Expression of HER2 in urothelial carcinoma and its significance

Abstract

Objectives: We explored the expression levels and clinical significance of human epidermal growth factor receptor 2 (HER2) in urothelial carcinoma (UC) tissues.

Materials and methods: Patient data were reviewed, and 111 paraffin specimens of UC obtained from the Department of Urology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, from 2020 to 2021 were collected. Immunohistochemistry was used to detect HER2 protein expression in all UC tumor tissues. The χ² and Fisher exact tests were used to analyze the relationship between HER2 protein expression and clinicopathological data (sex, age, histopathological diagnosis, invasiveness, histopathological grade, maximum tumor diameter, muscle invasion, regional lymph node metastasis, and clinical stage).

Results: In this study, 92 cases (82.88%) showed HER2 protein expression, and there was a statistically significant difference in the distribution of HER2 positivity (immunohistochemistry 2+ and 3+) according to the pathological grades of UC (p = 0.021). Human epidermal growth factor receptor 2 positivity was not associated with sex, age, histopathological diagnosis, invasiveness, maximum tumor diameter, muscle invasion, regional lymph node metastasis, or clinical stage (all p < 0.05).

Conclusions: Human epidermal growth factor receptor 2 protein is highly expressed in UC, and its expression may be closely related to the high pathological grade of UC.

Keywords

Urothelial carcinoma / Human epidermal growth factor receptor 2 / Immunohistochemistry

Acknowledgments

None.

Statement of ethics

Informed consent was obtained from all the patients, and the study was approved by the ethics committee of Shandong Provincial Hospital (SWYX: NO.2021-492). All procedures performed in the study involving human participants were in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Conflicts of interest statement

No conflict of interest has been declared by the authors.

Funding statement

This work was supported by Integrated Research on Intelligent Precision Diagnosis and Treatment of High-Risk Tumors of the Urinary System (grant 6020119027) and Shandong Provincial Natural Science Foundation (ZR2023LZL005, ZR2021QH313).

Author contributions

All authors listed gave a substantive contribution to this study and to this original article.

YC: Conceptualization, writing—original draft preparation;

DZ: Conceptualization, formal analysis and investigation;

ZW: Formal analysis and investigation;

KZ: Statistical analysis;

AG: Methodology;

JC: Methodology;

CW: Formal analysis and investigation;

SD: Writing—review and editing, conceptualization.

Data availability

The data used to support the findings of this study are available from the corresponding author upon request.

References

[1] Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2021; 71(3):209-249.

[2] Rodriguez Pena MDC, Chaux A, Eich ML, et al. Immunohistochemical assessment of basal and luminal markers in non-muscle invasive urothelial carcinoma of bladder. Virchows Arch 2019; 475(3):349-356.

[3] D'Angelo A, Chapman R, Sirico M, et al. An update on antibody-drug conjugates in urothelial carcinoma: State of the art strategies and what comes next. Cancer Chemother Pharmacol 2022; 90(3):191-205.

[4] Remmele W, Stegner HE. Recommendation for uniform definition of an immunoreactive score (IRS) for immunohistochemical estrogen receptor detection (ER-ICA) in breast cancer tissue [in German]. Pathologe 1987; 8(3):138-140.

[5] Jiang Q, Xie MX, Zhang XC. Complete response to trastuzumab and chemotherapy in recurrent urothelial bladder carcinoma with HER2 gene amplification:A case report. World J Clin Cases 2020; 8(3):594-599.

[6] Afatinib is active in platinum-refractory ERBB-mutant urothelial carcinoma. Cancer Discov 2016; 6(6):OF13.

[7] Matsubara H, Yamada Y, Naruse K, et al. 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(1):57-63.

[8] 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(6):881-888.

[9] Latif Z, Watters AD, Dunn I, et al. HER2/neu overexpression in the development of muscle-invasive transitional cell carcinoma of the bladder. Br J Cancer 2003; 89(7):1305-1309.

[10] Tumor Pathology Committee of Chinese Anti-Cancer Association; Expert Committee on Urothelial Carcinoma of Chinese Society of Clinical Oncology. Clinical pathological expert consensus on HER-2 testing in urothelial carcinoma in China [in Chinese]. Zhonghua Zhong Liu Za Zhi 2021; 43(10):1001-1006.

[11] Bellmunt J, Werner L, Bamias A, et al. HER2 as a target in invasive urothelial carcinoma. Cancer Med 2015; 4(6):844-852.

[12] Chivukula M, Bhargava R, Brufsky A, Surti U, Dabbs DJ. Clinical importance of HER2 immunohistologic heterogeneous expression in core-needle biopsies vs resection specimens for equivocal (immunohistochemical score 2+) cases. Mod Pathol 2008; 21(4):363-368.

[13] Cottu PH, Asselah J, Lae M, et al. Intratumoral heterogeneity of HER2/neu expression and its consequences for the management of advanced breast cancer. Ann Oncol 2008; 19(3):596-597.

[14] Yan M, Schwaederle M, Arguello D, et al. HER2 expression status in diverse cancers: Review of results from 37,992 patients. Cancer Metastasis Rev 2015; 34(1):157-164.

[15] Owens MA, Horten BC, Da Silva MM. HER2 amplification ratios by fluorescence in situ hybridization and correlation with immunohistochemistry in a cohort of 6556 breast cancer tissues. Clin Breast Cancer 2004; 5(1):63-69.

[16] Liu S, Chen X, Lin T. Emerging strategies for the improvement of chemotherapy in bladder cancer: Current knowledge and future perspectives. J Adv Res 2022;39:187-202.

[17] Kiss B, Wyatt AW, Douglas J, et al. Her2 alterations in muscle-invasive bladder cancer: Patient selection beyond protein expression for targeted therapy. Sci Rep 2017;7:42713.

[18] Gong J, Shen L, Wang W, et al. Safety, pharmacokinetics and efficacy of RC48-ADC in a phase I study in patients with HER2-overexpression advanced solid cancer. J Clin Oncol 2018;36:e16059.

[19] Eltze E, Wülfing C, Von Struensee D, Piechota H, Buerger H, Hertle L. Cox-2 and Her2/neu co-expression in invasive bladder cancer. Int J Oncol 2005; 26(6):1525-1531.

[20] Goodman AL, Osunkoya AO. Human epidermal growth factor receptor 2 expression in micropapillary urothelial carcinoma of the bladder: An analysis of 27 cases. Hum Pathol 2016;57:160-164.

[21] Bellmunt J, Valderrama BP, Puente J, et al. Recent therapeutic advances in urothelial carcinoma: A paradigm shift in disease management. Crit Rev Oncol Hematol 2022;174:103683.

[22] Zhao J, Xu W, Zhang Z, et al. Prognostic role of HER2 expression in bladder cancer: A systematic review and meta-analysis. Int Urol Nephrol 2015; 47(1):87-94.

[23] El-Moneim H, Tawfik H, El-Sherbiny Y, et al. Analysis of Her2/neu overexpression and amplification in urothelial carcinoma of the bladder associated with Cox-2 overexpression[J]. 2011;7:8-24.

[24] Krüger S, Weitsch G, Büttner H, et al. HER2 overexpression in muscle-invasive urothelial carcinoma of the bladder: Prognostic implications. Int J Cancer 2002; 102(5):514-518.

[25] Mitri Z, Constantine T, O'Regan R. The HER2 receptor in breast cancer: Pathophysiology, clinical use, and new advances in therapy. Chemother Res Pract 2012;2012:743193-743197.

[26] Pernas S, Tolaney SM. HER2-positive breast cancer: New therapeutic frontiers and overcoming resistance. Ther Adv Med Oncol 2019;11:1758835919833519.

[27] Bang YJ, van Cutsem E, Feyereislova 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(9742):687-697.

[28] Van Cutsem E, Bang YJ, Feng-Yi F, et al. HER2 screening data from ToGA: Targeting HER2 in gastric and gastroesophageal junction cancer. Gastric Cancer 2015; 18(3):476-484.

[29] Kaito A, Kuwata T, Tokunaga M, et al. HER2 heterogeneity is a poor prognosticator for HER2-positive gastric cancer. World J Clin Cases 2019; 7(15):1964-1977.

[30] Cimpean AM, Tarlui V, Cumpănaş AA, Bolintineanu S, Cumpănaş A, Raica M. Critical overview of HER2 assessement in bladder cancer: What is missing for a better therapeutic approach? Anticancer Res 2017; 37(9):4935-4942.

[31] Bolenz C, Shariat SF, Karakiewicz PI, et al. 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(8):1216-1222.

[32] Rizzo A, Mollica V, Giunchi F, et al. Impact of HER2 assessment by CISH in urothelial carcinoma: A retrospective single-center experience. Pathol Res Pract 2021;220:153410.

[33] Schneider SA, Sukov WR, Frank I, et al. Outcome of patients with micropapillary urothelial carcinoma following radical cystectomy: ERBB2 (HER2) amplification identifies patients with poor outcome. Mod Pathol 2014; 27(5):758-764.

[34] Ching CB, Amin MB, Tubbs RR, et al. HER2 gene amplification occurs frequently in the micropapillary variant of urothelial carcinoma: Analysis by dual-color in situ hybridization. Mod Pathol 2011; 24(8):1111-1119.

[35] Erben P, Wezel F, Wirtz R, et al. Role of the human ErbB family receptors in urothelial carcinoma of the bladder: mRNA expression status and prognostic relevance [in German]. Aktuelle Urol 2017; 48(4):356-362.

[36] Eriksson P, Sjödahl G, Chebil G, Liedberg F, Höglund M. HER2 and EGFR amplification and expression in urothelial carcinoma occurs in distinct biological and molecular contexts. Oncotarget 2017; 8(30):48905-48914.