The trend towards precision-based therapeutic approaches dictated by molecular alterations offers substantial promise for men with metastatic castration resistant prostate cancer (mCRPC). However, current approaches for molecular characterization are primarily tissue based, necessitating serial biopsies to understand changes over time and are limited by the challenges inherent to extracting genomic material from predominantly bone metastases. Therefore, a circulating tumor cell (CTC)-based assay was developed to determine gene expression across a panel of clinically relevant and potentially actionable prostate cancer related genes. CTCs were isolated from the whole blood of mCRPC patients (n=41) and multiplex qPCR was performed to evaluate expression prostate cancer related target genes (n=78). A large fraction of patients (27/41, 66%) had detectable CTCs. Increased androgen receptor (AR) expression (70% of samples) and evidence of Wnt signaling (67% of samples) was observed. The TMPRSS2:ERG fusion was expressed in 41% of samples and the aggressive prostate cancer associated long non-coding RNA SChLAP1 was upregulated in 70%. WNT5a (HR 3.62, 95% CI 1.63 - 8.05, p=0.002), AURKA (HR 5.56, 95% CI 1.79 - 17.20, p=0.003), and BMP7 (HR 3.86, 95% CI 1.60 - 9.32, p=0.003) were independently predictive of overall survival (FDR<10%) after adjusting for a panel of previously established prognostic variables in mCRPC (Halabi nomogram). A model including Halabi, WNT5a, and AURKA expression, termed the miCTC score, outperformed the Halabi nomogram alone (AUC=0.89 vs. AUC=0.70). Understanding the molecular landscape of CTCs has utility in predicting clinical outcomes in patients with aggressive prostate cancer and provides an additional tool in the arsenal of precision-based therapeutic approaches in oncology.
Molecular cancer research : MCR. 2018 Feb 16 [Epub ahead of print]
Udit Singhal, Yugang Wang, James Henderson, Yashar S Niknafs, Yuanyuan Qiao, Amy Gursky, Alexander Zaslavsky, Jae-Seung Chung, David C Smith, R Jeffrey Karnes, S Laura Chang, Felix Y Feng, Ganesh S Palapattu, Russell S Taichman, Arul M Chinnaiyan, Scott A Tomlins, Todd M Morgan
Urology, University of Michigan-Ann Arbor., Michigan Center for Translational Pathology, University of Michigan-Ann Arbor., Michigan Center for Translational Pathology, Department of Pathology, Comprehensive Cancer Center, University of Michigan., Division of Hematology/Oncology, University of Michigan-Ann Arbor., Urology, Mayo Clinic., Radiation Oncology, Helen Diller Comprehensive Cancer Center, University of California, San Francisco., Periodontics and Oral Medicine, University of Michigan School of Dentistry., Pathology, University of Michigan-Ann Arbor., Department of Pathology, Department of Urology, Michigan Center for Translational Pathology, Comprehensive Cancer Center, University of Michigan-Ann Arbor., Urology, University of Michigan-Ann Arbor .