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Dhanya CR, Mary AS, Madhavan M. Aptamer-siRNA chimeras: Promising tools for targeting HER2 signaling in cancer. Chem Biol Drug Des 2022; 101:1162-1180. [PMID: 36099164 DOI: 10.1111/cbdd.14143] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2021] [Revised: 08/28/2022] [Accepted: 09/11/2022] [Indexed: 11/30/2022]
Abstract
RNA interference is a transformative approach and has great potential in the development of novel and more efficient cancer therapeutics. Immense prospects exist in the silencing of HER2 and its downstream genes which are overexpressed in many cancers, through exogenously delivered siRNA. However, there is still a long way to exploit the full potential and versatility of siRNA therapeutics due to the challenges associated with the stability and delivery of siRNA targeted to specific sites. Aptamers offer several advantages as a vehicle for siRNA delivery, over other carriers such as antibodies. In this review, we discuss the progress made in the development and applications of aptamer-siRNA chimeras in HER2 targeting and gene silencing. A schematic workflow is also provided which will provide ample insight for all those researchers who are new to this field. Also, we think that a mechanistic understanding of the HER2 signaling pathway is crucial in designing extensive investigations aimed at the silencing of a wider array of genes. This review is expected to stimulate more research on aptamer-siRNA chimeras targeted against HER2 which might arm us with potential effective therapeutic interventions for the management of cancer.
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Affiliation(s)
- C R Dhanya
- Department of Biochemistry, Government College Kariavattom, Thiruvananthapuram, Kerala, India
| | - Aarcha Shanmugha Mary
- Department of Microbiology, Central University of Tamil Nadu, Thiruvarur, Tamil Nadu, India
| | - Maya Madhavan
- Department of Biochemistry, Government College for Women, Thiruvananthapuram, Kerala, India
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2
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McShane R, Arya S, Stewart AJ, Caie P, Bates M. Prognostic features of the tumour microenvironment in oesophageal adenocarcinoma. Biochim Biophys Acta Rev Cancer 2021; 1876:188598. [PMID: 34332022 DOI: 10.1016/j.bbcan.2021.188598] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 07/26/2021] [Accepted: 07/26/2021] [Indexed: 12/12/2022]
Abstract
Oesophageal adenocarcinoma (OAC) is a disease with an incredibly poor survival rate and a complex makeup. The growth and spread of OAC tumours are profoundly influenced by their surrounding microenvironment and the properties of the tumour itself. Constant crosstalk between the tumour and its microenvironment is key to the survival of the tumour and ultimately the death of the patient. The tumour microenvironment (TME) is composed of a complex milieu of cell types including cancer associated fibroblasts (CAFs) which make up the tumour stroma, endothelial cells which line blood and lymphatic vessels and infiltrating immune cell populations. These various cell types and the tumour constantly communicate through environmental cues including fluctuations in pH, hypoxia and the release of mitogens such as cytokines, chemokines and growth factors, many of which help promote malignant progression. Eventually clusters of tumour cells such as tumour buds break away and spread through the lymphatic system to nearby lymph nodes or enter the circulation forming secondary metastasis. Collectively, these factors need to be considered when assessing and treating patients clinically. This review aims to summarise the ways in which these various factors are currently assessed and how they relate to patient treatment and outcome at an individual level.
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Affiliation(s)
| | - Swati Arya
- School of Medicine, University of St Andrews, Fife, UK
| | | | - Peter Caie
- School of Medicine, University of St Andrews, Fife, UK
| | - Mark Bates
- Department of Surgery, Trinity Translational Medicine Institute, St. James's Hospital, Dublin 8, Ireland; Trinity St James's Cancer Institute, St James's Hospital, Dublin 8, Ireland.
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Isidori F, Bozzarelli I, Mastracci L, Malvi D, Lugaresi M, Molinari C, Söderström H, Räsänen J, D'Errico A, Fiocca R, Seri M, Krishnadath KK, Bonora E, Mattioli S. Targeted Sequencing of Sorted Esophageal Adenocarcinoma Cells Unveils Known and Novel Mutations in the Separated Subpopulations. Clin Transl Gastroenterol 2020; 11:e00202. [PMID: 33094962 PMCID: PMC7508445 DOI: 10.14309/ctg.0000000000000202] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2020] [Accepted: 06/12/2020] [Indexed: 01/22/2023] Open
Abstract
INTRODUCTION Our study aimed at investigating tumor heterogeneity in esophageal adenocarcinoma (EAC) cells regarding clinical outcomes. METHODS Thirty-eight surgical EAC cases who underwent gastroesophageal resection with lymph node dissection in 3 university centers were included. Archival material was analyzed via high-throughput cell sorting technology and targeted sequencing of 63 cancer-related genes. Low-pass sequencing and immunohistochemistry (IHC) were used to validate the results. RESULTS Thirty-five of 38 EACs carried at least one somatic mutation that was absent in the stromal cells; 73.7%, 10.5%, and 10.5% carried mutations in tumor protein 53, cyclin dependent kinase inhibitor 2A, and SMAD family member 4, respectively. In addition, 2 novel mutations were found for hepatocyte nuclear factor-1 alpha in 2 of 38 cases. Tumor protein 53 gene abnormalities were more informative than p53 IHC. Conversely, loss of SMAD4 was more frequently noted with IHC (53%) and was associated with a higher recurrence rate (P = 0.015). Only through cell sorting we were able to detect the presence of hyperdiploid and pseudodiploid subclones in 7 EACs that exhibited different mutational loads and/or additional copy number amplifications, indicating the high genetic heterogeneity of these cancers. DISCUSSION Selective cell sorting allowed the characterization of multiple molecular defects in EAC subclones that were missed in a significant number of cases when whole-tumor samples were analyzed. Therefore, this approach can reveal subtle differences in cancer cell subpopulations. Future studies are required to investigate whether these subclones are responsible for treatment response and disease recurrence.
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Affiliation(s)
- Federica Isidori
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy;
| | - Isotta Bozzarelli
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy;
| | - Luca Mastracci
- Department of Surgical and Diagnostic Sciences (DISC), University of Genova
- Department of Pathology, IRCCS Ospedale Policlinico San Martino, Genova, Italy;
| | - Deborah Malvi
- Department of Experimental, Institute of Oncology and Transplant Pathology, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy
| | - Marialuisa Lugaresi
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy;
- Division of Thoracic Surgery- Maria Cecilia Hospital, Cotignola, Italy;
| | - Chiara Molinari
- Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy;
| | - Henna Söderström
- Department of General Thoracic Surgery, Helsinki University Central Hospital, Helsinki, Finland;
| | - Jari Räsänen
- Department of General Thoracic Surgery, Helsinki University Central Hospital, Helsinki, Finland;
| | - Antonia D'Errico
- Department of Experimental, Institute of Oncology and Transplant Pathology, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy
| | - Roberto Fiocca
- Department of Surgical and Diagnostic Sciences (DISC), University of Genova
- Department of Pathology, IRCCS Ospedale Policlinico San Martino, Genova, Italy;
| | - Marco Seri
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy;
| | - Kausilia K. Krishnadath
- Department of Gastroenterology and Hepatology, Center for Experimental and Molecular Medicine, Academic Medical Center, Amsterdam, the Netherlands.
| | - Elena Bonora
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy;
| | - Sandro Mattioli
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy;
- Division of Thoracic Surgery- Maria Cecilia Hospital, Cotignola, Italy;
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Franks SE, Wolfson B, Hodge JW. Natural Born Killers: NK Cells in Cancer Therapy. Cancers (Basel) 2020; 12:E2131. [PMID: 32751977 PMCID: PMC7465121 DOI: 10.3390/cancers12082131] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Revised: 07/21/2020] [Accepted: 07/27/2020] [Indexed: 01/08/2023] Open
Abstract
Cellular therapy has emerged as an attractive option for the treatment of cancer, and adoptive transfer of chimeric antigen receptor (CAR) expressing T cells has gained FDA approval in hematologic malignancy. However, limited efficacy was observed using CAR-T therapy in solid tumors. Natural killer (NK) cells are crucial for tumor surveillance and exhibit potent killing capacity of aberrant cells in an antigen-independent manner. Adoptive transfer of unmodified allogeneic or autologous NK cells has shown limited clinical benefit due to factors including low cell number, low cytotoxicity and failure to migrate to tumor sites. To address these problems, immortalized and autologous NK cells have been genetically engineered to express high affinity receptors (CD16), CARs directed against surface proteins (PD-L1, CD19, Her2, etc.) and endogenous cytokines (IL-2 and IL-15) that are crucial for NK cell survival and cytotoxicity, with positive outcomes reported by several groups both preclinically and clinically. With a multitude of NK cell-based therapies currently in clinic trials, it is likely they will play a crucial role in next-generation cell therapy-based treatment. In this review, we will highlight the recent advances and limitations of allogeneic, autologous and genetically enhanced NK cells used in adoptive cell therapy.
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Affiliation(s)
- S Elizabeth Franks
- Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Benjamin Wolfson
- Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - James W Hodge
- Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
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Synthesis and Enhanced Cellular Uptake In Vitro of Anti-HER2 Multifunctional Gold Nanoparticles. Cancers (Basel) 2019; 11:cancers11060870. [PMID: 31234432 PMCID: PMC6628063 DOI: 10.3390/cancers11060870] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2019] [Revised: 06/13/2019] [Accepted: 06/17/2019] [Indexed: 11/20/2022] Open
Abstract
Nanoparticle carriers offer the possibility of enhanced delivery of therapeutic payloads in tumor tissues due to tumor-selective accumulation through the enhanced permeability and retention effect (EPR). Gold nanoparticles (AuNP), in particular, possess highly appealing features for development as nanomedicines, such as biocompatibility, tunable optical properties and a remarkable ease of surface functionalization. Taking advantage of the latter, several strategies have been designed to increase treatment specificity of gold nanocarriers by attaching monoclonal antibodies on the surface, as a way to promote selective interactions with the targeted cells—an approach referred to as active-targeting. Here, we describe the synthesis of spherical gold nanoparticles surface-functionalized with an anti-HER2 antibody-drug conjugate (ADC) as an active targeting agent that carries a cytotoxic payload. In addition, we enhanced the intracellular delivery properties of the carrier by attaching a cell penetrating peptide to the active-targeted nanoparticles. We demonstrate that the antibody retains high receptor-affinity after the structural modifications performed for drug-conjugation and nanoparticle attachment. Furthermore, we show that antibody attachment increases cellular uptake in HER2 amplified cell lines selectively, and incorporation of the cell penetrating peptide leads to a further increase in cellular internalization. Nanoparticle-bound antibody-drug conjugates retain high antimitotic potency, which could contribute to a higher therapeutic index in high EPR tumors.
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Budiarto BR, Pohan PU, Desriani. Nucleic acid amplification-based HER2 molecular detection for breast cancer. JOURNAL OF ONCOLOGICAL SCIENCES 2019. [DOI: 10.1016/j.jons.2018.12.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022] Open
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van der Kaaij RT, Snaebjornsson P, Voncken FE, van Dieren JM, Jansen EP, Sikorska K, Cats A, van Sandick JW. The prognostic and potentially predictive value of the Laurén classification in oesophageal adenocarcinoma. Eur J Cancer 2017; 76:27-35. [DOI: 10.1016/j.ejca.2017.01.031] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2016] [Revised: 01/11/2017] [Accepted: 01/29/2017] [Indexed: 12/25/2022]
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Gramlich TL, Fritsch C, Cohen C, Samuel M, Hunt D, Dean PJ, Gansler T. Oncogene Expression and Amplification in Barrett Adenocarcinoma. Int J Surg Pathol 2016. [DOI: 10.1177/106689699700400402] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Oncogene activation by amplification and/or overexpression has been implicated in the development and progression of a number of malignancies. To better define the role of oncogene activation in adenocarcinomas arising in the setting of Barrett esophagus, we examined 44 resected Barrett adenocarcinomas for c-erb B-2, epidermal growth factor receptor (EGFR), c-myc, and cyclin DI gene amplification as well as c-erb B-2 and EGFR expression. DNA was extracted from formalin-fixed paraffin-embedded tissue and analyzed by differential polymerase chain reaction, a technique that permits semiquantitative analysis of gene dosage on archival material. Formalinfixed paraffin-embedded sections were stained with monoclonal antibodies directed against either the internal domain of c-erb B-2 or the extracellular domain of EGFR with a labeled streptavidin biotin technique. C-erb B-2 amplification was identified in three (7%) cases. A plasma membrane pattern of c-erb B-2 immunoreactivity in >50% of tumor cells correlated highly with c-erb B-2 amplification ( P=.00008). EGFR amplification was noted in 18% of cases and correlated highly with the intensity of EGFR immunoreactivity ( P=.0004). C-myc amplification was present in 18% of cases. No tumors showed cyclin DI amplification. Follow-up was available regarding 29 patients and showed decreased mean survival ( P=.029) in patients with strong EGFR immunoreactivity (5.8 months) versus those with weak or absent EGFR labeling (11.8 months), and a trend toward decreased one-year survival (P=.069) for patients with (17%) versus those without (52%) c-myc amplification. Our results indicate one or more selected oncogenes are amplified/overexpressed in some Barrett adenocarcinomas and that EGFR and c-erb B-2 overexpression correlates with amplification. Additionally, strong EGFR expression in tumor cells indicates a poorer prognosis.
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Affiliation(s)
- Terry L. Gramlich
- Department of Pathology, Emory University Hospital, Atlanta, Georgia; Department of Anatomic Pathology (L25), Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, Ohio 44195
| | | | | | | | - Dirk Hunt
- Department of Pathology, Emory University Hospital, Atlanta, Georgia
| | - Patrick J. Dean
- Baptist Memorial Hospital, Memphis, Tennessee; Department of Pathology, Emory University Hospital, Atlanta, Georgia
| | - Ted Gansler
- Department of Pathology, Emory University Hospital, Atlanta, Georgia
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Chan E, Duckworth LV, Alkhasawneh A, Toro TZ, Lu X, Ben-David K, Hughes SJ, Rossidis G, Zlotecki R, Lightsey J, Daily KC, Dang L, Allegra CJ, King B, George TJ. Discordant HER2 expression and response to neoadjuvant chemoradiotherapy in esophagogastric adenocarcinoma. J Gastrointest Oncol 2016; 7:173-80. [PMID: 27034783 PMCID: PMC4783750 DOI: 10.3978/j.issn.2078-6891.2015.071] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2015] [Accepted: 06/05/2015] [Indexed: 01/11/2023] Open
Abstract
BACKGROUND Targeting human epidermal growth factor receptor 2 (HER2) with trastuzumab in metastatic esophagogastric adenocarcinoma (EGA) improves survival. The impact of HER2 inhibition in combination with chemoradiotherapy (CRT) in early stage EGA is under investigation. This study analyzed the pattern of HER2 overexpression in matched-pair tumor samples of patients who underwent neoadjuvant CRT followed by surgery. METHODS All patients with EGA who underwent standard neoadjuvant CRT followed by esophagectomy at the University of Florida were included. Demographics, risk factors, tumor features, and outcome data were analyzed. Descriptive statistics, Chi-square exact test, uni- and multivariate analyses, and Kaplan Meier method were used. HER2 expression determined by immunohistochemical (IHC) was scored as negative (0, 1+), indeterminate (2+) or positive (3+). RESULTS Among 49 sequential patients (41 M/8 F) with matched-pair tumor samples, 9/49 patients (18%) had pathologic complete response (pCR), 10/49 had near pCR or not enough tumor (NET) to examine in the post- treatment samples. Patients with initial HER2 negativity demonstrated conversion to HER2 positivity after neoadjuvant CRT (7/30 cases; 23%). Baseline HER2 overexpression was more common in lower stage/node negative patients (67% in stages I, IIA vs. 33% in stages IIB, III) and did not correlate with treatment response or survival. CONCLUSIONS Although limited by a relatively small sample size, our study failed to demonstrate that baseline HER2 protein over-expression in EGA predicts response to standard CRT. However, our data suggested that HER2 was up regulated by CRT resulting in unreliable concordance between pre-treatment (pre-tx) and post-treatment (post-tx) samples. Pre-therapy HER2 expression may not reliably reflect the HER2 status of persistent or recurrent disease.
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Nagaraja V, Shaw N, Morey AL, Cox MR, Eslick GD. HER2 expression in oesophageal carcinoma and Barrett's oesophagus associated adenocarcinoma: An Australian study. EUROPEAN JOURNAL OF SURGICAL ONCOLOGY 2016; 42:140-148. [PMID: 26422587 DOI: 10.1016/j.ejso.2015.08.159] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2015] [Revised: 08/05/2015] [Accepted: 08/06/2015] [Indexed: 12/11/2022]
Abstract
BACKGROUND Several studies have evaluated the prognostic value of HER2 in oesophageal cancer, but the prognostic influence of HER2 overexpression in oesophageal cancer remains uncertain. The aim of this study was to assess the incidence of HER2 positivity and relationship with clinicopathological features in patients with oesophageal cancer. DESIGN The study cohort consisted of 269 patients diagnosed with oesophageal carcinoma in a single institution. HER2 expression was analysed by immunohistochemistry (IHC) and silver in situ hybridization (SISH) in 152 archival oesophageal cancer specimens. Survival analysis was assessed using Hazard models. RESULTS HER2 expression was IHC3+ in 14 (9.2%), IHC2+ in 14 (9.2%), IHC1+ in 57 (37.5%), and IHC0 in 67 (44.1%) cases. SISH results confirmed that 15 specimens (9.9%) were HER2 gene amplified. Among 27 squamous cell carcinomas (SCCs) only 3.7% were HER2 positive whereas 11.2% of 125 adenocarcinomas were HER2 positive. The HER2 positive tumours were more likely to occur in men (OR: 5.00, 95% CI: 1.69-14.29), smokers (OR: 10.00, 95% CI: 4.17-25) and in patients with Barrett's oesophagus (OR: 8.33, 95% CI: 3.71-20.00). There was no significant difference in survival between the (HER2 +ve, 14.3 months vs HER2 -ve, 24.6 months, p = 0.42) CONCLUSION: A HER2 prevalence rate of 9.9% was found among patients with oesophageal cancer and no correlation with survival was detected overall.
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Affiliation(s)
- V Nagaraja
- The Whiteley-Martin Research Centre, Discipline of Surgery, The University of Sydney, Nepean Hospital, Penrith, New South Wales, Australia
| | - N Shaw
- Department of Pathology, St. Vincent's Hospital, Darlinghurst, New South Wales, Australia
| | - A L Morey
- Department of Pathology, St. Vincent's Hospital, Darlinghurst, New South Wales, Australia
| | - M R Cox
- The Whiteley-Martin Research Centre, Discipline of Surgery, The University of Sydney, Nepean Hospital, Penrith, New South Wales, Australia
| | - G D Eslick
- The Whiteley-Martin Research Centre, Discipline of Surgery, The University of Sydney, Nepean Hospital, Penrith, New South Wales, Australia.
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Iqbal N, Iqbal N. Human Epidermal Growth Factor Receptor 2 (HER2) in Cancers: Overexpression and Therapeutic Implications. Mol Biol Int 2014; 2014:852748. [PMID: 25276427 PMCID: PMC4170925 DOI: 10.1155/2014/852748] [Citation(s) in RCA: 799] [Impact Index Per Article: 72.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2014] [Revised: 08/18/2014] [Accepted: 08/19/2014] [Indexed: 02/07/2023] Open
Abstract
Human epidermal growth factor receptor 2 (HER2) is a member of the epidermal growth factor receptor family having tyrosine kinase activity. Dimerization of the receptor results in the autophosphorylation of tyrosine residues within the cytoplasmic domain of the receptors and initiates a variety of signaling pathways leading to cell proliferation and tumorigenesis. Amplification or overexpression of HER2 occurs in approximately 15-30% of breast cancers and 10-30% of gastric/gastroesophageal cancers and serves as a prognostic and predictive biomarker. HER2 overexpression has also been seen in other cancers like ovary, endometrium, bladder, lung, colon, and head and neck. The introduction of HER2 directed therapies has dramatically influenced the outcome of patients with HER2 positive breast and gastric/gastroesophageal cancers; however, the results have been proved disappointing in other HER2 overexpressing cancers. This review discusses the role of HER2 in various cancers and therapeutic modalities available targeting HER2.
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Affiliation(s)
- Nida Iqbal
- Department of Medical Oncology, Dr. B. R. A. Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi 110029, India
| | - Naveed Iqbal
- Department of Anaesthesia and Intensive Care Unit, Indraprastha Apollo Hospital, New Delhi 110076, India
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HER2/neu: an increasingly important therapeutic target. Part 2: Distribution of HER2/neu overexpression and gene amplification by organ, tumor site and histology. ACTA ACUST UNITED AC 2014. [DOI: 10.4155/cli.14.62] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
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Gowryshankar A, Nagaraja V, Eslick GD. HER2 status in Barrett's esophagus & esophageal cancer: a meta analysis. J Gastrointest Oncol 2014; 5:25-35. [PMID: 24490040 PMCID: PMC3904023 DOI: 10.3978/j.issn.2078-6891.2013.039] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2012] [Accepted: 06/07/2013] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND The oncogenic potential of the Human Epidermal Growth Factor Receptor 2 (HER2) is well known in the context of breast cancer however; its relationship with the development of Barrett's Esophagus (BE) and Esophageal Cancer (EC) is unclear. The aim of this meta-analysis was to determine the overall prevalence and survival of HER2+ in BE & EC. PATIENTS AND METHODS Several databases were searched including article reference lists. Inclusion criteria required that studies measured HER2 positivity in subjects with BE or EC. RESULTS 33 studies were included in the meta-analysis (10 BE & 23 EC studies). The prevalence of HER2+ was found to be 24% (95% CI: 15-36%) in BE and 26% (95% CI: 19-34%) in EC. Squamous cell carcinoma (SCC) had a higher ER of 32% (95% CI: 20-48%) in comparison with adenocarcinoma (ADC) with an ER of 21% (95% CI: 14-32%). Sub group analyses showed a high geographical variance, Asia was found to be the highest prevalent area with an ER 42% (95% CI: 22-64%). The difference in survival rate between groups HER2- & HER2+ was found to be 7 months. CONCLUSIONS Our results highlight a high prevalence of HER2+ in subjects with adenocarcinoma. HER2+ appears to decrease the survival time of EC patients.
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Affiliation(s)
- Ashwini Gowryshankar
- The Whiteley-Martin Research Centre, The Discipline of Surgery, The University of Sydney, Sydney Medical School, Nepean, Penrith, New South Wales, Australia
| | - Vinayak Nagaraja
- The Whiteley-Martin Research Centre, The Discipline of Surgery, The University of Sydney, Sydney Medical School, Nepean, Penrith, New South Wales, Australia
| | - Guy D Eslick
- The Whiteley-Martin Research Centre, The Discipline of Surgery, The University of Sydney, Sydney Medical School, Nepean, Penrith, New South Wales, Australia
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Abstract
Cancer of the esophagus is an aggressive disease with early lymphatic and hematogenous dissemination and at present often considered as one clinical entity because of their comparable increasing incidence, prognosis and optimal treatment options. However, it is still a matter of debate whether these malignancies have the same pathogenesis and genotype. Despite recent advances, treatment of upper gastrointestinal malignancies remains a significant challenge. Molecular pathology has revealed many molecular mechanisms of disease progression, which are related to prognosis. Better knowledge of molecular bases may lead to new paradigms, improved prognostication, early diagnosis and individually tailored therapeutic options. This review summarizes the rationale, preclinical evidence, retrospective clinical analyses and the interim clinical data pertaining HER2 therapy and many other molecular pathways.
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Affiliation(s)
- Vinayak Nagaraja
- The Whiteley-Martin Research Centre, Discipline of Surgery, The University of Sydney, Nepean Hospital, Sydney, NSW, Australia
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15
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Prins M, Ruurda J, van Diest P, van Hillegersberg R, ten Kate F. The significance of the HER-2 status in esophageal adenocarcinoma for survival: an immunohistochemical and an in situ hybridization study. Ann Oncol 2013; 24:1290-7. [DOI: 10.1093/annonc/mds640] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023] Open
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Yantiss RK, Samowitz WS. Molecular Pathology of Gastrointestinal Cancer. Surg Pathol Clin 2012; 5:821-42. [PMID: 26838505 DOI: 10.1016/j.path.2012.08.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
The purpose of this review is to discuss important molecular changes that aid decision making in patient management and play a role in emerging treatment strategies for gastrointestinal malignancies. Although screening and surveillance practices have had an impact on the natural history of some tumor types, gastric carcinoma is a major cause of morbidity and mortality in high prevalence regions and colorectal carcinoma is still the fourth leading cause of cancer related death in the United States.
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Affiliation(s)
- Rhonda K Yantiss
- Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, 525 East 68th Street, New York, NY 10065, USA
| | - Wade S Samowitz
- Department of Pathology, University of Utah, 15 N. Medical Drive East-2100, Salt Lake City, UT 84112.
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Tanaka T, Fujimura A, Ichimura K, Yanai H, Sato Y, Takata K, Okada H, Kawano S, Tanabe S, Yoshino T. Clinicopathological characteristics of human epidermal growth factor receptor 2-positive Barrett's adenocarcinoma. World J Gastroenterol 2012; 18:6263-6268. [PMID: 23180947 PMCID: PMC3501775 DOI: 10.3748/wjg.v18.i43.6263] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To compare the clinicopathological characteristics of human epidermal growth factor receptor 2 (HER2)-positive and HER2-negative Barrett’s adenocarcinoma in Japan.
METHODS: We performed immunohistochemical analysis of HER2 in 30 samples taken from patients with Barrett’s adenocarcinoma and dual color in situ hybridization in cases showing 2+ reactions. We compared the clinicopathological characteristics of HER2-positive and HER2-negative patients.
RESULTS: HER2 positivity was identified in 8 (27%) carcinoma samples. We found that HER2 expression was associated with p53 overexpression (100% vs 52.6% in pT1 tumor; 100% vs 54.5% in all stage tumor, P < 0.05) and protruding lesions at the early disease stage. There was no association between the mucin phenotype of the carcinomas and prognosis. HER2 expression and low clinical stage were unexpectedly different between Barrett’s adenocarcinoma patients and gastric cancer patients, but the macroscopic features may be associated with earlier diagnosis in these patients.
CONCLUSION: Our results suggest that HER2-positive Barrett’s adenocarcinomas are associated with p53 overexpression and lesion protrusion at the early disease stage.
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Systematic review and meta-analysis of the influence of HER2 expression and amplification in operable oesophageal cancer. J Gastrointest Surg 2012; 16:1821-9. [PMID: 22843084 DOI: 10.1007/s11605-012-1979-2] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2012] [Accepted: 07/19/2012] [Indexed: 01/31/2023]
Abstract
INTRODUCTION The prognostic significance of human epidermal growth factor 2 (HER2) overexpression in patients diagnosed with oesophageal cancer is controversial. We performed a systematic review and meta-analysis to determine the influence of HER2 overexpression and amplification on outcomes in operable oesophageal cancer. METHODS MEDLINE and Embase (January 1990 to November 2011) was searched for translational studies that correlated HER2 expression with survival in operable oesophageal cancer. RESULTS Fourteen studies involving 1,464 patients who had undergone potentially curative oesophagectomy for oesophageal cancer [322 (22%) HER2-positive] were included. Five-year mortality was significantly higher in HER2-positive patients [odds ratio (OR) 1.43, 95% confidence interval (CI) 1.04 to 1.95, p = 0.03]. Analysis related to histological cell type demonstrated significantly higher 5-year mortality in HER2-positive squamous cell carcinoma [OR 2.88, 95% CI 1.34 to 6.17, p = 0.006] and adenocarcinoma [OR 1.91, 95% CI 1.15 to 3.17, p = 0.01] on sensitivity analysis of higher-quality studies. CONCLUSION HER2 overexpression and gene amplification in operable oesophageal cancer was an indicator of poor prognosis.
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Chan DSY, Campbell F, Edwards P, Jasani B, Williams GT, Lewis WG. Relative Prognostic Value of Human Epidermal Growth Factor Receptor 2 (HER2) Expression in Operable Oesophagogastric Cancer. ISRN SURGERY 2012; 2012:804891. [PMID: 22900205 PMCID: PMC3412097 DOI: 10.5402/2012/804891] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/05/2012] [Accepted: 06/14/2012] [Indexed: 12/21/2022]
Abstract
Aims. The aim of this study was to determine the prognostic significance of HER2 receptor expression in operable oesophagogastric adenocarcinoma.
Methods. Eighty-five consecutive patients diagnosed with oesophagogastric adenocarcinoma [18 oesophageal (OC), 32 junctional (JC) and 35 gastric (GC)] undergoing potentially curative resection were studied retrospectively. Immunohistochemistry was used to determine HER2 status at endoscopic biopsy and resection specimen. The primary outcome measure was survival.
Results. Twenty (24%) patients had HER2 positive tumours which was commoner in JC (14/32, 44% versus 2/18, 11% in OC and 4/35, 11% in GC, P = 0.003). The sensitivity, specificity, positive and negative predictive values of HER2 status at endoscopic biopsy were 56%, 93%, 63%, 91% respectively (weighted Kappa = 0.504, P < 0.0001). Five-year survival in OC HER2 positive negative was 100% and 36% (P = 0.167) compared with 14% and 44% (P = 0.0726) in JC and 50% and 46% (P = 0.942) in GC respectively. Conclusions. Endoscopic biopsy had a high specificity and negative predictive value in determining HER2 status. Patients with JC had a significantly higher rate of HER2 overexpression and this was associated with a nonsignificant poorer survival trend. A larger study is needed to confirm these findings because of the implications for neoadjuvant and adjuvant chemotherapy regimens.
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Affiliation(s)
- David S Y Chan
- Department of Surgery, University Hospital of Wales, Heath Park, Cardiff, CF14 4XN, UK
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Radu OM, Foxwell T, Cieply K, Navina S, Dacic S, Nason KS, Davison JM. HER2 amplification in gastroesophageal adenocarcinoma: correlation of two antibodies using gastric cancer scoring criteria, H score, and digital image analysis with fluorescence in situ hybridization. Am J Clin Pathol 2012; 137:583-94. [PMID: 22431535 DOI: 10.1309/ajcpxqvs6yghpdcy] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023] Open
Abstract
We assessed 103 resected gastroesophageal adenocarcinomas for HER2 amplification by fluorescence in situ hybridization (FISH) and 2 commercial immunohistochemical assays. Of 103, 30 (29%) were FISH-amplified. Both immunohistochemical assays had greater than 95% concordance with FISH. However, as a screening test for FISH amplification, the Ventana Medical Systems (Tucson, AZ) 4B5 antibody demonstrated superior sensitivity (87%) compared with the DAKO (Carpinteria, CA) A0485 (70%). Of the cases, 28 were immunohistochemically 3+ or immunohistochemically 2+/FISH-amplified with the 4B5 assay compared with only 22 cases with the A0485 assay, representing a large potential difference in patient eligibility for anti-HER2 therapy. Cases with low-level FISH amplification (HER2/CEP17, 2.2-4.0) express lower levels of HER2 protein compared with cases with high-level amplification (HER2/CEP17, ≥4.0), raising the possibility of a differential response to anti-HER2 therapy. The H score and digital image analysis may have a limited role in improving HER2 test performance.
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Brankley SM, Fritcher EGB, Smyrk TC, Keeney ME, Campion MB, Voss JS, Clayton AC, Wang KK, Lutzke LS, Kipp BR, Halling KC. Fluorescence in situ hybridization mapping of esophagectomy specimens from patients with Barrett's esophagus with high-grade dysplasia or adenocarcinoma. Hum Pathol 2011; 43:172-9. [PMID: 21820152 DOI: 10.1016/j.humpath.2011.04.018] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2011] [Revised: 04/13/2011] [Accepted: 04/18/2011] [Indexed: 12/31/2022]
Abstract
The progression of intestinal metaplasia to esophageal adenocarcinoma in patients with Barrett's esophagus is partly driven by chromosomal alterations that activate oncogenes and inactivate tumor suppressor genes. The goal of this study was to determine how alterations of 4 frequently affected genes correlate with the range of histopathologic lesions observed in resected esophagi of patients with Barrett's esophagus. Fluorescence in situ hybridization was used to assess 83 tissue sections from 10 Barrett's esophagus esophagogastrectomy specimens for chromosomal alterations of 8q24 (MYC), 9p21 (CDKN2A; alias P16), 17q12 (ERBB2), and 20q13.2 (ZNF217). Histologic lesions assessed included gastric metaplasia (n = 8), intestinal metaplasia (n = 43), low-grade dysplasia (n = 28), high-grade dysplasia (n = 25), and adenocarcinoma (n = 16). Histologic maps showing the correlation between fluorescence in situ hybridization abnormalities and corresponding histology were created for all patients. Chromosomal abnormalities included 9p21 loss, single locus gain, and polysomy. A greater number of chromosomal alterations were detected as the severity of histologic diagnosis increased from intestinal metaplasia to adenocarcinoma. All patients had alterations involving the CDKN2A gene. CDKN2A loss was the only abnormality detected in 20 (47%) of 43 areas of intestinal metaplasia. Polysomy, the most common abnormality in dysplastic epithelium and adenocarcinoma, was observed in 16 (57%) of 28 low-grade dysplasia, 22 (88%) of 25 high-grade dysplasia, and 16 (100%) of 16 adenocarcinoma. The findings of this study improve our understanding of the role that chromosomal instability and alterations of tumor suppressor genes such as CDKN2A and oncogenes such as ERBB2 play in the progression of intestinal metaplasia to adenocarcinoma in patients with Barrett's esophagus.
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Affiliation(s)
- Shannon M Brankley
- Department of Laboratory Medicine and Pathology, Mayo Clinic and Foundation, Rochester, MN 55905, USA
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23
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Boers JE, Meeuwissen H, Methorst N. HER2 status in gastro-oesophageal adenocarcinomas assessed by two rabbit monoclonal antibodies (SP3 and 4B5) and two in situ hybridization methods (FISH and SISH). Histopathology 2011; 58:383-94. [PMID: 21323962 PMCID: PMC3085073 DOI: 10.1111/j.1365-2559.2011.03760.x] [Citation(s) in RCA: 63] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
AIMS HER2 gene amplification has been detected in 10-20% of gastric adenocarcinomas. In view of the recently demonstrated clinical benefit of the anti-human epidermal growth factor receptor 2 (HER2) drug trastuzumab in the treatment of advanced gastric cancer, reliable HER2 testing is of key importance. The aim of this study was to examine HER2 status in gastro-oesophageal adenocarcinomas comparing SP3 and 4B5 immunohistochemistry (IHC) with dual probe HER2 [fluorescence in situ hybridization (FISH) and silver in situ hybridization (SISH)]. METHODS AND RESULTS IHC and SISH were carried out on biopsy specimens of 146 patients with adenocarcinomas of the oesophagus and stomach. All SP3-IHC-positive cases and 91% of 4B5-IHC-positive cases were amplified. Sensitivity of SP3-IHC-positivity and 4B5-IHC-positivity for amplification was 77% and 96%, respectively. Results of FISH performed in 42 cases were identical to SISH. Amplification was heterogeneous in 73% of the adenocarcinomas; 24% of the oesophago-gastric carcinomas and 7% of distal stomach tumours were amplified. CONCLUSIONS HER2-positivity is present in a significant proportion of oesophago-gastric adenocarcinomas (24%), but at a lower rate in the distal stomach (7%). Sensitivity for amplification is higher with 4B5 IHC than with SP3. FISH and SISH yield identical results, but assessment is much easier with SISH. Our findings provide important guidance for HER2-testing in gastro-oesophageal adenocarcinomas for patients in whom anti-HER2 treatment is considered.
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Affiliation(s)
- James E Boers
- Department of Pathology, Isala klinieken, Zwolle, the Netherlands. /
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Thompson SK, Sullivan TR, Davies R, Ruszkiewicz AR. Her-2/neu gene amplification in esophageal adenocarcinoma and its influence on survival. Ann Surg Oncol 2011; 18:2010-7. [PMID: 21267790 DOI: 10.1245/s10434-011-1554-1] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2010] [Indexed: 11/18/2022]
Abstract
BACKGROUND HER-2/neu (c-erbB-2, HER2) gene amplification and protein overexpression have been associated with poor prognosis in several solid tumors, including breast and gastric cancer. Its incidence and significance in esophageal adenocarcinoma is unknown. MATERIALS AND METHODS Tissue microarrays were successfully constructed from 89 paraffin-embedded archival specimens of esophageal adenocarcinomas for HER2 gene amplification by silver-enhanced in situ hybridization (SISH). No patients had undergone neoadjuvant therapy. Protein overexpression was tested with immunohistochemistry (IHC) using automated immunostaining (Ventana Benchmark). Incidence of HER2 positivity, correlation to clinicopathological variables in esophageal cancer patients, and concordance between SISH and IHC were determined. RESULTS True HER2 gene amplification was detected in 14 esophageal cancer specimens (16%), and 92% of those with high-level HER2 amplification showed positive HER2 protein overexpression. No significant associations were found among gene amplification and clinicopathological factors. The 5-year survival rates were 57% for esophageal cancer patients with HER2 amplification compared with 32% without, but the difference in overall survival was not significant (P = .37). The correlation between SISH and IHC was statistically significant (P < .0001). CONCLUSION While molecular targeting may be possible for approximately 16% of esophageal adenocarcinoma patients, HER2 oncogene amplification did not influence survival in this study.
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Affiliation(s)
- Sarah K Thompson
- Discipline of Surgery, University of Adelaide, Adelaide, SA, Australia.
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25
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Moelans CB, van Diest PJ, Milne ANA, Offerhaus GJA. Her-2/neu testing and therapy in gastroesophageal adenocarcinoma. PATHOLOGY RESEARCH INTERNATIONAL 2010; 2011:674182. [PMID: 21188213 PMCID: PMC3005843 DOI: 10.4061/2011/674182] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/19/2010] [Accepted: 10/25/2010] [Indexed: 12/12/2022]
Abstract
Despite ongoing advances in the treatment of gastroesophageal cancer, prognosis remains poor. The best promise to improve this poor survival is provided by new targeted agents. Of these, human epidermal growth factor receptor 2 (HER2) is currently in the spotlight. In this review, we provide an overview of recent developments in HER2 testing and results of clinical trials targeting HER2 in gastroesophageal adenocarcinoma. Based on the encouraging ToGA trial findings it is now expected that routine HER2 testing will be included in the diagnostic work-up of patients with advanced gastric cancer. With regard to this testing, overexpression of the HER2 protein seems to possess the best predictive properties. However, HER2 immunohistochemistry (IHC) is subject to assay and interobserver variability, so standardization and internal and external proficiency testing is an absolute prerequisite, especially as the IHC scoring system in gastric cancer is different from that of breast cancer. Further study is needed to investigate the clinical meaning of the significant heterogeneity observed in both gene amplification and protein overexpression in gastroesophageal cancer. Highly effective therapies for gastroesophageal cancer can only be accomplished by a multi-targeted approach, considering crosstalk between pathways and continuing to optimize chemotherapy.
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Affiliation(s)
- Cathy B Moelans
- Department of Pathology, University Medical Center Utrecht, Heidelberglaan 100, P.O. Box 85500, 3508 GA Utrecht, The Netherlands
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Kutup A, Yekebas EF, Izbicki JR. Current diagnosis and future impact of micrometastases for therapeutic strategies in adenocarcinoma of the esophagus, gastric cardia, and upper gastric third. Recent Results Cancer Res 2010; 182:115-25. [PMID: 20676876 DOI: 10.1007/978-3-540-70579-6_10] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/10/2023]
Abstract
Esophageal and gastric cancers are aggressive neoplasms with a poor prognosis. Although postoperative mortality has declined and rates of complete resection have improved considerably, 5 year survival rates are still very low. Early metastatic relapse after complete resection of an apparently localized primary lesion indicates that disseminated tumor cells, undetectable by current methods, may already have been present at the time of surgery, even in patients with seemingly early tumor stages. Occult residual tumor disease is suggested when either bone marrow or lymph nodes from which tumor relapse may originate are affected by micrometastatic lesions undetectable by conventional histopathology. The presence of single tumor cells detected by immunohistological methods is increasingly regarded as a clinically relevant prognostic factor. The use of antibodies against tumor-associated targets enables detection of individual epithelial tumor cells in lymph nodes and in bone marrow in various tumor entities. The potential role and -benefit of an antibody-based treatment as a therapeutic target would be of particular interest in tumors with a notoriously poor prognosis such as esophageal cancer and cardia cancer.
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Gros SJ, Kurschat N, Dohrmann T, Reichelt U, Dancau AM, Peldschus K, Adam G, Hoffman RM, Izbicki JR, Kaifi JT. Effective Therapeutic Targeting of the Overexpressed HER-2 Receptor in a Highly Metastatic Orthotopic Model of Esophageal Carcinoma. Mol Cancer Ther 2010; 9:2037-45. [DOI: 10.1158/1535-7163.mct-10-0209] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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Low Level of Her-2 Locus Amplification by Fluorescent In Situ Hybridization Does Not Correlate with Her-2 Protein Overexpression by Immunohistochemistry in Barrett's Esophagus. JOURNAL OF ONCOLOGY 2010; 2010:382582. [PMID: 20628513 PMCID: PMC2902046 DOI: 10.1155/2010/382582] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/22/2009] [Accepted: 03/21/2010] [Indexed: 11/18/2022]
Abstract
An accurate evaluation of the Her-2 status has important prognostic and therapeutic implications in many carcinomas. The aim of the study was to correlate Her-2 locus (17q11.2) amplification and chromosome 17 gains as assessed by fluorescent in situ hybridization (FISH) with Her-2 protein overexpression by immunohistochemistry (IHC) in patients with Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC). We analyzed 34 patients with Her-2 amplification and/or chromosome 17gains using FISH on brush cytology specimens. Seven patients (21%) showed high Her-2 locus amplification (Her-2: Cep17 ≥ 5 : 1), 5 (15%) showed low Her-2 locus amplification (Her-2: Cep17 ≥ 2 < 5 : 1), and 22 (65%) displayed gains of chromosome 17 only. Further, we confirmed Her-2 amplification on corresponding biopsies that were taken at the same occasion as the cytologybrushings. Then, we compared the FISH results with IHC data obtained from the corresponding biopsies and showed that low level of Her-2 amplification does not correlate with Her-2 protein overexpression (score +3/+2; P = 1), in contrast to the high amplification level (P = .001). Thus, in our population of BE and EAC patients, low level of Her-2 amplification does not result in detectable level of Her-2 protein as assessed by IHC.
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Akagi T, Ito T, Kato M, Jin Z, Cheng Y, Kan T, Yamamoto G, Olaru A, Kawamata N, Boult J, Soukiasian HJ, Miller CW, Ogawa S, Meltzer SJ, Koeffler HP. Chromosomal abnormalities and novel disease-related regions in progression from Barrett's esophagus to esophageal adenocarcinoma. Int J Cancer 2009; 125:2349-59. [PMID: 19670330 DOI: 10.1002/ijc.24620] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
Barrett's esophagus (BE) is a metaplastic condition caused by chronic gastroesophageal reflux which represents an early step in the development of esophageal adenocarcinoma (EAC). Single-nucleotide polymorphism microarray (SNP-chip) analysis is a novel, precise, high-throughput approach to examine genomic alterations in neoplasia. Using 250K SNP-chips, we examined the neoplastic progression of BE to EAC, studying 11 matched sample sets: 6 sets of normal esophagus (NE), BE and EAC, 4 of NE and BE and 1 of NE and EAC. Six (60%) of 10 total BE samples and 4 (57%) of 7 total EAC samples exhibited 1 or more genomic abnormalities comprising deletions, duplications, amplifications and copy-number-neutral loss of heterozygosity (CNN-LOH). Several shared abnormalities were identified, including chromosome 9p CNN-LOH [2 BE samples (20%)], deletion of CDKN2A [4 BE samples (40%)] and amplification of 17q12-21.2 involving the ERBB2, RARA and TOP2A genes [3.1 Mb, 2 EAC (29%)]. Interestingly, 1 BE sample contained a homozygous deletion spanning 9p22.3-p22.2 (1.2 Mb): this region harbors only 1 known gene, basonuclin 2 (BNC2). Real-time PCR analysis confirmed the deletion of this gene and decreased the expression of BNC2 mRNA in the BE sample. Furthermore, transfection and stable expression of BNC2 caused growth arrest of OE33 EAC cells, suggesting that BNC2 functions as a tumor suppressor gene in the esophagus and that deletion of this gene occurs during the development of EAC. Thus, this SNP-chip analysis has identified several early cytogenetic events and novel candidate cancer-related genes that are potentially involved in the evolution of BE to EAC.
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Affiliation(s)
- Tadayuki Akagi
- Division of Hematology and Oncology, Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles, CA, USA.
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Ekman S, Dreilich M, Lennartsson J, Wallner B, Brattström D, Sundbom M, Bergqvist M. Esophageal cancer: current and emerging therapy modalities. Expert Rev Anticancer Ther 2008; 8:1433-48. [PMID: 18759695 DOI: 10.1586/14737140.8.9.1433] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
During the last few years, there has been a gradual increase in treatment options for patients with esophageal malignancies. Several clinical studies have been performed, covering not only radiation and chemotherapy, but also the introduction of novel biological agents into the treatment arsenal. Patients with esophageal carcinoma are now offered second-line and sometimes even third-line treatments, and the number of research protocols is increasing. Despite the newly awakened interest in this malignancy, the overall 5-year survival rate has remained at approximately 10% since the 1980s. This review contains a compilation of available studies of esophageal malignancies and discusses current treatment options as well as newly developed therapies targeted at growth factor receptors.
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Affiliation(s)
- Simon Ekman
- Department of Oncology, Uppsala University Hospital, S-751 85 Uppsala, Sweden.
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Wang KL, Wu TT, Resetkova E, Wang H, Correa AM, Hofstetter WL, Swisher SG, Ajani JA, Rashid A, Hamilton SR, Albarracin CT. Expression of annexin A1 in esophageal and esophagogastric junction adenocarcinomas: association with poor outcome. Clin Cancer Res 2007; 12:4598-604. [PMID: 16899607 DOI: 10.1158/1078-0432.ccr-06-0483] [Citation(s) in RCA: 69] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
PURPOSE Annexin A1 (ANXA1) is a calcium-binding protein involved in arachidonic acid metabolism and epidermal growth factor receptor tyrosine kinase pathway. ANXA1 has been implicated in early squamous cell carcinogenesis of esophagus and correlates with degree of tumor differentiation. However, the role of ANXA1 in esophageal adenocarcinoma is unclear. Our goal was to evaluate ANXA1 expression and determine its prognostic significance in adenocarcinoma of the esophagus and esophagogastric junction. EXPERIMENTAL DESIGN This study included 104 consecutive patients with primary resected esophageal and esophagogastric junction adenocarcinomas (11 stage I, 24 stage II, 53 stage III, and 16 stage IV). ANXA1 protein expression in each tumor was assessed by immunohistochemical staining of tissue microarrays. ANAX1 expression level was classified as high (>/=25% of tumor cells with cytoplasmic staining), low (<25% of tumor cells with cytoplasmic staining), or negative; and was correlated with clinicopathologic features and patients' outcomes. RESULTS High ANXA1 expression was present in 39% (41 of 104) of tumors and was associated with higher pathologic T stage (P = 0.03) and distant metastasis (P = 0.04). High ANXA1 expression correlated with increased recurrence rate (P = 0.004) and decreased overall survival (P = 0.003) in univariate analysis. In multivariate analysis, ANXA1 expression and pN stage significantly correlated with recurrence rate (P = 0.008 and P < 0.001, respectively) and overall survival (P = 0.02 and P < 0.001, respectively) independent of T stage. CONCLUSION Our results indicate that high ANXA1 expression is frequent in esophageal and esophagogastric junction adenocarcinomas, correlates with more advanced pathologic T stage and the presence of distant metastasis, and is an independent prognostic factor for patient survival.
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Affiliation(s)
- Kim L Wang
- Department of Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, 77030, USA
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Ekman S, Bergqvist M, Heldin CH, Lennartsson J. Activation of growth factor receptors in esophageal cancer--implications for therapy. Oncologist 2007; 12:1165-77. [PMID: 17962610 DOI: 10.1634/theoncologist.12-10-1165] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Esophageal cancer is a highly aggressive disease and is the seventh most common cause of cancer-related death in the western world. Worldwide, it ranks as the sixth most frequent cause of cancer death. Despite advances in surgical techniques and treatment, the prognosis of esophageal cancer remains poor, with very few long-term survivors. The need for novel strategies to detect esophageal cancer earlier and to improve current therapy is urgent. It is well established that growth factors and growth factor receptor-mediated signaling pathways are important components of the transformation process in many forms of cancer, including esophageal cancer. With the recent advances in drug development, there are emerging possibilities to use growth factor signal transduction pathways in targeted therapy. This review provides a summary of the role of growth factors and their receptors in esophageal cancer and discusses their potential roles as biomarkers and as targets in therapy.
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Affiliation(s)
- Simon Ekman
- Department of Oncology, University Hospital, Uppsala, Sweden.
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Rauser S, Weis R, Braselmann H, Feith M, Stein HJ, Langer R, Hutzler P, Hausmann M, Lassmann S, Siewert JR, Höfler H, Werner M, Walch A. Significance of HER2 low-level copy gain in Barrett's cancer: implications for fluorescence in situ hybridization testing in tissues. Clin Cancer Res 2007; 13:5115-23. [PMID: 17785566 DOI: 10.1158/1078-0432.ccr-07-0465] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
PURPOSE HER2 may be a relevant biomarker in Barrett's cancer. We compared three HER2 laboratory methods, standard fluorescence in situ hybridization (FISH), image-based three-dimensional FISH in thick (16 microm) sections, and immunohistochemistry, to predict patient outcome. EXPERIMENTAL DESIGN Tissue microarray sections from 124 Barrett's cancer patients were analyzed by standard FISH on thin (4 microm) sections and by image-based three-dimensional FISH on thick (16 microm) sections for HER2 and chromosome-17, as well for p185(HER2) by immunohistochemistry. Correlations with clinical and follow-up data were examined. RESULTS Only three-dimensional FISH on thick (16 microm) sections revealed HER2 gene copy gain to be associated with increased disease-specific mortality (relative risk, 2.1; 95% confidence interval, 1.06-4.26; P = 0.033). In contrast, standard FISH on thin (4 microm) sections and immunohistochemistry failed to predict clinical outcome. Low-level gain of HER2 occurred frequently in Barrett's cancer (>or=2.5-4.0 HER2 copies, 59.7%; HER2-to-chromosome-17 ratio, >or=1.1-2.0; 61.2%) and defined a subpopulation for patient outcome as unfavorable as HER2 gene amplification [disease-free survival, P = 0.017 (HER2 copies)]. This low-level group was neither definable by standard FISH nor immunohistochemistry. No prognostic significance was found for chromosome-17 aneusomy. CONCLUSIONS Low-level copy gains of HER2 define a biologically distinct subpopulation of Barrett's cancer patients. Importantly, these subtle copy number changes are not reliably detected by standard FISH in thin (4 microm) tissue sections, highlighting a thus far unrecognized weakness in HER2 FISH testing. These results should be taken into account for accurate evaluation of biomarkers by FISH and for HER2 FISH testing in tissue sections.
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Affiliation(s)
- Sandra Rauser
- Institute of Pathology , GSF-National Research Center for Environment and Health, Neuherberg, Germany
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Vallböhmer D, Marjoram P, Kuramochi H, Shimizu D, Jung H, DeMeester SR, Oh D, Chandrasoma PT, Danenberg KD, DeMeester TR, Danenberg PV, Peters JH. Towards the molecular characterization of disease: comparison of molecular and histological analysis of esophageal epithelia. J Gastrointest Surg 2007; 11:1095-104. [PMID: 17623264 DOI: 10.1007/s11605-007-0208-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Reliable quantification of gene expression offers the possibility of more accurate and prognostically relevant characterization of tissues than potentially subjective interpretations of histopathologists. We measured the expression of 18 selected genes and compared them to histological features in a spectrum of esophageal disease to evaluate the feasibility of molecular characterization of normal and pathologic esophageal epithelia. Esophageal tissue biopsies from 82 patients with foregut symptoms were laser capture microdissected, and the expression levels of 18 selected genes were measured by quantitative real-time polymerase chain reaction. Linear discriminant analysis, which uses combinations of genes to distinguish between histological groups, was performed to compare gene expression and the following five histological groups: (1) normal squamous epithelium (n = 35), (2) reflux esophagitis (n = 13), (3) non-dysplastic Barrett's (n = 33), (4) dysplastic Barrett's (n = 16), (5) adenocarcinoma (n = 31). A panel of seven genes had 90-94% predictive power to distinguish non-dysplastic and dysplastic Barrett's esophagus. Clustering analysis revealed structure in gene expression values even in the absence of histology. Expression levels in 17 genes differed significantly across histological groups. Classification based on gene expression agreed with histopathological assessment in the following percentage of cases: normal squamous epithelium = 53%, reflux esophagitis = 31%, non-dysplastic Barrett's = 76%, dysplastic Barrett's = 40%, and adenocarcinoma = 59%. Interestingly, predictive power improved markedly when inflammatory and dysplastic tissues were removed (77-94%). Gene expression classification agrees well with histopathological examination. When differences occur, it is unclear whether this effect is due to intraobserver variability in pathological diagnosis or to a genuine difference between gene expression and histopathology.
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Affiliation(s)
- Daniel Vallböhmer
- Department of Surgery, University of Southern California, Los Angeles, CA, USA
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Piessen G, Jonckheere N, Vincent A, Hémon B, Ducourouble MP, Copin MC, Mariette C, Seuningen I. Regulation of the human mucin MUC4 by taurodeoxycholic and taurochenodeoxycholic bile acids in oesophageal cancer cells is mediated by hepatocyte nuclear factor 1alpha. Biochem J 2007; 402:81-91. [PMID: 17037983 PMCID: PMC1783985 DOI: 10.1042/bj20061461] [Citation(s) in RCA: 51] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
MUC4 (mucin 4) is a membrane-bound mucin overexpressed in the early steps of oesophageal carcinogenesis and implicated in tumour progression. We previously showed that bile acids, main components of gastro-oesophageal reflux and tumour promoters, up-regulate MUC4 expression [Mariette, Perrais, Leteurtre, Jonckheere, Hemon, Pigny, Batra, Aubert, Triboulet and Van Seuningen (2004) Biochem. J. 377, 701-708]. HNF (hepatocyte nuclear factor) 1alpha and HNF4alpha transcription factors are known to mediate bile acid effects, and we previously identified cis-elements for these factors in MUC4 distal promoter. Our aim was to demonstrate that these two transcription factors were directly involved in MUC4 activation by bile acids. MUC4, HNF1alpha and HNF4alpha expressions were evaluated by immunohistochemistry in human oesophageal tissues. Our results indicate that MUC4, HNF1alpha and HNF4alpha were co-expressed in oesophageal metaplastic and adenocarcinomatous tissues. Studies at the mRNA, promoter and protein levels indicated that HNF1alpha regulates endogenous MUC4 expression by binding to two cognate cis-elements respectively located at -3332/-3327 and -3040/-3028 in the distal promoter. We also showed by siRNA (small interfering RNA) approach, co-transfection and site-directed mutagenesis that HNF1alpha mediates taurodeoxycholic and taurochenodeoxycholic bile acid activation of endogenous MUC4 expression and transcription in a dose-dependent manner. In conclusion, these results describe a new mechanism of regulation of MUC4 expression by bile acids, in which HNF1alpha is a key mediator. These results bring new insights into MUC4 up-regulation in oesophageal carcinoma associated with bile reflux.
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Affiliation(s)
- Guillaume Piessen
- *Unité INSERM 560, Place de Verdun, 59045 Lille Cedex, France
- †Department of Digestive and Oncological Surgery, C. Huriez Hospital, Centre Hospitalier Régional et Universitaire de Lille, 59037 Lille Cedex, France
| | | | - Audrey Vincent
- *Unité INSERM 560, Place de Verdun, 59045 Lille Cedex, France
| | - Brigitte Hémon
- *Unité INSERM 560, Place de Verdun, 59045 Lille Cedex, France
| | | | - Marie-Christine Copin
- *Unité INSERM 560, Place de Verdun, 59045 Lille Cedex, France
- ‡Department of Pathology, Parc Eurasanté, CHRU Lille, 59037 Lille Cedex, France
| | - Christophe Mariette
- *Unité INSERM 560, Place de Verdun, 59045 Lille Cedex, France
- †Department of Digestive and Oncological Surgery, C. Huriez Hospital, Centre Hospitalier Régional et Universitaire de Lille, 59037 Lille Cedex, France
| | - Isabelle VAN Seuningen
- *Unité INSERM 560, Place de Verdun, 59045 Lille Cedex, France
- To whom correspondence should be addressed (email )
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Reichelt U, Duesedau P, Tsourlakis MC, Quaas A, Link BC, Schurr PG, Kaifi JT, Gros SJ, Yekebas EF, Marx A, Simon R, Izbicki JR, Sauter G. Frequent homogeneous HER-2 amplification in primary and metastatic adenocarcinoma of the esophagus. Mod Pathol 2007; 20:120-9. [PMID: 17143264 DOI: 10.1038/modpathol.3800712] [Citation(s) in RCA: 143] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
HER-2 is the target for antibody based treatment of breast cancer (Herceptin). In order to evaluate the potential role of such a treatment in esophageal cancers, HER-2 amplification and overexpression was investigated in primary and metastatic cancers of the esophagus. A tissue microarray was constructed from 255 primary esophageal cancers (110 adenocarcinomas and 145 squamous cell carcinomas), 89 nodal and 33 distant metastases. Slides were analyzed by immunohistochemistry (HercepTest; DAKO) and fluorescence in situ hybridization (FISH; PathVysion; Vysis-Abbott) for HER-2 amplification and overexpression. Amplification was seen in 16/110 (15%) adenocarcinomas and in 7/145 (5%) squamous cell carcinomas. There was a strong association between HER-2 amplification and overexpression, especially in adenocarcinomas (P<0.0001, log rank). There was a 100% concordance of the HER-2 results in primary tumor and corresponding metastases in 84 analyzed pairs. Amplification was typically high-level with more than 10-15 HER-2 copies per tumor cell. Amplification was unrelated to survival, grading, pT, pN, pM or UICC stage. We conclude that esophageal adenocarcinomas belong to those cancer types with relevant frequency high-level HER-2 gene amplification clinical trials or individual case studies investigating the response of metastatic HER-2-positive esophageal cancers to Herceptin((R)) should be undertaken. The strong concordance of the HER-2 status in primary and metastatic cancers argues for a possible response of metastases from patients with HER-2-positive primary tumors to Herceptin.
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Affiliation(s)
- Uta Reichelt
- Department of Pathology, University Medical Center Hamburg-Eppendorf, University of Hamburg, Hamburg, Germany
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Safran H, Dipetrillo T, Akerman P, Ng T, Evans D, Steinhoff M, Benton D, Purviance J, Goldstein L, Tantravahi U, Kennedy T. Phase I/II study of trastuzumab, paclitaxel, cisplatin and radiation for locally advanced, HER2 overexpressing, esophageal adenocarcinoma. Int J Radiat Oncol Biol Phys 2006; 67:405-9. [PMID: 17097832 DOI: 10.1016/j.ijrobp.2006.08.076] [Citation(s) in RCA: 103] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2006] [Revised: 08/28/2006] [Accepted: 08/28/2006] [Indexed: 12/13/2022]
Abstract
PURPOSE To determine the overall survival for patients with locally advanced, HER2 overexpressing, esophageal adenocarcinoma receiving trastuzumab, paclitaxel, cisplatin, and radiation on a Phase I-II study. METHODS AND MATERIALS Patients with adenocarcinoma of the esophagus without distant organ metastases and 2+/3+ HER2 overexpression by immunohistochemistry (IHC) were eligible. All patients received cisplatin 25 mg/m2 and paclitaxel 50 mg/m2 weekly for 6 weeks with radiation therapy (RT) 50.4 Gy. Patients received trastuzumab at dose levels of 1, 1.5, or 2 mg/kg weekly for 5 weeks after an initial bolus of 2, 3, or 4 mg/kg. RESULTS Nineteen patients were entered: 7 (37%) had celiac adenopathy, and 7 (37%) had retroperitoneal, portal adenopathy, or scalene adenopathy. Fourteen of 19 patients (74%) had either 3+ HER2 expression by immunohistochemistry, or an increase in HER2 gene copy number by HER2 gene amplification or high polysomy by fluorescence in situ hybridization. The median survival of all patients was 24 months and the 2-year survival was 50%. CONCLUSIONS Assessment of the effect of trastuzumab in the treatment of patients with esophageal adenocarcinoma overexpressing HER2 is limited by the small number of patients in this study. Overall survival, however, was similar to prior studies without an increase in toxicity. Evaluation of HER2 status should be performed in future trials for patients with adenocarcinoma of the esophagus that investigate therapies targeting the HER family.
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Affiliation(s)
- Howard Safran
- Brown University Oncology Group, Providence, RI, USA.
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38
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Langer R, Von Rahden BHA, Nahrig J, Von Weyhern C, Reiter R, Feith M, Stein HJ, Siewert JR, Höfler H, Sarbia M. Prognostic significance of expression patterns of c-erbB-2, p53, p16INK4A, p27KIP1, cyclin D1 and epidermal growth factor receptor in oesophageal adenocarcinoma: a tissue microarray study. J Clin Pathol 2006; 59:631-4. [PMID: 16731604 PMCID: PMC1860401 DOI: 10.1136/jcp.2005.034298] [Citation(s) in RCA: 77] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
AIMS To correlate immunohistochemical expression patterns and prognosis in oesophageal adenocarcinoma. METHODS The expression of c-erbB-2, p53, p16INK4A, p27KIP1, cyclin D1 and epidermal growth factor receptor (EGFR) was studied in a series of 137 primarily resected oesophageal adenocarcinoma samples. The expression analysis on protein level was performed on routine paraffin wax-embedded material, with immunohistochemical staining of the samples, assembled on a tissue microarray. The results were correlated with clinicopathological features (pT, pN and G) and survival. RESULTS 22 (16%) tumours showed an overexpression of the c-erbB-2 oncoprotein. Expression of EGFR was observed in 72 (55%) cases, accumulation of p53 in 68 (52%) cases and of cyclin D1 in 102 (77%) cases. Loss of p16INK4A expression was observed in 101 (76%) cases and low expression of p27KIP1 in 91 (71%) cases. Expression of these proteins did not correlate with tumour stage, grade, Lauren's or World Health Organization classification or lymph node status. On univariate survival analysis, more advanced tumour stage (p = 0.002), lymph node involvement (p = 0.003), high tumour grade (p = 0.017) and lack of EGFR expression (p = 0.034) were found to be associated with poorer survival. On multiple regression analysis, only tumour stage (p = 0.03) and lymph node involvement (p = 0.004) were shown to have an association with the survival of the patient. CONCLUSION The immunohistochemical expression of c-erbB-2 oncoprotein, cylin D1, p16INK4A, p27KIP1, p53 and EGFR in most oesophageal adenocarcinomas suggests their implication in the pathogenesis of this entity. None of the molecular markers assessed, however, was of prognostic value. Identification of any marker superior to or even approaching the prognostic value of conventional histopathological markers (pT and pN) was therefore not possible.
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Affiliation(s)
- R Langer
- Institut für Pathologie, Technical University, München, Germany.
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Rossi E, Villanacci V, Bassotti G, Casa DD, Missale G, Minelli L, Cestari R. Her-2/neu in barrett esophagus: a comparative study between histology, immunohistochemistry, and fluorescence in situ hybridization. DIAGNOSTIC MOLECULAR PATHOLOGY : THE AMERICAN JOURNAL OF SURGICAL PATHOLOGY, PART B 2006; 15:125-130. [PMID: 16932066 DOI: 10.1097/01.pdm.0000213455.22527.f7] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Her-2/neu is a protooncogene frequently overexpressed in breast cancer, recently found to be also overexpressed in carcinoma arising on Barrett esophagus (BE). Immunohistochemistry and fluorescence in situ hybridization (FISH) are conventionally used for Her-2 testing in carcinomas, but a single assay is not yet accepted as a "gold standard" in BE. To evaluate the correlation between histopathology variables and gene expression/amplification in the sequence BE-low grade dysplasia-high grade dysplasia-adenocarcinoma, fifty esophageal specimens from patients with a diagnosis of BE (21 BE, 4 low-grade dysplasia, 12 high-grade dysplasia, and 13 adenocarcinomas) were evaluated. Histopathologic evaluation was carried out using hematoxylin and eosin staining. Paraffin-embedded tissues were investigated for Her-2 by immunohistochemistry (HercepTest) and FISH. HercepTest was scored 0, 1+, 2+, and 3+ depending on the percentage (cut off 10%) of membrane staining, whereas gene assessment evaluated by FISH was based on the ratio between Her-2/neu and the 17 chromosome copy number. There was a positive correlation between gene amplification and protein overexpression. No case with HercepTest scoring 0 or 1+ displayed gene amplification, but this was present in 20% of cases scoring 2+ and in all cases scoring 3+. Her-2/neu amplification or overexpression was never observed in BE. Gene amplification and overexpression was observed in more than 50% of dysplasias and adenocarcinomas. Her-2/neu amplification/overexpression might be considered as a marker of progression from BE to dysplasia. FISH may represent a useful diagnostic tool to integrate the result of HercepTest for selecting patients for more targeted therapeutic approaches.
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Affiliation(s)
- Elisa Rossi
- Second Department of Pathology, Spedali Civili, University of Brescia, Brescia, Italy
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Dreilich M, Wanders A, Brattström D, Bergström S, Hesselius P, Wagenius G, Bergqvist M. HER-2 overexpression (3+) in patients with squamous cell esophageal carcinoma correlates with poorer survival. Dis Esophagus 2006; 19:224-31. [PMID: 16866851 DOI: 10.1111/j.1442-2050.2006.00570.x] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The incidence of esophageal carcinoma is increasing worldwide. In Sweden, approximately 400 patients are diagnosed each year. The present study retrospectively investigates survival in 97 patients with esophageal carcinoma in regard to their HER-2 status as examined by immunohistochemistry (IHC) and chromogen in situ hybridization (CISH). Sixty-eight patients had localised disease and 29 patients had advanced disease. Seventy patients had squamous cell carcinoma, and nine of these patients (13%) had HER-2 overexpression (3+). Eight (30%) of 27 adenocarcinoma patients overexpressed (3+) HER-2. In patients overexpressing (3+) HER-2 a statistical trend towards poorer survival was observed (P = 0.057). In squamous cell carcinoma patients, HER-2 overexpression (3+) correlated with poorer survival (P = 0.035), whereas in adenocarcinoma patients, HER-2 status (3+) did not. HER-2 amplification according to CISH was present in five (two squamous cell carcinomas and three adenocarcinomas) out of 17 HER-2 overexpressing (3+) tumours. In conclusion, HER-2 overexpression (3+) seems to be associated with poorer survival in esophageal carcinomas, especially in patients with squamous cell esophageal carcinoma.
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Affiliation(s)
- M Dreilich
- Department of Oncology, Radiology and Clinical Immunology, Section of Oncology, Uppsala University Hospital, Uppsala, Sweden
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Mitas M, Almeida JS, Mikhitarian K, Gillanders WE, Lewin DN, Spyropoulos DD, Hoover L, Graham A, Glenn T, King P, Cole DJ, Hawes R, Reed CE, Hoffman BJ. Accurate discrimination of Barrett's esophagus and esophageal adenocarcinoma using a quantitative three-tiered algorithm and multimarker real-time reverse transcription-PCR. Clin Cancer Res 2005; 11:2205-14. [PMID: 15788668 DOI: 10.1158/1078-0432.ccr-04-1091] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Esophageal adenocarcinoma (EA) is increasing faster than any other cancer in the U.S. In this report, we first show that EA can be distinguished from normal esophagus (NE) and esophageal squamous cell carcinoma by plotting expression values for EpCam, TFF1, and SBEM in three-dimensional Euclidean space. For monitoring progression of Barrett's esophagus (BE) to EA, we developed a highly sensitive assay for limited quantities of tissue whereby 50 ng of RNA are first converted to cDNA using 16 gene-specific primers. Using a set of training tissues, we developed a novel quantitative three-tiered algorithm that allows for accurate (overall accuracy = 61/63, 97%) discrimination of BE versus EA tissues using only three genes. The gene used in the first tier of the algorithm is TSPAN: samples not diagnosed as BE or EA by TSPAN in the first tier are then subjected to a second-tier analysis using ECGF1, followed by a third-tier analysis using SPARC. Addition of TFF1 and SBEM to the first tier (i.e., a five-gene marker panel) increases the overall accuracy of the assay to 98% (62/63) and results in mean molecular diagnostic scores (+/- SD) that are significantly different between EA and BE samples (3.19 +/- 1.07 versus -2.74 +/- 1.73, respectively). Our results suggest that relatively few genes can be used to monitor progression of BE to EA.
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Affiliation(s)
- Michael Mitas
- Department of Surgery, Medical University of South Carolina, 96 Jonathan Lucas Street, Charleston, SC 29425, USA.
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Abstract
SUMMARY. Esophageal cancer is one of the most deadly forms of gastrointestinal cancer with a mortality rate exceeding 90%. The major risk factors for esophageal adenocarcinoma are gastroesophageal reflux disease (GERD) and its sequela, Barrett's esophagus. GERD commonly leads to esophagitis. In a minority of patients however, ongoing GERD leads to replacement of esophageal squamous mucosa with metaplastic, intestinal-type Barrett's mucosa. In the setting of continued peptic injury, Barrett's mucosa can give rise to esophageal adenocarcinoma. Despite the widespread use of potent acid suppressive therapies for patients with GERD, the incidence of esophageal adenocarcinoma, among white men in the USA, the UK and Europe has continued to rise. Cancers in Barrett's esophagus arise through a sequence of genetic events that endow the cells with six essential physiologic hallmarks of cancer as described by Hanahan and Weinberg in 2000. These cancer hallmarks include the ability to proliferate without exogenous stimulation, to resist growth-inhibitory signals, to avoid triggering the programmed death mechanism (apoptosis), to resist cell senescence, to develop new vascular supplies (angiogenesis), and to invade and metastasize. While the acquisition of these essential attributes is not specific to the neoplastic progression of Barrett's esophagus, this review will focus on the genetic alterations that occur in Barrett's cells that contribute to the acquisition of each of the hallmarks. Moreover, potential diagnostic and therapeutic strategies for Barrett's patients aimed at each of these cancer hallmarks will be reviewed.
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Affiliation(s)
- L A Feagins
- Department of Medicine, Dallas VA Medical Center and University of Texas Southwestern Medical School, Dallas 75216, USA
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Kyrgidis A, Kountouras J, Zavos C, Chatzopoulos D. New Molecular Concepts of Barrett’s Esophagus: Clinical Implications and Biomarkers. J Surg Res 2005; 125:189-212. [PMID: 15854673 DOI: 10.1016/j.jss.2004.12.022] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2004] [Revised: 12/20/2004] [Accepted: 12/26/2004] [Indexed: 12/30/2022]
Abstract
Barrett's esophagus (BE) represents the most serious histological consequence of gastroesophageal reflux disease (GERD) that develops in 5-10% of patients with GERD. Given that BE is the only known precursor to esophageal adenocarcinoma (EA), a systematic endoscopic biopsy protocol can detect EAs at an early stage. However, endoscopic and histopathological evaluation of BE are not adequate for effective screening of high risk patients. Therefore, molecular abnormalities associated with BE have been considered as surrogate markers and their use as such is proposed. Flow cytometry is the most useful adjunct to histology, and ploidy status of BE is an independent risk factor. Cyclin D1 overexpression is inversely correlated with survival in EA. C-erbB2 (+) patients have poorer prognosis. High plasma adenomatous polyposis coli levels correlate with reduced patient survival. p53 expression allows patient risk for EA stratification. Nuclear factor-kappaB overexpression inversely correlates with good response to adjuvant chemotherapy and radiotherapy in EA. Patients with cyclooxygenase-2 overexpression have reduced survival rates. Increased E-cadherin staining is associated with shorter survival in EA patients who received chemoradiotherapy. Finally, existing data cannot rule out a correlation between EA and colorectal tumors. Seventeen BE molecular alterations yielded noteworthy clinical implications. Apart from endoscopy and histology, these data allow for better risk stratification for patients with BE and for more efficient and timely therapeutic approaches.
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Affiliation(s)
- Athanassios Kyrgidis
- Department of Medicine, Second Medical Clinic, Aristotle University of Thessaloniki, Ippokration Hospital, Thessaloniki, Greece
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Sato S, Kajiyama Y, Sugano M, Iwanuma Y, Sonoue H, Matsumoto T, Sasai K, Tsurumaru M. Monoclonal antibody to HER-2/neu receptor enhances radiosensitivity of esophageal cancer cell lines expressing HER-2/neu oncoprotein. Int J Radiat Oncol Biol Phys 2005; 61:203-11. [PMID: 15629613 DOI: 10.1016/j.ijrobp.2004.05.017] [Citation(s) in RCA: 37] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2004] [Revised: 04/30/2004] [Accepted: 05/10/2004] [Indexed: 12/18/2022]
Abstract
PURPOSE The role of HER-2/neu in the response of esophageal cancer to radiation is not well known. The purpose of this study was to evaluate the effect of an anti-HER-2/neu antibody trastuzumab on the proliferation, cell cycle distribution, and radiosensitivity of esophageal cancer cell lines. EXPERIMENTAL DESIGN Expression of HER-2/neu protein by four esophageal squamous cancer cell lines (KE4, TE8, TE9, and TE10) and an esophageal adenocarcinoma cell line (SKGT4) was assessed using immunohistochemical (IHC) analysis and flow cytometry. We also evaluated HER-2/neu oncogene expression by fluorescence in situ hybridization. As a control for HER-2/neu protein expression and gene amplification, breast cancer cell lines (MCF7, MDA MB175VII, and SKBR3) were also examined. The cytotoxity of trastuzumab (0.1-200 microg/mL) was estimated by the MTT assay, and the cell cycle distribution was determined by flow cytometry. The effect of 10 microg/mL trastuzumab combined with radiation was assessed by a clonogenic assay. RESULTS Flow cytometry and IHC revealed that two esophageal cancer cell lines (TE9 and SKGT4) showed HER-2/neu expression (IHC 1+ and mean fluorescence intensity of 11-20), while the other esophageal cancer cell lines were negative for HER-2/neu expression. Although trastuzumab alone had no effect on the esophageal cancer cell lines, the combination of 10 microg/mL trastuzumab with radiation showed a synergistic effect on the HER-2/neu expressing cell lines. CONCLUSIONS This study suggested that trastuzumab plus irradiation may be effective for the treatment of esophageal cancers, including adenocarcinoma and squamous cell cancer with HER-2/neu expression.
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MESH Headings
- Antibodies, Monoclonal/therapeutic use
- Antibodies, Monoclonal, Humanized
- Carcinoma, Squamous Cell/metabolism
- Carcinoma, Squamous Cell/pathology
- Carcinoma, Squamous Cell/radiotherapy
- Cell Cycle/drug effects
- Cell Cycle/radiation effects
- Cell Division/drug effects
- Cell Division/radiation effects
- Cell Line, Tumor/drug effects
- Cell Line, Tumor/radiation effects
- Esophageal Neoplasms/metabolism
- Esophageal Neoplasms/pathology
- Esophageal Neoplasms/radiotherapy
- Humans
- In Situ Hybridization, Fluorescence
- Radiation Tolerance/drug effects
- Radiation-Sensitizing Agents/therapeutic use
- Receptor, ErbB-2/immunology
- Receptor, ErbB-2/metabolism
- Trastuzumab
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Affiliation(s)
- Shinsuke Sato
- Department of Gastrointestinal Surgery, Juntendo University School of Medicine, Tokyo, Japan.
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Koppert LB, Wijnhoven BPL, van Dekken H, Tilanus HW, Dinjens WNM. The molecular biology of esophageal adenocarcinoma. J Surg Oncol 2005; 92:169-90. [PMID: 16299787 DOI: 10.1002/jso.20359] [Citation(s) in RCA: 107] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
BACKGROUND Barrett's esophagus is an acquired metaplastic change that occurs in the distal esophagus secondary to chronic gastroesophageal reflux. This premalignant condition forms the most important risk factor for developing esophageal adenocarcinoma, which is an extremely aggressive tumor with a 5-year survival rate of less than 25%. Carcinomas that arise in the setting of Barrett's esophagus are thought to develop as part of the metaplasia-dysplasia-carcinoma sequence. OBJECTIVE To review the current knowledge on the genomic alterations involved in the development of Barrett's esophagus and its progression to dysplasia and/or cancer. RESULTS Several changes in gene structure, gene expression, and protein structure are associated with the progression of Barrett's esophagus to adenocarcinoma. Accumulation of these changes seems to be essential, rather than the exact sequence of these changes. Multiple molecular pathways are involved and interact with each other. Alterations in tumor suppressor genes, amongst which p53 and p16, are early events in the metaplasia-dysplasia-adenocarcinoma sequence, followed by loss of cell cycle checkpoints. Ongoing genomic instability leads to cumulative genetic errors and thereby the generation of multiple clones of transformed cells. CONCLUSIONS Within the multistep process of esophageal adenocarcinogenesis, to date no single molecular marker came forward able to predict who will and who will not develop cancer in the setting of Barrett's esophagus. Instead, panels of markers need to be developed in the future allowing to indicate disease progression. Identification of crucial molecular pathways involved in esophageal adenocarcinogenesis would ultimately improve therapy and facilitate development of new treatment strategies.
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Affiliation(s)
- Linetta B Koppert
- Department of Surgery, Erasmus MC, University Medical Center, Dr. Molewaterplein 50, 3015 GE Rotterdam, The Netherlands
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Caygill CPJ, Watson A, Lao-Sirieix P, Fitzgerald RC. Barrett's oesophagus and adenocarcinoma. World J Surg Oncol 2004; 2:12. [PMID: 15132744 PMCID: PMC420492 DOI: 10.1186/1477-7819-2-12] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2004] [Accepted: 05/07/2004] [Indexed: 12/23/2022] Open
Affiliation(s)
- Christine PJ Caygill
- Registrar UK National Barrett's Oesophagus Registry (UKBOR), and Honorary Senior Lecturer, University Department of Surgery, Royal Free Hospital, Rowland Hill Street, London NW3 2PF, UK
| | - Anthony Watson
- Joint director UK National Barrett's Oesophagus Registry (UKBOR), and visiting Professor, University Department of Surgery, Royal Free Hospital, Rowland Hill Street, London NW3 2PF, UK
| | | | - Rebecca C Fitzgerald
- Joint director UK National Barrett's Oesophagus Registry (UKBOR) and Group Leader MRC Cancer cell Unit, Hutchison Research Centre, Cambridge, CB2 2XZ, UK
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48
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Reynolds JC, Rahimi P, Hirschl D. Barrett's esophagus: clinical characteristics. Hematol Oncol Clin North Am 2003. [DOI: 10.1016/s0889-8588(03)00023-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Abstract
Significant progress has been made in clinicians' understanding of the molecular pathogenesis of BE, and the laboratory findings are beginning to lead to hypothesis-driven clinical studies; however, the following questions remain unanswered: (1) how can clinicians identify the persons most at risk for the development of esophageal adenocarcinoma, (2) what are the environmental gene interactions in esophageal carcinogenesis, and (3) can clinicians prevent the development of esophageal adenocarcinoma in the population at risk? As esophageal adenocarcinoma starts to reach epidemic proportions, further research in these areas is urgently required. With the advent of the genomic era and an explosion in studies in BE, significant progress can be made.
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50
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Beilstein M, Silberg D. Cellular and molecular mechanisms responsible for progression of Barrett's metaplasia to esophageal carcinoma. Hematol Oncol Clin North Am 2003. [DOI: 10.1016/s0889-8588(03)00010-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
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