Investigating longitudinal therapeutic resistance in serially treated metastatic castration resistant prostate cancer by liquid biopsy genome sequencing

Abstract Prostate cancer is the most commonly diagnosed cancer among men and a major cause of cancer-related deaths in the modern world. Metastatic castration-resistant prostate cancer (mCRPC) is the most lethal form and has complex and heterogeneous genomic patterns. Despite the recent development of life-prolonging therapies, mCRPC remains incurable since most patients develop resistance over time. A better understanding of the evolution of resistance to therapy in mCRPC is urgently needed. A major logistical challenge is that collecting serial tissue biopsies from the prostate and metastatic sites such as bone is not feasible. To overcome this issue, we developed a minimally invasive liquid biopsy approach to study the genomic basis of resistance through circulating tumor DNA (ctDNA) from longitudinally collected plasma samples. To best account for interpatient tumor heterogeneity and treatment history, we selected 60 mCRPC patients who were serially treated with life-prolonging second generation androgen signaling inhibitors (abiraterone, enzalutamide, or the combination) and taxane-based chemotherapy, and prospectively collected longitudinal blood samples (2 to 10 per patient). ctDNA was isolated from each blood plasma sample for sparse whole-genome sequencing and exome sequencing at 200x coverage depth. Somatic copy number alterations (CNA) and exome mutations were profiled and the resulting data was used to reconstruct the clonal substructure and infer clonal evolutionary dynamics across the treatment timepoints. The mutation signatures and the CNA signatures were also characterized. One of the CNA signatures identified the patients who carry CDK12 mutations through genome-wide focal tandem duplications in ctDNA. The subclones resistant to second-generation androgen signaling inhibitors and taxane-based chemotherapy were also identified, along with their associated genomic aberrations affecting AR, RB1, and PTEN. Furthermore, by analyzing the evolutionary dynamics patterns, we identified three distinct genomic responses to therapy: intrinsic resistance, clonal progression, and clonal responders, which correlated with overall survival outcomes. In summary, our data show that clonal evolutionary dynamics in mCRPC can be tracked over time and in response to treatment with minimally invasive liquid biopsy methods. Our results provide insights into the genomic evolution of life-prolonging therapy resistance in mCRPC and identified candidate resistance biomarkers for subsequent validation. Citation Format: Yuehui Zhao, Naveen Ramesh, Emi Sei, Min Hu, Shanshan Bai, Patricia Troncoso, Paul Corn, Ana Aparicio, Christopher J. Logothetis, Nicholas E. Navin, Amado J. Zurita. Investigating longitudinal therapeutic resistance in serially treated metastatic castration resistant prostate cancer by liquid biopsy genome sequencing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3791.