Investigation of biomarker determinants of treatment efficacy of fulvestrant +/- the RET inhibitor vandetanib in oestrogen receptor positive breast cancer

Hudson, Zoe Ann 2021. Investigation of biomarker determinants of treatment efficacy of fulvestrant +/- the RET inhibitor vandetanib in oestrogen receptor positive breast cancer. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

ER+ breast cancer affects millions of women worldwide. Disease relapse is common after initial treatment and causes significant morbidity and mortality. Many treatments focus on targeting the endocrine receptor but over time resistance to endocrine therapies emerges. The fulvestrant and vandetanib in advanced aromatase inhibitor resistant breast cancer (FURVA) clinical trial aimed to address this by adding vandetanib (a RET inhibitor) to a hormone directed backbone (fulvestrant). The work presented in this thesis documents the investigation into biomarker determinants of response to treatment. Three key areas are investigated (i) RET expression as determined by immunohistochemistry (IHC), (ii) presence of single nucleotide variants (SNVs) by NGS and digital droplet PCR (ddPCR) and (iii) copy number alterations determined by ddPCR. Tissue and plasma samples were collected during trial participation and allowed investigations of both primary tumour, represented by formalin fixed paraffin embedded tissue samples and metastatic disease, represented by circulating free DNA (cfDNA) extracted from plasma. Both high total-RET (t-RET) and phosphorylated-RET (p-RET) expression by IHC correlated with longer progression free survival (PFS) in participants in the FURVA clinical trial irrespective of treatment received. In addition, patients with no detectable circulating tumour DNA (ctDNA) in plasma samples during trial participation had a longer PFS. There were notable negative findings; increased RET expression did not appear to be related to SNVs in RET and copy number alterations in FGFR1 or MYC did not correlate with PFS but were detectable using ddPCR technology. In conclusion, this thesis has shown that high RET expression correlates with longer PFS and that detection of ctDNA during treatment correlates with shorter PFS when patients are treated with fulvestrant +/- vandetanib.

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Medicine
Date of First Compliant Deposit:	4 October 2021
Last Modified:	19 Apr 2023 08:26
URI:	https://orca.cardiff.ac.uk/id/eprint/144621

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