Novel mechanisms for neoadjuvant chemotherapeutic response monitoring in breast cancer

Abstract

Breast cancer is the most frequently diagnosed female malignancy worldwide, causing the majority of cancer-related deaths amongst women. While the management of this disease has transformed dramatically in recent years, personalised breast cancer management has not yet been achieved. To further inform the development of precision medicine, this thesis investigated novel mechanisms for neoadjuvant chemotherapeutic response-monitoring. With unprecedented access to scientific material, the field of microRNA (miRNA) research was analysed to enable the production of informed and targeted outputs. Recognising their known dysregulation in association with breast cancer, miRNAs were selected for analysis at the circulatory level as biomarkers of disease response to chemotherapy. Results outlined represent the initial blinded analysis of the first half of the national clinical trial that was undertaken to address this question. Upstream of miRNAs, the potential role of the miRNA-binding protein Argonaute-2 (Ago2) was analysed. Differential expression of Ago2 protein between the molecular subtypes of breast cancer was detected in-vitro, and at the tissue level in clinical breast specimens. Ago2 protein was significantly less abundant in luminal cancers, displaying inverse association with the presence of luminal receptors and direct association with metastasis, supporting a potential prognostic or predictive role. At the patient level, a novel imaging modality was introduced into the clinical setting to assess its ability to effectively visualise breast tissue. The system was optimised for clinical use, with individual breast pathologies displaying distinct photoacoustic signals. With the system optimised for clinical use and baseline parameters established, a study assessing early in-vivo tumour response detection to chemotherapy was developed and commenced. By further informing mechanisms to tailor breast cancer management on an individualised basis, work presented here contributes to the development of personalised or precision medicine, pursuing tailored chemotherapeutic administration and improved patient outcomes from this disease.