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Singh H, Kang A, Bloudek L, Hsu LI, Corinna Palanca-Wessels M, Stecher M, Siadak M, Ng K. Systematic literature review and meta-analysis of HER2 amplification, overexpression, and positivity in colorectal cancer. JNCI Cancer Spectr 2024; 8:pkad082. [PMID: 37815820 PMCID: PMC10868379 DOI: 10.1093/jncics/pkad082] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2023] [Revised: 08/25/2023] [Accepted: 09/21/2023] [Indexed: 10/11/2023] Open
Abstract
BACKGROUND Colorectal cancer (CRC) is the second most common cause of cancer death globally. Recent clinical trials suggest an emerging role for HER2 as a potential clinically relevant biomarker in CRC. Testing for HER2 in CRC is not standard practice; consequently, the prevalence of HER2 positivity (HER2+) in patients with CRC remains uncertain. METHODS A systematic literature review and meta-analysis were conducted to generate estimates of proportions of patients with CRC with HER2 overexpression or HER2 amplification and HER2+ (either overexpression or amplification), overall and in patients with rat sarcoma virus (RAS) wild-type cancer. HER2+ was defined as 1) immunohistochemistry with a score of 3+, 2) immunohistochemistry with a score of 2+ and in situ hybridization+, or 3) next-generation sequencing positive. RESULTS Of 224 studies identified with information on HER2 in CRC, 52 studies used a US Food and Drug Administration-approved assay and were selected for further analysis. Estimated HER2+ rate was 4.1% (95% confidence interval [CI] = 3.4% to 5.0%) overall (n = 17 589). HER2+ rates were statistically higher in RAS wild-type (6.1%, 95% CI = 5.4% to 6.9%) vs RAS mutant CRC (1.1%, 95% CI = 0.3% to 4.4%; P < .0001). Despite limited clinical information, we confirmed enrichment of HER2+ CRC in patients with microsatellite stable and left-sided CRC. CONCLUSION This meta-analysis provides an estimate of HER2+ CRC and confirms enrichment of HER2 in microsatellite stable, left-sided, RAS wild-type CRC tumors. Our work is important given the recently described clinical efficacy of HER2-targeted therapies in HER2+ CRC and informs strategies for incorporation of HER2 testing into standard of care.
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Affiliation(s)
- Harshabad Singh
- Division of Gastrointestinal Cancers, Dana-Farber Cancer Institute, Boston, MA, USA
| | | | | | | | | | | | | | - Kimmie Ng
- Division of Gastrointestinal Cancers, Dana-Farber Cancer Institute, Boston, MA, USA
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Cao Y, Efetov SK, He M, Fu Y, Beeraka NM, Zhang J, Zhang X, Bannimath N, Chen K. Updated Clinical Perspectives and Challenges of Chimeric Antigen Receptor-T Cell Therapy in Colorectal Cancer and Invasive Breast Cancer. Arch Immunol Ther Exp (Warsz) 2023; 71:19. [DOI: https:/doi.org/10.1007/s00005-023-00684-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2023] [Accepted: 06/28/2023] [Indexed: 09/20/2024]
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Cao Y, Efetov SK, He M, Fu Y, Beeraka NM, Zhang J, Zhang X, Bannimath N, Chen K. Updated Clinical Perspectives and Challenges of Chimeric Antigen Receptor-T Cell Therapy in Colorectal Cancer and Invasive Breast Cancer. Arch Immunol Ther Exp (Warsz) 2023; 71:19. [PMID: 37566162 DOI: 10.1007/s00005-023-00684-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2023] [Accepted: 06/28/2023] [Indexed: 08/12/2023]
Abstract
In recent years, the incidence of colorectal cancer (CRC) and breast cancer (BC) has increased worldwide and caused a higher mortality rate due to the lack of selective anti-tumor therapies. Current chemotherapies and surgical interventions are significantly preferred modalities to treat CRC or BC in advanced stages but the prognosis for patients with advanced CRC and BC remains dismal. The immunotherapy technique of chimeric antigen receptor (CAR)-T cells has resulted in significant clinical outcomes when treating hematologic malignancies. The novel CAR-T therapy target antigens include GUCY2C, CLEC14A, CD26, TEM8/ANTXR1, PDPN, PTK7, PODXL, CD44, CD19, CD20, CD22, BCMA, GD2, Mesothelin, TAG-72, CEA, EGFR, B7H3, HER2, IL13Ra2, MUC1, EpCAM, PSMA, PSCA, NKG2D. The significant aim of this review is to explore the recently updated information pertinent to several novel targets of CAR-T for CRC, and BC. We vividly described the challenges of CAR-T therapies when treating CRC or BC. The immunosuppressive microenvironment of solid tumors, the shortage of tumor-specific antigens, and post-treatment side effects are the major hindrances to promoting the development of CAR-T cells. Several clinical trials related to CAR-T immunotherapy against CRC or BC have already been in progress. This review benefits academicians, clinicians, and clinical oncologists to explore more about the novel CAR-T targets and overcome the challenges during this therapy.
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Affiliation(s)
- Yu Cao
- I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), Moscow, 119991, Russia
| | - Sergey K Efetov
- I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), Moscow, 119991, Russia
| | - Mingze He
- I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), Moscow, 119991, Russia
| | - Yu Fu
- I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), Moscow, 119991, Russia
| | - Narasimha M Beeraka
- I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), Moscow, 119991, Russia
- Raghavendra Institute of Pharmaceutical Education and Research (RIPER), Chiyyedu, Anantapuramu, Andhra Pradesh, 515721, India
| | - Jin Zhang
- I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), Moscow, 119991, Russia
| | - Xinliang Zhang
- I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), Moscow, 119991, Russia
| | - Namitha Bannimath
- Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education and Research (JSS AHER), Mysuru, Karnataka, India
| | - Kuo Chen
- Department of Breast Surgery, The First Affiliated Hospital of Zhengzhou University, #1 Jianshedong Str., Zhengzhou, 450052, People's Republic of China.
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Wu Z, Cheng Y, Wang H, Liu D, Qi X, Wang C, Zhang Y, Zhang Y, Cai R, Huo H, Zhang J, Cai Y, Li W, Hu H, Deng Y. Distinct Clinicopathological Features and Prognostic Values of High-, Low-, or Non-Expressing HER2 Status in Colorectal Cancer. Cancers (Basel) 2023; 15:cancers15020554. [PMID: 36672503 PMCID: PMC9856362 DOI: 10.3390/cancers15020554] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Revised: 01/05/2023] [Accepted: 01/12/2023] [Indexed: 01/18/2023] Open
Abstract
The encouraging effects of HER2-ADC in patients with HER2-low expression cancers indicated the classical classifications based on positive and negative HER2 might no longer be suitable. However, the biology and prognosis of colorectal cancer patients with different HER2 expression status were still not clear. This is a multi-center retrospective study that included patients with histologically confirmed colorectal cancer and determined HER2 status who received radical surgical resection. HER2 immunohistochemistry (IHC) 1+ and IHC 2+ groups were combined and defined as a HER2-low group because of the concordance of clinicopathological characteristics. As compared with the HER2-high group, both the HER2-zero and the HER2-low group had less tumor with perineural invasion (14.3%, 13.1% vs. 31.6%, p = 0.001 and p < 0.001), less stage III disease (41.8%, 39.9% vs. 56.1%, p = 0.044 and p = 0.022), more RAS/BRAF mutation (52.1%, 49.9% vs. 19.5%, p < 0.001 and p < 0.001) and better disease-free survival (DFS) (3y-DFS rate of 78.7%, 82.4% vs. 59.3%, p < 0.001 and p < 0.001). Multivariate analysis and propensity score matching also revealed that HER2-high expression was an independent prognostic factor of DFS. In conclusion, our study revealed that HER2-low colorectal cancer tumors are close to HER2-zero tumors, but different from HER2-high tumors. The routine examination of HER2 IHC is needed in early-stage colorectal cancer.
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Affiliation(s)
- Zehua Wu
- Department of Medical Oncology, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510655, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510655, China
| | - Yi Cheng
- Department of Medical Oncology, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510655, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510655, China
| | - Huaiming Wang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou 515000, China
| | - Dian Liu
- Department of Lymphoma and Abdominal Radiotherapy, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, China
| | - Xiaoxing Qi
- Department of Medical Oncology, The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang 453002, China
| | - Chao Wang
- Department of Pathology, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510655, China
| | - Yuanzhe Zhang
- Department of Medical Oncology, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510655, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510655, China
| | - Yuting Zhang
- Department of Medical Oncology, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510655, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510655, China
| | - Runkai Cai
- Department of Medical Oncology, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510655, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510655, China
| | - Hong Huo
- Department of Medical Oncology, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510655, China
| | - Jianwei Zhang
- Department of Medical Oncology, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510655, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510655, China
| | - Yue Cai
- Department of Medical Oncology, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510655, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510655, China
| | - Weiwei Li
- Department of Medical Oncology, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510655, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510655, China
| | - Huabin Hu
- Department of Medical Oncology, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510655, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510655, China
| | - Yanhong Deng
- Department of Medical Oncology, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510655, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510655, China
- Correspondence: ; Tel.: +86-13925106525
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Hao M, Wang K, Ding Y, Li H, Liu Y, Ding L. Which patients are prone to suffer liver metastasis? A review of risk factors of metachronous liver metastasis of colorectal cancer. Eur J Med Res 2022; 27:130. [PMID: 35879739 PMCID: PMC9310475 DOI: 10.1186/s40001-022-00759-z] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Accepted: 07/09/2022] [Indexed: 12/07/2022] Open
Abstract
Abstract
Background
In recent years, with the increasing incidence of colorectal cancer (CRC) and its high fatality rate, CRC has seized the attention of the world. And liver metastasis, as the main cause of death of CRC, has become the leading cause of treatment failure in CRC, especially metachronous liver metastasis, have caused patients who underwent bowel resection to experience multiple tortures.
Main body
Metachronous liver metastasis has severely affected the quality of life and prognosis of patients. Therefore, in this review, we discuss risk factors for metachronous liver metastasis of CRC, which is the premise for effective intervention for CRC patients who suffer metachronous liver metastasis after undergoing surgery, as well as the signaling pathways associated with CRC.
Conclusion
The occurrence of metachronous liver metastasis is closely related to histology-based prognostic biomarkers, serum-based biomarkers, tumor microenvironment, pre-metastatic niche, liquid biopsy and tissue-based biomarkers. Further research is required to explore the risk factors associated with liver metastasis of CRC.
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Volovat SR, Augustin I, Zob D, Boboc D, Amurariti F, Volovat C, Stefanescu C, Stolniceanu CR, Ciocoiu M, Dumitras EA, Danciu M, Apostol DGC, Drug V, Shurbaji SA, Coca LG, Leon F, Iftene A, Herghelegiu PC. Use of Personalized Biomarkers in Metastatic Colorectal Cancer and the Impact of AI. Cancers (Basel) 2022; 14:4834. [PMID: 36230757 PMCID: PMC9562853 DOI: 10.3390/cancers14194834] [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: 07/10/2022] [Revised: 09/18/2022] [Accepted: 09/29/2022] [Indexed: 12/09/2022] Open
Abstract
Colorectal cancer is a major cause of cancer-related death worldwide and is correlated with genetic and epigenetic alterations in the colonic epithelium. Genetic changes play a major role in the pathophysiology of colorectal cancer through the development of gene mutations, but recent research has shown an important role for epigenetic alterations. In this review, we try to describe the current knowledge about epigenetic alterations, including DNA methylation and histone modifications, as well as the role of non-coding RNAs as epigenetic regulators and the prognostic and predictive biomarkers in metastatic colorectal disease that can allow increases in the effectiveness of treatments. Additionally, the intestinal microbiota's composition can be an important biomarker for the response to strategies based on the immunotherapy of CRC. The identification of biomarkers in mCRC can be enhanced by developing artificial intelligence programs. We present the actual models that implement AI technology as a bridge connecting ncRNAs with tumors and conducted some experiments to improve the quality of the model used as well as the speed of the model that provides answers to users. In order to carry out this task, we implemented six algorithms: the naive Bayes classifier, the random forest classifier, the decision tree classifier, gradient boosted trees, logistic regression and SVM.
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Affiliation(s)
- Simona-Ruxandra Volovat
- Department of Medical Oncology-Radiotherapy, “Grigore T. Popa” University of Medicine and Pharmacy, 16 University Str., 700115 Iasi, Romania
| | - Iolanda Augustin
- Department of Medical Oncology, AI.Trestioreanu Institute of Oncology, 022328 Bucharest, Romania
| | - Daniela Zob
- Department of Medical Oncology, AI.Trestioreanu Institute of Oncology, 022328 Bucharest, Romania
| | - Diana Boboc
- Department of Medical Oncology-Radiotherapy, “Grigore T. Popa” University of Medicine and Pharmacy, 16 University Str., 700115 Iasi, Romania
| | - Florin Amurariti
- Department of Medical Oncology-Radiotherapy, “Grigore T. Popa” University of Medicine and Pharmacy, 16 University Str., 700115 Iasi, Romania
| | - Constantin Volovat
- Department of Medical Oncology, “Euroclinic” Center of Oncology, 2 Vasile Conta Str., 700106 Iasi, Romania
| | - Cipriana Stefanescu
- Department of Biophysics and Medical Physics-Nuclear Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 16 University Str., 700115 Iasi, Romania
| | - Cati Raluca Stolniceanu
- Department of Biophysics and Medical Physics-Nuclear Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 16 University Str., 700115 Iasi, Romania
| | - Manuela Ciocoiu
- Department of Pathophysiology, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania
| | - Eduard Alexandru Dumitras
- Department of Pathophysiology, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania
- Department of Anesthesiology and Intensive Care, Regional Institute of Oncology, 700115 Iasi, Romania
| | - Mihai Danciu
- Pathology Department, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania
| | | | - Vasile Drug
- Department of Gastroenterology, “Grigore T. Popa” University of Medicine and Pharmacy, 16 University Str., 700115 Iasi, Romania
- Gastroenterology Clinic, Institute of Gastroenterology and Hepatology, ‘St. Spiridon’ Clinical Hospital, 700115 Iasi, Romania
| | - Sinziana Al Shurbaji
- Gastroenterology Clinic, Institute of Gastroenterology and Hepatology, ‘St. Spiridon’ Clinical Hospital, 700115 Iasi, Romania
| | - Lucia-Georgiana Coca
- Faculty of Computer Science, Alexandru Ioan Cuza University, 700115 Iasi, Romania
| | - Florin Leon
- Faculty of Automatic Control and Computer Engineering, Gheorghe Asachi Technical University, 700115 Iasi, Romania
| | - Adrian Iftene
- Faculty of Computer Science, Alexandru Ioan Cuza University, 700115 Iasi, Romania
| | - Paul-Corneliu Herghelegiu
- Faculty of Automatic Control and Computer Engineering, Gheorghe Asachi Technical University, 700115 Iasi, Romania
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Affiliation(s)
- Ryohei Katayama
- Division of Experimental Chemotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan.
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Prospective analysis of the expression status of FGFR2 and HER2 in colorectal and gastric cancer populations: DS-Screen Study. Int J Colorectal Dis 2022; 37:1393-1402. [PMID: 35585358 PMCID: PMC9167213 DOI: 10.1007/s00384-022-04162-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/17/2022] [Indexed: 02/04/2023]
Abstract
PURPOSE Fibroblast growth factor receptor 2 (FGFR2) and human epidermal growth factor receptor 2 (HER2) proteins are both molecular targets for cancer therapy. The objective of this study was to evaluate the expression status of FGFR2 and HER2 in patients with gastric cancer (GC) or colorectal cancer (CRC). METHODS Archived tumor tissue samples from patients with histologically-confirmed GC or CRC suitable for chemotherapy were analyzed for FGFR2 and HER2 expression using immunohistochemistry and fluorescence in situ hybridization (HER2 in CRC only). RESULTS A total of 176 GC patients and 389 CRC patients were enrolled. Among patients with GC, 25.6% were FGFR2-positive and 26.1% were HER2-positive. Among patients with CRC, 2.9% were FGFR2-positive and 16.2% were HER2-positive. No clear relationship was found between FGFR2 and HER2 status in either GC or CRC. In GC, FGFR2 and HER2 statuses did not differ between different primary cancer locations, whereas there were some differences between histological types. Based on FGFR2- and/or HER2-positive status, 117 patients were identified as potentially suitable for inclusion in clinical trials of therapeutic agents targeting the relevant protein (GC = 45, CRC = 72; FGFR = 56, HER2 = 62), of whom 7 were eventually enrolled into such clinical trials. CONCLUSIONS This study indicated the prevalence of FGFR2 and HER2 in GC and CRC in the Japanese population. The screening performed in this study could be useful for identifying eligible patients for future clinical trials of agents targeting these proteins. TRIAL REGISTRATION Clinical trial registration Japic CTI No.: JapicCTI-163380. https://www. CLINICALTRIALS jp/cti-user/trial/ShowDirect.jsp?directLink=RNlzx1PPCuT.PrVNPxPRwA .
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Ahuja S, Arora V. Evaluation of human epidermal growth factor receptor 2 expression in colorectal cancer and its correlation with clinicopathological variables. JOURNAL OF MAHATMA GANDHI INSTITUTE OF MEDICAL SCIENCES 2021. [DOI: 10.4103/jmgims.jmgims_20_21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
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Moussa M, Badawy A, Helal N, Hegab F, Youssef M, Aboushousha T, Al Faruok L, Elwy D. Differential Expression of HER2 and SKP2 in Benign and Malignant Colorectal Lesions. Asian Pac J Cancer Prev 2020; 21:2357-2366. [PMID: 32856866 PMCID: PMC7771937 DOI: 10.31557/apjcp.2020.21.8.2357] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2020] [Indexed: 12/20/2022] Open
Abstract
Background: Colorectal cancer (CRC) is the fourth most common cancer worldwide. Both HER2 and SKP2 have a carcinogenic role in CRC making them attractive targets for tailored treatment. This work aims to correlate HER2 and SKP2 protein expression as well as HER2 gene amplification with clinicopathological parameters aiming at identifying potential candidates for targeted therapy. Methods: This Study was conducted on 127 paraffin-embedded tissue samples of different colorectal lesions [controls, chronic colitis, ulcerative colitis (UC), hyperplastic polyps (HPs), adenomas and CRCs] to investigate HER2 and SKP2 expression by immunohistochemistry (IHC), Selected CRC cases [equivocal (2+) and positive (3+) by IHC] were further evaluated by ISH (CISH and SISH ) to assess HER2 gene amplification. Results: Chronic colitis, UC, HPs and adenomas were HER2-negative. HER2 positivity (scores 2+ and 3+) was found only in15% of CRCs. Both SISH and CISH showed the same results with high concordance as 66.7% of equivocal and 100% of positive cases showed amplification of HER2 gene. SKP2 positivity was detected in 26.7% and 45% of adenomas and CRCs respectively, while other studied groups were negative. A significant correlation was noted between HER2 and SKP2 expression. Conclusion: A small percent of CRCs exhibited HER2 gene amplification, which would be potential candidates for anti HER2 therapy whereas IHC could be a primary screening test for patient selection. A potential carcinogenic role of SKP2 was suggested by the findings that SKP2 expression was undetectable in normal colonic mucosa but significantly increases from adenoma to carcinoma, hoping adenoma patients to get benefit from targeted therapy.
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Affiliation(s)
- Mona Moussa
- Department of Pathology, Theodor Bilharz Research Institute, Imbaba, Giza, Egypt
| | - Afkar Badawy
- Department of Pathology, Theodor Bilharz Research Institute, Imbaba, Giza, Egypt
| | - Noha Helal
- Department of Pathology, Theodor Bilharz Research Institute, Imbaba, Giza, Egypt
| | - Fatma Hegab
- Department of Pathology, Theodor Bilharz Research Institute, Imbaba, Giza, Egypt
| | - Magdy Youssef
- Department of Gastroenterology and Hepatology, Theodor Bilharz Research Institute, Imbaba, Giza, Egypt
| | - Tarek Aboushousha
- Department of Pathology, Theodor Bilharz Research Institute, Imbaba, Giza, Egypt
| | - Lubna Al Faruok
- Department of Pathology, Faculty of Medicine, Cairo University, Giza, Egypt
| | - Dalal Elwy
- Department of Pathology, Faculty of Medicine, Cairo University, Giza, Egypt
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Molavipordanjani S, Khodashenas S, Abedi SM, Moghadam MF, Mardanshahi A, Hosseinimehr SJ. 99mTc-radiolabeled HER2 targeted exosome for tumor imaging. Eur J Pharm Sci 2020; 148:105312. [PMID: 32198014 DOI: 10.1016/j.ejps.2020.105312] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2019] [Revised: 02/03/2020] [Accepted: 03/16/2020] [Indexed: 12/30/2022]
Abstract
Exosomes represent unique features including nontoxicity, non-immunogenicity, biodegradability, and targeting ability that make them suitable candidates for clinical applications. Therefore, in this study, 99mTc-radiolabel HER2 targeted exosomes (99mTc-exosomes) were provided for tumor imaging. These exomes are obtained from genetically engineered cells and possessed DARPin G3 as a ligand for HER2 receptors. These exosomes were radiolabeled using fac-[99mTc(CO)3(H2O)3]+ synthon. The quality control showed high radiochemical purity (RCP) for 99mTc-exosomes (>96%). 99mTc-exosomes displayed a higher affinity toward SKOV-3 cells (higher HER2 expression) in comparison with MCF-7, HT29, U87-MG, A549 cell lines at different levels of HER2 expression. Trastuzumab (an antibody with a high affinity toward HER2) inhibited the binding of 99mTc-exosomes to SKOV-3 cells up to 40%. Biodistribution study in SKOV-3 tumor bearing nude mice confirmed the ability of 99mTc-exosomes for accumulation in the tumor. 99mTc-exosomes can visualize tumor in SKOV-3 tumor-bearing nude mouse. The blockage of HER2 receptors using trastuzumab (excessive amount) suggests the 99mTc-exosomes binding to the receptors and reduced the accumulation of 99mTc-exosomes in the tumor site. This suggest that 99mTc-exosomes interact with HER2 receptors and act through specific targeting.
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Affiliation(s)
- Sajjad Molavipordanjani
- Department of Radiology and Nuclear Medicine, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran; Department of Radiopharmacy, Faculty of Pharmacy, Pharmaceutical Sciences Research Center, Mazandaran University of Medical Sciences, Sari, Iran
| | - Shabanali Khodashenas
- Immunogenetic Research Center, Mazandaran University of Medical Sciences, Sari, Iran
| | - Seyed Mohammad Abedi
- Department of Radiology and Nuclear Medicine, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Mehdi Forouzandeh Moghadam
- Department of Medical Biotechnology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Alireza Mardanshahi
- Department of Radiology and Nuclear Medicine, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.
| | - Seyed Jalal Hosseinimehr
- Department of Radiopharmacy, Faculty of Pharmacy, Pharmaceutical Sciences Research Center, Mazandaran University of Medical Sciences, Sari, Iran
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Cenaj O, Ligon AH, Hornick JL, Sholl LM. Detection of ERBB2 Amplification by Next-Generation Sequencing Predicts HER2 Expression in Colorectal Carcinoma. Am J Clin Pathol 2019; 152:97-108. [PMID: 31115453 DOI: 10.1093/ajcp/aqz031] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
OBJECTIVES ERBB2 (human epidermal growth factor receptor 2 [HER2]) amplification/overexpression in colorectal carcinomas (CRCs) may predict response to HER2 inhibitors. We correlated ERBB2 amplification by next-generation sequencing (NGS) with HER2 overexpression by immunohistochemistry. METHODS NGS was performed on specimens containing 20% or more tumor. HER2 immunohistochemistry (clone SP3) was scored semiquantitatively by H-score. ERBB2 fluorescence in situ hybridization (FISH) was performed to examine copy alterations in one HER2-heterogeneous tumor. RESULTS ERBB2 amplification was detected in 2% of 1,300 CRCs analyzed by NGS. HER2 immunohistochemistry was examined in 15 cases with ERBB2 amplification (six or more copies), 10 with low gain (three to five copies), and 77 copy neutral. ERBB2 amplification and HER2 immunohistochemistry showed perfect concordance at an H-score of 105 or more. FISH confirmed homogeneous ERBB2 amplification in a tumor showing HER2 protein expression heterogeneity. ERBB2 amplification anticorrelated with RAS/RAF mutations (P = .0001). No ERBB2-amplified cases showed mismatch repair deficiency. CONCLUSIONS NGS-detected ERBB2 amplification highly correlates with HER2 overexpression in CRC, but immunohistochemistry is required to capture protein-level heterogeneity.
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Affiliation(s)
- Odise Cenaj
- Department of Pathology, Brigham and Women’s Hospital, Boston, MA
| | - Azra H Ligon
- Department of Pathology, Brigham and Women’s Hospital, Boston, MA
| | - Jason L Hornick
- Department of Pathology, Brigham and Women’s Hospital, Boston, MA
| | - Lynette M Sholl
- Department of Pathology, Brigham and Women’s Hospital, Boston, MA
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13
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Wang XY, Zheng ZX, Sun Y, Bai YH, Shi YF, Zhou LX, Yao YF, Wu AW, Cao DF. Significance of HER2 protein expression and HER2 gene amplification in colorectal adenocarcinomas. World J Gastrointest Oncol 2019; 11:335-347. [PMID: 31040898 PMCID: PMC6475672 DOI: 10.4251/wjgo.v11.i4.335] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/25/2018] [Revised: 02/13/2019] [Accepted: 03/16/2019] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Human epidermal growth factor receptor 2 (HER2) is an oncogenic driver, and a well-established therapeutic target in breast and gastric cancers. While the role of HER2 as a prognostic biomarker in colorectal adenocarcinomas (CRCs) remains uncertain, its relevance as a therapeutic target has been established. We undertook the present study to evaluate the frequency of HER2 expression in CRC and to correlate it with various clinicopathological variables.
AIM To correlate HER2 protein expression and HER2 gene amplification with clinicopathological features and survival in surgically resected CRC.
METHODS About 1195 consecutive surgically resected CRCs were analyzed by immunohistochemical staining (IHC) to assess HER2 protein expression, and 141 selected tumors were further evaluated by fluorescence in situ hybridization (FISH) to assess HER2 gene amplification. Follow-up information was available for 1058 patients, and using this information we investigated the prevalence of HER2 protein overexpression and gene amplification in a large series of surgically resected CRCs, and evaluated the relationship between overexpression and clinicopathological parameters and prognosis.
RESULTS HER2 IHC scores of 3+, 2+, 1+, and 0 were seen in 31 (2.6%), 105 (8.8%), 475 (39.7%), and 584 (48.9%) tumors, respectively. HER2 gene amplification was seen in 24/29 tumors with an IHC score of 3+ (82.8%; unreadable in 2/31), 12/102 tumors with an IHC score of 2+ (11.8%; unreadable in 2/104), and 0 tumors with IHC score of 1+ (0/10). HER2 gene amplification was seen in 36/1191 tumors (3.0%; unreadable in 4/1195). Among the tumors with HER2 IHC scores of 3+ and 2+, the mean percentage of tumor cells with positive IHC staining was 90% (median 100%, range 40%-100%) and 67% (median 75%, range 5%-95%), respectively (P < 0.05). Among tumors with IHC scores of 2+, those with HER2 gene amplification had a higher number of tumors cells with positive IHC staining (n = 12, mean 93%, median 95%, range 90%-95%) than those without (n = 90, mean 70%, median 50%, range 5%-95%) (P < 0.05). HER2 gene status was significantly associated with distant tumor metastasis and stage (P = 0.028 and 0.025). HER2 protein overexpression as measured by IHC or HER2 gene amplification as measured by FISH was not associated with overall survival (OS) or disease-specific survival for the overall group of 1058 patients. However, further stratification revealed that among patients with tubular adenocarcinomas who were 65 years old or younger (n = 601), those exhibiting HER2 gene amplification had a shorter OS than those without (mean: 47.9 mo vs 65.1 mo, P = 0.04). Among those patients with moderately to poorly differentiated tubular adenocarcinomas, those with positive HER2 tumor IHC scores (2+, 3+) had a shorter mean OS than those with negative HER2 IHC scores (0, 1+) (47.2 mo vs 64.8 mo, P = 0.033). Moreover, among patients with T2 to T4 stage tumors, those with positive HER2 IHC scores also had a shorter mean OS than those with negative HER2 IHC scores (47.1 mo vs 64.8 mo, P = 0.031).
CONCLUSION HER2 protein levels are correlated with clinical outcomes, and positive HER2 expression as measured by IHC confers a worse prognosis in those patients 65 years old or younger with tubular adenocarcinomas.
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Affiliation(s)
- Xin-Yu Wang
- Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Pathology, Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Zhi-Xue Zheng
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Gastrointestinal Cancer Center, Peking University Cancer Hospital and Institute, Beijing 100142, China
- Department of General Surgery, Beijing Jishuitan Hospital, Beijing 100035, China
| | - Yu Sun
- Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Pathology, Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Yan-Hua Bai
- Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Pathology, Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Yun-Fei Shi
- Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Pathology, Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Li-Xin Zhou
- Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Pathology, Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Yun-Feng Yao
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Gastrointestinal Cancer Center, Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Ai-Wen Wu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Gastrointestinal Cancer Center, Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Deng-Feng Cao
- Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Pathology, Peking University Cancer Hospital and Institute, Beijing 100142, China
- Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO 63110, United States
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14
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Pellino G, Gallo G, Pallante P, Capasso R, De Stefano A, Maretto I, Malapelle U, Qiu S, Nikolaou S, Barina A, Clerico G, Reginelli A, Giuliani A, Sciaudone G, Kontovounisios C, Brunese L, Trompetto M, Selvaggi F. Noninvasive Biomarkers of Colorectal Cancer: Role in Diagnosis and Personalised Treatment Perspectives. Gastroenterol Res Pract 2018; 2018:2397863. [PMID: 30008744 PMCID: PMC6020538 DOI: 10.1155/2018/2397863] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2017] [Revised: 04/03/2018] [Accepted: 04/15/2018] [Indexed: 02/08/2023] Open
Abstract
Colorectal cancer (CRC) is the third leading cause of cancer-related deaths worldwide. It has been estimated that more than one-third of patients are diagnosed when CRC has already spread to the lymph nodes. One out of five patients is diagnosed with metastatic CRC. The stage of diagnosis influences treatment outcome and survival. Notwithstanding the recent advances in multidisciplinary management and treatment of CRC, patients are still reluctant to undergo screening tests because of the associated invasiveness and discomfort (e.g., colonoscopy with biopsies). Moreover, the serological markers currently used for diagnosis are not reliable and, even if they were useful to detect disease recurrence after treatment, they are not always detected in patients with CRC (e.g., CEA). Recently, translational research in CRC has produced a wide spectrum of potential biomarkers that could be useful for diagnosis, treatment, and follow-up of these patients. The aim of this review is to provide an overview of the newer noninvasive or minimally invasive biomarkers of CRC. Here, we discuss imaging and biomolecular diagnostics ranging from their potential usefulness to obtain early and less-invasive diagnosis to their potential implementation in the development of a bespoke treatment of CRC.
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Affiliation(s)
- Gianluca Pellino
- Unit of General Surgery, Department of Medical, Surgical, Neurological, Metabolic and Ageing Sciences, Università degli Studi della Campania “Luigi Vanvitelli”, Piazza Miraglia 2, 80138 Naples, Italy
- Colorectal Surgery Unit, Hospital Universitario y Politécnico La Fe, Valencia, Spain
| | - Gaetano Gallo
- Department of Medical and Surgical Sciences, OU of General Surgery, University of Catanzaro, Catanzaro, Italy
- Department of Colorectal Surgery, Clinic S. Rita, Vercelli, Italy
| | - Pierlorenzo Pallante
- Institute of Experimental Endocrinology and Oncology (IEOS), National Research Council (CNR), Via S. Pansini 5, Naples, Italy
| | - Raffaella Capasso
- Department of Medicine and Health Sciences, University of Molise, Via Francesco de Sanctis 1, 86100 Campobasso, Italy
| | - Alfonso De Stefano
- Department of Abdominal Oncology, Division of Abdominal Medical Oncology, Istituto Nazionale per lo Studio e la Cura dei Tumori, “Fondazione G. Pascale, ” IRCCS, Naples, Italy
| | - Isacco Maretto
- 1st Surgical Clinic, Department of Surgical, Oncological, and Gastroenterological Sciences, University of Padua, Padua, Italy
| | - Umberto Malapelle
- Dipartimento di Sanità Pubblica, Università degli Studi di Napoli Federico II, Naples, Italy
| | - Shengyang Qiu
- Department of Colorectal Surgery, Royal Marsden Hospital, London, UK
| | - Stella Nikolaou
- Department of Colorectal Surgery, Royal Marsden Hospital, London, UK
| | - Andrea Barina
- 1st Surgical Clinic, Department of Surgical, Oncological, and Gastroenterological Sciences, University of Padua, Padua, Italy
| | - Giuseppe Clerico
- Department of Colorectal Surgery, Clinic S. Rita, Vercelli, Italy
| | - Alfonso Reginelli
- Department of Internal and Experimental Medicine, Magrassi-Lanzara, Institute of Radiology, Università degli Studi della Campania “Luigi Vanvitelli”, Piazza Miraglia 2, 80138 Naples, Italy
| | - Antonio Giuliani
- Department of Medicine and Health Sciences “V. Tiberio”, University of Molise, Campobasso, Italy
| | - Guido Sciaudone
- Unit of General Surgery, Department of Medical, Surgical, Neurological, Metabolic and Ageing Sciences, Università degli Studi della Campania “Luigi Vanvitelli”, Piazza Miraglia 2, 80138 Naples, Italy
| | - Christos Kontovounisios
- Department of Colorectal Surgery, Royal Marsden Hospital, London, UK
- Department of Surgery and Cancer, Chelsea and Westminster Hospital Campus, Imperial College London, London, UK
| | - Luca Brunese
- Department of Medicine and Health Sciences, University of Molise, Via Francesco de Sanctis 1, 86100 Campobasso, Italy
| | - Mario Trompetto
- Department of Colorectal Surgery, Clinic S. Rita, Vercelli, Italy
| | - Francesco Selvaggi
- Unit of General Surgery, Department of Medical, Surgical, Neurological, Metabolic and Ageing Sciences, Università degli Studi della Campania “Luigi Vanvitelli”, Piazza Miraglia 2, 80138 Naples, Italy
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15
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Mondaca S, Yaeger R. Colorectal cancer genomics and designing rational trials. ANNALS OF TRANSLATIONAL MEDICINE 2018; 6:159. [PMID: 29911107 PMCID: PMC5985274 DOI: 10.21037/atm.2018.03.27] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/11/2017] [Accepted: 02/25/2018] [Indexed: 12/15/2022]
Abstract
The widespread use of next generation sequencing (NGS) has led to a refined understanding of the genomics of colorectal cancer (CRC). However, progress in the use of molecular biomarkers in standard practice has been slow, and there is no approved targeted therapy for CRC based on a positive predictive marker yet. In this review, we will first summarize biomarkers with clinical utility in standard practice or targeted therapy trials and then consider how to rationally design clinical trials to more effectively target CRC. Specifically, we will discuss current clinical applications of genomic information consisting of the use of the MAPK (mitogen-activated protein kinase) pathway genes KRAS, NRAS, and BRAF as prognostic and predictive biomarkers for standard treatment, risk stratification by primary tumor site and consideration of tumor laterality in patient selection for epidermal growth factor receptor (EGFR) antibody treatment, and the evaluation for genomic biomarkers, including BRAF V600E, HER2 amplification, and gene rearrangements, for targeted therapies in clinical trials. Applying lessons from targeted therapy trials in CRC, we now appreciate that both tumor genomics and tissue of origin affect targeted therapy response and that the development of resistance to targeted therapies is dynamic and often subclonal. Based on these understandings, we propose the design of adaptive clinical trials that evaluate real-time pharmacodynamic markers and monitor tumor subpopulations during the course of treatment to overcome challenges targeting genetic drivers in CRC.
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Affiliation(s)
- Sebastian Mondaca
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Rona Yaeger
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
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16
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Horimoto Y, Hirashima T, Arakawa A, Miura H, Saito M. Metastatic colonic and gastric polyps from breast cancer resembling hyperplastic polyps. Surg Case Rep 2018; 4:23. [PMID: 29572575 PMCID: PMC5866257 DOI: 10.1186/s40792-018-0433-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2017] [Accepted: 03/13/2018] [Indexed: 01/22/2023] Open
Abstract
Breast cancer metastasis to the gastrointestinal tract is relatively rare and is generally found when patients complain of symptoms such as gastrointestinal obstruction. Herein, we report a case with metastatic colonic and gastric lesions from breast cancer, with the formation of mucosal polyps which resembled typical hyperplastic polyps. A 47-year-old woman underwent curable surgery for breast cancer and received standard systemic treatments. Her primary tumor was composed of a mix of invasive lobular and ductal carcinomas. During adjuvant endocrine therapy, she developed multiple colonic metastases, identified by colonoscopy performed as part of a general health check-up. She had no symptoms. Small elevated sessile polyps in the transverse colon and rectum showed histological features of signet-ring cell type adenocarcinoma, similar to the invasive lobular component of the primary breast cancer. During treatments for recurrent disease, she also developed multiple gastric metastases, with the same endoscopic and pathological features as the colonic lesions. Her treatment regimen was switched to oral chemotherapy, and she has since maintained stable disease for nearly 3 years. Multiple bone metastases eventually developed, and she was again switched to another systemic treatment but, to date, has remained free of symptoms. We emphasize that the endoscopic findings of the metastatic lesions in the colon and stomach in this case highly resembled hyperplastic polyps. Since biopsy is not always performed for hyperplastic polyps in the gastrointestinal tract, we believe that this case report may encourage endoscopists to offer biopsies to the patient who has a history of breast cancer.
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Affiliation(s)
- Yoshiya Horimoto
- Department of Breast Oncology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan. .,Department of Pathology and Oncology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.
| | - Tetsuro Hirashima
- Tamaplaza South Gastrointestinal Clinic, 3-14-12 Shinishikawa, Aoba-ku, Yokohama-shi, Kanagawa, 225-0003, Japan
| | - Atsushi Arakawa
- Department of Human Pathology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
| | - Hiroyoshi Miura
- Department of Surgery, Koshigaya Municipal Hospital, 10-47-1 Higashikoshigaya, Koshigaya, Saitama, 343-8577, Japan
| | - Mitsue Saito
- Department of Breast Oncology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
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17
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Immunohistochemical Study of HER2/neu Expression in Colorectal Cancer and its Relation to other Clinicopathological Criteria and Prognostic Factors. INTERNATIONAL JOURNAL OF CANCER MANAGEMENT 2017. [DOI: 10.5812/ijcm.5700] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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18
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Khan SA, Zeng Z, Shia J, Paty PB. EGFR Gene Amplification and KRAS Mutation Predict Response to Combination Targeted Therapy in Metastatic Colorectal Cancer. Pathol Oncol Res 2016; 23:673-677. [PMID: 28025786 DOI: 10.1007/s12253-016-0166-2] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2016] [Accepted: 12/14/2016] [Indexed: 12/27/2022]
Abstract
Genetic variability in KRAS and EGFR predicts response to cetuximab in irinotecan refractory colorectal cancer. Whether these markers or others remain predictive in combination biologic therapies including bevacizumab is unknown. We identified predictive biomarkers from patients with irinotecan refractory metastatic colorectal cancer treated with cetuximab plus bevacizumab. Patients who received cetuximab plus bevacizumab for irinotecan refractory colorectal cancer in either of two Phase II trials conducted were identified. Tumor tissue was available for 33 patients. Genomic DNA was extracted and used for mutational analysis of KRAS, BRAF, and p53 genes. Fluorescence in situ hybridization was performed to assess EGFR copy number. The status of single genes and various combinations were tested for association with response. Seven of 33 patients responded to treatment. KRAS mutations were found in 14/33 cases, and 0 responded to treatment (p = 0.01). EGFR gene amplification was seen in 3/33 of tumors and in every case was associated with response to treatment (p < 0.001). TP53 and BRAF mutations were found in 18/33 and 0/33 tumors, respectively, and there were no associations with response to either gene. EGFR gene amplification and KRAS mutations are predictive markers for patients receiving combination biologic therapy of cetuximab plus bevacizumab for metastatic colorectal cancer. One marker or the other is present in the tumor of half of all patients allowing treatment response to be predicted with a high degree of certainty. The role for molecular markers in combination biologic therapy seems promising.
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Affiliation(s)
- Sajid A Khan
- Department of Surgery, Section of Surgical Oncology, Yale University School of Medicine, 310 Cedar Street, FMB 130, New Haven, CT, 06520, USA.
| | - Zhaoshi Zeng
- Colorectal Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
| | - Jinru Shia
- Colorectal Service, Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
| | - Philip B Paty
- Colorectal Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
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19
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Karaca H, Deniz K, Berk V, Inanc M, Ozkan M. Association of human epidermal growth factor receptor-2 expression and clinicopathological findings in patients with colorectal cancer. Asian Pac J Cancer Prev 2016; 13:6221-5. [PMID: 23464435 DOI: 10.7314/apjcp.2012.13.12.6221] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND To determine the frequency of HER-2 overexpression in colorectal cancer (CRC) patients, and to explore the relationship between clinicopathological prognostic factors and their effects on survival, based on immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH) analysis. MATERIALS AND METHODS The study included 80 patients with a histologically proven diagnosis of CRC that received adjuvant FOLFOX-4 chemotherapy at our department between March 2006 and September 2010. Patient data were analyzed retrospectively. RESULTS The median follow-up period and age of the patients were 24 months and 59 years, respectively. In immunohistochemical staining, 3+ staining was found in 2 patients (2.5%) while 2+ was in 13 (16%) . FISH for HER-2 was performed for all of these 15 patients; samples which were 3+ showed positivity but the ones with 2+ were negative. There was no significant correlation between HER-2 expression and age, gender, tumor localization, histological subtype, grade, lymphovascular and perineural invasion, or pTN stage (P>0.05), even when the patients with HER-2 overexpression were analyzed separately. There was also no significant relationship between progression-free survival (PFS) and overall survival (OS), and HER-2 expression, gender, tumor localization, obstruction-perforation, bleeding, histological type, grade, lymphovascular and perineural invasion, or pT staging (P>0.05); however, there was a significant relationship between lymph node involvement, and PFS and OS (P<0.05). CONCLUSIONS Evaluation of HER-2 overexpression in a more comprehensive, multi-center, prospective trial with standardized methods will be an appropriate approach.
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Affiliation(s)
- Halit Karaca
- Deparment of Medical Oncology, Erciyes University Medical Faculty, Kayseri, Turkey.
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20
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Roloff GW, Yang Z, Wood LV, Neychev VK. Colon cancer metastasis to the thyroid gland: report of a case with unique molecular profile. Clin Case Rep 2016; 4:549-53. [PMID: 27398194 PMCID: PMC4891476 DOI: 10.1002/ccr3.497] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2015] [Revised: 11/13/2015] [Accepted: 12/25/2015] [Indexed: 12/12/2022] Open
Abstract
A high index of suspicion is needed when a patient presents with thyroid mass in the settings of an advanced CRC. Secondary thyroid malignancy should be considered unless proven otherwise. reatment should be determined considering extent of CRC metastasis, patient's general condition, and presence of local symptoms.
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Affiliation(s)
- Gregory W Roloff
- Vaccine Branch Center for Cancer Research NCI Bethesda Maryland USA
| | - Zhiming Yang
- Laboratory of Pathology Center for Cancer Research NCI Bethesda Maryland USA
| | - Lauren V Wood
- Vaccine Branch Center for Cancer Research NCI Bethesda Maryland USA
| | - Vladimir K Neychev
- Endocrine Oncology Branch Center for Cancer Research NCI Bethesda Maryland USA; Department of Surgery "Alexandrovska" Hospital Medical University of Sofia Sofia Bulgaria
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21
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Richman SD, Southward K, Chambers P, Cross D, Barrett J, Hemmings G, Taylor M, Wood H, Hutchins G, Foster JM, Oumie A, Spink KG, Brown SR, Jones M, Kerr D, Handley K, Gray R, Seymour M, Quirke P. HER2 overexpression and amplification as a potential therapeutic target in colorectal cancer: analysis of 3256 patients enrolled in the QUASAR, FOCUS and PICCOLO colorectal cancer trials. J Pathol 2016; 238:562-70. [PMID: 26690310 PMCID: PMC4785607 DOI: 10.1002/path.4679] [Citation(s) in RCA: 181] [Impact Index Per Article: 20.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2015] [Revised: 11/25/2015] [Accepted: 12/12/2015] [Indexed: 12/23/2022]
Abstract
HER2 overexpression/amplification is linked to trastuzumab response in breast/gastric cancers. One suggested anti‐EGFR resistance mechanism in colorectal cancer (CRC) is aberrant MEK–AKT pathway activation through HER2 up‐regulation. We assessed HER2‐amplification/overexpression in stage II–III and IV CRC patients, assessing relationships to KRAS/BRAF and outcome. Pathological material was obtained from 1914 patients in the QUASAR stage II–III trial and 1342 patients in stage IV trials (FOCUS and PICCOLO). Tissue microarrays were created for HER2 immunohistochemistry. HER2‐amplification was assessed using FISH and copy number variation. KRAS/BRAF mutation status was assessed by pyrosequencing. Progression‐free survival (PFS) and overall survival (OS) data were obtained for FOCUS/PICCOLO and recurrence and mortality for QUASAR; 29/1342 (2.2%) stage IV and 25/1914 (1.3%) stage II–III tumours showed HER2 protein overexpression. Of the HER2‐overexpressing cases, 27/28 (96.4%) stage IV tumours and 20/24 (83.3%) stage II–III tumours demonstrated HER2 amplification by FISH; 41/47 (87.2%) also showed copy number gains. HER2‐overexpression was associated with KRAS/BRAF wild‐type (WT) status at all stages: in 5.2% WT versus 1.0% mutated tumours (p < 0.0001) in stage IV and 2.1% versus 0.2% in stage II–III tumours (p = 0.01), respectively. HER2 was not associated with OS or PFS. At stage II–III, there was no significant correlation between HER2 overexpression and 5FU/FA response. A higher proportion of HER2‐overexpressing cases experienced recurrence, but the difference was not significant. HER2‐amplification/overexpression is identifiable by immunohistochemistry, occurring infrequently in stage II–III CRC, rising in stage IV and further in KRAS/BRAFWT tumours. The value of HER2‐targeted therapy in patients with HER2‐amplified CRC must be tested in a clinical trial. © 2015 The Authors. Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
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Affiliation(s)
- Susan D Richman
- Section of Pathology and Tumour Biology, Leeds Institute of Cancer and Pathology, University of Leeds, UK
| | - Katie Southward
- Section of Pathology and Tumour Biology, Leeds Institute of Cancer and Pathology, University of Leeds, UK
| | - Philip Chambers
- Section of Pathology and Tumour Biology, Leeds Institute of Cancer and Pathology, University of Leeds, UK
| | - Debra Cross
- Histopathology and Molecular Pathology, St James University Hospital, Leeds, UK
| | - Jennifer Barrett
- Section of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, University of Leeds, UK
| | - Gemma Hemmings
- Section of Pathology and Tumour Biology, Leeds Institute of Cancer and Pathology, University of Leeds, UK
| | - Morag Taylor
- Section of Pathology and Tumour Biology, Leeds Institute of Cancer and Pathology, University of Leeds, UK
| | - Henry Wood
- Section of Pathology and Tumour Biology, Leeds Institute of Cancer and Pathology, University of Leeds, UK
| | - Gordon Hutchins
- Section of Pathology and Tumour Biology, Leeds Institute of Cancer and Pathology, University of Leeds, UK
| | | | | | | | - Sarah R Brown
- Clinical Trials Research Unit, University of Leeds, Leeds, UK
| | - Marc Jones
- Clinical Trials Research Unit, University of Leeds, Leeds, UK
| | - David Kerr
- Cancer Medicine, University of Oxford, UK
| | - Kelly Handley
- Birmingham Clinical Trials Unit, University of Birmingham, UK
| | - Richard Gray
- Clinical Trials Service Unit and Epidemiology Studies Unit, University of Oxford, UK
| | - Matthew Seymour
- Section of Oncology, Leeds Institute of Cancer and Pathology, University of Leeds, UK
| | - Philip Quirke
- Section of Pathology and Tumour Biology, Leeds Institute of Cancer and Pathology, University of Leeds, UK
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22
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Joshi BP, Zhou J, Pant A, Duan X, Zhou Q, Kuick R, Owens SR, Appelman H, Wang TD. Design and Synthesis of Near-Infrared Peptide for in Vivo Molecular Imaging of HER2. Bioconjug Chem 2015; 27:481-94. [PMID: 26709709 DOI: 10.1021/acs.bioconjchem.5b00565] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
We report the development, characterization, and validation of a peptide specific for the extracellular domain of HER2. This probe chemistry was developed for molecular imaging by using a structural model to select an optimal combination of amino acids that maximize the likelihood for unique hydrophobic and hydrophilic interactions with HER2 domain 3. The sequence KSPNPRF was identified and conjugated with either FITC or Cy5.5 via a GGGSK linker using Fmoc-mediated solid-phase synthesis to demonstrate flexibility for this chemical structure to be labeled with different fluorophores. A scrambled sequence was developed for control by altering the conformationally rigid spacer and moving both hydrophobic and hydrophilic amino acids on the C-terminus. We validated peptide specificity for HER2 in knockdown and competition experiments using human colorectal cancer cells in vitro, and measured a binding affinity of kd = 21 nM and time constant of k = 0.14 min(-1) (7.14 min). We used this peptide with either topical or intravenous administration in a preclinical model of colorectal cancer to demonstrate specific uptake in spontaneous adenomas and to show feasibility for real time in vivo imaging with near-infrared fluorescence. We used this peptide in immunofluorescence studies of human proximal colon specimens to evaluate specificity for sessile serrated and sporadic adenomas. Improved visualization can be used endoscopically to guide tissue biopsy and detect premalignant lesions that would otherwise be missed. Our peptide design for specificity to HER2 is promising for clinical translation in molecular imaging methods for early cancer detection.
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Affiliation(s)
- Bishnu P Joshi
- Department of Medicine, Division of Gastroenterology, ‡Department of Biomedical Engineering, §Department of Biostatistics, ∥Department of Pathology, and ⊥Department of Mechanical Engineering, University of Michigan , Ann Arbor, Michigan 48109, United States
| | - Juan Zhou
- Department of Medicine, Division of Gastroenterology, ‡Department of Biomedical Engineering, §Department of Biostatistics, ∥Department of Pathology, and ⊥Department of Mechanical Engineering, University of Michigan , Ann Arbor, Michigan 48109, United States
| | - Asha Pant
- Department of Medicine, Division of Gastroenterology, ‡Department of Biomedical Engineering, §Department of Biostatistics, ∥Department of Pathology, and ⊥Department of Mechanical Engineering, University of Michigan , Ann Arbor, Michigan 48109, United States
| | - Xiyu Duan
- Department of Medicine, Division of Gastroenterology, ‡Department of Biomedical Engineering, §Department of Biostatistics, ∥Department of Pathology, and ⊥Department of Mechanical Engineering, University of Michigan , Ann Arbor, Michigan 48109, United States
| | - Quan Zhou
- Department of Medicine, Division of Gastroenterology, ‡Department of Biomedical Engineering, §Department of Biostatistics, ∥Department of Pathology, and ⊥Department of Mechanical Engineering, University of Michigan , Ann Arbor, Michigan 48109, United States
| | - Rork Kuick
- Department of Medicine, Division of Gastroenterology, ‡Department of Biomedical Engineering, §Department of Biostatistics, ∥Department of Pathology, and ⊥Department of Mechanical Engineering, University of Michigan , Ann Arbor, Michigan 48109, United States
| | - Scott R Owens
- Department of Medicine, Division of Gastroenterology, ‡Department of Biomedical Engineering, §Department of Biostatistics, ∥Department of Pathology, and ⊥Department of Mechanical Engineering, University of Michigan , Ann Arbor, Michigan 48109, United States
| | - Henry Appelman
- Department of Medicine, Division of Gastroenterology, ‡Department of Biomedical Engineering, §Department of Biostatistics, ∥Department of Pathology, and ⊥Department of Mechanical Engineering, University of Michigan , Ann Arbor, Michigan 48109, United States
| | - Thomas D Wang
- Department of Medicine, Division of Gastroenterology, ‡Department of Biomedical Engineering, §Department of Biostatistics, ∥Department of Pathology, and ⊥Department of Mechanical Engineering, University of Michigan , Ann Arbor, Michigan 48109, United States
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Madani SH, Sadeghi E, Rezaee A, Sadeghi M, Khazaee S, Amirifard N, Payandeh M. Survey of HER2-neu Expression in Colonic Adenocarcinoma in the West of Iran. Asian Pac J Cancer Prev 2015; 16:7671-4. [PMID: 26625779 DOI: 10.7314/apjcp.2015.16.17.7671] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Overexpression of HER2-neu has been reported in many epithelial malignancies, including cancers of the breast, ovaries, lungs, prostate, bladder, pancreas, colorectum and stomach as well as osteosarcomas. The aim of this study was evaluation of expression of HER2-neu immunohistochemistry (IHC) status and clinicopathologic features in a series of colonic adenocarcinomas. MATERIALS AND METHODS In this descriptive and analytical study, we surveyed 211 samples of colon adenocarcinoma from 182 patients (86.3%) undergoing total or partial colectomy and 29 (7.13%) with biopsies by colonoscopy. A sufficient sample size was obtained from all cases and the slides were stained with hematoxylin and eosin and also by IHC (HER2) staining. RESULTS The mean age for the patients at diagnosis was 57.9 years (range, 15-88 years). One hundred and twenty one patients (57.3%) were male. Of all patients, 201 samples (95.3%) were conventional adenocarcinomas (159, 29 and 13 cases were well, moderately and poorly differentiated, respectively) and 10 (4.7%) were mucinous type. Out of 211 cases, 171 were checked for lymph nodes metastasis and 64 were positive. There is a correlation between HER2 scores and differentiation, most score 3 cases being well differentiated (P<0.05). CONCLUSIONS In patients with advanced colon cancer, surgery alone is not curative and other forms of therapy may be required to prolong patient survival. HER2 overexpression was found in some cases and this could be a guideline to new adjuvant therapy for these patients.
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Affiliation(s)
- Seyed-Hamid Madani
- Molecular Pathology Research Center, Imam Reza Hospital, Kermanshah, Iran E-mail :
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Omar N, Yan B, Salto-Tellez M. HER2: An emerging biomarker in non-breast and non-gastric cancers. ACTA ACUST UNITED AC 2015. [DOI: 10.1016/j.pathog.2015.05.002] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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Determination of Tumor Heterogeneity in Colorectal Cancers Using Heterogeneity Tissue Microarrays. Pathol Oncol Res 2015; 21:1183-9. [PMID: 26026893 DOI: 10.1007/s12253-015-9953-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2014] [Accepted: 05/14/2015] [Indexed: 02/08/2023]
Abstract
Cancer is often heterogeneous both on a morphological and on a genetic level. Though resected tumors are often large, molecular tumor analysis is usually restricted to one tissue block. In this project we introduce a new tool for a high-throughput heterogeneity analysis of colorectal cancer. A heterogeneity tissue microarray (TMA) was manufactured from tissues of 340 patients with colorectal cancer. For this purpose 8 different tissue spots were taken from as many different cancer blocks per patient as possible (at least 4 different blocks). Additional tissue samples from 1 to 4 corresponding lymph node metastases were added from 134 patients. The system was then validated by analysing one parameter each known for minimal (p53) or substantial (HER2) heterogeneity in colorectal cancer. P53 alterations as detected by immunohistochemistry were seen in 174 (51.3 %) of 339 analyzable primary tumors of which 23 (13.2 % of positive cases) showed a heterogeneous distribution pattern. HER2 overexpression was seen in 18 (5.4 %) of 336 evaluable tumors. HER2 amplification occurred in 6 (33.3 %) of the 18 cases with HER2 overexpression. Genomic heterogeneity was more prevalent for HER2 alterations than for p53 alterations. For immunohistochemical expression analysis, 16 of 18 positive cases were heterogeneous (88.9 %) and for amplification 3 of 6 cases (50 %) were heterogeneous. Large section validation revealed, however a considerable fraction of heterogeneous cases were due to technical artifacts. In summary, our data suggest, that heterogeneity TMAs are a powerful tool to rapidly screen for molecular heterogeneity in colorectal cancer.
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Yao S, Zheng P, Wu H, Song LM, Ying XF, Xing C, Li Y, Xiao ZQ, Zhou XN, Shen T, Chen L, Liu YH, Lai MD, Mei L, Gao TM, Li JM. Erbin interacts with c-Cbl and promotes tumourigenesis and tumour growth in colorectal cancer by preventing c-Cbl-mediated ubiquitination and down-regulation of EGFR. J Pathol 2015; 236:65-77. [PMID: 25521828 DOI: 10.1002/path.4502] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2014] [Revised: 12/10/2014] [Accepted: 12/13/2014] [Indexed: 01/20/2023]
Abstract
The epidermal growth factor receptor (EGFR) is implicated in many types of cancer, including colorectal cancer (CRC), and has become one of the most common candidates for targeted therapy. Here, we found that Erbin, a member of the leucine-rich repeat and PDZ domain (LAP) family, plays a key role in EGFR signalling. Erbin inhibited EGFR ubiquitination and stabilized the EGFR protein by interacting with c-Cbl. Moreover, the PDZ domain of Erbin was critical for the interaction between Erbin and c-Cbl and EGFR ubiquitination. Interestingly, Erbin expression was elevated in tumour samples from CRC patients, increased in advanced clinical stage disease and correlated with EGFR expression. In vivo studies using mouse xenograft models of CRC showed that Erbin promotes tumour growth, and that the effects of Erbin on tumour growth are mainly related to the regulatory effects of Erbin on EGFR. The azoxymethane (AOM)-induced colon carcinogenesis model in Erbin(ΔC) (/) (ΔC) mice, with the PDZ domain of Erbin deleted, demonstrated that the PDZ domain of Erbin and its regulation of EGFR signalling are necessary for the tumourigenesis and tumour growth of CRC. We found that Erbin promotes tumourigenesis and tumour growth in CRC by stabilizing EGFR. Our study sheds light on developing Erbin, especially its PDZ domain, as a potential target for CRC treatment.
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Affiliation(s)
- Su Yao
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China
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Danielsen SA, Eide PW, Nesbakken A, Guren T, Leithe E, Lothe RA. Portrait of the PI3K/AKT pathway in colorectal cancer. Biochim Biophys Acta Rev Cancer 2014; 1855:104-21. [PMID: 25450577 DOI: 10.1016/j.bbcan.2014.09.008] [Citation(s) in RCA: 173] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2014] [Accepted: 09/07/2014] [Indexed: 12/16/2022]
Abstract
PI3K/AKT signaling leads to reduced apoptosis, stimulates cell growth and increases proliferation. Under normal conditions, PI3K/AKT activation is tightly controlled and dependent on both extracellular growth signals and the availability of amino acids and glucose. Genetic aberrations leading to PI3K/AKT hyper-activation are observed at considerable frequency in all major nodes in most tumors. In colorectal cancer the most commonly observed pathway changes are IGF2 overexpression, PIK3CA mutations and PTEN mutations and deletions. Combined, these alterations are found in about 40% of large bowel tumors. In addition, but not mutually exclusive to these, KRAS mutations are observed at a similar frequency. There are however additional, less frequent and more poorly understood events that may also push the PI3K/AKT pathway into overdrive and thus promote malignant growth. Here we discuss aberrations of components at the genetic, epigenetic, transcriptional, post-transcriptional, translational and post-translational level where perturbations may drive excessive PI3K/AKT signaling. Integrating multiple molecular levels will advance our understanding of this cancer critical circuit and more importantly, improve our ability to pharmacologically target the pathway in view of clonal development, tumor heterogeneity and drug resistance mechanisms. In this review, we revisit the PI3K/AKT pathway cancer susceptibility syndromes, summarize the known aberrations at the different regulatory levels and the prognostic and predictive values of these alterations in colorectal cancer.
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Affiliation(s)
- Stine Aske Danielsen
- Department of Cancer Prevention, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway; K.G. Jebsen Colorectal Cancer Research Centre, Oslo University Hospital, Oslo, Norway
| | - Peter Wold Eide
- Department of Cancer Prevention, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway; K.G. Jebsen Colorectal Cancer Research Centre, Oslo University Hospital, Oslo, Norway
| | - Arild Nesbakken
- K.G. Jebsen Colorectal Cancer Research Centre, Oslo University Hospital, Oslo, Norway; Department of Gastrointestinal Surgery, Oslo University Hospital, Oslo, Norway
| | - Tormod Guren
- K.G. Jebsen Colorectal Cancer Research Centre, Oslo University Hospital, Oslo, Norway; Department of Oncology, Oslo University Hospital, Oslo, Norway
| | - Edward Leithe
- Department of Cancer Prevention, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway; K.G. Jebsen Colorectal Cancer Research Centre, Oslo University Hospital, Oslo, Norway
| | - Ragnhild A Lothe
- Department of Cancer Prevention, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway; K.G. Jebsen Colorectal Cancer Research Centre, Oslo University Hospital, Oslo, Norway.
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Luca T, Barresi V, Privitera G, Musso N, Caruso M, Condorelli DF, Castorina S. In vitro combined treatment with cetuximab and trastuzumab inhibits growth of colon cancer cells. Cell Prolif 2014; 47:435-47. [PMID: 25131935 DOI: 10.1111/cpr.12125] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2014] [Accepted: 06/20/2014] [Indexed: 12/13/2022] Open
Abstract
OBJECTIVES Overexpression or constitutive activation of epidermal growth factor receptors (EGFR) is involved in growth of human cancers. We investigated effects of EGFR and HER-2 blockade in colon cancer cell lines using cetuximab and trastuzumab, with the aim of developing novel approaches to cancer therapy. MATERIALS AND METHODS We studied effects of treatment on cell growth, cell cycle distribution, induction of apoptosis, changes in EGFR and HER-2 mRNA-protein expression and EGFR and HER-2 gene copy number in Caco-2, HT-29 and HCT-116 cells. RESULTS Treatment of cells resulted in no effect in one of the three cell lines and in inhibition of cell proliferation in a time- and dose-dependent manner in the other two, with modulation of EGFR and HER-2 mRNA and protein levels. Differences in sensitivity to cetuximab and trastuzumab were observed. Treatment induced specific changes in cell cycle distribution in both cell lines affected, while apoptosis was not increased. Fluorescence in situ hybridization analysis revealed abnormal copy number of two genes resulting from aneuploidy; this was not responsible for different sensitivity to combination between the two cell lines. CONCLUSIONS Targeting EGFR and HER-2 simultaneously could have useful applications in colorectal cancer treatment. To improve pharmacological efficacy of cetuximab and trastuzumab combination, molecular mechanisms involved in their activity need to be elucidated.
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Affiliation(s)
- T Luca
- Fondazione Mediterranea "G.B. Morgagni", 95125, Catania, Italy
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Farzand S, Siddique T, Saba K, Bukhari MH. Frequency of HER2/neu overexpression in adenocarcinoma of the gastrointestinal system. World J Gastroenterol 2014; 20:5889-5896. [PMID: 24914350 PMCID: PMC4024799 DOI: 10.3748/wjg.v20.i19.5889] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2013] [Revised: 07/12/2013] [Accepted: 12/04/2013] [Indexed: 02/06/2023] Open
Abstract
AIM: To determine the frequency of HER2/neu protein overexpression in gastric (group A), small intestine (group B), and colorectal (group C) adenocarcinoma.
METHODS: A descriptive, cross-sectional study was performed on 50 cases of gastrointestinal adenocarcinoma (stomach, small intestine, and colorectal); 11 from group A, 8 from group B, and 31 from group C. The samples were grossed and processed in the pathology department, and sections were stained with HE (hematoxylin and eosin stain) for histopathological confirmation of malignancy (well-differentiated, moderately-differentiated, and poorly-differentiated). The confirmed samples were processed for immunomarker study of HER2/neu.
RESULTS: HER2/neu protein overexpression was found in 33 (66%) patients overall (P = 0.000). Out of 33 HER2/neu positive subjects, 23 (69.6%) were from group C, while the remaining 10 (30%) were from group A. None of the patients from group B had positive HER2/neu protein overexpression. No protein overexpression or membrane staining in < 10% tumor cells was observed in 17 (34%) patients, which were labeled as score “0” and considered negative for HER2/neu protein overexpression. Faint/weak staining (in ≥ 10% of tumors cells) were observed in 8 (16%) patients and given the “1+” score. Similarly 13 (26%) patients reported moderate staining (in ≥ 10% tumor cells) and were thus labeled as “2+”, and strong staining (in ≥ 10% tumors cells), labeled as “3+”, was observed in 12 (24%) patients. Out of 50 patients, 26 (52%) were suffering from grade-II malignancy, 16 (32%) from grade-I, and 8 (16%) from grade-III. There was highly significant association between tumor grades and HER2/neu protein overexpression (P = 0.0000).
CONCLUSION: HER2/neu protein is credibly overexpressed in colon and gastric adenocarcinomas in immunohistochemistry. There is significant association between grade of tumor and HER2/neu protein overexpression.
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Zong L, Chen P, Wang DX. Death decoy receptor overexpression and increased malignancy risk in colorectal cancer. World J Gastroenterol 2014; 20:4440-4445. [PMID: 24764685 PMCID: PMC3989983 DOI: 10.3748/wjg.v20.i15.4440] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2013] [Accepted: 01/08/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate human epidermal growth factor receptor 2 (HER2) and death decoy receptor (DcR3) as colorectal cancer prognostic indicators.
METHODS: Colorectal carcinoma specimens from 300 patients were analyzed by immunohistochemistry to detect the staining patterns of HER2 and DcR3. Classification of HER2 staining was carried out using the United States Food and Drug Administration semi-quantitative scoring system, with scores of 0 or 1+ indicating a tumor-negative (normal expression) status and scores of 2+ and 3+ indicating a tumor-positive (overexpression) status. Classification of DcR3 was carried out by quantitating the percentage of positive cells within the stained section, with < 10% indicating a tumor-negative status and ≥ 10% indicating a tumor-positive status. Correlation of the HER2 and DcR3 staining status with clinicopathological parameters [age, sex, tumor size, differentiation, and the tumor, node, metastasis (pTNM) classification] and survival was statistically assessed.
RESULTS: Tumor-positive status for HER2 and DcR3 was found in 18.33% and 58.33% of the 300 colorectal carcinoma specimens, respectively. HER2 tumor-positive status showed a significant correlation with tumor size (P = 0.003) but not with other clinicopathological parameters. DcR3 tumor-positive status showed a significant correlation with tumor differentiation (P < 0.001), pTNM stage (P < 0.001), and lymph node metastasis (P < 0.001). However, correlation coefficient analysis did not indicate that a statistically significant correlation exists between tumor-positive status for the HER2 and DcR3 overexpression (P = 0.236). Patients with specimens classified as DcR3-overexpressing had a significantly worse overall survival (OS) rate than those without DcR3 overexpression (median OS: 42.11 vs 61.21 mo; HR = 50.27, 95%CI: 44.90-55.64, P < 0.001). HER2 overexpression had no significant impact on median OS (35.10 mo vs 45.25 mo; HR = 44.40, 95%CI: 39.32-49.48, P = 0.344). However, patients with specimens classified as both HER2- and DcR3-overexpressing had a significantly poorer median OS than those with only HER2 overexpression (31.80 mo vs 52.20 mo; HR = 35.10, 95%CI: 22.04-48.16, P = 0.006).
CONCLUSION: HER2 overexpression is not an independent prognostic marker of colorectal cancer, but DcR3 overexpression is highly correlated with lymph node metastasis and poor OS.
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Frequency of HER2 expression of circulating tumour cells in patients with metastatic or recurrent gastrointestinal cancer. Br J Cancer 2013; 109:2829-32. [PMID: 24201755 PMCID: PMC3844922 DOI: 10.1038/bjc.2013.680] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2013] [Revised: 09/24/2013] [Accepted: 10/08/2013] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND The clinical significance of circulating tumour cell (CTC) detection in gastrointestinal (GI) cancer remains controversial and the molecular biological characteristics of CTCs are poorly understood. METHODS A total of 87 patients with metastatic or recurrent GI cancer were prospectively enrolled. Circulating tumour cells and their HER2 status were assessed using the CellSearch System. RESULTS Among the 62 CTC-positive cases, we found 22 discordant cases (35.5%). Among the HER2-negative primary tumours, 17 of 54 developed HER2-positive CTCs. Five of eight had HER2-negative CTCs among the HER2-positive primary tumours. CONCLUSION The findings in the current study suggest that it is critical to evaluate the HER2 status of not only the primary tumour but also the CTCs because the metastasising tumour cells are the primary target of systemic therapy.
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Liu K, Chen H, You Q, Shi H, Wang Z. The siRNA cocktail targeting VEGF and HER2 inhibition on the proliferation and induced apoptosis of gastric cancer cell. Mol Cell Biochem 2013; 386:117-24. [PMID: 24158524 PMCID: PMC3889296 DOI: 10.1007/s11010-013-1850-0] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2013] [Accepted: 09/27/2013] [Indexed: 12/14/2022]
Abstract
The aim of this study was to investigate the inhibitory effect of a siRNA cocktail targeting Vascular endothelial growth factor (VEGF) and Human epidermal growth factor receptor 2 (HER2) on cell proliferation, induced apoptosis and the expression of VEGF and HER2 in human gastric carcinoma cell. The silencing rate of pre-designed siRNAs that targeted VEGF and HER2 was detected by Real-time Quantitative PCR (RT-QPCR) analysis. Furthermore, the best silencing siRNA that targeted VEGF and HER2 was prepared as a cocktail to co-knockdown VEGF and HER2 expression at both mRNA and protein levels which were detected by RT-QPCR and Western blot analysis. Cell proliferation inhibition rates were determined by CCK8 assay. The effect of siRNA cocktail on cell apoptosis was determined by flow cytometry. The migration inhibition of siRNA cocktail was analyzed by wound-healing assay. The ability of VEGF to induce endothelial cells to proliferate was examined in HUVECs by the method of tube formation assay. The pre-designed siRNAs could inhibit VEGF and HER2 mRNA level. siRNA cocktail, and co-downregulation of VEGF and HER2 result in significant inhibition of gastric cancer growth and migration in vitro. The inhibition of VEGF and HER2 expressions can induce apoptosis of SGC-7901 cells.
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Affiliation(s)
- Kun Liu
- Department of Cardiothoracic Surgery, The Affiliated Hospital of Nantong University, 20 Xisi Road, Nantong, 226001, Jiangsu, People's Republic of China
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Lim SW, Kim HR, Kim HY, Huh JW, Kim YJ, Shin JH, Suh SP, Ryang DW, Kim HR, Shin MG. Over-expression of Her-2 in colorectal cancer tissue, but not in serum, constitutes an independent worse prognostic factor. Cell Oncol (Dordr) 2013; 36:311-21. [PMID: 23722824 DOI: 10.1007/s13402-013-0136-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/20/2013] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Currently, conflicting information exists regarding Her-2 over-expression and its clinicopathological implications in colorectal cancer (CRC). This study was undertaken to determine Her-2 over-expression in both serum and tumor tissue of CRC patients, and to assess its clinicopathological and targeted therapeutic implications. METHODS Ninety five CRC patients and sixty healthy controls were prospectively enrolled. Her-2 expression status in serum and CRC tissue were examined by chemiluminescent immunoassay and immunohistochemical staining, respectively. The results were confirmed using fluorescent in situ hybridization. Clinicopathological parameters were analyzed according to Her-2 expression status. RESULTS Serum Her-2 levels were found to be increased in CRC patients as compared to those of healthy controls. However, serum Her-2 levels were not found to be significantly associated with prognostic parameters. Her-2 expression analysis of CRC tissues revealed Her-2 over-expression in 23 patients (25%), i.e., 13 patients (14%) showed moderate over-expression and 10 patients (11%) showed strong over-expression. The overall survival of patients negative for Her-2 expression was significantly better than that of patients positive for Her-2 expression (P=0.018). The disease-free survival of patients with Her-2 over-expression was significantly shorter than that of patients with no Her-2 expression (P=0.021). CONCLUSIONS Her-2 over-expression in CRC tissue, but not in serum, acts as a significant independent worse prognostic factor. Assessment of Her-2 expression status may be valuable for the targeted therapeutic management of CRC.
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Affiliation(s)
- Sang-Woo Lim
- Department of Surgery, Chonnam National University Medical School and Chonnam National University Hwasun Hospital, Hwasun, South Korea
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Blok EJ, Kuppen PJ, van Leeuwen JE, Sier CF. Cytoplasmic Overexpression of HER2: a Key Factor in Colorectal Cancer. CLINICAL MEDICINE INSIGHTS-ONCOLOGY 2013; 7:41-51. [PMID: 23471238 PMCID: PMC3583442 DOI: 10.4137/cmo.s10811] [Citation(s) in RCA: 55] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
Trastuzumab, a humanized mouse monoclonal antibody directed against HER2 (Human Epidermal Growth Factor Receptor 2), is currently a keystone in the treatment of breast cancer. Meanwhile, trastuzumab has been validated for use in other types of cancer too. But the data on HER2 expression in colorectal cancer are ambiguous, with reported overexpression of HER2 varying between zero and 84%. In this review these studies are evaluated and compared. It shows that many factors influence the determination of HER2-expression, especially of the intracellular fraction of HER2. It is concluded that although membranous overexpression of HER2 is low in colorectal cancer with only 5% of all patients being positive, a significant proportion of the patients (30%) shows cytoplasmic HER2 overexpression. The clinical impact of enhanced intracellular HER2 is not known, because the nature and origin have not completely been revealed yet. Enlightening this process could be a stepping stone towards targeting of intracellular HER2 as a treatment option.
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Affiliation(s)
- Erik J Blok
- Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands
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Expression of EGFR, HER2, phosphorylated ERK and phosphorylated MEK in colonic neoplasms of familial adenomatous polyposis patients. J Gastrointest Cancer 2013; 43:444-55. [PMID: 21989899 DOI: 10.1007/s12029-011-9330-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
PURPOSE The expression of epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) is associated with poor prognosis in sporadic colorectal carcinoma (CRC). EGFR inhibitors are approved for the treatment of refractory CRC. The aim of this study was to investigate the expression of EGFR and HER2 and downstream extracellular signal regulated kinase (ERK) and mitogen activated protein kinase (MAPK) in non-neoplastic colonic mucosa, adenomas and carcinomas from familial adenomatous polyposis coli (FAP) patients, exploring the expression along the adenoma-carcinoma sequence. METHODS The expression of EGFR, HER2, phosphorylated MAPK/ERK kinase (pMEK) and phosphorylated ERK (pERK) proteins was studied by immunohistochemistry in samples of colonic non-neoplastic mucosa (n = 65), adenomas (n = 149) and adenocarcinomas (n = 16) from each of the 16 FAP patients. RESULTS For HER2, only weak cytoplasmic expression was seen in 8% of adenomas, 6% of carcinomas and 3% of the non-neoplastic mucosa. EGFR was expressed in non-neoplastic mucosa, adenomas and carcinomas with a statistically significant increase in expression in adenomas compared with non-neoplastic mucosa (p < 0.001). There was also a statistically significant increase in nuclear staining intensity for pERK (p < 0.001) and pMEK (p < 0.001) in adenomas compared to non-neoplastic mucosa. CONCLUSIONS This is the first study investigating the expression of these receptors in non-neoplastic mucosa, adenomas and carcinomas from FAP patients. HER2 is not upregulated in the tumours of FAP patients, while EGFR appears to be upregulated in most adenomas and carcinomas, with associated upregulation of pERK and pMEK. We conclude that EGFR and downstream members of its signalling pathway, but not HER2, may be potential therapeutic targets in FAP patients.
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Li X, Kuang J, Shen Y, Majer MM, Nelson CC, Parsawar K, Heichman KA, Kuwada SK. The atypical histone macroH2A1.2 interacts with HER-2 protein in cancer cells. J Biol Chem 2012; 287:23171-83. [PMID: 22589551 DOI: 10.1074/jbc.m112.379412] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Because HER-2 has been demonstrated in the nuclei of cancer cells, we hypothesized that it might interact with transcription factors that activate ERBB2 transcription. Macrohistone 2A1 (H2AFY; mH2A1) was found to interact with HER-2 in cancer cells that overexpress HER-2. Of the two human mH2A1 isoforms, mH2A1.2, but not mH2A1.1, interacted with HER-2 in human cancer cell lines. Overexpression of mH2A1.2, but not mH2A1.1, in cancer cells significantly increased HER-2 expression and tumorigenicity. Inhibition of HER-2 kinase activity diminished mH2A1 expression and mH2A1.2-induced ERBB2 transcription in cancer cells. Chromatin immunoprecipitation of mH2A1.2 in cancer cells stably transfected with mH2A1.2 showed enrichment of mH2A1.2 at the HER-2 promoter, suggesting a role for mH2A1.2 in driving HER-2 overexpression. The evolutionarily conserved macro domain of mH2A1.2 was sufficient for the interaction between HER-2 and mH2A1.2 and for mH2A1.2-induced ERBB2 transcription. Within the macro domain of mH2A1.2, a trinucleotide insertion (-EIS-) sequence not found in mH2A1.1 was essential for the interaction between HER-2 and mH2A1.2 as well as mH2A1.2-induced HER-2 expression and cell proliferation.
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Affiliation(s)
- Xiufen Li
- Department of Medicine, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii 96813, USA
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Nautiyal J, Du J, Yu Y, Kanwar SS, Levi E, Majumdar APN. EGFR regulation of colon cancer stem-like cells during aging and in response to the colonic carcinogen dimethylhydrazine. Am J Physiol Gastrointest Liver Physiol 2012; 302:G655-63. [PMID: 22281474 PMCID: PMC3330776 DOI: 10.1152/ajpgi.00323.2011] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
One of the most consistent pathological conditions in the gastrointestinal tract with advancing age is malignancy, particularly gastrointestinal cancers, the incidence of which increases sharply with aging. Although the reasons for the age-related rise in colorectal cancer are not fully understood, we hypothesize that aging increases susceptibility of the colon to carcinogen(s)/toxicant(s), leading to an increase in cancer stem-like cells (CSLCs) that express cancer stem cell markers, in the colonic mucosa. The current study demonstrates that aging is associated with increased expression of several colon CSLC markers [CD44, CD166, and aldehyde dehydrogenase 1 (ALDH-1)] and a higher proportion of cells expressing these markers. Aging is also accompanied by increased expression of miR-21 in colon. These increases are further increased in response to the colonic carcinogen dimethylhydrazine (DMH). Aging is also associated with increased tyrosine-phosphorylated epidermal growth factor receptor (EGFR). Inhibition of EGFR using the EGFR inhibitor cetuximab abrogated the age-related increase in CD166 and ALDH-1 as well as miRNA (miR)-21. Our results provide new evidence that aging and DMH are associated with increases in CSLC biomarkers and miR21, each of which have been linked to colorectal cancer. EGFR inhibition attenuates these changes, indicating a role for EGFR in age- and mutagen-associated changes in CSLCs.
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Affiliation(s)
- Jyoti Nautiyal
- 1Veterans Affairs Medical Center, ,2Karmanos Cancer Institute, ,3Department of Internal Medicine,
| | - Jianhua Du
- 1Veterans Affairs Medical Center, ,3Department of Internal Medicine,
| | - Yingjie Yu
- 1Veterans Affairs Medical Center, ,3Department of Internal Medicine,
| | | | - Edi Levi
- 4Department of Pathology, Wayne State University, Detroit, Michigan
| | - Adhip P. N. Majumdar
- 1Veterans Affairs Medical Center, ,2Karmanos Cancer Institute, ,3Department of Internal Medicine,
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CDX-2 and HER-3 Expression in Canine Gastric and Colorectal Adenocarcinomas. J Comp Pathol 2011; 145:12-9. [DOI: 10.1016/j.jcpa.2010.11.007] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2010] [Revised: 08/26/2010] [Accepted: 11/12/2010] [Indexed: 11/15/2022]
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Marx AH, Burandt EC, Choschzick M, Simon R, Yekebas E, Kaifi JT, Mirlacher M, Atanackovic D, Bokemeyer C, Fiedler W, Terracciano L, Sauter G, Izbicki JR. Heterogenous high-level HER-2 amplification in a small subset of colorectal cancers. Hum Pathol 2010; 41:1577-85. [PMID: 20656317 DOI: 10.1016/j.humpath.2010.02.018] [Citation(s) in RCA: 64] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2009] [Revised: 01/04/2010] [Accepted: 02/05/2010] [Indexed: 12/12/2022]
Abstract
HER-2 is the molecular target for antibody-based treatment of breast cancer (trastuzumab). The potential benefit of anti-HER-2 therapy is currently investigated in several other HER-2 amplified cancers. For example, trastuzumab was recently shown to be effective in HER-2 positive gastric cancer. To address the potential applicability of anti-HER-2 therapy in colorectal cancer, tissue microarray sections and colorectal resection specimens of 1851 colorectal cancers were analyzed for HER-2 overexpression and amplification using FDA approved reagents for immunohistochemistry and fluorescence in situ hybridization. HER-2 amplification was seen in 2.5% and HER-2 overexpression in 2.7% of 1439 interpretable colorectal cancers. Amplification was often high level with HER-2 copies ranging from 4 to 60 per tumor cell and was strongly related to protein overexpression. HER-2 amplification and overexpression were unrelated to histological tumor type, tumor localization, grading, pT, pN, pM or survival. As heterogeneity of drug target expression could represent a major drawback for targeted cancer therapy we next studied HER-2 heterogeneity in selected cases. Extensive evaluation of all available large sections from patients with HER-2 positive colorectal cancer revealed heterogenous findings in 3 of 4 cases. In summary, high-level HER-2 amplification occurs in a small fraction of colorectal cancers. Heterogeneity of amplification may limit the utility of anti- HER-2 therapy in some of these tumors and therefore, adequate clinical trials are needed to further evaluate this approach.
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Affiliation(s)
- Andreas H Marx
- Institute for Pathology, Hubertus Wald Tumorzentrum-University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany.
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Shapira S, Lisiansky V, Arber N, Kraus S. Targeted immunotherapy for colorectal cancer: monoclonal antibodies and immunotoxins. Expert Opin Investig Drugs 2010; 19 Suppl 1:S67-77. [PMID: 20374033 DOI: 10.1517/13543781003737668] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Colorectal cancer (CRC) is a major health concern worldwide. It is the third most frequently diagnosed cancer and the second leading cause of cancer death. There currently are a number of treatment options for CRC, however many of them have failed to demonstrate desired therapeutic benefit. Therefore, significant efforts are being directed towards the development of new biological therapies with improved efficacy. Immunotherapy is an emerging treatment modality for a variety of cancers. Several promising treatments have already been approved by the US FDA and are being tested in clinical trials. Antibodies have been proved to be useful in cancer therapy due to their ability to recognize tumor-associated antigens expressed at higher density on malignant cells in comparison with those that are normal. Antibodies can be used as a single therapy or in combination with other therapies. A large variety of monoclonal antibodies have been developed. However, only a very few are able to kill a sufficient number of malignant cells and cause tumor regression. Hence, it is often necessary to arm the antibody with a cytotoxic agent to enhance the efficacy of the anti-tumor activity. This review provides a brief overview of some of the current agents being employed in targeted immunotherapy for CRC.
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Affiliation(s)
- Shiran Shapira
- The Integrated Cancer Prevention Center, Tel Aviv Medical Center, Israel
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ErbB family immunohistochemical expression in colorectal cancer patients with higher risk of recurrence after radical surgery. Int J Colorectal Dis 2009; 24:1059-68. [PMID: 19390858 DOI: 10.1007/s00384-009-0702-6] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/01/2009] [Indexed: 02/04/2023]
Abstract
PURPOSE Investigate ErbB family expression in colorectal cancer patients with higher risk of recurrence after surgical treatment. METHODS We studied 109 individuals with high risk stage II and stage III patients submitted to radical surgery. ErbB expression was assessed by tissue microarray technique. RESULTS The immunohistochemical expression was considered positive for EGFR, ErbB2, ErbB3, ErbB4 membrane, and ErbB4 cytoplasmic in respectively 57.8%, 8.3%, 69.7%, 11%, and 19.3% of patients. ErbB3 negative expression was associated with lymphovascular invasion. EGFR, ErbB2, and cytoplasmic ErbB4 expression was not associated with prognosis. Membranous positive ErbB4 expression was an independent prognostic factor for recurrence. ErbB3 negative expression was an independent prognostic factor for recurrence and survival in the multivariate analysis. CONCLUSIONS The immunohistochemical expression of ErbB3 and ErbB4 may identify a subgroup with stage II and III colorectal cancer at higher risk of recurrence.
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Farley J, Fuchiuji S, Darcy KM, Tian C, Hoskins WJ, McGuire WP, Hanjani P, Warshal D, Greer BE, Belinson J, Birrer MJ. Associations between ERBB2 amplification and progression-free survival and overall survival in advanced stage, suboptimally-resected epithelial ovarian cancers: a Gynecologic Oncology Group Study. Gynecol Oncol 2009; 113:341-7. [PMID: 19272639 DOI: 10.1016/j.ygyno.2009.02.009] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2008] [Revised: 01/29/2009] [Accepted: 02/04/2009] [Indexed: 10/21/2022]
Abstract
OBJECTIVE(S) The Gynecologic Oncology Group (GOG) examined the association between ERBB2 amplification and clinical covariates, tumor response, disease status post-chemotherapy, progression-free survival (PFS), and overall survival (OS) in epithelial ovarian cancer (EOC). METHODS Women with suboptimally-resected, advanced stage EOC who participated in GOG-111, a multi-center randomized phase III trial of cyclophosphamide+cisplatin versus paclitaxel+cisplatin, and provided a tumor block through the companion protocol GOG-9404 were eligible. ERBB2 amplification was examined using fluorescence in situ hybridization (FISH) with probes for ERBB2 and the centromere of chromosome 17 (CEP17). RESULTS ERBB2 amplification, defined as >2 copies of ERBB2/CEP17, was a rare event in EOC with 7% (9/133) of women exhibiting between 2.2 and 33.7 copies of ERBB2/CEP17, and was not associated with patient age, race, GOG performance status, stage, cell type, grade, measurable disease status, volume of ascites, tumor response or disease status post-chemotherapy. Women with >2 verses < or =2 copies of ERBB2/CEP17 did not have a reduced risk of disease progression (hazard ratio [HR]=0.56; 95% confidence interval [CI]=0.27-1.16; p=0.120) or death (HR=0.57; 95% CI=0.26-1.23; p=0.152), and ERBB2 amplification was not an independent prognostic factor for PFS or OS. ERBB2 amplification, defined as >4 copies of ERBB2/nuclei, was observed in 9% (12/133) of women with levels ranging from 4.2 to 49.2 copies of ERBB2/nuclei, and was associated with older age and volume of ascites, but not with the other clinical covariates or outcome. CONCLUSION(S) ERBB2 amplification is a rare event and has no predictive or prognostic value in suboptimally-resected, advanced stage EOC treated with platinum-based combination chemotherapy.
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Affiliation(s)
- John Farley
- Department of Obstetrics and Gynecology, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA
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Kavanagh DO, Chambers G, O'Grady L, Barry KM, Waldron RP, Bennani F, Eustace PW, Tobbia I. Is overexpression of HER-2 a predictor of prognosis in colorectal cancer? BMC Cancer 2009; 9:1. [PMID: 19118499 PMCID: PMC2648993 DOI: 10.1186/1471-2407-9-1] [Citation(s) in RCA: 105] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2008] [Accepted: 01/01/2009] [Indexed: 02/07/2023] Open
Abstract
Background The development of novel chemotherapeutic agents in colorectal cancer has improved survival. Following initial response to chemotherapeutic strategies many patients develop refractory disease. This poses a significant challenge common to many cancer subtypes. Newer agents such as Bevacizumab have successfully targeted the tyrosine kinase receptor epidermal growth factor receptor in metastatic colorectal cancer. Human epidermal growth factor receptor-2 is another member of the tyrosine kinase receptor family which has been successfully targeted in breast cancer. This may play a role in colorectal cancer. We conducted a clinicopathological study to determine if overexpression of human epidermal growth factor receptor-2 is a predictor of outcome in a cohort of patients with colorectal cancer. Methods Clinicopathological data and paraffin-embedded specimens were collected on 132 consecutive patients who underwent colorectal resections over a 24-month period at Mayo General Hospital. Twenty-six contained non-malignant disease. Her-2/neu protein overexpression was detected using immunohistochemistry (IHC). The HER-2 4B5 Ventana monoclonal antibody was used. Fluorescent insitu hybridisation (FISH) was performed using INFORM HER-2/Neu Plus. Results were correlated with established clinical and pathological predictors of outcome including TNM stage. Statistical analysis was performed using SPSS version 11.5. Results 114 were HER-2/Neu negative using IHC, 7 showed barely perceptible positivity (1+), 9 showed moderate staining (2+) and 2 were strongly positive (3+). There was no correlation with gender, age, grade, Dukes' stage, TNM stage, time to recurrence and 5-year survival (p > 0.05). FISH was applied to all 2+ and 3+ cases as well as some negative cases selected at random. Three were amplified (2 were 3+ and 1 was 2+). Similarly, HER-2 gene overexpression did not correlate with established prognostic indicators. Conclusion HER-2 protein is over expressed in 11% of colorectal cancer patients. The gene encoding HER-2 is amplified in 3% of cases. Overexpression of HER-2 is not a predictor of outcome. However, patients who over express HER-2 may respond to Herceptin therapy.
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Affiliation(s)
- Dara O Kavanagh
- Department of Surgery, Mayo General Hospital, Castlebar, Co Mayo, Ireland.
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Personeni N, Fieuws S, Piessevaux H, De Hertogh G, De Schutter J, Biesmans B, De Roock W, Capoen A, Debiec-Rychter M, Van Laethem JL, Peeters M, Humblet Y, Van Cutsem E, Tejpar S. Clinical usefulness of EGFR gene copy number as a predictive marker in colorectal cancer patients treated with cetuximab: a fluorescent in situ hybridization study. Clin Cancer Res 2008; 14:5869-76. [PMID: 18794099 DOI: 10.1158/1078-0432.ccr-08-0449] [Citation(s) in RCA: 142] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
PURPOSE To evaluate the usefulness and the pitfalls inherent to the assessment of the epidermal growth factor receptor (EGFR) gene copy number (GCN) by fluorescence in situ hybridization (FISH) for outcome prediction to cetuximab in metastatic colorectal cancer. The value of testing KRAS mutation status, in addition to EGFR GCN, was also explored. EXPERIMENTAL DESIGN FISH analysis of 87 metastatic colorectal cancer patients treated with cetuximab was done, recording individual GCN per cell and using different samples per tumor. Performances of published cutoff points and different summaries of EGFR GCN distribution were assessed for response prediction. RESULTS In our data set, two published cutoff points performed less well than in their training set, yielding positive predictive values and negative predictive values between 40.0% and 48.3% and between 81.0% and 86.5%, respectively. Among summaries of GCN distribution explored, mean and right-tailed distribution of GCN yielded the highest performances. A mean EGFR GCN > or = 2.83 provided an area under the curve of 0.71. Important heterogeneity of repeated measures of mean EGFR GCN was observed within tumors (intraclass correlation, 0.61; within-class SD, 0.40), leading to potential misclassifications of FISH status in 7 of 18 (38.8%) patients if a cutoff point were used. In multivariable analysis, EGFR GCN testing provided significant information independent of the KRAS status to predict response (P = 0.016) and overall survival (P = 0.005). CONCLUSIONS We confirm the association between increased EGFR GCN and outcome after cetuximab. However, because of reproducibility concerns, any decision making based on published cutoff points is not warranted.
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Affiliation(s)
- Nicola Personeni
- Digestive Oncology Unit, University Hospital Gasthuisberg, Leuven, Belgium
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Zeng ZS, Weiser MR, Kuntz E, Chen CT, Khan SA, Forslund A, Nash GM, Gimbel M, Yamaguchi Y, Culliford AT, D'Alessio M, Barany F, Paty PB. c-Met gene amplification is associated with advanced stage colorectal cancer and liver metastases. Cancer Lett 2008; 265:258-69. [PMID: 18395971 DOI: 10.1016/j.canlet.2008.02.049] [Citation(s) in RCA: 150] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2007] [Revised: 02/06/2008] [Accepted: 02/11/2008] [Indexed: 12/29/2022]
Abstract
The c-Met proto-oncogene encodes a receptor tyrosine kinase (TK) that promotes invasive tumor growth and metastasis. Recent studies show that the presence of c-Met gene amplification is predictive for selective c-Met TK inhibitors in gastric cancer and lung cancer. In this study, we utilized a highly quantitative PCR/ligase detection reaction technique to quantify c-Met gene copy number in primary colorectal cancer (CRC) (N=247), liver metastases (N=147), and paired normal tissues. We identified no differences in c-Met gene copy number between normal colonic mucosa and liver tissue. However, mean c-Met gene copy number was significantly elevated in CRC compared with normal mucosa (P<0.001), and in liver metastases compared with normal liver (P<0.001). Furthermore, a significant increase in c-Met was seen in liver metastases compared with primary CRC (P<0.0001). c-Met gene amplification was observed in 2% (3/177) of localized cancers, 9% (6/70) of cancers with distant metastases (P<0.02), and 18% (25/147) of liver metastases (P<0.01). Among patients treated by liver resection, there was a trend toward poorer 3-year survival in association with c-Met gene amplification (P=0.07). Slight increases in c-Met copy number can be detected in localized CRCs, but gene amplification is largely restricted to Stage IV primary cancers and liver metastases. c-Met gene amplification is linked to metastatic progression, and is a viable target for a significant subset of advanced CRC.
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Affiliation(s)
- Zhao-Shi Zeng
- Department of Surgery, Colorectal Service, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA
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Forslund A, Zeng Z, Qin LX, Rosenberg S, Ndubuisi M, Pincas H, Gerald W, Notterman DA, Barany F, Paty PB. MDM2 Gene Amplification Is Correlated to Tumor Progression but not to the Presence of SNP309 or TP53 Mutational Status in Primary Colorectal Cancers. Mol Cancer Res 2008; 6:205-11. [DOI: 10.1158/1541-7786.mcr-07-0239] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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Her-2 Protein Expression, Cellular Localization, and Gene Amplification in Colorectal Carcinoma. Appl Immunohistochem Mol Morphol 2007; 15:441-5. [DOI: 10.1097/01.pai.0000213156.94804.b5] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Lambropoulou M, Stefanou D, Alexiadis G, Tamiolakis D, Tripsianis G, Chatzaki E, Vandoros GP, Kiziridou A, Papadopoulou E, Papadopoulos N. Cytoplasmic expression of c-erb-B2 in endometrial carcinomas. Oncol Res Treat 2007; 30:495-500. [PMID: 17890888 DOI: 10.1159/000107734] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
BACKGROUND The aim of this study was to investigate the expression of c-erb-B2 in endometrial cancer with attention to both membranous and cytoplasmic staining, and to elucidate the significance of cytoplasmic signaling. MATERIALS AND METHODS c-erb-B2 reactivity was assessed by immunohistochemistry in 110 patients using a polyclonal antibody, and evaluated semiquantitatively according to the percentage of cells demonstrating membranous or diffuse cytoplasmic staining. Correlation was made with tumor stage, grade, myometrial invasion, histologic type, and disease outcome. RESULTS c-erb-B2 overexpression, indicated by membranous and cytoplasmic staining of at least 10% of the tumor cells, was found in 47 (42.7%) cases. Cytoplasmic expression of c-erb-B2 was observed more frequently than membranous (69.1 vs. 5.5%). Synchronous cytoplasmic and membranous signaling was noticed in 7.9% of cases. Interestingly, patients with cytoplasmic c-erb-B2-positive tumors had a significantly shorter survival (p = 0.047). CONCLUSIONS These results indicate that c-erb-B2 is a specific marker of endometrial cancer. It is also an independent prognostic indicator of poor outcome. Cytoplasmic staining is as important as membranous staining, and is also a specific finding.
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Affiliation(s)
- Maria Lambropoulou
- Department of Histology/Embryology, Democritus University of Thrace, Alexandroupolis, Greece
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Antonescu CR, Busam KJ, Francone TD, Wong GC, Guo T, Agaram NP, Besmer P, Jungbluth A, Gimbel M, Chen CT, Veach D, Clarkson BD, Paty PB, Weiser MR. L576P KIT mutation in anal melanomas correlates with KIT protein expression and is sensitive to specific kinase inhibition. Int J Cancer 2007; 121:257-64. [PMID: 17372901 DOI: 10.1002/ijc.22681] [Citation(s) in RCA: 206] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
Activating mutations in either BRAF or NRAS are seen in a significant number of malignant melanomas, but their incidence appears to be dependent to ultraviolet light exposure. Thus, BRAF mutations have the highest incidence in non-chronic sun damaged (CSD), and are uncommon in acral, mucosal and CSD melanomas. More recently, activating KIT mutations have been described in rare cases of metastatic melanoma, without further reference to their clinical phenotypes. This finding is intriguing since KIT expression is downregulated in most melanomas progressing to more aggressive lesions. In this study, we investigated a group of anal melanomas for the presence of BRAF, NRAS, KIT and PDGFRA mutations. A heterozygous KIT exon 11 L576P substitution was identified in 3 of 20 cases tested. The 3 KIT mutation-carrying tumors were strongly immunopositive for KIT protein. No KIT mutations were identified in tumors with less than 4+ KIT immunostaining. NRAS mutation was identified in one tumor. No BRAF or PDGFRA mutations were identified in either KIT positive or negative anal melanomas. In vitro drug testing of stable transformant Ba/F3 KIT(L576P) mutant cells showed sensitivity for dasatinib (previously known as BMS-354825), a dual SRC/ABL kinase inhibitor, and imatinib. However, compared to an imatinib-sensitive KIT mutant, dasatinib was potent at lower doses than imatinib in the KIT(L576P) mutant. These results suggest that a subset of anal melanomas show activating KIT mutations, which are susceptible for therapy with specific kinase inhibitors.
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Affiliation(s)
- Cristina R Antonescu
- Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
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Park DI, Kang MS, Oh SJ, Kim HJ, Cho YK, Sohn CI, Jeon WK, Kim BI, Han WK, Kim H, Ryu SH, Sepulveda AR. HER-2/neu overexpression is an independent prognostic factor in colorectal cancer. Int J Colorectal Dis 2007; 22:491-7. [PMID: 16947041 DOI: 10.1007/s00384-006-0192-8] [Citation(s) in RCA: 69] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/11/2006] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND AIMS The HER-2/neu protein is intimately involved with normal cell proliferation and tissue growth, as it is extensively homologous and is related to the epidermal growth factor receptor. This phenomenon has been most intensively studied in the context of breast carcinoma, in which its amplification and overexpression correlate with the overall course of disease and poor prognoses, and also constitute a predictive factor of poor response to chemotherapy and endocrine therapy. In this study, we investigated the relationships between the expression of HER-2/neu and the clinicopathological characteristics of colorectal cancer, including survival. This study was performed with a view toward the future introduction of Herceptin therapy for colorectal cancer patients. PATIENTS AND METHODS HER-2/neu overexpression and gene amplification were examined via semiquantitative standardized immunohistochemical staining and fluorescence in situ hybridization (FISH) in 137 colorectal cancer patients who underwent curative surgery at the Kangbuk Samsung Hospital. RESULTS Sixty-five (47.4%) out of 137 patients were determined by immunohistochemistry to have overexpressed HER-2/neu protein. HER-2/neu gene amplification was detected in two patients by FISH. Tumors with HER-2/neu overexpression showed higher postoperative recurrence rate (39.3% vs 14.6%, p=0.013). Tumors with HER-2/neu overexpression were associated with poor 3-year (70.8% vs 83.7%) and 5-year survival rates (55.1% vs 78.3%, p<0.05). Advanced TNM stage, postoperative recurrence, and overexpression of HER-2/neu were found to be independently related to survival by multivariate analysis. CONCLUSION HER-2/neu overexpression may constitute an independent prognostic factor in colorectal cancer patients, and patients exhibiting HER-2/neu overexpression might constitute potential candidates for a new adjuvant therapy which involves the use of humanized monoclonal antibodies.
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Affiliation(s)
- Dong Il Park
- Department of Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, South Korea
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