Urologic Oncology: Seminars and Original Investigations
Original articlep53-expression in patients with renal cell carcinoma correlates with a higher probability of disease progression and increased cancer-specific mortality after surgery but does not enhance the predictive accuracy of robust outcome models
Introduction
Renal cell carcinoma (RCC) accounts for approximately 2% to 3% of adult cancers [1], [2]. Despite a generally curative approach by radical or partial nephrectomy in patients diagnosed with localized or locally advanced tumors (T1–4, N0–1, and M0), about 20% to 30% develop metastasis during follow-up and up to decades after primary surgery [3], [4], [5]. As level 1 evidence for improvement of overall survival is lacking, current guidelines do not recommend adjuvant therapy after surgery; consequently, a well-structured follow-up to detect recurrence or progression at an early timepoint is vital [6].
High recurrence rates highlight the need for risk-stratification of patients at the time of primary surgery allowing for individual regimes with close follow-up and application of adjuvant treatment options in clinical studies for high-risk patients and less stringent schedules for patients at low risk of recurrence.
To identify reliable prognostic markers aside from clinical, anatomical, and histo-pathological parameters, molecular factors such as vascular endothelial growth factor (VEGF) or tumor suppressor gene p53 have been evaluated in recent years and moved into the spotlight as potentially relevant prognostic factors [7]. For surgically treated RCC patients, the prognostic impact of various molecular markers, mainly for the endpoint disease progression (DP) and cancer-specific mortality (CSM), has been evaluated. However, international guidelines do not endorse risk-stratification by molecular factors yet due to missing confirmation by external validation, and implementation in clinical routine is not established [8]. In 2009, Klatte et al. [9] developed a nomogram including several molecular factors such as p53 or Ki-67 based on 170 surgically treated RCC patients aiming to forecast disease-free survival (DFS). In the development cohort, a predictive accuracy (PA) of 90.4% could be accomplished for stratifying patients into a low, intermediate, and high-risk group with significantly distinct DFS estimates. As external validation is lacking, the aim of the present study was to validate for the first time the molecular marker panel applied in this nomogram on a contemporary external study cohort of 343 surgically treated RCC patients with clinically localized disease [9].
Section snippets
Patient selection, clinicopathological characteristics, and nomogram composition
The primary validation study cohort comprised 393 consecutive patients diagnosed with clinically localized (N0M0) RCC, who underwent surgery from 1999 to 2004 at a single academic center (Department of Urology, University of Regensburg). In accordance to the original development cohort, 40 patients categorized as c/pN+ and/or c/pM1 and additional 10 patients with failed immunohistochemical staining were excluded from the cohort [9]. The final validation cohort included 343 patients.
The
Results
Table 1 displays clinical and pathological criteria of the study cohort. The final study cohort comprised 211 men (61.5%) and 132 women (38.5%) with a median age of 64 years (range: 56–71). A total of 308 patients (89.8%) had an ECOG-PS of 0. In total, 247 patients were categorized as pT1, 31 as pT2, 64 as pT3, and 1 as pT4. The median follow-up of the study group was 100 months (interquartile range [IQR]: 81.5–120.6 months).
Results of the multivariable analysis for DP and CSM adjusted for
Discussion
The present study represents the first external validation of the molecular marker panel included in a nomogram developed by Klatte et al. [9] to predict DP for surgically treated RCC patients. In the validation cohort of 343 RCC patients CSM was evaluated as additional endpoint besides DP. Based on the validation analysis, with exception of p53 (HR = 1.31; P = 0.008) and in contrast to the findings by Klatte et al. [9] we were not able to confirm the independent impact of molecular markers
Conclusions
Besides a potential impact of p53 on DP, we could not confirm the independent prognostic value of the validated molecular markers. p53-expression had a significant impact on DP and CSM when applied with a cut-off of 20% in 2 optimized models, while the models’ PAs were not significantly enhanced. Hence, clinical implications for applying p53-expression for risk-stratification of surgically treated RCC patients are yet to be determined.
Acknowledgment
We thank Stephanie Kraus and Valentina Wenzel for their support.
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The induction of AMPK-dependent autophagy leads to P53 degradation and affects cell growth and migration in kidney cancer cells
2020, Experimental Cell ResearchCitation Excerpt :In this regard, interventions aimed at restoration of p53 expression by using MDM2-proteasome inhibitors showed encouraging results in pre-clinical models and have been approved for clinical trials in different tumors [35]. However, the role of p53 in kidney cancer remains unclear and is still debated, because the overexpression of this tumor suppressor may be associated with poor prognosis [36]. This apparent paradox could be due to the acquisition of sequential mutations of TP53 gene in cancer cells during tumorigenesis, which may generate oncogenic peptides, contributing to cancer development and progression [37].
BioScore (B7-H1, survivin, and Ki-67) does not predict cancer-specific mortality in surgically treated patients with renal cell carcinoma: An external validation study
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- 1
Laura Morshaeuser and Matthias May contributed equally to first authorship.
- 2
Lorenz Buser and Sabine Brookman-May contributed equally to senior authorship.