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