TY - JOUR
T1 - Multigene profiling of CTCs in mCRPC identifies a clinically relevant prognostic signature
AU - Singhal, Udit
AU - Wang, Yugang
AU - Henderson, James
AU - Niknafs, Yashar S.
AU - Qiao, Yuanyuan
AU - Gursky, Amy
AU - Zaslavsky, Alexander
AU - Chung, Jae Seung
AU - Smith, David C.
AU - Karnes, R. Jeffrey
AU - Chang, S. Laura
AU - Feng, Felix Y.
AU - Palapattu, Ganesh S.
AU - Taichman, Russell S.
AU - Chinnaiyan, Arul M.
AU - Tomlins, Scott A.
AU - Morgan, Todd M.
N1 - Funding Information:
This study was supported by a Department of Defense Physician Research Training Award (W81XWH-14-1-0287) and the Prostate Cancer Foundation (T.M. Morgan, R.S. Taichman, and S.A. Tomlins). T.M. Morgan and S.A. Tomlins are also supported by the A. Alfred Taubman Medical Research Institute. This work was also supported by the NIH: National Cancer Institute PO1CA093900-10 and the University of Michigan Comprehensive Cancer Center Prostate SPORE (P50CA 069568).
Funding Information:
This study was supported by a Department of Defense Physician Research Training Award (W81XWH-14-1-0287) and the Prostate Cancer Foundation (T.M. Morgan, R.S. Taichman, and S.A. Tomlins). T.M. Morgan and S.A. Tomlins are also supported by the A. Alfred Taubman Medical Research Institute. This work was also supported by the NIH: National Cancer Institute PO1CA093900- 10 and the University of Michigan Comprehensive Cancer Center Prostate SPORE (P50CA 069568) The authors would like to thank Jun Luo, PhD, and Ken Pienta, MD, for assistance andmentorship in conducting this work.Wealso thank Robin Kunkel for help with figure preparation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Publisher Copyright:
© 2018 American Association for Cancer Research.
PY - 2018/4/1
Y1 - 2018/4/1
N2 - The trend toward 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 of 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) were observed. The TMPRSS2:ERG fusion was expressed in 41% of samples, and the aggressive prostate cancer-associated long noncoding RNA SChLAP1 was upregulated in 70%. WNT5a [HR 3.62, 95% confidence interval (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. Implications: Analysis of CTC gene expression reveals a clinically prognostic "liquid biopsy" signature in patients with metastatic castrate-resistance prostate cancer. Mol Cancer Res; 16(4); 643-54.
AB - The trend toward 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 of 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) were observed. The TMPRSS2:ERG fusion was expressed in 41% of samples, and the aggressive prostate cancer-associated long noncoding RNA SChLAP1 was upregulated in 70%. WNT5a [HR 3.62, 95% confidence interval (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. Implications: Analysis of CTC gene expression reveals a clinically prognostic "liquid biopsy" signature in patients with metastatic castrate-resistance prostate cancer. Mol Cancer Res; 16(4); 643-54.
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U2 - 10.1158/1541-7786.MCR-17-0539
DO - 10.1158/1541-7786.MCR-17-0539
M3 - Article
C2 - 29453313
AN - SCOPUS:85045376854
SN - 1541-7786
VL - 16
SP - 643
EP - 654
JO - Molecular Cancer Research
JF - Molecular Cancer Research
IS - 4
ER -