Why are biomarkers needed for prostate cancer?
There are several reasons according to Dr. Wirth why biomarkers are needed for prostate cancer, including (i) for reliable diagnosis of significant prostate cancer and making therapy decisions; (ii) for early prediction of prognosis of the future course of disease, which may lead to adjusted monitoring and optimized therapy; (iii) for prediction of therapy response and thus stratifying potential treatment benefit; (iv) the identification of alternative therapeutic targets based on molecular analyses (eg. target expression and mutational status); (v) developing individualized treatment options and thus improve patient outcomes; (vi) standardization of study/cohort design, permitting standardized reporting. The ideal biomarker would be non-invasive/minimally invasive, have high accuracy and performance, and at low cost. As Dr. Wirth notes, since 2010 there has been an exponential increase in the number of prostate biomarker studies published in the literature. Most important is selecting the right biomarker at the right time, whether a diagnostic or prognostic biomarker. Among some of the more commonly used biomarkers, Dr. Wirth lists Phi, 4Kscore, PCA3, SelectMDx, ConfirmMDx, OncotypeDx, Prolaris and Decipher.
Promising biomarkers for PCa at all molecular levels
Proteomics involves biomarker proteins that are prognostic markers in prostate cancer. According to Dr. Wirth, there are multiple proteomics studies, however only several that are “in translation”. Tissue microarrays have been developed from radical prostatectomy specimens marked for highest and lowest Gleason score, allowing quantitative proteomics to select 12 of 160 promising protein markers for predicting prostate cancer aggressiveness and lethal outcomes. Since then, validation of an 8-biomarker assay (ProMark) has been developed and tested on Gleason 3+3/3+4 biopsy specimens for prediction of pT3 or Gleason pattern 4 after radical prostatectomy, which may help in counseling the need for aggressive therapy .
microRNAs are single-stranded, non-coding RNAs with ~22 nucleotides, which act as post-transcriptional regulators (~30% of human mRNAs). One miRNA can regulate numerous genes and one gene can be regulated by many different miRNAs. Indeed, miRNAs are involved in a variety of pathological and oncogenic pathways (proliferation, apoptosis, metastasis, androgen receptor signaling). miRNAs are ideal biomarkers in tissue, blood and urine, considering they are stable molecules and easily measurable. Furthermore, long non-coding RNAs (lncRNAs) are also ideal potential biomarkers, which are ~200 nucleotides in length. These entities have regulatory functions in a multitude of cellular processes and dysregulation of lncRNAs in disease has the potential for diagnostic and prognostic markers, as well as potential therapeutic targets. Early work is ongoing developing a signature of 8 novel lncRNAs through microarray analysis, leading to improved diagnostic performance between prostate cancer and BPH. One such lncRNAs is PCAT-14, which has been shown to be upregulated in prostate cancer compared to normal tissue, however interestingly downregulated in metastatic prostate cancer, OS and CSS .
Genomic defects in DNA damage repair genes (ie. BRCA1/2, ATM) are common in prostate cancer and increased mutational burden rates are associated with advanced CRPC. These entities are also potentially relevant to hereditary cancers and prediction of response to PARP inhibitors and platinum therapeutics. Increased combined mutation rates in ATM and BRCA1/2 has been shown to be an independent predictor of lethal prostate cancer and with early stage at death .
What is the future of biomarkers for PCa?
According to Dr. Wirth, the future of biomarkers is to develop comprehensive approaches to marker selection and evaluation. For example, IBM Watson is a question answering computing system based on cognitive solutions from pre-trained programming interfaces that allows hypothesis generating and evidence based learning capabilities – Dr. Wirth ponders if this may have future use for clinical decision support systems? As such, pilot projects at the Cleveland Clinic and MD Anderson Cancer Center are ongoing to identify personalized, evidence-based cancer care options. Certainly, questions about data security may stem from developing this technology.
Dr. Wirth concluded his presentation with several remarks, (i) there are numerous promising biomarkers at different molecular levels, however these require independent, prospective validation, and (ii) the future of prostate cancer biomarkers will include single-cell analysis (circulating tumor cells), liquid biopsies (exosomes, circulating tumor DNA), and “omics” at several levels will be feasible due to cost reduction for high-throughput analysis and new analytic approaches.
Speaker: Manfred Wirth, University Hospital Carl Gustav Carus, Dresden Technical University, Dresden, Germany
Written By: Zachary Klaassen, MD, Urologic Oncology Fellow, University of Toronto, Princess Margaret Cancer Centre
Twitter: @zklaassen_md at the EAU - Update on Prostate Cancer – September 15-16, 2017, Vienna, Austria
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