Elsevier

European Urology

Volume 64, Issue 3, September 2013, Pages 465-471
European Urology

Bladder Cancer
Prospective Evaluation of a Molecular Marker Panel for Prediction of Recurrence and Cancer-specific Survival After Radical Cystectomy

https://doi.org/10.1016/j.eururo.2013.03.043Get rights and content

Abstract

Background

Retrospective studies demonstrated that cell cycle–related and proliferation biomarkers add information to standard pathologic tumor features after radical cystectomy (RC). There are no prospective studies validating the clinical utility of markers in bladder cancer.

Objective

To prospectively determine whether a panel of biomarkers could identify patients with urothelial carcinoma of the bladder (UCB) who were likely to experience disease recurrence or mortality.

Design, setting, and participants

Between January 2007 and January 2012, every patient with high-grade bladder cancer, including 216 patients treated with RC and lymphadenectomy, underwent immunohistochemical staining for tumor protein p53 (Tp53); cyclin-dependent kinase inhibitor 1A (p21, Cip1) (CDKN1A); cyclin-dependent kinase inhibitor 1B (p27, Kip1); antigen identified by monoclonal antibody Ki-67 (MKI67); and cyclin E1.

Intervention

Every patient underwent RC and lymphadenectomy, and marker staining.

Outcome measurements and statistical analysis

Cox regression analyses tested the ability of the number of altered biomarkers to predict recurrence or cancer-specific mortality (CSM).

Results and limitations

Pathologic stage among the study population was pT0 (5%), pT1 (35%), pT2 (19%), pT3 (29%), and pT4 (13%); lymphovascular invasion (LVI) was seen in 34%. The median number of removed lymph nodes was 23, and 60 patients had lymph node involvement (LNI). Median follow-up was 20 mo. Expression of p53, p21, p27, cyclin E1, and Ki-67 were altered in 54%, 26%, 46%, 15%, and 75% patients, respectively. In univariable analyses, pT stage, LNI, LVI, perioperative chemotherapy (CTx), margin status, and number of altered biomarkers predicted disease recurrence. In a multivariable model adjusting for pathologic stage, margins, LNI, and adjuvant CTx, only LVI and number of altered biomarkers were independent predictors of recurrence and CSM. The concordance index of a baseline model predicting CSM (including pathologic stage, margins, LVI, LNI, and adjuvant CTx) was 80% and improved to 83% with addition of the number of altered markers.

Conclusions

Molecular markers improve the prediction of recurrence and CSM after RC. They may identify patients who might benefit from additional treatments and closer surveillance after cystectomy.

Introduction

Urothelial carcinoma of the bladder (UCB) is the fifth most common cancer worldwide, with an estimated 73 510 cases and 14 880 deaths in the United States for 2012 [1]. Up to 75% of UCB patients are diagnosed with non–muscle-invasive (NMI) disease, most of which can be managed by transurethral resection (TUR) and intravesical therapy. However, ≤30% of patients with high-grade NMI UCB will eventually experience disease progression to muscle-invasive (MI) disease [2]. For these patients and the 25% of patients who present with primary MI UCB, radical cystectomy (RC) and bilateral lymphadenectomy with or without perioperative chemotherapy (CTx) represents the best chance for cure [3], [4], [5]. Unfortunately, >25% of patients classified as having favorable pathologic features such as pathologic stages pT1–pT3a without nodal involvement (pN0) at the time of RC experience disease recurrence within 5 yr of their surgery. These patients eventually develop metastasis and succumb to their disease [3], [4], [5].

This variability in outcomes among patients illustrates the inherent biologic and clinical heterogeneity of UCB. The American Joint Committee on Cancer (AJCC) TNM staging system, which currently guides UCB management, is limited in its ability to accurately predict an individuals’ risk of disease recurrence and/or UCB-specific mortality [6], [7]. Even the combination of clinical and pathologic variables in mathematical algorithms such as nomograms reaches discrimination for UCB recurrence of only 78% [6], [7].

Over the last decade, various investigators have shown that alterations in candidate protein expression profiles may help refine the understanding of the biologic and clinical behavior of UCB, thereby improving the risk stratification and clinical management of UCB patients [8]. The development of emerging biomarkers might be considered a highly regulated process that is conceptually similar to therapeutic drug evaluation [9].

Therefore, we have undertaken a phased, systematic evaluation and validation of a panel of established biomarkers (cyclin E1; tumor protein p53 [Tp53; formerly p53]; cyclin-dependent kinase inhibitor 1A [p21, Cip1] [CDKN1A; formerly p21]; cyclin-dependent kinase inhibitor 1B (p27, Kip1); and antigen identified by monoclonal antibody Ki-67 [MKI67; formerly Ki-67]) selected based on extensive clinical data supporting their importance in UCB progression and metastasis [10], [11], [12]. As part of this staged approach, we have established the potential of this panel for UCB prognostication in retrospective, single-institution studies and in large, multi-institutional studies [11], [13], [14], [15], [16].

In the next phase, we initiated a prospective protocol to test the prognostic value of these biomarkers through improved staging of patients with high-grade UCB undergoing RC. If the additive value of the biomarkers panel is confirmed in this prospective study, we plan to integrate this panel in the design of clinical trials of adjuvant therapies.

Section snippets

Materials and methods

All procedures described in the present study were undertaken with the approval and oversight of the Institutional Review Board for the Protection of Human Subjects. All patients were treated at University of Texas Southwestern Medical Center Dallas, TX, USA.

Demographics

The patient demographics are shown in Table 1. The median patient age was 70 yr with most being men (n = 192, 79%). Most patients’ cancers were in clinical stage cTa/Tis/T1 (n = 96, 44%) and cT2 (n = 85, 39%). After RC, there was a significant upstaging, with 27% at stage pT3 (n = 59) and 13% at pT4 (n = 28) when compared to clinical staging at time of TURBT. Concomitant carcinoma in situ was seen in 96 (44%) patients and LVI in 73 (34%). The median number of removed lymph nodes was 23 (interquartile

Discussion

The utility and importance of biomarkers has been recognized and biomarker discovery efforts are now common in both academic and industrial settings. Yet despite intensified interest and investment, few novel biomarkers are used in clinical practice [9]. The reasons for this disjunction are manifold and reflect the long and difficult pathway from candidate biomarker discovery to clinical assay, and the lack of coherent and comprehensive processes for biomarker development. The development of

Conclusions

Cell cycle–related and proliferation-related markers at time of cystectomy improve the prediction of recurrence and CSM after RC. Such a marker panel may help identify patients who might benefit from additional treatments and closer surveillance after cystectomy.

References (26)

  • P.I. Karakiewicz et al.

    Nomogram for predicting disease recurrence after radical cystectomy for transitional cell carcinoma of the bladder

    J Urol

    (2006)
  • B.H. Bochner et al.

    Postoperative nomogram predicting risk of recurrence after radical cystectomy for bladder cancer

    J Clin Oncol

    (2006)
  • C. Bolenz et al.

    Molecular biomarkers for urothelial carcinoma of the bladder: challenges in clinical use

    Nat Clin Pract Urol

    (2008)
  • Cited by (0)

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