Skip to main content
Top
Published in: BMC Urology 1/2018

Open Access 01-12-2018 | Research article

Epidermal growth factor expression as a predictor of chemotherapeutic resistance in muscle-invasive bladder cancer

Authors: Ahmed M. Mansour, Mona Abdelrahim, Mahmoud Laymon, Mamdouh Elsherbeeny, Mohammed Sultan, Ahmed Shokeir, Ahmed Mosbah, Hassan Abol-Enein, Amira Awadalla, Eunho Cho, Vikram Sairam, Taeeun D. Park, Muhammad Shahid, Jayoung Kim

Published in: BMC Urology | Issue 1/2018

Login to get access

Abstract

Background

Epidermal growth factor receptor (EGFR) overexpression is believed to be associated with bladder cancer (BC) progression and poor clinical outcomes. In vivo studies have linked EGFR subcellular trafficking and chemo-resistance to cisplatin-based chemotherapies. This has not been studied in the clinical adjuvant setting. We aimed to investigate the prognostic significance of EGFR expression in patients receiving cisplatin-based adjuvant chemotherapy following radical cystectomy for advanced BC.

Methods

The database from the Urology and Nephrology Center at Mansoura University was reviewed. BC patients who were treated with radical cystectomy and adjuvant chemotherapy for adverse pathological features or node positive disease were identified. Patients who underwent palliative cystectomy, had histological diagnoses other than pure urothelial carcinoma, or received adjuvant radiotherapy were excluded from the study. Immunohistochemical staining for EGFR expression was performed on archived bladder specimens. The following in vitro functional analyses were performed to study the relationship of EGFR expression and chemoresponse.

Results

The study included 58 patients, among which the mean age was 57 years old. Majority of patients had node positive disease (n = 53, 91%). Mean follow up was 26.61 months. EGFR was overexpressed in 25 cystectomy specimens (43%). Kaplan-Meier analysis revealed that EGFR over-expression significantly correlated with disease recurrence (p = 0.021). Cox proportional hazard modeling identified EGFR overexpression as an independent predictor for disease recurrence (p = 0.04). Furthermore, in vitro experiments demonstrated that inhibition of EGFR may sensitize cellular responses to cisplatin.

Conclusions

Our findings suggest that EGFR overexpression is associated with disease recurrence following adjuvant chemotherapy for advanced BC. This may aid in patient prognostication and selection prior to chemotherapeutic treatment for BC.
Literature
1.
go back to reference Antoni S, Ferlay J, Soerjomataram I, Znaor A, Jemal A, Bray F. Bladder Cancer incidence and mortality: a global overview and recent trends. Eur Urol. 2017;71(1):96–108.CrossRef Antoni S, Ferlay J, Soerjomataram I, Znaor A, Jemal A, Bray F. Bladder Cancer incidence and mortality: a global overview and recent trends. Eur Urol. 2017;71(1):96–108.CrossRef
2.
go back to reference Kamat AM, Hahn NM, Efstathiou JA, Lerner SP, Malmstrom PU, Choi W, Guo CC, Lotan Y, Kassouf W. Bladder cancer. Lancet. 2016;388(10061):2796–810.CrossRef Kamat AM, Hahn NM, Efstathiou JA, Lerner SP, Malmstrom PU, Choi W, Guo CC, Lotan Y, Kassouf W. Bladder cancer. Lancet. 2016;388(10061):2796–810.CrossRef
3.
go back to reference Kaplan AL, Litwin MS, Chamie K. The future of bladder cancer care in the USA. Nature reviews Urology. 2014;11(1):59–62.CrossRef Kaplan AL, Litwin MS, Chamie K. The future of bladder cancer care in the USA. Nature reviews Urology. 2014;11(1):59–62.CrossRef
4.
go back to reference Mahdavifar N, Ghoncheh M, Pakzad R, Momenimovahed Z, Salehiniya H. Epidemiology, incidence and mortality of bladder cancer and their relationship with the development index in the world. Asian Pac J Cancer Prev. 2016;17(1):381–6.CrossRef Mahdavifar N, Ghoncheh M, Pakzad R, Momenimovahed Z, Salehiniya H. Epidemiology, incidence and mortality of bladder cancer and their relationship with the development index in the world. Asian Pac J Cancer Prev. 2016;17(1):381–6.CrossRef
5.
go back to reference Ibrahim AS, Khaled HM, Mikhail NN, Baraka H, Kamel H. Cancer incidence in Egypt: results of the national population-based cancer registry program. J Cancer Epidemiol. 2014;2014:437971.CrossRef Ibrahim AS, Khaled HM, Mikhail NN, Baraka H, Kamel H. Cancer incidence in Egypt: results of the national population-based cancer registry program. J Cancer Epidemiol. 2014;2014:437971.CrossRef
6.
go back to reference Zaghloul MS, Nouh A, Moneer M, El-Baradie M, Nazmy M, Younis A. Time-trend in epidemiological and pathological features of schistosoma-associated bladder cancer. J Egyp Natl Cancer Inst. 2008;20(2):168–74. Zaghloul MS, Nouh A, Moneer M, El-Baradie M, Nazmy M, Younis A. Time-trend in epidemiological and pathological features of schistosoma-associated bladder cancer. J Egyp Natl Cancer Inst. 2008;20(2):168–74.
7.
go back to reference Mostafa MH, Sheweita SA, O'Connor PJ. Relationship between schistosomiasis and bladder cancer. Clin Microbiol Rev. 1999;12(1):97–111.CrossRef Mostafa MH, Sheweita SA, O'Connor PJ. Relationship between schistosomiasis and bladder cancer. Clin Microbiol Rev. 1999;12(1):97–111.CrossRef
8.
go back to reference Ghoneim MA, Abdel-Latif M, el-Mekresh M, Abol-Enein H, Mosbah A, Ashamallah A, el-Baz MA. Radical cystectomy for carcinoma of the bladder: 2,720 consecutive cases 5 years later. J Urol. 2008;180(1):121–7.CrossRef Ghoneim MA, Abdel-Latif M, el-Mekresh M, Abol-Enein H, Mosbah A, Ashamallah A, el-Baz MA. Radical cystectomy for carcinoma of the bladder: 2,720 consecutive cases 5 years later. J Urol. 2008;180(1):121–7.CrossRef
9.
go back to reference Grossman HB, Natale RB, Tangen CM, Speights VO, Vogelzang NJ, Trump DL, deVere White RW, Sarosdy MF, Wood DP Jr, Raghavan D, et al. Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med. 2003;349(9):859–66.CrossRef Grossman HB, Natale RB, Tangen CM, Speights VO, Vogelzang NJ, Trump DL, deVere White RW, Sarosdy MF, Wood DP Jr, Raghavan D, et al. Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med. 2003;349(9):859–66.CrossRef
10.
go back to reference Mansour AM, Soloway MS, Eldefrawy A, Singal R, Joshi S, Manoharan M. Prognostic significance of cystoscopy findings following neoadjuvant chemotherapy for muscle-invasive bladder cancer. Can J Urol. 2015;22(2):7690–7.PubMed Mansour AM, Soloway MS, Eldefrawy A, Singal R, Joshi S, Manoharan M. Prognostic significance of cystoscopy findings following neoadjuvant chemotherapy for muscle-invasive bladder cancer. Can J Urol. 2015;22(2):7690–7.PubMed
11.
go back to reference Rosenblatt R, Sherif A, Rintala E, Wahlqvist R, Ullen A, Nilsson S, Malmstrom PU, Nordic Urothelial Cancer G. Pathologic downstaging is a surrogate marker for efficacy and increased survival following neoadjuvant chemotherapy and radical cystectomy for muscle-invasive urothelial bladder cancer. Eur Urol. 2012;61(6):1229–38.CrossRef Rosenblatt R, Sherif A, Rintala E, Wahlqvist R, Ullen A, Nilsson S, Malmstrom PU, Nordic Urothelial Cancer G. Pathologic downstaging is a surrogate marker for efficacy and increased survival following neoadjuvant chemotherapy and radical cystectomy for muscle-invasive urothelial bladder cancer. Eur Urol. 2012;61(6):1229–38.CrossRef
12.
go back to reference Black PC, Dinney CP. Growth factors and receptors as prognostic markers in urothelial carcinoma. Curr Urol Rep. 2008;9(1):55–61.CrossRef Black PC, Dinney CP. Growth factors and receptors as prognostic markers in urothelial carcinoma. Curr Urol Rep. 2008;9(1):55–61.CrossRef
13.
go back to reference Abbosh PH, McConkey DJ, Plimack ER. Targeting signaling transduction pathways in bladder Cancer. Curr Oncol Rep. 2015;17(12):58.CrossRef Abbosh PH, McConkey DJ, Plimack ER. Targeting signaling transduction pathways in bladder Cancer. Curr Oncol Rep. 2015;17(12):58.CrossRef
14.
go back to reference van Kessel KE, Zuiverloon TC, Alberts AR, Boormans JL, Zwarthoff EC. Targeted therapies in bladder cancer: an overview of in vivo research. Nature Rev Urol. 2015;12(12):681–94.CrossRef van Kessel KE, Zuiverloon TC, Alberts AR, Boormans JL, Zwarthoff EC. Targeted therapies in bladder cancer: an overview of in vivo research. Nature Rev Urol. 2015;12(12):681–94.CrossRef
15.
go back to reference Lee HH, Wang YN, Hung MC. Non-canonical signaling mode of the epidermal growth factor receptor family. Am J Cancer Res. 2015;5(10):2944–58.PubMedPubMedCentral Lee HH, Wang YN, Hung MC. Non-canonical signaling mode of the epidermal growth factor receptor family. Am J Cancer Res. 2015;5(10):2944–58.PubMedPubMedCentral
16.
go back to reference Tan X, Lambert PF, Rapraeger AC, Anderson RA. Stress-induced EGFR trafficking: mechanisms, functions, and therapeutic implications. Trends Cell Biol. 2016;26(5):352–66.CrossRef Tan X, Lambert PF, Rapraeger AC, Anderson RA. Stress-induced EGFR trafficking: mechanisms, functions, and therapeutic implications. Trends Cell Biol. 2016;26(5):352–66.CrossRef
17.
go back to reference Kim WT, Kim J, Yan C, Jeong P, Choi SY, Lee OJ, Chae YB, Yun SJ, Lee SC, Kim WJ. S100A9 and EGFR gene signatures predict disease progression in muscle invasive bladder cancer patients after chemotherapy. Ann Oncol. 2014;25(5):974–9.CrossRef Kim WT, Kim J, Yan C, Jeong P, Choi SY, Lee OJ, Chae YB, Yun SJ, Lee SC, Kim WJ. S100A9 and EGFR gene signatures predict disease progression in muscle invasive bladder cancer patients after chemotherapy. Ann Oncol. 2014;25(5):974–9.CrossRef
18.
go back to reference Symanowski JT, Kim ES. Gene expression and prognosis in bladder cancer--real progress? Editorial on 'S100A9 and EGFR gene signatures predict disease progression in muscle invasive bladder cancer patients after chemotherapy. Ann Oncol. 2014;25(5):919–20.CrossRef Symanowski JT, Kim ES. Gene expression and prognosis in bladder cancer--real progress? Editorial on 'S100A9 and EGFR gene signatures predict disease progression in muscle invasive bladder cancer patients after chemotherapy. Ann Oncol. 2014;25(5):919–20.CrossRef
19.
go back to reference 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. Nature Rev Urol. 2014;11(7):400–10.CrossRef 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. Nature Rev Urol. 2014;11(7):400–10.CrossRef
20.
go back to reference Shah JB, McConkey DJ, Dinney CP. New strategies in muscle-invasive bladder cancer: on the road to personalized medicine. Clin Cancer Res. 2011;17(9):2608–12.CrossRef Shah JB, McConkey DJ, Dinney CP. New strategies in muscle-invasive bladder cancer: on the road to personalized medicine. Clin Cancer Res. 2011;17(9):2608–12.CrossRef
21.
go back to reference Bladder cancers respond to EGFR inhibitors. Cancer discovery. 2014, 4(9):980–981. Bladder cancers respond to EGFR inhibitors. Cancer discovery. 2014, 4(9):980–981.
22.
go back to reference Rebouissou S, Bernard-Pierrot I, de Reynies A, Lepage ML, Krucker C, Chapeaublanc E, Herault A, Kamoun A, Caillault A, Letouze E, et al. EGFR as a potential therapeutic target for a subset of muscle-invasive bladder cancers presenting a basal-like phenotype. Sci Transl Med. 2014;6(244):244ra291.CrossRef Rebouissou S, Bernard-Pierrot I, de Reynies A, Lepage ML, Krucker C, Chapeaublanc E, Herault A, Kamoun A, Caillault A, Letouze E, et al. EGFR as a potential therapeutic target for a subset of muscle-invasive bladder cancers presenting a basal-like phenotype. Sci Transl Med. 2014;6(244):244ra291.CrossRef
Metadata
Title
Epidermal growth factor expression as a predictor of chemotherapeutic resistance in muscle-invasive bladder cancer
Authors
Ahmed M. Mansour
Mona Abdelrahim
Mahmoud Laymon
Mamdouh Elsherbeeny
Mohammed Sultan
Ahmed Shokeir
Ahmed Mosbah
Hassan Abol-Enein
Amira Awadalla
Eunho Cho
Vikram Sairam
Taeeun D. Park
Muhammad Shahid
Jayoung Kim
Publication date
01-12-2018
Publisher
BioMed Central
Published in
BMC Urology / Issue 1/2018
Electronic ISSN: 1471-2490
DOI
https://doi.org/10.1186/s12894-018-0413-9

Other articles of this Issue 1/2018

BMC Urology 1/2018 Go to the issue