Abstract 527: Integrated genomic cfDNA/cfRNA profiling for AR-V7 liquid biopsy test in prostate cancer

Abstract

Abstract The growth and survival of prostate cancer tumors relies primarily on the functioning of the androgen receptor (AR) signaling pathway. Recent studies suggested that the presence of AR-V7, a c-terminal truncated form of AR, in circulating tumor cells (CTCs) of patients with castration-resistant prostate cancer (CRPC) is associated with inherent and/or acquired resistance to enzalutamide and abiraterone, the stand of care androgen deprivation therapies in prostate cancer. A series of data also indicate that AR-Vs (eg, including AR-V7, ARv567es, AR-T878A, AR-F876L etc) may drive resistance in CRPC. Expression of AR-V7 has been shown to correlate with disease progression and shortened survival. Considering that truncated AR splicing variants with C-terminal loss lack a functional ligand-bingding domain (LBD) and are constitutively active, C-terminal AR-directed therapies may not be effective for patients with AR splicing variants. Circulating tumor cell (CTC)-based AR-V7 tests are currently being tested in the clinic. However, nearly half of the CRPC patients do not have enough CTCs for AR-V7 test, raising the request for a complementary, non-CTC platform to detect AR variants as well as other resistance markers in circulation. Here we report the development, validation and clinical application of PrediSeq-Prostate, a non-invasive next generation sequencing-based diagnostics platform that offers integrated genomic cell-free DNA (cfDNA) and cell-free RNA (cfRNA) profiling of prostate cancer, identifying known (such as AR-V7, AR-V9, AR-V2, etc) and novel AR splicing variants, point mutation, copy number, and translocation (such as TMPRSS2-ERG) using a single tube of blood. Using plasma samples from mCRPC patients that developed resistance to enzalutamide and/or abiraterone, PrediSeq-Prostate NGS test identified AR-V7, AR-V2, AR-V3, AR-V4 and other splicing variants that impact diagnosis and therapeutic selection. We also developed a Bio-Rad digital PCR assay measuring AR-V7 and AR-FL (full length) simultaneously. Collectively, PrediSeq NGS and ddPCR assays offer comprehensive genomic profiling of both cfDNA and cfRNA in all patients with prostate cancer, regardless of their status of CTC enumeration. The successful development and clinical validation of these tests has potential to enable precision medicine in prostate cancer. Citation Format: Shidong Jia. Integrated genomic cfDNA/cfRNA profiling for AR-V7 liquid biopsy test in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 527. doi:10.1158/1538-7445.AM2017-527