Study of the inter- and intra-patient heterogeneity within the intravenous compartment at progression of solid tumours and the potential predictive value in targeted therapy
21 December 2018
UAntwerp - Campus Drie Eiken - Building O - Auditorium O5 - Universiteitsplein 1 - 2610 WILRIJK (route: UAntwerpen, Campus Drie Eiken
Organization / co-organization:
Faculty of Medicine and Health Sciences
Bram De Laere
Prof S. Van Laere & Prof L. Dirix
PhD defense Bram De Laere - Faculty of Medicine and Health Sciences
The reliable identification of molecular drivers of cancer by next-generation sequencing is the backbone of precision medicine. Profiling a single tissue biopsy is incapable to unravel the full spectrum of the molecular heterogeneity that exists within a patient’s tumour and is not without risk for the patient. A minimal invasive sampling method, such as a peripheral blood sample, can circumvent this issue and allows for longitudinal monitoring. The general aim of this dissertation was to study the liquid biopsy, either in the form of circulating tumor cells (CTC) or tumor-derived cell-free DNA (cfDNA), focusing on metastatic castration-resistant prostate cancer (mCRPC) and assessing its clinical validity and utility.
During a multicenter, prospective and non-interventional clinical study in the context of second-generation androgen receptor (AR) signaling inhibitors (ARSi), we enumerated and monitored CTCs which recapitulated the independent prognostic value of CTCs in real-life mCRPC patients. Next, we developed workflows and methodologies, which allowed us to simultaneously detect CTC-derived AR splice variants and cfDNA-derived AR genomic alterations, introducing the concept of comprehensive AR profiling. Besides the molecular characterization of AR our cfDNA profiling efforts revealed for the first time that the microsatellite instability phenotype is detectable directly from cfDNA, that clonal expansions in the white blood cell compartment will cause false positive findings during cfDNA profiling and that genomic structural rearrangements in key tumor suppressor genes are frequent events. Finally, the developed methodologies were put to the test on our biobanked mCRPC samples. By performing comprehensive profiling of AR and TP53 in the prospectively recruited cohort of 168 men with mCRPC, prior to abiraterone or enzalutamide treatment, we demonstrated for the first time that TP53 perturbations outperform any AR-derived biomarker to identify patients with worse prognosis and that the use of AR biomarkers, when profiled comprehensively, may only be informative in TP53 wild-type mCRPC.
In conclusion, the study of the inter- and intrapatient heterogeneity in patient with advanced prostate cancer has resulted in knowledge, methodologies and workflows for geno- and transcriptomic analyses of liquid biopsies. This work has brought us closer to the implementation of precision urologic oncology. Knowing the accurate assessment of the genomic landscape of a tumour by means of a simple blood draw is feasible, we now need to understand its evolutionary and dynamic behavior throughout the course of the disease, as it is influenced by therapeutic interventions.