Jayaram, Anuradha Krishna; (2021) Leveraging circulating tumour DNA to dissect the evolutionary genomic dynamics of drug resistance in prostate cancer. Doctoral thesis (Ph.D), UCL (University College London).

Abstract

Several studies across multiple tumour types including metastatic castration-resistant prostate cancer (mCRPC) suggest plasma tumour DNA contains clinically relevant genomic aberrations representative of progressing metastases. The primary aim of this thesis was to better define drug resistance and tumour progression in mCRPC by leveraging circulating plasma DNA. Using an optimised multiplex droplet digital polymerase chain reaction (ddPCR) assay with four reference genes for androgen receptor (AR) copy number (CN), I studied the association of AR CN status and resistance to taxane chemotherapy. I observed a significant interaction between plasma AR CN status and treatment type (docetaxel or hormonal therapies). The data generated showed that patients with plasma AR CN normal favoured hormonal treatment, whilst plasma AR-gained patients may have a longer response to docetaxel. Utilising data from 501 mCRPC patients, I identified the optimal cut-point for calling AR CN gain which was 1.92. Patients with an AR CN >1.92 (AR CN gain) was associated with shorter overall survival and progression-free survival to AR targeting. Shorter times on primary androgen deprivation therapy was also observed in patients with plasma AR CN gain Utilising targeted capture based NGS, an orthogonal method for calling plasma tumour DNA (ptDNA) using the rolling b-allele method allowed detection of ptDNA independent of mutation calls. Patients with TP53, RB1 or PTEN alterations persisting after one cycle of treatment had the worst outcomes and patients with conversion of these alterations to undetectable after one cycle was associated with the similar outcomes as patients with undetectable alterations at baseline. AR point mutations appear de novo in ~16% of patients whilst plasma AR gain pre-treatment persisted at progression. Together the results of this 4 thesis confirm plasma DNA is a minimally invasive approach that has the potential to establish and identify genomic drivers of resistance to AR directed therapy in mCRP

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