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ESUR Lecture: Which biomarkers are ready to use in clinical practice?
13th Meeting of the EAU Section of Oncological Urology (ESOU)
ESUR Lecture: Which biomarkers are ready to use in clinical practice? Z. Culig, Innsbruck (AT) Prostate cancer biomarkers are subject of investigation in several areas; they could be used in studies on diagnostics, natural course of the disease, and response to therapy. Although prostate-specific antigen (PSA) has been used in diagnostics and monitoring prostate cancer therapy, there is a need to introduce other markers to facilitate clinical decision making. There are numerous attempts to improve use of diagnosis and therapy of prostate cancer with new biomarkers. However, a critical evaluation of these approaches will be presented. Although there are a large number of publications in that area, there is a problem with reproducibility and translation of data. A possible reason is that not all academical laboratories have implemented standard operating procedures for handling of serum, plasma, urinary and tissue samples. With progress in regulation of procedures associated with biobanking, one could expect that there could be an improvement with regard to general acceptance of data. Moreover, consensus conferences with regard to biomarkers in urological oncology may provide an answer to some of the key questions in the field. It is also notable that multiple genomic or proteomic studies have generated data which need to be confirmed in multiple laboratories. In this lecture there will be also a focus on some novel markers that could be used for therapy monitoring. The biomarkers discussed in the lecture are those related to signaling pathways of androgenic hormones and peptide growth factors. Numerous structural alterations have been discovered in androgen receptor (AR) in last decades. Some of these mutations are induced by anti-androgens and their presence may indicate unsatisfactory response with a specific drug. Screening for these mutations in tissue seems to be difficult because of heterogeneity of human prostate cancer. Importantly, constitutively active truncated AR have been described in advanced carcinoma of the prostate. Such receptors are activated even in the absence of androgen and their increased frequency may be a suitable marker for tumor progression. Most frequently, the researchers have investigated the role of the variant receptor AR V7 in prostate cancer. However, it should be mentioned that several questions regarding truncated constitutively active receptors have not been answered so far. It is not completely clear whether truncated AR activate the same transcriptional program as the wild-type receptor or not. Their determination in tissue may be important to judge potential responsiveness of an individual prostate cancer to therapy with abiraterone or enzalutamide. A specific biomarker for prostate cancer is ERG, whose fusion with TMPRSS2 is detectable in ca. 50% of tumors. In various experimental systems, ERG could stimulate proliferation, migration and invasion so that clinical pathological correlations that consider ERG are of high interest. Markers of epithelial to mesenchymal transition in prostate cancer are also of interest in order to determine potential responsiveness to therapy. Prostate cancers that develop resistance to chemotherapy may express low levels of E-cadherin, whereas the mesenchymal marker N-cadherin and vimentin may increase. In addition, such tumors may express high levels of stemness markers. Recently, the measurement of microRNA and long noncoding RNA in prostate cancer has been shown to be of some prognostic value. It was demonstrated that some long noncoding RNA are upregulated in prostate cancer. Several biomarker studies are focused on insulin-like growth factor (IGF) I and related proteins in malignant prostate disease. IGF is a growth factor that is implicated in inhibition of apoptosis in prostate cancer. Its biological activity is also determined by several binding proteins which could either inhibit or potentiate the action. IGF may bind to two receptors and the receptor type I is particularly important for transmission of growth factor signals in prostate cancer. The IGF/IGF receptor axis in prostate cancer is considered a valid therapy target. It has been reported that higher IGF-I levels in serum may indicate increased risk for prostate cancer. However, this finding was not confirmed by all authors and there are still open questions in relation to the usefulness of measurement of IGF and its binding proteins as prostate cancer biomarkers. The reasons for differences between results of different publications on this topic have not been clarified, however demographic and ethnic factors may also play a role. Single
13th Meeting of the EAU Section of Oncological Urology (ESOU)
nucleotide polymorphisms in the IGF pathway have also been associated with prostate cancer risk. The exact role of these polymorphism will be discussed in more detail. In summary, there is a discrepancy between a large number of data from various laboratories suggesting a potential role of marker proteins and clinical application. It is therefore important to clearly determine procedures for evaluation of biomarkers. It has been suggested that standardization of laboratory and statistical procedures in biomarker research and publication process is of primary importance in order to assess diagnostic importance of any candidate proposed in these studies. Eur Urol Suppl 2016;15(2):34
ESUR Lecture: Which biomarkers are ready to use in clinical practice? Z. Culig, Innsbruck (AT) Prostate cancer biomarkers are subject of investigation in several areas; they could be used in studies on diagnostics, natural course of the disease, and response to therapy. Although prostate-specific antigen (PSA) has been used in diagnostics and monitoring prostate cancer therapy, there is a need to introduce other markers to facilitate clinical decision making. There are numerous attempts to improve use of diagnosis and therapy of prostate cancer with new biomarkers. However, a critical evaluation of these approaches will be presented. Although there are a large number of publications in that area, there is a problem with reproducibility and translation of data. A possible reason is that not all academical laboratories have implemented standard operating procedures for handling of serum, plasma, urinary and tissue samples. With progress in regulation of procedures associated with biobanking, one could expect that there could be an improvement with regard to general acceptance of data. Moreover, consensus conferences with regard to biomarkers in urological oncology may provide an answer to some of the key questions in the field. It is also notable that multiple genomic or proteomic studies have generated data which need to be confirmed in multiple laboratories. In this lecture there will be also a focus on some novel markers that could be used for therapy monitoring. The biomarkers discussed in the lecture are those related to signaling pathways of androgenic hormones and peptide growth factors. Numerous structural alterations have been discovered in androgen receptor (AR) in last decades. Some of these mutations are induced by anti-androgens and their presence may indicate unsatisfactory response with a specific drug. Screening for these mutations in tissue seems to be difficult because of heterogeneity of human prostate cancer. Importantly, constitutively active truncated AR have been described in advanced carcinoma of the prostate. Such receptors are activated even in the absence of androgen and their increased frequency may be a suitable marker for tumor progression. Most frequently, the researchers have investigated the role of the variant receptor AR V7 in prostate cancer. However, it should be mentioned that several questions regarding truncated constitutively active receptors have not been answered so far. It is not completely clear whether truncated AR activate the same transcriptional program as the wild-type receptor or not. Their determination in tissue may be important to judge potential responsiveness of an individual prostate cancer to therapy with abiraterone or enzalutamide. A specific biomarker for prostate cancer is ERG, whose fusion with TMPRSS2 is detectable in ca. 50% of tumors. In various experimental systems, ERG could stimulate proliferation, migration and invasion so that clinical pathological correlations that consider ERG are of high interest. Markers of epithelial to mesenchymal transition in prostate cancer are also of interest in order to determine potential responsiveness to therapy. Prostate cancers that develop resistance to chemotherapy may express low levels of E-cadherin, whereas the mesenchymal marker N-cadherin and vimentin may increase. In addition, such tumors may express high levels of stemness markers. Recently, the measurement of microRNA and long noncoding RNA in prostate cancer has been shown to be of some prognostic value. It was demonstrated that some long noncoding RNA are upregulated in prostate cancer. Several biomarker studies are focused on insulin-like growth factor (IGF) I and related proteins in malignant prostate disease. IGF is a growth factor that is implicated in inhibition of apoptosis in prostate cancer. Its biological activity is also determined by several binding proteins which could either inhibit or potentiate the action. IGF may bind to two receptors and the receptor type I is particularly important for transmission of growth factor signals in prostate cancer. The IGF/IGF receptor axis in prostate cancer is considered a valid therapy target. It has been reported that higher IGF-I levels in serum may indicate increased risk for prostate cancer. However, this finding was not confirmed by all authors and there are still open questions in relation to the usefulness of measurement of IGF and its binding proteins as prostate cancer biomarkers. The reasons for differences between results of different publications on this topic have not been clarified, however demographic and ethnic factors may also play a role. Single
13th Meeting of the EAU Section of Oncological Urology (ESOU)
nucleotide polymorphisms in the IGF pathway have also been associated with prostate cancer risk. The exact role of these polymorphism will be discussed in more detail. In summary, there is a discrepancy between a large number of data from various laboratories suggesting a potential role of marker proteins and clinical application. It is therefore important to clearly determine procedures for evaluation of biomarkers. It has been suggested that standardization of laboratory and statistical procedures in biomarker research and publication process is of primary importance in order to assess diagnostic importance of any candidate proposed in these studies. Eur Urol Suppl 2016;15(2):34