American Association for Cancer Research
10780432ccr171034-sup-181726_3_supp_4213818_ffpfg0.docx (42.52 MB)

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

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posted on 2023-03-31, 19:26 authored by Himisha Beltran, Alexander W. Wyatt, Edmund C. Chedgy, Adam Donoghue, Matti Annala, Evan W. Warner, Kevin Beja, Michael Sigouros, Fan Mo, Ladan Fazli, Colin C. Collins, James Eastham, Michael Morris, Mary-Ellen Taplin, Andrea Sboner, Susan Halabi, Martin E. Gleave

Supplementary Methods, Figures, Table Legends Supplementary Figure 1: Representative Hematoxylin and Eosin stained photomicrographs of prostatectomy specimens demonstrating the effects of neoadjuvant chemohormonal therapy. Supplementary Figure 2: Quality metrics for targeted DNA sequencing of FFPE biopsy and RP specimens. Supplementary Figure 3: Somatic mutations detected pre- and post-treatment through targeted DNA sequencing. Supplementary Figure 4: Differences in the number and allelic frequency of somatic mutations between treated and untreated specimens. Supplementary Figure 5: Persistence of TP53 mutations in post-treated radical prostatectomy (RP) specimens. Supplementary Figure 6: Representative copy number plots from targeted sequencing of diagnostic biopsies and RP specimens from the untreated arm. Supplementary Figure 7: Pearson's correlation comparing the Nanostring platform (x axis) and RNA-seq (y axis) performed in 13 matched cases. Supplementary Figure 8: Scatterplots showing Pearson correlation between Nanostring data obtained from matched FFPE and fresh/frozen tissue in 7 patients. Supplementary Figure 9: Gene expression of PTEN (y axis) relative to genomic status (PTEN deletion or wild type (WT). Supplementary Figure 10: Left: Correlation of TMPRSS2-ERG fusion transcript expression (x axis) and ERG gene expression (y axis). Right: ERG expression vs. TMPRSS2-ERG fusion status with positive defined as normalized count> 50. Supplementary Figure 11: Principal component analysis plotted using the Biological Coefficient of Variation (BCV) distance as part of the edgeR package. Supplementary Figure 12: Unsupervised analysis of expression of all genes within the panel in radical prostatectomies from treated (green) and untreated (yellow) arms. Red= high expression; blue= low expression.



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Canadian Cancer Society Research Institute

Alliance for Clinical Trials in Oncology



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.

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