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Investigation of biomarker determinants of treatment response of fulvestrant and capivasertib in oestrogen receptor positive breast cancer

Meissner, Magdalena 2021. Investigation of biomarker determinants of treatment response of fulvestrant and capivasertib in oestrogen receptor positive breast cancer. PhD Thesis, Cardiff University.
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Abstract

Endocrine therapy is the standard treatment for patients with oestrogen-receptor positive advanced breast cancer. Half of such cancers progress through first-line therapy and half progress after an initial period of disease control. Endocrine resistance remains an ongoing issue. Many clinical trials have added targeted therapy to endocrine treatment to overcome endocrine resistance by inhibiting pathways involved in endocrine resistance, such as the PI3K/AKT pathway. FAKTION trial investigated the efficacy of capivasertib in combination with fulvestrant. Patients who received combinationtherapy have had improved progression-free survival (PFS) from 4.8 months to 10.6 months, p=0.0044 (Jones et al. 2020). A significant challenge remains to identify biomarkers which can guide the success of endocrine therapy in combination with capivasertib. As part of the trial formalin-fixed paraffin-embedded (FFPE) tumour tissue, were collected and translational blood samples were taken at baseline, eight weeks of treatment, and on progression. This thesis investigated the detection of biomarkers of resistance in the tissue DNA and circulating tumour DNA (ctDNA) in baseline samples and serial plasma samples from breast cancer patients undergoing trial treatment. Potential biomarkers indicative of resistance to endocrine therapy were successfully detected in FFPE DNA and ctDNA, using a commercially available, targeted 44 gene Next Generation Sequencing (NGS) panel and digital droplet PCR (ddPCR). In the first instance, the concordance of detected mutations in PIK3CA, AKT1, PTEN, ESR1 and TP53 genes between 34 baseline tissue and 34 baseline ctDNA samples, was assessed and potential reasons for discordance were identified. Mutations detected in baseline samples were trackable in longitudinal ctDNA samples of 15 patients. The allele frequency (AF) of detected mutations changed over time. In 40% of patients, the pattern ofmolecular response followed clinical response. However, in 60% of patients, did not follow the expected pattern, suggesting issues with sample handling or methods errors. Other biomarkers of endocrine resistance such as MYC, FGFR1, HER2 amplification detection were explored in the 55 ‘end of treatment’ ctDNA samples, using ddPCR. The study showed that the amplification could be detected in ctDNA but clinical threshold yet to be identified. This study showed that co-existence of other resistance biomarkers or bad prognostic factors like TP53 mutations can influence response to new trial treatment and should be considered in stratification in future trials.

Item Type: Thesis (PhD)
Date Type: Completion
Status: Unpublished
Schools: Medicine
Date of First Compliant Deposit: 7 September 2021
Last Modified: 07 Sep 2021 13:54
URI: https://orca.cardiff.ac.uk/id/eprint/143828

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