Background: The efficacy of androgen signaling inhibitors such as Abiraterone (Abi) or Enzalutamide (Enz) has changed the standard of care in mCRPC. However, adaptive resistance to these agents is a consistent outcome with this therapy that undermines their benefit. The mechanisms underlying acquired resistance to Abi or Enz are poorly understood. The goals of the WCDT project are to identify the molecular pathways underlying the adaptive response to these targeted therapies through expression and mutational analysis of metastatic biopsies.
Methods: Following central radiologic review, eligible mCRPC pts underwent biopsy at one of 5 WCDT clinical sites, using a uniform biopsy protocol. Tissue was both frozen, and formalin fixed/paraffin embedded (FFPE). Frozen samples were subject to laser capture microdissection for isolation of RNA and DNA enriched for mCRPC. FFPE tissue underwent a CLIA-certified assessment of a mutational panel, IHC for PTEN, and fluorescence in situ hybridization (FISH) for AR+. Pathway assessment is performed using RNA-seq and mutation data from mCRPC biopsies mapped onto a comprehensive pathway database connecting a tumor sample with genetic regulatory logic.
Results: 70 of 300 planned mCRPC pts have undergone a metastasis biopsy. To date, biopsies have been obtained prior to treatment and following progression from one patient receiving Abi and one receiving Enz. Data collection from biopsies has been possible in 52 of 72 samples (72% success rate), and clinically actionable results have been returned to the care providers for 50 samples. The most commonly mutated gene assessed by the mutational panel was p53. Importantly, acquired mutation did not appear to be a mechanism for drug resistance in mCRPC, as the prevalence of tumors positive for mutations in genes contained in the panel was lower in patients who had progressed on Abi or Enz (9 of 16, 56%) than it was in treatment naïve patients (14 of 17, 82%). Gene expression-based signatures uncovered several pathways enriched in Abiraterone naïve compared to resistant samples.
Conclusions: Genomic sequencing and expression analysis can be accomplished in small bone and soft tissue mCRPC biopsies. Pathway-based gene expression analysis appears to be a promising strategy to identify adaptive processes and targeting opportunities in Abi resistant mCRPC.
Citation Format: Jack F. Youngren, Adam Foye, George Thomas, Joshua M. Stuart, Ted Goldstein, Baertsch Robert, Adrian Bivol, Artem Sokolov, Charles J. Ryan, Nader Pourmand, Tomasz M. Beer, Christopher P. Evans, Christopher P. Evans, Primo Lara, Jr., Martin E. Gleave, Kim N. Chi, Robert E. Reiter, Matthew Rettig, Owen Witte, Eric J. Small. Identification of pathways associated with abiraterone resistance in metastatic castration resistant prostate cancer: Preliminary results from the SU2C/AACR West Coast Prostate Cancer Dream Team. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Drug Sensitivity and Resistance: Improving Cancer Therapy; Jun 18-21, 2014; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(4 Suppl): Abstract nr A12.