Applications of liquid biopsies in metastatic castration resistant prostate cancer
de Bono, J
Thesis or Dissertation
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Despite many recent advances, treating advanced prostate cancer (PC) remains clinically challenging. The need for vaildated circulating biomarkers is well recognised in almost all cancers, including in PC. Whilst circulating biomarkers such as plasma cell-free DNA (cfDNA) and circulating tumour cells (CTCs) are being investigated for their clinical utility, there has been a lack of consensus with regard to analyses, reporting and clinical effectiveness of these biomarkers. I begin by presenting the findings of experts in the field addressing these issues at an international consensus meeting. Following this, I present analysis of cfDNA concentrations of patients treated with taxanes on two large Phase III trials. Here I show that baseline cfDNA concentrations correlate with radiographic progression free survival and overall survival, but not with response to taxanes, confirming their use as independent prognostic marker but not a predictive biomarker in this setting. Low pass whole genome sequencing of plasma cfDNA performed in this same cohort of patients had superior clinical utility, with changes in tumour purity associating with response to taxane therapy, suggesting that it may be acting as a response biomarker evaluating changes in overall tumour burden. Genomic changes identified require further validation but may provide key insights into understanding drivers of taxane resistance. I also explored the role of apheresis in increasing CTC numbers, finding it to be a well-tolerated and safe procedure which allowed significant enrichment of CTCs and facilitated the interrogation of tumour genomics and dissection of inter- and intra-patient heterogeneity. Together, this work has highlighted the possible utility of less invasive liquid biopsies, with both cfDNA and CTCs (acquired by apheresis) showing promise. Currently, interrogating tumour genomics by tissue biopsy remains the gold standard but liquid biopsies have huge potential as multi-purpose biomarkers to serially and safely evaluate changes imposed by therapeutic selective pressures.
Prostate Cancer - Therapy
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Institute of Cancer Research (University Of London)