Abstract 1385: Prognostic and predictive utility of copy number variations (CNVs) in circulating tumor DNA (ctDNA) from metastatic castration-resistant prostate cancer (mCRPC) patients
Authors: Fettke Heidi , Kwan Edmond M. , Yu Jianjun , Wang Amy , Montesinos Carlos , Wong Calvin , Gong Xue , Zheng Tiantian , Du Peter Pan , Jia Shidong , Mant Andrew , Parente Phillip , Pezaro Carmel , Azad Arun A. 
Published: August 2019

Background: Due to difficulties with routine metastatic tissue biopsy in mCRPC, the identification of prognostic and predictive biomarkers for treatment with androgen-receptor signalling inhibitors (ARSI) and chemotherapy remains an unmet clinical need. Plasma circulating tumor DNA (ctDNA) has emerged as a promising minimally-invasive tool with which to interrogate the cancer genome. However, detection of copy number variations (CNVs) in ctDNA has proved challenging. This poses a major problem in mCRPC, which commonly harbours pathogenic CNVs. Here we use an ultra-sensitive next-generation sequencing (NGS) assay to identify CNVs in ctDNA from mCRPC patients and correlate findings with clinical outcomes in men commencing ARSI (abiraterone or enzalutamide) or chemotherapy (docetaxel or cabazitaxel).

Methods: mCRPC patients commencing ARSI or chemotherapy were prospectively recruited at two Australian centers. Plasma was collected and platelet poor plasma (PPP) fractions were processed uniformly and cell-free DNA (cfDNA) extracted. Plasma samples were analysed using the PredicineLITE NGS assay, which reports genomic alterations in 90 cancer genes. CNVs from this cohort were correlated with PSA response rate (Fisher’s exact test), PSA progression-free survival (PSA-PFS), clinical/radiographic progression-free survival (clinical/rPFS), and overall survival (OS).

Results: Median follow-up was 19.85 months (mo) (IQR 12.5-23.0). In total, 32 pre-treatment samples were analyzed (7 chemotherapy, 25 ARSI). The most common CNVs were PTEN loss (n=12, 38% of cohort), RB1 loss (n=5, 16%) and AR gain (n=12, 38%). Notably, OS was decreased in patients with PTEN loss (median 9.7 mo vs. not reached; p=0.03) and RB1 loss (median 7.1 mo vs. 17.1 mo; p=0.1), while PSA response rates were also lower in RB1 loss (1/5, 20% vs. 19/27, 71%; p=0.053). In addition, AR copy number gain was associated with decreased clinical/rPFS (median 3.4 mo vs. 10.7 mo; p=0.05) and inferior OS (median 9.7 mo vs. not reached; p=0.05).

Conclusion: Using an ultra-sensitive NGS assay, we demonstrate the robust detection of CNVs in plasma ctDNA of patients with mCRPC. Copy number losses of PTEN and RB1, and gains of AR were associated with worse clinical outcomes on chemotherapy and ARSI. Validation in a larger cohort is ongoing.

Citation Format: Heidi Fettke, Edmond M. Kwan, Jianjun Yu, Amy Wang, Carlos Montesinos, Calvin Wong, Xue Gong, Tiantian Zheng, Peter Pan Du, Shidong Jia, Andrew Mant, Phillip Parente, Carmel Pezaro, Arun A. Azad. Prognostic and predictive utility of copy number variations (CNVs) in circulating tumor DNA (ctDNA) from metastatic castration-resistant prostate cancer (mCRPC) patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1385.