Abstract 4579: The genetic heterogeneity and the molecular evolution of systemic metastatic castration resistant prostate cancer during therapy

Abstract

Abstract Background: Circulating tumour cells (CTCs) have a significant prognostic impact in metastatic castration-resistant prostate cancer (mCRPC) and provide direct access to the systemic disease. Here, we performed genome-wide copy number analysis of CellSearchTM detected CTCs to follow the genomic evolution of mCRPC during systemic therapy. Methods: Blood samples were collected from 13 patients with mCRPC before, during and after two different targeted therapy regimes. Single CTCs were isolated from CellSearchTM cartridges using the DEPArray™ system and the MoFlo XDP cell sorter. Genomes of sorted single cells were amplified using Ampli1™ WGA kit. Amplification products were analysed by array-based comparative genomic hybridization (aCGH) and low-pass sequencing (LPS) using Ampli1™ LowPass kit to detect somatic chromosomal copy number aberrations (CNAs) and explore the degree of genomic heterogeneity. Results: We analysed >300 CTCs for CNAs by aCGH and/or LPS. Although most CTCs displayed CNAs typical for mCRPC, we identified three genomic CTC-groups across all cells with the EpCAMpos/CKpos/DAPIpos/CD45neg phenotype: CTCs with typical mCRPC CNAs (Type A; 80%), extremely aberrant CTCs (Type B; 11%), CNA-negative/low CTCs (Type C; 9%). The occurrence of Type B and C was almost mutually exclusive. At baseline, we noted different levels of CTC-heterogeneity and different CTC-aberration levels between the different patients. Interestingly, CTCs of patients with a relevant decrease in CTC-count under PARP-inhibition (CTC-responder) displayed significantly elevated CNAs at baseline compared to CTC-non-responders. During therapy, we could observe clonal changes among all patients. Conclusions: Our data show that CTC-analysis enables the dissection of clinical relevant intra-patient heterogeneity and clonal evolution under therapy in mCRPC patients. Comprehensive genomic monitoring during therapy might help to tailor therapies more effectively and may pinpoint to molecular mechanism of therapeutic resistance. Citation Format: Rui PL Neves, Streit LRF Anna, Katharina Raba, Elina-Katharina Bongers, Bianca Behrens, Guus van Dalum, Penny Flohr, Joaquin Mateo, Semini Sumanasuriya, Mateus Crespo, Berni Ebbs, Gemma Fowler, Pasquale Rescigno, Suzanne Carreira, Maryou Lambros, Edoardo Petrini, Marianna Garonzi, Nicolò Manaresi, Johann de Bono, Nikolas H. Stoecklein. The genetic heterogeneity and the molecular evolution of systemic metastatic castration resistant prostate cancer during therapy [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 4579.