p53 and RB: Simple Interesting Correlates or Tumor Markers of Critical Predictive Nature? (2004)

Compared with the established phases a new drug must go through before regulatory approval and acceptance as part of a new standard of care, the course that brings a novel laboratory assay from discovery to clinical implementation has not been well delineated. This is particularly true when the assay is performed on tissue samples, and when it is aimed at identifying a predictive molecular marker. The National Cancer Institute, after several meetings on characterization of tumor markers and their clinical applications, recommended a strategy delineating the full development of biologic determinants (Fig 1) [1,2]. The process is based on clinical trial methodology and is guided by statistical rigor. Briefly, biologic markers of potential diagnostic or predictive value are first examined in a phase I stage consisting of pilot studies. In this initial step, intended to establish a robust assay, methods are tested using clinical material for assessment of the alteration of the marker in human normal and tumor samples. In this phase, cut points, if needed, are established in order to have a more reliable quantitative or semiquantitative method for interpretation of results. Once the assay is sufficiently robust, retrospective phase II studies using well-characterized clinical samples are conducted to assess the marker’s potential clinical value. These studies are then followed by phase III prospective confirmatory evaluations using large cohorts of patients, and then by phase IV validation studies open to multiple institutions in the context of a clinical trial (Fig 1). Numerous studies from different institutions and collaborative efforts have suggested the potential clinical relevance of detecting altered patterns of expression or mutations affecting TP53 and RB (the two prototype tumor suppressor genes) in bladder tumors [3-10]. More recently, several studies have extended these analyses to certain genes participating in their signaling pathways, such as Hdm2 (human homologue of the murine mdm2) and p21 for p53, and p16 for RB [11-13]. In this issue of the Journal of Clinical Oncology, Chatterjee et al [14] and Shariat et al [15] report confirmatory results using well-characterized cohorts of bladder cancer patients from whom appropriate clinicopathological variables and long follow-up times were available. More specifically, Chatterjee et al examined altered expression patterns of p53, p21, and pRB by immunohistochemistry (IHC) on tissue sections from 164 patients with invasive or high-grade recurrent superficial transitional cell carcinomas, with a median follow-up of 8.6 years [14]. As individual determinants, all three markers were independent predictors of time to recurrence and overall survival. Examined in combination after stratifying by stage, the number of altered proteins remained significantly correlated with both time to recurrence and overall survival. These investigators concluded that altered levels of the gene products studied have negative cooperative effects, promoting bladder cancer progression. Shariat et al analyzed altered expression of p53, p21, pRB, and p16 by IHC on tissue sections from 80 patients who underwent radical cystectomy and bilateral pelvic lymphadenectomy for bladder cancer, with a median follow-up of 101 months [15]. Al-