Although human epidermal growth factor receptor 2 (HER2) plays a prognostic and predictive role in breast and gastric cancer, its function in bladder cancer (BC) is still controversial. A comprehensive review of the literature has been carried out. An electronic search of databases from PubMed, Scopus, Google Scholar was implemented. The search terms were: “BC,” “bladder carcinoma,” “bladder neoplasm,” “human epidermal growth factor 2,” “HER2,” “HER-2,” “c-erbB-2,” “c-erbB2,” “erbB-2,” “erbB2,” “neu,” “marker,” “biomarker,” and “prognosis”. Results of the review consented to (a) summarize the available data on HER2 a predictor of recurrence and/or progression free survival on univariate and multivariate analysis, (b) explore the related issues in assessing HER2 status on these tumor samples, since they may severely impair its predictive function, and (c) report the state-of-the art of HER2 as a putative therapeutic target in BC and especially non-muscle invasive BC. HER2 stands out for being a prognostic factor as well as a therapeutic target in various cancers. Data from the literature concerning its use in BC provide conflicting results, probably due to the inherent complexity of BC biology. Efforts should be made to establish a suitable tumor-specific scoring system, and to assess single drugs’ efficacy in well-designed clinical trials.

Keywords:
Bladder cancer, Non-muscle invasive bladder cancer, Human epidermal growth factor receptor 2, Prognosis, Therapeutic target
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.
Clark PE, Agarwal N, Biagioli MC, Eisenberger MA, Greenberg RE, Herr HW, Inman BA, Kuban DA, Kuzel TM, Lele SM, et al: Bladder cancer. J Natl Compr Canc Netw 2013; 11: 446–475.
3.
Babjuk M, Böhle A, Burger M, Capoun O, Cohen D, Compérat EM, Hernández V, Kaasinen E, Palou J, Rouprêt M, et al: EAU guidelines on non-muscle-invasive urothelial carcinoma of the bladder: update 2016. Eur Urol 2017; 71: 447–461.
4.
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.
5.
van Rhijn BW, Burger M, Lotan Y, Solsona E, Stief CG, Sylvester RJ, Witjes JA, Zlotta AR: Recurrence and progression of disease in non-muscle-invasive bladder cancer: from epidemiology to treatment strategy. Eur Urol 2009; 56: 430–442.
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.
7.
Otto W, Denzinger S, Fritsche HM, Burger M, Rößler W, Bertz S, May M, Hartmann A, Hofstädter F, Wieland WF, et al: 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.
8.
Sanguedolce F, Cormio A, Bufo P, Carrieri G, Cormio L: Molecular markers in bladder cancer: novel research frontiers. Crit Rev Clin Lab Sci 2015; 52: 242–255.
9.
Cormio L, Tolve I, Annese P, Saracino A, Zamparese R, Sanguedolce F, Bufo P, Battaglia M, Selvaggi FP, Carrieri G: Retinoblastoma protein expression predicts response to bacillus Calmette-Guérin immunotherapy in patients with T1G3 bladder cancer. Urol Oncol 2010; 28: 285–289.
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, et al: 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, et al: A molecular taxonomy for urothelial carcinoma. Clin Cancer Res 2012; 18: 3377–3386.
13.
Mellon JK, Lunec J, Wright C, Horne CH, Kelly P, Neal DE: C-erbB-2 in bladder cancer: molecular biology, correlation with epidermal growth factor receptors and prognostic value. J Urol 1996; 155: 321–326.
14.
Olayioye MA, Neve RM, Lane HA, Hynes NE: The ErbB signaling network: receptor heterodimerization in development and cancer. EMBO J 2000; 19: 3159–3167.
15.
Yarden Y: Biology of HER2 and its importance in breast cancer. Oncology 2001; 61(suppl 2): 1–13.
16.
Wolff AC, Hammond ME, Hicks DG, Dowsett M, McShane LM, Allison KH, Allred DC, Bartlett JM, Bilous M, Fitzgibbons P, et al; American Society of Clinical Oncology; College of American Pathologists. Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. Arch Pathol Lab Med 2014; 138: 241–256.
17.
Kunz PL, Mojtahed A, Fisher GA, Ford JM, Chang DT, Balise RR, Bangs CD, Cherry AM, Pai RK: 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.
18.
Laé M, Couturier J, Oudard S, Radvanyi F, Beuzeboc P, Vieillefond A: Assessing HER2 gene amplification as a potential target for therapy in invasive urothelial bladder cancer with a standardized methodology: results in 1005 patients. Ann Oncol 2010; 21: 815–819.
19.
El Ochi MR, Oukabli M, Bouaiti E, Chahdi H, Boudhas A, Allaoui M, Ameur A, Abbar M, Al Bouzidi A: Expression of human epidermal growth factor receptor 2 in bladder urothelial carcinoma. BMC Clin Pathol 2017; 17: 3.
20.
Cheng L, Davison DD, Adams J, Lopez-Beltran A, Wang L, Montironi R, Zhang S: Biomarkers in bladder cancer: translational and clinical implications. Crit Rev Oncol Hematol 2014; 89: 73–111.
21.
Hansel DE, Swain E, Dreicer R, Tubbs RR: HER2 overexpression and amplification in urothelial carcinoma of the bladder is associated with MYC coamplification in a subset of cases. Am J Clin Pathol 2008; 130: 274–281.
22.
Kiss B, Wyatt AW, Douglas J, Skuginna V, Mo F, Anderson S, Rotzer D, Fleischmann A, Genitsch V, Hayashi T, et al: Her2 alterations in muscle-invasive bladder cancer: patient selection beyond protein expression for targeted therapy. Sci Rep 2017; 7: 42713.
23.
Joensuu H, Kellokumpu-Lehtinen PL, Bono P, Alanko T, Kataja V, Asola R, Utriainen T, Kokko R, Hemminki A, Tarkkanen M, et al: Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer. N Engl J Med 2006; 354: 809–820.
24.
Zhao J, Xu W, Zhang Z, Song R, Zeng S, Sun Y, Xu C: Prognostic role of HER2 expression in bladder cancer: a systematic review and meta-analysis. Int Urol Nephrol 2015; 47: 87–94.
25.
Bang YJ, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki A, Lordick F, Ohtsu A, Omuro Y, Satoh T, 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: 687–697.
26.
Bolenz C, Shariat SF, Karakiewicz PI, Ashfaq R, Ho R, Sagalowsky AI, Lotan Y: Human epidermal growth factor receptor 2 expression status provides independent prognostic information in patients with urothelial carcinoma of the urinary bladder. BJU Int 2010; 106: 1216–1222.
27.
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.
28.
Olsson H, Fyhr IM, Hultman P, Jahnson S: HER2 status in primary stage T1 urothelial cell carcinoma of the urinary bladder. Scand J Urol Nephrol 2012; 46: 102–107.
29.
Sato K, Moriyama M, Mori S, Saito M, Watanuki T, Terada K, Okuhara E, Akiyama T, Toyoshima K, Yamamoto T, et al: An immunohistologic evaluation of C-erbB-2 gene product in patients with urinary bladder carcinoma. Cancer 1992; 70: 2493–2498.
30.
Chow NH, Chan SH, Tzai TS, Ho CL, Liu HS: Expression profiles of ErbB family receptors and prognosis in primary transitional cell carcinoma of the urinary bladder. Clin Cancer Res 2001; 7: 1957–1962.
31.
Gandour-Edwards R, Lara PN Jr, Folkins AK, LaSalle JM, Beckett L, Li Y, Meyers FJ, DeVere-White R: Does HER2/neu expression provide prognostic information in patients with advanced urothelial carcinoma? Cancer 2002; 95: 1009–1015.
32.
Latif Z, Watters AD, Dunn I, Grigor KM, Underwood MA, Bartlett JM: HER2/neu overexpression in the development of muscle-invasive transitional cell carcinoma of the bladder. Br J Cancer 2003; 89: 1305–1309.
33.
Coogan CL, Estrada CR, Kapur S, Bloom KJ: HER-2/neu protein overexpression and gene amplification in human transitional cell carcinoma of the bladder. Urology 2004; 63: 786–790.
34.
Krüger S, Lange I, Kausch I, Feller AC: Protein expression and gene copy number analysis of topoisomerase 2alpha, HER2 and P53 in minimally invasive urothelial carcinoma of the urinary bladder – a multitissue array study with prognostic implications. Anticancer Res 2005; 25: 263–271.
35.
Kolla SB, Seth A, Singh MK, Gupta NP, Hemal AK, Dogra PN, Kumar R: Prognostic significance of Her2/neu overexpression in patients with muscle invasive urinary bladder cancer treated with radical cystectomy. Int Urol Nephrol 2008; 40: 321–327.
36.
Kassouf W, Black PC, Tuziak T, Bondaruk J, Lee S, Brown GA, Adam L, Wei C, Baggerly K, Bar-Eli M, et al: Distinctive expression pattern of ErbB family receptors signifies an aggressive variant of bladder cancer. J Urol 2008; 179: 353–358.
37.
Wester K, Sjöström A, de la Torre M, Carlsson J, Malmström PU: HER-2 – a possible target for therapy of metastatic urinary bladder carcinoma. ActaOncol 2002; 41: 282–288.
38.
Sauter G, Moch H, Moore D, Carroll P, Kerschmann R, Chew K, Mihatsch MJ, Gudat F, Waldman F: Heterogeneity of erbB-2 gene amplification in bladder cancer. Cancer Res 1993; 53(suppl): 2199–2203.
39.
Bellmunt J, Werner L, Bamias A, Fay AP, Park RS, Riester M, Selvarajah S, Barletta JA, Berman DM, de Muga S, et al: HER2 as a target in invasive urothelial carcinoma. Cancer Med 2015; 4: 844–852.
40.
Arikan O, Yyldyrym A, Ysbilen B, Canakci C, Atys G, Gurbuz C, Erol B, Ysman FK, Ozkanli S, Caskurlu T: Clinical significance of serum and urinary HER2/neu protein levels in primary non-muscle invasive bladder cancer. Int Braz J Urol 2015; 41: 1080–1087.
41.
Udager AM, Alva A, Mehra R: Current and proposed molecular diagnostics in a genitourinary service line laboratory at a tertiary clinical institution. Cancer J 2014; 20: 29–42.
42.
Perez EA, Roche PC, Jenkins RB, Reynolds CA, Halling KC, Ingle JN, Wold LE: HER2 testing in patients with breast cancer: poor correlation between weak positivity by immunohistochemistry and gene amplification by fluorescence in situ hybridization. Mayo Clin Proc 2002; 77: 148–154.
43.
Krüger S, Weitsch G, Büttner H, Matthiensen A, Böhmer T, Marquardt T, Sayk F, Feller AC, Böhle A: HER2 overexpression in muscle-invasive urothelial carcinoma of the bladder: prognostic implications. Int J Cancer 2002; 102: 514–518.
44.
Tsai YS, Tzai TS, Chow NH, Yang WH, Tong YC, Lin JS, Chang CC, Cheng HL, Lin YM: Prognostic values of p53 and HER-2/neu coexpression in invasive bladder cancer in Taiwan. Urol Int 2003; 71: 262–270.
45.
Rotterud R, Nesland JM, Berner A, Fosså SD: Expression of the epidermal growth factor receptor family in normal and malignant urothelium. BJU Int 2005; 95: 1344–1350.
46.
Gorgoulis VG, Barbatis C, Poulias I, Karameris AM: Molecular and immunohistochemical evaluation of epidermal growth factor receptor and c-erb-B-2 gene product in transitional cell carcinomas of the urinary bladder: a study in Greek patients. Mod Pathol 1995; 8: 758–764.
47.
Tetu B, Fradet Y, Allard P, Veilleux C, Roberge N, Bernard P: Prevalence and clinical significance of HER/2neu, p53 and Rb expression in primary superficial bladder cancer. J Urol 1996; 155: 1784–1788.
48.
Sasaki Y, Sasaki T, Kawai T, Morikawa T, Matsusaka K, Kunita A, Kume H, Aoki I, Homma Y, Fukayama M: HER2 protein overexpression and gene amplification in upper urinary tract urothelial carcinoma-an analysis of 171 patients. Int J Clin Exp Pathol 2014; 7: 699–708.
49.
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.
50.
Sanguedolce F, Bufo P: HER2 assessment by silver in situ hybridization: where are we now? Expert Rev Mol Diagn 2015; 15: 385–398.
51.
Lim SD, Cho YM, Choi GS, Park HK, Paick SH, Kim WY, Kim SN, Yoon G: Clinical significance of substaging and HER2 expression in papillary nonmuscle invasive urothelial cancers of the urinary bladder. J Korean Med Sci 2015; 30: 1068–1077.
52.
Simon R, Atefy R, Wagner U, Forster T, Fijan A, Bruderer J, Wilber K, Mihatsch MJ, Gasser T, Sauter G: HER-2 and TOP2A coamplification in urinary bladder cancer. Int J Cancer 2003; 107: 764–772.
53.
Cimpean AM, Tarlui V, Cumpanas AA, Bolintineanu S, Cumpanas A, Raica M: Critical overview of HER2 assessement in bladder cancer: what is missing for a better therapeutic approach? Anticancer Res 2017; 37: 4935–4942.
54.
Fleischmann A, Rotzer D, Seiler R, Studer UE, Thalmann GN: Her2 amplification is significantly more frequent in lymph node metastases from urothelial bladder cancer than in the primary tumours. Eur Urol 2011; 60: 350–357.
55.
Janane A, Hajji F, Ismail TO, Elondo JC, Ghadouane M, Ameur A, Abbar M, Bouzidi A: Evaluation of HER2 protein overexpression in non-muscle-invasive bladder cancer with emphasis on tumour grade and recurrence. Actas Urol Esp 2011; 35: 189–194.
56.
Ding W, Tong S, Gou Y, Sun C, Wang H, Chen Z, Tan J, Xu K, Xia G, Ding Q: Human epidermal growth factor receptor 2: a significant indicator for predicting progression in non-muscle-invasive bladder cancer especially in high-risk groups. World J Urol 2015; 33: 1951–1957.
57.
Cormio L, Sanguedolce F, Cormio A, Massenio P, Pedicillo MC, Cagiano S, Calò G, Pagliarulo V, Carrieri G, Bufo P: Human epidermal growth factor receptor 2 expression is more important than Bacillus Calmette Guerin treatment in predicting the outcome of T1G3 bladder cancer. Oncotarget 2017; 8: 25433–25441.
58.
Sanguedolce F, Cormio A, Massenio P, Pedicillo MC, Cagiano S, Fortunato F, Calò B, Di Fino G, Carrieri G, Bufo P, Cormio L: Altered expression of HER-2 and the mismatch repair genes MLH1 and MSH2 predicts the outcome of T1 high-grade bladder cancer. J Cancer Res Clin Oncol 2018; 144: 637–644.
59.
Krüger S, Weitsch G, Büttner H, Matthiensen A, Böhmer T, Marquardt T, Sayk F, Feller AC, Böhle A: Overexpression of c-erbB-2 oncoprotein in muscle-invasive bladder carcinoma: relationship with gene amplification, clinicopathological parameters and prognostic outcome. Int J Oncol 2002; 21: 981–987.
60.
Mejri N, Sellami R, Lamia C, Raoudha D, Hmida NB, Sriha B, Sihem H, Karima M, Romdhane KB: Status of Her2 over expression in muscle invasive urothelial bladder carcinoma: report of 21 cases. Urol Ann 2014; 6: 63–67.
61.
Simonetti S, Russo R, Ciancia G, Altieri V, De Rosa G, Insabato L: Role of polysomy 17 in transitional cell carcinoma of the bladder: immunohistochemical study of HER2/neu expression and fish analysis of c-erbB-2 gene and chromosome 17. Int J Surg Pathol 2009; 17: 198–205.
62.
Caner V, Turk NS, Duzcan F, Tufan NL, Kelten EC, Zencir S, Dodurga Y, Bagci H, Duzcan SE: No strong association between HER-2/neu protein overexpression and gene amplification in high-grade invasive urothelial carcinomas. Pathol Oncol Res 2008; 14: 261–266.
63.
Pu X, Shi J, Li Z, Feng A, Ye Q: Comparison of the 2007 and 2013 ASCO/CAP evaluation systems for HER2 amplification in breast cancer. Pathol Res Pract 2015; 211: 421–425.
64.
Onsum MD, Geretti E, Paragas V, Kudla AJ, Moulis SP, Luus L, Wickham TJ, McDonagh CF, MacBeath G, Hendriks BS: Single-cell quantitative HER2 measurement identifies heterogeneity and distinct subgroups within traditionally defined HER2-positive patients. Am J Pathol 2013; 183: 1446–1460.
65.
Iyer G, Al-Ahmadie H, Schultz N, Hanrahan AJ, Ostrovnaya I, Balar AV, Kim PH, Lin O, Weinhold N, Sander C, et al: Prevalence and co-occurrence of actionable genomic alterations in high-grade bladder cancer. J Clin Oncol 2013; 31: 3133–3140.
66.
Breyer J, Wirtz RM, Laible M, Schlombs K, Erben P, Kriegmair MC, Stoehr R, Eidt S, Denzinger S, Burger M, et al: ESR1, ERBB2, and Ki67 mRNA expression predicts stage and grade of non-muscle-invasive bladder carcinoma (NMIBC). Virchows Arch 2016; 469: 547–552.
67.
Breyer J, Otto W, Wirtz RM, Wullich B, Keck B, Erben P, Kriegmair MC, Stoehr R, Eckstein M, Laible M, et al: ERBB2 expression as potential risk-stratification for early cystectomy in patients with pT1 bladder cancer and concomitant carcinoma in situ. Urol Int 2017; 98: 282–289.
68.
Amsellem-Ouazana D, Bièche I, Molinié V, Elie C, Vieillefond A, Tozlu S, Botto H, Debré B, Lidereau R: Is quantitative real-time RT-PCR an adjunct to immunohistochemistry for the evaluation of ErbB2 status in transitional carcinoma of the bladder? Eur Urol 2006; 49: 1035–1042.
69.
Soria F, Moschini M, Haitel A, Wirth GJ, Gust KM, Briganti A, Rouprêt M, Klatte T, Hassler MR, Karakiewicz PI, et al: The effect of HER2 status on oncological outcomes of patients with invasive bladder cancer. Urol Oncol 2016; 34:e533.e1–e533.e10.
70.
Choi W, Czerniak B, Ochoa A, Su X, Siefker-Radtke A, Dinney C, McConkey DJ: Intrinsic basal and luminal subtypes of muscle-invasive bladder cancer. Nat Rev Urol 2014; 11: 400–410.
71.
Dadhania V, Zhang M, Zhang L, Bondaruk J, Majewski T, Siefker-Radtke A, Guo CC, Dinney C, Cogdell DE, Zhang S, et al: Meta-analysis of the luminal and basal subtypes of bladder cancer and the identification of signature immunohistochemical markers for clinical use. EBioMedicine 2016; 12: 105–117.
72.
Ching CB, Amin MB, Tubbs RR, Elson P, Platt E, Dreicer R, Fergany A, Hansel DE: HER2 gene amplification occurs frequently in the micropapillary variant of urothelial carcinoma: analysis by dual-color in situ hybridization. Mod Pathol 2011; 24: 1111–1119.
73.
Kumar S, Prajapati O, Vaiphei K, Parmar KM, Sriharsha AS, Singh SK: Human epidermal growth factor receptor 2/neu overexpression in urothelial carcinoma of the bladder and its prognostic significance: is it worth hype? South Asian J Cancer 2015; 4: 115–117.
74.
Vollmer RT, Humphrey PA, Swanson PE, Wick MR, Hudson ML: Invasion of the bladder by transitional cell carcinoma: its relation to histologic grade and expression of p53, MIB-1, c-erb B-2, epidermal growth factor receptor, and bcl-2. Cancer 1998; 82: 715–723.
75.
Rajjayabun PH, Keegan PE, Lunec J, Mellon JK: erbB receptor expression patterns in human bladder cancer. Urology 2005; 66: 196–200.
76.
Jalali Nadoushan MR, Taheri T, Jouian N, Zaeri F: Overexpression of HER-2/neu oncogene and transitional cell carcinoma of bladder. Urol J 2007; 4: 151–154.
77.
Skagias L, Politi E, Karameris A, Sambaziotis D, Archondakis A, Vasou O, Ntinis A, Michalopoulou F, Moreas I, Koutselini H, et al: Prognostic impact of HER2/neu protein in urothelial bladder cancer. Survival analysis of 80 cases and an overview of almost 20 years’ research. J BUON 2009; 14: 457–462.
78.
Nedjadi T, Al-Maghrabi J, Assidi M, Dallol A, Al-Kattabi H, Chaudhary A, Al-Sayyad A, Al-Ammari A, Abuzenadah A, Buhmeida A, et al: Prognostic value of HER2 status in bladder transitional cell carcinoma revealed by both IHC and BDISH techniques. BMC Cancer 2016; 16: 653.
79.
Yildirim A, Kosem M, Sayar I, Gelincik I, Yavuz A, Bozkurt A, Erkorkmaz U, Bayram I: Relationship of PCNA, C-erbB2 and CD44s expression with tumor grade and stage in urothelial carcinomas of the bladder. Int J Clin Exp Med 2014; 7: 1516–1523.
80.
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.
81.
Jung S, Wu C, Eslami Z, Tanguay S, Aprikian A, Kassouf W, Brimo F: The role of immunohistochemistry in the diagnosis of flat urothelial lesions: a study using CK20, CK5/6, P53, Cd138, and Her2/Neu. Ann Diagn Pathol 2014; 18: 27–32.
82.
Sanguedolce F, Brunelli M, D’Amuri A, Calò B, Mancini V, Carrieri G, Cormio L: Evolving concepts and use of immunohistochemical biomarkers in flat non-neoplastic urothelial lesions: WHO 2016 classification update with diagnostic algorithm. Biomarkers 2018; 23: 305–314.
83.
Matsubara H, Yamada Y, Naruse K, Nakamura K, Aoki S, Taki T, Tobiume M, Zennami K, Katsuda R, Honda N: Potential for HER-2/neu molecular targeted therapy for invasive bladder carcinoma: comparative study of immunohistochemistry and fluorescent in situ hybridization. Oncol Rep 2008; 19: 57–63.
84.
Jimenez RE, Hussain M, Bianco F Jr, Vaishampayan U, Tabazcka P, Sakr WA, Pontes JE, Wood DP Jr, Grignon DJ: Her-2/neu overexpression in muscle-invasive urothelial carcinoma of the bladder: prognostic significance and comparative analysis in primary and metastatic tumors. Clin Cancer Res 2001; 7: 2440–2447.
85.
Rink M, Chun FK, Dahlem R, Soave A, Minner S, Hansen J, Stoupiec M, Coith C, Kluth LA, Ahyai SA, et al: Prognostic role and HER2 expression of circulating tumor cells in peripheral blood of patients prior to radical cystectomy: a prospective study. Eur Urol 2012; 61: 810–817.
86.
Hayashi T, Seiler R, Oo HZ, Jäger W, Moskalev I, Awrey S, Dejima T, Todenhöfer T, Li N, Fazli L, et al: Targeting HER2 with T-DM1, an antibody cytotoxic drug conjugate, is effective in HER2 over expressing bladder cancer. J Urol 2015; 194: 1120–1131.
87.
Chakravarti A, Winter K, Wu CL, Kaufman D, Hammond E, Parliament M, Tester W, Hagan M, Grignon D, Heney N, et al: Expression of the epidermal growth factor receptor and Her-2 are predictors of favorable outcome and reduced complete response rates, respectively, in patients with muscle-invading bladder cancers treated by concurrent radiation and cisplatin-based chemotherapy: a report from the Radiation Therapy Oncology Group. Int J Radiat Oncol Biol Phys 2005; 62: 309–317.
88.
Joshi M, Millis SZ, Arguello D, Holder SL, Lamm D, Reddy S, Belani C, Drabick JJ, Vogelzang NJ: Molecular characterization of bladder cancer in smokers versus nonsmokers. Eur Urol Focus 2018; 4: 94–97.
89.
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.
90.
Breyer J, Wirtz RM, Otto W, Laible M, Schlombs K, Erben P, Kriegmair MC, Stoehr R, Eidt S, Denzinger S, et al: Predictive value of molecular subtyping in NMIBC by RT-qPCR of ERBB2, ESR1, PGR and MKI67 from formalin fixed TUR biopsies. Oncotarget 2017; 8: 67684–67695.
91.
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.
92.
Hegazy R, Kamel M, Salem EA, Salem NA, Fawzy A, Sakr A, El-farargy O, Nawar N, -El-atar A, Shahin AM, et al: The prognostic significance of p53, p63 and her2 expression in non-muscle-invasive bladder cancer in relation to treatment with bacille Calmette-Guerin. Arab J Urol 2015; 13: 225–230.
93.
Redondo-Gonzalez E, de Castro LN, Moreno-Sierra J, Maestro de las Casas ML, Vera-Gonzalez V, Ferrari DG, Corchado JM: Bladder carcinoma data with clinical risk factors and molecular markers: a cluster analysis. Bio Med Res Int 2015; 2015: 168682.
94.
Eissa S, Ali HS, Al Tonsi AH, Zaglol A, El Ahmady O: HER2/neu expression in bladder cancer: relationship to cell cycle kinetics. Clin Biochem 2005; 38: 142–148.
95.
De Paoli M, Gogalic S, Sauer U, Preininger C, Pandha H, Simpson G, Horvath A, Marquette C: Multiplatform biomarker discovery for bladder cancer recurrence diagnosis. Dis Markers 2016; 2016: 4591910.
96.
Lee E, Park I, Lee C: Prognostic markers of intravesical bacillus calmette-guerin therapy for multiple, high-grade, stage T1 bladder cancers. Int J Urol 1997; 4: 552–556.
97.
Morgan BE, Salup R, Morgan MB: Differential C-erbB-2 and VEGF expression following BCG immunotherapy in superficial papillary transitional cell carcinoma of the bladder. Urol Oncol 2002; 7: 67–72.
98.
Lima L, Dinis-Ribeiro M, Longatto-Filho A, Santos L: Predictive biomarkers of bacillus calmette-guérin immunotherapy response in bladder cancer: where are we now? Adv Urol 2012; 2012: 232609.
99.
Marin AP, Arranz EE, Sánchez AR, Auñón PZ, Barón MG: Role of anti-Her-2 therapy in bladder carcinoma. J Cancer Res Clin Oncol 2010; 136: 1915–1920.
100.
Carneiro BA, Meeks JJ, Kuzel TM, Scaranti M, Abdulkadir SA, Giles FJ: Emerging therapeutic targets in bladder cancer. Cancer Treat Rev 2015; 41: 170–178.
101.
Powles T, Huddart RA, Elliott T, Sarker SJ, Ackerman C, Jones R, Hussain S, Crabb S, Jagdev S, Chester J, et al: Phase III, double-blind, randomized trial that compared maintenance lapatinib versus placebo after first-line chemotherapy in patients with human epidermal growth factor receptor 1/2-positive metastatic bladder cancer. J Clin Oncol 2017; 35: 48–55.
102.
Hussain MH, MacVicar GR, Petrylak DP, Dunn RL, Vaishampayan U, Lara PN Jr, Chatta GS, Nanus DM, Glode LM, Trump DL, et al: 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.
103.
Kriegmair MC, Wirtz RM, Worst TS, Breyer J, Ritter M, Keck B, Boehmer C, Otto W, Eckstein M, Weis CA, et al: Prognostic value of molecular breast cancer subtypes based on Her2, ESR1, PGR and Ki67 mRNA-expression in muscle invasive bladder cancer. Transl Oncol 2018; 11: 467–476.
104.
Duffy MJ, Harbeck N, Nap M, Molina R, Nicolini A, Senkus E, Cardoso F: Clinical use of biomarkers in breast cancer: updated guidelines from the European Group on Tumor Markers (EGTM). Eur J Cancer 2017; 75: 284–298.
105.
Michaelson MD, Hu C, Pham HT, Dahl DM, Lee-Wu C, Swanson GP, Vuky J, Lee RJ, Souhami L, Chang B, et al: A phase 1/2 trial of a combination of paclitaxel and trastuzumab with daily irradiation or paclitaxel alone with daily irradiation after transurethral surgery for noncystectomy candidates with muscle-invasive bladder cancer (Trial NRG Oncology RTOG 0524). Int J Radiat Oncol Biol Phys 2017; 97: 995–1001.
106.
Oudard S, Culine S, Vano Y, Goldwasser F, Théodore C, Nguyen T, Voog E, Banu E, Vieillefond A, Priou F, et al: Multicentre randomised phase II trial of gemcitabine+ platinum, with or without trastuzumab, in advanced or metastatic urothelial carcinoma overexpressing Her2. Eur J Cancer 2015; 51: 45–54.
107.
Lewis Phillips GD, Li G, Dugger DL, Crocker LM, Parsons KL, Mai E, Blättler WA, Lambert JM, Chari RV, Lutz RJ, et al: Targeting HER2-positive breast cancer with trastuzumab-DM1, an antibody-cytotoxic drug conjugate. Cancer Res 2008; 68: 9280–6290.
108.
Barok M, Tanner M, Köninki K, Isola J: Trastuzumab-DM1 is highly effective in preclinical models of HER2-positive gastric cancer. Cancer Lett 2011; 306: 171–179.
109.
LoRusso PM, Weiss D, Guardino E, Girish S, Sliwkowski MX: Trastuzumab emtansine: a unique antibody-drug conjugate in development for human epidermal growth factor receptor 2-positive cancer. Clin Cancer Res 2011; 17: 6437–6447.
110.
Girish S, Gupta M, Wang B, Lu D, Krop IE, Vogel CL, Burris Iii HA, LoRusso PM, Yi JH, Saad O, et al: Clinical pharmacology of trastuzumab emtansine (T-DM1): an antibody-drug conjugate in development for the treatment of HER2-positive cancer. Cancer Chemother Pharmacol 2012; 69: 1229–1240.
111.
Grivas PD, Day KC, Karatsinides A, Paul A, Shakir N, Owainati I, Liebert M, Kunju LP, Thomas D, Hussain M, et al: Evaluation of the antitumor activity of dacomitinib in models of human bladder cancer. Mol Med 2013; 19: 367–376.
112.
Tamura S, Wang Y, Veeneman B, Hovelson D, Bankhead A 3rd, Broses LJ, Lorenzatti Hiles G, Liebert M, Rubin JR, Day KC, et al: Molecular correlates of in vitro responses to Dacomitinib and Afatinib in bladder cancer. Bladder Cancer 2018; 4: 77–90.
113.
Wülfing C, Machiels JP, Richel DJ, Grimm MO, Treiber U, De Groot MR, Beuzeboc P, Parikh R, Pétavy F, El-Hariry IA: A single-arm, multicenter, open-label phase 2 study of lapatinib as the second-line treatment of patients with locally advanced or metastatic transitional cell carcinoma. Cancer 2009; 115: 2881–2890.
114.
de Martino M, Zhuang D, Klatte T, Rieken M, Rouprêt M, Xylinas E, Clozel T, Krzywinski M, Elemento O, Shariat SF: Impact of ERBB2 mutations on in vitro sensitivity of bladder cancer to lapatinib. Cancer Biol Ther 2014; 15: 1239–1247.
115.
McHugh LA, Kriajevska M, Mellon JK, Griffiths TR: Combined treatment of bladder cancer cell lines with lapatinib and varying chemotherapy regimens – evidence of scheduled-dependent synergy. Urology 2007; 69: 390–394.
116.
McHugh LA, Sayan AE, Mejlvang J, Griffiths TR, Sun Y, Manson MM, Tulchinsky E, Mellon JK, Kriajevska M: Lapatinib, a dual inhibitor of ErbB-1/-2 receptors, enhances effects of combination chemotherapy in bladder cancer cells. Int J Oncol 2009; 34: 1155–1163.
117.
Nagasawa J, Mizokami A, Koshida K, Yoshida S, Naito K, Namiki M: Novel HER2 selective tyrosine kinase inhibitor, TAK-165, inhibits bladder, kidney and androgen-independent prostate cancer in vitro and in vivo. Int J Urol 2006; 13: 587–592.
118.
Reynolds JG, Geretti E, Hendriks BS, Lee H, Leonard SC, Klinz SG, Noble CO, Lücker PB, Zandstra PW, Drummond DC, et al: HER2-targeted liposomal doxorubicin displays enhanced anti-tumorigenic effects without associated cardiotoxicity. Toxicol Appl Pharmacol 2012; 262: 1–10.
119.
McDonagh CF, Huhalov A, Harms BD, Adams S, Paragas V, Oyama S, Zhang B, Luus L, Overland R, Nguyen S, et al: Antitumor activity of a novel bispecific antibody that targets the ErbB2/ErbB3 oncogenic unit and inhibits heregulin-induced activation of ErbB3. Mol Cancer Ther 2012; 11: 582–593.
120.
Carlsson J, Wester K, De La Torre M, Malmström PU, Gårdmark T: EGFR-expression in primary urinary bladder cancer and corresponding metastases and the relation to HER2-expression. On the possibility to target these receptors with radionuclides. Radiol Oncol 2015; 49: 50–58.
121.
Hegazy R, Hegazy A, Kamel M, El-Farargy O, Nawar N, El-Atar A: Role of human epidermal growth factor receptor 2 antagonist (Trastuzumab) in the management of nonmuscle-invasive urinary bladder carcinoma. Tumor Microenviron 2018; 1: 25–29.
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2018
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