Scientific literature review: Prostate cancer
CTC-derived AR-V7 detection as a prognostic and predictive biomarker in advanced prostate cancer
Bastos DA, Antonarakis ES. Expert Rev Mol Diagn 2018; 18(2): 155–163
Prostate cancer is a highly heterogeneous disease, with remarkably different prognosis across all stages. Increased circulating tumour cell (CTC) count (≥5) using the CellSearch assay has been identified as one of the markers that can be used to predict survival, with added value beyond currently available prognostic factors. Recently, androgen receptor splice variant 7 (AR-V7) detection has been associated with worse outcomes for patients with castration-resistant prostate cancer (CRPC) treated with novel androgen receptor-signalling (ARS) inhibitors such as abiraterone and enzalutamide but not taxane chemotherapies. Areas covered: In this manuscript, the authors review the available biomarkers in CRPC and discuss emerging data on the value of CTC-derived AR-V7 status to assess prognosis and its potential role to guide treatment selection for patients with advanced prostate cancer. Expert commentary: Current evidence supports AR-V7 status as a prognostic biomarker and also as a potential predictive biomarker for patients with mCRPC. The authors expect that the incorporation of AR-V7 status and other biomarkers (e.g. AR mutations) in the sequential assessment of patients with advanced prostate cancer will lead to a more rational use of available and future therapies, with significant improvements in outcomes for our patients.
Defining a cohort of men who may not require repeat prostate biopsy based on PCA3 score and MRI: The dual negative effect
Perlis N, Al-Kasab T, Ahmad A, Goldberg E, Fadak K, Sayid R, et al. J Urol 2017; doi: 10.1016/j.juro.2017.11.07
PURPOSE: Prostate cancer over diagnosis and overtreatment are concerns for clinicians and policy makers. Multiparametric magnetic resonance imaging and the PCA3 (prostate cancer antigen 3) urine test select for clinically significant cases. We explored how well the tests performed together in with previous biopsies.
MATERIALS AND METHODS: In accordance with ethics committee approval we collected clinicopathological data on all patients in whom a PCA3 test from was done 2011 to June 2016. This included patients on active surveillance for low-risk prostate cancer and those without prostate cancer who had previous negative biopsies and suspicion of occult disease. We explored whether age, prostate-specific antigen, PCA3 score, multiparametric magnetic resonance imaging, digital rectal examination, family history and prostate size would predict clinically significant prostate cancer on repeat biopsy. The negative predictive value of multiparametric magnetic resonance imaging and PCA3 score was calculated.
RESULTS: A total of 470 patients were included in study. The PCA3 score was abnormal at 35 or greater in 32.5 % of cases. In the multivariate model including 154 men only age (OR 1.08, 95 % CI 1.01–1.16), multiparametric magnetic resonance imaging PI-RADS™ (Prostate Imaging-Reporting and Data System) score 4 (OR 16.6, 95 % CI 3.9–70.0) or 5 (OR 28.3, 95 % CI 5.7–138) and PCA3 score (OR 2.9, 95 % CI 1.0–8.8) predicted clinically significant cancer on biopsy. No patient with negative multiparametric magnetic resonance imaging and a normal PCA3 score had clinically significant prostate cancer on biopsy for a negative predictive value of 100 % (p<0.0001).
CONCLUSIONS: In patients with dual negative tests (multiparametric magnetic resonance imaging and PCA3 score) clinically significant prostate cancer was never found on biopsy, which may be unnecessary in this group. This study was limited by its retrospective design, selection bias and lack of cost-effectiveness data.
Quantitative mass spectrometry-based proteomic profiling for precision medicine in prostate cancer
Flores-Morales A, Iglesias-Gato D. Front Oncol 2017; 7: 267
Prostate cancer (PCa) is one of the most frequently diagnosed cancer among men in the western societies. Many PCa patients bear tumours that will not threat their lives if left untreated or if treatment is delayed. Our inability for early identification of these patients has resulted in massive overtreatment. Therefore, there is a great need of finding biomarkers for patient stratification according to prognostic risk; as well as there is a need for novel targets that can allow the development of effective treatments for patients that progress to castration-resistant PCa. Most biomarkers in cancer are proteins, including the widely-used prostate-specific antigen (PSA). Recent developments in mass spectrometry allow the identification and quantification of thousands of proteins and posttranslational modifications from small amounts of biological material, including formalin-fixed paraffin-embedded tissues, and biological fluids. Novel diagnostic and prognostic biomarkers have been identified in tissue, blood, urine, and seminal plasma of PCa patients, and new insights in the ethology and progression of this disease have been achieved using this technology. In this review, we summarize these findings and discuss the potential of this technology to pave the way toward the clinical implementation of precision medicine in PCa.
Biomarkers for prostate biopsy and risk stratification of newly diagnosed prostate cancer patients
Loeb S. Urol Pract 2017; 4(4): 315–321
INTRODUCTION: Many new markers are now available as an aid for decisions about prostate biopsy for men without prostate cancer, and/or to improve risk stratification for men with newly diagnosed prostate cancer.
METHODS: A literature review was performed on currently available markers for use in decisions about prostate biopsy and initial prostate cancer treatment.
RESULTS: Although total prostate-specific antigen cutoffs were traditionally used for biopsy decisions, PSA elevations are not specific. Repeating the PSA test, and adjusting for factors like age, prostate volume and changes over time can increase specificity for biopsy decisions. The Prostate Health Index (phi) and 4K Score are new PSA-based markers that can be offered as second-line tests to decide on initial or repeat prostate biopsy. The PCA3 urine test and ConfirmMDx tissue test are additional options for repeat biopsy decisions. For men with newly diagnosed prostate cancer, genomic tests are available to refine risk classification and may influence treatment decisions.
CONCLUSIONS: Numerous secondary testing options are now available that can be offered to patients deciding whether to undergo prostate biopsy and those with newly diagnosed prostate cancer.
Bidirectional electrochemiluminescence color switch: an application in detecting multimarkers of prostate cancer
Wang YZ, Ji SY, Xu HY, Zhao W, Xu JJ, Chen HY. Anal Chem 2018; doi: 10.1021/acs.analchem.8b00014
A selective excitation of [Ir(df-ppy)2(pic)] and [Ru(bpy)3]2+ through tuning the electrode potential is reported in this work. Bidirectional colour change from blue-green to red could be observed along with increase and decrease of the potential, which was ascribed to the dual-potential excitation property of [Ir(df-ppy)2(pic)]. Similar to the three-electrode system, selective excitation of ECL could be achieved at the anode of the bipolar electrode (BPE). Both increase and decrease of the faradic reactions at the cathode of the BPE could induce ECL reporting colour at the other pole switched from blue-green to red. We applied a closed BPE device for the bioanalysis of multicolour ECL since the organic solvent containing electrochemiluminophores could be separated from the bioanalytes. On the basis of BPE arrays coupled with the ECL switch, the detection of three biomarkers of prostate cancer, PSA, microRNA-141, and sarcosine were integrated in a same device. The cutoff values of the biomarkers could be recognized directly by the naked eye. Such a device holds great potential in the early diagnosis of prostate cancer.
Molecular biomarkers in the clinical management of prostate cancer
Udager AM, Tomlins SA. Cold Spring Harb Perspect Med 2018; doi: 10.1101/cshperspect.a030601
Prostate cancer, one of the most common non-cutaneous malignancies in men, is a heterogeneous disease with variable clinical outcome. Although the majority of patients harbour indolent tumours that are essentially cured by local therapy, subsets of patients present with aggressive disease or recur/progress after primary treatment. With this in mind, modern clinical approaches to prostate cancer emphasize the need to reduce overdiagnosis and overtreatment via personalized medicine. Advances in our understanding of prostate cancer pathogenesis, coupled with recent technologic innovations, have facilitated the development and validation of numerous molecular biomarkers, representing a range of macromolecules assayed from a variety of patient sample types, to help guide the clinical management of prostate cancer, including early detection, diagnosis, prognostication, and targeted therapeutic selection. Herein, we review the current state of the art regarding prostate cancer molecular biomarkers, emphasizing those with demonstrated utility in clinical practice.
Genomic markers in prostate cancer decision making
Cucchiara V, Cooperberg MR, Dall’Era M, Lin DW, Montorsi F, Schalken JA, et al. Eur Urol. 2017; doi: 10.1016/j.eururo.2017.10.036
CONTEXT: Although the widespread use of prostate-specific antigen (PSA) has led to an early detection of prostate cancer (PCa) and a reduction of metastatic disease at diagnosis, PSA remains one of the most controversial biomarkers due to its limited specificity. As part of emerging efforts to improve both detection and management decision making, a number of new genomic tools have recently been developed.
OBJECTIVE: This review summarizes the ability of genomic biomarkers to recognize men at high risk of developing PCa, discriminate clinically insignificant and aggressive tumours, and facilitate the selection of therapies in patients with advanced disease.
EVIDENCE ACQUISITION: A PubMed-based literature search was conducted up to May 2017. The most recent and relevant original articles and clinical trials that have provided indispensable information to guide treatment decisions were selected.
EVIDENCE SYNTHESIS: Genome-wide association studies have identified several genetic polymorphisms and inherited variants associated with PCa susceptibility. Moreover, the urine-based assays SelectMDx, Mi-Prostate Score, and ExoDx have provided new insights into the identification of patients who may benefit from prostate biopsy. In men with previous negative pathological findings, Prostate Cancer Antigen 3 and ConfirmMDx predicted the outcome of subsequent biopsy. Commercially available tools (Decipher, Oncotype DX, and Prolaris) improved PCa risk stratification, identifying men at the highest risk of adverse outcome. Furthermore, other biomarkers could assist in treatment selection in castration-resistant PCa. AR-V7 expression predicts resistance to abiraterone/enzalutamide, while poly(ADP-ribose) polymerase-1 inhibitor and platinum-based chemotherapy could be indicated in metastatic patients who are carriers of mutations in DNA mismatch repair genes.
CONCLUSIONS: Introduction of genomic biomarkers has dramatically improved the detection, prognosis, and risk evaluation of PCa. Despite the progress made in discovering suitable biomarker candidates, few have been used in a clinical setting. Large-scale and multi-institutional studies are required to validate the efficacy and cost utility of these new technologies.
PATIENT SUMMARY: Prostate cancer is a heterogeneous disease with a wide variability. Genomic biomarkers in combination with clinical and pathological variables are useful tools to reduce the number of unnecessary biopsies, stratify low-risk from high-risk tumours, and guide personalized treatment decisions.
The use of biomarkers in prostate cancer screening and treatment
Ashley VA, Joseph MB, Kamlesh KY, Shalini SY, Ashutosh KT, Joseph R. Rev Urol 2017; 19(4): 221–234
Prostate cancer screening and diagnosis has been guided by prostate-specific antigen levels for the past 25 years, but with the most recent US Preventive Services Task Force screening recommendations, as well as concerns regarding overdiagnosis and overtreatment, a new wave of prostate cancer biomarkers has recently emerged. These assays allow the testing of urine, serum, or prostate tissue for molecular signs of prostate cancer, and provide information regarding both diagnosis and prognosis. In this review, we discuss 12 commercially available biomarker assays approved for the diagnosis and treatment of prostate cancer. The results of clinical validation studies and clinical decision-making studies are presented. This information is designed to assist urologists in making clinical decisions with respect to ordering and interpreting these tests for different patients. There are numerous fluid and biopsy-based genomic tests available for prostate cancer patients that provide the physician and patient with different information about risk of future disease and treatment outcomes. It is important that providers be able to recommend the appropriate test for each individual patient; this decision is based on tissue availability and prognostic information desired. Future studies will continue to emphasize the important role of genomic biomarkers in making individualized treatment decisions for prostate cancer patients.
A four-kallikrein panel and β-microseminoprotein in predicting high-grade prostate cancer on biopsy: an independent replication from the Finnish Section of the European Randomized Study of Screening for Prostate Cancer
Assel M, Sjöblom L, Murtola TJ, Talala K, Kujala P, Stenman UH, et al. Eur Urol Focus 2017; doi: 10.1016/j.euf.2017.11.002
BACKGROUND: A panel of four kallikrein markers (total, free, and intact prostate-specific antigen [PSA] and human kallikrein-related peptidase 2 [hK2]) improves predictive accuracy for Gleason score ≥7 (high-grade) prostate cancer among men biopsied for elevated PSA. A four-kallikrein panel model was originally developed and validated by the Dutch centre of the European Randomized Study of Screening for Prostate Cancer (ERSPC). The kallikrein panel is now commercially available as 4Kscore™.
OBJECTIVE: To assess whether these findings could be replicated among participants in the Finnish section of ERSPC (FinRSPC) and whether β-microseminoprotein (MSP), a candidate prostate cancer biomarker, adds predictive value.
DESIGN, SETTING, AND PARTICIPANTS: Among 4861 biopsied screening-positive participants in the first three screening rounds of FinRSPC, a case-control subset was selected that included 1632 biopsy-positive cases matched by age at biopsy to biopsy-negative controls.
OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The predictive accuracy of prespecified prediction models was compared with biopsy outcomes.
RESULTS AND LIMITATIONS: Among men with PSA of 4.0–25 ng/ml, 1111 had prostate cancer, 318 of whom had high-grade disease. Total PSA and age predicted high-grade cancer with an area under the curve of 0.648 (95 % confidence interval [CI] 0.614–0.681) and the four-kallikrein panel increased discrimination to 0.746 (95 % CI 0.717–0.774). Adding MSP to the four-kallikrein panel led to a significant (Wald test; p=0.015) but small increase (0.003) in discrimination. Limitations include a risk of verification bias among men with PSA of 3.0–3.99 ng/ml and the absence of digital rectal examination results.
CONCLUSIONS: These findings provide additional evidence that kallikrein markers can be used to inform biopsy decision making. Further studies are needed to define the role of MSP.
PATIENT SUMMARY: Four kallikrein markers and β-microseminoprotein in blood improve discrimination of high-grade prostate cancer at biopsy in men with elevated prostate-specific antigen.
Combinations of elevated tissue miRNA-17-92 cluster expression and serum prostate-specific
antigen as potential diagnostic biomarkers for prostate cancer
Feng S, Qian X, Li H, Zhang X. Oncol Lett 2017; 14(6): 6943–6949
The aim of the present study was to investigate the effectiveness of the miR-17-92 cluster as a disease progression marker in prostate cancer (PCa). Reverse transcription-quantitative polymerase chain reaction analysis was used to detect the microRNA (miR)-17-92 cluster expression levels in tissues from patients with PCa or benign prostatic hyperplasia (BPH), in addition to in PCa and BPH cell lines. Spearman correlation was used for comparison and estimation of correlations between miRNA expression levels and clinicopathological characteristics such as the Gleason score and prostate-specific antigen (PSA). Receiver operating curve (ROC) analysis was performed for evaluation of specificity and sensitivity of miR-17-92 cluster expression levels for discriminating patients with PCa from patients with BPH. Kaplan-Meier analysis was plotted to investigate the predictive potential of miR-17-92 cluster for PCa biochemical recurrence. Expression of the majority of miRNAs in the miR-17-92 cluster was identified to be significantly increased in PCa tissues and cell lines. Bivariate correlation analysis indicated that the high expression of unregulated miRNAs was positively correlated with Gleason grade, but had no significant association with PSA. ROC curves demonstrated that high expression of miR-17-92 cluster predicted a higher diagnostic accuracy compared with PSA. Improved discriminating quotients were observed when combinations of unregulated miRNAs with PSA were used. Survival analysis confirmed a high combined miRNA score of miR-17-92 cluster was associated with shorter biochemical recurrence interval. miR-17-92 cluster could be a potential diagnostic and prognostic biomarker for PCa, and the combination of the miR-17-92 cluster and serum PSA may enhance the accuracy for diagnosis of PCa.
Prostate-specific antigen screening impacts on biochemical recurrence in patients with clinically localized prostate cancer
Hashimoto T, Ohori M, Shimodaira K, Kaburaki N, Hirasawa Y, Satake N, Gondo T, Nakagami Y, Namiki K, Ohno Y. Int J Urol 2018; doi: 10.1111/iju.13563
OBJECTIVE: To clarify the impact of prostate-specific antigen screening on surgical outcomes of prostate cancer.
METHODS: Patients who underwent radical prostatectomy were divided into two groups according to prostate-specific antigen testing opportunity (group 1, prostate-specific antigen screening; group 2, non-prostate-specific antigen screening). Perioperative clinical characteristics were compared using the Wilcoxon rank-sum and χ2 -tests. Cox proportional hazards models were used to identify independent predictors of postoperative biochemical recurrence-free survival.
RESULTS: In total, 798 patients (63.2 %) and 464 patients (36.8 %) were categorized into groups 1 and 2, respectively. Group 2 patients were more likely to have a higher prostate-specific antigen level and age at diagnosis and larger prostate volume. Clinical T stage, percentage of positive cores and pathological Gleason score did not differ between the groups. The 5-year biochemical recurrence-free survival rate was 83.9 % for group 1 and 71.0 % for group 2 (p<0.001). On multivariate analysis, prostate-specific antigen testing opportunity (hazard ratio 2.530; p<0.001) was an independent predictive factor for biochemical recurrence after surgery, as well as pathological T stage, pathological Gleason score, positive surgical margin and lymphovascular invasion. Additional analyses showed that prostate-specific antigen screening had a greater impact on biochemical recurrence in a younger patients, patients with a high prostate-specific antigen level, large prostate volume and D’Amico high risk, and patients meeting the exclusion criteria of the Prostate Cancer Research International Active Surveillance study.
CONCLUSIONS: Detection by screening results in favourable outcomes after surgery. Prostate-specific antigen screening might contribute to reducing biochemical recurrence in patients with localized prostate cancer.
