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Originally published as JCO Early Release 10.1200/JCO.2004.12.994 on February 23 2004 © 2004 American Society of Clinical Oncology.
p53 and RB: Simple Interesting Correlates or Tumor Markers of Critical Predictive Nature?Memorial Sloan-Kettering Cancer Center, New York, NY 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]. Altered expression of each marker seemed independently associated with disease progression and disease-specific survival. These investigators also found that the incremental number of altered markers was independently associated with an increased risk of bladder cancer progression and mortality, and p53 was the strongest molecular predictor in their study. According to the National Cancer Institute scheme outlined above, these studies could be considered phase III confirmatory analyses, since in previous reports these research groups had already established IHC methods for the detection of altered expression of the evaluated markers, set up cutoff points for their interpretation, and conducted retrospective studies to determine their predictive value. The next step is the design and implementation of a multi-institutional clinical trial to validate the clinical significance of p53 and pRB, and to bring such determinations to the clinical arena to better manage the bladder cancer patient. But what is the biologic relevance of identifying altered patterns of p53 and pRB expression, along with altered expression levels of other genes in these pathways? Growth control in mammalian cells is accomplished largely by the action of pRB, regulating exit from the G1 phase of the cell division cycle, and the p53 protein, triggering apoptosis or G1 checkpoint arrest in response to cellular stress (Fig 2) [16]. The critical activities of pRB require stringent positive and negative multilevel regulation by other factors, such as cyclin D1 and p16. Similarly, levels of p53 are tightly regulated by Hdm2, an oncoprotein that binds to p53, repressing its activity and triggering its degradation. So, while pRB is the critical regulator of the cell growth, the main function of p53 is the activation of apoptotic signals. In neoplastic diseases, including bladder cancer, pRB and p53 are frequently altered. The mechanistic basis for this dual inactivation stems, in part, from the need of inhibiting a p53-dependent cell suicide program that would normally be triggered in response to unchecked cellular proliferation resulting from pRB-deficiency [17]. Moreover, tumor cells that eradicate apoptotic responses are likely to be deficient in mechanisms of cell killing, such as those imposed by treatment modalities, such as certain chemotherapeutic regimens.
Thus when could be of clinical value the identification of p53 and pRB alterations for patients with bladder cancer. Superficial bladder tumors (stages Ta, Tis, and T1) account for 75% to 85% of neoplasms at the time of presentation. Over 70% of patients affected with these early lesions will have one or more recurrences after initial treatment, and about one-third of those patients will progress and eventually succumb to their disease. Alterations of p53 and pRB could assist in identifying patients presenting with "high-risk" superficial tumors likely to develop invasive carcinoma for whom an aggressive intervention would be indicated. This means that certain patients could be spared from radical cystectomy. The remaining 15% to 25% of bladder cancer patients at clinical presentation have already invasive (T2, T3, T4) or metastatic lesions. For this group of individuals, despite aggressive surgical resection and adjuvant radiotherapy and/or chemotherapy, the overall cure remains in the range of 20% to 50%. Aberrant levels of p53 and pRB may contribute in categorizing advanced bladder cancer patients that will fail conventional treatment approaches for whom alternative or novel therapies could be of benefit. Clinical protocols based on the integration of conventional clinical and anatomic information with molecular approaches, should be further supported and implemented. The ultimate goal of any translational program is to bring basic discoveries regarding mechanisms of cancer development and progression to the clinic, with the objective of assisting in selecting individualized treatment regimens to give each patient a better chance for cure and a better quality of life. In this context, p53 and RB appear to be more than just interesting molecular correlates, but predictive biologic determinants whose integration into patient management through well-designed protocols should not be delayed. Author's Disclosures of Potential Conflicts of Interest The author indicated no potential conflicts of interest.
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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