Original article
p53-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

https://doi.org/10.1016/j.urolonc.2017.11.011Get rights and content

Highlights

  • p53 independently impacted disease progression when using the 10% nomogram cut-off.

  • The prognostic value of all other nomogram markers could not be confirmed.

  • Using a 20% cut-off, p53 impacted tumor progression and cancer-specific mortality.

  • However, the predictive accuracy of multivariable models was not enhanced by p53.

  • Hence, it is not recommendable yet to use p53 for routine decision-making.

Abstract

Objective

Due to lacking external validation, molecular biomarkers are currently not applied for risk-stratification of patients with localized renal cell carcinoma. The objective of this study was to externally validate a molecular multi-marker panel included in a previously proposed prognostic nomogram for the prediction of postoperative disease-free survival.

Methods and materials

Besides pathologic tumor stage (pT) and ECOG-Performance Status, the nomogram includes 5 molecular markers (Ki-67, p53, VEGFR-1 endothelial or epithelial, and VEGF-D epithelial). The validation cohort comprised 343 renal cell carcinoma patients treated by radical nephrectomy or nephron-sparing surgery from 1999 to 2004 at a single academic center (median follow-up: 100 months). By multivariable Cox proportional-hazards regression models, the impact of clinical and molecular markers included in the nomogram on disease progression (DP) and cancer-specific mortality (CSM) was assessed; in addition, it was evaluated to what extent molecular markers added to the models’ predictive accuracy (PA).

Results

Of all parameters included in the nomogram, ECOG-PS and pT-stage only revealed a significant impact on both endpoints. p53 (per 10% measures) showed a significant impact on DP (HR = 1.31; P = 0.008), albeit not on CSM, while all other molecular markers did not impact study endpoints. Using Martingale residuals, a cut-off value for p53-expression<20% (negative) vs. ≥20% (positive) yielded the highest impact on DP and CSM. In outcome-models including further well-established histo-pathological factors, p53-expression dichotomized at 20% independently impacted DP (HR = 4.13; P = 0.004) and CSM (HR = 3.74; P = 0.033), while no significant PA gain was achieved.

Conclusions

p53 showed a statistically significant impact on DP, albeit not on CSM, when applying the 10% expression cut-off as used in the original nomogram, while the prognostic value of all other examined markers included in the nomogram could not be confirmed. When an alternative cut-off of 20% was applied in multivariable models, p53 independently impacted DP and CSM, while the PA was not significantly enhanced. Hence, the clinical significance of p53 is still to be determined. Based on the results of this study it is not recommendable to use p53-expression and the Klatte nomogram in routine clinical decision-making.

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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    1

    Laura Morshaeuser and Matthias May contributed equally to first authorship.

    2

    Lorenz Buser and Sabine Brookman-May contributed equally to senior authorship.

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