Abstract 3665: Longitudinal monitoring of prostate cancer evolution by plasma genome sequencing

Castration-resistant prostate cancer (CRPC) is associated with poor survival and frequent metastasis to the bone. Disease progression and evolution of therapy resistance have been challenging to study, in part due to the difficulty in collecting invasive core biopsy samples longitudinally over time. While liquid biopsy methods hold great potential for longitudinal monitoring, they are currently limited to targeted measurements of single genes, or small cancer gene panels. To address this challenge, we developed an unbiased whole-genome sequencing method called PEGASUS (Plasma Exome and Genome Analysis by Size-Selection and Unbiased Sequencing) that enables the detection of copy number aberrations and exome mutations from circulating-tumor DNA (ctDNA). We applied PEGASUS to 15 CRPC patients, which identified common driver mutations and copy number aberrations in plasma DNA including AR, MYC, RB1 and PTEN. We compared matched ctDNA and metastatic tumor samples in 8 CRPC patients, which showed a high correlation (r=0.79) of copy number profiles and moderate concordance of exome mutations (~56%), but also revealed a number of ctDNA and metastasis-specific mutations. We further applied PEGASUS to analyze longitudinal samples from 10 prostate cancer patients that were treated with chemotherapy or androgen inhibition to delineate clonal evolution in response to therapy. Clonal subpopulations and dynamics were inferred from mutation frequencies, revealing both chemoresistant and chemosensitive clones. These data showed that while a subset of point mutations were under positive and negative selection; most copy number aberrations remained stable and did not change in response to therapy. Our data show the technical feasibility of performing whole-genome and exome profiling of plasma DNA and pave the way for future clinical applications in biomarker discovery and informing clinical treatment decisions in prostate cancer patients. Citation Format: Naveen Ramesh, Emi Sei, Ruli Gao, Pei Ching Tsai, Christopher Logothetis, Amado J. Zurita, Nicholas E. Navin. Longitudinal monitoring of prostate cancer evolution by plasma genome sequencing [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 3665.