Liquid biopsy and prostate cancer. Current evidence applied to clinical practice | Actas Urológicas Españolas (English Edition)

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B) Bilateral direct subclinical inguinal hernia." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "R. Bertolo, M.C. Mir Maresma, P. Bove, J. Rubio-Briones, M. Ramírez-Backhaus" "autores" => array:5 [ 0 => array:2 [ "nombre" => "R." "apellidos" => "Bertolo" ] 1 => array:2 [ "nombre" => "M.C." "apellidos" => "Mir Maresma" ] 2 => array:2 [ "nombre" => "P." "apellidos" => "Bove" ] 3 => array:2 [ "nombre" => "J." "apellidos" => "Rubio-Briones" ] 4 => array:2 [ "nombre" => "M." 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Current evidence applied to clinical practice" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "139" "paginaFinal" => "147" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "I. Puche-Sanz, A. Rodríguez-Martínez, M.C. Garrido-Navas, I. Robles-Fernández, F. Vázquez-Alonso, M.J. Álvarez Cubero, J.A. Lorente-Acosta, M.J. Serrano-Fernández, J.M. Cózar-Olmo" "autores" => array:9 [ 0 => array:4 [ "nombre" => "I." "apellidos" => "Puche-Sanz" "email" => array:1 [ 0 => "nacho.puchesanz@gmail.com" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "A." "apellidos" => "Rodríguez-Martínez" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] ] ] 2 => array:3 [ "nombre" => "M.C." 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"apellidos" => "Cózar-Olmo" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] ] "afiliaciones" => array:4 [ 0 => array:3 [ "entidad" => "Departamento de Urología, Hospital Universitario Virgen de las Nieves, Instituto de Investigación Biosanitaria-IBS, Granada, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Departamento de Medicina Legal, Laboratorio de Identificación Genética, Universidad de Granada, Granada, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Comprehensive Oncology Division. Hospital Clínico-Hospital Universitario Virgen de las Nieves, Universidad de Granada, Granada, Spain" "etiqueta" => "c" "identificador" => "aff0015" ] 3 => array:3 [ "entidad" => "Departamento de Bioquímica y Biología Molecular III, Facultad de Medicina, Universidad de Granada, Granada, Spain" "etiqueta" => "d" "identificador" => "aff0020" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1550 "Ancho" => 2917 "Tamanyo" => 357707 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0165" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "Main scientific milestones of liquid biopsy in prostate cancer<a class="elsevierStyleCrossRefs" href="#bib0075">15,23,35–39</a>." ] ] ] "textoCompleto" => "BackgroundThe development and approval of new medications over the last 10 years has generated a wide range of therapeutic options for the management of prostate cancer (PCa). Although these new molecules have improved survival and quality of life of patients, they have also revealed another reality: the absence of predictive biomarkers that determine their optimal indication and allow adequate assessment of their clinical effectiveness.<a class="elsevierStyleCrossRef" href="#bib0005">1</a>Liquid biopsy (LB) refers to any minimally invasive test performed on a body fluid (blood, urine, semen, saliva), which make the detection of cellular or molecular biomarkers possible in order to obtain diagnostic, prognostic or predictive information of the disease. Thus, LB presents two advantages, temporal and spatial, over solid biopsy. On the one hand, being a minimally invasive technique, it allows frequent repetition providing "real time" data and facilitating the monitoring of the disease. On the other hand, it provides global information of all tumor subclones, since it is not limited to one single region.<a class="elsevierStyleCrossRef" href="#bib0005">1</a> The investigation on LB in PCa began in peripheral blood and, therefore, has been the most studied body fluid to date.Despite being a novel source of biomarkers, the actual clinical impact of LB in patients with PCa is still unclear. The truth is that very few biomarkers undergo an adequate, prospective and independent validation of their predictive or prognostic value, and this fact has impeded their translation into clinical practice so far.ObjectivePerform a pragmatic clinical synthesis of current scientific evidence on blood LB in PCa and highlight those key biological concepts to analyze the usefulness of LB in the management of PCa.Evidence acquisitionA non-systematic review of the literature is carried out through PubMed with the keywords liquid biopsy and prostate cancer. Only those works related to blood LB with significant clinical endpoints-such as overall survival (OS), progression-free survival (PFS) or biochemical recurrence studied in PCa- are selected.Evidence synthesisThe blood LB in PCa has focused on two large lines of research: circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA). In addition, due to its current clinical relevance, we include a section referring to the androgen receptor splice variant 7 (AR-V7).Circulating tumor cellsAccording to the current model of the metastasis process, these cells are released into the bloodstream from the primary tumor or from the metastasis itself and, after a series of -still unknown- changes, some of them are able to "survive" in the bloodstream, reach other target organs and cause metastatic disease.One of these changes required in CTCs is the loss of epithelial characteristics and the acquisition of mesenchymal characteristics (epithelial-mesenchymal transition, EMT).<a class="elsevierStyleCrossRef" href="#bib0005">1</a> This process includes those biological changes required for the adaptation of CTCs to the blood environment and their survival in it. In addition, cell dissemination seems to be associated with the role of the cells of the immune system (for example, activated platelets or macrophages).<a class="elsevierStyleCrossRef" href="#bib0010">2</a>It must be noted that there is currently only one FDA-approved CTCs detection platform with prognostic value in mCRPC: CellSearch® (Menarini Silicon Biosystems). Therefore, most clinical relevance studies with CTCs in PCa have used this platform. CellSearch® is based on the immunomagnetic isolation of CTCs that express the epithelial cell adhesion molecule (EpCAM).<a class="elsevierStyleCrossRef" href="#bib0015">3</a> This is a transmembrane glycoprotein involved in cell proliferation and differentiation, with oncogenic potential, which is expressed exclusively in epithelial cells or tumors of epithelial origin.Circulating tumor cells and metastatic prostate cancerThe value of CTCs as a prognostic biomarker in metastatic PCa has been widely demonstrated. The most important study that validated the prognostic capacity of CTCs in metastatic PCa was the IMMC<a class="elsevierStyleCrossRef" href="#bib0020">4</a> trial, with a total of 164 patients with mCRPC who began treatment with chemotherapy and whose CTCs values were analyzed by CellSearch® system in 3-4-week intervals. After adjusting the data according to the main prognostic indicators identified (LDH, ECOG performance status, hemoglobin, alkaline phosphatase), a multivariate analysis revealed that patients with an unfavorable baseline count (≥5 CTC/7,5mL) presented lower OS rates than patients with a favorable one (<5 CTC/7,5mL). This study also analyzed the conversion of patients from one group to another after treatment. We must highlight that patients who maintained favorable counts in all determinations were those who showed a higher OS (26 months), followed by patients who went from unfavorable to favorable (21.3 months), those who went from favorable to unfavorable (9.3 months) and, finally, those who remained unfavorable (6.8 months). Subsequently, the multivariate analysis of the data assessed the capacity of CTCs as a continuous variable in the prediction of OS before treatment initiation, which showed that only CTCs and LDH were independent predictors of OS, a fact that could not be demonstrated with PSA.<a class="elsevierStyleCrossRef" href="#bib0015">3</a>De Bono et al.<a class="elsevierStyleCrossRef" href="#bib0020">4</a> had already shown that the survival predictive ability of the qualitative determination of CTCs (>5 o<5 CTC/7,5mL) was higher than that of a decreased PSA, especially at onset. Their work showed that, at 12 weeks of treatment, the ROC curves demonstrated a significant superiority of the CTCs over the 30% decrease in PSA when predicting the death of the patient at 12 months (area under the curve, AUC of 81.5% vs. 67.5%, respectively). However, the objective of the establishment of a standard cut-off point has not been achieved so far. A study of the Memorial Sloan-Kettering Cancer Center analyzed a cohort of 112 patients with mCRPC, showing a strong correlation between CTCs and OS, but with no threshold effect. Baseline CTC counts were modestly related to other standard indicators such as PSA or bone scintigraphy.<a class="elsevierStyleCrossRef" href="#bib0025">5</a> On the other hand, in another study of the Royal Marsden analyzing 119 mCRPC patients, they established 3 survival prognostic groups (<5 CTC/7,5mL, 5–50 CTC/7,5mL y>50 CTC/7,5mL). The multivariate analysis showed that >5 CTC/7,5mL was an independent factor of OS.<a class="elsevierStyleCrossRef" href="#bib0030">6</a>However, these works revealed a biologically relevant fact: the survival of patients in whom CTCs were not detected was significantly variable. Therefore, the "absence" of CTCs (according to the CellSearch® platform) did not guarantee a good prognosis.<a class="elsevierStyleCrossRef" href="#bib0025">5</a>Once the prognostic value of the CTCs was demonstrated, these began to be included as biomarkers in several phase III clinical trials aiming to establish their value as surrogate biomarkers of OS. The first one was the COU-AA-301, which showed that the 2-year survival of patients with>5 CTC/7,5mL vs.<5 CTC/7,5mL at 12 weeks of treatment was 2 vs. 46%, respectively. Moreover, it was demonstrated that they met the four Prentice criteria required to be considered a surrogate marker for OS.<a class="elsevierStyleCrossRef" href="#bib0035">7</a> This quality of CTCs was studied in four phase III clinical trials. A recent joint analysis of the 6081 patients included in these trials established 2 new end-points with a high discriminatory power of OS at 13 weeks of treatment: the CTCs=0 from having any CTCs before treatment, to have none at 13 weeks and CTCs conversion from 5 or more CTCs before treatment initiation to less than 5 CTCs at 13 weeks.<a class="elsevierStyleCrossRef" href="#bib0040">8</a>Circulating tumor cells and localized prostate cancerCTCs detection rates when disease is incipient are very low and variable (8-27%).<a class="elsevierStyleCrossRefs" href="#bib0045">9–13</a> Specifically, the CellSearch® system has shown low CTCs detection capacity in patients with localized PCa. Up to 34% of patients may have EpCAM-negative CTCs (invisible to CellSearch® but detectable by other methods) due to changes related to mesenchymal epithelial transition.<a class="elsevierStyleCrossRef" href="#bib0045">9</a>The clinical evidence of localized disease is heterogeneous. Davis et al.<a class="elsevierStyleCrossRef" href="#bib0050">10</a> used the CellSearch® system in 97 patients with localized PCa and a group of patients with high PSA and negative biopsy. The presence of CTCs was similar in both groups (21 and 20%, respectively). In addition, no relationship was observed between the presence of CTCs and tumor volume, pathological stage or Gleason score, which led the authors to conclude that CTCs have no prognostic value in these patients. On the contrary, Maestro et al. demonstrated -also with CellSearch®<a class="elsevierStyleCrossRef" href="#bib0055">11</a>- the presence of CTCs in 100% of patients (26/26) with localized PCa of their series. However, in this study, the definition of "localized" PCa was probably indeterminate. Any PCa in the absence of metastases, but with any lymphatic involvement, was classified as localized PCa. The largest series in this scenario studied the presence of CTCs using CellSearch® in 152 patients before and after radical prostatectomy. Only 11% of patients had CTCs before surgery and no relationship was found with the subsequent biochemical recurrence rate.<a class="elsevierStyleCrossRef" href="#bib0060">12</a>These data show that the currently approved technology to quantify CTCs in mCRPC is still limited for early stages of PCa. However, other methodologies have shown that it is possible to detect different CTCs subpopulations, even at early stages of the disease,<a class="elsevierStyleCrossRef" href="#bib0065">13</a> and the development of new isolation platforms, such as those based on size and deformability, as well as proper cell characterization, will probably clarify the role of CTCs in this scenario.Circulating tumor DNANecrotic and apoptotic tumor cells (derived from the primary tumor, their metastases or the circulating tumor cells themselves) can release DNA fragments into the blood, called ctDNA (which can be detected).Most PCa studies with ctDNA have focused on the detection of nucleic acids associated to the altered expression of AR. One of the first works in this regard<a class="elsevierStyleCrossRef" href="#bib0070">14</a> performed a whole-genome sequencing (genome-wide analysis) of ctDNA in patients with CRPC, revealing the presence of multiple copy number aberrations in the AR locus (losses in 8p and gains in 8q). Later, Azad et al.<a class="elsevierStyleCrossRef" href="#bib0075">15</a> demonstrated that AR gene amplification was significantly more frequent in patients with progression on enzalutamide than in those on abiraterone. In another study, the presence of the AR F876L mutation was associated with resistance in ARN-509-treated CRPC patients.<a class="elsevierStyleCrossRef" href="#bib0080">16</a> A recent study by Wyatt et al.<a class="elsevierStyleCrossRef" href="#bib0085">17</a> evaluated ctDNA in serial samples (before and 3 months after treatment) of 65 patients with mCRPC treated with enzalutamide. In this study, array comparative genomic hybridization copy number profiling and deep AR gene sequencing was performed. Samples collected at the end of treatment were also subjected to targeted sequencing of 19 prostate cancer-associated genes. The authors observed AR mutations in 23% of baseline samples. In addition, they demonstrated that all patients with gains in AR copies, AR amplifications, multiple AR mutations, RB1 loss or MET and MYC gain were at greater risk of having resistance to enzalutamide than those patients without these genetic characteristics in their ctDNA.All studies point in the same direction: aberrations in the AR gene detected in the ctDNA demonstrate prognostic factors in response to androgen deprivation therapy.Circulating tumor cells or ctDNA?CTCs and ctDNA have demonstrated their value as biomarkers in PCa. However, we must not choose only one as the most efficient modality to implement into clinical practice, as both provide real-time photographs of the molecular biology of the tumor, including the assessment of AR, and each one will give us different and complementary information. Hence, the appropriate use of both sources will provide the highest clinical utility<a class="elsevierStyleCrossRef" href="#bib0090">18</a> (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>). Their prognostic value in clinical practice is comparable, and the correlation between ctDNA levels and CTC>5<a class="elsevierStyleCrossRef" href="#bib0075">15</a> counts has been demonstrated (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>).<elsevierMultimedia ident="tbl0005"></elsevierMultimedia><elsevierMultimedia ident="tbl0010"></elsevierMultimedia>The detection of ctDNA alterations has the advantage of lower speed and cost compared to CTCs, so it could be more suitable for large-scale serial analysis of specific tumor mutations. The accelerated development and the progressively decreasing cost of these analyses will probably facilitate the implementation of the ctDNA study (before the detection of CTCs) in routine clinical practice. However, the determination of ctDNA is not yet standardized or clinically validated in PCa. To date, the cobas® EGFR Mutation Test v2 (Roche Molecular Systems, Pleasanton, CA, USA) is the only test that has been standardized and validated by the FDA, specifically used for the prediction of response to erlotinib in non-small cell lung cancer. A disadvantage of ctDNA is cfDNA dilution bias (total cell-free DNA). It is currently impossible to know if the absence of ctDNA is real (true negative) or whether it is bias due to dilution in the cfDNA (false negative) in a sample that does not show copy number alterations or mutations in the analyzed genes. In addition, unlike gains, the detection of losses is especially difficult with a low amount of available ctDNA, and it is estimated that at least a minimum ratio of 10% is necessary to determine them.<a class="elsevierStyleCrossRef" href="#bib0085">17</a>With CTCs, the detection implies higher costs and is technically more complex. However, it has some advantages over ctDNA. There is a standardized platform (CellSearch®) approved by the FDA for its detection, which can perform many expression analyses (e.g., mRNA of the AR and its splice variants, whole transcriptome or specific proteins sequencing, among others). In addition, CTCs enable the analysis of the phenotypic and genetic heterogeneity of tumor tissue.<a class="elsevierStyleCrossRef" href="#bib0095">19</a> The last positive aspect of CTCs is their ability to grow in vitro and, therefore, their potential to undergo individualized testing for drug susceptibility. CTCs culture has shown its potential in patients with CRPC, but there is still a long way to go for its optimization and clinical applicability.<a class="elsevierStyleCrossRefs" href="#bib0100">20,21</a>AR-V7, the first predictive biomarker using liquid biopsy for the management of prostate cancerAR C terminal loss (where testosterone must naturally bind to activate it) results in alternative AR variants which have been associated to castration-resistant prostate cancer, especially in the case of the AR-V7 variant. It is known that the expression of AR-V7 in primary PCa is very low (<1% of patients), however, in mCRPC it can reach to 75% and, in addition, its expression increases after treatment with abiraterone or enzalutamide.<a class="elsevierStyleCrossRef" href="#bib0110">22</a>The first study showing the predictive capacity of AR-V7 was the one of Antonarakis et al.,<a class="elsevierStyleCrossRef" href="#bib0115">23</a> which demonstrated that the detection of AR-V7 mRNA levels in CTCs (Johns Hopkins University AdnaTest CTC AR-V7 mRNA assay) of patients with mCRPC was strongly associated with resistance to abiraterone or enzalutamide in terms of lower rates PSA response, PFS and OS. These data determined that AR-V7 could provide predictive utility and guide treatment decisions. After this study, several groups devised other methods of detection of AR-V7 and obtained similar results in different clinical scenarios.<a class="elsevierStyleCrossRefs" href="#bib0120">24–26</a> Most detection techniques apply quantitative PCR techniques on previously lysed CTCs.Another detection system of AR-V7 is the EPIC Sciences platform (Epic Sciences CTC nuclear-specific AR-V7 protein assay).<a class="elsevierStyleCrossRef" href="#bib0130">26</a> This platform is based on the detection of epithelial CTCs and subsequent detection by immunofluorescence for AR-V7 protein on the morphologically intact cell. It allows quantification of CTCs, AR-V7 expression analysis and its cellular localization. Nuclear-localized AR-V7 (not its cytoplasmic expression) was shown to be related to a lower OS of mCRPC patients treated with novel antiandrogens and a higher OS in those treated with taxanes (7.3 vs. 14 months, respectively).<a class="elsevierStyleCrossRef" href="#bib0135">27</a>Beside AR-V7 detection in CTCs, AR-V7 can also be detected in exosomes. Del Re et al.<a class="elsevierStyleCrossRef" href="#bib0140">28</a> achieved AR-V7 detection using Droplet Digital PCR (ddPCR) system from plasma-derived exosomal RNA of 36 mCRPC patients. They also confirmed a worse PFS and shorter OS in the AR-V7+ patients (39% of the total). While CTC isolation and processing are complex and expensive, the detection of AR-V7 in circulating exosomes is simpler and can be achieved at lower costs, which would facilitate disease monitoring. However, this detection technique requires more extensive validation.The clinical limitation of the previously mentioned works is, above all, the small number of patients included. Although the effect of the predictive capacity of AR-V7 on the management of patients with CRPC seems to be evident,<a class="elsevierStyleCrossRef" href="#bib0145">29</a> a standardized operating procedure is still required, as well as multicenter and prospective validation that clinically support the results obtained with the different detection techniques. In this sense, there are two interesting published studies which aim to answer this question. In one of them, Tommasi et al.<a class="elsevierStyleCrossRef" href="#bib0150">30</a> develop for the first time a standardized procedure for the determination of AR-V7 in CPRC patients, opening the door to a clinical trial that will solidly analyze the role of this variant in clinical decision making. The second one is a prospective, multicenter clinical trial (PROPHECY trial, NCT02269982)<a class="elsevierStyleCrossRef" href="#bib0155">31</a> with the objective of independently validating -in 118 patients with high-risk mCRPC who started treatment with abiraterone or enzalutamide- the prognostic capacity of AR-V7 in CTCs using the Epic Biosciences CTC nuclear-specific AR-V7 protein assay<a class="elsevierStyleCrossRef" href="#bib0130">26</a> and the Johns Hopkins University modified AdnaTest CTC AR-V7 mRNA assay.<a class="elsevierStyleCrossRef" href="#bib0115">23</a> The study showed a 10–24 % AR-V7+ patients at baseline, and there was 82% observed agreement between tests. AR-V7+ patients showed similar outcomes: little clinical benefit, very low probability of PSA decline and shorter PFS and OS by either assay. Therefore, the authors recommend avoiding the use of abiraterone or enzalutamide in AR-V7+ patients with any of these 2 detection techniques, especially if they have been previously treated before with these molecules.Despite all these, AR-V7 detection can possibly explain only 25% of resistance to novel antiandrogens; meaning that most resistance mechanisms are still unknown.<a class="elsevierStyleCrossRefs" href="#bib0090">18,31</a> However, basic research on castration-resistant disease is very abundant and will yield new evidence in the near future.Future perspectives and cost-effectivenessIn order to be implemented in clinical practice, LB should demonstrate its cost-effectiveness through greater methodological efficiency. Due to the basic technology and the heterogeneity of the evidence, studies in this regard have not yet been carried out (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). The costs of LB determination depend on the technology used and the type and number of biomarkers under study. Cost estimation is not easy, as there is still no consensus regarding technology (especially CTC isolation) and the specific biomarkers to analyze. However, we believe that once these (biomarkers and technologies) are validated, the implementation of these determinations will improve the cost-benefit balance. The goal is to accurately stratify patients in order to predict treatment and prevention strategies for a particular disease (precision medicine). This will reduce costs, not only associated with determinations, but also with over-treatments. In our opinion, this fact depends on two eventual milestones: greater technological development, which will allow automation and methodological standardization, and a wider understanding of molecular biology for better selection of sufficiently sensitive and specific biomarkers.<elsevierMultimedia ident="fig0005"></elsevierMultimedia>In addition to the standardization of procedures, technological development is currently focused on new bioinformatics tools for computational analysis capable of developing complex interpretive algorithms that can reliably and reproducibly correlate molecular data with clinical data.<a class="elsevierStyleCrossRefs" href="#bib0160">32,33</a> Methodological automation will reduce the high costs of currently required personnel and infrastructure.<a class="elsevierStyleCrossRef" href="#bib0170">34</a> In parallel, nonspecific next-generation sequencing techniques provide more and more information to the general library of molecular biology of cancer. A wise interpretation of this information will allow the establishment of the most clinically relevant molecular targets to be detected, as well as a more adequate selection of candidates for each test.<a class="elsevierStyleCrossRef" href="#bib0165">33</a> This technical optimization will allow large-scale cost-effectiveness studies that will foster the uptake of LB in the clinic.ConclusionsCTCs have unequivocally demonstrated their prognostic value in PCa, but further evidence is still required to elucidate the full value of CTC enumeration as surrogate for overall survival. Once the predictive capacity of the CTCs has been demonstrated, especially with the determination of AR-V7, its implementation into routine clinical practice will imply methodological standardization and the adequate clinical validation of the different detection methods available. The detection of CTCs in early stages of the disease still depends on the optimization of these methods and the development of the biological characterization of these cells.Regarding ctDNA, given the lower frequency of specific mutations in PCa, analyses are necessary to detect structural genomic alterations or copy number changes. There are not many comparative clinical studies of CTCs and ctDNA. The future will provide proper analysis of both markers in the same sample.LB has not yet managed to establish in routine clinical practice due to the absence of methodological standards and multicenter, prospective clinical studies that support its results. Therefore, consensus, the unification of criteria and the adequate design of clinical trials constitute the real short-term challenge for this discipline.Conflicts of interestThe authors declare no conflicts of interest." "textoCompletoSecciones" => array:1 [ "secciones" => array:8 [ 0 => array:3 [ "identificador" => "xres1330670" "titulo" => "Abstract" "secciones" => array:10 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Context" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Objective" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Evidence acquisition" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Evidence synthesis" ] 4 => array:2 [ "identificador" => "abst0025" "titulo" => "Conclusions" ] 5 => array:2 [ "identificador" => "abst0030" "titulo" => "Contexto" ] 6 => array:2 [ "identificador" => "abst0035" "titulo" => "Objetivo" ] 7 => array:2 [ "identificador" => "abst0040" "titulo" => "Adquisición de la evidencia" ] 8 => array:2 [ "identificador" => "abst0045" "titulo" => "Síntesis de la evidencia" ] 9 => array:2 [ "identificador" => "abst0050" "titulo" => "Conclusiones" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1226035" "titulo" => "Keywords" ] 2 => array:2 [ "identificador" => "xpalclavsec1226034" "titulo" => "Palabras clave" ] 3 => array:2 [ "identificador" => "sec0005" "titulo" => "Background" ] 4 => array:3 [ "identificador" => "sec0010" "titulo" => "Objective" "secciones" => array:9 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Evidence acquisition" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Evidence synthesis" ] 2 => array:2 [ "identificador" => "sec0025" "titulo" => "Circulating tumor cells" ] 3 => array:2 [ "identificador" => "sec0030" "titulo" => "Circulating tumor cells and metastatic prostate cancer" ] 4 => array:2 [ "identificador" => "sec0035" "titulo" => "Circulating tumor cells and localized prostate cancer" ] 5 => array:2 [ "identificador" => "sec0040" "titulo" => "Circulating tumor DNA" ] 6 => array:2 [ "identificador" => "sec0045" "titulo" => "Circulating tumor cells or ctDNA?" ] 7 => array:2 [ "identificador" => "sec0050" "titulo" => "AR-V7, the first predictive biomarker using liquid biopsy for the management of prostate cancer" ] 8 => array:2 [ "identificador" => "sec0055" "titulo" => "Future perspectives and cost-effectiveness" ] ] ] 5 => array:2 [ "identificador" => "sec0060" "titulo" => "Conclusions" ] 6 => array:2 [ "identificador" => "sec0065" "titulo" => "Conflicts of interest" ] 7 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2019-05-03" "fechaAceptado" => "2019-08-27" "PalabrasClave" => array:1 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1226035" "palabras" => array:5 [ 0 => "Liquid biopsy" 1 => "Prostate cancer" 2 => "Circulating tumor cells" 3 => "Circulating tumor DNA" 4 => "ARV7." ] ] ] ] "tieneResumen" => true "resumen" => array:1 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "ContextDespite being a validated source of biomarkers, liquid biopsy has not yet succeeded in becoming part of the standard clinical practice in prostate cancer patients. Few biomarkers undergo adequate validation, prospective and independent, of their predictive and/or prognostic value, which results in a lack of the different available tests in the clinical practice. ObjectiveTo carry out a pragmatic synthesis of current scientific evidence on liquid biopsy for prostate cancer patients. Evidence acquisitionNon-systematic literature review, narrowing the search to papers on liquid biopsy from blood samples in prostate cancer patients. We mainly selected works evaluating clinical endpoints in prostate cancer. Evidence synthesisThe most clinically advanced forms of liquid biopsy are circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA). Both CTCs and ctDNA have demonstrated their prognostic value in metastatic disease. ARV7 determination is the first predictive biomarker of the disease. Its implementation into routine clinical practice requires methodological standardization and adequate clinical validation of the different available ways to detect it. The detection of CTCs in the early stages of the disease still depends on the optimization of the diagnostic methods and on the development of the biological characterization of these cells. The biological information provided by CTCs and ctDNA is different; therefore, the study of its adequate combination is the object of cutting-edge research. ConclusionsThe absence of protocols and methodological standards is the limiting factor when aiming to reach conclusions that could have a potential impact on clinical practice. Therefore, the real short-term challenge for liquid biopsy is the establishment of consensus and common criteria.Resumen ContextoA pesar de ser una demostrada fuente de biomarcadores, la biopsia líquida aún no ha conseguido dar el paso a la práctica clínica habitual en pacientes con cáncer de próstata. Pocos biomarcadores se someten a una adecuada validación de su valor predictivo y/o pronóstico, prospectiva e independiente,; y ello resulta en una falta de traslación real a la clínica de los diferentes test disponibles. ObjetivoRealizar una síntesis, clínicamente pragmática, de la evidencia científica actual sobre la biopsia líquida sanguínea en cáncer de próstata. Adquisición de la evidenciarevisión no sistemática de la literatura acotando la búsqueda a trabajos sobre biopsia líquida de origen sanguíneo en cáncer de próstata. Se seleccionan preferentemente aquellos trabajos en los cuales se estudian end-points clínicos aplicados al cáncer de próstata. Síntesis de la evidenciaLas formas de biopsia líquida más avanzadas en términos clínicos son las células tumorales circulantes (CTCs) y el ADN tumoral circulante (ctDNA). Tanto CTCs como ctDNA han demostrado su valor pronóstico en enfermedad metastásica. La determinación de ARV7 constituye el primer biomarcador predictivo de la enfermedad. Su traslación a la práctica clínica habitual pasa por la estandarización metodológica y la adecuada validación clínica de las distintas formas de detección disponibles. La detección de CTCs en estadios iniciales de la enfermedad depende aún de la optimización de los métodos de detección y del desarrollo de la caracterización biológica de estas células. La información biológica aportada por CTCs y ctDNA es distinta; por ello, el estudio de su adecuada conjunción es objeto de la investigación más actual. ConclusionesLa ausencia de protocolos y estándares metodológicos es el factor limitante para llegar a conclusiones de impacto clínico. Por ello, el consenso y la unificación de criterios constituyen el verdadero desafío a corto plazo para la biopsia líquida." "secciones" => array:10 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Context" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Objective" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Evidence acquisition" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Evidence synthesis" ] 4 => array:2 [ "identificador" => "abst0025" "titulo" => "Conclusions" ] 5 => array:2 [ "identificador" => "abst0030" "titulo" => "Contexto" ] 6 => array:2 [ "identificador" => "abst0035" "titulo" => "Objetivo" ] 7 => array:2 [ "identificador" => "abst0040" "titulo" => "Adquisición de la evidencia" ] 8 => array:2 [ "identificador" => "abst0045" "titulo" => "Síntesis de la evidencia" ] 9 => array:2 [ "identificador" => "abst0050" "titulo" => "Conclusiones" ] ] ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Puche-Sanz I. et al. Biopsia líquida y cáncer de próstata. Evidencia actual aplicada a la clínica. Actas Urol Esp. 2020;44:139–147." ] ] "multimedia" => array:3 [ 0 => array:8 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1550 "Ancho" => 2917 "Tamanyo" => 357707 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0165" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "Main scientific milestones of liquid biopsy in prostate cancer<a class="elsevierStyleCrossRefs" href="#bib0075">15,23,35–39</a>." ] ] 1 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0170" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">CTCs \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">ctDNA \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">More adequate for: RNA and protein expression, assessment of tumor heterogeneity, possibility of cultures and susceptibility testing \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">More suitable for: specific mutations, copy number alterations \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Difficult long-term storage for posterior analysis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Feasible long-term storage for posterior analysis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Low detection rate in localized disease \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">More useful for minimal residual or localized disease \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">More complex and expensive detection but with standardized and validated technique (CellSearch) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Easier and less expensive detection, but without standardized or validated techniques \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Difficult clinical implementation due to high technical and economic costs \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Feasible clinical implementation, but still at risk of cfDNA dilution bias \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2280555.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Differences between CTCs and ctDNA." ] ] 2 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0175" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Reference \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Technology \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Number / type of patients \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Most important findings \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">CTCs \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Scher et al.<a class="elsevierStyleCrossRef" href="#bib0015">3</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">CellSearch® \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">164/CRPC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">CTC<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> count has a higher OS prognostic factor than PSA in mCRPC patients. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">De Bono et al.<a class="elsevierStyleCrossRef" href="#bib0020">4</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">CellSearch® \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">231/CRPC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">CTC<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> count has a higher OS prognostic factor than PSA in mCRPC patients. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Danila et al.<a class="elsevierStyleCrossRef" href="#bib0025">5</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">CellSearch® \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">112/CRPC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Higher CTC<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> count in patients with bone metastasis compared to other types of metastasesBaseline CTC count insignificantly related to OS \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Olmos et al.<a class="elsevierStyleCrossRef" href="#bib0030">6</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">CellSearch® \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">119/CRPC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">The CTC<a class="elsevierStyleCrossRef" href="#tblfn0010">b</a> count has OS prognostic factorThe comparison of baseline and follow-up CTCs is a prognostic factor of treatment response. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Scher et al.<a class="elsevierStyleCrossRef" href="#bib0035">7</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">CellSearch® \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1432/CRPC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">The combination of the CTC<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> count and LDH levels satisfy the Prentice criteria as prognostic biomarkers of OS \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Heller et al.<a class="elsevierStyleCrossRef" href="#bib0040">8</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">CellSearch® \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4196/CRPC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Going from detectable to undetectable CTCs is a prognostic biomarker associated with increased survival and certain clinical benefit. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Davis et al.<a class="elsevierStyleCrossRef" href="#bib0050">10</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">CellSearch® \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">97/localized PCa \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Low CTC count which does not correlate with prognostic factors \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Maestro et al.<a class="elsevierStyleCrossRef" href="#bib0055">11</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">CellSearch® \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">26/localized PCa24/CRPC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">CTCs detected in all patients, but significant differences were found from localized to mCRPC patients \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Meyer et al.<a class="elsevierStyleCrossRef" href="#bib0060">12</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">CellSearch® \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">152/localized PCa \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">CTCs detected in some patients with cut-off point>1 CTC but no correlation was observed with clinical data to consider it as prognostic biomarker \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Puche-Sanz et al.<a class="elsevierStyleCrossRef" href="#bib0065">13</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">MACS technology \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">86/localized PCa \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Positive correlation between tissue expression of AR and presence of CTCsNegative correlation for EGFR expression in tissue and AR in CTCsThe prognostic role of AR expression within CTCs is proposed. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Scher et al.<a class="elsevierStyleCrossRef" href="#bib0095">19</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Epic Sciences \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">179/mCRPC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">CTCs heterogeneity was associated with OS (low heterogeneity in patients with lower CTC count associated with better OS) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Antonarakis et al.<a class="elsevierStyleCrossRef" href="#bib0115">23</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">AdnaTest \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">62/mCRPC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Presence of AR-V7 in CTCs was associated with resistance to enzalutamide and abiraterone \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Onstek et al.<a class="elsevierStyleCrossRef" href="#bib0125">25</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">CellSearch® \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">76/mCRPC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Prevalence of AR-V7 in CTCs of abiraterone-resistant patients \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Scher et al.<a class="elsevierStyleCrossRef" href="#bib0130">26</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Epic Sciences \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">191/mCRPC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Validation of nuclear or cytoplasmic localization of AR-V7Nuclear localization of AR-V7 associated with lower OS \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Scher et al.<a class="elsevierStyleCrossRef" href="#bib0135">27</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Epic Sciences \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">142/mCRPC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Validation of study 26 (nuclear localization of AR-V7 and lower OS) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Tommasi et al.<a class="elsevierStyleCrossRef" href="#bib0015">3</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">AdnaTest \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">44/mCRPC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Validation of the inverse correlation between AR-V7 expression and PSA-based response \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Amstrong et al.<a class="elsevierStyleCrossRef" href="#bib0155">31</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Epic SciencesAdnaTest \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">118/mCRPC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Presence of AR-V7 in CTCs is associated to hormone therapy resistanceBoth platforms obtained comparable results \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">ctDNA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Heitzer et al.<a class="elsevierStyleCrossRef" href="#bib0070">14</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">WGS (Illumina) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">9 mCRPC4 castration sensitive \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Identification of multiple aberrations (interstitial deletion of 21q22.2–3, 8p loss, 8q gain, AR amplification, etc.)The results are not correlated to clinical variables despite performance of serial analysis in some patients \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Azad et al.<a class="elsevierStyleCrossRef" href="#bib0075">15</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">aCGH \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">62 mCRPC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">More frequent AR amplification in patients who progress to enzalutamide than in those who progress to abirateroneDetection of AR mutations associated with treatment resistance \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Joseph et al.<a class="elsevierStyleCrossRef" href="#bib0080">16</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">BEAMing \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">29 RNA-509-treated patients \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Presence of F876L mutation associated with resistance in 3/29 patients \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Wyatt et al.<a class="elsevierStyleCrossRef" href="#bib0085">17</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">AR deep seq (Illumina)Ampliseq custom panel \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">65 mCRPC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">AR amplification associated with primary resistanceMutations and copy number changes were detected during progression in all patients (including AR amplification, and mutations in RB1, MET, MYC, PI3K and CTNNB1) \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2280554.png" ] ] ] "notaPie" => array:2 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "a" "nota" => "Cutoff value> 5 CTC/7,5ml of blood." ] 1 => array:3 [ "identificador" => "tblfn0010" "etiqueta" => "b" "nota" => "Divided into 3 groups: <5,>5 y <50, >50 per 7,5ml of blood." ] ] ] "descripcion" => array:1 [ "en" => "Main clinical studies with CTCs and ctDNA in prostate cancer." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:39 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Circulating Tumor Cells (CTCs): From Detection to Dissection" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "M.J. Serrano" 1 => "J.L. Garcia-Puche" 2 => "J. Exposito" 3 => "J.A. Lorente" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:4 [ "tituloSerie" => "J Clin Diagnosis Res." "fecha" => "2015" "volumen" => "3" "paginaInicial" => "120" ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0010" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The metastasis-promoting roles of tumor associated immune cells" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "H.A. Smith" 1 => "Y. 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Review article

Liquid biopsy and prostate cancer. Current evidence applied to clinical practice

I. Puche-Sanza,

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nacho.puchesanz@gmail.com

Corresponding author.

, A. Rodríguez-Martínezb, M.C. Garrido-Navasc, I. Robles-Fernándezb, F. Vázquez-Alonsoa, M.J. Álvarez Cuberod, J.A. Lorente-Acostab, M.J. Serrano-Fernándezc, J.M. Cózar-Olmoa

a Departamento de Urología, Hospital Universitario Virgen de las Nieves, Instituto de Investigación Biosanitaria-IBS, Granada, Spain

b Departamento de Medicina Legal, Laboratorio de Identificación Genética, Universidad de Granada, Granada, Spain

c Comprehensive Oncology Division. Hospital Clínico-Hospital Universitario Virgen de las Nieves, Universidad de Granada, Granada, Spain

d Departamento de Bioquímica y Biología Molecular III, Facultad de Medicina, Universidad de Granada, Granada, Spain

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          "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Main scientific milestones of liquid biopsy in prostate cancer<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">15&#44;23&#44;35&#8211;39</span></a>&#46;</p>"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Background</span><p id="par0005" class="elsevierStylePara elsevierViewall">The development and approval of new medications over the last 10 years has generated a wide range of therapeutic options for the management of prostate cancer &#40;PCa&#41;&#46; Although these new molecules have improved survival and quality of life of patients&#44; they have also revealed another reality&#58; the absence of predictive biomarkers that determine their optimal indication and allow adequate assessment of their clinical effectiveness&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Liquid biopsy &#40;LB&#41; refers to any minimally invasive test performed on a body fluid &#40;blood&#44; urine&#44; semen&#44; saliva&#41;&#44; which make the detection of cellular or molecular biomarkers possible in order to obtain diagnostic&#44; prognostic or predictive information of the disease&#46; Thus&#44; LB presents two advantages&#44; temporal and spatial&#44; over solid biopsy&#46; On the one hand&#44; being a minimally invasive technique&#44; it allows frequent repetition providing &#34;real time&#34; data and facilitating the monitoring of the disease&#46; On the other hand&#44; it provides global information of all tumor subclones&#44; since it is not limited to one single region&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> The investigation on LB in PCa began in peripheral blood and&#44; therefore&#44; has been the most studied body fluid to date&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">Despite being a novel source of biomarkers&#44; the actual clinical impact of LB in patients with PCa is still unclear&#46; The truth is that very few biomarkers undergo an adequate&#44; prospective and independent validation of their predictive or prognostic value&#44; and this fact has impeded their translation into clinical practice so far&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Objective</span><p id="par0020" class="elsevierStylePara elsevierViewall">Perform a pragmatic clinical synthesis of current scientific evidence on blood LB in PCa and highlight those key biological concepts to analyze the usefulness of LB in the management of PCa&#46;</p><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Evidence acquisition</span><p id="par0025" class="elsevierStylePara elsevierViewall">A non-systematic review of the literature is carried out through <span class="elsevierStyleItalic">PubMed</span> with the keywords liquid biopsy and prostate cancer&#46; Only those works related to blood LB with significant clinical <span class="elsevierStyleItalic">endpoints</span>-such as overall survival &#40;OS&#41;&#44; progression-free survival &#40;PFS&#41; or biochemical recurrence studied in PCa- are selected&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Evidence synthesis</span><p id="par0030" class="elsevierStylePara elsevierViewall">The blood LB in PCa has focused on two large lines of research&#58; circulating tumor cells &#40;CTCs&#41; and circulating tumor DNA &#40;ctDNA&#41;&#46; In addition&#44; due to its current clinical relevance&#44; we include a section referring to the androgen receptor splice variant 7 &#40;AR-V7&#41;&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Circulating tumor cells</span><p id="par0035" class="elsevierStylePara elsevierViewall">According to the current model of the metastasis process&#44; these cells are released into the bloodstream from the primary tumor or from the metastasis itself and&#44; after a series of -still unknown- changes&#44; some of them are able to &#34;survive&#34; in the bloodstream&#44; reach other target organs and cause metastatic disease&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">One of these changes required in CTCs is the loss of epithelial characteristics and the acquisition of mesenchymal characteristics &#40;epithelial-mesenchymal transition&#44; EMT&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> This process includes those biological changes required for the adaptation of CTCs to the blood environment and their survival in it&#46; In addition&#44; cell dissemination seems to be associated with the role of the cells of the immune system &#40;for example&#44; activated platelets or macrophages&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">It must be noted that there is currently only one FDA-approved CTCs detection platform with prognostic value in mCRPC&#58; CellSearch&#174; &#40;Menarini Silicon Biosystems&#41;&#46; Therefore&#44; most clinical relevance studies with CTCs in PCa have used this platform&#46; CellSearch&#174; is based on the immunomagnetic isolation of CTCs that express the epithelial cell adhesion molecule &#40;EpCAM&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> This is a transmembrane glycoprotein involved in cell proliferation and differentiation&#44; with oncogenic potential&#44; which is expressed exclusively in epithelial cells or tumors of epithelial origin&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Circulating tumor cells and metastatic prostate cancer</span><p id="par0050" class="elsevierStylePara elsevierViewall">The value of CTCs as a prognostic biomarker in metastatic PCa has been widely demonstrated&#46; The most important study that validated the prognostic capacity of CTCs in metastatic PCa was the IMMC<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> trial&#44; with a total of 164 patients with mCRPC who began treatment with chemotherapy and whose CTCs values were analyzed by CellSearch&#174; system in 3-4-week intervals&#46; After adjusting the data according to the main prognostic indicators identified &#40;LDH&#44; ECOG performance status&#44; hemoglobin&#44; alkaline phosphatase&#41;&#44; a multivariate analysis revealed that patients with an unfavorable baseline count &#40;&#8805;5 CTC&#47;7&#44;5<span class="elsevierStyleHsp" style=""></span>mL&#41; presented lower OS rates than patients with a favorable one &#40;&#60;5 CTC&#47;7&#44;5<span class="elsevierStyleHsp" style=""></span>mL&#41;&#46; This study also analyzed the conversion of patients from one group to another after treatment&#46; We must highlight that patients who maintained favorable counts in all determinations were those who showed a higher OS &#40;26 months&#41;&#44; followed by patients who went from unfavorable to favorable &#40;21&#46;3 months&#41;&#44; those who went from favorable to unfavorable &#40;9&#46;3 months&#41; and&#44; finally&#44; those who remained unfavorable &#40;6&#46;8 months&#41;&#46; Subsequently&#44; the multivariate analysis of the data assessed the capacity of CTCs as a continuous variable in the prediction of OS before treatment initiation&#44; which showed that only CTCs and LDH were independent predictors of OS&#44; a fact that could not be demonstrated with PSA&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">De Bono et al&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> had already shown that the survival predictive ability of the qualitative determination of CTCs &#40;&#62;5 o<span class="elsevierStyleHsp" style=""></span>&#60;5 CTC&#47;7&#44;5<span class="elsevierStyleHsp" style=""></span>mL&#41; was higher than that of a decreased PSA&#44; especially at onset&#46; Their work showed that&#44; at 12 weeks of treatment&#44; the ROC curves demonstrated a significant superiority of the CTCs over the 30&#37; decrease in PSA when predicting the death of the patient at 12 months &#40;<span class="elsevierStyleItalic">area under the curve&#44;</span> AUC of 81&#46;5&#37; vs&#46; 67&#46;5&#37;&#44; respectively&#41;&#46; However&#44; the objective of the establishment of a standard cut-off point has not been achieved so far&#46; A study of the Memorial Sloan-Kettering Cancer Center analyzed a cohort of 112 patients with mCRPC&#44; showing a strong correlation between CTCs and OS&#44; but with no threshold effect&#46; Baseline CTC counts were modestly related to other standard indicators such as PSA or bone scintigraphy&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> On the other hand&#44; in another study of the Royal Marsden analyzing 119 mCRPC patients&#44; they established 3<span class="elsevierStyleHsp" style=""></span> survival prognostic groups &#40;&#60;5 CTC&#47;7&#44;5<span class="elsevierStyleHsp" style=""></span>mL&#44; 5&#8211;50 CTC&#47;7&#44;5<span class="elsevierStyleHsp" style=""></span>mL y<span class="elsevierStyleHsp" style=""></span>&#62;50 CTC&#47;7&#44;5<span class="elsevierStyleHsp" style=""></span>mL&#41;&#46; The multivariate analysis showed that <span class="elsevierStyleHsp" style=""></span>&#62;5 CTC&#47;7&#44;5<span class="elsevierStyleHsp" style=""></span>mL was an independent factor of OS&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">However&#44; these works revealed a biologically relevant fact&#58; the survival of patients in whom CTCs were not detected was significantly variable&#46; Therefore&#44; the &#34;absence&#34; of CTCs &#40;according to the CellSearch&#174; platform&#41; did not guarantee a good prognosis&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">Once the prognostic value of the CTCs was demonstrated&#44; these began to be included as biomarkers in several phase III clinical trials aiming to establish their value as surrogate biomarkers of OS&#46; The first one was the COU-AA-301&#44; which showed that the 2-year survival of patients with<span class="elsevierStyleHsp" style=""></span>&#62;5 CTC&#47;7&#44;5<span class="elsevierStyleHsp" style=""></span>mL vs&#46;<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>5 CTC&#47;7&#44;5<span class="elsevierStyleHsp" style=""></span>mL at 12 weeks of treatment was 2 vs&#46; 46&#37;&#44; respectively&#46; Moreover&#44; it was demonstrated that they met the four Prentice criteria required to be considered a surrogate marker for OS&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> This quality of CTCs was studied in four phase III clinical trials&#46; A recent joint analysis of the 6081 patients included in these trials established 2 new end-points with a high discriminatory power of OS at 13 weeks of treatment&#58; the CTCs<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0 from having any CTCs before treatment&#44; to have none at 13 weeks and CTCs conversion from 5 or more CTCs before treatment initiation to less than 5 CTCs at 13 weeks&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a></p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Circulating tumor cells and localized prostate cancer</span><p id="par0070" class="elsevierStylePara elsevierViewall">CTCs detection rates when disease is incipient are very low and variable &#40;8-27&#37;&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0045"><span class="elsevierStyleSup">9&#8211;13</span></a> Specifically&#44; the CellSearch&#174; system has shown low CTCs detection capacity in patients with localized PCa&#46; Up to 34&#37; of patients may have EpCAM-negative CTCs &#40;invisible to CellSearch&#174; but detectable by other methods&#41; due to changes related to mesenchymal epithelial transition&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a></p><p id="par0075" class="elsevierStylePara elsevierViewall">The clinical evidence of localized disease is heterogeneous&#46; Davis et al&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> used the CellSearch&#174; system in 97 patients with localized PCa and a group of patients with high PSA and negative biopsy&#46; The presence of CTCs was similar in both groups &#40;21 and 20&#37;&#44; respectively&#41;&#46; In addition&#44; no relationship was observed between the presence of CTCs and tumor volume&#44; pathological stage or Gleason score&#44; which led the authors to conclude that CTCs have no prognostic value in these patients&#46; On the contrary&#44; Maestro et al&#46; demonstrated -also with CellSearch&#174;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a>- the presence of CTCs in 100&#37; of patients &#40;26&#47;26&#41; with localized PCa of their series&#46; However&#44; in this study&#44; the definition of &#34;localized&#34; PCa was probably indeterminate&#46; Any PCa in the absence of metastases&#44; but with any lymphatic involvement&#44; was classified as localized PCa&#46; The largest series in this scenario studied the presence of CTCs using CellSearch&#174; in 152 patients before and after radical prostatectomy&#46; Only 11&#37; of patients had CTCs before surgery and no relationship was found with the subsequent biochemical recurrence rate&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">These data show that the currently approved technology to quantify CTCs in mCRPC is still limited for early stages of PCa&#46; However&#44; other methodologies have shown that it is possible to detect different CTCs subpopulations&#44; even at early stages of the disease&#44;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> and the development of new isolation platforms&#44; such as those based on size and deformability&#44; as well as proper cell characterization&#44; will probably clarify the role of CTCs in this scenario&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Circulating tumor DNA</span><p id="par0085" class="elsevierStylePara elsevierViewall">Necrotic and apoptotic tumor cells &#40;derived from the primary tumor&#44; their metastases or the circulating tumor cells themselves&#41; can release DNA fragments into the blood&#44; called ctDNA &#40;which can be detected&#41;&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">Most PCa studies with ctDNA have focused on the detection of nucleic acids associated to the altered expression of AR&#46; One of the first works in this regard<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> performed a whole-genome sequencing &#40;genome-wide analysis&#41; of ctDNA in patients with CRPC&#44; revealing the presence of multiple copy number aberrations in the AR locus &#40;losses in 8<span class="elsevierStyleHsp" style=""></span>p and gains in 8<span class="elsevierStyleHsp" style=""></span>q&#41;&#46; Later&#44; Azad et al&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> demonstrated that AR gene amplification was significantly more frequent in patients with progression on enzalutamide than in those on abiraterone&#46; In another study&#44; the presence of the AR F876<span class="elsevierStyleHsp" style=""></span>L mutation was associated with resistance in ARN-509-treated CRPC patients&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> A recent study by Wyatt et al&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> evaluated ctDNA in serial samples &#40;before and 3 months after treatment&#41; of 65 patients with mCRPC treated with enzalutamide&#46; In this study&#44; array comparative genomic hybridization copy number profiling and deep AR gene sequencing was performed&#46; Samples collected at the end of treatment were also subjected to targeted sequencing of 19 prostate cancer-associated genes&#46; The authors observed AR mutations in 23&#37; of baseline samples&#46; In addition&#44; they demonstrated that all patients with gains in AR copies&#44; AR amplifications&#44; multiple AR mutations&#44; RB1 loss or MET and MYC gain were at greater risk of having resistance to enzalutamide than those patients without these genetic characteristics in their ctDNA&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">All studies point in the same direction&#58; aberrations in the AR gene detected in the ctDNA demonstrate prognostic factors in response to androgen deprivation therapy&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Circulating tumor cells or ctDNA&#63;</span><p id="par0100" class="elsevierStylePara elsevierViewall">CTCs and ctDNA have demonstrated their value as biomarkers in PCa&#46; However&#44; we must not choose only one as the most efficient modality to implement into clinical practice&#44; as both provide real-time photographs of the molecular biology of the tumor&#44; including the assessment of AR&#44; and each one will give us different and complementary information&#46; Hence&#44; the appropriate use of both sources will provide the highest clinical utility<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; Their prognostic value in clinical practice is comparable&#44; and the correlation between ctDNA levels and CTC<span class="elsevierStyleHsp" style=""></span>&#62;5<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> counts has been demonstrated &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0105" class="elsevierStylePara elsevierViewall">The detection of ctDNA alterations has the advantage of lower speed and cost compared to CTCs&#44; so it could be more suitable for large-scale serial analysis of specific tumor mutations&#46; The accelerated development and the progressively decreasing cost of these analyses will probably facilitate the implementation of the ctDNA study &#40;before the detection of CTCs&#41; in routine clinical practice&#46; However&#44; the determination of ctDNA is not yet standardized or clinically validated in PCa&#46; To date&#44; the <span class="elsevierStyleItalic">cobas</span>&#174; <span class="elsevierStyleItalic">EGFR</span> Mutation Test v2 &#40;Roche Molecular Systems&#44; Pleasanton&#44; CA&#44; USA&#41; is the only test that has been standardized and validated by the FDA&#44; specifically used for the prediction of response to erlotinib in non-small cell lung cancer&#46; A disadvantage of ctDNA is cfDNA dilution bias &#40;total cell-free DNA&#41;&#46; It is currently impossible to know if the absence of ctDNA is real &#40;true negative&#41; or whether it is bias due to dilution in the cfDNA &#40;false negative&#41; in a sample that does not show copy number alterations or mutations in the analyzed genes&#46; In addition&#44; unlike gains&#44; the detection of losses is especially difficult with a low amount of available ctDNA&#44; and it is estimated that at least a minimum ratio of 10&#37; is necessary to determine them&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a></p><p id="par0110" class="elsevierStylePara elsevierViewall">With CTCs&#44; the detection implies higher costs and is technically more complex&#46; However&#44; it has some advantages over ctDNA&#46; There is a standardized platform &#40;CellSearch&#174;&#41; approved by the FDA for its detection&#44; which can perform many expression analyses &#40;e&#46;g&#46;&#44; mRNA of the AR and its splice variants&#44; whole transcriptome or specific proteins sequencing&#44; among others&#41;&#46; In addition&#44; CTCs enable the analysis of the phenotypic and genetic heterogeneity of tumor tissue&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> The last positive aspect of CTCs is their ability to grow in vitro and&#44; therefore&#44; their potential to undergo individualized testing for drug susceptibility&#46; CTCs culture has shown its potential in patients with CRPC&#44; but there is still a long way to go for its optimization and clinical applicability&#46;<a class="elsevierStyleCrossRefs" href="#bib0100"><span class="elsevierStyleSup">20&#44;21</span></a></p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">AR-V7&#44; the first predictive biomarker using liquid biopsy for the management of prostate cancer</span><p id="par0115" class="elsevierStylePara elsevierViewall">AR C terminal loss &#40;where testosterone must naturally bind to activate it&#41; results in alternative AR variants which have been associated to castration-resistant prostate cancer&#44; especially in the case of the AR-V7 variant&#46; It is known that the expression of AR-V7 in primary PCa is very low &#40;&#60;1&#37; of patients&#41;&#44; however&#44; in mCRPC it can reach to 75&#37; and&#44; in addition&#44; its expression increases after treatment with abiraterone or enzalutamide&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a></p><p id="par0120" class="elsevierStylePara elsevierViewall">The first study showing the predictive capacity of AR-V7 was the one of Antonarakis et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> which demonstrated that the detection of AR-V7 mRNA levels in CTCs &#40;Johns Hopkins University AdnaTest CTC AR-V7 mRNA assay&#41; of patients with mCRPC was strongly associated with resistance to abiraterone or enzalutamide in terms of lower rates PSA response&#44; PFS and OS&#46; These data determined that AR-V7 could provide predictive utility and guide treatment decisions&#46; After this study&#44; several groups devised other methods of detection of AR-V7 and obtained similar results in different clinical scenarios&#46;<a class="elsevierStyleCrossRefs" href="#bib0120"><span class="elsevierStyleSup">24&#8211;26</span></a> Most detection techniques apply quantitative PCR techniques on previously lysed CTCs&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">Another detection system of AR-V7 is the EPIC Sciences platform &#40;Epic Sciences CTC nuclear-specific AR-V7 protein assay&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a> This platform is based on the detection of epithelial CTCs and subsequent detection by immunofluorescence for AR-V7 protein on the morphologically intact cell&#46; It allows quantification of CTCs&#44; AR-V7 expression analysis and its cellular localization&#46; Nuclear-localized AR-V7 &#40;not its cytoplasmic expression&#41; was shown to be related to a lower OS of mCRPC patients treated with novel antiandrogens and a higher OS in those treated with taxanes &#40;7&#46;3 vs&#46; 14 months&#44; respectively&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a></p><p id="par0130" class="elsevierStylePara elsevierViewall">Beside AR-V7 detection in CTCs&#44; AR-V7 can also be detected in exosomes&#46; Del Re et al&#46;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a> achieved AR-V7 detection using Droplet Digital PCR &#40;ddPCR&#41; system from plasma-derived exosomal RNA of 36 mCRPC patients&#46; They also confirmed a worse PFS and shorter OS in the AR-V7<span class="elsevierStyleSup">&#43;</span> patients &#40;39&#37; of the total&#41;&#46; While CTC isolation and processing are complex and expensive&#44; the detection of AR-V7 in circulating exosomes is simpler and can be achieved at lower costs&#44; which would facilitate disease monitoring&#46; However&#44; this detection technique requires more extensive validation&#46;</p><p id="par0135" class="elsevierStylePara elsevierViewall">The clinical limitation of the previously mentioned works is&#44; above all&#44; the small number of patients included&#46; Although the effect of the predictive capacity of AR-V7 on the management of patients with CRPC seems to be evident&#44;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a> a standardized operating procedure is still required&#44; as well as multicenter and prospective validation that clinically support the results obtained with the different detection techniques&#46; In this sense&#44; there are two interesting published studies which aim to answer this question&#46; In one of them&#44; Tommasi et al&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a> develop for the first time a standardized procedure for the determination of AR-V7 in CPRC patients&#44; opening the door to a clinical trial that will solidly analyze the role of this variant in clinical decision making&#46; The second one is a prospective&#44; multicenter clinical trial &#40;PROPHECY trial&#44; NCT02269982&#41;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a> with the objective of independently validating -in 118 patients with high-risk mCRPC who started treatment with abiraterone or enzalutamide- the prognostic capacity of AR-V7 in CTCs using the Epic Biosciences CTC nuclear-specific AR-V7 protein assay<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a> and the Johns Hopkins University modified AdnaTest CTC AR-V7 mRNA assay&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> The study showed a 10&#8211;24 &#37; AR-V7<span class="elsevierStyleSup">&#43;</span> patients at baseline&#44; and there was 82&#37; observed agreement between tests&#46; AR-V7<span class="elsevierStyleSup">&#43;</span> patients showed similar outcomes&#58; little clinical benefit&#44; very low probability of PSA decline and shorter PFS and OS by either assay&#46; Therefore&#44; the authors recommend avoiding the use of abiraterone or enzalutamide in AR-V7<span class="elsevierStyleSup">&#43;</span> patients with any of these 2 detection techniques&#44; especially if they have been previously treated before with these molecules&#46;</p><p id="par0140" class="elsevierStylePara elsevierViewall">Despite all these&#44; AR-V7 detection can possibly explain only 25&#37; of resistance to novel antiandrogens&#59; meaning that most resistance mechanisms are still unknown&#46;<a class="elsevierStyleCrossRefs" href="#bib0090"><span class="elsevierStyleSup">18&#44;31</span></a> However&#44; basic research on castration-resistant disease is very abundant and will yield new evidence in the near future&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Future perspectives and cost-effectiveness</span><p id="par0145" class="elsevierStylePara elsevierViewall">In order to be implemented in clinical practice&#44; LB should demonstrate its cost-effectiveness through greater methodological efficiency&#46; Due to the basic technology and the heterogeneity of the evidence&#44; studies in this regard have not yet been carried out &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; The costs of LB determination depend on the technology used and the type and number of biomarkers under study&#46; Cost estimation is not easy&#44; as there is still no consensus regarding technology &#40;especially CTC isolation&#41; and the specific biomarkers to analyze&#46; However&#44; we believe that once these &#40;biomarkers and technologies&#41; are validated&#44; the implementation of these determinations will improve the cost-benefit balance&#46; The goal is to accurately stratify patients in order to predict treatment and prevention strategies for a particular disease &#40;precision medicine&#41;&#46; This will reduce costs&#44; not only associated with determinations&#44; but also with over-treatments&#46; In our opinion&#44; this fact depends on two eventual milestones&#58; greater technological development&#44; which will allow automation and methodological standardization&#44; and a wider understanding of molecular biology for better selection of sufficiently sensitive and specific biomarkers&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0150" class="elsevierStylePara elsevierViewall">In addition to the standardization of procedures&#44; technological development is currently focused on new bioinformatics tools for computational analysis capable of developing complex interpretive algorithms that can reliably and reproducibly correlate molecular data with clinical data&#46;<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">32&#44;33</span></a> Methodological automation will reduce the high costs of currently required personnel and infrastructure&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a> In parallel&#44; nonspecific next-generation sequencing techniques provide more and more information to the general library of molecular biology of cancer&#46; A wise interpretation of this information will allow the establishment of the most clinically relevant molecular targets to be detected&#44; as well as a more adequate selection of candidates for each test&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">33</span></a> This technical optimization will allow large-scale cost-effectiveness studies that will foster the uptake of LB in the clinic&#46;</p></span></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Conclusions</span><p id="par0155" class="elsevierStylePara elsevierViewall">CTCs have unequivocally demonstrated their prognostic value in PCa&#44; but further evidence is still required to elucidate the full value of CTC enumeration as surrogate for overall survival&#46; Once the predictive capacity of the CTCs has been demonstrated&#44; especially with the determination of AR-V7&#44; its implementation into routine clinical practice will imply methodological standardization and the adequate clinical validation of the different detection methods available&#46; The detection of CTCs in early stages of the disease still depends on the optimization of these methods and the development of the biological characterization of these cells&#46;</p><p id="par0160" class="elsevierStylePara elsevierViewall">Regarding ctDNA&#44; given the lower frequency of specific mutations in PCa&#44; analyses are necessary to detect structural genomic alterations or copy number changes&#46; There are not many comparative clinical studies of CTCs and ctDNA&#46; The future will provide proper analysis of both markers in the same sample&#46;</p><p id="par0165" class="elsevierStylePara elsevierViewall">LB has not yet managed to establish in routine clinical practice due to the absence of methodological standards and multicenter&#44; prospective clinical studies that support its results&#46; Therefore&#44; consensus&#44; the unification of criteria and the adequate design of clinical trials constitute the real short-term challenge for this discipline&#46;</p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Conflicts of interest</span><p id="par0170" class="elsevierStylePara elsevierViewall">The authors declare no conflicts of interest&#46;</p></span></span>"
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              "titulo" => "Adquisici&#243;n de la evidencia"
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              "titulo" => "S&#237;ntesis de la evidencia"
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          "titulo" => "Background"
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              "identificador" => "sec0015"
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              "titulo" => "Evidence synthesis"
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              "titulo" => "Circulating tumor cells"
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              "identificador" => "sec0030"
              "titulo" => "Circulating tumor cells and metastatic prostate cancer"
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            4 => array:2 [
              "identificador" => "sec0035"
              "titulo" => "Circulating tumor cells and localized prostate cancer"
            ]
            5 => array:2 [
              "identificador" => "sec0040"
              "titulo" => "Circulating tumor DNA"
            ]
            6 => array:2 [
              "identificador" => "sec0045"
              "titulo" => "Circulating tumor cells or ctDNA&#63;"
            ]
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              "identificador" => "sec0050"
              "titulo" => "AR-V7&#44; the first predictive biomarker using liquid biopsy for the management of prostate cancer"
            ]
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              "titulo" => "Future perspectives and cost-effectiveness"
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          "titulo" => "Conclusions"
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          "titulo" => "Conflicts of interest"
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            0 => "Liquid biopsy"
            1 => "Prostate cancer"
            2 => "Circulating tumor cells"
            3 => "Circulating tumor DNA"
            4 => "ARV7&#46;"
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Context</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Despite being a validated source of biomarkers&#44; liquid biopsy has not yet succeeded in becoming part of the standard clinical practice in prostate cancer patients&#46; Few biomarkers undergo adequate validation&#44; prospective and independent&#44; of their predictive and&#47;or prognostic value&#44; which results in a lack of the different available tests in the clinical practice&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Objective</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">To carry out a pragmatic synthesis of current scientific evidence on liquid biopsy for prostate cancer patients&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Evidence acquisition</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Non-systematic literature review&#44; narrowing the search to papers on liquid biopsy from blood samples in prostate cancer patients&#46; We mainly selected works evaluating clinical endpoints in prostate cancer&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Evidence synthesis</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">The most clinically advanced forms of liquid biopsy are circulating tumor cells &#40;CTCs&#41; and circulating tumor DNA &#40;ctDNA&#41;&#46; Both CTCs and ctDNA have demonstrated their prognostic value in metastatic disease&#46; ARV7 determination is the first predictive biomarker of the disease&#46; Its implementation into routine clinical practice requires methodological standardization and adequate clinical validation of the different available ways to detect it&#46; The detection of CTCs in the early stages of the disease still depends on the optimization of the diagnostic methods and on the development of the biological characterization of these cells&#46; The biological information provided by CTCs and ctDNA is different&#59; therefore&#44; the study of its adequate combination is the object of cutting-edge research&#46;</p></span> <span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Conclusions</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">The absence of protocols and methodological standards is the limiting factor when aiming to reach conclusions that could have a potential impact on clinical practice&#46; Therefore&#44; the real short-term challenge for liquid biopsy is the establishment of consensus and common criteria&#46;</p><p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Resumen</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Contexto</span><p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">A pesar de ser una demostrada fuente de biomarcadores&#44; la biopsia l&#237;quida a&#250;n no ha conseguido dar el paso a la pr&#225;ctica cl&#237;nica habitual en pacientes con c&#225;ncer de pr&#243;stata&#46; Pocos biomarcadores se someten a una adecuada validaci&#243;n de su valor predictivo y&#47;o pron&#243;stico&#44; prospectiva e independiente&#44;&#59; y ello resulta en una falta de traslaci&#243;n real a la cl&#237;nica de los diferentes test disponibles&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Objetivo</span><p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Realizar una s&#237;ntesis&#44; cl&#237;nicamente pragm&#225;tica&#44; de la evidencia cient&#237;fica actual sobre la biopsia l&#237;quida sangu&#237;nea en c&#225;ncer de pr&#243;stata&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Adquisici&#243;n de la evidencia</span><p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">revisi&#243;n no sistem&#225;tica de la literatura acotando la b&#250;squeda a trabajos sobre biopsia l&#237;quida de origen sangu&#237;neo en c&#225;ncer de pr&#243;stata&#46; Se seleccionan preferentemente aquellos trabajos en los cuales se estudian <span class="elsevierStyleItalic">end-points</span> cl&#237;nicos aplicados al c&#225;ncer de pr&#243;stata&#46;</p></span> <span id="abst0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">S&#237;ntesis de la evidencia</span><p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">Las formas de biopsia l&#237;quida m&#225;s avanzadas en t&#233;rminos cl&#237;nicos son las c&#233;lulas tumorales circulantes &#40;CTCs&#41; y el ADN tumoral circulante &#40;ctDNA&#41;&#46; Tanto CTCs como ctDNA han demostrado su valor pron&#243;stico en enfermedad metast&#225;sica&#46; La determinaci&#243;n de ARV7 constituye el primer biomarcador predictivo de la enfermedad&#46; Su traslaci&#243;n a la pr&#225;ctica cl&#237;nica habitual pasa por la estandarizaci&#243;n metodol&#243;gica y la adecuada validaci&#243;n cl&#237;nica de las distintas formas de detecci&#243;n disponibles&#46; La detecci&#243;n de CTCs en estadios iniciales de la enfermedad depende a&#250;n de la optimizaci&#243;n de los m&#233;todos de detecci&#243;n y del desarrollo de la caracterizaci&#243;n biol&#243;gica de estas c&#233;lulas&#46; La informaci&#243;n biol&#243;gica aportada por CTCs y ctDNA es distinta&#59; por ello&#44; el estudio de su adecuada conjunci&#243;n es objeto de la investigaci&#243;n m&#225;s actual&#46;</p></span> <span id="abst0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Conclusiones</span><p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">La ausencia de protocolos y est&#225;ndares metodol&#243;gicos es el factor limitante para llegar a conclusiones de impacto cl&#237;nico&#46; Por ello&#44; el consenso y la unificaci&#243;n de criterios constituyen el verdadero desaf&#237;o a corto plazo para la biopsia l&#237;quida&#46;</p></span>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0015">Please cite this article as&#58; Puche-Sanz I&#46; et al&#46; Biopsia l&#237;quida y c&#225;ncer de pr&#243;stata&#46; Evidencia actual aplicada a la cl&#237;nica&#46; Actas Urol Esp&#46; 2020&#59;44&#58;139&#8211;147&#46;</p>"
      ]
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          "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Main scientific milestones of liquid biopsy in prostate cancer<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">15&#44;23&#44;35&#8211;39</span></a>&#46;</p>"
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                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">CTCs&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">ctDNA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">More adequate for&#58; RNA and protein expression&#44; assessment of tumor heterogeneity&#44; possibility of cultures and susceptibility testing&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">More suitable for&#58; specific mutations&#44; copy number alterations&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Difficult long-term storage for posterior analysis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Feasible long-term storage for posterior analysis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Low detection rate in localized disease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">More useful for minimal residual or localized disease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">More complex and expensive detection but with standardized and validated technique &#40;CellSearch&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Easier and less expensive detection&#44; but without standardized or validated techniques&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Difficult clinical implementation due to high technical and economic costs&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Feasible clinical implementation&#44; but still at risk of cfDNA dilution bias&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Differences between CTCs and ctDNA&#46;</p>"
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        "tabla" => array:2 [
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Reference&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Technology&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Number &#47; type of patients&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Most important findings&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CTCs&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Scher et al&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CellSearch&#174;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">164&#47;CRPC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CTC<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a> count has a higher OS prognostic factor than PSA in mCRPC patients&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">De Bono et al&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CellSearch&#174;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">231&#47;CRPC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CTC<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a> count has a higher OS prognostic factor than PSA in mCRPC patients&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Danila et al&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CellSearch&#174;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">112&#47;CRPC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Higher CTC<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a> count in patients with bone metastasis compared to other types of metastasesBaseline CTC count insignificantly related to OS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Olmos et al&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CellSearch&#174;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">119&#47;CRPC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">The CTC<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a> count has OS prognostic factorThe comparison of baseline and follow-up CTCs is a prognostic factor of treatment response&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Scher et al&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CellSearch&#174;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1432&#47;CRPC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">The combination of the CTC<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a> count and LDH levels satisfy the Prentice criteria as prognostic biomarkers of OS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Heller et al&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CellSearch&#174;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4196&#47;CRPC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Going from detectable to undetectable CTCs is a prognostic biomarker associated with increased survival and certain clinical benefit&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Davis et al&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CellSearch&#174;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">97&#47;localized PCa&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Low CTC count which does not correlate with prognostic factors&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Maestro et al&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CellSearch&#174;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">26&#47;localized PCa24&#47;CRPC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CTCs detected in all patients&#44; but significant differences were found from localized to mCRPC patients&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Meyer et al&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CellSearch&#174;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">152&#47;localized PCa&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CTCs detected in some patients with cut-off point<span class="elsevierStyleHsp" style=""></span>&#62;1 CTC but no correlation was observed with clinical data to consider it as prognostic biomarker&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Puche-Sanz et al&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">MACS technology&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">86&#47;localized PCa&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Positive correlation between tissue expression of AR and presence of CTCsNegative correlation for EGFR expression in tissue and AR in CTCsThe prognostic role of AR expression within CTCs is proposed&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Scher et al&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Epic Sciences&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">179&#47;mCRPC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CTCs heterogeneity was associated with OS &#40;low heterogeneity in patients with lower CTC count associated with better OS&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Antonarakis et al&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">AdnaTest&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">62&#47;mCRPC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Presence of AR-V7 in CTCs was associated with resistance to enzalutamide and abiraterone&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Onstek et al&#46;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CellSearch&#174;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">76&#47;mCRPC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Prevalence of AR-V7 in CTCs of abiraterone-resistant patients&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Scher et al&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Epic Sciences&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">191&#47;mCRPC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Validation of nuclear or cytoplasmic localization of AR-V7Nuclear localization of AR-V7 associated with lower OS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Scher et al&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Epic Sciences&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">142&#47;mCRPC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Validation of study 26 &#40;nuclear localization of AR-V7 and lower OS&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Tommasi et al&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">AdnaTest&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">44&#47;mCRPC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Validation of the inverse correlation between AR-V7 expression and PSA-based response&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Amstrong et al&#46;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Epic SciencesAdnaTest&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">118&#47;mCRPC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Presence of AR-V7 in CTCs is associated to hormone therapy resistanceBoth platforms obtained comparable results&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">ctDNA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Heitzer et al&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">WGS &#40;Illumina&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">9 mCRPC4 castration sensitive&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Identification of multiple aberrations &#40;interstitial deletion of 21q22&#46;2&#8211;3&#44; 8<span class="elsevierStyleHsp" style=""></span>p loss&#44; 8<span class="elsevierStyleHsp" style=""></span>q gain&#44; AR amplification&#44; etc&#46;&#41;The results are not correlated to clinical variables despite performance of serial analysis in some patients&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Azad et al&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">aCGH&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">62 mCRPC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">More frequent AR amplification in patients who progress to enzalutamide than in those who progress to abirateroneDetection of AR mutations associated with treatment resistance&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Joseph et al&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">BEAMing&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">29 RNA-509-treated patients&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Presence of F876<span class="elsevierStyleHsp" style=""></span>L mutation associated with resistance in 3&#47;29 patients&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Wyatt et al&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">AR deep seq &#40;Illumina&#41;Ampliseq custom panel&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">65 mCRPC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">AR amplification associated with primary resistanceMutations and copy number changes were detected during progression in all patients &#40;including AR amplification&#44; and mutations in <span class="elsevierStyleItalic">RB1&#44; MET&#44; MYC&#44; PI3K</span> and <span class="elsevierStyleItalic">CTNNB1</span>&#41;&nbsp;\t\t\t\t\t\t\n
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Article information

ISSN: 21735786
Original language: English

DOI:10.1016/j.acuroe.2019.08.009

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