Association between HER2 status in gastric cancer and clinicopathological features: a retrospective study using whole-tissue sections

BMC Gastroenterology

Helenice Gobbi²  Mônica Maria Demas Álvares Cabral²  Rafael Malagoli Rocha²  Cristiana Buzelin Nunes²  Marina De Brot²  Débora Balabram²  Marcelo Araújo Buzelin²  Renato Santos Laboissiere¹ 

[1] Departamento de Medicina DEMED-UFSJ, Campus Dom Bosco. Praça Dom Helvécio, 74. Fábricas, São João del-Rei 36301-160, MG, Brazil;Departamento de Anatomia Patológica FM-UFMG, Avenida Prof. Alfredo Balena, 190 - 3o. andar, Belo Horizonte 30130-100, MG, Brazil

关键词: Clinicopathological features;    Gene amplification;    Immunohistochemistry;    Gastric cancer;    HER2;   

Others  :  1234288
DOI  :  10.1186/s12876-015-0384-1

 received in 2015-08-17, accepted in 2015-10-21,  发布年份 2015

【 摘 要 】

Background

Gastric cancer is usually diagnosed in an advanced stage of disease and treatment options are sparse. Trastuzumab was recently approved for metastatic or locally advanced carcinomas arising in the stomach or in the gastroesophageal junction in patients with HER2-positive tumors. However, data on the frequency of HER2-positive cases among Brazilian patients are limited. Our aim was to characterize HER2 protein and gene status in a series of Brazilian patients with gastric cancer and to evaluate its association with clinicopathological data.

Methods

Histological slides from 124 primary gastrectomies were reviewed and their pathological reports were retrieved from the files at a Brazilian university hospital. Automated immunohistochemistry for HER2 was performed on whole-tissue sections from each tumor. HER2-equivocal cases by immunohistochemistry were submitted to automated dual in situ hybridization for gene amplification evaluation. HER2 status was confronted with clinicopathological parameters in order to assess statistically significant associations.

Results

Immunohistochemistry analysis revealed that 13/124 cases (10.5 %) were HER2 positive (3+), 10/124 cases (8.1 %) were equivocal (2+) and 101/124 cases (81.4 %) were negative, being 7 cases 1+. None of the equivocal cases showed gene amplification. The overall HER2 positivity rate was 10.5 %. There was an association between HER2 expression and Laurén’s intestinal histological subtype (P = 0.048), well to moderately differentiated tumors (P = 0.004) and presence of lymphovascular invasion (P = 0.031). No association was found between HER2 status and tumor topography.

Conclusions

Confronted with data published by other authors, the lower percentage of HER2-positive cases found in our series might be partially explained by the lower frequency of tumors arising at the gastroesophageal junction in comparison with distal gastric carcinomas in Brazilian patients. This could also account for the lack of statistically significant association between HER2 status and tumor topography in our study.

【 授权许可】

   
2015 Laboissiere et al.

【 图 表 】

Fig. 1.

Fig. 2.

【 参考文献 】

• [1]Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D: Global cancer statistics. CA Cancer J Clin 2011, 61:69-90.
• [2]Power DG, Kelsen DP, Shah MA: Advanced gastric cancer--slow but steady progress. Cancer Treat Rev 2010, 36:384-92.
• [3]Sugano K: Gastric cancer: pathogenesis, screening, and treatment. Gastrointest Endosc Clin N Am 2008, 18:513-22.
• [4]Instituto Nacional de Câncer José Alencar Gomes da Silva: Coordenação de Prevenção e Vigilância. Estimativa 2014: Incidência de Câncer no Brasil. INCA, Rio de Janeiro; 2014.
• [5]Kamangar F, Dores GM, Anderson WF: Patterns of cancer incidence, mortality, and prevalence across five continents: defining priorities to reduce cancer disparities in different geographic regions of the world. J Clin Oncol 2006, 24:2137-50.
• [6]Bang YJ, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki A, et al.: Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet 2010, 376:687-97.
• [7]Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL: Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 1987, 235:177-182.
• [8]Hudis CA: Trastuzumab – mechanism of action and use in clinical practice. N Engl J Med 2007, 357:39-51.
• [9]Moasser MM: The oncogene HER2: its signaling and transforming functions and its role in human cancer pathogenesis. Oncogene 2007, 26:6469-87.
• [10]Bilici A: Treatment options in patients with metastatic gastric cancer: current status and future perspectives. World J Gastroenterol 2014, 20:3905-15.
• [11]Hofmann M, Stoss O, Shi D, Büttner R, van de Vijver M, Kim W, et al.: Assessment of a HER2 scoring system for gastric cancer: results from a validation study. Histopathology 2008, 52:797-805.
• [12]Rüschoff J, Dietel M, Baretton G, Arbogast S, Walch A, Monges G, et al.: HER2 diagnostics in gastric cancer-guideline validation and development of standardized immunohistochemical testing. Virchows Arch 2010, 457:299-307.
• [13]Yan B, Yau EX, Bte Omar SS, Ong CW, Pang B, Yeoh KG, et al.: A study of HER2 gene amplification and protein expression in gastric cancer. J Clin Pathol 2010, 63:839-42.
• [14]Yano T, Doi T, Ohtsu A, Boku N, Hashizume K, Nakanishi M, et al.: Comparison of HER2 gene amplification assessed by fluorescence in situ hybridization and HER2 protein expression assessed by immunohistochemistry in gastric cancer. Oncol Rep 2006, 15:65-71.
• [15]Boers JE, Meeuwissen H, Methorst N: HER2 status in gastro-oesophageal adenocarcinomas assessed by two rabbit monoclonal antibodies (SP3 and 4B5) and two in situ hybridization methods (FISH and SISH). Histopathology 2011, 58:383-94.
• [16]Kunz PL, Mojtahed A, Fisher GA, Ford JM, Chang DT, Balise RR, et al.: HER2 expression in gastric and gastroesophageal junction adenocarcinoma in a US population: clinicopathologic analysis with proposed approach to HER2 assessment. Appl Immunohistochem Mol Morphol 2012, 20:13-24.
• [17]Shan L, Ying J, Lu N: HER2 expression and relevant clinicopathological features in gastric and gastroesophageal junction adenocarcinoma in a Chinese population. Diagn Pathol 2013, 8:76. BioMed Central Full Text
• [18]Chua TC, Merrett ND: Clinicopathologic factors associated with HER2-positive gastric cancer and its impact on survival outcomes - a systematic review. Int J Cancer 2012, 130:2845-56.
• [19]Begnami MD, Fukuda E, Fregnani JH, Nonogaki S, Montagnini AL, da Costa WL Jr, et al.: Prognostic implications of altered human epidermal growth factor receptors (HERs) in gastric carcinomas: HER2 and HER3 are predictors of poor outcome. J Clin Oncol 2011, 29:3030-6.
• [20]Jung JE, Ioshii SO: Immunohistochemical assessment of HER2 expression in gastric cancer in a cohort of 118 Brazilian patients. J Bras Patol Med Lab 2013, 49:361-367.
• [21]Abrahão-Machado LF, Jácome AA, Wohnrath DR, dos Santos JS, Carneseca EC, Fregnani JH, et al.: HER2 in gastric cancer: comparative analysis of three different antibodies using whole-tissue sections and tissue microarrays. World J Gastroenterol 2013, 19:6438-46.
• [22]Jácome AA, Wohnrath DR, Scapulatempo Neto C, Carneseca EC, Serrano SV, Viana LS, et al.: Prognostic value of epidermal growth factor receptors in gastric cancer: a survival analysis by Weibull model incorporating long-term survivors. Gastric Cancer 2014, 17:76-86.
• [23]Begnami MD, Campos AH, Silva E, Montagnini A, Nascimento CF, Nonogaki S, et al.: Expressão imuno-histoquimica de c-erb-B2 e p53 em carcinomas gástricos. J Bras Pato Med Lab 2005, 41(4):279-86.
• [24]Cirne-Lima FK, Rosa Ade S, Kulczynski JM, Mattana DS, Corezolla K, Moreira LF: Immunohistochemical expression of HER-2/NEU-CERBB-2 in patients with adenocarcinoma of the stomach. Rev Col Bras Cir 2009, 36(2):131-4.
• [25]Damasceno EA, Carneiro FP, Magalhães AV, Carneiro Mde V, Takano GH, Vianna LM, et al.: IMP3 expression in gastric cancer: association with clinicopathological features and HER2 status. J Cancer Res Clin Oncol 2014, 140(12):2163-8.
• [26]De Carli DM, Rocha MP, Antunes LC, Fagundes RB: Immunohistochemical expression of her2 in adenocarcinoma of the stomach. Arq Gastroenterol 2015, 52(2):152-5.
• [27]TNM classification of malignant tumours. 7th edition. Wiley-Blackwell, New York; 2009.
• [28]AJCC cancer staging manual. 7th edition. Springer, New York; 2009.
• [29]Laurén P: The two histological main types of gastric carcinoma: diffuse and so-called intestinal-type carcinoma. An attempt at a histo-clinical classification. Acta Pathol Microbiol Scand 1965, 64:31-49.
• [30]Van Cutsem E, Bang YJ, Feng-Yi F, Xu JM, Lee KW, Jiao SC, et al.: HER2 screening data from ToGA: targeting HER2 in gastric and gastroesophageal junction cancer. Gastric Cancer 2015, 18(3):476-84.
• [31]Moelans CB, Van Diest PJ, Milne AN, Offerhaus GJ: Her-2/neu testing and therapy in gastroesophageal adenocarcinoma. Patholog Res Int 2010, 2011:674182.
• [32]Cho J, Jeong J, Sung J, Sung CO, Kim KM, Park CK, et al.: A large cohort of consecutive patients confirmed frequent HER2 positivity in gastric carcinomas with advanced stages. Ann Surg Oncol 2013, 20:S477-84.
• [33]Fan XS, Chen JY, Li CF, Zhang YF, Meng FQ, Wu HY, et al.: Differences in HER2 over-expression between proximal and distal gastric cancers in the Chinese population. World J Gastroenterol 2013, 19:3316-23.
• [34]Cappellesso R, Fassan M, Hanspeter E, Bornschein J, d’Amore ES, Cuorvo LV, et al.: HER2 status in gastroesophageal cancer: a tissue microarray study of 1040 cases. Hum Pathol 2015, 46:665-72.
• [35]Matsusaka S, Nashimoto A, Nishikawa K, Miki A, Miwa H, Yamaguchi K, et al. Clinicopathological factors associated with HER2 status in gastric cancer: results from a prospective multicenter observational cohort study in a Japanese population (JFMC44-1101). Gastric Cancer. 2015 Aug 12. [Epub ahead of print]
• [36]Menendez JA, Papadimitropoulou A, Vellon L, Lupu R: A genomic explanation connecting “Mediterranean diet”, olive oil and cancer: oleic acid, the main monounsaturated fatty acid of olive oil, induces formation of inhibitory “PEA3 transcription factor-PEA3 DNA binding site” complexes at the Her-2/neu (erbB-2) oncogene promoter in breast, ovarian and stomach cancer cells. Eur J Cancer 2006, 42:2425-32.
• [37]Yoo MW, Han HS, Kim SY, Cho YH, Lee HG, Kim JH, et al.: Is Helicobacter pylori associated with Her2/neu Overexpression in Gastric Cancer Patients who Underwent Curative Resection? Hepatogastroenterology 2014, 61:858-62.
• [38]Yoshida H, Yamamoto N, Taniguchi H, Oda I, Katai H, Kushima R, et al.: Comparison of HER2 status between surgically resected specimens and matched biopsy specimens of gastric intestinal-type adenocarcinoma. Virchows Arch 2014, 465:145-54.
• [39]Yang J, Luo H, Li Y, Li J, Cai Z, Su X, et al.: Intratumoral heterogeneity determines discordant results of diagnostic tests for human epidermal growth factor receptor (HER) 2 in gastric cancer specimens. Cell Biochem Biophys 2012, 62:221-8.
• [40]Lee S, De Boer WB, Fermoyle S, Platten M, Kumarasinghe MP: Human epidermal growth factor receptor 2 testing in gastric carcinoma: issues related to heterogeneity in biopsies and resections. Histopathology 2011, 59:832-40.
• [41]Radu OM, Foxwell T, Cieply K, Navina S, Dacic S, Nason KS, et al.: HER2 amplification in gastroesophageal adenocarcinoma: correlation of two antibodies using gastric cancer scoring criteria, H score, and digital image analysis with fluorescence in situ hybridization. Am J Clin Pathol 2012, 137:583-94.
• [42]Park YS, Hwang HS, Park HJ, Ryu MH, Chang HM, Yook JH, et al.: Comprehensive analysis of HER2 expression and gene amplification in gastric cancers using immunohistochemistry and in situ hybridization: which scoring system should we use? Hum Pathol 2012, 43:413-22.
• [43]Fassan M, Mastracci L, Grillo F, Zagonel V, Bruno S, Battaglia G, et al.: Early HER2 dysregulation in gastric and oesophageal carcinogenesis. Histopathology 2012, 61:769-76.
• [44]Kataoka Y, Okabe H, Yoshizawa A, Minamiguchi S, Yoshimura K, Haga H, et al.: HER2 expression and its clinicopathological features in resectable gastric cancer. Gastric Cancer 2013, 16:84-93.
• [45]Cruz-Reyes C, Gamboa-Dominguez A: HER2 amplification in gastric cancer is a rare event restricted to the intestinal phenotype. Int J Surg Pathol 2013, 21:240-6.
• [46]Kim KC, Koh YW, Chang HM, Kim TH, Yook JH, Kim BS, et al.: Evaluation of HER2 protein expression in gastric carcinomas: comparative analysis of 1,414 cases of whole-tissue sections and 595 cases of tissue microarrays. Ann Surg Oncol 2011, 18:2833-40.
• [47]Fisher SB, Fisher KE, Squires MH 3rd, Patel SH, Kooby DA, El-Rayes BF, et al.: HER2 in resected gastric cancer: Is there prognostic value? J Surg Oncol 2014, 109:61-6.
• [48]Liang JW, Zhang JJ, Zhang T, Zheng ZC: Clinicopathological and prognostic significance of HER2 overexpression in gastric cancer: a meta-analysis of the literature. Tumour Biol 2014, 35:4849-58.