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Title: Reply from Authors re: Leah Gerber, Lionel L. Bañez, Stephen J. Freeland. Defining and Treating High-Risk Prostate Cancer: Can We Do Better? Eur Urol 2010;58:8-9
Other Titles: Platinum Priority
Authors: Spahn, Martin ×
Joniau, Steven
Kneitz, Burkhard
Gontero, Paolo
Van Poppel, Hendrik #
Issue Date: Jul-2010
Publisher: Elsevier Science
Series Title: European Urology vol:58 issue:1 pages:10-11
Conference: Meeting of the EAU Section of Oncological Urology edition:8 location:London (GB) date:21-23 January 2011
Abstract: We thank Gerber et al for the editorial underlining the relevance of surgery in the treatment of high-risk prostate cancer (PCa) [1].

PCa is the most frequent cancer of the male population. In Europe, the number of newly diagnosed cases increased from 145 000 in 1996 to 345 000 in 2006 [2] and [3]. Despite this dramatic increase, the number of deaths attributed to the disease over the same time period remained almost unchanged (75 000 in 1996 vs 68 000 in 2006) [2] and [3]. The current inability to accurately distinguish the risk of life-threatening, aggressive PCa from indolent cases contributes to the dilemma. The identification of factors specifically associated with the risk of more aggressive PCa is urgently needed in order to reduce overtreatment and develop more effective targeted therapies. Considering the ageing of the European population, this issue is of particular importance.

Research energy should be focused on further stratifying PCa according to risk of progression following local therapy. This stratification can be done in the “classical” way using either preoperative (prostate-specific antigen [PSA], stage, and grade) or postoperative parameters (stage, lymph node, and margin status). Our results indicate heterogeneous outcomes after surgery for a group of patients with PSA values >20 ng/ml. When using an intuitive stratification method, incorporating additional preoperative high-risk factors (cT3 and/or Gleason score >8) more accurate risk stratification is evident. This tool might be useful for urologists in managing high-risk PCa patients. However, such risk stratification inherently misclassifies a number of patients and thus is still far away from personalised treatment. We absolutely agree with Gerber et al that a better understanding of the marked disparity between the biological behaviours—which varies from an indolent disease that might not cause symptoms during a patient's lifetime to a highly aggressive cancer that metastasises quickly and causes severe pain and untimely death—is urgently needed. To come to a more accurate risk stratification for prostate cancer, several potential prognostic markers, including mRNA-based gene expression signatures, have been identified over the years [4]. Unfortunately, such molecular genetic approaches have had only limited success up to now. One reason for these poor results is related to the patient cohorts used for such analysis. One of the principal limitations of working with human material concerns the nature of the tissue itself.

The identification of reliable prognostic factors might be more complicated or even impossible when using contemporary surgical series, which usually include only low- and intermediate-risk PCa which represent tumours associated with <5% risk of tumour-related death at 10 yr, even with conservative treatment [5]. However, as shown in our paper, even in a high-risk population, the risk of metastatic disease and cancer-related death varies significantly and is lower than expected initially [6]. To overcome this problem and to enhance the number of tumour samples, we initiated a European multicenter study on surgically treated high-risk PCa that we used for our published study [6]. In addition, we are now able to search for new molecular risk factors and to translate the biological role of these factors into the clinic. To do so, we are now focussing a new class of regulatory molecules known as microRNAs (miRNA) [7]. Various alterations in miRNA expression have been detected in malignant tissues and functional studies and have shown that miRNAs might act as either tumour suppressors or oncogenes (onco-miRNAs) through post-transcriptional regulation of target mRNAs [8]. Previous expression studies have shown the presence of characteristic miRNA signatures in PCa [9] and [10]. Our recent research has revealed a specific pattern of dysregulated miRNAs in high-risk PCa (eg, microRNA-221) that is associated with tumour progression, poor prognosis, and the development of metastasis [11]. In addition, we have recent unpublished evidence that miR-221 regulates the growth of prostate carcinoma cells by modulating a proliferative pathway. Using our model systems, we are in the process of determining whether the modulation of this pathway by miR-221 could provide a new therapeutic strategy for PCa.

A final point that must be kept in mind is that such research is strongly based on clinical data. Especially, sufficient follow-up is necessary and should not only focus on PSA relapse rates but also on clinical progression and survival. The prognostic relevance of molecular markers must be compared with the traditionally used clinical parameters to show improvements either as a single-outcome predictor or in combination with these. We are currently focusing on surgically treated patients, but such translational research should not be limited to surgical treatment. Similar analysis should also focus on irradiated and conservatively treated patients. Based on such information, it might not only be possible in the future to predict the personal risk for PCa progression and cancer related death, but it might also be possible to choose the best therapeutic strategy for each individual patient.
URI: 
ISSN: 0302-2838
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Urology Section (-)
× corresponding author
# (joint) last author

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