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Alfarsi, Lutfi (2020) Development of a clinically relevant subclassification of luminal breast cancer related to response to endocrine therapy. PhD thesis, University of Nottingham.

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Abstract

Endocrine therapy is widely used in clinical practice as adjuvant treatment for luminal breast cancer. Although clinical outcome of patients with this subtype have markedly improved with endocrine therapy, around 30-50% of patients relapse despite treatment. Therefore, as part of the growing concept of personalised medicine, research priorities are required to more accurately identify predictive markers of endocrine therapy response to aid clinician decision-making. This thesis aimed to identify markers that are able to classify luminal breast tumours into distinct groups with different outcomes in the context of response to endocrine therapy.

Large, well-characterised cohorts of primary luminal breast cancer patients with long-term follow-up were assessed for the clinical impact of selected markers at the transcriptomic and proteomic levels. Prognostic significance of these markers with clinical outcome and benefit of endocrine therapy as well as their association with clinicopathological variables and other related-genes were analysed. Bioinformatic analysis was performed to identify differentially expressed genes (DEGs) in terms of response to adjuvant endocrine therapy. In vitro experiments were conducted to investigate the effect of knockdown of key markers in the proliferation of cancer cells and to the sensitivity to endocrine treatment.

This thesis has identified key markers with different function including amino acid transporters (SLC1A5, SLC3A2/SLC7A5), cell cycle regulators (KIF18A) and markers of cell motility (PPFIA1 and DBN1) that are associated with worse outcome in luminal tumours. Additionally, results indicate that assessment of their expression prior to adjuvant treatment could subclassify luminal subtype tumours into distinct groups with different outcome in the context of response to endocrine therapy. This could have a great clinical impact in helping guide clinician decision-making. Additional or alternative targeted therapies could then be given to those who have been predicted to have resistance to endocrine therapy, this would be a significant shift toward a more truly individualised medicine. This thesis provides a set of useful targets for future investigation, which could pave the way for novel targeted therapy to overcome endocrine therapy resistance.

Item Type:	Thesis (University of Nottingham only) (PhD)
Supervisors:	Green, Andrew Rakha, Emad
Keywords:	Breast cancer; Endocrine therapy; Predictive markers; Luminal breast tumour classification
Subjects:	W Medicine and related subjects (NLM Classification) > WP Gynecology
Faculties/Schools:	UK Campuses > Faculty of Medicine and Health Sciences > School of Medicine
Item ID:	61919
Depositing User:	Alfarsi, Lutfi
Date Deposited:	20 Oct 2023 09:18
Last Modified:	20 Oct 2023 09:18
URI:	https://eprints.nottingham.ac.uk/id/eprint/61919

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