#AACR19: Genomic characterization of circulating tumor cells in de novo metastatic prostate cancer
Shoujie Chai1, Paymaneh D. Malihi1, Ana M. Apariciop2, Brian F. Chapin2, Matthew Lin1, Ryan Storgard1, Carmen Ruiz Velasco1, Anand Kolatkar1, James Hicks1, Peter Kuhn1. 1University of Southern California, Los Angeles, CA; 2The University of Texas MD Anderson Cancer Center, Houston, TX
Background: The absence of biomarkers that identify clinically meaningful biological subsets of prostate cancer results in the homogeneous application of systemic therapies to a heterogeneous disease and hampers therapy development. This heterogeneity may become more evident at the molecular level under the pressure of androgen withdrawal. Here, we longitudinally characterized peripheral blood circulating tumor cells (CTCs) from patients with de novo metastatic prostate cancer to examine the phenotypic and genomic changes induced by androgen suppression.
Methods: Peripheral blood samples were collected at MD Anderson Cancer Center from a cohort of DNM1PCa patients under clinical trial NCT01751438. Timepoints of collection includes baseline (BSL, before treatment) and 6 months (6mo, after 6 months of systemic therapy). We used the High-Definition Single Cell Assay (HD-SCA) workflow for CTC enumeration, morphology (nuclear size, DAPI intensity, cytokeratin (CK), androgen receptor (AR) intensity and genomics (whole-genome copy number aberration analysis) evaluation. This workflow utilizes an enrichment-free fluorescence based (DAPI/ CK/ CD45/ AR) CTC identification system and single-cell genomic sequencing.
Results: Twenty-nine of the 58 available blood samples contained CTCs: 15 of the 28 (53.6%) collected at BSL (median 2.00 CTCs/mL, range 0.84-74.15) and 14 of the 30 (46.7%) collected at 6mo (median 2.43 CTCs/mL, range 0.96-13.85). However, at the 6mo timepoint, the CTCs had undergone a significant morphological shift in nuclear area local ratio (BSL vs 6mo: 1.036 vs 1.165, p=0.039), DAPI intensity (0.199 vs 1.030, p=0.036), CK intensity (18.978 vs 15.651, p=0.006), AR intensity (0.681 vs -0.468, p=0.037) and AR+ percentage (36.25% vs 15.38%, p=0.020). Further, genomic analysis of two patients at BSL indicated copy number aberrations including PTEN, TP53, RB1 and BRCA2 loss and MYC gain.
Discussion: This study aims at characterizing changes induced by systemic therapies in CTC potential biomarkers that identify distinct subsets of disease biology. The changes observed in patient subsets may serve as clinically relevant biomarkers to optimize treatment and improve prognosis.
For discussion with Shoujie Chai, please visit him at #AACR19: April 2, 2019, 1:00 PM – 5:00 PM – Section 41
PhD student in molecular biology
Approximately 5-10% of new prostate cancer patients are diagnosed with DNM1PCa, relying on a variety of sequential life-prolonging treatments to reduce the high risk of disease-specific mortality. However, the therapeutic response and disease progression time varies among DNM1PCa patients due to tumor heterogeneity. Previous studies have indicated that loss of ≥2 of tumor suppressors PTEN, RB1 or TP53 are the key molecular signatures which drives roughly 10% of patients with metastatic castrate resistant prostate cancer (mCRPC) evolving into aggressive variant prostate cancer (AVPC), with more aggressive phenotype, less response to androgen deprivation therapy but more benefit from platinum-based chemotherapy. We are investigating molecular characterization of CTCs to identity DNM1PCa with worse response and faster progression based on AVPC signatures and new signatures.
The impact of this trial, the early identification of DNM1PCa patients harboring key signatures to optimize the treatment strategy and improve the patient survival.