correlated with tumor size (P=0.02) and differentiation (P<0.001), and Lauren histologic type (P=0.04). Multivariate analysis showed HER2 overexpression, large tumor size, and differentiation (P=0.022, P=0.002, P<0.001) were significantly correlated with the high level of SUV in advanced gastric carcinoma. No association was found between SUV and T stage and lymph node metastasis. A receiver-operating characteristic curve demonstrated a SUVmax of 3.5 to be the optimal cutoff for predicting HER2 overexpression (sensitivity; 76.9%, specificity; 60.2%). CONCLUSION An association exists between high SUV and HER2 overexpression and (18)F-FDG PET/CT could be a useful tool to predict the biological characteristics of gastric carcinoma.
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Affiliation(s)
- Jin Suk Kim
- Department of Nuclear Medicine, Konyang University College of Medicine, Daejeon, Korea,Konyang University Myunggok Medical Research Institute, Daejeon, Korea
| | - Shin Young Park
- Department of Pathology, Konyang University College of Medicine, Daejeon, Korea,Konyang University Myunggok Medical Research Institute, Daejeon, Korea,
*Corresponding author: Shin Young Park, Department of Nuclear Medicine, Konyang University Hospital, 685 Gasuwon-dong, Seo-gu, Daejeon 302-718, Korea. Tel: 82-42-600-9280; Fax: 82-42-600-9280; E-mail:
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Li X, Tang D, Yao Y, Qi W, Liang J. Clinical significance and positive correlation of FoxM1 and Her-2 expression in gastric cancer. Clin Exp Med 2013; 14:447-55. [PMID: 24101296 DOI: 10.1007/s10238-013-0261-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2013] [Accepted: 09/16/2013] [Indexed: 12/23/2022]
Abstract
The transcription factor forkhead box protein M1 (FoxM1) and tyrosine kinase receptor Her-2, aberrantly expressing in various kinds of human malignancies, are closely related to the development of cancer. However, the correlation of them is still little explored, especially in gastric cancer. In current study, we examined FoxM1 and Her-2 levels in gastric cancers, and the clinical significance and association of them were further explored. As a result, FoxM1 and Her-2 expression were significantly higher in gastric cancer compared with para-cancer tissues and gastric cell lines (P < 0.01), while a positive association was found between the two genes at both RNA and protein levels (P = 0.007, P = 0.025). No significant association was observed between FoxM1 expression and clinic-pathological parameters (P > 0.1), whereas the positive frequency of Her-2 correlated with TNM stage significantly (P = 0.045). In addition, multivariate analysis showed Her-2 was not a prognostic predictor in gastric cancer (P = 0.625), while FoxM1 was independently associated with prognosis (P = 0.001), which especially affected the survival in patients with advanced stage (P < 0.01). These results suggest that FoxM1 and Her-2 are important diagnostic markers for gastric cancer, and FoxM1 is a favorable prognostic indicator in gastric cancer. FoxM1 may be a potential cellular target for therapeutic intervention, especially in Her2-targeted therapy-resistant cancers.
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Affiliation(s)
- Xiaoxiao Li
- Department of Oncology, Affiliated Hospital of Medical College Qingdao University, 16 Jiangsu Road, Qingdao, 266003, China
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Gu MJ, Hong SM, Jung SJ. HER2 protein expression and HER2 gene amplification are infrequent in small intestinal carcinomas. Virchows Arch 2013; 462:603-7. [DOI: 10.1007/s00428-013-1425-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2013] [Revised: 04/07/2013] [Accepted: 05/06/2013] [Indexed: 01/31/2023]
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He C, Bian XY, Ni XZ, Shen DP, Shen YY, Liu H, Shen ZY, Liu Q. Correlation of human epidermal growth factor receptor 2 expression with clinicopathological characteristics and prognosis in gastric cancer. World J Gastroenterol 2013; 19:2171-2178. [PMID: 23599643 PMCID: PMC3627881 DOI: 10.3748/wjg.v19.i14.2171] [Citation(s) in RCA: 74] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2012] [Revised: 09/20/2012] [Accepted: 02/08/2013] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate human epidermal growth factor receptor 2 (HER2) gene amplification and protein expression in Chinese patients with resectable gastric cancer and the association with clinicopathological characteristics and survival.
METHODS: One hundred and ninety-seven gastric cancer patients who underwent curative surgery procedures were enrolled into this study. HER2 gene amplification and protein expression were examined using fluorescence in-situ hybridization (FISH) and immunohistochemistry (IHC) analysis on formalin-fixed paraffin-embedded gastric cancer samples from all patients. For scoring, Hofmann’s HER2 gastric cancer scoring system was adopted. All cases showing IHC3+ or FISH positivity were defined as HER2 positive. Patient clinicopathological data and survival information were collected. Finally, χ2 statistical analysis was performed to analyze the HER2 positivity rate amongst the subgroups with different clinicopathological characteristics including; gender, age, tumor location, Lauren classification, differentiation, TNM staging, depth of invasion, lymph node metastases and distant metastasis. The probability of survival for different subgroups with different clinicopathological characteristics was calculated using the Kaplan-Meier method and survival curves plotted using log rank inspection.
RESULTS: According to Hofmann’s HER2 gastric cancer scoring criteria, 31 cases (15.74%) were identified as HER2 gene amplified and 19 cases (9.64%) were scored as strongly positive for HER2 membrane staining (3+), 25 cases (12.69%) were moderately positive (2+) and 153 cases (77.66%) were HER2 negative (0/1+). The concordance rate between IHC and FISH analyses was 88.83% (175/197). Thirty-six cases were defined as positive for HER2 gene amplification and/or protein expression, with 24 of these cases being eligible for Herceptin treatment according to United States recommendations, and 29 of these cases eligible according to EU recommendations. Highly consistent results were detected between IHC3+, IHC0/1 and FISH (73.68% and 95.42%), but low consistency was observed between IHC2+ and FISH (40.00%). The positivity rates in intestinal type and well-differentiated gastric cancer were higher than those in diffuse/mixed type and poorly-differentiated gastric cancer respectively (28.57% vs 13.43%, P = 0.0103; 37.25% vs 11.64%, P < 0.0001), but were not correlated with gender, age, tumor location or TNM stage, depth of invasion, lymph node metastases and distant metastasis. In poorly-differentiated gastric cancer patients, those without lymph node metastasis showed a higher HER2 positivity rate than those with lymph node metastasis (26.47% vs 7.14%, P = 0.0021). This association was not present in those patients with well-differentiated gastric cancer (28.57% vs 43.33%, P = 0.2832). Within our patient cohort, 26 cases were lost to follow-up. The median survival time for the remaining 171 patients was 18 mo. The median survival times of the HER2 positive and negative groups were 17 and 18.5 mo respectively. Overall survival was not significantly different between HER2-positive and negative groups (χ2 = 0.9157, P = 0.3386), but in patients presenting well-differentiated tumors, the overall survival of the HER2-positive group was significantly worse than that of the HER2-negative group (P = 0.0123). In contrast, patients with poorly differentiated and diffuse/mixed subtype gastric cancers showed no significant differences in overall survival associated with HER2. Furthermore, the median survival time of the HER2 positive group did not show any statistically significant differences when compared to the subgroups of gender, age, tumor location, TNM classification, lymph node metastases and distant metastasis.
CONCLUSION: Patients with intestinal type gastric cancer (GC), well-differentiated GC and poorly-differentiated GC without lymph node metastasis, may all represent suitable candidates for targeted therapy using Herceptin.
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