Uncovering biomarkers of response to neoadjuvant endocrine therapy in oestrogen receptor-positive breast cancer

Neoadjuvant endocrine therapy (NET) in oestrogen receptor-positive (ER+) / HER2-negative (HER2-) breast cancer (BC) allows real-time evaluation of treatment sensitivity and offers the opportunity of personalised BC therapy. However, the lack of reproducible biomarkers to assess response and long-term prognosis after NET is a significant barrier to increase its indications. In this context, this work sought to identify robust and reproducible biomarkers of NET response in a multicentre cohort of 131 ER+/HER2- BC patients in whom paired pre- and post-NET tumour samples were collected. For that, we used various approaches including analyses of clinical data and molecular characterisation by different techniques. First, we observed that the radiological measurements of tumour size pre-NET (at diagnosis) correlate more accurately with the pathological tumour size observed post-NET (at surgery) than the radiological assessment after NET. Additionally, we identified a novel biomarker, tumour cellularity size, as a promising indicator of response to NET and prognosis. Furthermore, we observed a decrease in the HER2-low status after NET. Later, analyses using the PAM50 gene expression assay revealed that those tumours changing from Luminal A to Normal-Like showed increased response to NET. Next, our immunohistochemical analyses showed that p53 (and p21, in a lesser extent) expression was associated with NET outcomes. Finally, we successfully established a workflow to apply the spatial transcriptomics technique in our samples. In conclusion, this thesis characterises the response of ER+/HER2- BC tumours after NET and identifies potential biomarkers of response.