Investigating the prognostic and predictive role of biomarkers in breast cancer

These biomarkers were analysed in a cohort of 303 patients from the "Breast 300" study, all treated with anthracycline-based chemotherapy. Digital pathology software (QuPath) was used to quantify biomarker expression in tissue samples from a tissue microarray (TMA), with matched clinical and pathological data. Differential expression analysis revealed that all five biomarkers were significantly associated with patient outcomes, particularly relapse-free survival (RFS).

A composite five-biomarker signature was generated, which demonstrated superior predictive power compared to any individual marker, identifying patients with a high likelihood of a favourable outcome to standard-of-care chemotherapy. In contrast, patients with a score of zero or below were less likely to benefit from chemotherapy, suggesting the potential for alternative, targeted treatments. <br><br>The second approach focused on TNBC, a particularly aggressive subtype with the poorest prognosis.

Previous transcriptomic analysis by the Buckley group identified MST4 as a gene differentially expressed in relation to patient relapse within the Breast 300 cohort. The hypothesis was that MST4 expression contributes to poor outcomes specifically in TNBC. Bioinformatic analyses using in-house and publicly available datasets confirmed that high MST4 expression was significantly associated with poor prognosis in TNBC.

Further investigation in in vitro models demonstrated that MST4 regulates cell proliferation and apoptosis, primarily through the ERK signalling pathway, which is known to play a critical role in cell cycle progression and survival. The study also explored the potential therapeutic implications of targeting MST4, showing that TNBC cell lines with high MST4 expression were sensitive to treatments with Hesperadin (MST4 inhibitor) and MEK/ERK inhibitors, suggesting new avenues for targeted therapies in TNBC. <br><br>In conclusion, this study identified a five-biomarker signature with the potential to predict response to adjuvant anthracycline-based chemotherapy in breast cancer.

MST4 was also highlighted as a key regulator in TNBC, offering potential as a therapeutic target. Together, these findings may aid patient stratification and contribute to more personalised treatment strategies, ultimately improving outcomes and quality of life. <br><br><i>Thesis is embargoed until 31 July 2028.</i>