Characterization of circulating tumor cells in patients with localized high risk prostate cancer, post-prostatectomy.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e23055-e23055
Author(s):  
Archana Anantharaman ◽  
Terence W. Friedlander ◽  
Christopher J. Welty ◽  
Kreshnik Zejnullahu ◽  
Jeffrey Hough ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
High Risk ◽  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Biochemical Recurrence ◽  
Copy Number ◽  
Large Scale ◽  
Proportional Hazards ◽  
Predictive Biomarkers ◽  
Cox Proportional Hazards

e23055 Background: Approximately 15% of men with newly diagnosed prostate cancer (PCa) have high-risk features, which increase the risk of recurrence. Better predictive biomarkers, such as circulating tumor cells (CTCs), could allow for earlier detection of biochemical recurrence. Here, we aim to evaluate the ability to detect CTCs using an enrichment free, unbiased CTC identification technology from men with high risk, localized PCa after radical prostatectomy (RP) and correlate their presence with prospective clinical data. Methods: Blood samples of 31 patients with high risk, localized PCa obtained 2-4 months post RP were shipped to Epic Sciences on an IRB approved protocol. All nucleated cells were subjected to immunofluorescent (IF) staining for cytokeratin (CK), CD45, and AR N terminus. CTCs were identified by fluorescent scanners using algorithmic analysis. CK expressing (CK+) CTCs were enumerated and analyzed for AR expression and individually sequenced for copy number variation (CNV) and large scale transition (LST, a surrogate of genomic instability). Patients were followed prospectively for biochemical recurrence, defined as detectable PSA. Progression free survival was calculated using Kaplan-Meier and Cox proportional hazards. Results: CTCs were detected in 87.1% (27/31) samples with an average of 5.6 CTCs/ml (range: 0 – 22.87) detected per patient. AR expression was detected in 12.9% (4/31) of patients. Ninety-nine CTCs from 14 patients were amenable to LST and CNV sequencing and analyses. 10.1% (10/99) CTCs from 7 patients exhibited higher ( > = 6) LSTs than control WBCs (95% WBCs had LST < 6). Copy number alterations were identified in CTCs in commonly mutated genes in PCa, including AR, MYC, and TP53 amplification and deletions in PTEN and RB1. Patients with higher CTC burdens exhibited a trend toward shorter PFS (hazard ratio: 1.65; 95% CI: 0.7-3.86; p: 0.13). Conclusions: There was a high incidence of CTC detection after RP in patients with high risk, localized PCa. We observed a trend toward shorter PFS in those with higher CTC burden and genomic alterations detectable in CTCs are consistent with established CNAs in PCa. Tissue genomic correlatives are under analysis.

Characterization of circulating tumor cells in patients with localized high risk prostate cancer, post-prostatectomy.

2017 ◽  
Vol 35 (6_suppl) ◽  
pp. 110-110 ◽  
Author(s):  
Terence W. Friedlander ◽  
Archana Anantharaman ◽  
Christopher Welty ◽  
Kreshnik Zejnullahu ◽  
Jeffrey Hough ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
High Risk ◽  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Copy Number ◽  
Large Scale ◽  
Proportional Hazards ◽  
Predictive Biomarkers ◽  
Cox Proportional Hazards ◽  
Definitive Therapy

110 Background: Approximately 15% of men with newly diagnosed prostate cancer (PCa) have high-risk features, many of these patients will recur despite definitive therapy. Better predictive biomarkers could allow for earlier detection of recurrence and change surveillance paradigms. The role of circulating tumor cells (CTCs) as biomarkers in this context is not well defined. Here, we evaluate the ability to detect CTCs from men with high risk, localized PCa after radical prostatectomy (RP) and correlate their presence with prospective clinical data. Methods: Blood samples from 31 patients with high risk, localized PCa were obtained 2-4 months post RP and sent to Epic Sciences on an IRB approved protocol. Nucleated cells were subjected to immunofluorescent (IF) staining for cytokeratin (CK), CD45, and AR N-terminus. CTCs were identified by fluorescent scanners using algorithmic analysis. Cytokeratin expressing (CK+) CTCs were enumerated and subsequently analyzed for AR expression and individually sequenced for copy number variation (CNV) and large scale transitions (LST, a surrogate of genomic instability). Patients were followed prospectively for biochemical recurrence, defined as detectable PSA. Progression free survival (PFS) was calculated using Kaplan-Meier and Cox proportional hazards. Results: CTCs were detected in 87.1% (27/31) samples with an average of 5.6 CTCs/ml (range: 0 – 22.87) detected per patient. AR expression was detected in 12.9% (4/31) of patients. Ninety-nine CTCs from 14 patients were amenable to LST and CNV analyses. 10.1% (10/99) CTCs from 7 patients exhibited higher ( > = 6) LSTs than control WBCs (95% WBCs had LST < 6). Copy number alterations were detected in CTCs in commonly mutated genes in PCa, including AR, MYC, and TP53 amplification and deletions in PTEN and RB1. Patients with higher CTC burdens exhibited a trend toward shorter PFS (hazard ratio: 1.65; 95% confidence interval: 0.7-3.86; p: 0.13). Conclusions: There was a high incidence of CTC detection after RP in this population using a novel platform. We observed a trend toward shorter PFS in those with higher CTC burden. Genomic alterations were detectable in CTCs and consistent with established CNAs in PCa.

Identification and characterization of circulating tumor cells in post prostatectomy patients with localized high risk prostate cancer.

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. 69-69 ◽  
Author(s):  
Terence W. Friedlander ◽  
Christopher J. Welty ◽  
Archana Anantharaman ◽  
Jeffrey Hough ◽  
Matthew Edwards ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
High Risk ◽  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Proportional Hazards ◽  
Progression Free Survival ◽  
Recurrence Risk ◽  
Cox Proportional Hazards ◽  
Immunofluorescent Staining ◽  
Primary Therapy

69 Background: Over 15% of men with newly diagnosed prostate cancer (PCa) have high-risk features that raise the recurrence risk. Better biomarkers could allow for even earlier detection of biochemical recurrence (BCR) and inform adjuvant treatment decisions. Circulating tumor cells (CTCs) may represent the earliest form of metastases, however their role as biomarkers in men with localized PCa is not well defined. Here, we aim to enumerate and molecularly and genomically analyze CTCs using an enrichment-free, unbiased CTC identification technology from men with high-risk, localized PCa after radical prostatectomy (RP) and correlate the analysis with clinical outcomes. Methods: Blood samples from 37 patients with high-risk, localized PCa were obtained 2-5 mos post RP and shipped to Epic. All nucleated cells were subjected to immunofluorescent staining for cytokeratin (CK), CD45, and AR. CTCs were identified using algorithmic analysis. CK+ CTCs were enumerated and subsequently analyzed for AR expression and individually sequenced for copy number alterations (CNA). Patients were followed for BCR, defined as detectable PSA > 0.2ng/dL. Progression free survival (PFS) was calculated using Kaplan-Meier and Cox proportional hazards. Results: CTCs were detected in 81.1%(30/37) of patients with an average of 5.2 CTCs/ml (range: 0 – 22.9) detected per patient. AR expression was detected in 18.9% (7/37) of patients. Ninety nine CTCs from 14 patients were picked and sequenced. CNAs were identified in CTCs in commonly mutated genes in PCa, including MYC amplification and CHD1 deletions. Patients with higher traditional CTC (CK+) burdens exhibited a trend towards shorter PFS (hazard ratio: 1.65; 95% confidence interval: 0.7-3.86; p = 0.13). Conclusions: There was a high incidence of CTC detection after RP in patients with high-risk, localized PCa. A trend toward shorter PFS was seen in those with higher CTC burden. Genomic alterations were detectable in CTCs and consistent with established CNAs in PCa. With further testing in appropriately powered cohorts early CTC detection after primary therapy could represent an informative biomarker to stratify patients with high risk PCa.

scholarly journals High expression of Sterol-O-Acyl transferase 1 (SOAT1), an enzyme involved in cholesterol metabolism, is associated with earlier biochemical recurrence in high risk prostate cancer

2021 ◽  
Author(s):  
Carolin Eckhardt ◽  
Iuliu Sbiera ◽  
Markus Krebs ◽  
Silviu Sbiera ◽  
Martin Spahn ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
High Risk ◽  
Biochemical Recurrence ◽  
Proportional Hazards ◽  
Cholesterol Metabolism ◽  
Cox Proportional Hazards ◽  
Clinical Recurrence ◽  
Free Survival ◽  
Kaplan Meier ◽  
Cancer Aggressiveness

Abstract Background Prostate cancer (PCa) is the most frequent cancer in men. The prognosis of PCa is heterogeneous with many clinically indolent tumors and rare highly aggressive cases. Reliable tissue markers of prognosis are lacking. Active cholesteryl ester synthesis has been associated with prostate cancer aggressiveness. Sterol-O-Acyl transferases (SOAT) 1 and 2 catalyze cholesterol esterification in humans. Objective To investigate the value of SOAT1 and SOAT2 tissue expression as prognostic markers in high risk PCa. Patients and methods Formalin-fixed paraffin-embedded tissue samples from 305 high risk PCa cases treated with radical prostatectomy were analyzed for SOAT1 and SOAT2 protein expression by semi-quantitative immunohistochemistry. The Kaplan–Meier method and Cox proportional hazards modeling were used to compare outcome. Main outcome measure Biochemical recurrence (BCR) free survival. Results SOAT1 expression was high in 73 (25%) and low in 219 (75%; not evaluable: 13) tumors. SOAT2 was highly expressed in 40 (14%) and at low levels in 249 (86%) samples (not evaluable: 16). By Kaplan–Meier analysis, we found significantly shorter median BCR free survival of 93 months (95% confidence interval 23.6–123.1) in patients with high SOAT1 vs. 134 months (112.6–220.2, Log-rank p < 0.001) with low SOAT1. SOAT2 expression was not significantly associated with BCR. After adjustment for age, preoperative PSA, tumor stage, Gleason score, resection status, lymph node involvement and year of surgery, high SOAT1 but not SOAT2 expression was associated with shorter BCR free survival with a hazard ratio of 2.40 (95% CI 1.57–3.68, p < 0.001). Time to clinical recurrence and overall survival were not significantly associated with SOAT1 and SOAT2 expression Conclusions SOAT1 expression is strongly associated with BCR free survival alone and after multivariable adjustment in high risk PCa. SOAT1 may serve as a histologic marker of prognosis and holds promise as a future treatment target.

Genomic analysis of circulating tumor cells (CTCs) from men with metastatic castration resistant prostate cancer (mCRPC) in the context of enzalutamide therapy.

2014 ◽  
Vol 32 (4_suppl) ◽  
pp. 65-65
Author(s):  
Andrew J. Armstrong ◽  
Jing Li ◽  
Joshua Beaver ◽  
Rhonda Lynn Bitting ◽  
Simon Gregory
Keyword(s):  
Prostate Cancer ◽  
Exome Sequencing ◽  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Copy Number ◽  
Predictive Biomarkers ◽  
Castration Resistant Prostate Cancer ◽  
Dna Copy Number ◽  
Pten Loss ◽  
Castration Resistant

65 Background: Given the evolving treatments available in metastatic castration resistant prostate cancer (mCRPC), predictive biomarkers are desirable that maximize benefit and minimize harms and costs.The goal of this study was to determine the feasibility of DNA copy number and whole exome sequencing (WES) analysis of circulating tumor cells (CTCs) from men with mCRPC receiving enzalutamide. Methods: We collected CTCs from men with mCRPC in the context of enzalutamide therapy. CTCs were isolated from EDTA blood through red cell lysis, CD45 depletion, and flow sorting on EpCAM/CD45 expression. Whole genomic amplification and array based comparative genomic hybridization (CGH) was performed using Qiagen Repli-Gene Single Cell kit, multiple displacement amplification, and Agilent microarray analysis. CTC copy number changes were compared with patient leukocyte DNA and reference metastatic PC datasets. CTC AR amplification and PTEN loss was confirmed with FISH. WES on REPLI-g amplified CTC and leukocyte DNA was performed using GeneWiz and TruSeq Exome Capture Kit, and sequenced with Illumina HiSeq 2000 (20x). Results: A novel method for CTC array CGH was developed that reproducibly identified genomic lesions previously reported in metastatic CRPC including: AR amplification or focal deletions, deletions of CHD1, Rb, PHLLP, FGFR2, FOXA1, and NCOA2, and amplifications of EZH2 and MYC. AR amplification was noted in a man with mCRPC who subsequently responded to enzalutamide, with loss of AR amplification and gain of MYCN and c-MET amplification noted at progression. CGH analysis was feasible down to 10 to 20 cells using spiked cell lines. Interpatient tumor specific genomic heterogeneity was observed. FISH confirmed AR changes and PTEN loss heterogeneity. WES demonstrated acquired PTEN, MAGI1, SMAD4, and RB1 mutations in a patient who progressed through enzalutamide therapy, in addition to AR region deletion detected by CGH. Conclusions: Whole genome DNA copy number and exome sequencing analysis from CTCs in men with mCRPC is feasible in men with high CTCs and identified previously validated and novel genomic lesions and suggest the potential to identify predictive biomarkers of enzalutamide efficacy and resistance in the clinic.

scholarly journals Circulating Tumor Cells as a Marker of Disseminated Disease in Patients with Newly Diagnosed High-Risk Prostate Cancer

Cancers ◽  
2020 ◽  
Vol 12 (1) ◽  
pp. 160 ◽  
Author(s):  
Wojciech A. Cieślikowski ◽  
Joanna Budna-Tukan ◽  
Monika Świerczewska ◽  
Agnieszka Ida ◽  
Michał Hrab ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
High Risk ◽  
Cancer Patients ◽  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Metastatic Disease ◽  
Newly Diagnosed ◽  
High Risk Prostate Cancer ◽  
Intergroup Comparison ◽  
Risk Prostate Cancer

The aim of this study was to investigate whether the enumeration of circulating tumor cells (CTCs) in blood can differentiate between true localized and metastatic prostate cancer. A cross-sectional study of 104 prostate cancer patients with newly diagnosed high-risk prostate cancer was conducted. In total, 19 patients presented metastatic disease and 85 were diagnosed with localized disease. Analyses included intergroup comparison of CTC counts, determined using the CellSearch® system, EPISPOT assay and GILUPI CellCollector®, and ROC analysis verifying the accuracy of CTC count as a maker of disseminated prostate cancer. The vast majority (94.7%) of patients with advanced-stage cancer tested positively for CTCs in at least one of the assays. However, significantly higher CTC counts were determined with the CellSearch® system compared to EPISPOT assay and GILUPI CellCollector®. Identification of ≥4 CTCs with the CellSearch® system was the most accurate predictor of metastatic disease (sensitivity 0.500; specificity 0.900; AUC (95% CI) 0.760 (0.613–0.908). Furthermore, we tried to create a model to enhance the specificity and sensitivity of metastatic prediction with CTC counts by incorporating patient’s clinical data, including PSA serum levels, Gleason score and clinical stage. The composite biomarker panel achieved the following performance: sensitivity, 0.611; specificity, 0.971; AUC (95% CI), 0.901 (0.810–0.993). Thus, although the sensitivity of CTC detection needs to be further increased, our findings suggest that high CTC counts might contribute to the identification of high-risk prostate cancer patients with occult metastases at the time of diagnosis.

2138 CIRCULATING TUMOR CELLS (CTCS) ARE DETECTABLE IN PATIENTS WITH HIGH-RISK, LOCALIZED PROSTATE CANCER THROUGH USE OF THE CELLSEARCH PLATFORM

2013 ◽  
Vol 189 (4S) ◽  
Author(s):  
Sumanta Pal ◽  
Clayton Lau ◽  
Miaoling He ◽  
Jennifer Linehan ◽  
Timothy Wilson ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
High Risk ◽  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Localized Prostate Cancer

Circulating Tumor Cells in Biochemical Recurrence of Prostate Cancer

2015 ◽  
Vol 13 (5) ◽  
pp. e341-e345 ◽  
Author(s):  
Jeanny B. Aragon-Ching ◽  
Robert S. Siegel ◽  
Harold Frazier ◽  
Ramez Andrawis ◽  
Frederick Hendricks ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Biochemical Recurrence

Detecting circulating tumor cells (CTCs) in patients with high-risk, localized prostate cancer using the CellSearch platform.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e15178-e15178
Author(s):  
Sumanta Kumar Pal ◽  
Clayton Lau ◽  
Miaoling He ◽  
Przemyslaw Twardowski ◽  
Timothy G. Wilson ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
High Risk ◽  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Gleason Score ◽  
Prognostic Value ◽  
Localized Prostate Cancer ◽  
Cellsearch System ◽  
Mesenchymal Transition ◽  
E Cadherin

e15178 Background: Enumeration of circulating tumor cells (CTCs) using the CellSearch platform has prognostic value in patients with metastatic castration resistant prostate cancer. However, the prognostic value of CTC enumeration in high-risk, localized prostate cancer (HRLPC) remains undefined. Methods: Patients with HRLPC (defined by ≥1 of the following criteria: ≥ cT3a disease, Gleason score 8-10, or PSA > 20 ng/mL) who have chosen prostatectomy for their definitive management were prospectively identified. Patients were consented to receive 4 sequential 30 mL blood draws, each collected in 3 separate 10 mL EDTA tubes. The first 2 blood draws were conducted 2 weeks prior and immediately prior to surgery, while the second 2 blood draws were conducted 4-6 weeks and 3 months following surgery. Within 4 hrs of blood collection, the white blood cell (WBC) fraction was pooled and Ficoll purified. The WBC fraction was transferred to a CellSave tube, and CTCs were enumerated using the CellSearch system. Expression of CD133 and E-cadherin was characterized using the CellSearch system in patients with detectable CTCs. Results: Within 3 monthsof study initiation in Nov 2011, 19 of a planned 37 patients have been accrued. Median age in the cohort was 65 (range, 51-74), and the number of patients with Gleason score 8-10, ≥ cT3a disease, or PSA > 20 ng/mL was 16, 4, and 2, respectively. The majority of patients (17/19, or 89%) had only one high-risk feature. Mean baseline PSA for the cohort was 11.4 (range, 3.4-37). CTCs were detectable in 67% of patients prior to surgery, 27% of patients at 1 month following surgery and 67% of patients at 3 months following surgery. Amongst those patients with detectable CTCs, the median count was 3 (range, 1-7). Further, in these patients, CD133 and E-cadherin were detected in 44% and 46% of specimens assessed, respectively. Full details of these analyses will be provided at the time of the meeting. Conclusions: Using a modified methodology, CTC enumeration using the CellSearch platform is feasible in patients with HRLPC. Interestingly, markers of epithelial-mesenchymal transition and stem cell lineage are detectable in a proportion of patients with localized disease.

Molecular Characterization and Clinical Utility of Circulating Tumor Cells in the Treatment of Prostate Cancer

2014 ◽  
pp. e197-e203 ◽  
Author(s):  
David Lorente ◽  
Joaquin Mateo ◽  
Johann S. de Bono
Keyword(s):  
Prostate Cancer ◽  
Clinical Trials ◽  
Tumor Cells ◽  
Molecular Characterization ◽  
Circulating Tumor Cells ◽  
Predictive Biomarkers ◽  
Phase Iii ◽  
Response To Treatment ◽  
Molecular Characteristics ◽  
Wide Range

Circulating tumor cells (CTCs) are rare cancer cells that can be detected in the blood of patients with solid malignancies. The Veridex CellSearch Assay was analytically and clinically validated, and has received U.S. Food and Drug Administration (FDA) clearance for the enumeration of CTCs in breast, colorectal, and prostate cancer. A number of alternative assays, with potential advantages, are currently undergoing clinical and/or analytic validation before their routine use can be established. In prostate cancer, high pretreatment CTC counts have been associated with worse survival, and changes in CTC counts in response to treatment have been established as indicators of response to treatment. Additional analyses are ongoing to establish the value of CTC counts as a surrogate of survival in prospective, phase III trials, which could influence the process of drug development and regulatory approval. Additionally, CTCs have a potential role in the molecular characterization of prostate cancer, serving as “liquid biopsies” to determine the molecular characteristics of the disease. The study of androgen receptor (AR) mutations or amplification, chromosomal rearrangements, or the determination of DNA repair biomarkers has been evaluated in clinical trials. CTCs have a wide range of potential applications, from their prognostic use in stratification of patients in clinical trials or the assessment of response to treatment, to the pharmacodynamic evaluation of novel agents, or the discovery and use of predictive biomarkers that can aid in the development of personalized medicine.

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