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Bach Y, Sharma D, Aoyama H, Ma LX, Barron CC, Wang X, Akhtar S, Yang Y, St Bernard A, McLaughlin R, Megid TBC, Farooq AR, Chen EX, Jang RWJ, Elimova E. Ramucirumab and paclitaxel in second or greater lines of therapy in patients with HER2-positive gastroesophageal cancer: a single center study. Oncologist 2025; 30:oyaf037. [PMID: 40152313 PMCID: PMC11950916 DOI: 10.1093/oncolo/oyaf037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2024] [Accepted: 02/04/2025] [Indexed: 03/29/2025] Open
Abstract
BACKGROUND Human epidermal growth factor receptor 2 (HER2) overexpression is present in approximately 20-25 of patients with advanced gastroesophageal adenocarcinoma (GEA). Upon progression on 1st line therapy, ramucirumab and paclitaxel (rampac) is given in ≥2 line setting regardless of HER2 status. We aim to assess whether ramucirumab is associated with better survival in HER2 positive(+) pts compared to those with HER2(-) disease. METHODS We reviewed all consecutive adult patients with metastatic/unresectable GEA who were treated with rampac for ≥2nd line therapy at Princess Margaret Cancer Centre from 2010 to 2021. Progression free survival (PFS) and overall survival (OS) were defined as time from starting rampac to progression or death and estimated using the Kaplan-Meier method. RESULTS There were 126 patients who received rampac following progression of 1st line chemotherapy, 96(76%) were male. The age at time of presentation and starting rampac was 59.0 ± 10.3 years and 59.9 ± 10.3 years, respectively. At the time of diagnosis, 32(25%) patients were HER2+. The majority of patients (n = 99;78%) received rampac in the 2L line setting compared to 28(22%) patients who received it in the 3rd/4th line setting. The median PFS and OS for HER2 + pts were 3.6 months and 9.4 months, respectively, which were similar to HER2- patients (median PFS = 3.6 months; median OS = 8.2 months). There was no statistically significant association between HER2 positivity and PFS (adjusted hazards ratio (HR) = 0.76, 95% confidence interval (CI) 0.48-1.22, P = .26), nor OS (adjusted HR = 0.88, 95% CI, 0.55-1.41, P = .59). CONCLUSION Rampac remains a valid treatment option for patients who are unable to participate in trials or do not have access to further HER2-directed therapy beyond first line.
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Affiliation(s)
- Yvonne Bach
- Princess Margaret Cancer Centre, 700 University Avenue, Toronto, ON, Canada M5G 1X6
| | - Divya Sharma
- Princess Margaret Cancer Centre, 700 University Avenue, Toronto, ON, Canada M5G 1X6
| | - Hiroko Aoyama
- Princess Margaret Cancer Centre, 700 University Avenue, Toronto, ON, Canada M5G 1X6
| | - Lucy X Ma
- Princess Margaret Cancer Centre, 700 University Avenue, Toronto, ON, Canada M5G 1X6
| | - Carly C Barron
- Princess Margaret Cancer Centre, 700 University Avenue, Toronto, ON, Canada M5G 1X6
| | - Xin Wang
- Princess Margaret Cancer Centre, 700 University Avenue, Toronto, ON, Canada M5G 1X6
| | - Sokaina Akhtar
- Princess Margaret Cancer Centre, 700 University Avenue, Toronto, ON, Canada M5G 1X6
| | - Yahan Yang
- Princess Margaret Cancer Centre, 700 University Avenue, Toronto, ON, Canada M5G 1X6
| | - Alana St Bernard
- Princess Margaret Cancer Centre, 700 University Avenue, Toronto, ON, Canada M5G 1X6
| | - Ronan McLaughlin
- Princess Margaret Cancer Centre, 700 University Avenue, Toronto, ON, Canada M5G 1X6
| | - Thais B C Megid
- Princess Margaret Cancer Centre, 700 University Avenue, Toronto, ON, Canada M5G 1X6
| | - Abdul R Farooq
- Princess Margaret Cancer Centre, 700 University Avenue, Toronto, ON, Canada M5G 1X6
| | - Eric X Chen
- Princess Margaret Cancer Centre, 700 University Avenue, Toronto, ON, Canada M5G 1X6
| | - Raymond W J Jang
- Princess Margaret Cancer Centre, 700 University Avenue, Toronto, ON, Canada M5G 1X6
| | - Elena Elimova
- Princess Margaret Cancer Centre, 700 University Avenue, Toronto, ON, Canada M5G 1X6
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Lee HS. Spatial and Temporal Tumor Heterogeneity in Gastric Cancer: Discordance of Predictive Biomarkers. J Gastric Cancer 2025; 25:192-209. [PMID: 39822175 PMCID: PMC11739643 DOI: 10.5230/jgc.2025.25.e3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2024] [Accepted: 12/09/2024] [Indexed: 01/19/2025] Open
Abstract
Gastric cancer (GC) is a highly heterogeneous disease that varies in both histological presentation and genetic characteristics. Recent advances in the treatment of metastatic and unresectable GC have made several biomarker tests essential for patient management. Predictive biomarkers such as human epidermal growth factor receptor 2 (HER2), programmed death-ligand 1 (PD-L1), mismatch-repair (MMR) proteins, claudin 18.2, and fibroblast growth factor receptor 2b (FGFR2b) are commonly evaluated using immunohistochemistry. However, the expression levels of these biomarkers may vary across different tumor areas, and the accuracy of biomarker diagnosis can be affected by sample quantity, sample location, and collection method. Therefore, tumor heterogeneity presents substantial challenges for accurate biomarker-based diagnosis and prediction of therapeutic responses. Tumor heterogeneity can be categorized into spatial heterogeneity, which refers to variations within the primary tumor (intra-tumoral) or between primary and metastatic sites, and temporal heterogeneity, which encompasses changes over time. This review addresses the tumor heterogeneity in predictive biomarker expression in GC, focusing on HER2, PD-L1, MMR, the Epstein-Barr virus, claudin 18.2, and FGFR2b.
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Affiliation(s)
- Hye Seung Lee
- Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea.
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Soeratram TTD, Beentjes I, Egthuijsen JMP, Mookhoek A, Lange MM, Meershoek-Klein Kranenbarg E, Hartgrink HH, van de Velde CJH, Ylstra B, van Laarhoven HWM, van Grieken NCT. A biopsy-based Immunoscore in patients with treatment-naïve resectable gastric cancer. Ther Adv Med Oncol 2024; 16:17588359241287747. [PMID: 39444424 PMCID: PMC11497501 DOI: 10.1177/17588359241287747] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2024] [Accepted: 09/09/2024] [Indexed: 10/25/2024] Open
Abstract
Background The prognostic significance of T-cell densities in gastric cancer (GC) was previously demonstrated in surgical resection specimens. For prognosis or response prediction, it is preferable to identify biomarkers in pre-treatment biopsies; yet, its representativeness of the tumor immune microenvironment is unclear. Objectives This study aimed to evaluate the concordance and prognostic value of T-cell densities in paired biopsies and resections. Methods Paired diagnostic biopsies and surgical resections were available for 131 patients with resectable GC who were treated with surgery alone in the D1/D2 trial. T-cell markers such as CD3, CD45RO, CD8, FOXP3, and Granzyme B were assessed by immunohistochemistry and digitally quantified. Tumors were categorized into high and low subgroups for each marker. The concordance between biopsies and resections was determined for each marker with Cohen's κ. To determine the prognostic value of T cells in biopsies, Cox regression was performed. Results The concordance of T-cell high and low tumors was moderate for CD8 (κ = 0.58) and weak for other markers (κ < 0.3). CD8 and FOXP3 densities in biopsies were significantly associated with cancer-specific survival. Multivariable analysis showed that an Immunoscore incorporating CD8 and FOXP3 served as an independent prognostic marker (low vs high: hazard ratio 3.40, 95% confidence interval: 1.27-9.10; p = 0.015). Conclusion Although the concordance in T-cell densities between biopsy and resection specimens is modest, a biopsy-based Immunoscore identified distinct biological subgroups with prognostic potential. To fully evaluate the prognostic performance of this biopsy Immunoscore, additional studies are warranted.
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Affiliation(s)
- Tanya T. D. Soeratram
- Department of Pathology, Amsterdam UMC location VUmc, Amsterdam, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
- Cancer Center Amsterdam, Cancer Biology and Immunology, Amsterdam, The Netherlands
| | - Isis Beentjes
- Department of Pathology, Amsterdam UMC location VUmc, Amsterdam, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
- Cancer Center Amsterdam, Cancer Biology and Immunology, Amsterdam, The Netherlands
| | - Jacqueline M. P. Egthuijsen
- Department of Pathology, Amsterdam UMC location VUmc, Amsterdam, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
- Cancer Center Amsterdam, Cancer Biology and Immunology, Amsterdam, The Netherlands
| | - Aart Mookhoek
- Institute of Tissue Medicine and Pathology, University of Bern, Bern, Switzerland
| | - Marilyne M. Lange
- Department of Pathology, Amsterdam UMC location VUmc Amsterdam, Amsterdam, The Netherlands
| | | | - Henk H. Hartgrink
- Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands
| | | | - Bauke Ylstra
- Department of Pathology, Amsterdam UMC location VUmc, Amsterdam, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
- Cancer Center Amsterdam, Cancer Biology and Immunology, Amsterdam, The Netherlands
| | - Hanneke W. M. van Laarhoven
- Cancer Center Amsterdam, Cancer Biology and Immunology, Amsterdam, The Netherlands
- Department of Medical Oncology, Amsterdam UMC location University of Amsterdam, Amsterdam, The Netherlands
| | - Nicole C. T. van Grieken
- Department of Pathology, Amsterdam UMC location VUmc, Amsterdam, Vrije Universiteit Amsterdam, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands
- Cancer Center Amsterdam, Cancer Biology and Immunology, Amsterdam, The Netherlands
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Mo C, Sterpi M, Jeon H, Bteich F. Resistance to Anti-HER2 Therapies in Gastrointestinal Malignancies. Cancers (Basel) 2024; 16:2854. [PMID: 39199625 PMCID: PMC11352490 DOI: 10.3390/cancers16162854] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2024] [Revised: 08/13/2024] [Accepted: 08/14/2024] [Indexed: 09/01/2024] Open
Abstract
Human epidermal growth factor 2 (HER2) is a tyrosine kinase receptor that interacts with multiple signaling pathways related to cellular growth and proliferation. Overexpression or amplification of HER2 is linked to various malignancies, and there have been decades of research dedicated to targeting HER2. Despite the landmark ToGA trial, progress in HER2-positive gastrointestinal malignancies has been hampered by drug resistance. This review examines current HER2 expression patterns and therapies for gastroesophageal, colorectal, biliary tract, and small bowel cancers, while dissecting potential resistance mechanisms that limit treatment effectiveness.
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Affiliation(s)
- Christiana Mo
- Department of Medical Oncology, Albert Einstein College of Medicine, Bronx, NY 10461, USA; (C.M.); (M.S.); (H.J.)
- Department of Medical Oncology, Montefiore Medical Center, Bronx, NY 10467, USA
| | - Michelle Sterpi
- Department of Medical Oncology, Albert Einstein College of Medicine, Bronx, NY 10461, USA; (C.M.); (M.S.); (H.J.)
- Department of Medical Oncology, Montefiore Medical Center, Bronx, NY 10467, USA
| | - Hyein Jeon
- Department of Medical Oncology, Albert Einstein College of Medicine, Bronx, NY 10461, USA; (C.M.); (M.S.); (H.J.)
- Department of Medical Oncology, Montefiore Medical Center, Bronx, NY 10467, USA
| | - Fernand Bteich
- Department of Medical Oncology, Albert Einstein College of Medicine, Bronx, NY 10461, USA; (C.M.); (M.S.); (H.J.)
- Department of Medical Oncology, Montefiore Medical Center, Bronx, NY 10467, USA
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Kolbe K, Haffner I, Schierle K, Maier D, Geier B, Luber B, Bläker H, Wittekind C, Lordick F. Deviating HER2 test results in gastric cancer: analysis from the prospective multicenter VARIANZ study. J Cancer Res Clin Oncol 2023; 149:1319-1329. [PMID: 36030286 PMCID: PMC9984518 DOI: 10.1007/s00432-022-04208-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2022] [Accepted: 07/12/2022] [Indexed: 11/09/2022]
Abstract
PURPOSE The prospective multicenter VARIANZ study aimed to identify resistance biomarkers for HER2-targeted treatment in advanced gastric and esophago-gastric junction cancer (GC, EGJC). HER2 test deviations were found in 90 (22.3%) of 404 cases (central versus local testing) and were associated with negative impact on survival for trastuzumab-treated patients. Here, we investigated methodological and biological variables that may promote deviating HER2 test results. METHODS We analyzed HER2 testing procedures and participation in quality assurance programs of 105 participating local pathology laboratories. Furthermore, tumor localization and histological subtypes were compared between patients with centrally confirmed (central HER2 + /local HER2 + , n = 68) and unconfirmed HER2 status (central HER2 -/local HER2 + , n = 68). RESULTS For central HER2 testing, concordance between in situ hybridization (ISH) and immunohistochemistry (IHC) was 98.3%, with IHC sensitivity of 93.3% (84 IHC + of 90 ISH +), specificity of 99.5% (389 IHC- of 391 ISH-), and a positive diagnosis rate of 97.7%. Central confirmation of the local HER2 IHC scores were seen for the majority of locally HER2- IHC 0/1 (172/178; 96.6%), but less frequently for locally IHC3 + (57/124; 46.0%) cases. Deviation rate was not associated with IHC antibody platform used in the local pathology institute neither with participation in quality-assuring tests. Regarding tumor characteristics, deviating test results were more frequently found in GC vs. EGJC (69.1% vs. 39.7%; p = 0.001) and in Laurén diffuse vs. intestinal subtype (23.5% vs. 5.9%, p = 0.004). CONCLUSION Tumor localization and histological subtype have an impact on HER2 test deviation rates. Assessment of HER2 remains challenging for GC and EGJC.
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Affiliation(s)
- Katharina Kolbe
- Department of Oncology, Gastroenterology, Hepatology, Pulmonology and Infectious Disease, Leipzig University Medical Center, University Cancer Center Leipzig (UCCL), Leipzig, Germany
| | - Ivonne Haffner
- Department of Oncology, Gastroenterology, Hepatology, Pulmonology and Infectious Disease, Leipzig University Medical Center, University Cancer Center Leipzig (UCCL), Leipzig, Germany.
| | - Katrin Schierle
- Institute of Pathology, Heilbronn SLK-Kliniken GmbH, Heilbronn, Germany
| | | | | | - Birgit Luber
- Institute of Pathology, Technische Universität München, Munich, Germany
| | - Hendrik Bläker
- Department of Pathology, Leipzig University Medical Center, Leipzig, Germany
| | - Christian Wittekind
- Department of Pathology, Leipzig University Medical Center, Leipzig, Germany
| | - Florian Lordick
- Department of Oncology, Gastroenterology, Hepatology, Pulmonology and Infectious Disease, Leipzig University Medical Center, University Cancer Center Leipzig (UCCL), Leipzig, Germany
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Prediction of Biomarker Expression on Primary Pancreatic Ductal Adenocarcinoma Tissues Using Fine-Needle Biopsies: Paving the Way for a Patient-Tailored Molecular Imaging Approach. Mol Diagn Ther 2023; 27:261-273. [PMID: 36656512 PMCID: PMC10008234 DOI: 10.1007/s40291-022-00635-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/05/2022] [Indexed: 01/20/2023]
Abstract
BACKGROUND Targeted molecular imaging may improve tumor cell identification during diagnosis and resection of pancreatic ductal adenocarcinoma (PDAC). Although many molecular imaging biomarkers are (over)expressed in PDAC, intertumoral heterogeneity of biomarker expression hampers universal tracer administration. Preoperative, patient-specific screening and selection of the most optimal biomarker could therefore improve tumor delineation. OBJECTIVE This study evaluated whether fine-needle biopsy (FNB) specimens could be used to preoperatively predict biomarker expression in the corresponding primary PDAC specimen. METHODS Expression of previously identified PDAC biomarkers αvβ6, CEACAM5, EGFR, mesothelin, Lea/c/x, and sdi-Lea on FNB and corresponding primary tumor (PT) specimens (n = 45) was evaluated using immunohistochemistry and quantified using a semi-automated image analysis workflow. RESULTS Biomarker expression on FNB and PT tissues showed high concordance (∆H-score ≤ 50), i.e. was present in 62% of cases for αvβ6, 61% for CEACAM5, 85% for EGFR, 69% for mesothelin, 76% for Lea/c/x, and 79% for sdi-Lea, indicating high concordance. Except for αvβ6, biomarker expression on FNB tissues was positively correlated with PT expression for all biomarkers. Subgroup analyses showed that neoadjuvant therapy (NAT) had no major and/or significant effect on concordance, expression difference and, except for mesothelin, correlation of biomarker expression between FNB and PT tissues. CONCLUSION This study demonstrated that biomarker expression in FNB tissues is predictive for PT expression, irrespective of the application of NAT. These findings thereby provide the foundation for the clinical application of an FNB-based biomarker-screening workflow, eventually facilitating a patient-specific approach of molecular imaging tracer administration in PDAC.
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Xu C, Sun M, Jin M, Li Z, Qin R, Ren G, Sun W, Chen L, Luan L, Liu Y, Jiang D, Chen L, Luo R, Hou Y. Dual block HER2 assessment increased HER2 immunohistochemistry positive rate in resected specimens of gastric cancer: a prospective multicenter clinical trial from China. Diagn Pathol 2022; 17:54. [PMID: 35765007 PMCID: PMC9238183 DOI: 10.1186/s13000-022-01230-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Accepted: 05/18/2022] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
Former single center studies indicated that HER2 assessment with two primary tumor blocks (dual block HER2 assessment) could be an efficient and practical approach to overcome the adverse impact of heterogeneity and acquire a HER2 positive rate in gastric cancer (GC). This multicenter prospective clinical trial (NCT 02843412) was launched to verify its value and generality.
Methods
A total of 3806 participants with primary GCs have been enrolled from 8 hospitals in China. Two primary tumor blocks were selected and recorded as block 1 and block 2 after histological evaluation. An HER2 (4B5) rabbit monoclonal antibody was used for the immunohistochemistry (IHC) analysis.
Results
In total patients, HER2 IHC positive (3+) rate with dual block assessment (9.4%) was higher than that with single block assessment (block 1: 7.8%, block 2: 7.8%) (P < 0.001). Compared with single-block assessment, dual-block assessment increased the positive rate by approximate 20%. Similarly, HER2 equivocal (2+) rate was increased in dual block assessment (25.8%), which was higher than that in single block assessment (block 1: 20.3%, block 2: 20.9%) (P < 0.001). Conversely, dual block assessment demonstrated a lower HER2 negative (0/1+) rate (64.8%) than single block assessment (block1: 71.9%, block 2: 71.3%) (P < 0.001). These findings were also confirmed in individual hospitals.
Conclusions
Dual block HER2 assessment effectively increased HER2 IHC positive rate in resected specimens of GC. We recommended dual block HER2 assessment be promoted in routine clinical practice in GC.
Trial registration
ClinicalTrials.gov, NCT 02843412. Registered 1 July 2016 - Retrospectively registered.
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Biomarker-targeted therapies for advanced-stage gastric and gastro-oesophageal junction cancers: an emerging paradigm. Nat Rev Clin Oncol 2021; 18:473-487. [PMID: 33790428 DOI: 10.1038/s41571-021-00492-2] [Citation(s) in RCA: 177] [Impact Index Per Article: 44.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/22/2021] [Indexed: 02/02/2023]
Abstract
Advances in cancer biology and sequencing technology have enabled the selection of targeted and more effective treatments for individual patients with various types of solid tumour. However, only three molecular biomarkers have thus far been demonstrated to predict a response to targeted therapies in patients with gastric and/or gastro-oesophageal junction (G/GEJ) cancers: HER2 positivity for trastuzumab and trastuzumab deruxtecan, and microsatellite instability (MSI) status and PD-L1 expression for pembrolizumab. Despite this lack of clinically relevant biomarkers, distinct molecular subtypes of G/GEJ cancers have been identified and have informed the development of novel agents, including receptor tyrosine kinase inhibitors and monoclonal antibodies, several of which are currently being tested in ongoing trials. Many of these trials include biomarker stratification, and some include analysis of circulating tumour DNA (ctDNA), which both enables the noninvasive assessment of biomarker expression and provides an indication of the contributions of intratumoural heterogeneity to response and resistance. The results of these studies might help to optimize the selection of patients to receive targeted therapies, thus facilitating precision medicine approaches for patients with G/GEJ cancers. In this Review, we describe the current evidence supporting the use of targeted therapies in patients with G/GEJ cancers and provide guidance on future research directions.
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Rottmann D, Assem H, Matsumoto N, Wong S, Hui P, Buza N. Does Specimen Type Have an Impact on HER2 Status in Endometrial Serous Carcinoma? Discordant HER2 Status of Paired Endometrial Biopsy and Hysterectomy Specimens in the Presence of Frequent Intratumoral Heterogeneity. Int J Gynecol Pathol 2021; 40:263-271. [PMID: 32897955 DOI: 10.1097/pgp.0000000000000690] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
A recent clinical trial showed prolonged progression-free survival in human epidermal growth factor receptor 2 (HER2)-positive advanced stage and recurrent endometrial serous carcinomas when trastuzumab was added to traditional chemotherapy. Approximately one third of these tumors are HER2-positive and have been described to show unique characteristics of HER2 protein expression and gene amplification, including significant intratumoral heterogeneity, in recent studies. However, currently, there are no standard protocols for the selection of optimal specimen type or algorithm for HER2 testing in endometrial serous carcinomas. The current study aimed to evaluate the concordance of HER2 status between endometrial biopsy/curettage and subsequent hysterectomy specimens in endometrial serous carcinoma. A total of 57 patients with endometrial serous carcinoma with available HER2 status were identified during the study period, 14 of which (14/57, 25%) were HER2-positive by immunohistochemistry and/or fluorescent in situ hybridization (FISH). The final study cohort consisted of 40 paired endometrial biopsies/curettings and hysterectomies to include all 14 HER2-positive tumors and 26 selected HER2-negative tumors to represent an equal distribution of HER2 immunohistochemical scores. HER2 FISH was performed on all tumors with an immunohistochemical score of 2+. HER2 immunohistochemical scores, heterogeneity of HER2 expression, FISH results, and the overall HER2 status were compared between the 2 specimen types. HER2 status was successfully assigned in both specimen types in 37 cases, as three specimens showed inadequate FISH signals. Concordant HER2 status was observed in 84% of cases (31/37), with identical HER2 immunohistochemical scores in 65% (26/40) of tumors. Among the 6 tumors with a discordant HER2 status, 2 were HER2 negative in the biopsy and positive in the hysterectomy, and 4 were HER2-positive in the biopsy and negative in the hysterectomy. The false-negative rate would be 15.4% and 26.7% if only the biopsy or only the hysterectomy would be the basis for the result, respectively. Intratumoral heterogeneity of HER2 protein expression was present in 22 tumors (55%), including all cases with a discordant HER2 status. The concordance rate of HER2 status between paired endometrial biopsies/curettings and hysterectomies of endometrial serous carcinoma is lower than the reported rates of breast cancer, and comparable to those of gastric carcinomas. Frequent heterogeneity of HER2 protein expression combined with the possibility of a spatially more heterogenous sampling of endometrial cavity in biopsies and curettings, and the potential differences in specimen handling/fixation between the 2 specimen types may explain our findings. HER2 testing of multiple specimens may help identify a greater proportion of patients eligible for targeted trastuzumab therapy and should be taken into account in future efforts of developing endometrial cancer-specific HER2 testing algorithm.
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Affiliation(s)
- Douglas Rottmann
- Department of Pathology, Yale School of Medicine, New Haven, Connecticut
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Kasochi C, Julius P, Mweemba I, Kayamba V. Human epidermal growth factor receptor 2 overexpression in gastric and gastroesophageal junction adenocarcinoma in patients seen at the University Teaching Hospital, Lusaka, Zambia. Afr Health Sci 2020; 20:1857-1864. [PMID: 34394249 PMCID: PMC8351871 DOI: 10.4314/ahs.v20i4.41] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND There are scanty data on the occurrence of gastric tumours overexpressing human epidermal growth factor receptor 2 (HER2) in Africa. OBJECTIVE To assess HER2 protein overexpression in gastric and gastroesophageal junction adenocarcinoma (GGEAC) samples from a single centre in Zambia. METHODOLOGY This was a cross-sectional study of formalin-fixed paraffin-embedded blocks with GGEAC. Prepared slides were first stained with Haematoxylin and Eosin and then evaluated for HER2 protein overexpression by immunohistochemistry. RESULTS A total of 57 gastric tissues were stained and evaluated for HER2 overexpression. Thirteen (23%) showed overexpression, 41/57 (72%) had negative and 3/57 (5%) had equivocal staining. The equivocal cases were excluded from the final analysis. Of the remaining 54 tissues, 28 (52%) were from females, and 26 (48%) were from males. The mean age was 59 years (SD 15 years). HER2 overexpression was highest in moderately differentiated tumours (p=0.0005). Intestinal type tumours had a higher occurrenc of HER2 overexpression than diffuse or mixed sub-types (p=0.0087). HER2 overexpression was not associated with age (p=0.27), sex (p=1.00) or anatomical location (p=1.00). CONCLUSION The occurrence of GGEAC HER2 overexpression in Zambian patients is similar to proportions reported elsewhere, and it is associated with moderately differentiated tumours of the intestinal type.
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Affiliation(s)
- Chimwasu Kasochi
- University Teaching Hospital, Department of Pathology, Nationalist Road, Private Bag RW1X, Lusaka, Zambia
| | - Peter Julius
- The University of Zambia, School of Medicine, Nationalist Road, PO Box 50110, Lusaka, Zambia
| | - Isaac Mweemba
- University Teaching Hospital, Department of Pathology, Nationalist Road, Private Bag RW1X, Lusaka, Zambia
| | - Violet Kayamba
- The University of Zambia, School of Medicine, Nationalist Road, PO Box 50110, Lusaka, Zambia
- Tropical Gastroenterology & Nutrition Group, Department of Internal Medicine, PO Box 50398, Nationalist Road, Lusaka, Zambia
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Zhang H, Wang Y, Wang Y, Wu D, Lin E, Xia Q. Intratumoral and intertumoral heterogeneity of HER2 immunohistochemical expression in gastric cancer. Pathol Res Pract 2020; 216:153229. [PMID: 33010699 DOI: 10.1016/j.prp.2020.153229] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Revised: 09/14/2020] [Accepted: 09/17/2020] [Indexed: 01/15/2023]
Abstract
BACKGROUND Given the high heterogeneity of tumor tissue in gastric cancer (GC), inaccurate detection of tumor biomarkers will inevitably hamper a precise diagnosis and selection of patients for targeted therapies. Human epidermal growth factor receptor 2 (HER2) has been widely accepted as an underlying treatment biomarker of GC. The objective of this study is to investigate the heterogeneity (both intratumoral and intertumoral) of HER2 expression in GC, and the relationship between heterogeneity and the clinicopathological features. METHODS A total of 618 patients with primary gastric adenocarcinoma were recruited, and two formalin-fixed paraffin-embedded (FFPE) tumor-containing blocks of each patient were selected for HER2 immunohistochemical (IHC) assay. Clinicopathological characteristics were recorded, and intratumoral and intertumoral heterogeneity of HER2 IHC expression was determined. RESULTS The results indicated that the dual-block assays significantly increased the HER2 overexpression (IHC 2+ and 3+) rate compared with the single paraffin block detection. Approximately 50 % of the cases showed intratumoral HER2 heterogeneity within a single tissue section, and 30.10 % of cases showed intertumoral heterogeneity between a patient's two blocks. Furthermore, intertumoral heterogeneity was associated with tumors of small size (P = 0.029) and distal location (P = 0.032) characters, while the intratumoral heterogeneity was correlated with poorly differentiated carcinomas. Laurén's diffuse type showed a notably higher intratumoral heterogeneity rate, and the mixed type exhibited higher intertumoral HER2 discordance between the dual-block cohorts (P < 0.001). Besides, HER2 heterogenous overexpression was not associated with age, gender, type of resection, lymphatic or venous invasion, perineural invasion or pTNM (P > 0.05) for both cohorts. CONCLUSION The research findings in this paper indicate that the intratumoral and intertumoral heterogeneity of HER2 overexpression is common in GC patients, and these variations are associated with certain clinicopathological features. We highly recommend multi-block HER2 assessment for accurate diagnosis of GC.
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Affiliation(s)
- He Zhang
- Department of Pathology, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou 450008, Henan, China
| | - Yi Wang
- Department of Pathology, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou 450008, Henan, China
| | - Yanfeng Wang
- Department of Pathology, Heilongjiang Province Land Reclamation Headquarter General Hospital, Harbin 150086, Heilongjiang, China
| | - Daoyuan Wu
- Department of Pathology, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou 450008, Henan, China
| | - Enguang Lin
- Department of Pathology, Heilongjiang Province Land Reclamation Headquarter General Hospital, Harbin 150086, Heilongjiang, China
| | - Qingxin Xia
- Department of Pathology, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou 450008, Henan, China.
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12
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Chen J, Cao J, Wang P, He X. NT5DC2 is a novel prognostic marker in human hepatocellular carcinoma. Oncol Lett 2020; 20:70. [PMID: 32863903 PMCID: PMC7436888 DOI: 10.3892/ol.2020.11931] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2020] [Accepted: 07/01/2020] [Indexed: 12/26/2022] Open
Abstract
Reliable biomarkers for the prognosis of hepatocellular carcinoma (HCC) are rare, and novel biomarkers are required for the appropriate management of HCC. 5′-Nucleotidase domain containing 2 (NT5DC2) acts as an oncogene in various tumors, but its functions as a biomarker have not been confirmed. Therefore, the present study aimed to resolve these functions by analyzing the prognostic value of NT5DC2 in patients with HCC. A tissue microarray (TMA) was prepared and NT5DC2 expression was measured via IHC staining in TMA dots. The liver cancer (LIHC) cohort in The Cancer Genome Atlas (TCGA) was enrolled as a secondary cohort. Kaplan-Meier survival analyses and Cox regression models were used for assessment of the prognostic value of NT5DC2. Gene set enrichment analysis (GSEA) was performed in TCGA LIHC cohort. A total of 134 patients with HCC were retrospectively enrolled in the Peking Union Medical College Hospital cohort and clinical data were collected. A total of 359 patients with HCC in TCGA were enrolled as TCGA cohort. NT5DC2 was used as an indicator of overall survival (OS) and relapse-free survival (RFS) in multiple cohorts. In the multivariate Cox regression model, NT5DC2 upregulation was an independent prognostic factor of OS in both cohorts. GSEA indicated the enrichment of a series of survival- and metastasis-related gene-sets, such as LEE_LIVER_CANCER_SURVIVAL_UP and LIAO_METASTASIS. Collectively, it was suggested that NT5DC2 upregulation was associated with poor OS and RFS in HCC, and was a potential predictive marker for HCC stratification.
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Affiliation(s)
- Jiemin Chen
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, P.R. China
| | - Jianzhong Cao
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, P.R. China
| | - Penghui Wang
- Department of General Surgery, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, P.R. China
| | - Xiaodong He
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, P.R. China
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13
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Hirose S, Moriwaki T, Yamaura M, Suganuma D, Tajima H, Sato M, Enami C, Yamada T, Yamamoto Y, Sakamoto N, Hyodo I. A case of advanced gastric cancer showing HER2 positivity after chemotherapy. Int Cancer Conf J 2020; 9:112-115. [PMID: 32582513 PMCID: PMC7297895 DOI: 10.1007/s13691-020-00412-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2019] [Accepted: 03/19/2020] [Indexed: 01/14/2023] Open
Abstract
A 63-year-old man had advanced poorly differentiated gastric adenocarcinoma with para-aortic lymph node metastases. No HER2 expression was observed in four endoscopic biopsies from the primary tumor. Tumors shrunk after S-1 with cisplatin treatment, and he underwent simple gastrectomy due to stenosis. Interestingly, HER2 diffusely overexpressed in the resected surgical specimen. His disease was stable with trastuzumab-containing therapy for 6.4 months. This case may suggest a selection of HER2-positive cells that were insensitive to the chemotherapy, and further study is needed for the change of intratumoral HER2 heterogeneity after chemotherapy.
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Affiliation(s)
- Suguru Hirose
- Division of Gastroenterology, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575 Japan
| | - Toshikazu Moriwaki
- Division of Gastroenterology, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575 Japan
| | - Masamichi Yamaura
- Division of Gastroenterology, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575 Japan
| | - Daisuke Suganuma
- Division of Gastroenterology, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575 Japan
| | - Hiroki Tajima
- Division of Gastroenterology, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575 Japan
| | - Masashi Sato
- Division of Gastroenterology, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575 Japan
| | - Chiaki Enami
- Division of Gastroenterology, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575 Japan
| | - Takeshi Yamada
- Division of Gastroenterology, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575 Japan
| | - Yoshiyuki Yamamoto
- Division of Gastroenterology, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575 Japan
| | - Noriaki Sakamoto
- Department of Pathology, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki Japan
| | - Ichinosuke Hyodo
- Division of Gastroenterology, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575 Japan
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14
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Machado-Neves R, Vale J, Eloy C, Polónia A. HER2 genomic heterogeneity is a frequent event in gastroesophageal adenocarcinoma and correlates with tumor morphology. Pathol Res Pract 2020; 216:153090. [PMID: 32825958 DOI: 10.1016/j.prp.2020.153090] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Revised: 06/25/2020] [Accepted: 06/26/2020] [Indexed: 01/08/2023]
Abstract
AIM To characterize a cohort of gastro-esophageal adenocarcinomas (GEA) evaluated for HER2 gene amplification using bright field in situ hybridization (ISH) following the 2016 guidelines for GEA and correlating the results with clinico-pathological features. It was also aimed to evaluate the effect of applying the ISH criteria from the 2018 guidelines for breast cancer (BC) in the same GEA cases. MATERIALS AND METHODS 159 GEA cases collected in a period of 59 months were evaluated for HER2 gene amplification by ISH according to GEA and BC guidelines. All cases were reviewed for histological type, grading and presence of signet ring cells. RESULTS Most of the cases refereed to ISH were HER2 equivocal (57.9 %) by immunohistochemistry. According to the GEA guideline, 131 cases were HER2-negative (87.3 %) and 19 cases were HER2-positive (12.7 %). According to the BC guideline, 133 cases were HER2-negative (88.7 %) and 17 cases were HER2-positive (11.3 %), being statistically similar to the results obtained with the GEA guideline. HER2 genomic heterogeneity was detected in 31.6 % of the HER2-positive cases, almost exclusively in tubular adenocarcinoma. We observed a significant association between HER2 gene amplification and tubular adenocarcinomas, and absence of signet ring cells. The only case with HER2 gene amplification and presence of signet ring cells was a mixed carcinoma, where the signet ring cells represented the non-amplified component. CONCLUSIONS HER2 positivity rate was similar when applying the GEA or the BC guidelines. We also establish a tight association between morphology and HER2 gene amplification.
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Affiliation(s)
- Raquel Machado-Neves
- Department of Pathology, Hospital Pedro Hispano, ULS Matosinhos, Rua Dr. Eduardo Torres, 4464-513, Senhora da Hora, Matosinhos, Portugal
| | - João Vale
- Department of Pathology, Ipatimup Diagnostics, Institute of Molecular Pathology and Immunology, University of Porto, Rua Júlio Amaral de Carvalho, 45, 4200-135, Porto, Portugal; I3S - Instituto de Investigação e Inovação em Saúde, University of Porto, Rua Alfredo Allen, 208, 4200-135, Porto, Portugal
| | - Catarina Eloy
- Department of Pathology, Ipatimup Diagnostics, Institute of Molecular Pathology and Immunology, University of Porto, Rua Júlio Amaral de Carvalho, 45, 4200-135, Porto, Portugal; I3S - Instituto de Investigação e Inovação em Saúde, University of Porto, Rua Alfredo Allen, 208, 4200-135, Porto, Portugal; Faculty of Medicine, University of Porto, Alameda Prof Hernâni Monteiro, 4200-319, Porto, Portugal
| | - António Polónia
- Department of Pathology, Ipatimup Diagnostics, Institute of Molecular Pathology and Immunology, University of Porto, Rua Júlio Amaral de Carvalho, 45, 4200-135, Porto, Portugal; I3S - Instituto de Investigação e Inovação em Saúde, University of Porto, Rua Alfredo Allen, 208, 4200-135, Porto, Portugal.
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15
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Xi Y, Xu C, Liu Y, Yan X, Huang C, Liu Y, Mei J, Wang Z, Liu B, Li X, Li W, Lan J, Gao P, Wu J, Zheng J, Hou Y. The age variation of HER2 immunohistochemistry positive rate in biopsy specimens of gastric cancer. Pathol Res Pract 2020; 216:152882. [PMID: 32113795 DOI: 10.1016/j.prp.2020.152882] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2019] [Revised: 01/23/2020] [Accepted: 02/12/2020] [Indexed: 02/07/2023]
Abstract
AIMS The aim of this study was to explore HER2 status and characteristics in biopsy specimens of gastric cancer (GC) in Chinese population. METHODS AND RESULTS A total of 27,787 biopsy specimens of GC from 103 hospitals were obtained. Immunohistochemistry (IHC) staining of HER2 was performed. Overall HER2 IHC positive rate was 11.2 %. HER2 positive rate elevated with the increase of age in total patients and both genders. The rates were 7.1 %, 8.1 %, 9.0 %, 10.9 %, 11.8 %, 12.6 %, and 12.1 % when patient age was ≤30, 31-40, 41-50, 51-60, 61-70, 71-80, and >80, respectively (P < 0.001). In male, the rates were 6.5 %, 8.4 %, 9.6 %, 11.5 %, 12.4 %, 13.3 %, and 12.1 % (P < 0.001). In female, the rates were 7.4 %, 7.9 %, 8.0 %, 9.0 %, 9.6 %, 10.6 %, and 11.9 % (P = 0.128). The changes in male were more dramatic than in female (P < 0.001). Furthermore, the proportion of the intestinal type GCs increased with age in total patients and both genders (P < 0.001), and in male the changes were more dramatic (P < 0.001). While the proportion of the diffuse type showed the opposite tendency to that of the intestinal type (P < 0.001). HER2 IHC positive rate showed a positive correlation with the proportion of the intestinal type (r=0.986, P < 0.001), and a negative correlation with the proportion of the diffuse type (r=0.984, P < 0.001). CONCLUSIONS The HER2 IHC positive rate showed age variation in biopsy specimens of GC. In male the variation was more dramatic than in female. The variation of HER2 positive rate can be attributed to the age variation of the Lauren subtypes.
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Affiliation(s)
- Yanfeng Xi
- Department of Pathology, Shanxi Cancer Hospital, Taiyuan, China
| | - Chen Xu
- Department of Pathology, Zhongshan Hospital; Department of Pathology, School of Basic Sciences & Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yiqiang Liu
- Department of Pathology, Beijing Cancer Hospital, Beijing, China
| | - Xiaochu Yan
- Department of Pathology, The First Hospital Affiliated to AMU (Southwest Hospital), Chongqing, China
| | - Chuansheng Huang
- Department of Pathology, Jiangxi Cancer Hospital, Nanchang, China
| | - Yueping Liu
- Department of Pathology, Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Jinhong Mei
- Department of Pathology, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Zhe Wang
- Department of Pathology, Xijing Hospital, Air Force Medical University (The Fourth Military Medical University), Xi'an, China
| | - Bin Liu
- Department of Pathology, Lanzhou General Hospital of People's Liberation Army, Lanzhou, China
| | - Xiaoming Li
- Department of Pathology, Lanzhou University Second Hospital, Lanzhou, China
| | - Wencai Li
- Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Jianyun Lan
- Department of Pathology, Yancheng City No.1 People's Hospital, Yancheng, China
| | - Peng Gao
- Department of Pathology, Qilu Hospital of Shandong University, Jinan, China
| | - Jifeng Wu
- Department of Pathology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Jianming Zheng
- Department of Pathology, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Yingyong Hou
- Department of Pathology, Zhongshan Hospital; Department of Pathology, School of Basic Sciences & Zhongshan Hospital, Fudan University, Shanghai, China.
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16
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Late stage gastric cancer patients with extra gained HER2 positivity by dual block assessment may not show compromised efficacy to trastuzumab treatment. Aging (Albany NY) 2019; 11:10052-10060. [PMID: 31739285 PMCID: PMC6914406 DOI: 10.18632/aging.102415] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2019] [Accepted: 10/28/2019] [Indexed: 01/15/2023]
Abstract
Dual block HER2 assessment can effectively increase the HER2 positive rate in resected specimens of gastric cancer (GC). The aim of this study is to explore whether GC patients with extra gained HER2 positivity by dual block assessment can benefit from trastuzumab therapy. Twenty-eight GC patients receiving gastrectomy prior to trastuzumab treatment were retrospectively analyzed. All the cases routinely accepted dual block HER2 assessment. The cases were divided into 2 cohorts based on HER2 status: cohort A with concordant HER2 results and cohort B with discordant HER2 results between the two blocks (cases with extra gained HER2 positivity). Response rate (RR), progress free survival (PFS) and overall survival (OS) were compared between the two cohorts. The results showed that no significant differences were found between the two cohorts in main clinicopathologic characteristics. No statistical difference was found in response rate (47.6% vs 57.1%) (P=1.0), either. The two cohorts did not demonstrate statistical differences in the PFS (10.5 months (95%CI 6.4-14.6) vs 8.0 months (95%CI 3.2-12.8), P=0.686) and the OS (23.3 months (95%CI 12.1-34.5) vs 20.0 months (95%CI 10.1-29.9), P=0.776). In conclusion, our study suggests that patients with extra gained HER2 positivity may not show compromised efficacy to trastuzumab treatment.
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17
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Kim H, Son SM, Woo CG, Lee OJ, Kim DH, Yun HY, Yun J, Kim HK, Yang Y, Han HS. Discordance in HER2 status between primary gastric adenocarcinoma tumors and cells from the corresponding malignant effusions. BMC Cancer 2019; 19:834. [PMID: 31477048 PMCID: PMC6721206 DOI: 10.1186/s12885-019-6035-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2018] [Accepted: 08/13/2019] [Indexed: 01/21/2023] Open
Abstract
BACKGROUND Metastasis of gastric cancer commonly manifests as a malignant effusion, which presents an alternative cell source for human epidermal growth factor receptor 2 (HER2) status identification. This study aimed to compare HER2 status in primary gastric adenocarcinoma tumors and corresponding cell blocks prepared from malignant effusions (CB-MEs). METHODS HER2 status was retrospectively evaluated by immunohistochemistry (IHC) in primary gastric adenocarcinomas and paired pathologically confirmed CB-MEs of 45 patients. Silver in situ hybridization (SISH) was also performed in cases with IHC 2+ for primary gastric adenocarcinomas and above IHC 1+ for CB-MEs. RESULTS HER2 positivity was observed in 4.4% (2/45) of primary gastric adenocarcinomas and 6.7% (3/45) of CB-MEs. The HER2 concordance rate between primary gastric adenocarcinomas and CB-MEs was 88.9% (40/45) (κ = - 0.056). All five patients with HER2 positivity in the primary tumor or a CB-ME had a negative result in the corresponding paired sample. Of the 15 patients with two or more serially sampled CB-MEs, HER2 expression determined by IHC differed between each CB-ME in six (40%) patients, and all three patients with HER2 positivity in CB-MEs exhibited HER2 positivity in one of the serially sampled CB-MEs. CONCLUSIONS The HER2 positivity rate was very low in gastric cancer patients with malignant effusions. Our results suggest that HER2 positivity was discordant between the primary gastric adenocarcinoma and corresponding CB-MEs and among serially sampled CB-MEs. The possibility of detecting HER2 positivity can be improved if the primary gastric adenocarcinoma tumor as well as all the available CB-MEs from each patient are analyzed.
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Affiliation(s)
- Hongsik Kim
- Department of Internal Medicine, Chungbuk National University Hospital, Chungdae-ro 1, Seowon-gu, Cheongju, 28644, South Korea
| | - Seung-Myoung Son
- Department of Pathology, Chungbuk National University Hospital, Cheongju, South Korea.,Department of Pathology, Chungbuk National University College of Medicine, Cheongju, South Korea
| | - Chang Gok Woo
- Department of Pathology, Chungbuk National University Hospital, Cheongju, South Korea
| | - Ok-Jun Lee
- Department of Pathology, Chungbuk National University Hospital, Cheongju, South Korea.,Department of Pathology, Chungbuk National University College of Medicine, Cheongju, South Korea
| | - Dae Hoon Kim
- Department of Surgery, Chungbuk National University Hospital, Cheongju, South Korea
| | - Hyo Yung Yun
- Department of Surgery, Chungbuk National University Hospital, Cheongju, South Korea.,Department of Surgery, Chungbuk National University College of Medicine, Cheongju, South Korea
| | - Jieun Yun
- Department of Pharmaceutical Engineering, College of Science & Engineering, Cheongju University, Cheongju, South Korea
| | - Hee Kyung Kim
- Department of Internal Medicine, Chungbuk National University Hospital, Chungdae-ro 1, Seowon-gu, Cheongju, 28644, South Korea
| | - Yaewon Yang
- Department of Internal Medicine, Chungbuk National University Hospital, Chungdae-ro 1, Seowon-gu, Cheongju, 28644, South Korea
| | - Hye Sook Han
- Department of Internal Medicine, Chungbuk National University Hospital, Chungdae-ro 1, Seowon-gu, Cheongju, 28644, South Korea. .,Department of Internal Medicine, Chungbuk National University College of Medicine, Cheongju, South Korea.
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18
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Huber AR, Buscaglia B, Koltz BR, Henry J, McMahon L, Guo J, Hicks DG, Whitney-Miller CL. Impact of Specimen Type and Specimen Number on HER2 Status in Gastroesophageal Junction and Gastric Adenocarcinoma. Am J Clin Pathol 2019; 151:461-468. [PMID: 30624589 DOI: 10.1093/ajcp/aqy166] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
OBJECTIVES Human epidermal growth factor receptor 2 (HER2) is expressed in some gastric and gastroesophageal junction adenocarcinomas. There were two goals: assess the impact of specimen type on HER2 status and evaluate HER2 concordance with multiple specimens. METHODS All cases were evaluated by immunohistochemistry (IHC) for HER2 and interpreted using established criteria. Fluorescence in situ hybridization (FISH) was performed on a subset. RESULTS Of 460 specimens, 83.9% were IHC negative, 5.4% were equivocal, and 10.7% were IHC positive. Of those with FISH testing, 78.5% were FISH negative, and 21.5% were FISH positive. IHC-FISH concordance for biopsy specimens, resections, and metastases was 82%, 84%, and 86%, respectively. With one vs two vs three or more specimens, the HER2-positive rate increased from 10.5% to 18.1% to 24.1%, respectively. CONCLUSIONS HER2 testing may be performed on biopsy specimens with a relatively high concordance rate with resection specimens, and if multiple samples are analyzed from a single patient, the HER2-positive rate increases over twofold.
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Affiliation(s)
- Aaron R Huber
- Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY
| | - Brandon Buscaglia
- Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY
| | - Brooke R Koltz
- Department of Pathology, University of Toledo, Toledo, OH
| | - Jill Henry
- Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY
| | - Loralee McMahon
- Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY
| | - James Guo
- Northwestern University, Feinberg School of Medicine, Chicago, IL
| | - David G Hicks
- Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY
| | - Christa L Whitney-Miller
- Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY
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19
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Wang FH, Shen L, Li J, Zhou ZW, Liang H, Zhang XT, Tang L, Xin Y, Jin J, Zhang YJ, Yuan XL, Liu TS, Li GX, Wu Q, Xu HM, Ji JF, Li YF, Wang X, Yu S, Liu H, Guan WL, Xu RH. The Chinese Society of Clinical Oncology (CSCO): clinical guidelines for the diagnosis and treatment of gastric cancer. Cancer Commun (Lond) 2019; 39:10. [PMID: 30885279 PMCID: PMC6423835 DOI: 10.1186/s40880-019-0349-9] [Citation(s) in RCA: 311] [Impact Index Per Article: 51.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2019] [Accepted: 02/01/2019] [Indexed: 02/08/2023] Open
Abstract
China is one of the countries with the highest incidence of gastric cancer. There are differences in epidemiological characteristics, clinicopathological features, tumor biological characteristics, treatment patterns, and drug selection between gastric cancer patients from the Eastern and Western countries. Non-Chinese guidelines cannot specifically reflect the diagnosis and treatment characteristics for the Chinese gastric cancer patients. The Chinese Society of Clinical Oncology (CSCO) arranged for a panel of senior experts specializing in all sub-specialties of gastric cancer to compile, discuss, and revise the guidelines on the diagnosis and treatment of gastric cancer based on the findings of evidence-based medicine in China and abroad. By referring to the opinions of industry experts, taking into account of regional differences, giving full consideration to the accessibility of diagnosis and treatment resources, these experts have conducted experts' consensus judgement on relevant evidence and made various grades of recommendations for the clinical diagnosis and treatment of gastric cancer to reflect the value of cancer treatment and meeting health economic indexes. This guideline uses tables and is complemented by explanatory and descriptive notes covering the diagnosis, comprehensive treatment, and follow-up visits for gastric cancer.
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Affiliation(s)
- Feng-Hua Wang
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060 Guangdong P. R. China
| | - Lin Shen
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Oncology, Peking University Cancer Hospital and Institute, Beijing, 100142 P. R. China
| | - Jin Li
- Department of Oncology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120 P. R. China
| | - Zhi-Wei Zhou
- Department of Gastric Surgery, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060 Guangdong P. R. China
| | - Han Liang
- Department of Gastric Cancer, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center of Cancer, Tianjin’s Clinical Research Cancer for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060 P. R. China
| | - Xiao-Tian Zhang
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Oncology, Peking University Cancer Hospital and Institute, Beijing, 100142 P. R. China
| | - Lei Tang
- Medical Imaging Department, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Oncology, Peking University Cancer Hospital and Institute, Beijing, 100142 P. R. China
| | - Yan Xin
- Pathology Laboratory of Gastrointestinal Tumor, The First Hospital of China Medical University, Shenyang, 110001 Liaoning P. R. China
| | - Jing Jin
- Department of Radiation Oncology, National Cancer Center, China and Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021 P. R. China
| | - Yu-Jing Zhang
- Department of Radiotherapy, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060 Guangdong P. R. China
| | - Xiang-Lin Yuan
- Department of Medical Oncology, Tongji Hospital Affiliated to Tongji Medical College of Huazhong University of Science and Technology, Wuhan, 430030 Hubei P. R. China
| | - Tian-Shu Liu
- Department of Medical Oncology, Zhongshan Hospital Affiliated to Fudan University, Shanghai, 200032 P. R. China
| | - Guo-Xin Li
- Department of General Surgery, Nanfang Hospital Affiliated to Southern Medical University, Guangzhou, 510515 Guangdong P. R. China
| | - Qi Wu
- Department of Endoscopy Center, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Oncology, Peking University Cancer Hospital and Institute, Beijing, 100142 P. R. China
| | - Hui-Mian Xu
- Department of Surgical Oncology, The First Hospital of China Medical University, Shenyang, 110001 Liaoning P. R. China
| | - Jia-Fu Ji
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Oncology, Peking University Cancer Hospital and Institute, Beijing, 100142 P. R. China
| | - Yuan-Fang Li
- Department of Gastric Surgery, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060 Guangdong P. R. China
| | - Xin Wang
- Department of Radiation Oncology, National Cancer Center, China and Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021 P. R. China
| | - Shan Yu
- Department of Medical Oncology, Zhongshan Hospital Affiliated to Fudan University, Shanghai, 200032 P. R. China
| | - Hao Liu
- Department of General Surgery, Nanfang Hospital Affiliated to Southern Medical University, Guangzhou, 510515 Guangdong P. R. China
| | - Wen-Long Guan
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060 Guangdong P. R. China
| | - Rui-Hua Xu
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060 Guangdong P. R. China
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20
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Kai K, Yoda Y, Kawaguchi A, Minesaki A, Iwasaki H, Aishima S, Noshiro H. Formalin fixation on HER-2 and PD-L1 expression in gastric cancer: A pilot analysis using the same surgical specimens with different fixation times. World J Clin Cases 2019; 7:419-430. [PMID: 30842953 PMCID: PMC6397813 DOI: 10.12998/wjcc.v7.i4.419] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2018] [Revised: 12/24/2018] [Accepted: 12/29/2018] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND The needs for human epidermal growth factor receptor 2 (HER-2) and/or programmed death-ligand 1 (PD-L1) evaluations in gastric cancer are dramatically increasing. Although the importance of standardization of sample fixation has been widely recognized, most of the evidence regarding the fixation duration or type of fixing solution are based on breast cancer. AIM To investigate the real effects of fixation conditions on HER-2 testing or PD-L1 testing for gastric cancer using gastrectomy specimens. METHODS Thirty-two patients who underwent gastrectomy for gastric cancer were enrolled. Their resected specimens were each divided into four pieces and fixed in four strictly controlled different durations (6 h, 24 h, and 48 h, and 1 wk) by 10% formalin (n = 22) or 10% neutral buffered formalin (NBF) (n = 10). Immunohistochemistry (IHC) of HER-2 and PD-1 was performed, and a pathology examination was conducted. In the HER-2-immunoreactive cases, all four specimens were subjected to dual-color in situ hybridization (DISH). Five cases were assessed as HER-2-positive by IHC and DISH. We used the cut-off values of 1%, 10%, and 50% to assess the IHC findings of PD-L1. RESULTS No significant difference was observed in comparisons between the shorter fixation period groups (6 h, 24 h, and 48 h) and the prolonged fixation period (1 wk) group in the HER-2 and PD-L1 analyses. Although no significant difference was observed between 10% formalin and 10% NBF within 1 wk of fixation, the superiority of 10% NBF was confirmed in a long-term (> 3 mo) fixation in both the HER-2 and PD-L1 analyses. CONCLUSION In this small-numbered pilot study, prolonged fixation within 1 wk showed no inferiority in HER-2 or PD-L1 testing. However, a large-numbered prospective study is needed to obtain conclusive results.
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Affiliation(s)
- Keita Kai
- Department of Pathology, Saga University Hospital, Saga 849-8501, Japan
| | - Yukie Yoda
- Department of Surgery, Saga University Faculty of Medicine, Saga 849-8501, Japan
| | - Atsushi Kawaguchi
- Center for Comprehensive Community Medicine, Saga University Faculty of Medicine, Saga 849-8501, Japan
| | - Akimichi Minesaki
- Department of Pathology and Microbiology, Saga University Faculty of Medicine, Saga 849-8501, Japan
- Department of Otolaryngology - Head and Neck Surgery, Saga University Faculty of Medicine, Saga 849-8501, Japan
| | - Hironori Iwasaki
- Department of Surgery, Saga University Faculty of Medicine, Saga 849-8501, Japan
| | - Shinichi Aishima
- Department of Pathology, Saga University Hospital, Saga 849-8501, Japan
- Department of Pathology and Microbiology, Saga University Faculty of Medicine, Saga 849-8501, Japan
| | - Hirokazu Noshiro
- Department of Surgery, Saga University Faculty of Medicine, Saga 849-8501, Japan
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21
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Xu C, Liu Y, Jiang D, Li Q, Ge X, Zhang Y, Huang J, Su J, Ji Y, Hou J, Lu S, Hou Y, Liu T. Poor efficacy response to trastuzumab therapy in advanced gastric cancer with homogeneous HER2 positive and non-intestinal type. Oncotarget 2018; 8:33185-33196. [PMID: 28388541 PMCID: PMC5464860 DOI: 10.18632/oncotarget.16567] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2016] [Accepted: 03/16/2017] [Indexed: 12/20/2022] Open
Abstract
Introduction Factors affecting trastuzumab efficacy in advanced gastric cancer (GC) are largely unknown. Heterogeneity is a notable feature of HER2 in GC. Whether the heterogeneity influences trastuzumab efficacy is still unknown. Results The HER2homogeneous group and HER2heterogeneous group showed no statistical difference in RR (46.4% vs 55.0%, P = 0.558), PFS (5.80 vs 6.30 months, P = 0.804) and OS (16.00 vs 16.00 months, P = 0.787). The Laurenintestinal group and Laurennon-intestinal group demonstrated no discrepancy in PFS (6.00 vs 6.00 months, P = 0.912) and OS (16.50 vs 14.00 months, P = 0.227). However, by combining HER2 heterogeneity and Lauren classification, PFS and OS of HER2homogeneous/Laurennon-intestinal subgroup was the shortest among the 4 subgroups (P = 0.012 and P = 0.037), which was much shorter than the other patients (PFS:3.00 vs 6.30 months, P = 0.003; OS: 4.50 vs 16.50 months, P = 0.004). Univariate and multivariate analysis showed that HER2 heterogeneity combined with Lauren classification was an independent prognostic factor in both PFS (P = 0.031 and P = 0.002) and OS (P = 0.039 and P = 0.013). Materials and Methods 48 patients with HER2 positive advanced GCs accepting trastuzumab treatment were retrospectively analyzed. Based on HER2 heterogeneity, the patients were divided into a HER2homogeneous group and a HER2heterogeneous group. Response rate (RR), progression free survival (PFS), and overall survival (OS) were compared. Main clinicopathological factors including Lauren classification were subjected to subgroup analysis. Conclusions HER2 heterogeneity alone may not correlate with trastuzumab efficacy in HER2 positive advanced GCs. HER2 heterogeneity combined with Lauren classification may help to identify a subgroup with poor response to trastuzumab which is homogeneous HER2 positive and non-intestinal type.
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Affiliation(s)
- Chen Xu
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China.,Department of Pathology, School of Basic Medical Sciences and Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yalan Liu
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China.,Department of Pathology, School of Basic Medical Sciences and Zhongshan Hospital, Fudan University, Shanghai, China
| | - Dongxian Jiang
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China.,Department of Pathology, School of Basic Medical Sciences and Zhongshan Hospital, Fudan University, Shanghai, China
| | - Qian Li
- Department of Oncology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Xiaowen Ge
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China.,Department of Pathology, School of Basic Medical Sciences and Zhongshan Hospital, Fudan University, Shanghai, China
| | - Ying Zhang
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China.,Department of Pathology, School of Basic Medical Sciences and Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jie Huang
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China.,Department of Pathology, School of Basic Medical Sciences and Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jieakesu Su
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China.,Department of Pathology, School of Basic Medical Sciences and Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yuan Ji
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China.,Department of Pathology, School of Basic Medical Sciences and Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jun Hou
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China.,Department of Pathology, School of Basic Medical Sciences and Zhongshan Hospital, Fudan University, Shanghai, China
| | - Shaohua Lu
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China.,Department of Pathology, School of Basic Medical Sciences and Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yingyong Hou
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China.,Department of Pathology, School of Basic Medical Sciences and Zhongshan Hospital, Fudan University, Shanghai, China
| | - Tianshu Liu
- Department of Oncology, Zhongshan Hospital, Fudan University, Shanghai, China
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22
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Kumarasinghe MP, Morey A, Bilous M, Farshid G, Francis G, Lampe G, McCue G, Von Neumann-Cosel V, Fox SB. HER2 testing in advanced gastric and gastro-oesophageal cancer: analysis of an Australia-wide testing program. Pathology 2017; 49:575-581. [PMID: 28823752 DOI: 10.1016/j.pathol.2017.05.009] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2017] [Revised: 05/15/2017] [Accepted: 05/21/2017] [Indexed: 01/29/2023]
Abstract
This Australian human epidermal growth factor receptor 2 (HER2) testing program aimed to analyse >800 cases tested in a coordinated setting to further evaluate the criteria to establish HER2 status in advanced gastric and gastro-oesophageal junction (GOJ) cancer. Heterogeneity, and minimum number of biopsy fragments for reliable HER2 assessment were also examined in a subset of samples. Five laboratories tested 891 samples referred to determine HER2 status for potential anti-HER2 treatment. Cancer site, specimen type (endoscopic biopsy/resection/metastases), immunohistochemistry (IHC) score, HER2 gene and CEP17 copy number (CN) and HER2:CEP17 ratios were recorded. Samples were derived from stomach (53.1%), GOJ (28.2%) or metastases (18.5%). IHC for HER2 and dual probe HER2:CEP17 in situ hybridisation (ISH) were performed in parallel. A stringent definition (SD) of HER2 positivity was used (IHC2+/3+ plus CN>6 and ratio>2) and compared with other published criteria. HER2 positive rate was 13.9% (114/820) by SD, and 12.9-16.0% using other definitions. There was higher concordance between IHC and HER2 CN by ISH than with ratio. The HER2 positive rate was significantly higher in GOJ samples than others (p = 0.03) and in endoscopic biopsies than resections (p = 0.047). In a subset of 98 positive cases, 39 (39.8%) showed heterogeneity, and in 282 endoscopic biopsies positivity rate plateaued at five tumour fragments, suggesting this is the minimum number of biopsies that should be examined.
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Affiliation(s)
- M Priyanthi Kumarasinghe
- PathWest, QEII Medical Centre and School of Pathology & Laboratory Medicine, University of Western Australia, Perth, WA, Australia.
| | | | - Michael Bilous
- Australian Clinical Labs, Norwest Private Hospital, Bella Vista, NSW, Australia
| | - Gelareh Farshid
- Discipline of Medicine, Adelaide University and Directorate of Surgical Pathology, SA Pathology, Adelaide, SA, Australia
| | | | - Guy Lampe
- Pathology Queensland, Brisbane, Qld, Australia
| | | | | | - Stephen B Fox
- Peter MacCallum Cancer Centre and the Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Vic, Australia
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23
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Fazlollahi L, Remotti HE, Iuga A, Yang HM, Lagana SM, Sepulveda AR. HER2 Heterogeneity in Gastroesophageal Cancer Detected by Testing Biopsy and Resection Specimens. Arch Pathol Lab Med 2017; 142:516-522. [PMID: 28782986 DOI: 10.5858/arpa.2017-0039-oa] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
CONTEXT - In advanced gastric, esophageal, and gastroesophageal junction adenocarcinomas (GE-GEJ-AC) that overexpress ERBB2 (erb-b2 receptor tyrosine kinase 2 or HER2), anti-HER2 monoclonal antibody therapy confers survival benefit. To select patients for treatment, HER2 expression and gene amplification are evaluated by immunohistochemistry (IHC) and in situ hybridization. OBJECTIVE - To determine whether GE-GEJ-AC tested for HER2 on biopsy specimens of a primary tumor show different IHC scores and/or HER2 amplification by in situ hybridization in matched resection specimens, potentially changing therapy eligibility. DESIGN - Immunohistochemistry and silver in situ hybridization were performed in biopsy and/or resection specimens from 100 patients. HER2 testing was performed in matched resection and biopsy specimens of 15 cases to determine whether GE-GEJ-AC with IHC scores of 0, 1+, and 2+ in biopsy and resection specimens had different IHC and silver in situ hybridization results. RESULTS - The IHC 3+ cases showed HER2 amplification in 4 of 5 cases (80%), and IHC scores of 0, 1+, and 2+ showed 3.5%, 14.3%, and 23.5% HER2 amplification by silver in situ hybridization. Among the 15 paired biopsy and resection specimens, 9 (60%) had at least pT2 stage GE-GEJ-AC with HER2 IHC scores of 0, 1+, or 2+ in the biopsy, and 2 of those 9 cases (22%) had IHC 3+ and HER2 amplification by silver in situ hybridization on the resection specimen. CONCLUSIONS - Our data suggest that HER2 testing should be repeated on resection specimens of GE-GEJ-AC with HER2 IHC scores of negative (0 and 1+) or equivocal (2+) and in situ hybridization amplification negative biopsy specimen results to evaluate for HER2 heterogeneity when patients are being considered for anti-HER2 therapy.
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Affiliation(s)
| | | | | | | | | | - Antonia R Sepulveda
- From the Department of Pathology and Cell Biology, Columbia University Medical Center, New York Presbyterian Hospital, New York
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24
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Xu C, Liu Y, Jiang D, Ge X, Zhang Y, Su J, Zeng H, Huang J, Ji Y, Hou J, Sun Y, Shen K, Liu T, Hou Y, Qin J. HER2 assessment in locally advanced gastric cancer: comparing the results obtained with the use of two primary tumour blocks versus those obtained with the use of all primary tumour blocks. Histopathology 2017; 71:570-579. [PMID: 28513868 DOI: 10.1111/his.13257] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2016] [Accepted: 05/13/2017] [Indexed: 12/31/2022]
Affiliation(s)
- Chen Xu
- Department of Pathology; Zhongshan Hospital; Fudan University; Shanghai China
- Department of Pathology; School of Basic Medical Sciences & Zhongshan Hospital; Fudan University; Shanghai China
| | - Yalan Liu
- Department of Pathology; Zhongshan Hospital; Fudan University; Shanghai China
- Department of Pathology; School of Basic Medical Sciences & Zhongshan Hospital; Fudan University; Shanghai China
| | - Dongxian Jiang
- Department of Pathology; Zhongshan Hospital; Fudan University; Shanghai China
- Department of Pathology; School of Basic Medical Sciences & Zhongshan Hospital; Fudan University; Shanghai China
| | - Xiaowen Ge
- Department of Pathology; Zhongshan Hospital; Fudan University; Shanghai China
- Department of Pathology; School of Basic Medical Sciences & Zhongshan Hospital; Fudan University; Shanghai China
| | - Ying Zhang
- Department of Pathology; Zhongshan Hospital; Fudan University; Shanghai China
- Department of Pathology; School of Basic Medical Sciences & Zhongshan Hospital; Fudan University; Shanghai China
| | - Jieakesu Su
- Department of Pathology; Zhongshan Hospital; Fudan University; Shanghai China
- Department of Pathology; School of Basic Medical Sciences & Zhongshan Hospital; Fudan University; Shanghai China
| | - Haiying Zeng
- Department of Pathology; Zhongshan Hospital; Fudan University; Shanghai China
- Department of Pathology; School of Basic Medical Sciences & Zhongshan Hospital; Fudan University; Shanghai China
| | - Jie Huang
- Department of Pathology; Zhongshan Hospital; Fudan University; Shanghai China
- Department of Pathology; School of Basic Medical Sciences & Zhongshan Hospital; Fudan University; Shanghai China
| | - Yuan Ji
- Department of Pathology; Zhongshan Hospital; Fudan University; Shanghai China
- Department of Pathology; School of Basic Medical Sciences & Zhongshan Hospital; Fudan University; Shanghai China
| | - Jun Hou
- Department of Pathology; Zhongshan Hospital; Fudan University; Shanghai China
- Department of Pathology; School of Basic Medical Sciences & Zhongshan Hospital; Fudan University; Shanghai China
| | - Yihong Sun
- Department of General Surgery; Fudan University; Shanghai China
| | - Kuntang Shen
- Department of General Surgery; Fudan University; Shanghai China
| | - Tianshu Liu
- Department of Oncology; Zhongshan Hospital; Fudan University; Shanghai China
| | - Yingyong Hou
- Department of Pathology; Zhongshan Hospital; Fudan University; Shanghai China
- Department of Pathology; School of Basic Medical Sciences & Zhongshan Hospital; Fudan University; Shanghai China
| | - Jing Qin
- Department of General Surgery; Fudan University; Shanghai China
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25
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Xu C, Liu Y, Ge X, Jiang D, Zhang Y, Ji Y, Hou J, Huang J, Su J, Zeng H, Qin J, Hou Y. Tumor containing fragment number influences immunohistochemistry positive rate of HER2 in biopsy specimens of gastric cancer. Diagn Pathol 2017; 12:41. [PMID: 28549444 PMCID: PMC5446751 DOI: 10.1186/s13000-017-0616-5] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2016] [Accepted: 02/28/2017] [Indexed: 02/07/2023] Open
Abstract
Background HER2 assessment in biopsy specimens of gastric cancer (GC) is challenging because of the intratumoral heterogeneity. False negative results may be get because of limited biopsy material. The aim of this study is to explore how tumor-containing fragment number and biopsy specimen number affect HER2 immunohistochemistry (IHC) positive rate. Methods Eight hundred and ninety biopsy specimens and 459 paired resected specimens were collected. IHC staining of HER2 was performed. HER2 IHC positive (scored 3+) rate was compared based on tumor-containing fragment number, biopsy specimen number, average size and tumor tissue proportion of tumor-containing fragments. The positive predictability of biopsy specimens to resected specimens was analyzed based on tumor fragment number. Results HER2 IHC positive rates were 2.0, 3.5, 7.0, 13.2, 17.1, and 15.9% when tumor fragment numbers were 1, 2, 3, 4, 5 and 6 respectively. The rate rose with the increase of tumor fragment number (P = 0.004). ROC curve analysis showed that biopsy specimens exhibited positive predictability when tumor fragment number reached 3, but showed better performance when the number was ≥4 (P < 0.05). After fragment number reached 4, no statistic differences were reached in either HER2 IHC positive rate or positive predictability with further increase of the number (P > 0.05). HER2 IHC positive rate was not associated with biopsy number (P = 0.127), average size of tumor fragments (P = 0.397), and tumor tissue proportion of tumor fragments (P = 0.825) directly. Conclusions The number of tumor-containing fragments influences HER2 IHC positive (scored 3+) rate. Greater than or equal to 4 (≥4) tumor fragments give better results in the positive rate as well as positive predictability. We recommend the number of tumor containing fragments be described in the HER2 IHC pathology reports for clinical reference in endoscopic biopsy specimens of GC.
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Affiliation(s)
- Chen Xu
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, 20032, China.,Department of Pathology, School of Basic Medical Sciences & Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Yalan Liu
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, 20032, China.,Department of Pathology, School of Basic Medical Sciences & Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Xiaowen Ge
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, 20032, China.,Department of Pathology, School of Basic Medical Sciences & Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Dongxian Jiang
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, 20032, China.,Department of Pathology, School of Basic Medical Sciences & Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Ying Zhang
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, 20032, China.,Department of Pathology, School of Basic Medical Sciences & Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Yuan Ji
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, 20032, China.,Department of Pathology, School of Basic Medical Sciences & Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Jun Hou
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, 20032, China.,Department of Pathology, School of Basic Medical Sciences & Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Jie Huang
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, 20032, China.,Department of Pathology, School of Basic Medical Sciences & Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Jieakesu Su
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, 20032, China.,Department of Pathology, School of Basic Medical Sciences & Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Haiying Zeng
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, 20032, China.,Department of Pathology, School of Basic Medical Sciences & Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Jing Qin
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, 20032, China.
| | - Yingyong Hou
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, 20032, China. .,Department of Pathology, School of Basic Medical Sciences & Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
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26
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Personeni N, Baretti M, Bozzarelli S, Spaggiari P, Rubino L, Tronconi MC, Fumagalli Romario U, Rosati R, Giordano L, Roncalli M, Santoro A, Rimassa L. Assessment of HER2 status in patients with gastroesophageal adenocarcinoma treated with epirubicin-based chemotherapy: heterogeneity-related issues and prognostic implications. Gastric Cancer 2017; 20:428-437. [PMID: 27530622 DOI: 10.1007/s10120-016-0625-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2015] [Accepted: 08/02/2016] [Indexed: 02/07/2023]
Abstract
BACKGROUND HER2 and topoisomerase 2 alpha (TOP2A) genomic status was previously reported to predict benefit from anthracyclines in breast cancer. We sought to define the prognostic impact and possible pitfalls related to these biomarkers in resectable gastroesophageal adenocarcinoma. METHODS HER2 and TOP2A gene amplification by fluorescent in situ hybridization and HER2 protein expression by immunohistochemistry (IHC) were assessed on whole tissue sections from 101 patients receiving peri- or postoperative epirubicin-based chemotherapy. In a subgroup of patients, at least two matched tumor blocks, originating either from surgical procedures (n = 88) or diagnostic biopsies (n = 32), were available for HER2 analyses by IHC. RESULTS Eighteen of 101 patients (17.8 %) were HER2 positive, whereas TOP2A was amplified in 4 of 84 patients (4.7 %). HER2 positivity was significantly associated with improved disease-free survival [HR = 0.47 (95 % CI 0.22-0.99), P = 0.046] and overall survival [HR = 0.33 (95 % CI 0.13-0.83), P < 0.018], independent of clinical-pathologic features. HER2 expression in matched tumor blocks from the same resection specimen was discordant in up to 11.8 % of pairs, while this rate increased up to 27.2 % when diagnostic biopsies and paired surgical samples were compared. CONCLUSIONS HER2 status is an independent prognostic biomarker in gastroesophageal adenocarcinomas receiving epirubicin-based chemotherapy. Compared to diagnostic biopsies, HER2 assessment in multiple resection specimens might lower the risk of sampling errors. These findings have several implications with respect to the optimal choice of the sample to be submitted to IHC testing of HER2.
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Affiliation(s)
- Nicola Personeni
- Humanitas Cancer Center, Humanitas Clinical and Research Center, Via Manzoni 56 Rozzano, 20089, Milan, Italy. .,Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy.
| | - Marina Baretti
- Humanitas Cancer Center, Humanitas Clinical and Research Center, Via Manzoni 56 Rozzano, 20089, Milan, Italy
| | - Silvia Bozzarelli
- Humanitas Cancer Center, Humanitas Clinical and Research Center, Via Manzoni 56 Rozzano, 20089, Milan, Italy
| | - Paola Spaggiari
- Department of Pathology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy
| | - Luca Rubino
- Humanitas Cancer Center, Humanitas Clinical and Research Center, Via Manzoni 56 Rozzano, 20089, Milan, Italy
| | - Maria Chiara Tronconi
- Humanitas Cancer Center, Humanitas Clinical and Research Center, Via Manzoni 56 Rozzano, 20089, Milan, Italy
| | | | - Riccardo Rosati
- Department of General Surgery, Humanitas Clinical and Research Center, Rozzano, Milan, Italy.,Ospedale San Raffaele, Milan, Italy
| | - Laura Giordano
- Humanitas Cancer Center, Humanitas Clinical and Research Center, Via Manzoni 56 Rozzano, 20089, Milan, Italy
| | - Massimo Roncalli
- Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy.,Department of Pathology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy
| | - Armando Santoro
- Humanitas Cancer Center, Humanitas Clinical and Research Center, Via Manzoni 56 Rozzano, 20089, Milan, Italy.,Humanitas University, Rozzano, Milan, Italy
| | - Lorenza Rimassa
- Humanitas Cancer Center, Humanitas Clinical and Research Center, Via Manzoni 56 Rozzano, 20089, Milan, Italy
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27
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Cetin B, Ozet A. HER2/neu as target in gastric adenocarcinoma. Transl Gastroenterol Hepatol 2017; 1:59. [PMID: 28138626 DOI: 10.21037/tgh.2016.06.08] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2016] [Accepted: 06/20/2016] [Indexed: 12/18/2022] Open
Affiliation(s)
- Bulent Cetin
- Department of Internal Medicine, Division of Medical Oncology, Recep Tayyip Erdogan University Faculty of Medicine, Rize 53100, Turkey
| | - Ahmet Ozet
- Department of Internal Medicine, Division of Medical Oncology, Gazi University Faculty of Medicine, Ankara, Turkey
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28
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Bartley AN, Washington MK, Colasacco C, Ventura CB, Ismaila N, Benson AB, Carrato A, Gulley ML, Jain D, Kakar S, Mackay HJ, Streutker C, Tang L, Troxell M, Ajani JA. HER2 Testing and Clinical Decision Making in Gastroesophageal Adenocarcinoma: Guideline From the College of American Pathologists, American Society for Clinical Pathology, and the American Society of Clinical Oncology. J Clin Oncol 2017; 35:446-464. [PMID: 28129524 DOI: 10.1200/jco.2016.69.4836] [Citation(s) in RCA: 283] [Impact Index Per Article: 35.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Context ERBB2 (erb-b2 receptor tyrosine kinase 2 or HER2) is currently the only biomarker established for selection of a specific therapy for patients with advanced gastroesophageal adenocarcinoma (GEA). However, there are no comprehensive guidelines for the assessment of HER2 in patients with GEA. Objectives To establish an evidence-based guideline for HER2 testing in patients with GEA, formalize the algorithms for methods to improve the accuracy of HER2 testing while addressing which patients and tumor specimens are appropriate, and to provide guidance on clinical decision making. Design The College of American Pathologists (CAP), American Society for Clinical Pathology (ASCP), and the American Society of Clinical Oncology (ASCO) convened an Expert Panel to conduct a systematic review of the literature to develop an evidence-based guideline with recommendations for optimal HER2 testing in patients with GEA. Results The Panel is proposing 11 recommendations with strong agreement from the open comment participants. Recommendations The Panel recommends that tumor specimen(s) from all patients with advanced GEA, who are candidates for HER2-targeted therapy, should be assessed for HER2 status before the initiation of HER2-targeted therapy. Clinicians should offer combination chemotherapy and an HER2-targeted agent as initial therapy for all patients with HER2-positive advanced GEA. For pathologists, guidance is provided for morphologic selection of neoplastic tissue, testing algorithms, scoring methods, interpretation and reporting of results, and laboratory quality assurance. Conclusion This guideline provides specific recommendations for assessment of HER2 in patients with advanced GEA while addressing pertinent technical issues and clinical implications of the results.
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Affiliation(s)
- Angela N Bartley
- Angela N. Bartley, St Joseph Mercy Hospital, Ann Arbor, MI; Mary Kay Washington, Vanderbilt University Medical Center, Nashville, TN; Carol Colasacco and Christina B. Ventura, College of American Pathologists, Northfield; Al B. Benson III, Northwestern University, Chicago, IL; Nofisat Ismaila, American Society of Clinical Oncology, Alexandria, VA; Alfredo Carrato, Ramón y Cajal University Hospital, Madrid, Spain; Margaret L. Gulley, University of North Carolina, Chapel Hill, NC; Dhanpat Jain, Yale University School of Medicine, New Haven, CT; Sanjay Kakar, University of California, San Francisco, CA; Helen J. Mackay, Princess Margaret Cancer Centre; Catherine Streutker, St Michael's Hospital, University of Toronto, Toronto, Canada; Laura Tang, Memorial Sloan Kettering Cancer Center, New York, NY; Megan Troxell, Stanford University Medical Center, Stanford, CA; and Jaffer A. Ajani, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Mary Kay Washington
- Angela N. Bartley, St Joseph Mercy Hospital, Ann Arbor, MI; Mary Kay Washington, Vanderbilt University Medical Center, Nashville, TN; Carol Colasacco and Christina B. Ventura, College of American Pathologists, Northfield; Al B. Benson III, Northwestern University, Chicago, IL; Nofisat Ismaila, American Society of Clinical Oncology, Alexandria, VA; Alfredo Carrato, Ramón y Cajal University Hospital, Madrid, Spain; Margaret L. Gulley, University of North Carolina, Chapel Hill, NC; Dhanpat Jain, Yale University School of Medicine, New Haven, CT; Sanjay Kakar, University of California, San Francisco, CA; Helen J. Mackay, Princess Margaret Cancer Centre; Catherine Streutker, St Michael's Hospital, University of Toronto, Toronto, Canada; Laura Tang, Memorial Sloan Kettering Cancer Center, New York, NY; Megan Troxell, Stanford University Medical Center, Stanford, CA; and Jaffer A. Ajani, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Carol Colasacco
- Angela N. Bartley, St Joseph Mercy Hospital, Ann Arbor, MI; Mary Kay Washington, Vanderbilt University Medical Center, Nashville, TN; Carol Colasacco and Christina B. Ventura, College of American Pathologists, Northfield; Al B. Benson III, Northwestern University, Chicago, IL; Nofisat Ismaila, American Society of Clinical Oncology, Alexandria, VA; Alfredo Carrato, Ramón y Cajal University Hospital, Madrid, Spain; Margaret L. Gulley, University of North Carolina, Chapel Hill, NC; Dhanpat Jain, Yale University School of Medicine, New Haven, CT; Sanjay Kakar, University of California, San Francisco, CA; Helen J. Mackay, Princess Margaret Cancer Centre; Catherine Streutker, St Michael's Hospital, University of Toronto, Toronto, Canada; Laura Tang, Memorial Sloan Kettering Cancer Center, New York, NY; Megan Troxell, Stanford University Medical Center, Stanford, CA; and Jaffer A. Ajani, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Christina B Ventura
- Angela N. Bartley, St Joseph Mercy Hospital, Ann Arbor, MI; Mary Kay Washington, Vanderbilt University Medical Center, Nashville, TN; Carol Colasacco and Christina B. Ventura, College of American Pathologists, Northfield; Al B. Benson III, Northwestern University, Chicago, IL; Nofisat Ismaila, American Society of Clinical Oncology, Alexandria, VA; Alfredo Carrato, Ramón y Cajal University Hospital, Madrid, Spain; Margaret L. Gulley, University of North Carolina, Chapel Hill, NC; Dhanpat Jain, Yale University School of Medicine, New Haven, CT; Sanjay Kakar, University of California, San Francisco, CA; Helen J. Mackay, Princess Margaret Cancer Centre; Catherine Streutker, St Michael's Hospital, University of Toronto, Toronto, Canada; Laura Tang, Memorial Sloan Kettering Cancer Center, New York, NY; Megan Troxell, Stanford University Medical Center, Stanford, CA; and Jaffer A. Ajani, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Nofisat Ismaila
- Angela N. Bartley, St Joseph Mercy Hospital, Ann Arbor, MI; Mary Kay Washington, Vanderbilt University Medical Center, Nashville, TN; Carol Colasacco and Christina B. Ventura, College of American Pathologists, Northfield; Al B. Benson III, Northwestern University, Chicago, IL; Nofisat Ismaila, American Society of Clinical Oncology, Alexandria, VA; Alfredo Carrato, Ramón y Cajal University Hospital, Madrid, Spain; Margaret L. Gulley, University of North Carolina, Chapel Hill, NC; Dhanpat Jain, Yale University School of Medicine, New Haven, CT; Sanjay Kakar, University of California, San Francisco, CA; Helen J. Mackay, Princess Margaret Cancer Centre; Catherine Streutker, St Michael's Hospital, University of Toronto, Toronto, Canada; Laura Tang, Memorial Sloan Kettering Cancer Center, New York, NY; Megan Troxell, Stanford University Medical Center, Stanford, CA; and Jaffer A. Ajani, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Al B Benson
- Angela N. Bartley, St Joseph Mercy Hospital, Ann Arbor, MI; Mary Kay Washington, Vanderbilt University Medical Center, Nashville, TN; Carol Colasacco and Christina B. Ventura, College of American Pathologists, Northfield; Al B. Benson III, Northwestern University, Chicago, IL; Nofisat Ismaila, American Society of Clinical Oncology, Alexandria, VA; Alfredo Carrato, Ramón y Cajal University Hospital, Madrid, Spain; Margaret L. Gulley, University of North Carolina, Chapel Hill, NC; Dhanpat Jain, Yale University School of Medicine, New Haven, CT; Sanjay Kakar, University of California, San Francisco, CA; Helen J. Mackay, Princess Margaret Cancer Centre; Catherine Streutker, St Michael's Hospital, University of Toronto, Toronto, Canada; Laura Tang, Memorial Sloan Kettering Cancer Center, New York, NY; Megan Troxell, Stanford University Medical Center, Stanford, CA; and Jaffer A. Ajani, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Alfredo Carrato
- Angela N. Bartley, St Joseph Mercy Hospital, Ann Arbor, MI; Mary Kay Washington, Vanderbilt University Medical Center, Nashville, TN; Carol Colasacco and Christina B. Ventura, College of American Pathologists, Northfield; Al B. Benson III, Northwestern University, Chicago, IL; Nofisat Ismaila, American Society of Clinical Oncology, Alexandria, VA; Alfredo Carrato, Ramón y Cajal University Hospital, Madrid, Spain; Margaret L. Gulley, University of North Carolina, Chapel Hill, NC; Dhanpat Jain, Yale University School of Medicine, New Haven, CT; Sanjay Kakar, University of California, San Francisco, CA; Helen J. Mackay, Princess Margaret Cancer Centre; Catherine Streutker, St Michael's Hospital, University of Toronto, Toronto, Canada; Laura Tang, Memorial Sloan Kettering Cancer Center, New York, NY; Megan Troxell, Stanford University Medical Center, Stanford, CA; and Jaffer A. Ajani, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Margaret L Gulley
- Angela N. Bartley, St Joseph Mercy Hospital, Ann Arbor, MI; Mary Kay Washington, Vanderbilt University Medical Center, Nashville, TN; Carol Colasacco and Christina B. Ventura, College of American Pathologists, Northfield; Al B. Benson III, Northwestern University, Chicago, IL; Nofisat Ismaila, American Society of Clinical Oncology, Alexandria, VA; Alfredo Carrato, Ramón y Cajal University Hospital, Madrid, Spain; Margaret L. Gulley, University of North Carolina, Chapel Hill, NC; Dhanpat Jain, Yale University School of Medicine, New Haven, CT; Sanjay Kakar, University of California, San Francisco, CA; Helen J. Mackay, Princess Margaret Cancer Centre; Catherine Streutker, St Michael's Hospital, University of Toronto, Toronto, Canada; Laura Tang, Memorial Sloan Kettering Cancer Center, New York, NY; Megan Troxell, Stanford University Medical Center, Stanford, CA; and Jaffer A. Ajani, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Dhanpat Jain
- Angela N. Bartley, St Joseph Mercy Hospital, Ann Arbor, MI; Mary Kay Washington, Vanderbilt University Medical Center, Nashville, TN; Carol Colasacco and Christina B. Ventura, College of American Pathologists, Northfield; Al B. Benson III, Northwestern University, Chicago, IL; Nofisat Ismaila, American Society of Clinical Oncology, Alexandria, VA; Alfredo Carrato, Ramón y Cajal University Hospital, Madrid, Spain; Margaret L. Gulley, University of North Carolina, Chapel Hill, NC; Dhanpat Jain, Yale University School of Medicine, New Haven, CT; Sanjay Kakar, University of California, San Francisco, CA; Helen J. Mackay, Princess Margaret Cancer Centre; Catherine Streutker, St Michael's Hospital, University of Toronto, Toronto, Canada; Laura Tang, Memorial Sloan Kettering Cancer Center, New York, NY; Megan Troxell, Stanford University Medical Center, Stanford, CA; and Jaffer A. Ajani, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Sanjay Kakar
- Angela N. Bartley, St Joseph Mercy Hospital, Ann Arbor, MI; Mary Kay Washington, Vanderbilt University Medical Center, Nashville, TN; Carol Colasacco and Christina B. Ventura, College of American Pathologists, Northfield; Al B. Benson III, Northwestern University, Chicago, IL; Nofisat Ismaila, American Society of Clinical Oncology, Alexandria, VA; Alfredo Carrato, Ramón y Cajal University Hospital, Madrid, Spain; Margaret L. Gulley, University of North Carolina, Chapel Hill, NC; Dhanpat Jain, Yale University School of Medicine, New Haven, CT; Sanjay Kakar, University of California, San Francisco, CA; Helen J. Mackay, Princess Margaret Cancer Centre; Catherine Streutker, St Michael's Hospital, University of Toronto, Toronto, Canada; Laura Tang, Memorial Sloan Kettering Cancer Center, New York, NY; Megan Troxell, Stanford University Medical Center, Stanford, CA; and Jaffer A. Ajani, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Helen J Mackay
- Angela N. Bartley, St Joseph Mercy Hospital, Ann Arbor, MI; Mary Kay Washington, Vanderbilt University Medical Center, Nashville, TN; Carol Colasacco and Christina B. Ventura, College of American Pathologists, Northfield; Al B. Benson III, Northwestern University, Chicago, IL; Nofisat Ismaila, American Society of Clinical Oncology, Alexandria, VA; Alfredo Carrato, Ramón y Cajal University Hospital, Madrid, Spain; Margaret L. Gulley, University of North Carolina, Chapel Hill, NC; Dhanpat Jain, Yale University School of Medicine, New Haven, CT; Sanjay Kakar, University of California, San Francisco, CA; Helen J. Mackay, Princess Margaret Cancer Centre; Catherine Streutker, St Michael's Hospital, University of Toronto, Toronto, Canada; Laura Tang, Memorial Sloan Kettering Cancer Center, New York, NY; Megan Troxell, Stanford University Medical Center, Stanford, CA; and Jaffer A. Ajani, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Catherine Streutker
- Angela N. Bartley, St Joseph Mercy Hospital, Ann Arbor, MI; Mary Kay Washington, Vanderbilt University Medical Center, Nashville, TN; Carol Colasacco and Christina B. Ventura, College of American Pathologists, Northfield; Al B. Benson III, Northwestern University, Chicago, IL; Nofisat Ismaila, American Society of Clinical Oncology, Alexandria, VA; Alfredo Carrato, Ramón y Cajal University Hospital, Madrid, Spain; Margaret L. Gulley, University of North Carolina, Chapel Hill, NC; Dhanpat Jain, Yale University School of Medicine, New Haven, CT; Sanjay Kakar, University of California, San Francisco, CA; Helen J. Mackay, Princess Margaret Cancer Centre; Catherine Streutker, St Michael's Hospital, University of Toronto, Toronto, Canada; Laura Tang, Memorial Sloan Kettering Cancer Center, New York, NY; Megan Troxell, Stanford University Medical Center, Stanford, CA; and Jaffer A. Ajani, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Laura Tang
- Angela N. Bartley, St Joseph Mercy Hospital, Ann Arbor, MI; Mary Kay Washington, Vanderbilt University Medical Center, Nashville, TN; Carol Colasacco and Christina B. Ventura, College of American Pathologists, Northfield; Al B. Benson III, Northwestern University, Chicago, IL; Nofisat Ismaila, American Society of Clinical Oncology, Alexandria, VA; Alfredo Carrato, Ramón y Cajal University Hospital, Madrid, Spain; Margaret L. Gulley, University of North Carolina, Chapel Hill, NC; Dhanpat Jain, Yale University School of Medicine, New Haven, CT; Sanjay Kakar, University of California, San Francisco, CA; Helen J. Mackay, Princess Margaret Cancer Centre; Catherine Streutker, St Michael's Hospital, University of Toronto, Toronto, Canada; Laura Tang, Memorial Sloan Kettering Cancer Center, New York, NY; Megan Troxell, Stanford University Medical Center, Stanford, CA; and Jaffer A. Ajani, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Megan Troxell
- Angela N. Bartley, St Joseph Mercy Hospital, Ann Arbor, MI; Mary Kay Washington, Vanderbilt University Medical Center, Nashville, TN; Carol Colasacco and Christina B. Ventura, College of American Pathologists, Northfield; Al B. Benson III, Northwestern University, Chicago, IL; Nofisat Ismaila, American Society of Clinical Oncology, Alexandria, VA; Alfredo Carrato, Ramón y Cajal University Hospital, Madrid, Spain; Margaret L. Gulley, University of North Carolina, Chapel Hill, NC; Dhanpat Jain, Yale University School of Medicine, New Haven, CT; Sanjay Kakar, University of California, San Francisco, CA; Helen J. Mackay, Princess Margaret Cancer Centre; Catherine Streutker, St Michael's Hospital, University of Toronto, Toronto, Canada; Laura Tang, Memorial Sloan Kettering Cancer Center, New York, NY; Megan Troxell, Stanford University Medical Center, Stanford, CA; and Jaffer A. Ajani, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Jaffer A Ajani
- Angela N. Bartley, St Joseph Mercy Hospital, Ann Arbor, MI; Mary Kay Washington, Vanderbilt University Medical Center, Nashville, TN; Carol Colasacco and Christina B. Ventura, College of American Pathologists, Northfield; Al B. Benson III, Northwestern University, Chicago, IL; Nofisat Ismaila, American Society of Clinical Oncology, Alexandria, VA; Alfredo Carrato, Ramón y Cajal University Hospital, Madrid, Spain; Margaret L. Gulley, University of North Carolina, Chapel Hill, NC; Dhanpat Jain, Yale University School of Medicine, New Haven, CT; Sanjay Kakar, University of California, San Francisco, CA; Helen J. Mackay, Princess Margaret Cancer Centre; Catherine Streutker, St Michael's Hospital, University of Toronto, Toronto, Canada; Laura Tang, Memorial Sloan Kettering Cancer Center, New York, NY; Megan Troxell, Stanford University Medical Center, Stanford, CA; and Jaffer A. Ajani, The University of Texas MD Anderson Cancer Center, Houston, TX
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Amato M, Perrone G, Righi D, Pellegrini C, Rabitti C, Di Matteo F, Crucitti P, Caputo D, Coppola R, Tonini G, Santini D, Onetti Muda A. HER2 Status in Gastric Cancer: Comparison between Primary and Distant Metastatic Disease. Pathol Oncol Res 2017; 23:55-61. [PMID: 27363700 DOI: 10.1007/s12253-016-0082-5] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2016] [Accepted: 06/14/2016] [Indexed: 01/21/2023]
Abstract
HER2 (human epidermal growth factor receptor-2) assessment in histological samples of gastric cancer is essential to determine which patients might benefit from trastuzumab therapy. HER2 is often evaluated in primary tumor even if trastuzumab therapy is used to treat metastatic disease. However, the exact relationship in terms of HER2 status between primary and metastatic tumors has not been fully clarified. We aimed to evaluate the HER2 status concordance between primary gastric cancer and corresponding distant metastasis. HER2 status was evaluated by IHC (immunohistochemistry) and/or FISH ( fluorescence in situ hybridization) in 41 patients in primary gastric cancer and in paired metastasis. HER2 was assessed according scoring criteria applied in clinical approach. HER2 positivity was found in 14,6 % primary tumors and in 24,4%corresponding metastasis. HER2 concordance rate between primary and metastasis was 80,5 % (K-value = 0,388). Eight/41 (19,5 %)cases resulted discordant: 6 patients with metastatic HER2 positive lesions were found HER2 negative in primary cancers while 2 patient HER2 positive in primary lesion showed a negative conversion in metastasis. Our results showed a good concordance in terms of HER2 status between primary and metastatic lesions, as well as in biopsy and surgical removed specimens. However, the higher rate of HER2 positive status found in metastatic lesions underlined the importance of HER2 assessment in all samples obtained from different sites of gastric cancer disease.
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Affiliation(s)
- Michelina Amato
- Department of Pathology, Campus Bio-Medico University of Rome, Via Alvaro del Portillo, 200, Rome, Italy
| | - Giuseppe Perrone
- Department of Pathology, Campus Bio-Medico University of Rome, Via Alvaro del Portillo, 200, Rome, Italy.
| | - Daniela Righi
- Department of Pathology, Campus Bio-Medico University of Rome, Via Alvaro del Portillo, 200, Rome, Italy
| | - Claudio Pellegrini
- Department of Pathology, Campus Bio-Medico University of Rome, Via Alvaro del Portillo, 200, Rome, Italy
| | - Carla Rabitti
- Department of Pathology, Campus Bio-Medico University of Rome, Via Alvaro del Portillo, 200, Rome, Italy
| | - Francesco Di Matteo
- Endoscopic Unit, Campus Bio-Medico University of Rome, Via Alvaro del Portillo, 200, Rome, Italy
| | - Pierfilippo Crucitti
- Department of Surgery, Campus Bio-Medico University of Rome, Via Alvaro del Portillo, 200, Rome, Italy
| | - Damiano Caputo
- Department of Surgery, Campus Bio-Medico University of Rome, Via Alvaro del Portillo, 200, Rome, Italy
| | - Roberto Coppola
- Department of Surgery, Campus Bio-Medico University of Rome, Via Alvaro del Portillo, 200, Rome, Italy
| | - Giuseppe Tonini
- Oncology Unit, Campus Bio-Medico University of Rome, Via Alvaro del Portillo, 200, Rome, Italy
| | - Daniele Santini
- Oncology Unit, Campus Bio-Medico University of Rome, Via Alvaro del Portillo, 200, Rome, Italy
| | - Andrea Onetti Muda
- Department of Pathology, Campus Bio-Medico University of Rome, Via Alvaro del Portillo, 200, Rome, Italy
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Bartley AN, Washington MK, Ventura CB, Ismaila N, Colasacco C, Benson AB, Carrato A, Gulley ML, Jain D, Kakar S, Mackay HJ, Streutker C, Tang L, Troxell M, Ajani JA. HER2 Testing and Clinical Decision Making in Gastroesophageal Adenocarcinoma: Guideline From the College of American Pathologists, American Society for Clinical Pathology, and American Society of Clinical Oncology. Arch Pathol Lab Med 2016; 140:1345-1363. [PMID: 27841667 DOI: 10.5858/arpa.2016-0331-cp] [Citation(s) in RCA: 123] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
CONTEXT - ERBB2 (erb-b2 receptor tyrosine kinase 2 or HER2) is currently the only biomarker established for selection of a specific therapy for patients with advanced gastroesophageal adenocarcinoma (GEA). However, there are no comprehensive guidelines for the assessment of HER2 in patients with GEA. OBJECTIVES - To establish an evidence-based guideline for HER2 testing in patients with GEA, to formalize the algorithms for methods to improve the accuracy of HER2 testing while addressing which patients and tumor specimens are appropriate, and to provide guidance on clinical decision making. DESIGN - The College of American Pathologists, American Society for Clinical Pathology, and American Society of Clinical Oncology convened an expert panel to conduct a systematic review of the literature to develop an evidence-based guideline with recommendations for optimal HER2 testing in patients with GEA. RESULTS - The panel is proposing 11 recommendations with strong agreement from the open-comment participants. RECOMMENDATIONS - The panel recommends that tumor specimen(s) from all patients with advanced GEA, who are candidates for HER2-targeted therapy, should be assessed for HER2 status before the initiation of HER2-targeted therapy. Clinicians should offer combination chemotherapy and a HER2-targeted agent as initial therapy for all patients with HER2-positive advanced GEA. For pathologists, guidance is provided for morphologic selection of neoplastic tissue, testing algorithms, scoring methods, interpretation and reporting of results, and laboratory quality assurance. CONCLUSIONS - This guideline provides specific recommendations for assessment of HER2 in patients with advanced GEA while addressing pertinent technical issues and clinical implications of the results.
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Affiliation(s)
- Angela N Bartley
- From the Department of Pathology, St. Joseph Mercy Hospital, Ann Arbor, Michigan (Dr Bartley); the Department of Pathology, Vanderbilt University Medical Center, Nashville, Tennessee (Dr Washington); Surveys (Ms Ventura) and Governance (Ms Colasacco), College of American Pathologists, Northfield, Illinois; Quality and Guidelines Department, American Society of Clinical Oncology, Alexandria, Virginia (Dr Ismaila); the Division of Hematology/Oncology, Northwestern University, Chicago, Illinois (Dr Benson); Medical Oncology Department, Ramon y Cajal University Hospital, Madrid, Spain (Dr Carrato); the Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill (Dr Gulley); the Department of Pathology, Yale University School of Medicine, New Haven, Connecticut (Dr Jain); the Department of Pathology and Laboratory Medicine, UCSF, San Francisco, California (Dr Kakar); the Division of Medical Oncology and Hematology, University of Toronto/Sunnybrook Odette Cancer Centre, Toronto, Ontario, Canada (Dr Mackay); the Department of Laboratory Medicine, St. Michael's Hospital, Toronto, Ontario, Canada (Dr Streutker); the Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York (Dr Tang); the Department of Pathology, Stanford University Medical Center, Stanford, California (Dr Troxell); and the Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston (Dr Ajani)
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31
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Bartley AN, Washington MK, Ventura CB, Ismaila N, Colasacco C, Benson AB, Carrato A, Gulley ML, Jain D, Kakar S, Mackay HJ, Streutker C, Tang L, Troxell M, Ajani JA. HER2 Testing and Clinical Decision Making in Gastroesophageal Adenocarcinoma: Guideline From the College of American Pathologists, American Society for Clinical Pathology, and American Society of Clinical Oncology. Am J Clin Pathol 2016; 146:647-669. [PMID: 28077399 PMCID: PMC6272805 DOI: 10.1093/ajcp/aqw206] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
CONTEXT ERBB2 (erb-b2 receptor tyrosine kinase 2 or HER2) is currently the only biomarker established for selection of a specific therapy for patients with advanced gastroesophageal adenocarcinoma (GEA). However, there are no comprehensive guidelines for the assessment of HER2 in patients with GEA. OBJECTIVES To establish an evidence-based guideline for HER2 testing in patients with GEA, to formalize the algorithms for methods to improve the accuracy of HER2 testing while addressing which patients and tumor specimens are appropriate, and to provide guidance on clinical decision making. DESIGN The College of American Pathologists, American Society for Clinical Pathology, and American Society of Clinical Oncology convened an expert panel to conduct a systematic review of the literature to develop an evidence-based guideline with recommendations for optimal HER2 testing in patients with GEA. RESULTS The panel is proposing 11 recommendations with strong agreement from the open-comment participants. RECOMMENDATIONS The panel recommends that tumor specimen(s) from all patients with advanced GEA, who are candidates for HER2-targeted therapy, should be assessed for HER2 status before the initiation of HER2-targeted therapy. Clinicians should offer combination chemotherapy and a HER2-targeted agent as initial therapy for all patients with HER2-positive advanced GEA. For pathologists, guidance is provided for morphologic selection of neoplastic tissue, testing algorithms, scoring methods, interpretation and reporting of results, and laboratory quality assurance. CONCLUSIONS This guideline provides specific recommendations for assessment of HER2 in patients with advanced GEA while addressing pertinent technical issues and clinical implications of the results.
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Affiliation(s)
- Angela N Bartley
- From the Department of Pathology, St Joseph Mercy Hospital, Ann Arbor, MI
| | - Mary Kay Washington
- Department of Pathology, Vanderbilt University Medical Center, Nashville, TN
| | | | - Nofisat Ismaila
- Quality and Guidelines Department, American Society of Clinical Oncology, Alexandria, VA
| | - Carol Colasacco
- Surveys and Governance, College of American Pathologists, Northfield, IL
| | - Al B Benson
- Division of Hematology/Oncology, Northwestern University, Chicago, IL
| | - Alfredo Carrato
- Medical Oncology Department, Ramon y Cajal University Hospital, Madrid, Spain
| | - Margaret L Gulley
- Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill
| | - Dhanpat Jain
- Department of Pathology, Yale University School of Medicine, New Haven, CT
| | - Sanjay Kakar
- Department of Pathology and Laboratory Medicine, UCSF, San Francisco, CA
| | - Helen J Mackay
- Division of Medical Oncology and Hematology, University of Toronto/Sunnybrook Odette Cancer Centre, Toronto, Canada
| | | | - Laura Tang
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Megan Troxell
- Department of Pathology, Stanford University Medical Center, Stanford, CA
| | - Jaffer A Ajani
- Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston
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Ahn S, Ahn S, Van Vrancken M, Lee M, Ha SY, Lee H, Min BH, Lee JH, Kim JJ, Choi S, Jung SH, Choi MG, Lee JH, Sohn TS, Bae JM, Kim S, Kim KM. Ideal number of biopsy tumor fragments for predicting HER2 status in gastric carcinoma resection specimens. Oncotarget 2016; 6:38372-80. [PMID: 26460823 PMCID: PMC4742006 DOI: 10.18632/oncotarget.5368] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2015] [Accepted: 09/29/2015] [Indexed: 12/15/2022] Open
Abstract
Intratumoral heterogeneity of HER2 expression is common in gastric cancers and pose a challenge for identifying patients who would benefit from anti-HER2 therapy. The aim of this study is to compare HER2 expression in biopsy and resection specimens of gastric carcinoma by immunohistochemistry (IHC) and to find the ideal number of biopsy tumor fragments that can accurately predict HER2 overexpression in the corresponding surgically resected specimen. The HER2 IHC results of 702 paired biopsy and resection specimens of gastric cancer were compared.The mean number of biopsy fragments among all cases was 4.3 (range 1-11). HER2 was positive in 130 (18.5%) endoscopic biopsies and in 102 (14.5%) gastrectomy specimens. Intratumoral heterogeneity of HER2 was found in 80 (61.5%) biopsies and 70 (68.6%) resection specimens. Out of the 70 surgical specimens with intratumoral heterogeneity, 24 (34.3%) of the corresponding biopsies were categorized as negative (positive conversion). In the 86 (12.3%) discrepant cases, negative conversion was observed in 57 (66.3%) cases and positive conversion in 29 (33.7%). The fragment numbers were significantly correlated with the discrepancy of results and positive predictability (P = 0.0315 and P = 0.0052). ROC curve analysis and positive predictability showed that 4 fragments should be obtained to minimize the differences in HER2 scores between biopsy and resection specimen.In gastric carcinomas with discrepant HER2 results between biopsy and surgical resection specimens, intratumoral heterogeneity is common with most of them showing positive conversion. To predict HER2 status precisely, at least 4 biopsy fragments containing tumor cells are required.
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Affiliation(s)
- Sangjeong Ahn
- Department of Pathology & Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.,Present address: Department of Pathology, Pusan National University Hospital and Pusan National University School of Medicine and BioMedical Research Institute, Pusan National University Hospital, Pusan, Korea
| | - Soomin Ahn
- Department of Pathology & Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.,Center for Companion Diagnostics, Innovative Cancer Medicine Institute, Samsung Medical Center, Seoul, Korea
| | - Michael Van Vrancken
- Department of Pathology & Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Minju Lee
- Department of Pathology & Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Sang Yun Ha
- Department of Pathology & Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Hyuk Lee
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Byung-Hoon Min
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jun Haeng Lee
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jae J Kim
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Sunkyu Choi
- Biostatistics and Clinical Epidemiology Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Sin-Ho Jung
- Biostatistics and Clinical Epidemiology Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Min Gew Choi
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jun-Ho Lee
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Tae Sung Sohn
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jae Moon Bae
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Sung Kim
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Kyoung-Mee Kim
- Department of Pathology & Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.,Center for Companion Diagnostics, Innovative Cancer Medicine Institute, Samsung Medical Center, Seoul, Korea
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33
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Treacy AD, Karamchandani JR, Streutker CJ, Grin A. HER2 Genetic Heterogeneity in Gastric Cancer: Evaluation According to the College of American Pathologists Breast Cancer Criteria. Appl Immunohistochem Mol Morphol 2016; 23:628-32. [PMID: 25611242 DOI: 10.1097/pai.0000000000000136] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
Gastric and gastroesophageal junction (GEJ) adenocarcinomas have been shown to display significant HER2 genetic heterogeneity (GH). This is typically seen as a cluster of HER2-positive cells but can also take the form of intermingled cells, referred to a "mosaic" pattern. GH is not well defined in gastric/GEJ tumors and the "mosaic" pattern has never been studied. We sought to evaluate the frequency and distribution of the "mosaic" pattern of GH in gastric/GEJ tumors using the College of American Pathologists-endorsed breast criteria of 5% to <50% amplified nuclei. We also postulated that the lower limit of this GH definition might be seen by chance in normal gastric epithelium. A total of 360 consecutive gastric/GEJ tumors were tested for HER2 by immunohistochemistry and in situ hybridization. Individual tumor cell HER2:CEP17 ratios were calculated for each case and the percentage of tumor cells with a ratio ≥2.0 determined. In addition, 300 normal gastric epithelial cells were scored for HER2 and CEP17 signals. Overall, 265 cases (73.4%) showed GH. The percentage of amplified cells in GH cases linearly correlated with the overall HER2:CEP17 ratio. In normal gastric epithelium, a cell with an "amplified" 2:1 ratio was seen in 9.7% (29/300) of cells, thus reaching GH. The chance of "GH" in scoring 20 normal epithelial cells was 87%. We conclude that GH is very common in gastric/GEJ tumors when College of American Pathologists breast criteria are applied and the lower threshold is likely of little clinical significance due to the finding "amplified" 2:1 nuclei in normal cells.
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Affiliation(s)
- Ann D Treacy
- St. Michael's Hospital, Department of Laboratory Medicine, Li Ka Shing Knowledge Institute and the University of Toronto, ON, Canada
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Grillo F, Fassan M, Sarocchi F, Fiocca R, Mastracci L. HER2 heterogeneity in gastric/gastroesophageal cancers: From benchside to practice. World J Gastroenterol 2016; 22:5879-5887. [PMID: 27468182 PMCID: PMC4948273 DOI: 10.3748/wjg.v22.i26.5879] [Citation(s) in RCA: 82] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2016] [Revised: 05/13/2016] [Accepted: 05/21/2016] [Indexed: 02/06/2023] Open
Abstract
HER2 is overexpressed in approximately 10%-20% of gastric and gastroesophageal junction carcinomas. In these types of cancer, accurate assessment of HER2 status is mandatory, for selecting patients who may benefit from targeted therapies with anti-HER2 drugs such as Trastuzumab. This manuscript focuses on HER2 in gastric carcinogenesis, on optimal evaluation of HER2 and on the possible causes which may contribute to inaccurate HER2 evaluation. Similarly to breast cancer HER2 evaluation, standardization of HER2 testing in gastric cancer is necessary in diagnostic practice. The three principle aspects which require consideration are: (1) the choice of sample with regards to cancer morphology - intestinal vs diffuse areas; (2) the choice of scoring criteria - use of HER2 scoring criteria specific for gastric cancer; and (3) the choice of HER2 evaluation methods - use of an algorithm in which both immunohistochemistry and in situ hybridization play a role. Problematic issues include: (1) pre-analytic variables with particular emphasis on fixation; (2) recommended methodology for HER2 assessment (immunohistochemistry vs in situ hybridization); (3) HER2 heterogeneity both within the primary tumor and between primary tumor and metastases; (4) reliability of biopsies in HER 2 evaluation; and (5) quantity of sample (FFPE blocks from surgical specimens or endoscopic biopsies) necessary for an adequate assessment.
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Lordick F, Janjigian YY. Clinical impact of tumour biology in the management of gastroesophageal cancer. Nat Rev Clin Oncol 2016; 13:348-60. [PMID: 26925958 PMCID: PMC5521012 DOI: 10.1038/nrclinonc.2016.15] [Citation(s) in RCA: 114] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
The characterization of oesophageal and gastric cancer into subtypes based on genotype has evolved in the past decade. Insights into the molecular landscapes of gastroesophageal cancer provide a roadmap to assist the development of new drugs and their use in combinations, for patient stratification, and for trials of targeted therapies. Trastuzumab is the only approved treatment for gastroesophageal cancers that overexpress HER2. Acquired resistance usually limits the duration of response to this treatment, although a number of new agents directed against HER2 have the potential to overcome or prolong the time until resistance occurs. Beyond that, anti-VEGFR2 therapy with ramucirumab was the first biological treatment strategy to produce a survival benefit in an unselected population of patients with chemotherapy-refractory gastroesophageal cancer. Large initiatives are starting to address the role of biomarker-driven targeted therapy in the metastatic and in the perioperative setting for patients with this disease. Immunotherapy also holds promise, and our understanding of subsets of gastroesophageal cancer based on patterns of immune response continues to evolve. Efforts are underway to identify more relevant genomic subsets through genomic screening, functional studies, and molecular characterization. Herein, we provide an overview of the key developments in the treatment of gastroesophageal cancer, and discuss potential strategies to further optimize therapy by targeting disease subtypes.
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Affiliation(s)
- Florian Lordick
- University Cancer Center Leipzig, University Medicine Leipzig, Liebigstraße 20 D, 04103 Leipzig, Germany
| | - Yelena Y Janjigian
- Gastrointestinal Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, 1275 York Avenue, New York, New York 10065, USA
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Chen XZ, Zhang WH, Chen HN, Liu JP, He D, Liu Y, Liu K, Chen XL, Mo XM, Zhou ZG, Hu JK. Associations between serum CA724 and HER2 overexpression among stage II-III resectable gastric cancer patients: an observational study. Oncotarget 2016; 7:23647-23657. [PMID: 27027339 PMCID: PMC5029653 DOI: 10.18632/oncotarget.8145] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2015] [Accepted: 02/28/2016] [Indexed: 02/05/2023] Open
Abstract
OBJECTIVES Associations between serum tumor biomarkers and human epidermal growth factor receptor 2 (HER2) overexpression among locally advanced gastric cancer patients were yet to be determined and therefore warranted investigation. RESULTS A total of 318 patients were analyzed. The odds ratios of CA724 were 4.79 (95% CI 1.55-14.79) and 6.29 (1.40-28.19) in comparing the HER2 (2+/3+) and HER2 (3+) with the negative group, respectively (p < 0.05). A combination of the four biomarkers yielded slightly but not significantly greater areas under the curve (AUC = 0.83; 0.71-0.94) than that of serum CA724 alone (0.80; 0.68-0.91); however, an index generated from the combination had better diagnostic performance with 85.7% sensitivity, 80.4% specificity and 97.8% negative predictive value to predict the strong overexpression of HER2 (3+). CA199, CEA or CA125 alone was not associated with HER2 overexpression. Leave-one-out cross-validation found a consistent association between serum CA724 and HER2 (2+/3+) overexpression. METHODS Patients undergoing radical gastrectomy from 8/2012 to 12/2013 and with pathological stage II-III gastric cancer were retrospectively analyzed. HER2 expression of the surgical samples was estimated using immunohistochemistry; serum CA724, CA199, CEA and CA125 were preoperatively tested. Internal validation was performed using the leave-one-out approach. CONCLUSIONS Serum CA724 is significantly associated with the overexpression of HER2 among locally advanced gastric cancer patients. The combination of CA724, CA199, CEA and CA125 is better than serum CA724 alone in predicting HER2 overexpression. External validation and further investigation of the biological mechanisms of these associations are required.
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Affiliation(s)
- Xin-Zu Chen
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, China
- Laboratory of Gastric Cancer, State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Wei-Han Zhang
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, China
- Laboratory of Gastric Cancer, State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Hai-Ning Chen
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Jian-Ping Liu
- Department of Pathology, West China Hospital, Sichuan University, Chengdu, China
| | - Du He
- Department of Pathology, West China Hospital, Sichuan University, Chengdu, China
| | - Yang Liu
- West China School of Public Health, Sichuan University, Chengdu, China
| | - Kai Liu
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, China
- Laboratory of Gastric Cancer, State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Xiao-Long Chen
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, China
- Laboratory of Gastric Cancer, State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Xian-Ming Mo
- Laboratory of Stem Cell Biology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Zong-Guang Zhou
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Jian-Kun Hu
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, China
- Laboratory of Gastric Cancer, State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
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Kanayama K, Imai H, Yoneda M, Hirokawa YS, Shiraishi T. Significant intratumoral heterogeneity of human epidermal growth factor receptor 2 status in gastric cancer: A comparative study of immunohistochemistry, FISH, and dual-color in situ hybridization. Cancer Sci 2016; 107:536-42. [PMID: 26752196 PMCID: PMC4832862 DOI: 10.1111/cas.12886] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2015] [Revised: 01/04/2016] [Accepted: 01/07/2016] [Indexed: 01/14/2023] Open
Abstract
The assessment of human epidermal growth factor receptor 2 (HER2) status is crucial for selecting patients with gastric cancer who may benefit from HER2‐targeted therapy. Accurate assessment using biopsy specimens is important for patients with advanced‐stage cancer. Intratumoral heterogeneity of HER2, however, is a major challenge in HER2 testing. Here, we aimed to examine whether assessment of HER2 status could be accurately carried out with currently used methods, namely, immunohistochemistry (IHC), FISH, and dual‐color in situ hybridization (DISH). Human epidermal growth factor receptor 2 status was evaluated in 108 biopsy tissues from patients with gastric adenocarcinoma and 70 matched surgical specimens by IHC, FISH, and DISH; HER2 amplification was detected in 11 (10.2%) out of 108 biopsy specimens. The IHC and FISH results were well correlated, and FISH and DISH results were consistent for all cases. The overall concordance rate of HER2 status between biopsy tissues and surgical specimens was 91.4%. All six discordant cases were false negative on biopsy; of these cases, five showed HER2 heterogeneity on surgical resection. Assessment of the HER2 status of biopsy tissues could predict the status of the whole tumor; however, a proportion of these cases may be discordant because of intratumoral heterogeneity. This study demonstrated that HER2 assessment in biopsy tissues may predict the HER2 status of the whole tumor by IHC, FISH, and DISH. However, some cases of discordance may occur because of intratumoral HER2 heterogeneity in gastric cancers. In cases of intratumoral heterogeneity, more accurate HER2 assessment can be achieved by analysis of whole sections and by using a combination of IHC and DISH, if possible.
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Affiliation(s)
- Kazuki Kanayama
- Department of Oncologic Pathology, Mie University Graduate School of Medicine, Tsu, Japan
| | - Hiroshi Imai
- Department of Oncologic Pathology, Mie University Graduate School of Medicine, Tsu, Japan
| | - Misao Yoneda
- Department of Clinical Nutrition, Suzuka University of Medical Science, Suzuka, Japan
| | - Yoshifumi S Hirokawa
- Department of Oncologic Pathology, Mie University Graduate School of Medicine, Tsu, Japan
| | - Taizo Shiraishi
- Department of Oncologic Pathology, Mie University Graduate School of Medicine, Tsu, Japan
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Wada R, Hirabayashi K, Ohike N, Morii E. New guidelines for HER2 pathological diagnostics in gastric cancer. Pathol Int 2016; 66:57-62. [PMID: 26814046 DOI: 10.1111/pin.12390] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Affiliation(s)
- Ryo Wada
- Department of Pathology, Juntendo University Shizuoka Hospital, Shizuoka, Japan
| | - Kenichi Hirabayashi
- Department of Pathology, Tokai University School of Medicine, Kanagawa, Japan
| | - Nobuyuki Ohike
- Department of Pathology, Showa University Fujigaoka Hospital, Kanagawa, Japan
| | - Eiichi Morii
- Department of Pathology, Osaka University Graduate School of Medicine, Osaka, Japan
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Huang SC, Ng KF, Lee SE, Chen KH, Yeh TS, Chen TC. HER2 testing in paired biopsy and excision specimens of gastric cancer: the reliability of the scoring system and the clinicopathological factors relevant to discordance. Gastric Cancer 2016; 19:176-82. [PMID: 25512144 DOI: 10.1007/s10120-014-0453-0] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2014] [Accepted: 11/28/2014] [Indexed: 02/06/2023]
Abstract
BACKGROUND Inclusion of trastuzumab in chemotherapy regimens is advantageous for patients with advanced or metastatic gastric cancer who overexpress HER2. Therefore, accurate assessment of HER2 status in tumor tissue is critical when weighing treatment options. METHODS We examined HER2 expression in 180 paired endoscopic biopsy and surgical excision specimens of gastric cancers via immunohistochemistry (IHC). Equivocal IHC results (IHC 2+) were resolved by HER2 fluorescence in situ hybridization (FISH). The relationships of several clinical and pathological features with discordant HER2 results in paired specimens were determined. RESULTS Fourteen biopsy specimens and surgical specimens (7.8%) were HER2-positive. Discordant HER2 IHC scores were observed in 90 paired specimens (50%) and 8 paired specimens (4.4%) had discordant results. The kappa coefficients for an HER2 diagnostic algorithm were 0.264, 0.339, and 0.690 for IHC scores, IHC categories, and final results, respectively (p < 0.001). Discordant HER2 results were significantly associated with discordant tumor differentiation in the paired biopsy and excision specimens (p = 0.01). Intratumoral heterogeneity did not predict HER2 discordance. There was no association between HER2 discordance and the number of biopsy tissue fragments (p = 0.764). CONCLUSIONS Hofmann's HER2 scoring system is a fairly reliable tool for evaluating HER2 status in biopsy and excision specimens. Discordant HER2 results in paired specimens were observed in a small percentage of gastric cancers. Testing all available specimens should be considered in order to eliminate discrepancies, especially when discordant tumor differentiation is observed.
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Affiliation(s)
- Shih-Chiang Huang
- Department of Anatomical Pathology, Chang Gung Memorial Hospital, Chang Gung University, College of Medicine, Taoyuan, Taiwan, ROC
| | - Kwai-Fong Ng
- Department of Anatomical Pathology, Chang Gung Memorial Hospital, Chang Gung University, College of Medicine, Taoyuan, Taiwan, ROC
| | - Shang-En Lee
- Cancer Diagnostic Laboratory, Chang Gung Memorial Hospital, Taoyuan, Taiwan, ROC
| | - Kuang-Hua Chen
- Department of Anatomical Pathology, Chang Gung Memorial Hospital, Chang Gung University, College of Medicine, Taoyuan, Taiwan, ROC
| | - Ta-Sen Yeh
- Department of Surgery, Chang Gung Memorial Hospital, Chang Gung University, College of Medicine, Taoyuan, Taiwan, ROC
| | - Tse-Ching Chen
- Department of Anatomical Pathology, Chang Gung Memorial Hospital, Chang Gung University, College of Medicine, Taoyuan, Taiwan, ROC.
- Department of Pathology, Chang Gung Memorial Hospital, No. 5 Fuxing St., Guishan Township, Taoyuan County, 333, Taiwan, ROC.
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Lee J, Bass AJ, Ajani JA. Gastric Adenocarcinoma: An Update on Genomics, Immune System Modulations, and Targeted Therapy. Am Soc Clin Oncol Educ Book 2016; 35:104-11. [PMID: 27249691 DOI: 10.1200/edbk_159091] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/05/2023]
Abstract
Gastric adenocarcinoma (GAC) is a global health burden on all societies, and it was the third-leading cause of cancer-related mortality in 2012, causing 723,000 deaths worldwide. The prognosis of patients with metastatic GAC remains poor, with a median overall survival of less than 1 year in patients treated with currently available therapies. A limited number of therapeutic agents is currently available. Recent additions to the armamentarium include trastuzumab and ramucirumab, which have shown some survival advantage when added to cytotoxic(s). Genomic analyses have defined various genotypes of GACs. The novel genomic knowledge can lead to discovery of novel targets and novel therapeutic agents. In this update, we focus on the current genomic data, targeted therapies including immune system modulators, and expand on HER2/neu testing and the use of agents against this target. Several other facets of GAC and its therapy are not to be included in this review but have been discussed elsewhere.
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Affiliation(s)
- Jeeyun Lee
- From the Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Kangnamgu, Seoul, South Korea; Division of Molecular and Cellular Oncology, Dana-Farber Cancer Institute, Boston, MA; Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Adam J Bass
- From the Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Kangnamgu, Seoul, South Korea; Division of Molecular and Cellular Oncology, Dana-Farber Cancer Institute, Boston, MA; Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Jaffer A Ajani
- From the Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Kangnamgu, Seoul, South Korea; Division of Molecular and Cellular Oncology, Dana-Farber Cancer Institute, Boston, MA; Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
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Ieni A, Barresi V, Rigoli L, Caruso RA, Tuccari G. HER2 Status in Premalignant, Early, and Advanced Neoplastic Lesions of the Stomach. DISEASE MARKERS 2015; 2015:234851. [PMID: 26494937 PMCID: PMC4606090 DOI: 10.1155/2015/234851] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/05/2015] [Accepted: 07/30/2015] [Indexed: 02/06/2023]
Abstract
OBJECTIVES HER2 expression in gastric cancer (GC) has received attention as a potential target for therapy with Trastuzumab. We reviewed the current knowledge on HER2 status in premalignant gastric lesions and in early (EGC) and advanced (AGC) GC to discuss the possible pathogenetic and prognostic roles of HER2 overexpression in GC. RESULTS HER2 overexpression was documented in gastric low-grade (LG) and high-grade intraepithelial neoplasia (HG-IEN), with higher frequency in gastric type dysplasia. HER2 overexpression was significantly associated with disease recurrence and poor prognosis in EGC representing an independent risk factor for lymph node metastases. HER2 overexpression was more frequent in AGC characterized by high grade, advanced stage, and high Ki-67 labeling index. The discordance in HER2 status was evidenced between primitive GC and synchronous or metachronous metastases. CONCLUSIONS HER2 overexpression in premalignant gastric lesions suggests its potential involvement in the early steps of gastric carcinogenesis. The assessment of HER2 status in EGC may be helpful for the identification of patients who are at low risk for developing nodal metastases. Finally, the possible discordance in HER2 status between primary GC and its synchronous metastases support routine assessment of HER2 both in the primary GC and in its metastatic lesions.
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Affiliation(s)
- A. Ieni
- Department of Human Pathology “Gaetano Barresi”, Section of Anatomic Pathology, Azienda Ospedaliera Universitaria “Gaetano Martino, University of Messina,” Via Consolare Valeria 1, 98125 Messina, Italy
| | - V. Barresi
- Department of Human Pathology “Gaetano Barresi”, Section of Anatomic Pathology, Azienda Ospedaliera Universitaria “Gaetano Martino, University of Messina,” Via Consolare Valeria 1, 98125 Messina, Italy
| | - L. Rigoli
- Department of Pediatrics, Gynecology and Microbiology Sciences, Azienda Ospedaliera Universitaria “Gaetano Martino, University of Messina,” Via Consolare Valeria 1, 98125 Messina, Italy
| | - R. A. Caruso
- Department of Human Pathology “Gaetano Barresi”, Section of Anatomic Pathology, Azienda Ospedaliera Universitaria “Gaetano Martino, University of Messina,” Via Consolare Valeria 1, 98125 Messina, Italy
| | - G. Tuccari
- Department of Human Pathology “Gaetano Barresi”, Section of Anatomic Pathology, Azienda Ospedaliera Universitaria “Gaetano Martino, University of Messina,” Via Consolare Valeria 1, 98125 Messina, Italy
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Abstract
The human epidermal growth factor receptor 2 (HER2) is overexpressed in 10% to 35% of gastric and gastroesophageal junction (GEJ) adenocarcinomas. In 2010, the phase III Trastuzumab for Gastric Cancer (ToGA) trial showed that addition of the anti-HER2 monoclonal antibody trastuzumab to chemotherapy significantly improved survival of patients with advanced or metastatic tumors that were positive for HER2 overexpression. As a result, HER2 testing is now recommended for all patients with advanced or metastatic disease, although there is still some debate as to the optimal methods of assessment. HER2 expression in gastric and GEJ tumors shows several differences compared with breast tumors and, for this reason, the proposed criteria for scoring HER2 expression in biopsies and resections of gastric and GEJ carcinomas differ from those used in breast carcinomas. This review discusses what is currently known about the patterns of HER2 expression in gastric and GEJ adenocarcinomas, summarizes the findings of the ToGA trial and its clinical implications, and provides an overview of the recommended guidelines for the most accurate evaluation of HER2 status in gastric and GEJ cancer.
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Saito T, Kondo C, Shitara K, Ito Y, Saito N, Ikehara Y, Yatabe Y, Yamamichi K, Tanaka H, Nakanishi H. Comparison of intratumoral heterogeneity of HER2 expression between primary tumor and multiple organ metastases in gastric cancer: Clinicopathological study of three autopsy cases and one resected case. Pathol Int 2015; 65:309-17. [PMID: 25828363 DOI: 10.1111/pin.12290] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2015] [Accepted: 02/27/2015] [Indexed: 12/17/2022]
Abstract
Intratumoral heterogeneity of HER2 expression in the metastatic foci of HER2-positive advanced gastric cancer remains unclear. In this study, we compared HER2 expression between primary and metastatic tumors in HER2-positive three autopsied cases and one resected case with multiple organ metastases by immunohistochemistry (IHC) and dual color in situ hybridization (DISH). All four cases judged positive (IHC3+) at the primary tumor tissues showed varying HER2 gene amplification (GA) status. One homogeneously HER2-positive autopsied case (Case 1) and one intratumorally heterogeneous positive resected case (Case 2) with high GA showed a homogeneous positive staining pattern in all the metastatic foci. One heterogeneously HER2-positive autopsied case (Case 3) with low GA showed a partially heterogeneous HER2 staining pattern in all the metastatic foci. In contrast, one heterogeneously HER2-positive autopsied case (Case 4) with equivocal GA showed a completely heterogeneous HER2 staining pattern in the metastatic foci. These results indicate that HER2-positive gastric cancers with low to high GA at the primary tumor show substantially homogeneous HER2 overexpression in the metastatic foci, whereas HER2-positive gastric cancers with equivocal GA expressed HER2 heterogeneously within the metastatic tumor, suggesting that metastatic foci of the latter HER2-positive cases would be potentially resistant to trastuzumab.
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Affiliation(s)
- Takuya Saito
- Department of Epidemiology, Program in Health and Community Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Chihiro Kondo
- Department of Clinical Oncology, Japanese Red Cross Nagoya Daiichi Hospital, Nagoya, Japan
| | - Kohei Shitara
- Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Chiba, Japan
| | - Yuichi Ito
- Department of Gastroenterological Surgery, Aichi Cancer Center Central Hospital, Nagoya, Japan
| | - Noriko Saito
- Division of Oncological Pathology, Aichi Cancer Center Research Institute, Nagoya, Japan
| | - Yuzuru Ikehara
- Molecular Medicine Team, Research Centre for Medical Glycoscience, National Institute of Advanced Industrial Science and Technology, Ibaraki, Japan
| | - Yasushi Yatabe
- Department of Pathology and Molecular Diagnostics, Aichi Cancer Center Central Hospital, Nagoya, Japan
| | - Keigo Yamamichi
- Department of Surgery, Osaka Saiseikai Izuo Hospital, Osaka, Japan
| | - Hideo Tanaka
- Department of Epidemiology, Program in Health and Community Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Hayao Nakanishi
- Laboratory of Pathology and Clinical Research, Aichi Cancer Center, Aichi Hospital, Okazaki, Japan
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Yan M, Schwaederle M, Arguello D, Millis SZ, Gatalica Z, Kurzrock R. HER2 expression status in diverse cancers: review of results from 37,992 patients. Cancer Metastasis Rev 2015; 34:157-64. [PMID: 25712293 PMCID: PMC4368842 DOI: 10.1007/s10555-015-9552-6] [Citation(s) in RCA: 332] [Impact Index Per Article: 33.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Human epidermal growth factor receptor 2 (HER2) amplification/overexpression is an effective therapeutic target in breast and gastric cancer. Although HER2 positivity has been reported in other malignancies, previous studies generally focused on one cancer type, making it challenging to compare HER2 positivity across studies/malignancies. Herein, we examined 37,992 patient samples for HER2 expression (+/- amplification) in a single laboratory. All 37,992 patients were tested by immunohistochemistry (IHC); 21,642 of them were also examined for HER2 amplification with either fluorescent in situ hybridization (FISH) (11,670 patients) or chromogenic in situ hybridization (CISH) (9,972 patients); 18,262 patients had tumors other than breast or gastric cancer. All tissues were analyzed in a Clinical Laboratory Improvement Amendments (CLIA) laboratory (Caris Life Sciences) at the request of referring physicians. HER2 protein overexpression was found in 2.7 % of samples. Over-expressed HER2 was detected predominantly in malignancies of epithelial origin; for cancers derived from mesenchyme, neuroendocrine tissue, central nervous system, and kidney, HER2 expression and amplification were remarkably rare or non-existent. Bladder carcinomas, gallbladder, extrahepatic cholangiocarcinomas, cervical, uterine, and testicular cancers showed HER2 positivity rates of 12.4, 9.8, 6.3, 3.9, 3.0, and 2.4 %, respectively. HER2 overexpression and/or amplification is frequently found across tumor types. These observations may have significant therapeutic implications in cancers not traditionally thought to benefit from anti-HER2 therapies.
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Affiliation(s)
- Min Yan
- Center for Personalized Cancer Therapy, UC San Diego Moores Cancer Center, 3855 Health Sciences Drive, MC #0658, La Jolla, CA 92093-0658 USA
| | - Maria Schwaederle
- Center for Personalized Cancer Therapy, UC San Diego Moores Cancer Center, 3855 Health Sciences Drive, MC #0658, La Jolla, CA 92093-0658 USA
| | | | | | | | - Razelle Kurzrock
- Center for Personalized Cancer Therapy, UC San Diego Moores Cancer Center, 3855 Health Sciences Drive, MC #0658, La Jolla, CA 92093-0658 USA
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Hale MD, Gotoda T, Hayden JD, Grabsch HI. Endoscopic biopsies from gastrointestinal carcinomas and their suitability for molecular analysis: a review of the literature and recommendations for clinical practice and research. Histopathology 2015; 67:147-57. [PMID: 25431371 DOI: 10.1111/his.12626] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Affiliation(s)
| | - Takuji Gotoda
- Department of Gastroenterology and Hepatology; Tokyo Medical University; Tokyo Japan
| | - Jeremy David Hayden
- Department of Upper Gastrointestinal Surgery; St James's Institute of Oncology; Leeds Teaching Hospitals NHS Trust; Leeds UK
| | - Heike Irmgard Grabsch
- Leeds Institute of Cancer and Pathology; University of Leeds; Leeds UK
- Department of Pathology; Maastricht University Medical Center; Maastricht The Netherlands
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Stahl P, Seeschaaf C, Lebok P, Kutup A, Bockhorn M, Izbicki JR, Bokemeyer C, Simon R, Sauter G, Marx AH. Heterogeneity of amplification of HER2, EGFR, CCND1 and MYC in gastric cancer. BMC Gastroenterol 2015; 15:7. [PMID: 25649416 PMCID: PMC4324419 DOI: 10.1186/s12876-015-0231-4] [Citation(s) in RCA: 101] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2014] [Accepted: 01/13/2015] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Intra-tumor heterogeneity is a potential cause for failure of targeted therapy in gastric cancer, but the extent of heterogeneity of established (HER2) or potential (EGFR, CCND1) target genes and prognostic gene alterations (MYC) had not been systematically studied. METHODS To study heterogeneity of these genes in a large patient cohort, a heterogeneity tissue microarray was constructed containing 0.6 mm tissue cores from 9 different areas of the primary gastric cancers of 113 patients and matched lymph node metastases from 61 of these patients. Dual color fluorescence in-situ hybridization was performed to assess amplification of HER2, EGFR, CCND1 and MYC using established thresholds (ratio ≥ 2.0). Her2 immunohistochemistry (IHC) was performed in addition. RESULTS Amplification was found in 17.4% of 109 interpretable cases for HER2, 6.4% for EGFR, 17.4% for CCND1, and 24.8% for MYC. HER2 amplification was strongly linked to protein overexpression by IHC in a spot-by-spot analysis (p < 0.0001). Intra-tumor heterogeneity was found in the primary tumors of 9 of 19 (47.3%) cancers with HER2, 8 of 17 (47.0%) cancers with CCND1, 5 of 7 (71.4%) cancers with EGFR, and 23 of 27 (85.2%) cancers with MYC amplification. Amplification heterogeneity was particularly frequent in case of low-level amplification (<10 gene copies). While the amplification status was often different between metastases, unequivocal intra-tumor heterogeneity was not found in individual metastases. CONCLUSION The data of our study demonstrate that heterogeneity is common for biomarkers in gastric cancer. Given that both TMA tissue cores and clinical tumor biopsies analyze only a small fraction of the tumor bulk, it can be concluded that such heterogeneity may potentially limit treatment decisions based on the analysis of a single clinical cancer biopsy.
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Affiliation(s)
- Phillip Stahl
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
| | - Carsten Seeschaaf
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
| | - Patrick Lebok
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
| | - Asad Kutup
- General, Visceral and Thoracic Surgery Department and Clinic, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
| | - Maximillian Bockhorn
- General, Visceral and Thoracic Surgery Department and Clinic, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
| | - Jakob R Izbicki
- General, Visceral and Thoracic Surgery Department and Clinic, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
| | - Carsten Bokemeyer
- II Med. Klinik, Oncology, Hematology with section Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
| | - Ronald Simon
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
| | - Guido Sauter
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
| | - Andreas H Marx
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
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