Current and potential diagnostic modalities in the detection and management of breast cancer

Global statistics have demonstrated that breast cancer is the most frequently diagnosed cancer and the leading cause of cancer death among female patients, accounting for 23 percent of total cancer cases and 14 percent of cancer deaths. Survival following a diagnosis of breast cancer is grossly determined by the stage of the disease at the time of initial diagnosis, highlighting the gravity of early detection. Improving early diagnosis will require a multi-faceted approach, including optimising the use of current available imaging modalities, in addition to investigating new methods of detection from a biochemical and radiological perspective. To further improve our knowledge on the use of current modalities, this thesis investigated the use of preoperative breast MRI in patients with invasive lobular breast cancer. While MRI was associated with minor delays in treatment and did not reduce overall rates of margin re-excision or completion mastectomy, it altered the choice of surgical procedure in almost a quarter of cases where MRI was utilised. Next, the potential role of microwave breast imaging was explored, and a First-in-Human trial conducted where the Wavelia system was introduced into the clinical setting. This novel system demonstrated exciting potential in the detection, localisation and characterisation of breast lesions. This modality may have the potential to offer a non-invasive, non-ionizing and painless adjunct to breast cancer diagnosis. Further larger studies are planned to validate the findings of this study. Finally, the potential of a circulating biomarker of breast cancer was investigated. Extracellular vesicles (EVs) are secreted by cells and shuttle bioactive materials including microRNAs (miRNA) throughout the circulation and are believed to represent a fingerprint of the cell of origin. As a result, recent years have seen an immense interest in their potential as a biomarker of breast cancer. In this work, EVs derived from breast-tumour bearing animals, breast cancer patients and healthy control volunteers were isolated and detailed characterisation performed. An array-based interrogation of the microRNA profile was performed and absolute quantitative polymerase chain reaction (AQ-PCR) employed to analyse EV-miRNA-451a expression. A significant increase in miRNA-451a copies/EV was detected in sera of breast cancer patients compared to healthy controls, suggesting a role for EV miRNA- 451a as a novel biomarker of breast cancer. A further novel finding from this work is that the previously widely used approach of indirectly quantifying EVs based on protein yield, bears no relationship with the number of EVs present in a sample when quantified directly using Nanoparticle Tracking Analysis (NTA). This has important implications for reproducibility of In Vitro, In Vivo, and clinical trials investigating the biomarker potential of EVs. When testing the therapeutic potential of an EV population, it is imperative that equal amounts of EVs from different cell sources or with different modifications are loaded to ensure standardised comparison. The findings presented in this thesis offer a multimodal contribution to the ongoing efforts to optimise and accelerate breast cancer detection and offers insight into the potential role of novel diagnostic strategies.2023-07-0