Abstract 448: Genomic instability as a marker of poor prognosis in advanced prostate cancer: Subclonal insights from whole-genome sequencing of single circulating tumor cells
Authors: Malihi Paymaneh D. , Graf Ryon P. , Velasco Carmen Ruiz , Kolatkar Anand , Rodriguez Angel E. , Lee Jerry , Sutton Ramsay , Corn Paul G. , Logothetis Christopher , Aparicio Ana , Hicks James , Dittamore Ryan , Zurita Amado , Kuhn Peter 
Published: August 2019

Abstract
A subset of castration-resistant prostate cancer (CRPC) patients present with atypical clinical features and aggressive disease behavior. These patients have a poor prognosis and may derive increased benefit from platinum-based chemotherapy. Heterogeneity in clinical presentations and insufficient understanding of biological drivers of progression underscore the need for more precise molecular stratification methods. We hypothesized that genomic characterization of circulating tumor cells (CTCs) at the single cell level would identify biomarkers relevant to the classification of aggressive CRPC tumors. Peripheral blood samples were collected before initiation of cabazitaxel +/- carboplatin from a cohort of 62 metastatic CRPC patients with and without clinically defined aggressive variant prostate cancer (AVPC) enrolled in NCT01505868. Samples were processed and analyzed for CTCs using the Epic Sciences detection and characterization platform in a CLIA-like environment. After CTC detection, single cells were picked and individually sequenced to assess gene gains and losses and genomic large-scale segment transitions (LST). Of 62 collected blood samples, 49 were positive for CTCs. Patients with more rapidly progressive disease (as assessed by a clinician) had higher CTC/mL, higher AR+CTC/mL, and higher median LST per CTC (p-values: 0.00669, 0.0358, and 0.00623, respectively). AVPC status, as marked by clinical features, was also associated with a higher number of LSTs in CTCs (median 24 per patient CTC vs. 10.5 in non-AVPC, p = 0.02672), whereas no difference in AR+CTC/mL or CTC/mL enumeration was observed. CTC count and LST were additive to prognosticate death by 12 months (AUC = 0.753 combined). The individual copy number was further assessed across 574 genes to identify alterations more commonly associated with poor prognosis. Myc gain, TP53 loss, and other aberrations in genes affecting DNA repair, resistance to anchorage-independent apoptosis, and cell motility showed significant positive association with LST. The presence of high genomic LST, a marker of genomic instability, in individual CTC was associated with more aggressive CRPC behavior (faster rate of progression, shorter survival) and specific gene copy number aberrations. High LST added independent prognostic significance to CTC enumeration. These data suggest that single CTC genomic analysis may provide clinically relevant insights and point to genomic instability in CTCs as a candidate marker of poor prognosis in advanced prostate cancer.
Citation Format: Paymaneh D. Malihi, Ryon P. Graf, Carmen Ruiz Velasco, Anand Kolatkar, Angel E. Rodriguez, Jerry Lee, Ramsay Sutton, Paul G. Corn, Christopher Logothetis, Ana Aparicio, James Hicks, Ryan Dittamore, Amado Zurita, Peter Kuhn. Genomic instability as a marker of poor prognosis in advanced prostate cancer: Subclonal insights from whole-genome sequencing of single circulating tumor cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 448.