Abstract 4350: Integrative and multiregional molecular analysis of localized, high grade prostate cancer treated with neoadjuvant androgen deprivation treatment
Authors: Wankowicz Stephanie A. , Bowden Michaela , Lis Rosina , Margolis Claire , Livitz Dimitri , Leshchiner Ignaty , Liu David , He Meng Xiao , Zhang Zhenwei , Getz Gad , Taplin Mary-Ellen , Allen Eliezer Van 
Published: August 2018

Abstract
Neoadjuvant intense androgen deprivation treatment (ADT) in localized, high risk prostate cancer (HG PCa) has varied degrees of response. While some patients have an outstanding response with minimal residual disease [MRD; ≤0.5mm of tumor at radical prostatectomy (RP)], others have no response but delay potential curative treatment. Previous studies have demonstrated that HG PCa is heterogenous, however previous studies have not investigated whether heterogeneity itself or specific genetic molecular features correlate with response to intense neoadjuvant ADT. Herein, we provide an integrated molecular analysis of the spatial heterogeneity of HG PCa treated with neoadjuvant ADT. We examined 53 pre-treatment biopsy samples (n=35 biopsies containing tumor, n=18 normal prostate tissue) from 14 patients with matched blood normals who were treated with an intense neoadjuvant regimen of lupron plus abiraterone/enzalutamide. Patients were stratified as exceptional responders (n=8; MRD at RP) or non-responders (n=6; pT3 or lymph node positive at RP). We performed whole exome and whole transcriptome sequencing on multiple, spatially heterogeneous biopsies within each patient to examine the role of heterogeneity in response to therapy. We called somatic and germline variants, inferred mutational clonality, phylogenetic relationships, called genetic fusion, and analyzed differentially expressed genes. After QC, we observed well known prostate driver mutations (SPOP, ATM, TP53, FOXA1, PTEN, and APC) across the entire cohort (n=14 patients). Within each individual, all driver mutations were clonal across tumor cores, but the proportion of all mutations that were always clonal varied widely (0.08-0.57), median 0.3). Among known drivers, SPOP mutations were only observed in exceptional responders (4/8 v. 0/6), and TP53 and PTEN mutations were only observed in non-responders (4/6 v. 0/8). Responders and non-responders did not differ by mutational or copy number burden. Mutational heterogeneity varied greatly between samples, however this did not split between responders and non-responders. In terms of gene expression, exceptional responders showed upregulation of androgen and estrogen response pathways, while non-responders had increased expression of E2F targets and cell cycle pathways. We confirmed that a subset of localized, HG PCa are molecularly heterogeneous in terms of mutations and expression. We are presently underpowered to explain the genomic differences between excpetional responders and non-responders. However, molecular heterogeneous and homogenous HG PCa tumors can respond to intense neoadjuvant ADT therapy. We are currently analyzing a larger cohort.
Citation Format: Stephanie A. Wankowicz, Michaela Bowden, Rosina Lis, Claire Margolis, Dimitri Livitz, Ignaty Leshchiner, David Liu, Meng Xiao He, Zhenwei Zhang, Gad Getz, Mary-Ellen Taplin, Eliezer Van Allen. Integrative and multiregional molecular analysis of localized, high grade prostate cancer treated with neoadjuvant androgen deprivation treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4350.