Multigene profiling of CTCs in mCRPC identifies a clinically relevant prognostic signature

Udit Singhal, Yugang Wang, James Henderson, Yashar S. Niknafs, Yuanyuan Qiao, Amy Gursky, Alexander Zaslavsky, Jae Seung Chung, David C. Smith, Robert Jeffrey Karnes, S. Laura Chang, Felix Y. Feng, Ganesh S. Palapattu, Russell S. Taichman, Arul M. Chinnaiyan, Scott A. Tomlins, Todd M. Morgan

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)643-654
Number of pages12
JournalMolecular Cancer Research
Volume16
Issue number4
DOIs
StatePublished - Apr 1 2018

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Castration
Prostatic Neoplasms
Aurora Kinase A
Circulating Neoplastic Cells
Nomograms
Confidence Intervals
Area Under Curve
Long Noncoding RNA
Biopsy
Gene Expression
Neoplasm Genes
Androgen Receptors
Neoplasm Metastasis
Bone and Bones
Survival
Therapeutics
Genes

ASJC Scopus subject areas

  • Molecular Biology
  • Oncology
  • Cancer Research

Cite this

Singhal, U., Wang, Y., Henderson, J., Niknafs, Y. S., Qiao, Y., Gursky, A., ... Morgan, T. M. (2018). Multigene profiling of CTCs in mCRPC identifies a clinically relevant prognostic signature. Molecular Cancer Research, 16(4), 643-654. https://doi.org/10.1158/1541-7786.MCR-17-0539

Multigene profiling of CTCs in mCRPC identifies a clinically relevant prognostic signature. / Singhal, Udit; Wang, Yugang; Henderson, James; Niknafs, Yashar S.; Qiao, Yuanyuan; Gursky, Amy; Zaslavsky, Alexander; Chung, Jae Seung; Smith, David C.; Karnes, Robert Jeffrey; Chang, S. Laura; Feng, Felix Y.; Palapattu, Ganesh S.; Taichman, Russell S.; Chinnaiyan, Arul M.; Tomlins, Scott A.; Morgan, Todd M.

In: Molecular Cancer Research, Vol. 16, No. 4, 01.04.2018, p. 643-654.

Research output: Contribution to journalArticle

Singhal, U, Wang, Y, Henderson, J, Niknafs, YS, Qiao, Y, Gursky, A, Zaslavsky, A, Chung, JS, Smith, DC, Karnes, RJ, Chang, SL, Feng, FY, Palapattu, GS, Taichman, RS, Chinnaiyan, AM, Tomlins, SA & Morgan, TM 2018, 'Multigene profiling of CTCs in mCRPC identifies a clinically relevant prognostic signature', Molecular Cancer Research, vol. 16, no. 4, pp. 643-654. https://doi.org/10.1158/1541-7786.MCR-17-0539
Singhal, Udit ; Wang, Yugang ; Henderson, James ; Niknafs, Yashar S. ; Qiao, Yuanyuan ; Gursky, Amy ; Zaslavsky, Alexander ; Chung, Jae Seung ; Smith, David C. ; Karnes, Robert Jeffrey ; Chang, S. Laura ; Feng, Felix Y. ; Palapattu, Ganesh S. ; Taichman, Russell S. ; Chinnaiyan, Arul M. ; Tomlins, Scott A. ; Morgan, Todd M. / Multigene profiling of CTCs in mCRPC identifies a clinically relevant prognostic signature. In: Molecular Cancer Research. 2018 ; Vol. 16, No. 4. pp. 643-654.
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