Research Article| Volume 235, P77-84, September 2021

Download started.


Combination of biomarkers for neoadjuvant systemic chemotherapy before cystectomy in patients with urinary bladder cancer

Published:March 21, 2021DOI:
      Clinical utility of cisplatin based neoadjuvant chemotherapy (NAC) prior to radical cystectomy is limited because of lack of tools that can guide for a better patient selection. We aim to explore if a combination of biomarkers is superior to a single marker. Pretreatment tumor specimens and clinical data from two randomized trials including 250 patients with T2-T4 urothelial bladder cancer, were used. The information on the expressions on tumor tissue of four biomarkers; CCTα, emmprin, survivin, and BCL-2, detected by immunohistochemistry in our previous studies, was used. Cox proportional hazard models, including treatment-by-biomarker interaction terms, were used to assess the predictive value of the biomarkers for efficacy of NAC on overall survival. CCTα provided predictive information about the efficacy of NAC (interaction P=0.009). None of the other biomarkers provided statistically significant information additional to CCTα. The adjusted hazard ratio for NAC treated versus no-NAC was 0.42 (95% CI: 0.27-0.64) for patients with negative CCTα expression, when adding information about emmprin it decreased to 0.33 (95% CI: 0.19-0.56) for patients with both negative CCTα and emmprin. This corresponds to a decrease in number needed to treat from 4 to 3 patients. The combination of CCTα with survivin or BCL-2 yielded similar results. In a group of patients with muscle invasive bladder cancer a combination of two biomarkers might improve the possibility to identify patients most likely to benefit from the use of NAC. Further studies designed to have sufficient power to detect an interaction effect are needed.


      NAC (Neoadjuvant Cisplatin-based chemotherapy), CCTα (phosphate cytidylyltransferase 1 choline alpha.)
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Translational Research
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Advanced Bladder Cancer Meta-Analysis Collaboration
        Neoadjuvant chemotherapy in invasive bladder cancer: a systematic review and meta-analysis.
        Lancet. 2003; 361: 1927
        • Sherif A
        • Holmberg L
        • Rintala E
        • et al.
        Neoadjuvant cisplatinum based combination chemotherapy in patients with invasive bladder cancer: a combined analysis of two Nordic studies.
        Eur Urol. 2004; 45: 297
        • Burger M
        • Mulders P
        • Witjes W
        Use of neoadjuvant chemotherapy for muscle-invasive bladder cancer is low among major European centers: results of a feasibility questionnaire.
        Eur Urol. 2012; 61: 1070
        • Als AB
        • Dyrskjøt L
        • von der Maase H
        • et al.
        Emmprin and survivin predict response and survival following cisplatin-containing chemotherapy in patients with advanced bladder cancer.
        Clin Cancer Res. 2007; 13: 4407
      1. Kiss B, Skuginna V, Fleischmann A, et al: Bcl-2 predicts response to neoadjuvant chemotherapy and is overexpressed in lymph node metastases of urothelial cancer of the bladder. Urol Oncol 33:166 e1-8, 201.

        • Hemdan T
        • Malmstrom PU
        • Jahnson S
        • et al.
        Emmprin expression predicts response and survival following cisplatin containing chemotherapy for bladder cancer: a validation study.
        J Urol. 2015; 194: 1575-1581
        • Turker P
        • Segersten U
        • Malmström PU
        • et al.
        Is Bcl-2 a predictive marker of neoadjuvant chemotherapy response in patients with urothelial bladder cancer undergoing radical cystectomy?.
        Scand J Urol. 2019; 53: 45-50
        • Bhagwat NR
        • Roginskaya VY
        • Acquafondata MB
        • et al.
        Immunodetection of DNA repair endonuclease ERCC1-XPF in human tissue.
        Cancer Res. 2009; 69: 6831-6838
        • Vaezi AE
        • Bepler G
        • Bhagwat NR
        • et al.
        Choline phosphate cytidylyltransferase-a is a novel antigen detected by the anti-ERCC1 antibody 8F1 with biomarker value in patients with lung and head and neck squamous cell carcinomas.
        Cancer. 2014; 120: 1898-1907
        • Hemdan T
        • Turker P
        • Malmström PU
        • et al.
        Choline-phosphate cytidylyltransferase-α as a possible predictor of survival and response to cisplatin neoadjuvant chemotherapy in urothelial cancer of the bladder.
        Scand J Urol. 2018; 52: 200-205
        • Segersten MU
        • Edlund EK
        • Micke P
        • et al.
        A novel strategy based on histological protein profiling in-silico for identifying potential biomarkers in urinary bladder cancer.
        BJU Int. 2009; 104: 1780-1785
        • Kent C.
        CTP:phosphocholine cytidylyltransferase.
        Biochim Biophys Acta. 1997; 1348: 79-90
        • Glunde K
        • Bhujwalla ZM
        • Ronen SM.
        Choline metabolism in malignant transformation.
        Nat Rev Cancer. 2011; 11: 835-848
        • Sugimoto H
        • Banchio C
        • Vance DE.
        Transcriptional regulation of phosphatidylcholine biosynthesis.
        Prog Lipid Res. 2008; 47: 204-220
        • Xin X
        • Zeng X
        • Gu H
        • et al.
        CD147/EMMPRIN overexpression and prognosis in cancer: a systematic review and meta-analysis.
        Sci Rep. 2016; 6: 32804
        • Misra S
        • Ghatak S
        • Zoltan-Jones A
        • et al.
        Regulation of multidrug resistance in cancer cells by hyaluronan.
        J Biol Chem. 2003; 278 (25285 8)
        • Ghatak S
        • Misra S
        • Toole BP.
        Hyaluronan constitutively regulates ErbB2 phosphorylation and signaling complex formation in carcinoma cells.
        J Biol Chem. 2005; 280: 8875-8883
        • Misra S
        • Ghatak S
        • Toole BP.
        Regulation of MDR1 expression and drug resistance by a positive feedback loop involving hyaluronan, phosphoinositide 3-kinase, and ErbB2.
        J Biol Chem. 2005; 280: 20310-20315
        • Qin Z
        • Dai L
        • Bratoeva M
        • et al.
        Cooperative roles for emmprin and LYVE-1 in the regulation of chemoresistance for primary effusion lymphoma.
        Leukemia. 2011; 25: 1598-1609
        • Toole BP.
        The CD147-hyaluran axis in cancer.
        Anat Rec. 2020; 303: 1573-1583
        • Tse J
        • Ghandour R
        • Singla N
        • et al.
        Molecular predictors of complete response following neoadjuvant chemotherapy in urothelial carcinoma of the bladder and upper tracts.
        Int J Mol Sci. 2019; 20: 793
        • Kunze D
        • Erdmann K
        • Froehner M
        • et al.
        Sirna-mediated inhibition of antiapoptotic genes enhances chemotherapy efficacy in bladder cancer cells.
        Anticancer Res. 2012; 32: 4313-4318
        • Vale CL.
        Neoadjuvant chemotherapy in invasive bladder cancer: update of a systematic review and meta-analysis of individual patient data: advanced bladder cancer (ABC) meta-analysis collaboration.
        Eur Urol. 2005; 48: 202-206