Sequential monitoring of androgen receptor expression and copy number variation in castration-resistant prostate cancer (CRPC).

Abstract

11047 Background: The high-definition circulating tumor cell (HD-CTC) assay provides for an enrichment-free approach to identify and characterize CTCs. Here, we utilized the HD-CTC assay to study androgen receptor (AR) expression combined with single-nucleus sequencing for genome-wide analysis of copy number variation (CNV) in sequential samples obtained from patients with CRPC treated with abiraterone acetate (AA). Methods: Patients were approached for participation in a study to provide peripheral blood at baseline, at 2-5 weeks, and at 9-12 weeks (or at progression). In each sample, 106cells (defined with a DAPI-intact nucleus) were quantitatively examined for the presence of cytokeratin and AR (CTCs) and CD45 (leukocytes). Initial results are available from 9 subjects treated with AA as standard of care. Results: At baseline, the median (range) CTC was 7.8 (1.1-57.2) cells/ml. Using a definition of AR positive (AR+) as >6 standard deviations over mean signal observed in leukocytes, the median (range) of AR+ and total CTCs observed at baseline were 3.1(0-33.8) and 7.8 (1.1-57.2) cells/ml, respectively. Detailed single-nucleus CNV analysis was performed in sequential samples in a single subject (Table). Complex genomic rearrangements were observed including AR amplification and 8p deletion in both AR+ and AR- negative (AR-) cells at baseline. During AA treatment, the frequency of AR+ CTCs decreased along with changes in the CNV pattern including loss of AR amplification. At 10 weeks, disease progression occurred coincident with re-emergence of an AR+ CTC population exhibiting AR amplification and a novel CNV pattern only distantly related to that of the baseline CTCs. While multiple complex abnormalities were noted, MYC amplification was observed at higher frequency in cells present at progression. Conclusions: Overall, our results demonstrate the feasibility of monitoring of CTCs for treatment emergent changes in protein which may be used to better monitoring and predict therapeutic responses in patients with metastatic cancer. [Table: see text]