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Wang SN, Wang YK, Zhu CY, Jiang B, Ge DF, Li YY. Significance of concurrent evaluation of HER2 gene amplification and p53 and Ki67 expression in gastric cancer tissues. Clin Transl Oncol 2025; 27:126-134. [PMID: 38907827 DOI: 10.1007/s12094-024-03534-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2024] [Accepted: 05/16/2024] [Indexed: 06/24/2024]
Abstract
OBJECTIVE The primary objective of this study is to explore the significance of concurrent evaluation of HER2 gene amplification and p53 and Ki67 expression in gastric cancer tissues. METHODS Fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) methodologies were used to detect HER2 gene amplification, as well as the expression levels of HER2, p53, and Ki67 proteins, across a group of 78 gastric cancer cases. RESULTS The expression rate of the HER2 protein was determined to be 43.6% (34/78), with 17.9% (14/78) categorized as HER2 protein 3 + , 14.1% (11/78) as HER2 protein 2 + , and 11.5% (9/78) as HER2 protein 1 + . Using FISH technology, the HER2 gene amplification rate was identified as 19.2% (15/78), including 3 cases of HER2 gene cluster amplification, 5 cases of large granular amplification, 4 cases of punctate amplification, and 3 cases of high polysomy. The positive rate of p53 in gastric cancer cells was 52.6% (41/78), with 62.8% (49/78) of patients exhibiting a ki67 proliferation index ≤ 30, and 37.2% (29/78) accounting for a ki67 proliferation index > 30. The expression rates of the HER2 gene, p53, and ki67 in gastric cancer tissues were significantly associated with both gastric cancer staging and lymph node metastasis (P < 0.05). CONCLUSION The HER2 gene amplification rate and gene copy number exhibit a positive correlation with the expression rates of p53 and ki67. Combining these assessments can provide crucial insights into the assessment of metastatic potential, disease progression, and prognosis of gastric tumor cells. This holds paramount importance in steering the formulation of individualized treatment strategies.
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Affiliation(s)
- Su-Nan Wang
- Shenzhen Polytechnic, Xilihu Town, Nanshan District, Shenzhen, 518055, Guangdong, China
| | - Yang-Kun Wang
- Department of Pathology, The Fourth People's Hospital of Longgang District, Shenzhen, 518123, China
| | - Chao-Ya Zhu
- Department of Pathology, Third Affiliated Hospital of Zhengzhou University, Shenzhen, 450052, China
| | - Bo Jiang
- Department of Pathology, No. 990 Hospital of the PLA Joint Logistics Support Force, Zhumadian, 463000, China
| | - Dong-Feng Ge
- Department of Pathology, The First Affiliated Hospital of Henan University of Science and Technology, No. 24 Jinghua Road, Jianxi District, Luoyang, 471000, China.
| | - Ying-Ying Li
- Shenzhen Polytechnic, Xilihu Town, Nanshan District, Shenzhen, 518055, Guangdong, China.
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Nered SN, Torosyan RO, Kozlov NA, Sun H, Avdyukhin IG, Kononets PV, Stilidi IS. [Frequency of MSI, PD-L1 (CPS), HER2 in poorly cohesive gastric carcinomas]. Arkh Patol 2025; 87:11-17. [PMID: 40289427 DOI: 10.17116/patol20258702111] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/30/2025]
Abstract
Gastric cancer (GC) is a heterogeneous tumor with various molecular changes. An active search for molecular markers is crucial to determine the effectiveness of drug treatment and prognosis of the disease. Several biomarkers have the greatest clinical significance: HER2, MSI / dMMR, PD-L1 (CPS), EBV and Claudin 18. OBJECTIVE To study the frequency of HER2, MSI / dMMR and PD-L1 (CPS) in patients with operable GC depending on the tumor type according to P. Lauren. MATERIAL AND METHODS The study included 600 patients with GC who underwent radical surgical treatment at the N.N. Blokhin National Medical Research Center of Oncology from 2018 to 2023. RESULTS In the study, the proportion of diffuse GC was 21.5% (120/600). HER2 overexpression was found in 5.2% (5/96) of cases with diffuse GC, 20.4% (37/181) of cases with intestinal GC, 10.1% (7/69) of cases with mixed GC (p=0.0029). The incidence of MSI was 3.3% (4/120) of cases with diffuse GC, 11.2% (28/251) of cases with intestinal GC, 7.3% (7/97) of cases with mixed GC (p=0.0378). PD-L1 expression (CPS> 1) was found in 42.3% (11/26) of cases with diffuse GC, 59.4% (35/59) of cases with intestinal GC, 27.3% (9/33) of cases with mixed GC (p=0.006). In poorly cohesive/signet ring cell cancer MSI occurred in 2.5% (2/79) of cases; HER2 overexpression - in 2.9% (2/68) of cases; PD-L1 (CPS> 1) - in 42.1% (8/19) of cases. CONCLUSION Our study demonstrated that in diffuse and poorly cohesive/signet ring cell GC the frequency of occurrence of the above clinically significant tumor biomarkers is lower compared to intestinal/mixed GC.
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Affiliation(s)
- S N Nered
- N.N. Blokhin National Medical Research Center of Oncology, Moscow, Russia
- Russian Medical Academy of Continuous Professional Education, Moscow, Russia
| | - R O Torosyan
- N.N. Blokhin National Medical Research Center of Oncology, Moscow, Russia
| | - N A Kozlov
- N.N. Blokhin National Medical Research Center of Oncology, Moscow, Russia
| | - H Sun
- N.N. Blokhin National Medical Research Center of Oncology, Moscow, Russia
| | - I G Avdyukhin
- N.N. Blokhin National Medical Research Center of Oncology, Moscow, Russia
| | - P V Kononets
- N.N. Blokhin National Medical Research Center of Oncology, Moscow, Russia
| | - I S Stilidi
- N.N. Blokhin National Medical Research Center of Oncology, Moscow, Russia
- N.I. Pirogov Russian National Research Medical University, Moscow, Russia
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Cheng J, Cai M, Wang G, Tao K. HER2 becomes a novel survival biomarker for gastric cancer patients: a pooled analysis. Ther Adv Med Oncol 2024; 16:17588359241271913. [PMID: 39281969 PMCID: PMC11401144 DOI: 10.1177/17588359241271913] [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: 12/03/2023] [Accepted: 07/02/2024] [Indexed: 09/18/2024] Open
Abstract
Background Although anti-HER2 therapies have been widely used against gastric carcinoma, the prognostic significance of HER2 overexpression remains unclear. Previous studies failed to provide convincible evidence due to inconsistent HER2 evaluation criteria and heterogeneous clinical characteristics. Objectives To figure out the prognostic significance of HER2 expression in gastric cancer, we rigorously designed and conducted this study. Design Meta-analysis. Data sources and methods Record retrieval was performed by searching PubMed, Web of Science, Cochrane Library, Embase, ASCO, and ESMO meeting libraries from inception to November 2022. Cohort studies investigating overall survival comparison between HER2-positive and HER2-negative gastric cancer patients were included. Both resectable and advanced cases were separately collected while HER2 evaluation standards should be consistent across eligible studies. Newcastle-Ottawa Scale was used for quality assessment. Overall survival was the only endpoint and effect size was presented by hazard ratio (HR) with its 95% confidence interval. The pooled calculation was conducted on Review Manager 5.4. Results Thirty studies were eligible, including 9945 patients. Eligible studies were mostly high quality (n = 31). Regarding resectable cases (n = 22), HER2-positive groups had significantly worse prognosis than HER2-negative counterparts (HR 1.56, 95%CI 1.32-1.85, p < 0.00001). For HER2-positive patients with advanced gastric cancer (n = 10), HER2 overexpression was also an unfavorable survival indicator (HR 1.70, 95%CI 1.23-2.35, p = 0.001). Potential heterogeneous studies had been eliminated while outcomes remained stable by sensitivity analysis. Subgroup analysis suggested HER2-positive patients had a poorer prognosis in both East Asian (resectable: HR 1.56; advanced: HR 1.32) and non-East Asian countries (HR 1.58; HR 3.27). Conclusion As a novel survival biomarker in gastric cancer, HER2 overexpression indicates unfavorable prognosis among both resectable and advanced patients, irrespective of East Asian or non-East Asian populations. Trial registration PROSPERO (CRD42020168051).
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Affiliation(s)
- Ji Cheng
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, Wuhan 430022, China
| | - Ming Cai
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Guobin Wang
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Kaixiong Tao
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 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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Shaik R, Venkata Renuka I, Ramamoorthy S, Potti R, Pranathi L. Human Epidermal Growth Factor 2 (Her-2) Expression in Gastric and Gastroesophageal Carcinomas: A Clinicopathological Evaluation in a Tertiary Care Institute. Cureus 2024; 16:e67895. [PMID: 39193056 PMCID: PMC11348447 DOI: 10.7759/cureus.67895] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/27/2024] [Indexed: 08/29/2024] Open
Abstract
Introduction Gastric carcinoma is a significant global health concern, known for its high mortality rate. HER-2 overexpression is observed in a notable proportion of gastric carcinoma and is associated with a worse prognosis. However, HER-2 expression enables targeting the protein by monoclonal antibodies that improve overall survival in HER-2-positive gastric cancers. This study aims to evaluate the HER-2 expression in gastric and gastroesophageal carcinomas. Materials and methods This observational study was conducted in the Department of Pathology, involving 60 endoscopic biopsy and resection specimens of gastric and gastroesophageal carcinomas. HER-2 expression was assessed by immunohistochemistry (IHC) based on the Trastuzumab for GAstric Cancer (ToGA) trial's scoring system. The primary outcome was HER-2 status, with statistical analysis performed to evaluate associations with various clinicopathological parameters. Results Among 60 cases, 26 (43.3%) showed HER-2 positivity. HER-2 positivity was significantly (p=0.004) associated with age, being higher in 20-39 years and ≥80 years age groups. Gender and tumor location were not significantly associated with HER-2 positivity. Moderate and poorly differentiated carcinomas exhibited higher HER-2 positivity. Histological types, tubular adenocarcinoma, and papillary adenocarcinoma showed significant (p=0.01) association with HER-2 positivity compared to other types. Conclusion HER-2 status assessment is crucial in managing gastric and gastroesophageal carcinomas. HER-2 positivity is notably higher in certain age groups and histological types particularly tubular and papillary adenocarcinoma, and in moderately to poorly differentiated carcinomas. These insights can aid in selecting appropriate gastric and gastroesophageal carcinomas that warrant HER-2 testing on IHC. Identifying gastric and gastroesophageal carcinomas that show HER2 expression may highlight potential candidates for targeted therapy.
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Ma XT, Ou K, Yang WW, Cao BY, Yang L. Human epidermal growth factor receptor 2 expression level and combined positive score can evaluate efficacy of advanced gastric cancer. World J Clin Oncol 2024; 15:635-643. [PMID: 38835847 PMCID: PMC11145957 DOI: 10.5306/wjco.v15.i5.635] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/02/2024] [Revised: 02/08/2024] [Accepted: 04/02/2024] [Indexed: 05/21/2024] Open
Abstract
BACKGROUND Although treatment options for gastric cancer (GC) continue to advance, the overall prognosis for patients with GC remains poor. At present, the predictors of treatment efficacy remain controversial except for high microsatellite instability. AIM To develop methods to identify groups of patients with GC who would benefit the most from receiving the combination of a programmed cell death protein 1 (PD-1) inhibitor and chemotherapy. METHODS We acquired data from 63 patients with human epidermal growth factor receptor 2 (HER2)-negative GC with a histological diagnosis of GC at the Cancer Hospital, Chinese Academy of Medical Sciences between November 2020 and October 2022. All of the patients screened received a PD-1 inhibitor combined with chemotherapy as the first-line treatment. RESULTS As of July 1, 2023, the objective response rate was 61.9%, and the disease control rate was 96.8%. The median progression-free survival (mPFS) for all patients was 6.3 months. The median overall survival was not achieved. Survival analysis showed that patients with a combined positive score (CPS) ≥ 1 exhibited an extended trend in progression-free survival (PFS) when compared to patients with a CPS of 0 after receiving a PD-1 inhibitor combined with oxaliplatin and tegafur as the first-line treatment. PFS exhibited a trend for prolongation as the expression level of HER2 increased. Based on PFS, we divided patients into two groups: A treatment group with excellent efficacy and a treatment group with poor efficacy. The mPFS of the excellent efficacy group was 8 months, with a mPFS of 9.1 months after excluding a cohort of patients who received interrupted therapy due to surgery. The mPFS was 4.5 months in patients in the group with poor efficacy who did not receive surgery. Using good/poor efficacy as the endpoint of our study, univariate analysis revealed that both CPS score (P = 0.004) and HER2 expression level (P = 0.015) were both factors that exerted significant influence on the efficacy of treatment the combination of a PD-1 inhibitor and chemotherapy in patients with advanced GC (AGC). Finally, multivariate analysis confirmed that CPS score was a significant influencing factor. CONCLUSION CPS score and HER2 expression both impacted the efficacy of immunotherapy combined with chemotherapy in AGC patients who were non-positive for HER2.
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Affiliation(s)
- Xiao-Ting Ma
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Kai Ou
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Wen-Wei Yang
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Bi-Yang Cao
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Lin Yang
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
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7
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Gao X, Zhao L, Zhang N, Han W, Liu K, Yan J, Chen L, Pan Y, Li R, Li W, Zhang H, Li H, Wang S, Gao X, Niu P, Wang W, Ji G, Zhao Q, Lu Y, Li Z, Shang L, Liang H, Wu K, Deng J, Chen Y, Nie Y. Impact of HER2 on prognosis and benefit from adjuvant chemotherapy in stage II/III gastric cancer patients: a multicenter observational study. Int J Surg 2023; 109:1330-1341. [PMID: 37037586 PMCID: PMC10389606 DOI: 10.1097/js9.0000000000000370] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Accepted: 03/16/2023] [Indexed: 04/12/2023]
Abstract
BACKGROUND Human epidermal growth factor receptor 2 (HER2) is a well-developed therapeutic target in breast and gastric cancer (GC). However, the impact of HER2 on survival and benefit from fluorouracil-based adjuvant chemotherapy remains unclear in patients with GC. MATERIALS AND METHODS This multicenter cohort study involved 5622 consecutive stage II/III GC patients. HER2 expression was assessed prospectively via immunohistochemistry (IHC). The staining intensity was graded on a scale of 0 to 3+. An IHC score of 2+or 3+was defined as high expression, and a score of 3+was defined as overexpression. RESULTS HER2 overexpression was independently associated with a lower 5-year overall survival (OS) in stage II [hazard ratio (HR), 2.10; 95% CI: 1.41-3.11], but not in stage III GC (HR, 1.00; 95% CI, 0.82-1.20). Further analysis revealed that stage II patients with high HER2 expression showed a poorer response to chemotherapy than stage II patients with low HER2 expression ( Pinteraction =0.024). The HRs for 5-year OS were 0.51 (95% CI, 0.38-0.70) for stage II patients with low HER2 expression, 0.58 (95% CI, 0.51-0.66) for stage III patients with low HER2 expression, 1.13 (95% CI, 0.61-2.09) for stage II patients with high HER2 expression, and 0.47 (95% CI, 0.36-0.61) for stage III patients with high HER2 expression. CONCLUSIONS Fluorouracil-based adjuvant chemotherapy is insufficient for stage II GC patients with high HER2 expression, indicating that prospective trials are required to validate alternative HER2-targeted adjuvant therapies in the individuals above.
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Affiliation(s)
- Xianchun Gao
- State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases
- Department of Health Statistics, Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health
| | - Lulu Zhao
- Department of Pancreatic and Gastric Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing
| | - Nannan Zhang
- State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases
- Department of Gastric Surgery, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer
- Key Laboratory of Cancer Prevention and Therapy
- Tianjin’s Clinical Research Center for Cancer, Tianjin, People’s Republic of China
| | - Weili Han
- State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases
| | - Kun Liu
- State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases
| | - Junya Yan
- State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases
| | - Ling Chen
- State Key Laboratory of Cancer Biology, Department of Pathology, Xijing Hospital and School of Basic Medicine, Fourth Military Medical University, Xi’an
| | - Yan Pan
- State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases
| | - Renlong Li
- State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases
| | - Wenjiao Li
- State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases
| | - Haohao Zhang
- State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases
| | - Hongwei Li
- State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases
| | - Shibo Wang
- State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases
| | - Xiaoliang Gao
- State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases
| | - Penghui Niu
- Department of Pancreatic and Gastric Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing
| | - Wanqing Wang
- Department of Pancreatic and Gastric Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing
| | - Gang Ji
- State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases
| | - Qingchuan Zhao
- State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases
| | - Yuanyuan Lu
- State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases
| | - Zengshan Li
- State Key Laboratory of Cancer Biology, Department of Pathology, Xijing Hospital and School of Basic Medicine, Fourth Military Medical University, Xi’an
| | - Lei Shang
- Department of Health Statistics, Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health
| | - Han Liang
- Department of Gastric Surgery, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer
- Key Laboratory of Cancer Prevention and Therapy
- Tianjin’s Clinical Research Center for Cancer, Tianjin, People’s Republic of China
| | - Kaichun Wu
- State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases
| | - Jingyu Deng
- Department of Gastric Surgery, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer
- Key Laboratory of Cancer Prevention and Therapy
- Tianjin’s Clinical Research Center for Cancer, Tianjin, People’s Republic of China
| | - Yingtai Chen
- Department of Pancreatic and Gastric Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing
| | - Yongzhan Nie
- State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases
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Subasinghe D, Acott N, Mahesh PKB, Sivaganesh S, Munasinghe S, Kumarasinghe MP, Samarasekera DN, Lokuhetty MDS. Human epidermal growth factor receptor-2 gene expression positivity determined by silver in situ hybridization/immunohistochemistry methods and associated factors in a cohort of Sri Lankan patients with gastric adenocarcinoma: a prospective study. J Int Med Res 2023; 51:3000605231154403. [PMID: 36814374 PMCID: PMC9950620 DOI: 10.1177/03000605231154403] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/24/2023] Open
Abstract
OBJECTIVE Positive human epidermal growth factor 2 (HER2) expression and its predictive clinicopathological features remain unclear in Sri Lankan gastric cancer (GC) patients. Here, we aimed to determine GC HER2 status predictors by analyzing associations between clinicopathological features and HER2 expression using immunohistochemistry (IHC) and silver in situ hybridization (SISH). METHODS During this 4-year prospective study, clinicopathological data were collected from participants in the National Hospital of Sri Lanka. HER2 IHC and SISH were performed using commercial reagents. Using chi-square tests, associations of HER2-IHC/SISH with clinicopathological features were analyzed. RESULTS Overall, 145 GC patients were included, 69 had gastrectomies and 76 had biopsies. Positive HER2 expression by IHC was associated with age <60 years, high T stage (assessed pathologically in resections and radiologically in biopsies), high nuclear grade, tumor necrosis, mitosis >5/high-power field, with additional perineural invasion and lymphovascular invasion in resections. These features, excluding lymphovascular invasion but including male sex, were associated with HER2 expression by SISH. CONCLUSIONS Age <60 years, high nuclear grade, tumor necrosis, and perineural invasion are associated factors of HER2 status. These could be used to triage GC patients for HER2 status testing in limited resource settings where IHC/SISH analysis is costly.
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Affiliation(s)
- Duminda Subasinghe
- Department of Surgery, Faculty of Medicine, University of
Colombo, University Surgical Unit, The National Hospital of Sri Lanka, Colombo,
Sri Lanka,PathWest Laboratory Medicine, Perth, & School of Pathology
and Laboratory Medicine, University of Western Australia, Perth, Australia,Duminda Subasinghe, Department of Surgery,
Faculty of Medicine, University of Colombo, University Surgical Unit, The
National Hospital of Sri Lanka, Colombo 00800, Sri Lanka.
| | - Nathan Acott
- PathWest Laboratory Medicine, Perth, & School of Pathology
and Laboratory Medicine, University of Western Australia, Perth, Australia
| | | | - Sivasuriya Sivaganesh
- Department of Surgery, Faculty of Medicine, University of
Colombo, University Surgical Unit, The National Hospital of Sri Lanka, Colombo,
Sri Lanka
| | - Sithum Munasinghe
- Translational Health Research Institute, Western Sydney
University, Campbelltown Campus, Campbelltown, New South Wales, Australia
| | - Mariyan Priyanthi Kumarasinghe
- PathWest Laboratory Medicine, Perth, & School of Pathology
and Laboratory Medicine, University of Western Australia, Perth, Australia
| | - Dharmabandu Nandaveva Samarasekera
- Department of Surgery, Faculty of Medicine, University of
Colombo, University Surgical Unit, The National Hospital of Sri Lanka, Colombo,
Sri Lanka
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9
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Chu Y, Li H, Wu D, Guo Q. HER2 protein expression correlates with Lauren classification and P53 in gastric cancer patients. Medicine (Baltimore) 2022; 101:e30647. [PMID: 36123933 PMCID: PMC9478214 DOI: 10.1097/md.0000000000030647] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
Abstract
Human epidermal growth factor receptor 2 (HER2) is a key pathological characteristic of gastric cancer (GC). However, the clinical significance of HER2 expression in gastric carcinoma remains controversial. The purpose of this study was to analyze the clinicopathological characteristics of HER2 protein expression, Lauren classification and tumor protein p53 (P53) expression and to evaluate the clinical significance of HER2 protein expression. A total of 176 consecutive patients were prospectively recruited between January 2014 and December 2016 at the Second Affiliated Hospital of Zhejiang University School of Medicine. Histological analysis of the resected tissue was performed for HER2 protein expression using immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). Additionally, the expression status of HER2 protein and clinicopathological features were analyzed using the chi-squared (χ2) test. Survival analysis was performed using the Kaplan-Meier method, and differences between the survival curves were determined using the log-rank test. All statistical analyses were conducted using SPSS 22.0 statistical software program (IBM Corp., Armonk, NY). A total of 176 patients with GC were enrolled in this study. Intratumoral heterogeneity of HER2 protein overexpression was observed in 42 of 176 cases with IHC grade 2+, accompanied by FISH positivity and IHC grade 3+. HER2 protein expression was correlated with tumor differentiation (P < .001), Lauren classification (P = .001), Borrmann type (P = .003) and P53 expression (P < .001). HER2 protein positivity was associated with significantly higher overall survival (OS) (P = .038). Overexpression of HER2 protein was observed in 23.9% of the cases and was significantly related to the Lauren intestinal subtype and P53 negative expression. HER2 protein overexpression was independently associated with higher OS.
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Affiliation(s)
- Yiming Chu
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Zhejiang Chinese Medicine University, Hangzhou, Zhejiang, China
- Department of Surgery, The Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Hongbo Li
- Department of Surgery, The Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Dan Wu
- Department of Surgery, The Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Qingqu Guo
- Department of Surgery, The Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
- *Correspondence: Qingqu Guo, Department of Surgery, The Second Affiliated Hospital, College of Medicine, Zhejiang University, Cancer Institute of Zhejiang University, 88 Jiefang Road, Hangzhou, Zhejiang 310009, China (e-mail: )
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10
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Tumor Characteristics Associated with Lymph Node Metastasis and Prognosis in Patients with ERBB2-Positive Gastric Cancer. JOURNAL OF ONCOLOGY 2022; 2022:7592046. [PMID: 36059809 PMCID: PMC9436560 DOI: 10.1155/2022/7592046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Revised: 07/18/2022] [Accepted: 07/28/2022] [Indexed: 11/17/2022]
Abstract
Gastric cancers (GCs) that express human erb-b2 receptor tyrosine kinase 2 (ERBB2, also known as HER2) account for 7.3%–20.2% of GCs. The pathological and prognostic factors associated with lymph node metastasis of such tumors are still unclear. Therefore, we aimed to identify the risk factors for lymph node metastasis and prognostic factors of patients with ERBB2-positive GC. We conducted a retrospective analysis of pathological specimens after D2 radical surgery for locally advanced GC and D1+ surgery performed for early GC in our hospital from January 2015 to December 2018. Patients with ERBB2-positive GC were selected and the potential risk factors for lymph node metastasis and potential factors affecting prognosis were evaluated. Among 1,124 GC patients, 122 diagnosed with ERBB2-positive GC were included in the study. We found that risk factors for lymph node metastasis included tumor size (hazard ratio (HR)- 6.213, 95% confidence interval (CI)- 2.097–18.407, p = 0.001), neural invasion (HR- 2.876, 95% CI - 1.011–8.184, p = 0.048), and vascular invasion (HR- 16.881, 95% CI - 5.207–54.727, p < 0.001). T stage (HR- 4.615, 95% CI - 2.182–9.759, p < 0.001) and vascular invasion (HR- 3.036, 95% CI - 1.369–6.736, p = 0.006) were significant prognostic variables. These findings shed new light on the pathology and prognosis of patients with ERBB2-positive GC.
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11
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Ooki A, Yamaguchi K. The dawn of precision medicine in diffuse-type gastric cancer. Ther Adv Med Oncol 2022; 14:17588359221083049. [PMID: 35281349 PMCID: PMC8908406 DOI: 10.1177/17588359221083049] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Accepted: 01/31/2022] [Indexed: 12/24/2022] Open
Abstract
Gastric cancer (GC) is one of the most common malignancies worldwide. The histology- and morphology-based Lauren classification of GC has been widely used for over 50 years in clinical practice. The Lauren classification divides GC into intestinal and diffuse types, which have distinct etiology, molecular profiles, and clinicopathological features. Diffuse-type GC (DGC) accounts for approximately 30% of GCs. Tumor cells lack adhesion and infiltrate the stroma as single cells or small subgroups, leading to easy dissemination in the abdominal cavity. Clinically, DGC has aggressive traits with a high risk of recurrence and metastasis, which results in unfavorable prognosis. Although systemic chemotherapy is the main therapeutic approach for recurrent or metastatic GC patients, clinical benefits are limited for patients with DGC. Therefore, it is urgent to develop effective therapeutic strategies for DGC patients. Considerable research studies have characterized the molecular and genomic landscape of DGC, of which tight junction protein claudin-18 isoform 2 (CLDN18.2) and fibroblast growing factors receptor-2 isoform IIIb (FGFR2-IIIb) are the most attractive targets because of their close association with DGC. Recently, the impressive results of two phase II FAST and FIGHT trials demonstrate proof-of-concept, suggesting that anti-CLDN18.2 antibody (zolbetuximab) and FGFR2-IIIb antibody (bemarituzumab) are promising approaches for patients with CLDN18.2-positive and FGFR2-IIIb-positive GC, respectively. In this review, we summarize the clinicopathological features and molecular profiles of DGC and highlight a potential therapeutic target based on the findings of pivotal clinical trials.
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Affiliation(s)
- Akira Ooki
- Department of Gastroenterological Chemotherapy, Cancer Institute Hospital of Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550, Japan
| | - Kensei Yamaguchi
- Department of Gastroenterological Chemotherapy, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan
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12
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Cen S, Xu H, Liu Z, Zhao R, Pan H, Han W. Immune microenvironment characteristics and their implications for immune checkpoint inhibitor efficacy in HER2-overexpressing gastric cancer. Clin Exp Immunol 2022; 207:318-328. [PMID: 35553632 PMCID: PMC9113110 DOI: 10.1093/cei/uxac007] [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: 09/28/2021] [Revised: 12/14/2021] [Accepted: 02/02/2022] [Indexed: 02/06/2023] Open
Abstract
HER2-positive gastric cancer is a distinct tumor subtype, accounting for ~10% of gastric cancer cases. It is characterized by HER2 overexpression and responds well to HER2-targeting therapies. Recently, the addition of immune checkpoint inhibitors to HER2-targeting therapies produced satisfactory outcomes in these patients. In the present study, we used gene expression profiles and patient surgical sections to analyze the tumor immune microenvironment characteristics of gastric tumors with high HER2 expression. Several differentially enriched pathways were identified between the HER2 high-expression group and the low-expression group, such as pathways related to cytokine-cytokine receptor interactions, calcium signaling, and cell adhesion molecules. Tumors with high HER2 expression comprised fewer stromal cells and fewer immune cells, and had higher tumor purity. They also presented with lower expression of PD-1, PD-L1, CTLA-4, TIGIT, and LAG-3. In conclusion, our study provides a comprehensive blueprint of the immune microenvironment of HER2-positive gastric tumors. This analysis highlights the importance of considering the tumor microenvironment when assessing response to immune checkpoint inhibitors.
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Affiliation(s)
| | | | | | - Rongjie Zhao
- Department of Medical Oncology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, People’s Republic of China
| | - Hongming Pan
- Hongming Pan, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, 3# East Qinchun Road, Hangzhou, Zhejiang 310016, China.
| | - Weidong Han
- Correspondence: Weidong Han, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, 3# East Qinchun Road, Hangzhou, Zhejiang 310016, China.
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13
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Clinicopathologic features and treatment advances in cancers with HER2 alterations. Biochim Biophys Acta Rev Cancer 2021; 1876:188605. [PMID: 34358635 DOI: 10.1016/j.bbcan.2021.188605] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Revised: 07/28/2021] [Accepted: 07/28/2021] [Indexed: 12/14/2022]
Abstract
HER2 is one of the most important proteins of the epidermal growth factor receptor (EGFR) family, whose alterations include amplification, overexpression and gene mutation. Growing attention has been given to HER2 as a biomarker for prognosis, an indicator for treatment response and a target for new drugs. Tumors with HER2 alterations have been well studied in multiple locations as distinct entities for treatment, especially breast cancer, gastric cancer, lung cancer and colorectal cancer. These four cancers are the leading causes of cancer incidence and cancer-related death worldwide. The present study details the landscape of HER2 amplification/overexpression and mutations and gives an up-to-date analysis of current clinical trials in the four cancers mentioned above. Different HER2-altered cancers not only respond differently to HER2-targeting therapies but also display diverse survival outcomes. Even in the same type of cancer, HER2 amplification/overexpression differs from HER2 mutation in terms of clinicopathologic features and treatment strategies. As an emerging strategy in cancer treatment, immune checkpoint inhibitors demonstrate distinct outcomes in HER2-altered breast cancer, gastric cancer and lung cancer.
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14
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Sentani K, Imai T, Kobayashi G, Hayashi T, Sasaki N, Oue N, Yasui W. Histological diversity and molecular characteristics in gastric cancer: relation of cancer stem cell-related molecules and receptor tyrosine kinase molecules to mixed histological type and more histological patterns. Gastric Cancer 2021; 24:368-381. [PMID: 33118117 DOI: 10.1007/s10120-020-01133-w] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2020] [Accepted: 09/28/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND Gastric cancers (GCs) are still one of the leading causes of cancer-related mortality. The histological and molecular features of GC may differ widely from area to area within the same tumor. Intratumoral heterogeneity has been considered a major obstacle to an efficient diagnosis and successful molecular treatment. METHODS We selected and reevaluated 842 GC cases and analyzed the relationship between numbers or composites of histological patterns within tumors, and clinicopathological parameters in mucosal and invasive areas. In addition, we searched for the GC-associated molecules or molecular subtypes marking histological diversities. RESULTS GC cases with more histological numbers or mixed types in invasive areas showed significantly higher T grade and staging, whereas those in mucosal areas did not show any significant associations. GCs with histological diversities showed poorer prognosis and characteristically expressed cancer stem cell-related molecules (CD44, CD133 or ALDH1) and receptor tyrosine kinase molecules (HER2, EGFR or c-MET) as well as Helicobacter pylori infection. Expressions of CD44, HER2, c-MET, laminin 5·2 or retained E-cadherin in mucosal areas were predictive of more histological numbers and mixed types in invasive areas. In addition, the chromosomal instability subtype of GC showed significant associations with more histological numbers and mixed histological type, whereas the genomic stability subtype of GC showed a significant relationship with pure type. CONCLUSIONS We displayed the relationship between histological diversity and molecular features in GC, and we hope that the present data can contribute to the early diagnosis and prevention, and effective treatment of GC.
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Affiliation(s)
- Kazuhiro Sentani
- Department of Molecular Pathology, Graduate School of Biomedical and Health Sciences, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.
| | - Takeharu Imai
- Department of Molecular Pathology, Graduate School of Biomedical and Health Sciences, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Go Kobayashi
- Department of Molecular Pathology, Graduate School of Biomedical and Health Sciences, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Tetsutaro Hayashi
- Department of Molecular Pathology, Graduate School of Biomedical and Health Sciences, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Naomi Sasaki
- Department of Pathology, Kure-Kyosai Hospital, Federation of National Public Service Personnel Mutual Aid Associations, Hiroshima, Japan
| | - Naohide Oue
- Department of Molecular Pathology, Graduate School of Biomedical and Health Sciences, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Wataru Yasui
- Department of Molecular Pathology, Graduate School of Biomedical and Health Sciences, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
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15
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Liu Z, Shi M, Li X, Song S, Liu N, Du H, Ye J, Li H, Zhang Z, Zhang L. HER2 copy number as predictor of disease-free survival in HER2-positive resectable gastric adenocarcinoma. J Cancer Res Clin Oncol 2021; 147:1315-1324. [PMID: 33543328 PMCID: PMC8021510 DOI: 10.1007/s00432-021-03522-9] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2020] [Accepted: 01/10/2021] [Indexed: 01/28/2023]
Abstract
Purpose The identification of HER2 overexpression in a subset of gastric adenocarcinoma (GA) patients represents a significant step forward in unveiling the molecular complexity of this disease. The predictive and prognostic value of HER2 amplification in advanced HER2 inhibitor-treated GA patients has been investigated. However, its predictive value in resectable patients remains elusive. Methods We enrolled 98 treatment-naïve resectable Chinese GA patients with HER2 overexpression assessed using IHC. Capture-based targeted sequencing using a panel consisting of 41 gastrointestinal cancer-related genes was performed on tumor tissues. Furthermore, we also investigated the correlation between HER2 copy number (CN) and survival outcomes. Results Of the 98 HER2-overexpressed patients, 90 had HER2 CN amplification assessed using next-generation sequencing, achieving 92% concordance. The most commonly seen concurrent mutations were occurring in TP53, EGFR and PIK3CA. We found HER2 CN as a continuous variable was an independent predictor associated with DFS (p = 0.029). Our study revealed HER2 CN-high patients showed a trend of intestinal-type GA predominant (p = 0.075) and older age (p = 0.07). The median HER2 CN was 15.34, which was used to divide the cohort into CN-high and CN-low groups. Patients with high HER2 CN had a significantly shorter DFS than patients with low HER2 CN (p = 0.002). Furthermore, HER2 CN as a categorical variable was also an independent predictor associated with DFS in patients. Conclusion We elucidated the mutation spectrum of HER2-positive resectable Chinese GA patients and the association between HER2 CN and DFS. Our work revealed HER2 CN as an independent risk factor predicted unfavorable prognosis in HER2-positive GA patients and allowed us to further stratify HER2-positive resectable GA patients for disease management.
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Affiliation(s)
- Zimin Liu
- Oncology Department, The Affiliated Hospital of Qingdao University, Qingdao, 266000, China.
| | - Mingpeng Shi
- Operating Room of Neurosurgery, The Affiliated Hospital of Qingdao University, Qingdao, 266000, China
| | - Xiaoxiao Li
- Oncology Department, The Affiliated Hospital of Qingdao University, Qingdao, 266000, China
| | - Shanai Song
- Oncology Department, The Affiliated Hospital of Qingdao University, Qingdao, 266000, China
| | - Ning Liu
- Oncology Department, The Affiliated Hospital of Qingdao University, Qingdao, 266000, China
| | - Haiwei Du
- Burning Rock Biotech, Guangzhou, China
| | - Junyi Ye
- Burning Rock Biotech, Guangzhou, China
| | - Haiyan Li
- Burning Rock Biotech, Guangzhou, China
| | | | - Lu Zhang
- Burning Rock Biotech, Guangzhou, China
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16
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Lv H, Zhang J, Sun K, Nie C, Chen B, Wang J, Xu W, Wang S, Liu Y, Chen X. Expression of Human Epidermal Growth Factor Receptor-2 Status and Programmed Cell Death Protein-1 Ligand Is Associated With Prognosis in Gastric Cancer. Front Oncol 2021; 10:580045. [PMID: 33598422 PMCID: PMC7882725 DOI: 10.3389/fonc.2020.580045] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2020] [Accepted: 12/14/2020] [Indexed: 11/23/2022] Open
Abstract
Background PD-L1 and HER-2 are routine biomarkers for gastric cancer (GC). However, little research has been done to investigate the correlation among PD-L1, HER-2, immune microenvironment, and clinical features in GC. Methods Between January 2013 and May 2020, a total of 120 GC patients treated with chemotherapy were admitted to Henan Tumor Hospital. We retrospectively identified PD-L1, HER-2 level before chemotherapy and abstracted clinicopathologic features and treatment outcomes. Univariate and multivariate survival analyses were performed to assess the relationship between PD-L1/HER-2 levels and progression-free survival (PFS). The mRNA and tumor microenvironment of 343 patients with GC from The Cancer Genome Atlas (TCGA) were used to explore the underlying mechanism. Results We retrospectively analyzed 120 patients with gastric cancer, including 17 patients with HER-2 positive and 103 patients with HER-2 negative GC. The results showed that the expression of PD-L1 was closely correlated with HER-2 (P = 0.015). Patients with PD-L1/HER-2 positive obtained lower PFS compared to PD-L1/HER-2 negative (mPFS: 6.4 vs. 11.1 months, P = 0.014, mPFS: 5.3 vs. 11.1 months, P = 0.002, respectively), and the PD-L1 negative and HER-2 negative had the best PFS than other groups (P = 0.0008). In a multivariate model, PD-L1 status, HER-2 status, tumor location, and tumor differentiation remained independent prognostic indicators for PFS (P < 0.05). The results of database further analysis showed that the proportion of PD-L1+/CD8A+ in HER-2 negative patients was higher than that in HER-2 positive patients (37.6 vs 20.3%), while PD-L1−/CD8A− was significantly higher in HER-2 positive patients than HER-2 negative patients (57.8 vs. 28.8%). In addition, it showed that not only CD4+T cells, macrophages, and CD8+T cells, but also the associated inflammatory pathways such as IFN-γ/STAT1 were associated with HER-2. Conclusion HER-2 status could predict the efficacy of immune checkpoint inhibitors, and HER-2 status combined with PD-L1 level could predict the prognosis of GC patients.
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Affiliation(s)
- Huifang Lv
- Department of Oncology, Henan Cancer Hospital, Zhengzhou, China
| | - Junling Zhang
- Medical Department, 3D Medicines Inc., Shanghai, China
| | - Keran Sun
- Department of Oncology, Henan Cancer Hospital, Zhengzhou, China
| | - Caiyun Nie
- Department of Oncology, Henan Cancer Hospital, Zhengzhou, China
| | - Beibei Chen
- Department of Oncology, Henan Cancer Hospital, Zhengzhou, China
| | - Jianzheng Wang
- Department of Oncology, Henan Cancer Hospital, Zhengzhou, China
| | - Weifeng Xu
- Department of Oncology, Henan Cancer Hospital, Zhengzhou, China
| | - Saiqi Wang
- Department of Oncology, Henan Cancer Hospital, Zhengzhou, China
| | - Yingjun Liu
- Department of Surgery, Henan Cancer Hospital, Zhengzhou, China
| | - Xiaobing Chen
- Department of Oncology, Henan Cancer Hospital, Zhengzhou, China
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17
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Ramos MFKP, Pereira MA, de Castria TB, Ribeiro RRE, Cardili L, de Mello ES, Zilberstein B, Ribeiro-Júnior U, Cecconello I. Remnant gastric cancer: a neglected group with high potential for immunotherapy. J Cancer Res Clin Oncol 2020; 146:3373-3383. [PMID: 32671505 DOI: 10.1007/s00432-020-03322-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Accepted: 07/10/2020] [Indexed: 02/05/2023]
Abstract
PURPOSE The importance of targeted therapy and interest in the study of predictive markers in gastric cancer (GC) have increased in recent years with the use of anti-HER2 therapy and immunotherapy with anti-PD1/PD-L1 for microsatellite instability (MSI) and PD-L1 + tumors. However, the behavior of remnant GC (RGC) in this scenario is poorly reported. Thus, this study aims to evaluate the clinicopathological characteristics and prognosis of RGC and its association with the expression of current markers for targeted therapy. METHODS All RGC resections performed in a single center from 2009 to 2019 were retrospectively reviewed. As a comparison group, 53 primary proximal GC (PGC) who underwent total D2-gastrectomy were selected. HER2, MSI status and PD-L1 expression were analyzed by immunohistochemistry. Combined Positive Score (CPS) was used to determine PD-L1 positivity. RESULTS A total of 40 RGC were included. RGC patients were older (p = 0.001), had lower BMI (p = 0.001) and number of resected lymph nodes (p < 0.001) compared to the PGC. Regarding markers expression, MSI was higher in RGC than PGC (27.5% vs 9.4%, p = 0.022). The frequency of CPS-positive was 32.5% and 26.4% in RGC and PGC, respectively (p = 0.522). HER2 positivity was 17.5% and 22.6% for RGC and PGC, respectively (p = 0.543). In survival analysis, DFS was better for RGC CPS-positive than RGC CPS-negative (p = 0.039) patients. There was no difference in survival considering MSI status. CONCLUSION RGC had higher incidence of MSI than PGC, and CPS-positive RGC was associated with better survival. The immunological profile of RGC patients suggests that they would be good candidates for immunotherapy.
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Affiliation(s)
- Marcus Fernando Kodama Pertille Ramos
- Instituto do Cancer, Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Av Dr Arnaldo 251, Sao Paulo, SP, 01249000, Brazil.
| | - Marina Alessandra Pereira
- Instituto do Cancer, Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Av Dr Arnaldo 251, Sao Paulo, SP, 01249000, Brazil
| | - Tiago Biachi de Castria
- Instituto do Cancer, Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Av Dr Arnaldo 251, Sao Paulo, SP, 01249000, Brazil
| | - Renan Ribeiro E Ribeiro
- Instituto do Cancer, Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Av Dr Arnaldo 251, Sao Paulo, SP, 01249000, Brazil
| | - Leonardo Cardili
- Instituto do Cancer, Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Av Dr Arnaldo 251, Sao Paulo, SP, 01249000, Brazil
| | - Evandro Sobroza de Mello
- Instituto do Cancer, Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Av Dr Arnaldo 251, Sao Paulo, SP, 01249000, Brazil
| | - Bruno Zilberstein
- Instituto do Cancer, Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Av Dr Arnaldo 251, Sao Paulo, SP, 01249000, Brazil
| | - Ulysses Ribeiro-Júnior
- Instituto do Cancer, Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Av Dr Arnaldo 251, Sao Paulo, SP, 01249000, Brazil
| | - Ivan Cecconello
- Instituto do Cancer, Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Av Dr Arnaldo 251, Sao Paulo, SP, 01249000, Brazil
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18
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Zhang G, Li L, Bi J, Wu Y, Li E. Targeting DNA and mutant p53 by a naphthalimide derivative, NA20, exhibits selective inhibition in gastric tumorigenesis by blocking mutant p53-EGFR signaling pathway. Eur J Pharmacol 2020; 887:173584. [PMID: 32950500 DOI: 10.1016/j.ejphar.2020.173584] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Revised: 09/09/2020] [Accepted: 09/15/2020] [Indexed: 12/11/2022]
Abstract
Mutations of p53 in cancer cells not only subvert its antiproliferative properties but can also promote various oncogenic responses through a gain-of-function activity. Pharmacological manipulation of the mutant p53 pathway by specific compounds could be an effective strategy for cancer therapy. We show here that gain-of-function p53 mutation in gastric cancer cells promotes tumorigenesis by enhancing p53-EGFR (epidermal growth factor receptor) signaling pathway, and such process can be blocked by small molecule NA20, a naphthalimide derivative that exhibited selective inhibition in p53 mutant gastric cancer cell lines. We found that targeting DNA and blocking the mutant p53-drived carcinogenicity accounted for the primary antitumor effect of NA20 in gastric tumor models. NA20 bound to DNA and p53 identified by a combination of drug tracking, DNA relaxation assay and coimmunoprecipitation-mass spectrometry (CoIP-MS) detection, which led to the p21 activation and the suppression of EGFR signal cascading, thereby evoking cell cycle arrest and cell apoptosis, finally leading to cancer cell inhibition both in vitro and in vivo. Taken together, these results suggest that NA20 may be a potential candidate for gastric cancer therapy.
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Affiliation(s)
- Guohai Zhang
- State Key Laboratory of Pharmaceutical Biotechnology, Medical School of Nanjing University, Nanjing, China; State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Ministry of Science and Technology of China, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin, China.
| | - Liangping Li
- State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Ministry of Science and Technology of China, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin, China
| | - Jingai Bi
- State Key Laboratory of Pharmaceutical Biotechnology, Medical School of Nanjing University, Nanjing, China
| | - Yiming Wu
- State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Ministry of Science and Technology of China, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin, China
| | - Erguang Li
- State Key Laboratory of Pharmaceutical Biotechnology, Medical School of Nanjing University, Nanjing, China.
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19
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Gao J, Yu T, Xuan Y, Zhu Z. High expression of GNB4 predicts poor prognosis in patients with Helicobacter pylori-positive advanced gastric cancer. Transl Cancer Res 2020; 9:4224-4238. [PMID: 35117790 PMCID: PMC8798254 DOI: 10.21037/tcr-19-2914] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2019] [Accepted: 06/03/2020] [Indexed: 12/16/2022]
Abstract
Background Helicobacter pylori (H. pylori) is recognized as the most evident etiologic factor of infection-related gastric cancer (GC) and its involvement in GC initiation and progression has been well investigated. However, only a limited number of studies were performed to identify prognostic biomarkers and evaluate their clinical significance in GC patients infected with H. pylori. This study was conducted to investigate the clinical significance as well as its potential prognostic value of GNB4 in H. pylori-positive GC patients receiving standard treatment. Methods Retrospective statistical analysis was performed on 448 H. pylori-positive GC patients, with 137 early gastric cancer (EGC) patients undergoing radical gastrectomy alone and 311 advanced gastric cancer (AGC) patients receiving the same surgical procedure followed by fluorouracil-based chemotherapy. GNB4 expression was detected by immunohistochemistry staining on patient samples. H. pylori infection was routinely examined on endoscopic biopsy and/or surgical specimen of GC patients. Results High expression of GNB4 was 65.7% (90/137) in EGC and 62.7% (195/311) in AGC patients infected with H. pylori, respectively. In EGC patients, GNB4 expression was not associated with either clinicopathological parameters or 5-year overall survival (OS). In AGC patients however, high expression of GNB4 was significantly associated with patient’s pathological stage (P=0.047). Univariate analysis showed that tumor invasion depth (P=0.001), lymph node metastasis (P<0.001), pathological stage (P<0.001) as well as high expression of GNB4 (P=0.002) were significantly associated with 5-year OS. Multivariate analysis further identified lymph node metastasis (P=0.013) and GNB4 high expression (P=0.020) as independent prognostic factors for long-term outcome of H. pylori-positive AGC patients. Conclusions This study demonstrates that high expression of GNB4 is significantly associated with pathological stage of AGC patients with H. pylori infection. GNB4 expression independently predicts the 5-year OS of H. pylori-positive AGC patients undergoing radical gastrectomy and adjuvant chemotherapy.
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Affiliation(s)
- Jianpeng Gao
- Department of Gastric Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Teng Yu
- Department of Pathology, Ruijin hospital affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Yi Xuan
- Department of Gastric Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Zhenglun Zhu
- Department of Gastrointestinal Surgery, Ruijin hospital affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China
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20
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Machado-Neves R, Vale J, Eloy C, Polónia A. HER2 genomic heterogeneity is a frequent event in gastroesophageal adenocarcinoma and correlates with tumor morphology. Pathol Res Pract 2020; 216:153090. [PMID: 32825958 DOI: 10.1016/j.prp.2020.153090] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Revised: 06/25/2020] [Accepted: 06/26/2020] [Indexed: 01/08/2023]
Abstract
AIM To characterize a cohort of gastro-esophageal adenocarcinomas (GEA) evaluated for HER2 gene amplification using bright field in situ hybridization (ISH) following the 2016 guidelines for GEA and correlating the results with clinico-pathological features. It was also aimed to evaluate the effect of applying the ISH criteria from the 2018 guidelines for breast cancer (BC) in the same GEA cases. MATERIALS AND METHODS 159 GEA cases collected in a period of 59 months were evaluated for HER2 gene amplification by ISH according to GEA and BC guidelines. All cases were reviewed for histological type, grading and presence of signet ring cells. RESULTS Most of the cases refereed to ISH were HER2 equivocal (57.9 %) by immunohistochemistry. According to the GEA guideline, 131 cases were HER2-negative (87.3 %) and 19 cases were HER2-positive (12.7 %). According to the BC guideline, 133 cases were HER2-negative (88.7 %) and 17 cases were HER2-positive (11.3 %), being statistically similar to the results obtained with the GEA guideline. HER2 genomic heterogeneity was detected in 31.6 % of the HER2-positive cases, almost exclusively in tubular adenocarcinoma. We observed a significant association between HER2 gene amplification and tubular adenocarcinomas, and absence of signet ring cells. The only case with HER2 gene amplification and presence of signet ring cells was a mixed carcinoma, where the signet ring cells represented the non-amplified component. CONCLUSIONS HER2 positivity rate was similar when applying the GEA or the BC guidelines. We also establish a tight association between morphology and HER2 gene amplification.
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Affiliation(s)
- Raquel Machado-Neves
- Department of Pathology, Hospital Pedro Hispano, ULS Matosinhos, Rua Dr. Eduardo Torres, 4464-513, Senhora da Hora, Matosinhos, Portugal
| | - João Vale
- Department of Pathology, Ipatimup Diagnostics, Institute of Molecular Pathology and Immunology, University of Porto, Rua Júlio Amaral de Carvalho, 45, 4200-135, Porto, Portugal; I3S - Instituto de Investigação e Inovação em Saúde, University of Porto, Rua Alfredo Allen, 208, 4200-135, Porto, Portugal
| | - Catarina Eloy
- Department of Pathology, Ipatimup Diagnostics, Institute of Molecular Pathology and Immunology, University of Porto, Rua Júlio Amaral de Carvalho, 45, 4200-135, Porto, Portugal; I3S - Instituto de Investigação e Inovação em Saúde, University of Porto, Rua Alfredo Allen, 208, 4200-135, Porto, Portugal; Faculty of Medicine, University of Porto, Alameda Prof Hernâni Monteiro, 4200-319, Porto, Portugal
| | - António Polónia
- Department of Pathology, Ipatimup Diagnostics, Institute of Molecular Pathology and Immunology, University of Porto, Rua Júlio Amaral de Carvalho, 45, 4200-135, Porto, Portugal; I3S - Instituto de Investigação e Inovação em Saúde, University of Porto, Rua Alfredo Allen, 208, 4200-135, Porto, Portugal.
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Pereira MA, Ramos MFKP, Dias AR, Faraj SF, Ribeiro RRE, de Castria TB, Zilberstein B, Alves VAF, Ribeiro U, de Mello ES. Expression Profile of Markers for Targeted Therapy in Gastric Cancer Patients: HER-2, Microsatellite Instability and PD-L1. Mol Diagn Ther 2019; 23:761-771. [PMID: 31595457 DOI: 10.1007/s40291-019-00424-y] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
BACKGROUND The assessment of human epidermal growth factor receptor 2 (HER2), microsatellite instability (MSI) and programmed cell death-ligand 1 (PD-L1) expression is relevant for the selection and effectiveness of targeted therapy in gastric cancer (GC). OBJECTIVE We aimed to investigate the clinicopathological characteristics and prognosis of GC patients according to these profiles. METHODS GC patients who underwent gastrectomy with D2 lymphadenectomy were eligible. HER2, MSI status and PD-L1 expression were analyzed by immunohistochemistry (IHC). Patients were grouped as follows: HER2+ group, immunotherapy (IT) group (MSI and/or PD-L1+), and non-targeted therapy (NTT) group (stable microsatellite and HER2/PD-L1-). RESULTS Among 282 patients, 50 (17.7%) were HER2+ and 79 (28%) MSI/PD-L1+. Fifteen had HER2+ and MSI/PD-L1+, while 168 (59.6%) were in the NTT group. HER2+ GCs were related to male gender (p = 0.007), intestinal type (p = 0.001) and less advanced pTNM stage (p = 0.029). Older age (p = 0.003), subtotal gastrectomy (p = 0.025), intestinal type (p = 0.008), pN0 status (p = 0.002) and less advanced pTNM stage (p = 0.001) were associated with the IT group. IT GC had better disease-free survival (DFS) and overall survival than the NTT group (p = 0.015 and p = 0.027, respectively). Concerning patients eligible for the standard adjuvant therapy, the treatment impacted positively on DFS for HER2+ and NTT groups (p = 0.003 and p = 0.042, respectively). No difference in DFS was seen between IT patients who received perioperative/adjuvant therapy and those treated only with surgery (p = 0.160). CONCLUSIONS GC patients who exhibited markers that can serve as an indication for known targeted therapy represent 40.4% of cases. The IT group was associated with a better prognosis. No benefit with standard adjuvant treatment appears to be achieved in MSI/PD-L1+ GCs.
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Affiliation(s)
- Marina Alessandra Pereira
- Department of Gastroenterology, Instituto do Cancer, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Avenida Doutor Arnaldo, 251, São Paulo, 01246-000, Brazil.
- Centro de Investigação Translacional em Oncologia (LIM24), Instituto do Cancer, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, São Paulo, Brazil.
| | - Marcus Fernando Kodama Pertille Ramos
- Department of Gastroenterology, Instituto do Cancer, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Avenida Doutor Arnaldo, 251, São Paulo, 01246-000, Brazil
- Centro de Investigação Translacional em Oncologia (LIM24), Instituto do Cancer, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, São Paulo, Brazil
| | - André Roncon Dias
- Department of Gastroenterology, Instituto do Cancer, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Avenida Doutor Arnaldo, 251, São Paulo, 01246-000, Brazil
- Centro de Investigação Translacional em Oncologia (LIM24), Instituto do Cancer, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, São Paulo, Brazil
| | - Sheila Friedrich Faraj
- Centro de Investigação Translacional em Oncologia (LIM24), Instituto do Cancer, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, São Paulo, Brazil
- Department of Pathology, Instituto do Cancer, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, São Paulo, Brazil
| | - Renan Ribeiro E Ribeiro
- Centro de Investigação Translacional em Oncologia (LIM24), Instituto do Cancer, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, São Paulo, Brazil
- Department of Pathology, Instituto do Cancer, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, São Paulo, Brazil
| | - Tiago Biachi de Castria
- Department of Radiology and Oncology, Instituto do Cancer, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, São Paulo, Brazil
| | - Bruno Zilberstein
- Department of Gastroenterology, Instituto do Cancer, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Avenida Doutor Arnaldo, 251, São Paulo, 01246-000, Brazil
| | - Venancio Avancini Ferreira Alves
- Department of Pathology, Instituto do Cancer, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, São Paulo, Brazil
| | - Ulysses Ribeiro
- Department of Gastroenterology, Instituto do Cancer, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Avenida Doutor Arnaldo, 251, São Paulo, 01246-000, Brazil
- Centro de Investigação Translacional em Oncologia (LIM24), Instituto do Cancer, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, São Paulo, Brazil
| | - Evandro Sobroza de Mello
- Centro de Investigação Translacional em Oncologia (LIM24), Instituto do Cancer, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, São Paulo, Brazil
- Department of Pathology, Instituto do Cancer, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, São Paulo, Brazil
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Koh J, Lee KW, Nam SK, Seo AN, Kim JW, Kim JW, Park DJ, Kim HH, Kim WH, Lee HS. Development and Validation of an Easy-to-Implement, Practical Algorithm for the Identification of Molecular Subtypes of Gastric Cancer: Prognostic and Therapeutic Implications. Oncologist 2019; 24:e1321-e1330. [PMID: 31371521 DOI: 10.1634/theoncologist.2019-0058] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2019] [Accepted: 06/10/2019] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND Gastric cancer (GC) is a heterogeneous disease, and substantial efforts have been made to develop a molecular biology-based classification system for GC. Analysis of the genomic signature is not always feasible, and thus, we aimed to (i) develop and validate a practical immunohistochemistry (IHC)- and polymerase chain reaction (PCR)-based molecular classification of GC and (ii) to assess HER2 status according to this classification. MATERIALS AND METHODS A total of 894 consecutive patients with GC from two individual cohorts (training, n = 507; validation, n = 387) were classified using Epstein-Barr virus (EBV) in situ hybridization, microsatellite instability (MSI) testing, and IHC for E-cadherin and p53. RESULTS We were able to classify patients into five groups in the training cohort: group 1 (MSI+), group 2 (EBV-, MSI-, non-epithelial-mesenchymal transition [non-EMT]-like, p53-), group 3 (EBV+), group 4 (EBV-, MSI-, non-EMT-like, p53+), and group 5 (EBV-, MSI-, EMT-like). In the training cohort, each group showed different overall survival (OS) after gastrectomy (p < .001); group 1 had the best prognosis, and group 5 showed the worst survival outcome. The significant impact of the classification system on OS was also verified in the validation cohort (p = .004). HER2 positivity was observed in 6.5% of total population, and most of HER2-positive cases (93.1%) were included in groups 2 and 4. CONCLUSION We developed and validated a modified IHC- and PCR-based molecular classification system in GC, which showed significant impact on survival, irrespective of stage or other clinical variables. We also found close association between HER2 status and non-EMT phenotype in our classification system. IMPLICATIONS FOR PRACTICE Molecular classification of gastric cancer suggested by previous studies mostly relies on extensive genomic data analysis, which is not always available in daily practice. The authors developed a simplified immunohistochemistry- and polymerase chain reaction-based molecular classification of gastric cancer and proved the prognostic significance of this classification, as well as the close association between HER2 status and certain groups of the classification, in the largest consecutive cohort of gastric cancer. Results of this study suggest that this scheme is a cost-effective, easy-to-implement, and feasible way of classifying gastric cancer in daily clinical practice, also serving as a practical tool for aiding therapeutic decisions and predicting prognosis.
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Affiliation(s)
- Jiwon Koh
- Department of Pathology, Seoul National University Hospital, Seoul, Republic of Korea
| | - Keun-Wook Lee
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Soo Kyung Nam
- Department of Pathology, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
| | - An Na Seo
- Department of Pathology, School of Medicine, Kyungpook National University, Kyungpook National University Chilgok Hospital, Daegu, Republic of Korea
| | - Ji-Won Kim
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Jin Won Kim
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Do Joong Park
- Department of Surgery, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
| | - Hyung-Ho Kim
- Department of Surgery, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
| | - Woo Ho Kim
- Department of Pathology, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Hye Seung Lee
- Department of Pathology, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
- Department of Pathology, Seoul National University College of Medicine, Seoul, Republic of Korea
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Kim H, Seo S, Kim K, Park YH, An M, Baik H, Choi C, Oh S. Prognostic significance of Human epidermal growth factor receptor-2 expression in patients with resectable gastric adenocarcinoma. World J Surg Oncol 2019; 17:122. [PMID: 31296222 PMCID: PMC6624940 DOI: 10.1186/s12957-019-1652-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2019] [Accepted: 06/19/2019] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND The purpose of this study was to investigate the correlation between human epidermal growth factor receptor 2 (HER2) overexpression and clinicopathologic factors and overall survival rate in patients who underwent curative gastrectomy for gastric adenocarcinoma. METHODS Among patients who underwent curative gastrectomy for gastric adenocarcinoma at Inje University Paik Hospital from January 2012 to December 2015, 782 patients underwent an immunohistochemical analysis to evaluate HER2 expression levels. Clinicopathologic records that were collected from a gastric cancer database were retrospectively reviewed to identify clinicopathologic factors and survival rates of the patients. RESULTS HER2 overexpression was detected in 166 patients (21.2%). There was a statistically significant correlation between HER2 expression level and sex (p = 0.013), histologic differentiation (p < 0.001), Lauren classification (p < 0.001), and T pathologic stage (p = 0.022). There were no statistically significant relationships between HER2 expression level and overall 5-year survival rate (p = 0.775) and overall 5-year survival rate of gastric adenocarcinoma classified according to the TNM stage (stage I: p = 0.756, stage II: p = 0.571, stage III: p = 0.704). The HER2 expression level was not affected by the overall 5-year survival rate in the uni- and multivariate analyses. CONCLUSIONS In this study, the HER2 overexpression rate in gastric adenocarcinoma was 21.2% and was observed in well- and moderately differentiated types according to histologic differentiation, intestinal type according to the Lauren classification, male, and low T stage. There was no correlation between HER2 expression level and overall 5-year survival rate, and HER2 expression level was not associated with independent prognostic factors.
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Affiliation(s)
- Hyeongbin Kim
- Department of Surgery, Busan Paik Hospital, Inje University, Bokgiro 75, Busanjin-gu, Busan, Republic of Korea
| | - SangHyuk Seo
- Department of Surgery, Busan Paik Hospital, Inje University, Bokgiro 75, Busanjin-gu, Busan, Republic of Korea
| | - KwangHee Kim
- Department of Surgery, Busan Paik Hospital, Inje University, Bokgiro 75, Busanjin-gu, Busan, Republic of Korea.
| | - Yo-Han Park
- Department of Surgery, Busan Paik Hospital, Inje University, Bokgiro 75, Busanjin-gu, Busan, Republic of Korea
| | - MinSung An
- Department of Surgery, Busan Paik Hospital, Inje University, Bokgiro 75, Busanjin-gu, Busan, Republic of Korea
| | - HyungJoo Baik
- Department of Surgery, Busan Paik Hospital, Inje University, Bokgiro 75, Busanjin-gu, Busan, Republic of Korea
| | - ChangSoo Choi
- Department of Surgery, Busan Paik Hospital, Inje University, Bokgiro 75, Busanjin-gu, Busan, Republic of Korea
| | - SangHoon Oh
- Department of Surgery, Busan Paik Hospital, Inje University, Bokgiro 75, Busanjin-gu, Busan, Republic of Korea
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24
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HER2 Status in Gastric and Gastroesophageal Junction Cancer: Results of the Large, Multinational HER-EAGLE Study. Appl Immunohistochem Mol Morphol 2019; 26:239-245. [PMID: 27490762 DOI: 10.1097/pai.0000000000000423] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
Human epidermal growth factor receptor 2 (HER2) dysregulation is associated with tumorigenesis in gastric/gastroesophageal junction cancer; however, the number of patients with HER2-positive disease is unclear, possibly due to differing scoring criteria/assays. Data are also lacking for early disease. We aimed to assess the HER2-positivity rate using approved testing criteria in a large, real-life multinational population. HER2-positivity was defined as an immunohistochemistry staining score of 3+, or immunohistochemistry 2+ and HER2 amplification detected by in situ hybridization. A total of 4949 patients were enrolled and results showed that 14.2% of 4920 samples with immunohistochemistry results were HER2-positive. HER2-positivity was significantly higher in males (16.1% vs. 9.6% in females), in gastroesophageal versus stomach tumors (22.1% vs. 12.9%), in biopsy versus surgical samples (18.3% vs. 13.0%), in intestinal tumor subtypes versus diffuse (21.5% vs. 4.8%) and mixed types (21.5% vs. 8.5%) (P<0.001), in mixed versus diffuse types (8.5% vs. 4.8%), and in "other" versus diffuse types (11.7% vs. 4.8%; P=0.002). There were no significant differences between stages. Patients in the youngest age percentile had significantly lower HER2-positivity rates than patients in the remaining percentiles (9.2% vs. 15.9%, 15.7%, and 15.1%; P<0.001). HER2-positivity was highest in France (20.2%) and lowest in Hong Kong (10.4%). In conclusion, HER-EAGLE, the first study of its kind to be conducted in a large, multinational population of almost 5000 patients, gives valuable insights into the real-world HER2-positivity rate in a gastric/gastroesophageal junction cancer patient population not selected for disease stage or histology.
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25
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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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Raj N, Verma D, Kumar A, Rai P, Rao RN. HER2 Oncogene Amplification and Immunohistochemical Profiling in Gastric Adenocarcinoma. Discoveries (Craiova) 2018; 6:e83. [PMID: 32309603 PMCID: PMC7086066 DOI: 10.15190/d.2018.6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Background and Objectives: Gastric adenocarcinoma is one of the most common malignant tumors and a major cause of cancer death worldwide, especially in developing countries. Her2/neu gene amplification and protein overexpression in breast cancer is a golden criterion for the targeted therapy with trastuzumab. However, the role of Her2 as a prognostic factor in gastric cancer is still controversial. The purpose of this study was to evaluate the frequency of Her2 oncogene overexpression and concordance between the results for Her2 protein expression and gene amplification. Materials and Methods: A total of 65 retroprospective cases with gastric adenocarcinoma, including biopsy and resected specimens obtained between July 2015 to December 2017, were analyzed. Her2/neu expression was determined by Immuno-histochemistry (IHC). Equivocal and some selected cases were submitted for FISH to detect Her2/neu gene amplification. Results: In the present study, out of 65 patients of gastric adenocarcinoma, there were 50 males and 15 females, with mean age of 54.52 years. The majority of tumors were located within the antropyloric region. We found 27 (41.4%) positivity, scored as IHC 3+ and IHC 2+, and 38 (58.3%) negativity, scored as IHC 1+ and IHC 0. We also evidentiated a significant difference between Her2/neu expression with age (p=0.010) and depth of invasion (p=0.020).Her2/neu gene was amplified only in 13 cases, 4 cases were of Her2/neu (3+) positive, 11 cases (39.3%) Her2/neu (2+) with IHC staining. The concordance rate between the results of IHC and FISH in all 18 cases was 83.3%. Conclusion: IHC detection can be carried out to guide the treatment when FISH detection cannot be performed. Overexpression of Her 2/neu in gastric adenocarcinoma could potentially be used in selecting the patients who can get benefit from the anti-Her2/neu targeted therapy.
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Affiliation(s)
- Nisha Raj
- Department of Pathology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India
| | - Divya Verma
- Department of Pathology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India
| | - Ashok Kumar
- Department of Surgical Gastroenterology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India
| | - Praveer Rai
- Department of Gastroenterology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India
| | - Ram Nawal Rao
- Department of Pathology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India
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Ahmed A, Al-Tamimi DM. Incorporation of p-53 mutation status and Ki-67 proliferating index in classifying Her2-neu positive gastric adenocarcinoma. Libyan J Med 2018; 13:1466573. [PMID: 29697008 PMCID: PMC5917891 DOI: 10.1080/19932820.2018.1466573] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Her2-neu overexpression has a pathogenetic, therapeutic and a controversial prognostic role in gastric cancer. p-53 mutation status and Ki-67 proliferation index are established prognostic markers in many tumors. In this study we evaluated p-53 and Ki-67 in relation to Her2-neu positive and negative gastric adenocarcinoma (GA). This cross-sectional study was carried out at King Fahd Hospital of Imam Abdulrahman bin Faisal University. Fifty cases of GA were retrieved from pathology archives. Clinico-pathological parameters were evaluated. Immunohistochemical protein analysis for Her2-neu, Ki-67 and p-53 was carried out. Fluorescent in situ hybridization (FISH) analysis was done for Her2-neu positive cases showing 2+ immunoexpression. Frequency of Ki-67 and p-53 positivity in Her2-neu positive cases was calculated and compared with those in Her2-neu negative cases. Correlation of clinicopatological parameters with Her2 positive and negative cases, p-53 mutation status and Ki-67 proliferation index was carried out. Her2-neu overexpression was present in 12% (n = 6) cases. A high Ki-67 was seen predominantly in Her2-neu positive cases (83%, n = 5). Her2-neu negative cases (n = 44) showed moderate (31.88%, n = 14) to low (34%, n = 15) Ki-67. Diffuse p-53 positivity was seen predominantly in Her2-neu positive cases (33.33%, n = 2). Focal p-53 was seen mainly in Her2-neu negative cases 56.8% (n = 25). Negative p-53 was seen to be independent of Her2-neu status. Her2-neu positivity is strongly associated with diffuse p-53 mutation status and high Ki-67 proliferation. Her 2-neu negative status is associated with focal p-53 positivity and low to moderate Ki-67 proliferation index. Such stratifications in prognostic markers could not only be predictive in patient's prognostics but could also form a basis of molecular classification of gastric cancer.
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Affiliation(s)
- Ayesha Ahmed
- a Department of Pathology, College of Medicine , King Fahd Hospital of Imam Abdulrahman Bin Faisal University , Dammam , Saudi Arabia
| | - Dalal M Al-Tamimi
- a Department of Pathology, College of Medicine , King Fahd Hospital of Imam Abdulrahman Bin Faisal University , Dammam , Saudi Arabia
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Association of HER2 gene amplification and tumor progression in early gastric cancer. Virchows Arch 2018; 473:559-565. [PMID: 30120594 DOI: 10.1007/s00428-018-2433-y] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2018] [Revised: 07/20/2018] [Accepted: 08/06/2018] [Indexed: 12/20/2022]
Abstract
Overexpression of human epidermal growth factor receptor 2 (HER2) protein in association with HER2 gene amplification is found in 7-34% of gastric cancers. In breast cancer, HER2 overexpression is a prognostic factor in advanced cases and is associated with tumor progression in ductal carcinoma in situ. However, the biological and clinical significance of HER2 status in early gastric cancer is unknown. Here, we aimed to examine the correlation between HER2 gene amplification and tumor progression in early gastric cancer. The HER2 status was evaluated in 149 lesions from 141 consecutive patients with early gastric cancer who underwent endoscopic resection by immunohistochemistry and dual color in situ hybridization. HER2 gene amplification was detected in 35 (23.5%) of 149 lesions, and of those, 26 cases (74.3%) showed intratumoral heterogeneity. HER2 gene amplification was found in noninvasive carcinoma, and there was a significant correlation between HER2 status and T factor (P = 0.0290). Our study demonstrated that HER2 gene amplification occurred during the early stages of gastric cancer and showed heterogeneity in several cases. HER2 gene amplification may be involved in tumor progression in early gastric cancer.
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Nadaf AS, Rani H, Dinesh US. Immuno-Histochemical Assessment of HER2NEU Expression in Gastric Adenocarcinoma in North Karnataka, India. Asian Pac J Cancer Prev 2018; 19:1381-1385. [PMID: 29802704 PMCID: PMC6031826 DOI: 10.22034/apjcp.2018.19.5.1381] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
Abstract
Background and Objectives: Gastric cancer is the fourth most common cancer worldwide and ranks fifth in India.
Surgical resection is curative in early stage gastric cancers. Most of the gastric cancers are diagnosed at an advanced
stage necessitating multimodality treatment strategies. Based on the ToGA trial, the international regulatory agencies
have recently approved trastuzumab in locally advanced and metastatic gastric and gastroesophageal adenocarcinomas
expressing HER2. Since there are limited studies from India and no published data available from this part of North
Karnataka, we undertook this study to evaluate the frequency of expression of HER2 in gastric and gastroesophageal
adenocarcinomas and to correlate it with various clinicopathological variables. Methodology: The study was conducted
in the Department of Pathology, SDM College of Medical Sciences and Hospital, Dharwad, Karnataka from May 2012
to January 2016. The samples included both endoscopic biopsies and gastrectomies. Histopathological slides from 70
cases were reviewed. Immunohistochemical staining for HER2 was performed in all the cases and Hoffman’s gastric
cancer scoring system was employed. The results of HER2 expression was correlated with various clinicopathological
parameters. Results: HER2 positivity was seen in 16/70 cases (23%). 6 cases (8.5%) were equivocal and 48/70 cases
(68.5%) were HER2 negative. HER2 positivity was more common in GEJ cancers and intestinal type of adenocarcinoma.
However, it did not correlate with age, gender, grade and stage. Conclusion: HER2 positivity was noted in 23% of the
cases. 23.4% of intestinal type and 21.7% of diffuse type were HER2 positive. HER2 positivity did not significantly
depend on age, gender, tumour type, grade and stage. Hence, HER2 remains as an independent biomarker and should be
tested in all patients of gastric cancer regardless of the clinicopathological findings for offering a personalized treatment.
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Affiliation(s)
- Asmanaz Saleem Nadaf
- Department of Pathology, SDM Medical College and Hospital, Dharwad, Karnataka, India.
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Xie GD, Liu YR, Jiang YZ, Shao ZM. Epidemiology and survival outcomes of mucinous adenocarcinomas: A SEER population-based study. Sci Rep 2018; 8:6117. [PMID: 29666453 PMCID: PMC5904162 DOI: 10.1038/s41598-018-24540-7] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2017] [Accepted: 04/05/2018] [Indexed: 12/26/2022] Open
Abstract
To investigate the epidemiology, demographics and survival of mucinous adenocarcinomas (MACs), we identified 80,758 MAC patients in the Surveillance, Epidemiology and End Results (SEER) database. The reported incidence of MACs ebbed and flowed over time; however, a significant increase in reported annual age-adjusted incidences of MACs in the appendix, lung and bronchus was observed from 1981 to 2014. The demographics and outcomes of MACs differed by anatomic sites. MACs of the stomach had the largest percentage of poorly differentiated or undifferentiated tumors (41.2%), while MACs of the appendix and pancreas were associated with more advanced tumor stage (P < 0.001). MACs of the pancreas, lung and bronchus and stomach showed worse survival than other sites, despite localized, regional or distant stage (P < 0.001). In univariate and multivariate analysis, site, tumor grade, tumor stage, regional nodes, sex, race, surgery and year of diagnosis were identified as independent prognostic factors of cancer-specific survival. In conclusion, the incidence of MACs of certain specific sites, such as the appendix, lung and bronchus, is rapidly increasing. We also revealed a series of prognostic factors of MACs, including tumor sites, tumor grade and tumor stage, which may improve the current understanding of the clinical and biological patterns of MACs.
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Affiliation(s)
- Guang-Dong Xie
- Department of Breast Surgery, Fudan University Shanghai Cancer Center; Cancer Institute, Fudan University Shanghai Cancer Center, 399 Ling-Ling Road, Shanghai, 200032, People's Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, Xuhui Qu, P.R. China
| | - Yi-Rong Liu
- Department of Breast Surgery, Fudan University Shanghai Cancer Center; Cancer Institute, Fudan University Shanghai Cancer Center, 399 Ling-Ling Road, Shanghai, 200032, People's Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, Xuhui Qu, P.R. China
| | - Yi-Zhou Jiang
- Department of Breast Surgery, Fudan University Shanghai Cancer Center; Cancer Institute, Fudan University Shanghai Cancer Center, 399 Ling-Ling Road, Shanghai, 200032, People's Republic of China.
- Department of Oncology, Shanghai Medical College, Fudan University, Xuhui Qu, P.R. China.
| | - Zhi-Ming Shao
- Department of Breast Surgery, Fudan University Shanghai Cancer Center; Cancer Institute, Fudan University Shanghai Cancer Center, 399 Ling-Ling Road, Shanghai, 200032, People's Republic of China.
- Department of Oncology, Shanghai Medical College, Fudan University, Xuhui Qu, P.R. China.
- Institutes of Biomedical Sciences, Fudan University, Shanghai, P.R. China.
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Clinicopathological features and endoscopic findings of HER2-positive gastric cancer. Surg Endosc 2018; 32:3964-3971. [PMID: 29500656 DOI: 10.1007/s00464-018-6138-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2017] [Accepted: 02/23/2018] [Indexed: 12/18/2022]
Abstract
BACKGROUND Human epidermal growth factor receptor 2 (HER2) expression in gastric cancer is highly heterogeneous. Therefore, it is important to take endoscopic samples from appropriate tumor sites. METHODS Between January 2008 and April 2015, patients with gastric or gastroesophageal junction cancer with histologically confirmed adenocarcinoma were included. Surgical samples or endoscopic biopsy samples were examined for HER2 using immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). Tissues were considered to be HER2 positive when either assessment revealed either an IHC score of 3+ or an IHC score of 2+ accompanied by a positive FISH result. Endoscopic findings were retrieved in all cases where available, and we examined the portion from which a biopsy was obtained. RESULTS Out of the 612 patients included in the study, 104 (17%) were HER2 positive. The proportion of HER2-positive gastric tumors with differentiated (vs. undifferentiated) histology was significantly higher (29 vs. 6%, respectively; p < 0.001). The HER2-positive rate of papillary adenocarcinomas (vs. tubular) was particularly high (62%, 8/13; p = 0.023). The proportion of HER2-positive gastric tumors of Borrmann classification 0 or 1 was significantly higher than that of tumors of classified as 2, 3, or 4 (45 vs. 16%, respectively; p < 0.001). The HER2-positive rates per biopsy specimen from the superficial spreading portion, ulcer mound, ulcer bed, and mass portion were 100, 91, 45, and 100%, respectively. CONCLUSIONS HER2-positive gastric cancer tends to be associated with a differentiated histology, particularly papillary adenocarcinoma, and a Borrmann classification of 0 or 1 tumors. Based on these endoscopic findings, it is important to recognize the superficial spreading portion and the mass portion of gastric malignancies.
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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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Abstract
BACKGROUND The treatment of patients with advanced gastric cancer remains a most challenging task in the clinical practice. Recently, targeted therapies have significantly impacted the treatment strategy for many common malignancies. The use of trastuzumab, a monoclonal antibody against human epidermal growth factor receptor 2 (HER2; also known as ERBB2), plus chemotherapy proved to improve median overall survival in patients with advanced gastric cancer, compared with chemotherapy alone in Trastuzumab for Gastric Cancer (ToGA) trial. However, the prognostic value of HER2 status in gastric cancer remains controversial. Therefore, the aim of this study was to investigate the clinical pathology significance of HER2 overexpression in resectable gastric cancer for selecting the right patients with gastric cancer who may benefit from trastuzumab treatment. METHODS Publications reported the clinicopathological factors associated with HER2 status in gastric cancer from 2012 to 2017 were collected. The literature databases, such as "Cochrane Library", "Sciencedirect", "Springer", "PubMed", "Embase", were extensively searched to retrieve the clinical studies of HER2 expression in gastric cancer. The major outcomes measures were odds ratios (ORs) and their 95% CIs. Statistical analysis was carried out by Revman software 5.3. The Newcastle-Ottawa scale was used to assess the quality of evidence. RESULT Fifteen studies met our inclusion criteria. This study demonstrated that the pooled OR for HER2 positivity was associated with being male (OR: 1.42; 95% CI: 1.23-1.64), well/moderately differentiated tumor (OR: 2.76; 95% CI: 1.72-4.45), and for intestinal-type tumor (OR: 0.31; 95% CI: 0.25-0.38). However, it had no correlation with depth of tumor (P = .07), venous invasion (P = .82), and lymphovascular invasion (P = .24). CONCLUSION HER2-positive expression was associated with male gender, intestinal type, and well/moderate cell differentiation. We recommend that those gastric cancer patients who may benefit from trastuzumab treatment should be subjected to targeted therapies. However, detecting HER2 status may contribute to the target therapy for gastric carcinoma using trastuzumab. This would be strengthened by further studies incorporating comorbidity data, and outcomes from centralized programs.
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Diagnostic, Predictive, Prognostic, and Therapeutic Molecular Biomarkers in Third Millennium: A Breakthrough in Gastric Cancer. BIOMED RESEARCH INTERNATIONAL 2017; 2017:7869802. [PMID: 29094049 PMCID: PMC5637861 DOI: 10.1155/2017/7869802] [Citation(s) in RCA: 61] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/07/2017] [Accepted: 07/12/2017] [Indexed: 02/08/2023]
Abstract
Introduction Gastric cancer is the fifth most common cancer and the third cause of cancer death. The clinical outcomes of the patients are still not encouraging with a low rate of 5 years' survival. Often the disease is diagnosed at advanced stages and this obviously negatively affects patients outcomes. A deep understanding of molecular basis of gastric cancer can lead to the identification of diagnostic, predictive, prognostic, and therapeutic biomarkers. Main Body This paper aims to give a global view on the molecular classification and mechanisms involved in the development of the tumour and on the biomarkers for gastric cancer. We discuss the role of E-cadherin, HER2, fibroblast growth factor receptor (FGFR), MET, human epidermal growth factor receptor (EGFR), hepatocyte growth factor receptor (HGFR), mammalian target of rapamycin (mTOR), microsatellite instability (MSI), PD-L1, and TP53. We have also considered in this manuscript new emerging biomarkers as matrix metalloproteases (MMPs), microRNAs, and long noncoding RNAs (lncRNAs). Conclusions Identifying and validating diagnostic, prognostic, predictive, and therapeutic biomarkers will have a huge impact on patients outcomes as they will allow early detection of tumours and also guide the choice of a targeted therapy based on specific molecular features of the cancer.
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Halder S, Mallick D, Mondal P, Roy DS, Halder A, Chakrabarti S. Detection and Significance of Human Epidermal Growth Factor Receptor 2 Expression in Gastric Adenocarcinoma. INDIAN JOURNAL OF MEDICAL AND PAEDIATRIC ONCOLOGY : OFFICIAL JOURNAL OF INDIAN SOCIETY OF MEDICAL & PAEDIATRIC ONCOLOGY 2017; 38:153-157. [PMID: 28900323 PMCID: PMC5582552 DOI: 10.4103/ijmpo.ijmpo_159_16] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
Background: Human epidermal growth factor receptor 2 (HER2) is involved in the pathogenesis of several types of cancer, including gastric cancer. Overexpression of HER2 is noted in 10%–22.8% of gastric adenocarcinoma and its identification is of immense importance for management by targeted drugs. Detection of HER2 expression in gastric malignancies has not been undertaken previously in the local population. Objective: To ascertain HER2 immunohistochemical expression in gastric adenocarcinoma and its relationship with the anatomic location and histomorphology. Materials and Methods: A total of 47 cases of gastric adenocarcinoma diagnosed over 2 years constituted the study group. Clinical history, type of operation, gross morphology, and hematoxylin and eosin (H and E) stained sections were reviewed. Two paraffin blocks were selected, immunostain was performed using rabbit monoclonal HER2 antibody and Hoffmann scoring system was applied. Results: Most of gastric carcinomas occurred in male (42 cases), having a mean age of 53.6 years. A total of eight cases (17.1%) had expressed a score of 3+ HER2 positivity. All positivity was noted in intestinal type according to Lauren classification (25%) and none in diffuse type. All HER2 score of 3+ was noted in histological grade of well and moderately differentiated adenocarcinoma. Score 2+ was noted in seven cases, among them, only two were poorly differentiated gastric adenocarcinoma. Conclusion: HER2 overexpression was noticeably associated with an intestinal subtype, and well and moderately differentiated adenocarcinomas. Such cases of gastric adenocarcinoma are considered for targeted therapy with trastuzumab in the local population.
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Affiliation(s)
- Sutapa Halder
- Department of Pathology, ESI PGIMSR, Manicktala, West Bengal, India
| | - Debjani Mallick
- Department of Pathology, ESI PGIMSR and ESIC Medical College, Joka, West Bengal, India
| | - Priyanka Mondal
- Department of Pathology, ESI PGIMSR, Manicktala, West Bengal, India
| | | | - Aniket Halder
- Department of Pathology, School of Digestive and Liver Diseases, IPGME and R-SSKM Hospitals, Kolkata, West Bengal, India
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Uesugi N, Sugai T, Sugimoto R, Eizuka M, Fujita Y, Sato A, Osakabe M, Ishida K, Koeda K, Sasaki A, Matsumoto T. Clinicopathological and molecular stability and methylation analyses of gastric papillary adenocarcinoma. Pathology 2017; 49:596-603. [PMID: 28830689 DOI: 10.1016/j.pathol.2017.07.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2017] [Revised: 07/20/2017] [Accepted: 07/24/2017] [Indexed: 02/07/2023]
Abstract
The molecular alterations and pathological features of gastric papillary adenocarcinoma (GPA) remain unknown. We examined GPA samples and compared their molecular and pathological characteristics with those of gastric tubular adenocarcinoma (GTA). Additionally, we identified pathological and molecular features of GPA that vary with microsatellite stability. In the present study, samples from 63 GPA patients and 47 GTA patients were examined using a combination of polymerase chain reaction (PCR)-microsatellite assays and PCR-pyrosequencing in order to detect microsatellite instability (microsatellite instability, MSI; microsatellite stable, MSS), methylation status (low methylation, intermediate methylation and high methylation level), and chromosomal AI in multiple cancer-related loci. Additionally, the expression levels of TP53 and Her2 were evaluated using immunohistochemistry. GTA and GPA are statistically different in their frequency of pathological features, including mucinous, poorly differentiated and invasive micropapillary components. Clear genetic patterns differentiating GPA and GTA could not be identified with a hierarchical cluster analysis, but microsatellite stability was linked with TP53 and Her2 overexpression. Methylation status in GPA was also associated with the development of high microsatellite instability. However, no pathological differences were associated with microsatellite stability. We suggest that although molecular alterations in a subset of GPAs are closely associated with microsatellite stability, they play a minor role in GPA carcinogenesis.
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Affiliation(s)
- Noriyuki Uesugi
- Department of Molecular Diagnostic Pathology, Iwate Medical University, Morioka, Japan
| | - Tamotsu Sugai
- Department of Molecular Diagnostic Pathology, Iwate Medical University, Morioka, Japan.
| | - Ryo Sugimoto
- Department of Molecular Diagnostic Pathology, Iwate Medical University, Morioka, Japan
| | - Makoto Eizuka
- Department of Molecular Diagnostic Pathology, Iwate Medical University, Morioka, Japan
| | - Yasuko Fujita
- Department of Molecular Diagnostic Pathology, Iwate Medical University, Morioka, Japan
| | - Ayaka Sato
- Department of Molecular Diagnostic Pathology, Iwate Medical University, Morioka, Japan
| | - Mitsumasa Osakabe
- Department of Molecular Diagnostic Pathology, Iwate Medical University, Morioka, Japan
| | - Kazuyuki Ishida
- Department of Molecular Diagnostic Pathology, Iwate Medical University, Morioka, Japan
| | - Keisuke Koeda
- Department of Surgery, Iwate Medical University, Morioka, Japan
| | - Akira Sasaki
- Department of Surgery, Iwate Medical University, Morioka, Japan
| | - Takayuki Matsumoto
- Division of Gastroenterology, Department of Internal Medicine, School of Medicine, Iwate Medical University, Morioka, Japan
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Ji C, Zhang Q, Guan W, Guo T, Chen L, Liu S, He J, Zhou Z. Role of intravoxel incoherent motion MR imaging in preoperative assessing HER2 status of gastric cancers. Oncotarget 2017; 8:49293-49302. [PMID: 28514733 PMCID: PMC5564768 DOI: 10.18632/oncotarget.17570] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2016] [Accepted: 04/17/2017] [Indexed: 12/18/2022] Open
Abstract
PURPOSE To explore the role of intravoxel incoherent motion (IVIM) magnetic resonance (MR) imaging in evaluating human epidermal growth factor receptor 2 (HER2) status of gastric cancers preoperatively. RESULTS The apparent diffusion coefficient (ADC) and pure diffusion coefficient (D) values correlated positively with HER2 scores of gastric cancers significantly (r = 0.276, P = 0.048; r = 0.481, P < 0.001, respectively). The ADC and D values of HER2 positive gastric cancers were significantly higher than those of HER2 negative tumors (P = 0.033, 0.007, respectively). With a cut-off value of 1.321 and 1.123 × 10-3 mm2/sec, the ADC and D values could distinguish HER2 positive gastric cancers from HER2 negative ones with an area under the curve of 0.733 and 0.762, respectively (P = 0.023, 0.011, respectively). MATERIALS AND METHODS Fifty-three patients with gastric cancers underwent IVIM MR imaging preoperatively. The values of ADC, D, pseudo diffusion coefficient (D*) and perfusion related fraction (f) of the lesions were obtained. Partial correlation test including tumor volume was performed to analyze correlations between IVIM values and HER2 scores excluding the impact of tumor size. IVIM parameters of gastric cancers with different HER2 status were compared using independent samples t test. Diagnostic performance of IVIM parameters in distinguishing HER2 positive gastric cancers from negative ones was tested with receiver operating characteristic analysis. CONCLUSIONS We confirmed the feasibility of IVIM MR imaging in preoperative assessment of HER2 status of gastric cancers, which might make up the shortfall of biopsy and facilitate personalized treatment for patients with gastric cancers.
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Affiliation(s)
- Changfeng Ji
- Department of Radiology, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, China, 210008
| | - Qinglei Zhang
- Department of Radiology, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, China, 210008
| | - Wenxian Guan
- Department of Gastrointestinal Surgery, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, China, 210008
| | - Tingting Guo
- Department of Radiology, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China, 210008
| | - Ling Chen
- Department of Pathology, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, China, 210008
| | - Song Liu
- Department of Radiology, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, China, 210008
| | - Jian He
- Department of Radiology, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, China, 210008
| | - Zhengyang Zhou
- Department of Radiology, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, China, 210008
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Deguchi Y, Okabe H, Oshima N, Hisamori S, Minamiguchi S, Muto M, Sakai Y. PTEN loss is associated with a poor response to trastuzumab in HER2-overexpressing gastroesophageal adenocarcinoma. Gastric Cancer 2017; 20:416-427. [PMID: 27517839 DOI: 10.1007/s10120-016-0627-z] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2016] [Accepted: 08/02/2016] [Indexed: 02/07/2023]
Abstract
BACKGROUND Although trastuzumab improves the outcome of patients with human epidermal growth factor receptor 2 (HER2)-overexpressing gastric or gastroesophageal junction adenocarcinoma (collectively referred to as "gastroesophageal adenocarcinoma"; GEA), no clinical response is observed in a substantial population of patients. A predictive biomarker of trastuzumab response is required. The aim of this study was to evaluate whether the hyperactivation of the downstream phosphatidylinositol 3-kinase pathway, due to phosphatase and tensin homolog (PTEN) loss or PIK3CA mutations, could provide trastuzumab resistance in GEA. METHODS Expression of HER2 and PTEN, and PIK3CA gene mutations were screened in 264 surgically resected GEA specimens. The effects of PTEN knockdown on the response to trastuzumab on cell viability, HER2 downstream signaling, apoptosis, and cell cycle were evaluated in HER2-overexpressing NCI-N87 gastric adenocarcinoma and OE19 esophageal adenocarcinoma cell lines. Inhibition of xenograft tumor growth by trastuzumab was investigated in OE19 cells with or without PTEN knockdown. The PTEN expression and objective response were analyzed in 23 GEA patients who received trastuzumab-based therapy. RESULTS PTEN loss was identified in 34.5 % of HER2-overexpressing GEA patients, whereas PIK3CA mutations were rare (5.6 %). Trastuzumab-mediated growth suppression, apoptosis, and G1 cell cycle arrest were inhibited by PTEN knockdown through Akt activation in NCI-N87 and OE19 cells. PTEN knockdown impaired the antiproliferative effect of trastuzumab in OE19 xenograft models. A clinical response was observed in 50 % of PTEN-positive tumors (9 of 18) but in no tumors with PTEN loss (none of 5). CONCLUSIONS PTEN loss was frequently found in HER2-overexpressing tumors, and was associated with a poor response to trastuzumab-based therapy in patients with GEA.
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Affiliation(s)
- Yasunori Deguchi
- Department of Surgery, Graduate School of Medicine, Kyoto University, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan
| | - Hiroshi Okabe
- Department of Surgery, Graduate School of Medicine, Kyoto University, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan. .,Department of Surgery, Otsu Municipal Hospital, 2-9-9 Motomiya, Otsu, Shiga, 520-0804, Japan.
| | - Nobu Oshima
- Department of Surgery, Graduate School of Medicine, Kyoto University, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan
| | - Shigeo Hisamori
- Department of Surgery, Graduate School of Medicine, Kyoto University, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan
| | - Sachiko Minamiguchi
- Department of Diagnostic Pathology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Manabu Muto
- Department of Therapeutic Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Yoshiharu Sakai
- Department of Surgery, Graduate School of Medicine, Kyoto University, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan
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Bartley AN, Washington MK, Colasacco C, Ventura CB, Ismaila N, Benson AB, Carrato A, Gulley ML, Jain D, Kakar S, Mackay HJ, Streutker C, Tang L, Troxell M, Ajani JA. HER2 Testing and Clinical Decision Making in Gastroesophageal Adenocarcinoma: Guideline From the College of American Pathologists, American Society for Clinical Pathology, and the American Society of Clinical Oncology. J Clin Oncol 2017; 35:446-464. [PMID: 28129524 DOI: 10.1200/jco.2016.69.4836] [Citation(s) in RCA: 267] [Impact Index Per Article: 33.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Context ERBB2 (erb-b2 receptor tyrosine kinase 2 or HER2) is currently the only biomarker established for selection of a specific therapy for patients with advanced gastroesophageal adenocarcinoma (GEA). However, there are no comprehensive guidelines for the assessment of HER2 in patients with GEA. Objectives To establish an evidence-based guideline for HER2 testing in patients with GEA, formalize the algorithms for methods to improve the accuracy of HER2 testing while addressing which patients and tumor specimens are appropriate, and to provide guidance on clinical decision making. Design The College of American Pathologists (CAP), American Society for Clinical Pathology (ASCP), and the American Society of Clinical Oncology (ASCO) convened an Expert Panel to conduct a systematic review of the literature to develop an evidence-based guideline with recommendations for optimal HER2 testing in patients with GEA. Results The Panel is proposing 11 recommendations with strong agreement from the open comment participants. Recommendations The Panel recommends that tumor specimen(s) from all patients with advanced GEA, who are candidates for HER2-targeted therapy, should be assessed for HER2 status before the initiation of HER2-targeted therapy. Clinicians should offer combination chemotherapy and an HER2-targeted agent as initial therapy for all patients with HER2-positive advanced GEA. For pathologists, guidance is provided for morphologic selection of neoplastic tissue, testing algorithms, scoring methods, interpretation and reporting of results, and laboratory quality assurance. Conclusion This guideline provides specific recommendations for assessment of HER2 in patients with advanced GEA while addressing pertinent technical issues and clinical implications of the results.
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Affiliation(s)
- Angela N Bartley
- Angela N. Bartley, St Joseph Mercy Hospital, Ann Arbor, MI; Mary Kay Washington, Vanderbilt University Medical Center, Nashville, TN; Carol Colasacco and Christina B. Ventura, College of American Pathologists, Northfield; Al B. Benson III, Northwestern University, Chicago, IL; Nofisat Ismaila, American Society of Clinical Oncology, Alexandria, VA; Alfredo Carrato, Ramón y Cajal University Hospital, Madrid, Spain; Margaret L. Gulley, University of North Carolina, Chapel Hill, NC; Dhanpat Jain, Yale University School of Medicine, New Haven, CT; Sanjay Kakar, University of California, San Francisco, CA; Helen J. Mackay, Princess Margaret Cancer Centre; Catherine Streutker, St Michael's Hospital, University of Toronto, Toronto, Canada; Laura Tang, Memorial Sloan Kettering Cancer Center, New York, NY; Megan Troxell, Stanford University Medical Center, Stanford, CA; and Jaffer A. Ajani, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Mary Kay Washington
- Angela N. Bartley, St Joseph Mercy Hospital, Ann Arbor, MI; Mary Kay Washington, Vanderbilt University Medical Center, Nashville, TN; Carol Colasacco and Christina B. Ventura, College of American Pathologists, Northfield; Al B. Benson III, Northwestern University, Chicago, IL; Nofisat Ismaila, American Society of Clinical Oncology, Alexandria, VA; Alfredo Carrato, Ramón y Cajal University Hospital, Madrid, Spain; Margaret L. Gulley, University of North Carolina, Chapel Hill, NC; Dhanpat Jain, Yale University School of Medicine, New Haven, CT; Sanjay Kakar, University of California, San Francisco, CA; Helen J. Mackay, Princess Margaret Cancer Centre; Catherine Streutker, St Michael's Hospital, University of Toronto, Toronto, Canada; Laura Tang, Memorial Sloan Kettering Cancer Center, New York, NY; Megan Troxell, Stanford University Medical Center, Stanford, CA; and Jaffer A. Ajani, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Carol Colasacco
- Angela N. Bartley, St Joseph Mercy Hospital, Ann Arbor, MI; Mary Kay Washington, Vanderbilt University Medical Center, Nashville, TN; Carol Colasacco and Christina B. Ventura, College of American Pathologists, Northfield; Al B. Benson III, Northwestern University, Chicago, IL; Nofisat Ismaila, American Society of Clinical Oncology, Alexandria, VA; Alfredo Carrato, Ramón y Cajal University Hospital, Madrid, Spain; Margaret L. Gulley, University of North Carolina, Chapel Hill, NC; Dhanpat Jain, Yale University School of Medicine, New Haven, CT; Sanjay Kakar, University of California, San Francisco, CA; Helen J. Mackay, Princess Margaret Cancer Centre; Catherine Streutker, St Michael's Hospital, University of Toronto, Toronto, Canada; Laura Tang, Memorial Sloan Kettering Cancer Center, New York, NY; Megan Troxell, Stanford University Medical Center, Stanford, CA; and Jaffer A. Ajani, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Christina B Ventura
- Angela N. Bartley, St Joseph Mercy Hospital, Ann Arbor, MI; Mary Kay Washington, Vanderbilt University Medical Center, Nashville, TN; Carol Colasacco and Christina B. Ventura, College of American Pathologists, Northfield; Al B. Benson III, Northwestern University, Chicago, IL; Nofisat Ismaila, American Society of Clinical Oncology, Alexandria, VA; Alfredo Carrato, Ramón y Cajal University Hospital, Madrid, Spain; Margaret L. Gulley, University of North Carolina, Chapel Hill, NC; Dhanpat Jain, Yale University School of Medicine, New Haven, CT; Sanjay Kakar, University of California, San Francisco, CA; Helen J. Mackay, Princess Margaret Cancer Centre; Catherine Streutker, St Michael's Hospital, University of Toronto, Toronto, Canada; Laura Tang, Memorial Sloan Kettering Cancer Center, New York, NY; Megan Troxell, Stanford University Medical Center, Stanford, CA; and Jaffer A. Ajani, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Nofisat Ismaila
- Angela N. Bartley, St Joseph Mercy Hospital, Ann Arbor, MI; Mary Kay Washington, Vanderbilt University Medical Center, Nashville, TN; Carol Colasacco and Christina B. Ventura, College of American Pathologists, Northfield; Al B. Benson III, Northwestern University, Chicago, IL; Nofisat Ismaila, American Society of Clinical Oncology, Alexandria, VA; Alfredo Carrato, Ramón y Cajal University Hospital, Madrid, Spain; Margaret L. Gulley, University of North Carolina, Chapel Hill, NC; Dhanpat Jain, Yale University School of Medicine, New Haven, CT; Sanjay Kakar, University of California, San Francisco, CA; Helen J. Mackay, Princess Margaret Cancer Centre; Catherine Streutker, St Michael's Hospital, University of Toronto, Toronto, Canada; Laura Tang, Memorial Sloan Kettering Cancer Center, New York, NY; Megan Troxell, Stanford University Medical Center, Stanford, CA; and Jaffer A. Ajani, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Al B Benson
- Angela N. Bartley, St Joseph Mercy Hospital, Ann Arbor, MI; Mary Kay Washington, Vanderbilt University Medical Center, Nashville, TN; Carol Colasacco and Christina B. Ventura, College of American Pathologists, Northfield; Al B. Benson III, Northwestern University, Chicago, IL; Nofisat Ismaila, American Society of Clinical Oncology, Alexandria, VA; Alfredo Carrato, Ramón y Cajal University Hospital, Madrid, Spain; Margaret L. Gulley, University of North Carolina, Chapel Hill, NC; Dhanpat Jain, Yale University School of Medicine, New Haven, CT; Sanjay Kakar, University of California, San Francisco, CA; Helen J. Mackay, Princess Margaret Cancer Centre; Catherine Streutker, St Michael's Hospital, University of Toronto, Toronto, Canada; Laura Tang, Memorial Sloan Kettering Cancer Center, New York, NY; Megan Troxell, Stanford University Medical Center, Stanford, CA; and Jaffer A. Ajani, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Alfredo Carrato
- Angela N. Bartley, St Joseph Mercy Hospital, Ann Arbor, MI; Mary Kay Washington, Vanderbilt University Medical Center, Nashville, TN; Carol Colasacco and Christina B. Ventura, College of American Pathologists, Northfield; Al B. Benson III, Northwestern University, Chicago, IL; Nofisat Ismaila, American Society of Clinical Oncology, Alexandria, VA; Alfredo Carrato, Ramón y Cajal University Hospital, Madrid, Spain; Margaret L. Gulley, University of North Carolina, Chapel Hill, NC; Dhanpat Jain, Yale University School of Medicine, New Haven, CT; Sanjay Kakar, University of California, San Francisco, CA; Helen J. Mackay, Princess Margaret Cancer Centre; Catherine Streutker, St Michael's Hospital, University of Toronto, Toronto, Canada; Laura Tang, Memorial Sloan Kettering Cancer Center, New York, NY; Megan Troxell, Stanford University Medical Center, Stanford, CA; and Jaffer A. Ajani, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Margaret L Gulley
- Angela N. Bartley, St Joseph Mercy Hospital, Ann Arbor, MI; Mary Kay Washington, Vanderbilt University Medical Center, Nashville, TN; Carol Colasacco and Christina B. Ventura, College of American Pathologists, Northfield; Al B. Benson III, Northwestern University, Chicago, IL; Nofisat Ismaila, American Society of Clinical Oncology, Alexandria, VA; Alfredo Carrato, Ramón y Cajal University Hospital, Madrid, Spain; Margaret L. Gulley, University of North Carolina, Chapel Hill, NC; Dhanpat Jain, Yale University School of Medicine, New Haven, CT; Sanjay Kakar, University of California, San Francisco, CA; Helen J. Mackay, Princess Margaret Cancer Centre; Catherine Streutker, St Michael's Hospital, University of Toronto, Toronto, Canada; Laura Tang, Memorial Sloan Kettering Cancer Center, New York, NY; Megan Troxell, Stanford University Medical Center, Stanford, CA; and Jaffer A. Ajani, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Dhanpat Jain
- Angela N. Bartley, St Joseph Mercy Hospital, Ann Arbor, MI; Mary Kay Washington, Vanderbilt University Medical Center, Nashville, TN; Carol Colasacco and Christina B. Ventura, College of American Pathologists, Northfield; Al B. Benson III, Northwestern University, Chicago, IL; Nofisat Ismaila, American Society of Clinical Oncology, Alexandria, VA; Alfredo Carrato, Ramón y Cajal University Hospital, Madrid, Spain; Margaret L. Gulley, University of North Carolina, Chapel Hill, NC; Dhanpat Jain, Yale University School of Medicine, New Haven, CT; Sanjay Kakar, University of California, San Francisco, CA; Helen J. Mackay, Princess Margaret Cancer Centre; Catherine Streutker, St Michael's Hospital, University of Toronto, Toronto, Canada; Laura Tang, Memorial Sloan Kettering Cancer Center, New York, NY; Megan Troxell, Stanford University Medical Center, Stanford, CA; and Jaffer A. Ajani, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Sanjay Kakar
- Angela N. Bartley, St Joseph Mercy Hospital, Ann Arbor, MI; Mary Kay Washington, Vanderbilt University Medical Center, Nashville, TN; Carol Colasacco and Christina B. Ventura, College of American Pathologists, Northfield; Al B. Benson III, Northwestern University, Chicago, IL; Nofisat Ismaila, American Society of Clinical Oncology, Alexandria, VA; Alfredo Carrato, Ramón y Cajal University Hospital, Madrid, Spain; Margaret L. Gulley, University of North Carolina, Chapel Hill, NC; Dhanpat Jain, Yale University School of Medicine, New Haven, CT; Sanjay Kakar, University of California, San Francisco, CA; Helen J. Mackay, Princess Margaret Cancer Centre; Catherine Streutker, St Michael's Hospital, University of Toronto, Toronto, Canada; Laura Tang, Memorial Sloan Kettering Cancer Center, New York, NY; Megan Troxell, Stanford University Medical Center, Stanford, CA; and Jaffer A. Ajani, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Helen J Mackay
- Angela N. Bartley, St Joseph Mercy Hospital, Ann Arbor, MI; Mary Kay Washington, Vanderbilt University Medical Center, Nashville, TN; Carol Colasacco and Christina B. Ventura, College of American Pathologists, Northfield; Al B. Benson III, Northwestern University, Chicago, IL; Nofisat Ismaila, American Society of Clinical Oncology, Alexandria, VA; Alfredo Carrato, Ramón y Cajal University Hospital, Madrid, Spain; Margaret L. Gulley, University of North Carolina, Chapel Hill, NC; Dhanpat Jain, Yale University School of Medicine, New Haven, CT; Sanjay Kakar, University of California, San Francisco, CA; Helen J. Mackay, Princess Margaret Cancer Centre; Catherine Streutker, St Michael's Hospital, University of Toronto, Toronto, Canada; Laura Tang, Memorial Sloan Kettering Cancer Center, New York, NY; Megan Troxell, Stanford University Medical Center, Stanford, CA; and Jaffer A. Ajani, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Catherine Streutker
- Angela N. Bartley, St Joseph Mercy Hospital, Ann Arbor, MI; Mary Kay Washington, Vanderbilt University Medical Center, Nashville, TN; Carol Colasacco and Christina B. Ventura, College of American Pathologists, Northfield; Al B. Benson III, Northwestern University, Chicago, IL; Nofisat Ismaila, American Society of Clinical Oncology, Alexandria, VA; Alfredo Carrato, Ramón y Cajal University Hospital, Madrid, Spain; Margaret L. Gulley, University of North Carolina, Chapel Hill, NC; Dhanpat Jain, Yale University School of Medicine, New Haven, CT; Sanjay Kakar, University of California, San Francisco, CA; Helen J. Mackay, Princess Margaret Cancer Centre; Catherine Streutker, St Michael's Hospital, University of Toronto, Toronto, Canada; Laura Tang, Memorial Sloan Kettering Cancer Center, New York, NY; Megan Troxell, Stanford University Medical Center, Stanford, CA; and Jaffer A. Ajani, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Laura Tang
- Angela N. Bartley, St Joseph Mercy Hospital, Ann Arbor, MI; Mary Kay Washington, Vanderbilt University Medical Center, Nashville, TN; Carol Colasacco and Christina B. Ventura, College of American Pathologists, Northfield; Al B. Benson III, Northwestern University, Chicago, IL; Nofisat Ismaila, American Society of Clinical Oncology, Alexandria, VA; Alfredo Carrato, Ramón y Cajal University Hospital, Madrid, Spain; Margaret L. Gulley, University of North Carolina, Chapel Hill, NC; Dhanpat Jain, Yale University School of Medicine, New Haven, CT; Sanjay Kakar, University of California, San Francisco, CA; Helen J. Mackay, Princess Margaret Cancer Centre; Catherine Streutker, St Michael's Hospital, University of Toronto, Toronto, Canada; Laura Tang, Memorial Sloan Kettering Cancer Center, New York, NY; Megan Troxell, Stanford University Medical Center, Stanford, CA; and Jaffer A. Ajani, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Megan Troxell
- Angela N. Bartley, St Joseph Mercy Hospital, Ann Arbor, MI; Mary Kay Washington, Vanderbilt University Medical Center, Nashville, TN; Carol Colasacco and Christina B. Ventura, College of American Pathologists, Northfield; Al B. Benson III, Northwestern University, Chicago, IL; Nofisat Ismaila, American Society of Clinical Oncology, Alexandria, VA; Alfredo Carrato, Ramón y Cajal University Hospital, Madrid, Spain; Margaret L. Gulley, University of North Carolina, Chapel Hill, NC; Dhanpat Jain, Yale University School of Medicine, New Haven, CT; Sanjay Kakar, University of California, San Francisco, CA; Helen J. Mackay, Princess Margaret Cancer Centre; Catherine Streutker, St Michael's Hospital, University of Toronto, Toronto, Canada; Laura Tang, Memorial Sloan Kettering Cancer Center, New York, NY; Megan Troxell, Stanford University Medical Center, Stanford, CA; and Jaffer A. Ajani, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Jaffer A Ajani
- Angela N. Bartley, St Joseph Mercy Hospital, Ann Arbor, MI; Mary Kay Washington, Vanderbilt University Medical Center, Nashville, TN; Carol Colasacco and Christina B. Ventura, College of American Pathologists, Northfield; Al B. Benson III, Northwestern University, Chicago, IL; Nofisat Ismaila, American Society of Clinical Oncology, Alexandria, VA; Alfredo Carrato, Ramón y Cajal University Hospital, Madrid, Spain; Margaret L. Gulley, University of North Carolina, Chapel Hill, NC; Dhanpat Jain, Yale University School of Medicine, New Haven, CT; Sanjay Kakar, University of California, San Francisco, CA; Helen J. Mackay, Princess Margaret Cancer Centre; Catherine Streutker, St Michael's Hospital, University of Toronto, Toronto, Canada; Laura Tang, Memorial Sloan Kettering Cancer Center, New York, NY; Megan Troxell, Stanford University Medical Center, Stanford, CA; and Jaffer A. Ajani, The University of Texas MD Anderson Cancer Center, Houston, TX
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Bartley AN, Washington MK, Ventura CB, Ismaila N, Colasacco C, Benson AB, Carrato A, Gulley ML, Jain D, Kakar S, Mackay HJ, Streutker C, Tang L, Troxell M, Ajani JA. HER2 Testing and Clinical Decision Making in Gastroesophageal Adenocarcinoma: Guideline From the College of American Pathologists, American Society for Clinical Pathology, and American Society of Clinical Oncology. Arch Pathol Lab Med 2016; 140:1345-1363. [PMID: 27841667 DOI: 10.5858/arpa.2016-0331-cp] [Citation(s) in RCA: 121] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
CONTEXT - ERBB2 (erb-b2 receptor tyrosine kinase 2 or HER2) is currently the only biomarker established for selection of a specific therapy for patients with advanced gastroesophageal adenocarcinoma (GEA). However, there are no comprehensive guidelines for the assessment of HER2 in patients with GEA. OBJECTIVES - To establish an evidence-based guideline for HER2 testing in patients with GEA, to formalize the algorithms for methods to improve the accuracy of HER2 testing while addressing which patients and tumor specimens are appropriate, and to provide guidance on clinical decision making. DESIGN - The College of American Pathologists, American Society for Clinical Pathology, and American Society of Clinical Oncology convened an expert panel to conduct a systematic review of the literature to develop an evidence-based guideline with recommendations for optimal HER2 testing in patients with GEA. RESULTS - The panel is proposing 11 recommendations with strong agreement from the open-comment participants. RECOMMENDATIONS - The panel recommends that tumor specimen(s) from all patients with advanced GEA, who are candidates for HER2-targeted therapy, should be assessed for HER2 status before the initiation of HER2-targeted therapy. Clinicians should offer combination chemotherapy and a HER2-targeted agent as initial therapy for all patients with HER2-positive advanced GEA. For pathologists, guidance is provided for morphologic selection of neoplastic tissue, testing algorithms, scoring methods, interpretation and reporting of results, and laboratory quality assurance. CONCLUSIONS - This guideline provides specific recommendations for assessment of HER2 in patients with advanced GEA while addressing pertinent technical issues and clinical implications of the results.
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Affiliation(s)
- Angela N Bartley
- From the Department of Pathology, St. Joseph Mercy Hospital, Ann Arbor, Michigan (Dr Bartley); the Department of Pathology, Vanderbilt University Medical Center, Nashville, Tennessee (Dr Washington); Surveys (Ms Ventura) and Governance (Ms Colasacco), College of American Pathologists, Northfield, Illinois; Quality and Guidelines Department, American Society of Clinical Oncology, Alexandria, Virginia (Dr Ismaila); the Division of Hematology/Oncology, Northwestern University, Chicago, Illinois (Dr Benson); Medical Oncology Department, Ramon y Cajal University Hospital, Madrid, Spain (Dr Carrato); the Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill (Dr Gulley); the Department of Pathology, Yale University School of Medicine, New Haven, Connecticut (Dr Jain); the Department of Pathology and Laboratory Medicine, UCSF, San Francisco, California (Dr Kakar); the Division of Medical Oncology and Hematology, University of Toronto/Sunnybrook Odette Cancer Centre, Toronto, Ontario, Canada (Dr Mackay); the Department of Laboratory Medicine, St. Michael's Hospital, Toronto, Ontario, Canada (Dr Streutker); the Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York (Dr Tang); the Department of Pathology, Stanford University Medical Center, Stanford, California (Dr Troxell); and the Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston (Dr Ajani)
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Bartley AN, Washington MK, Ventura CB, Ismaila N, Colasacco C, Benson AB, Carrato A, Gulley ML, Jain D, Kakar S, Mackay HJ, Streutker C, Tang L, Troxell M, Ajani JA. HER2 Testing and Clinical Decision Making in Gastroesophageal Adenocarcinoma: Guideline From the College of American Pathologists, American Society for Clinical Pathology, and American Society of Clinical Oncology. Am J Clin Pathol 2016; 146:647-669. [PMID: 28077399 PMCID: PMC6272805 DOI: 10.1093/ajcp/aqw206] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
CONTEXT ERBB2 (erb-b2 receptor tyrosine kinase 2 or HER2) is currently the only biomarker established for selection of a specific therapy for patients with advanced gastroesophageal adenocarcinoma (GEA). However, there are no comprehensive guidelines for the assessment of HER2 in patients with GEA. OBJECTIVES To establish an evidence-based guideline for HER2 testing in patients with GEA, to formalize the algorithms for methods to improve the accuracy of HER2 testing while addressing which patients and tumor specimens are appropriate, and to provide guidance on clinical decision making. DESIGN The College of American Pathologists, American Society for Clinical Pathology, and American Society of Clinical Oncology convened an expert panel to conduct a systematic review of the literature to develop an evidence-based guideline with recommendations for optimal HER2 testing in patients with GEA. RESULTS The panel is proposing 11 recommendations with strong agreement from the open-comment participants. RECOMMENDATIONS The panel recommends that tumor specimen(s) from all patients with advanced GEA, who are candidates for HER2-targeted therapy, should be assessed for HER2 status before the initiation of HER2-targeted therapy. Clinicians should offer combination chemotherapy and a HER2-targeted agent as initial therapy for all patients with HER2-positive advanced GEA. For pathologists, guidance is provided for morphologic selection of neoplastic tissue, testing algorithms, scoring methods, interpretation and reporting of results, and laboratory quality assurance. CONCLUSIONS This guideline provides specific recommendations for assessment of HER2 in patients with advanced GEA while addressing pertinent technical issues and clinical implications of the results.
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Affiliation(s)
- Angela N Bartley
- From the Department of Pathology, St Joseph Mercy Hospital, Ann Arbor, MI
| | - Mary Kay Washington
- Department of Pathology, Vanderbilt University Medical Center, Nashville, TN
| | | | - Nofisat Ismaila
- Quality and Guidelines Department, American Society of Clinical Oncology, Alexandria, VA
| | - Carol Colasacco
- Surveys and Governance, College of American Pathologists, Northfield, IL
| | - Al B Benson
- Division of Hematology/Oncology, Northwestern University, Chicago, IL
| | - Alfredo Carrato
- Medical Oncology Department, Ramon y Cajal University Hospital, Madrid, Spain
| | - Margaret L Gulley
- Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill
| | - Dhanpat Jain
- Department of Pathology, Yale University School of Medicine, New Haven, CT
| | - Sanjay Kakar
- Department of Pathology and Laboratory Medicine, UCSF, San Francisco, CA
| | - Helen J Mackay
- Division of Medical Oncology and Hematology, University of Toronto/Sunnybrook Odette Cancer Centre, Toronto, Canada
| | | | - Laura Tang
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Megan Troxell
- Department of Pathology, Stanford University Medical Center, Stanford, CA
| | - Jaffer A Ajani
- Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston
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Hadi AA, Hindawi AE, Hareedy A, Khalil H, Ashiry RA, Elia S, Sadek A, Magdy M, Atta R, Anas A, Bakr H, Hammam O. Her2/neu Protein Expression and Oncogene Amplification in Gastric Carcinoma with Clinico-Pathological Correlation in Egyptian Patients. Open Access Maced J Med Sci 2016; 4:535-542. [PMID: 28028387 PMCID: PMC5175495 DOI: 10.3889/oamjms.2016.104] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2016] [Revised: 09/04/2016] [Accepted: 09/05/2016] [Indexed: 12/28/2022] Open
Abstract
AIM Amplification of the Her2/neu gene and overexpression of the Her2/neu protein in gastric carcinoma (GC) is a golden criterion for target therapy with trastuzumab (Herceptin). We aim to evaluate the immunohistochemical protein expression and amplification of the oncogene Her2/neu by FISH technique in the epithelial gastric carcinoma and to compare their association with different clinicopathologic parameters aiming at identifying positive cases that may benefit from targeted therapy. MATERIALS AND METHODS This study was done on eighty-five tumour tissue samples from patients with GC as well as thirty non-malignant lesions (Gastritis, intestinal metaplasia, adenoma with low-grade dysplasia, adenoma with high-grade dysplasia). All were immunohistochemically stained with Her2/neu antibody. RESULTS All equivocal and some selected GC cases were submitted for FISH technique to detect Her2/neu gene amplification. By immunohistochemistry twenty-three cases (27%) were defined as positive for Her2/neu gene amplification and/or protein overexpression. The levels of Her2/neu positive (3+), Her2/neu equivocal (2+) and Her2/neu negative (1+/0) were measurable in 14.2%, 32.9% and 52.9% of the samples, respectively. FISH showed that Her2/neu gene was amplified in 22 cases, 10 Her2/neu positive (3+), 11 (39.3%) Her2/neu equivocal (2+) and 1 Her2/neu negative (1+) cases with IHC staining those who can benefit from anti Her2/neu target therapy. Her2/neu was overexpressed positivity (3+) more in intestinal type and mixed carcinoma, and moderately differentiated tumours. None of gastritis, intestinal metaplasia or adenoma with low-grade dysplasia cases showed positivity for Her2/neu (3+). The Her2/neu positivity (3+) was associated with both adenocarcinoma cases and high-grade dysplasia (P = 0.002). CONCLUSIONS The results highlight the necessity of FISH test for further categorization when gastric cancer cases are equivocal (2+) by IHC to determine eligibility for the targeted therapy. Stepwise increase in the expression of Her2/neu was seen in low-grade dysplasia, high-grade dysplasia and carcinoma cases implying its role in cancer evolution. Overexpression of Her 2/neu in GC patients can be promising in selecting those who can get benefit from anti-Her2/neu target therapy.
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Affiliation(s)
| | | | - Amal Hareedy
- Faculty of Medicine Cairo University, Cairo, Egypt
| | - Heba Khalil
- Theodor Bilharz Research Institute, Imbaba, Giza, Cairo, Egypt
| | - Ranya Al Ashiry
- Theodor Bilharz Research Institute, Imbaba, Giza, Cairo, Egypt
| | - Shady Elia
- Faculty of Medicine Cairo University, Cairo, Egypt
| | - Ahmed Sadek
- Theodor Bilharz Research Institute, Imbaba, Giza, Cairo, Egypt
| | - Mona Magdy
- Theodor Bilharz Research Institute, Imbaba, Giza, Cairo, Egypt
| | - Rafatt Atta
- Theodor Bilharz Research Institute, Imbaba, Giza, Cairo, Egypt
| | - Amgad Anas
- Theodor Bilharz Research Institute, Imbaba, Giza, Cairo, Egypt
| | - Hisham Bakr
- General Surgery & Surgical Oncology, Ain Shams University, Cairo, Egypt
| | - Olfat Hammam
- Theodor Bilharz Research Institute, Imbaba, Giza, Cairo, Egypt
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Baniak N, Senger JL, Ahmed S, Kanthan SC, Kanthan R. Gastric biomarkers: a global review. World J Surg Oncol 2016; 14:212. [PMID: 27514667 PMCID: PMC4982433 DOI: 10.1186/s12957-016-0969-3] [Citation(s) in RCA: 74] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2016] [Accepted: 08/02/2016] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Gastric cancer is an aggressive disease with a poor 5-year survival and large global burden of disease. The disease is biologically and genetically heterogeneous with a poorly understood carcinogenesis at the molecular level. Despite the many prognostic, predictive, and therapeutic biomarkers investigated to date, gastric cancer continues to be detected at an advanced stage with resultant poor clinical outcomes. MAIN BODY This is a global review of gastric biomarkers with an emphasis on HER2, E-cadherin, fibroblast growth factor receptor, mammalian target of rapamycin, and hepatocyte growth factor receptor as well as sections on microRNAs, long noncoding RNAs, matrix metalloproteinases, PD-L1, TP53, and microsatellite instability. CONCLUSION A deeper understanding of the pathogenesis and biological features of gastric cancer, including the identification and characterization of diagnostic, prognostic, predictive, and therapeutic biomarkers, hopefully will provide improved clinical outcomes.
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Affiliation(s)
- Nick Baniak
- Department of Pathology and Laboratory Medicine, University of Saskatchewan, 103 Hospital Drive, Saskatoon, SK S7N 0W8 Canada
| | - Jenna-Lynn Senger
- Department of Surgery, University of Alberta, 116 St & 85 Ave, Edmonton, T6G 2R3, T6G 2B7 AB Canada
| | - Shahid Ahmed
- Division of Medical Oncology, University of Saskatchewan, 103 Hospital Drive, Saskatoon, SK S7N 0W8 Canada
| | - S. C. Kanthan
- Department of General Surgery, University of Saskatchewan, 103 Hospital Drive, Saskatoon, SK S7N 0W8 Canada
| | - Rani Kanthan
- Department of General Surgery, University of Saskatchewan, 103 Hospital Drive, Saskatoon, SK S7N 0W8 Canada
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Gonzalez RS, Messing S, Tu X, McMahon LA, Whitney-Miller CL. Immunohistochemistry as a surrogate for molecular subtyping of gastric adenocarcinoma. Hum Pathol 2016; 56:16-21. [PMID: 27342907 DOI: 10.1016/j.humpath.2016.06.003] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2016] [Revised: 05/26/2016] [Accepted: 06/11/2016] [Indexed: 12/16/2022]
Abstract
The Cancer Genome Atlas Research Network recently classified gastric adenocarcinoma into 4 molecular subtypes: Epstein-Barr virus-positive tumors, microsatellite-unstable tumors, tumors with chromosomal instability, and genomically stable tumors. We theorized that immunohistochemistry might be useful in similar categorization and that that HER2 expression might relate to subtype. We stained 104 gastric adenocarcinomas for MLH1, p53, and EBER in situ hybridization. We grouped them based on staining pattern and compared the groups. Cases were categorized as follows: group 1 (EBER positive), 7 cases (7%); group 2 (MLH1 deficient), 17 cases (16%); group 3 (aberrant p53 staining, EBER negative, retained MLH1), 40 cases (38%); group 4 (unremarkable staining), 40 cases (38%). This distribution was comparable to that found by the Research Network after accounting for the TP53 mutation rate in the chromosomal instability group. Group 1 patients had significantly longer follow-up times (median, 70 months versus 13 months for other groups; P = .0324). No group 2 cases overexpressed HER2. In group 3, 3 of 40 cases were HER2 immunohistochemistry positive, but 7 of 27 were HER2 positive by fluorescence in situ hybridization. Staining offers an efficient, reasonably accurate alternative for molecular subtyping of gastric adenocarcinoma, although some cases with chromosomal instability cannot be identified. These findings have potential prognostic and therapeutic implications.
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Affiliation(s)
- Raul S Gonzalez
- Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY 14642.
| | - Susan Messing
- Department of Biostatistics and Computational Biology, University of Rochester Medical Center, Rochester, NY 14642
| | - Xin Tu
- Department of Biostatistics and Computational Biology, University of Rochester Medical Center, Rochester, NY 14642
| | - Loralee A McMahon
- Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY 14642
| | - Christa L Whitney-Miller
- Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY 14642
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Shen GS, Zhao JD, Zhao JH, Ma XF, Du F, Kan J, Ji FX, Ma F, Zheng FC, Wang ZY, Xu BH. Association of HER2 status with prognosis in gastric cancer patients undergoing R0 resection: A large-scale multicenter study in China. World J Gastroenterol 2016; 22:5406-5414. [PMID: 27340357 PMCID: PMC4910661 DOI: 10.3748/wjg.v22.i23.5406] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2016] [Revised: 05/11/2016] [Accepted: 05/23/2016] [Indexed: 02/06/2023] Open
Abstract
AIM: To determine whether the positive status of human epidermal growth receptor 2 (HER2) can be regarded as an effective prognostic factor for patients with gastric cancer (GC) undergoing R0 resection.
METHODS: A total of 1562 GC patients treated by R0 resection were recruited. HER2 status was evaluated in surgically resected samples of all the patients using immunohistochemical (IHC) staining. Correlations between HER2 status and clinicopathological characteristics were retrospective analyzed. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazard model, stratified by age, gender, tumor location and tumor-node-metastasis (TNM) stage, with additional adjustment for potential prognostic factors.
RESULTS: Among 1562 patients, 548 (positive rate = 35.08%, 95%CI: 32.72%-37.45%) were HER2 positive. Positive status of HER2 was significantly correlated with gender (P = 0.004), minority (P < 0.001), tumor location (P = 0.001), pathological grade (P < 0.001), TNM stage (P < 0.001) and adjuvant radiotherapy (74.67% vs 23.53%, P = 0.011). No significant associations were observed between HER2 status and disease free survival (HR = 0.19, 95%CI: 0.96-1.46, P = 0.105) or overall survival (HR = 1.19, 95%CI: 0.96-1.48, P = 0.118) using multivariate analysis, although stratified analyses showed marginally statistically significant associations both in disease free survival and overall survival, especially among patients aged < 60 years or with early TNM stages (I and II). Categorical age, TNM stage, neural invasion, and adjuvant chemotherapy were, as expected, independent prognostic factors for both disease free survival and overall survival.
CONCLUSION: The positive status of HER2 based on IHC staining was not related to the survival in patients with GC among the Chinese population.
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Chen XZ, Zhang WH, Chen HN, Liu JP, He D, Liu Y, Liu K, Chen XL, Mo XM, Zhou ZG, Hu JK. Associations between serum CA724 and HER2 overexpression among stage II-III resectable gastric cancer patients: an observational study. Oncotarget 2016; 7:23647-23657. [PMID: 27027339 PMCID: PMC5029653 DOI: 10.18632/oncotarget.8145] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2015] [Accepted: 02/28/2016] [Indexed: 02/05/2023] Open
Abstract
OBJECTIVES Associations between serum tumor biomarkers and human epidermal growth factor receptor 2 (HER2) overexpression among locally advanced gastric cancer patients were yet to be determined and therefore warranted investigation. RESULTS A total of 318 patients were analyzed. The odds ratios of CA724 were 4.79 (95% CI 1.55-14.79) and 6.29 (1.40-28.19) in comparing the HER2 (2+/3+) and HER2 (3+) with the negative group, respectively (p < 0.05). A combination of the four biomarkers yielded slightly but not significantly greater areas under the curve (AUC = 0.83; 0.71-0.94) than that of serum CA724 alone (0.80; 0.68-0.91); however, an index generated from the combination had better diagnostic performance with 85.7% sensitivity, 80.4% specificity and 97.8% negative predictive value to predict the strong overexpression of HER2 (3+). CA199, CEA or CA125 alone was not associated with HER2 overexpression. Leave-one-out cross-validation found a consistent association between serum CA724 and HER2 (2+/3+) overexpression. METHODS Patients undergoing radical gastrectomy from 8/2012 to 12/2013 and with pathological stage II-III gastric cancer were retrospectively analyzed. HER2 expression of the surgical samples was estimated using immunohistochemistry; serum CA724, CA199, CEA and CA125 were preoperatively tested. Internal validation was performed using the leave-one-out approach. CONCLUSIONS Serum CA724 is significantly associated with the overexpression of HER2 among locally advanced gastric cancer patients. The combination of CA724, CA199, CEA and CA125 is better than serum CA724 alone in predicting HER2 overexpression. External validation and further investigation of the biological mechanisms of these associations are required.
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Affiliation(s)
- Xin-Zu Chen
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, China
- Laboratory of Gastric Cancer, State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Wei-Han Zhang
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, China
- Laboratory of Gastric Cancer, State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Hai-Ning Chen
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Jian-Ping Liu
- Department of Pathology, West China Hospital, Sichuan University, Chengdu, China
| | - Du He
- Department of Pathology, West China Hospital, Sichuan University, Chengdu, China
| | - Yang Liu
- West China School of Public Health, Sichuan University, Chengdu, China
| | - Kai Liu
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, China
- Laboratory of Gastric Cancer, State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Xiao-Long Chen
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, China
- Laboratory of Gastric Cancer, State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Xian-Ming Mo
- Laboratory of Stem Cell Biology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Zong-Guang Zhou
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Jian-Kun Hu
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, China
- Laboratory of Gastric Cancer, State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
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Concordance rate between HER2 immunohistochemistry and in situ hybridization in gastric carcinoma: systematic review and meta-analysis. Int J Biol Markers 2016; 31:e1-10. [PMID: 26349670 DOI: 10.5301/jbm.5000171] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/24/2015] [Indexed: 12/17/2022]
Abstract
PURPOSE The aim of this study was to investigate the diagnostic accuracy of HER2 immunohistochemistry (IHC) in gastric carcinoma (GC) through a systematic review, meta-analysis and diagnostic test accuracy review. METHOD The current study included 12,679 GC cases and 181 subsets in 45 eligible studies. We performed concordance analysis between HER2 IHC and in situ hybridization (ISH) in GC. Diagnostic test accuracy was analyzed and the area under the curve (AUC) on the summary receiver operating characteristic (SROC) curve was calculated. RESULTS HER2 amplification rates were 3.0%, 31.8%, and 93.0% in the IHC score 0/1+, 2+, and 3+ groups, respectively. The concordance rates between IHC and ISH were 0.969 (95% confidence interval [CI] 0.962-0.975), 0.393 (95% CI 0.331-0.458) and 0.915 (95% CI 0.882-0.939) in the HER2 IHC score 0/1+, 2+, and 3+ groups, respectively. For all the HER2 IHC score groups, the positive rates were higher in the silver ISH (SISH) subgroup than in the fluorescence ISH (FISH) and chromogenic ISH (CISH) subgroups. In diagnostic test accuracy review, the pooled sensitivity and specificity were 0.86 (95% CI 0.84-0.87) and 0.91 (95% CI 0.90-0.91). The AUC on SROC curve was 0.958. However, there was no significant difference in the values of AUC between the ISH methods. CONCLUSIONS Our results showed that HER2 IHC was well concordant with ISH in HER2 IHC score 0/1+ or 3+. Although this meta-analysis showed higher diagnostic accuracy of HER2 IHC, more detailed criteria for HER2 IHC score 2+ cases will be required to predict HER2 status.
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Laboissiere RS, Buzelin MA, Balabram D, De Brot M, Nunes CB, Rocha RM, Cabral MMDÁ, Gobbi H. Association between HER2 status in gastric cancer and clinicopathological features: a retrospective study using whole-tissue sections. BMC Gastroenterol 2015; 15:157. [PMID: 26530403 PMCID: PMC4632681 DOI: 10.1186/s12876-015-0384-1] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2015] [Accepted: 10/21/2015] [Indexed: 01/16/2023] Open
Abstract
BACKGROUND Gastric cancer is usually diagnosed in an advanced stage of disease and treatment options are sparse. Trastuzumab was recently approved for metastatic or locally advanced carcinomas arising in the stomach or in the gastroesophageal junction in patients with HER2-positive tumors. However, data on the frequency of HER2-positive cases among Brazilian patients are limited. Our aim was to characterize HER2 protein and gene status in a series of Brazilian patients with gastric cancer and to evaluate its association with clinicopathological data. METHODS Histological slides from 124 primary gastrectomies were reviewed and their pathological reports were retrieved from the files at a Brazilian university hospital. Automated immunohistochemistry for HER2 was performed on whole-tissue sections from each tumor. HER2-equivocal cases by immunohistochemistry were submitted to automated dual in situ hybridization for gene amplification evaluation. HER2 status was confronted with clinicopathological parameters in order to assess statistically significant associations. RESULTS Immunohistochemistry analysis revealed that 13/124 cases (10.5 %) were HER2 positive (3+), 10/124 cases (8.1 %) were equivocal (2+) and 101/124 cases (81.4 %) were negative, being 7 cases 1+. None of the equivocal cases showed gene amplification. The overall HER2 positivity rate was 10.5 %. There was an association between HER2 expression and Laurén's intestinal histological subtype (P = 0.048), well to moderately differentiated tumors (P = 0.004) and presence of lymphovascular invasion (P = 0.031). No association was found between HER2 status and tumor topography. CONCLUSIONS Confronted with data published by other authors, the lower percentage of HER2-positive cases found in our series might be partially explained by the lower frequency of tumors arising at the gastroesophageal junction in comparison with distal gastric carcinomas in Brazilian patients. This could also account for the lack of statistically significant association between HER2 status and tumor topography in our study.
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Affiliation(s)
- Renato Santos Laboissiere
- Departamento de Medicina DEMED-UFSJ, Campus Dom Bosco. Praça Dom Helvécio, 74. Fábricas, São João del-Rei, MG, 36301-160, Brazil.
| | - Marcelo Araújo Buzelin
- Departamento de Anatomia Patológica FM-UFMG, Avenida Prof. Alfredo Balena, 190 - 3o. andar, Belo Horizonte, MG, 30130-100, Brazil.
| | - Débora Balabram
- Departamento de Anatomia Patológica FM-UFMG, Avenida Prof. Alfredo Balena, 190 - 3o. andar, Belo Horizonte, MG, 30130-100, Brazil.
| | - Marina De Brot
- Departamento de Anatomia Patológica FM-UFMG, Avenida Prof. Alfredo Balena, 190 - 3o. andar, Belo Horizonte, MG, 30130-100, Brazil.
| | - Cristiana Buzelin Nunes
- Departamento de Anatomia Patológica FM-UFMG, Avenida Prof. Alfredo Balena, 190 - 3o. andar, Belo Horizonte, MG, 30130-100, Brazil.
| | - Rafael Malagoli Rocha
- Departamento de Anatomia Patológica FM-UFMG, Avenida Prof. Alfredo Balena, 190 - 3o. andar, Belo Horizonte, MG, 30130-100, Brazil.
| | | | - Helenice Gobbi
- Departamento de Anatomia Patológica FM-UFMG, Avenida Prof. Alfredo Balena, 190 - 3o. andar, Belo Horizonte, MG, 30130-100, Brazil.
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Aydin D, Bilici A, Kayahan S, Yavuzer D, Basar M, Aliustaoglu M. Prognostic importance of RASSF2 expression in patients with gastric cancer who had undergone radical gastrectomy. Clin Transl Oncol 2015; 18:608-16. [PMID: 26459248 DOI: 10.1007/s12094-015-1405-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2015] [Accepted: 09/03/2015] [Indexed: 12/12/2022]
Abstract
BACKGROUND Although Ras-association domain family of gene 2 (RASSF2) has been shown to undergo promoter methylation at high frequency in some cancer types and in brain metastases, its clinical utility as a useful prognostic molecular marker remains unclear in gastric cancer. METHODS Prognostic significance of RASSF2 expression was retrospectively analysed by immunohistochemically in 105 patients with gastric cancer who underwent curative gastrectomy. RESULTS Low RASSF2 expression was detected in 58 (55 %) patients, whereas 47 patients (45 %) had high RASSF2 expression. Lymph node involvement, pT stage, TNM stage, vascular invasion, perineural invasion and the presence of recurrence were found to be significantly related to RASSF2 expression levels. Low PRL-3 expression was closely correlated with lymph node metastasis (p = 0.001), advanced pT stage (p = 0.021), advanced TNM stage (p < 0.001), the presence of vascular invasion (p < 0.001), perineural invasion (p = 0.018) and high prevalence of recurrence (p = 0.003) compared with high RASSF2 expression. The median disease-free survival (DFS) time for patients with low RASSF2 expression was significantly worse than that of patients with high RASSF2 expression (10.2 vs. 50.6 months, p < 0.001). In addition, patients with high RASSF2 expression had the higher overall survival (OS) interval compared to patients with low RASSF2 expression (NR vs. 14.9 months, p < 0.001). In the multivariate analysis, the rate of RASSF2 expression levels was an independent prognostic factor, for DFS [p < 0.001, HR 0.12 (0.10-0.88)] and OS [p < 0.001, HR 0.10 (0.04-0.46)], as were pT stage and TNM stage, respectively. CONCLUSIONS RASSF2 may be an important molecular marker for carcinogenesis, prognosis and progression in gastric cancer, but the potential value of RASSF2 expression as a useful molecular marker in gastric cancer progression should be evaluated, comprehensively. It would be possible to develop treatments targeting RASSF2 and advance new treatment strategies for gastric cancer.
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Affiliation(s)
- D Aydin
- Department of Medical Oncology, Dr. Lutfi Kırdar Kartal Education and Research Hospital, Istanbul, Turkey
| | - A Bilici
- Department of Medical Oncology, Medical Faculty, Istanbul Medipol University, TEM Avrupa Otoyolu, Goztepe Cikisi, No:1, Bağcılar, 34214, Istanbul, Turkey.
| | - S Kayahan
- Department of Pathology, Dr. Lutfi Kirdar Kartal Education and Research Hospital, Istanbul, Turkey
| | - D Yavuzer
- Department of Pathology, Dr. Lutfi Kirdar Kartal Education and Research Hospital, Istanbul, Turkey
| | - M Basar
- Department of Pathology, Dr. Lutfi Kirdar Kartal Education and Research Hospital, Istanbul, Turkey
| | - M Aliustaoglu
- Department of Medical Oncology, Dr. Lutfi Kırdar Kartal Education and Research Hospital, Istanbul, Turkey
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Saito T, Nakanishi H, Mochizuki Y, Ito S, Ito Y, Misawa K, Yatabe Y, Yamamichi K, Kondo E. Preferential HER2 expression in liver metastases and EGFR expression in peritoneal metastases in patients with advanced gastric cancer. Gastric Cancer 2015; 18:711-9. [PMID: 25173363 DOI: 10.1007/s10120-014-0417-4] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2014] [Accepted: 07/28/2014] [Indexed: 02/07/2023]
Abstract
BACKGROUND Despite recent clinical trials, the sensitivity and resistance of metastatic gastric cancer to anti-HER2 and anti-EGFR therapy are still unclear. MATERIALS AND METHODS To clarify the HER2 and EGFR expression status in the metastatic sites, we immunohistochemically compared HER2 and EGFR expression between primary and metastatic tumors from 52 gastric cancer patients with liver metastases and 85 patients with peritoneal metastases. RESULTS The HER2 positivity rate of primary and metastatic tumors in patients with liver metastases, especially with intestinal-type histology (70.6 and 80.0 %, respectively), was significantly higher than in primary and metastatic tumors (22.4 and 16.4 %, respectively) in patients with peritoneal metastases. HER2 positivity of the primary tumor and liver metastases showed good concordance (87.5 %) in patients with liver metastases. In contrast, the EGFR positivity rate of metastatic tumors (70.1 %) in patients with peritoneal metastases was significantly higher than that of metastatic tumors (37.5 %) in patients with liver metastases. HER2 and EGFR expression tended to be mutually exclusive, and HER2/EGFR double-positive cases were rare in patients with liver or peritoneal metastases. In four such patients with HER2/EGFR double-positive primary tumors, the HER2- and EGFR-positive areas were separate, and corresponding liver metastasis was only positive for HER2 and peritoneal metastasis only positive for EGFR. CONCLUSION These results indicate that HER2 and EGFR are preferentially expressed in the liver and peritoneal metastases, respectively, which would be potential targets for anti-HER2 and anti-EGFR molecular therapy in metastatic gastric cancer patients.
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Affiliation(s)
- Takuya Saito
- Program in Health and Community Medicine, Department of Epidemiology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Hayao Nakanishi
- Division of Oncological Pathology, Aichi Cancer Center Research Institute, 1-1 Kanokoden, Chikusa-ku, Nagoya, 464-8681, Japan.
| | | | - Seiji Ito
- Department of Gastroenterological Surgery, Aichi Cancer Center Central Hospital, Nagoya, Japan
| | - Yuichi Ito
- Department of Gastroenterological Surgery, Aichi Cancer Center Central Hospital, Nagoya, Japan
| | - Kazunari Misawa
- Department of Gastroenterological Surgery, Aichi Cancer Center Central Hospital, Nagoya, Japan
| | - Yasushi Yatabe
- Department of Pathology and Molecular Diagnostics, Aichi Cancer Center Central Hospital, Nagoya, Japan
| | - Keigo Yamamichi
- Department of Surgery, Osaka Saiseikai Izuo Hospital, Osaka, Japan
| | - Eisaku Kondo
- Program in Health and Community Medicine, Department of Epidemiology, Nagoya University Graduate School of Medicine, Nagoya, Japan
- Division of Oncological Pathology, Aichi Cancer Center Research Institute, 1-1 Kanokoden, Chikusa-ku, Nagoya, 464-8681, Japan
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