Liquid biopsies in metastatic breast cancer : a guide to personalized medicine
During tumour development, cancer cells acquire various genetic and epigenetic aberrations that contribute to the ‘hallmarks of cancer’, in which unrestricted cell growth and manipulation of the tumour micro-environment are central. Due to selection and clonal expansion, multiple genetically distinct subclones emerge, that have phenotypic advantages and expand simultaneously resulting in intra-tumour heterogeneity. Efficacy of targeted therapy depends on their ability to block specific molecular aberrations. Primary tumour biopsies provide only a snapshot of cancer evolution, hence therapeutic targets for treatment of metastatic disease might be missed. This thesis focusses on liquid biopsies, more specifically on circulating tumour cells (CTCs) and circulating tumour (ct)DNA, which are the most clinically well-developed biomarkers. CTCs are shed from various tumour sites and represent a ‘real-time’ snapshot of the actual tumour burden. CTCs offer the potential to obtain information at DNA, RNA, and protein level using various molecular techniques. This enables researchers to detect the presence of multiple aberrations within the same cell to decipher tumour heterogeneity and map clonal evolution. Chapter 2 of this thesis is an extensive literature review focussed on the genomic and transcriptional heterogeneity found in the CTC compartment. It further discusses the technical considerations of CTC analysis and its significance for clinical decision making. In chapter 3 we performed targeted and shallow whole genome sequencing of numerous single and sorted pools of tumour cells from three patients in order to unveil heterogeneity within the CTC and disseminated tumour cell (DTC) compartment. HER2 is an frequently used target in the treatment of breast cancer. Multiple prospective studies investigated if anti-HER2 therapy can improve progression-free survival in patients that “gained” HER2 on CTCs at the metastatic stage. In chapter 4 we compare different analysis methods for HER2 on CTCs (at DNA, RNA, and protein level). Compared to CTCs, cfDNA is easier to obtain, ship and store, however it is restricted to genetic and epigenetic analysis of the DNA. Due to the very low concentration of ctDNA, highly sensitive and specific methods are needed for detection of cancer alterations like mutations or copy number changes. In chapter 5 we discuss how ctDNA fraction can be used to predict treatment outcome and progression-free survival. Many studies have been performed towards the use of liquid biopsies in early detection, as well as determining its prognostic and predictive value in local and advanced disease. These will be extensively reviewed in the discussion of this thesis.
Antwerp : University of Antwerp, Faculty of Medicine and Health Sciences , 2023
154 p.
Supervisor: Peeters, Marc [Supervisor]
Supervisor: van Laere, Steven [Supervisor]
Supervisor: Dirix, Luc [Supervisor]
Supervisor: Beddowes, Emma [Supervisor]
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The publisher created published version Available from 12.10.2024
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Creation 19.09.2023
Last edited 04.03.2024
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