Impact of therapy on genomics and transcriptomics in high-risk prostate cancer treated with neoadjuvant docetaxel and androgen deprivation therapy

Background: 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 predictive biomarkers. Methods: 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: 3/52 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), SPOP (n=4) mutation, with no significant enrichment in post-treated specimens. We did not observe AR amplification or mutations. The degree of AR signaling suppression varied among treated tumors and there was up-regulation 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 post-treatment provides new insight into potential early markers of resistance.

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