Background/Aims/Objectives: It is difficult to identify patients with a non-muscle-invasive bladder cancer (NMIBC) at stage pT1 with concomitant carcinoma in situ (Cis) who will benefit from an early cystectomy. Methods: We retrospectively analyzed clinical data and formalin-fixed paraffin-embedded tissues of patients with NMIBC. Messenger ribonucleic acid (mRNA) expression of progesterone receptor (PGR), estrogen receptor (ESR1), ERBB2, and marker of proliferation Ki-67 (MKI67) was measured by single-step reverse transcription quantitative real-time polymerase chain reaction using RNA-specific TaqMan assays. Relative gene expression was determined by the normalization of 2 reference genes (CALM2, B2M) using the 40 ΔΔCT method and relative gene expression was correlated to the histopathological stage and oncological outcome. Results: Of 302 patients with pT1 NMIBC in the initial transurethral resection of the bladder, 65 had a concomitant Cis. Elevated ERBB2 expression (>40.1) significantly correlated with progress in patients with and without concomitant Cis (p = 0.020 and p = 0.049, respectively). For the subgroup of pT1 with concomitant Cis, elevated ERBB2 expression significantly discriminated between a high-risk group of 55% progression-free survival (PFS) and a low-risk group of 90% PFS after a 5-year follow-up (p = 0.020). Cox-regression analysis revealed ERBB2 expression as the only independent prognostic factor for PFS (p = 0.0037). Conclusions: High mRNA expression of ERBB2 can identify patients with pT1 NMIBC with concomitant Cis, who have a high risk of progression and might benefit from an early cystectomy.

Keywords:
Bladder cancer, Non-muscle-invasive bladder cancer , ERBB2, Carcinoma in situ, Progression, Prognostic factors
1.
Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F: Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 2015;136:E359-E386.
2.
Babjuk M, Böhle A, Burger M, Capoun O, Cohen D, Compérat EM, Hernández V, Kaasinen E, Palou J, Rouprêt M, van Rhijn BW, Shariat SF, Soukup V, Sylvester RJ, Zigeuner R: EAU guidelines on non-muscle-invasive urothelial carcinoma of the bladder: update 2016. Eur Urol 2016;pii:S0302-2838(16)30249-4.
3.
Prout GR Jr, Barton BA, Griffin PP, Friedell GH: Treated history of noninvasive grade 1 transitional cell carcinoma. The National Bladder Cancer Group. J Urol 1992;148:1413-1419.
4.
Denzinger S, Fritsche HM, Otto W, Blana A, Wieland WF, Burger M: Early versus deferred cystectomy for initial high-risk pT1G3 urothelial carcinoma of the bladder: do risk factors define feasibility of bladder-sparing approach? Eur Urol 2008;53:146-152.
5.
Griffiths TR, Charlton M, Neal DE, Powell PH: Treatment of carcinoma in situ with intravesical bacillus Calmette-Guerin without maintenance. J Urol 2002;167:2408-2412.
6.
Sylvester RJ, van der Meijden AP, Oosterlinck W, Witjes JA, Bouffioux C, Denis L, Newling DW, Kurth K: Predicting recurrence and progression in individual patients with stage Ta T1 bladder cancer using EORTC risk tables: a combined analysis of 2596 patients from seven EORTC trials. Eur Urol 2006;49:466-475; discussion 475-477.
7.
Limas C, Bigler A, Bair R, Bernhart P, Reddy P: Proliferative activity of urothelial neoplasms: comparison of BrdU incorporation, Ki67 expression, and nucleolar organiser regions. J Clin Pathol 1993;46:159-165.
8.
Otto W, Denzinger S, Fritsche HM, Burger M, Rößler W, Bertz S, May M, Hartmann A, Hofstädter F, Wieland WF, Eder F: Introduction and first clinical application of a simplified immunohistochemical validation system confirms prognostic impact of KI-67 and CK20 for stage T1 urothelial bladder carcinoma: single-center analysis of eight biomarkers in a series of three hundred six patients. Clin Genitourin Cancer 2013;11:537-544.
9.
Lopez-Beltran A, Luque RJ, Alvarez-Kindelan J, Quintero A, Merlo F, Carrasco JC, Requena MJ, Montironi R: Prognostic factors in stage T1 grade 3 bladder cancer survival: the role of G1-S modulators (p53, p21Waf1, p27kip1, Cyclin D1, and Cyclin D3) and proliferation index (ki67-MIB1). Eur Urol 2004;45:606-612.
10.
Cancer Genome Atlas Research Network: Comprehensive molecular characterization of urothelial bladder carcinoma. Nature 2014;507:315-322.
11.
Choi W, Porten S, Kim S, Willis D, Plimack ER, Hoffman-Censits J, Roth B, Cheng T, Tran M, Lee IL, Melquist J, Bondaruk J, Majewski T, Zhang S, Pretzsch S, Baggerly K, Siefker-Radtke A, Czerniak B, Dinney CP, McConkey DJ: Identification of distinct basal and luminal subtypes of muscle-invasive bladder cancer with different sensitivities to frontline chemotherapy. Cancer Cell 2014;25:152-165.
12.
Sjödahl G, Lauss M, Lövgren K, Chebil G, Gudjonsson S, Veerla S, Patschan O, Aine M, Fernö M, Ringnér M, Månsson W, Liedberg F, Lindgren D, Höglund M: A molecular taxonomy for urothelial carcinoma. Clin Cancer Res 2012;18:3377-3386.
13.
Losa A, Hurle R, Lembo A: Low dose bacillus Calmette-Guerin for carcinoma in situ of the bladder: long-term results. J Urol 2000;163:68-71; discussion 71-72.
14.
Guiu S, Michiels S, André F, et al: Molecular subclasses of breast cancer: how do we define them? The IMPAKT 2012 Working Group Statement. Ann Oncol 2012;23:2997-3006.
15.
Shokouh TZ, Ezatollah A, Barand P: Interrelationships between Ki67, HER2/neu, p53, ER, and PR status and their associations with tumor grade and lymph node involvement in breast carcinoma subtypes: Retrospective-Observational Analytical Study. Medicine (Baltimore) 2015;94:e1359.
16.
Rodríguez-Alonso A, Pita-Fernández S, González-Carreró J, Nogueira-March JL: p53 and ki67 expression as prognostic factors for cancer-related survival in stage T1 transitional cell bladder carcinoma. Eur Urol 2002;41:182-188; discussion 188-189.
17.
Ding W, Gou Y, Sun C, Xia G, Wang H, Chen Z, Tan J, Xu K, Qiang D: Ki-67 is an independent indicator in non-muscle invasive bladder cancer (NMIBC); combination of EORTC risk scores and Ki-67 expression could improve the risk stratification of NMIBC. Urol Oncol 2014;32:42.e13-e19.
18.
Gunia S, Koch S, Hakenberg OW, May M, Kakies C, Erbersdobler A: Different HER2 protein expression profiles aid in the histologic differential diagnosis between urothelial carcinoma in situ (CIS) and non-CIS conditions (dysplasia and reactive atypia) of the urinary bladder mucosa. Am J Clin Pathol 2011;136:881-888.
19.
Chen PC, Yu HJ, Chang YH, Pan CC: Her2 amplification distinguishes a subset of non-muscle-invasive bladder cancers with a high risk of progression. J Clin Pathol 2013;66:113-119.
20.
Iyer G, Al-Ahmadie H, Schultz N, Hanrahan AJ, Ostrovnaya I, Balar AV, Kim PH, Lin O, Weinhold N, Sander C, Zabor EC, Janakiraman M, Garcia-Grossman IR, Heguy A, Viale A, Bochner BH, Reuter VE, Bajorin DF, Milowsky MI, Taylor BS, Solit DB: Prevalence and co-occurrence of actionable genomic alterations in high-grade bladder cancer. J Clin Oncol 2013;31:3133-3140.
21.
de Pinieux G, Colin D, Vincent-Salomon A, Couturier J, Amsellem-Ouazana D, Beuzeboc P, Vieillefond A: Confrontation of immunohistochemistry and fluorescent in situ hybridization for the assessment of HER-2/neu (c-erbb-2) status in urothelial carcinoma. Virchows Arch 2004;444:415-419.
22.
Bongiovanni L, Arena V, Vecchio FM, Racioppi M, Bassi P, Pierconti F: HER-2 immunohistochemical expression as prognostic marker in high-grade T1 bladder cancer (T1G3). Arch Ital Urol Androl 2013;85:73-77.
23.
Hayashi T, Seiler R, Oo HZ, Jäger W, Moskalev I, Awrey S, Dejima T, Todenhöfer T, Li N, Fazli L, Matsubara A, Black PC: Targeting HER2 with T-DM1, an antibody cytotoxic drug conjugate, is effective in HER2 over expressing bladder cancer. J Urol 2015;194:1120-1131.
24.
Grivas PD, Day KC, Karatsinides A, Paul A, Shakir N, Owainati I, Liebert M, Kunju LP, Thomas D, Hussain M, Day ML: Evaluation of the antitumor activity of dacomitinib in models of human bladder cancer. Mol Med 2013;19:367-376.
25.
Hussain MH, MacVicar GR, Petrylak DP, Dunn RL, Vaishampayan U, Lara PN Jr, Chatta GS, Nanus DM, Glode LM, Trump DL, Chen H, Smith DC; National Cancer Institute: Trastuzumab, paclitaxel, carboplatin, and gemcitabine in advanced human epidermal growth factor receptor-2/neu-positive urothelial carcinoma: results of a multicenter phase II National Cancer Institute trial. J Clin Oncol 2007;25:2218-2224.
26.
Wezel F, Erben P, Gaiser T, Budjan J, von Hardenberg J, Michel MS, Bolenz C: Complete and durable remission of human epidermal growth factor receptor 2-positive metastatic urothelial carcinoma following third-line treatment with trastuzumab and gemcitabine. Urol Int 2016, Epub ahead of print.
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2016
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