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Clin Cancer Res. 2017 Nov 15;23(22):6802-6811. doi: 10.1158/1078-0432.CCR-17-1034. Epub 2017 Aug 25.

Impact of Therapy on Genomics and Transcriptomics in High-Risk Prostate Cancer Treated with Neoadjuvant Docetaxel and Androgen Deprivation Therapy.

Author information

1
Division of Medical Oncology, Department of Medicine, Weill Medical College of Cornell University, New York, New York. hip9004@med.cornell.edu m.gleave@ubc.ca.
2
Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
3
Division of Medical Oncology, Department of Medicine, Weill Medical College of Cornell University, New York, New York.
4
Institute of Biosciences and Medical Technology, University of Tampere, Tampere, Finland.
5
Department of Medical Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.
6
Department of Medical Oncology, Dana-Farber/Partners Cancer Care, Boston, Massachusetts.
7
Department of Pathology and Laboratory Medicine, Weill Medical College of Cornell University, New York New York.
8
Department of Urology, Memorial Sloan Kettering Cancer Center, New York, New York.
9
Institute for Computational Biomedicine, Weill Medical College of Cornell University, New York, New York.
10
Alliance Statistics and Data Center and Department of Biostatistics and Bioinformatics, Duke University, Durham, North Carolina.
11
Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada. hip9004@med.cornell.edu m.gleave@ubc.ca.

Abstract

Purpose: The combination of docetaxel chemotherapy and androgen deprivation therapy (ADT) has become a standard treatment for patients with metastatic prostate cancer. The recently accrued phase III CALGB 90203 trial was designed to investigate the clinical effectiveness of this treatment approach earlier in the disease. Specimens from this trial offer a unique opportunity to interrogate the acute molecular response to docetaxel and ADT and identify potential biomarkers.Experimental Design: We evaluated baseline clinical data, needle biopsies, and radical prostatectomy (RP) specimens from 52 (of 788) patients enrolled on CALGB 90203 at one high volume center. Pathology review, tumor and germline-targeted DNA sequencing (n = 72 genes), and expression profiling using NanoString platform (n = 163 genes) were performed to explore changes in critical prostate cancer pathways linked to aggression and resistance.Results: Three of 52 patients had only microfocal residual cancer at prostatectomy. The most common alterations included TMPRSS2-ERG fusion (n = 32), TP53 mutation or deletion (n = 11), PTEN deletion (n = 6), FOXA1 (n = 6), and SPOP (n = 4) mutation, with no significant enrichment in posttreated specimens. We did not observe AR amplification or mutations. The degree of AR signaling suppression varied among treated tumors and there was upregulation of both AR and AR-V7 expression as well as a subset of neuroendocrine and plasticity genes.Conclusions: These data support the feasibility of targeted and temporal genomic and transcriptome profiling of neoadjuvant-treated prostate cancer with limited formalin-fixed paraffin embedded tissue requirement. Characterization of the heterogeneity of treatment response and molecular outliers that arise posttreatment provides new insight into potential early markers of resistance. Clin Cancer Res; 23(22); 6802-11. ©2017 AACR.

PMID:
28842510
PMCID:
PMC5690882
DOI:
10.1158/1078-0432.CCR-17-1034
[Indexed for MEDLINE]
Free PMC Article

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