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      Circulating Tumor Cells in Prostate Cancer: From Discovery to Clinical Utility

      1 , 1 , 2
      Clinical Chemistry
      American Association for Clinical Chemistry (AACC)

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          Abstract

          BACKGROUND

          Prostate cancer represents the most common non–skin cancer type in men. Unmet needs include understanding prognosis to determine when intervention is needed and what type, prediction to guide the choice of a systemic therapy, and response indicators to determine whether a treatment is working. Over the past decade, the “liquid biopsy,” characterized by the analysis of tumor cells and tumor cell products such as cell-free nucleic acids (DNA, microRNA) or extracellular vesicles circulating in the blood of cancer patients, has received considerable attention.

          CONTENT

          Among those biomarkers, circulating tumor cells (CTCs) have been most intensively analyzed in prostate cancer. Here we discuss recent studies on the enumeration and characterization of CTCs in peripheral blood and how this information can be used to develop biomarkers for each of these clinical contexts. We focus on clinical applications in men with metastatic castration-resistant prostate cancer, in whom CTCs are more often detected and at higher numbers, and clinical validation for different contexts of use is most mature.

          SUMMARY

          The overall goal of CTC-based liquid biopsy testing is to better inform medical decision-making so that patient outcomes are improved.

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          Most cited references60

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          Tumor cells circulate in the peripheral blood of all major carcinomas but not in healthy subjects or patients with nonmalignant diseases.

          The purpose of this study was to determine the accuracy, precision, and linearity of the CellSearch system and evaluate the number of circulating tumor cells (CTCs) per 7.5 mL of blood in healthy subjects, patients with nonmalignant diseases, and patients with a variety of metastatic carcinomas. The CellSearch system was used to enumerate CTCs in 7.5 mL of blood. Blood samples spiked with cells from tumor cell lines were used to establish analytical accuracy, reproducibility, and linearity. Prevalence of CTCs was determined in blood from 199 patients with nonmalignant diseases, 964 patients with metastatic carcinomas, and 145 healthy donors. Enumeration of spiked tumor cells was linear over the range of 5 to 1,142 cells, with an average recovery of >/=85% at each spike level. Only 1 of the 344 (0.3%) healthy and nonmalignant disease subjects had >/=2 CTCs per 7.5 mL of blood. In 2,183 blood samples from 964 metastatic carcinoma patients, CTCs ranged from 0 to 23,618 CTCs per 7.5 mL (mean, 60 +/- 693 CTCs per 7.5 mL), and 36% (781 of 2,183) of the specimens had >/=2 CTCs. Detection of >/=2 CTCs occurred at the following rates: 57% (107 of 188) of prostate cancers, 37% (489 of 1,316) of breast cancers, 37% (20 of 53) of ovarian cancers, 30% (99 of 333) of colorectal cancers, 20% (34 of 168) of lung cancers, and 26% (32 of 125) of other cancers. The CellSearch system can be standardized across multiple laboratories and may be used to determine the clinical utility of CTCs. CTCs are extremely rare in healthy subjects and patients with nonmalignant diseases but present in various metastatic carcinomas with a wide range of frequencies.
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            Circulating tumor cells predict survival benefit from treatment in metastatic castration-resistant prostate cancer.

            A method for enumerating circulating tumor cells (CTC) has received regulatory clearance. The primary objective of this prospective study was to establish the relationship between posttreatment CTC count and overall survival (OS) in castration-resistant prostate cancer (CRPC). Secondary objectives included determining the prognostic utility of CTC measurement before initiating therapy, and the relationship of CTC to prostate-specific antigen (PSA) changes and OS at these and other time points. Blood was drawn from CRPC patients with progressive disease starting a new line of chemotherapy before treatment and monthly thereafter. Patients were stratified into predetermined Favorable or Unfavorable groups ( or =5 CTC/7.5mL). Two hundred thirty-one of 276 enrolled patients (84%) were evaluable. Patients with Unfavorable pretreatment CTC (57%) had shorter OS (median OS, 11.5 versus 21.7 months; Cox hazard ratio, 3.3; P 26 to 9.3 months). CTC are the most accurate and independent predictor of OS in CRPC. These data led to Food and Drug Administration clearance of this assay for the evaluation of CRPC.
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              Antitumour activity of MDV3100 in castration-resistant prostate cancer: a phase 1-2 study.

              MDV3100 is an androgen-receptor antagonist that blocks androgens from binding to the androgen receptor and prevents nuclear translocation and co-activator recruitment of the ligand-receptor complex. It also induces tumour cell apoptosis, and has no agonist activity. Because growth of castration-resistant prostate cancer is dependent on continued androgen-receptor signalling, we assessed the antitumour activity and safety of MDV3100 in men with this disease. This phase 1-2 study was undertaken in five US centres in 140 patients. Patients with progressive, metastatic, castration-resistant prostate cancer were enrolled in dose-escalation cohorts of three to six patients and given an oral daily starting dose of MDV3100 30 mg. The final daily doses studied were 30 mg (n=3), 60 mg (27), 150 mg (28), 240 mg (29), 360 mg (28), 480 mg (22), and 600 mg (3). The primary objective was to identify the safety and tolerability profile of MDV3100 and to establish the maximum tolerated dose. The trial is registered with ClinicalTrials.gov, number NCT00510718. We noted antitumour effects at all doses, including decreases in serum prostate-specific antigen of 50% or more in 78 (56%) patients, responses in soft tissue in 13 (22%) of 59 patients, stabilised bone disease in 61 (56%) of 109 patients, and conversion from unfavourable to favourable circulating tumour cell counts in 25 (49%) of the 51 patients. PET imaging of 22 patients to assess androgen-receptor blockade showed decreased (18)F-fluoro-5alpha-dihydrotestosterone binding at doses from 60 mg to 480 mg per day (range 20-100%). The median time to progression was 47 weeks (95% CI 34-not reached) for radiological progression. The maximum tolerated dose for sustained treatment (>28 days) was 240 mg. The most common grade 3-4 adverse event was dose-dependent fatigue (16 [11%] patients), which generally resolved after dose reduction. We recorded encouraging antitumour activity with MDV3100 in patients with castration-resistant prostate cancer. The results of this phase 1-2 trial validate in man preclinical studies implicating sustained androgen-receptor signalling as a driver in this disease. Medivation, the Prostate Cancer Foundation, National Cancer Institute, the Howard Hughes Medical Institute, Doris Duke Charitable Foundation, and Department of Defense Prostate Cancer Clinical Trials Consortium. Copyright 2010 Elsevier Ltd. All rights reserved.
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                Author and article information

                Journal
                Clinical Chemistry
                American Association for Clinical Chemistry (AACC)
                0009-9147
                1530-8561
                January 01 2019
                January 01 2019
                January 01 2019
                January 01 2019
                January 01 2019
                January 01 2019
                : 65
                : 1
                : 87-99
                Affiliations
                [1 ]Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
                [2 ]Department of Medicine, Memorial Sloan Kettering Cancer Center, Weill Cornell College of Medicine, New York, NY
                Article
                10.1373/clinchem.2018.287102
                30602476
                644852cb-cdf6-42a4-ba3f-e584bc3f544a
                © 2019

                https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model

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