Abstract 5231: Plasma genetic and genomic abnormalities predict treatment response and clinical outcome in advanced prostate cancer
Authors: Wang Liang , Xia Shu , Du Meijun , Ditmar Rachel , Yuan Tiezheng , Guo Yongchen , Wang Yuan , Lee Adam , Tschannen Michael , Worthey Elizabeth , Jacobs Howard , Huang Chiang-Ching , Kohli Manish 
Published: August 2015

Abstract
Androgen deprivation therapy (ADT) for hormone-sensitive prostate cancer (HSPC) and chemotherapy for castration-resistant prostate cancer (CRPC) are considered standard of care. However, there are no clinical tests or factors that can reliably predict treatment responses for the advanced prostate cancer patients. Examination of tumor component in circulation, also known as liquid biopsy, has shown promise for predicting treatment outcomes and survival. To capture the tumor-derived genomic alterations and decrease the surrogacy of using PSA measurements as is currently performed, we propose a Plasma Genomic Abnormality (PGA) score and Treatment Efficacy (TEff) index based on copy number variations as estimated by cell free DNA (cfDNA) in plasma. We first performed whole genome and targeted sequencing (NimbleGen comprehensive cancer panel) to examine plasma cfDNA for tumor-associated genetic and genomic aberrations in 10 HSPC patients receiving ADT and 10 CRPC patients receiving chemotherapy. For each patient, we tested plasma from two time points: pre-treatment and 4 months post-treatment. We then calculated the PGA score by summing the most significant genomic abnormalities with higher PGA score indicating greater tumor DNA content in cfDNA. TEff index was derived from comparison of PGA score difference between treatments with higher TEff index reflecting a better treatment response. The sequencing-based copy number analysis revealed locus-specific gains or losses including those previously reported in prostate cancers, such as 8q gains, AR amplifications, PTEN losses and TMPRSS2-ERG fusions. We found that overall PGA score was significantly higher in CRPC patients than in HSPC patients (p&lt;0.0005), possibly reflecting increased tumor burden during the disease progression. Patients with low TEff index often demonstrated poor response to treatments, and patients with high initial PGA score or low TEff index tended to have poor overall survival. As examples of the PGA-based TEff associations with outcome we presented three CRPC patients including two with neuro-endocrine origin (small cell carcinoma). Comparison of mutational profiles between pre- and post-treatments showed that treatments caused more diverse gene mutations, in particular, in the genes involving androgen biosynthesis, AR activation, DNA repair and chemotherapy resistance, suggesting subclonal evolution of heterogeneous tumor genomes in response to these treatments. Our results strongly support the feasibility of using non-invasive liquid biopsy as a potential powerful tool to study biological mechanisms underlying therapy-specific resistance and monitor disease progression in the advanced prostate cancer. Further studies are needed to develop and validate the genomics-based PGA score and TEff index for clinical applications.
Citation Format: Liang Wang, Shu Xia, Meijun Du, Rachel Ditmar, Tiezheng Yuan, Yongchen Guo, Yuan Wang, Adam Lee, Michael Tschannen, Elizabeth Worthey, Howard Jacobs, Chiang-Ching Huang, Manish Kohli. Plasma genetic and genomic abnormalities predict treatment response and clinical outcome in advanced prostate cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5231. doi:10.1158/1538-7445.AM2015-5231