Sir Peter MacCallum Department of Oncology - Theses

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Author: Lo, Louisa Lisa × Type: PhD thesis × Subject: breast cancer ×

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    Tracking Disease In Breast Cancer Using Circulating Tumour DNA
    Lo, Louisa Lisa ( 2023-03)
    Plasma circulating tumour DNA (ctDNA) correlates with disease status in breast cancer and can provide more comprehensive genomic information than the heterogeneous nature of a single biopsy site. In metastatic breast cancer it allows the study of underlying cancer driving mutations, characterization of treatment resistance and can potentially guide future treatment adaptation and selection to improve patient survival. In early breast cancer, it has also been explored as a potential minimal residual disease (MRD) biomarker with the promise that it can significantly predict disease relapse and aid in prognostic stratification. This work has utilised ctDNA as a minimally invasive strategy to study molecular information in patients undergoing novel combination and targeted therapies in breast cancer. Using different sequencing technologies, this work has shown the feasibility and ability of ctDNA to predict and profile the molecular subtypes of breast cancer that would respond to different treatments. Additionally, serial analysis of ctDNA has been able to accurately monitor disease during therapy. When breast cancer patients progress on treatment, the molecular changes captured by ctDNA were studied to characterize genomic resistance mechanisms associated with the applied therapies, providing insights into future strategies to circumvent these changes. Nevertheless, the reliance on genetic information alone has limited the sensitivity and specificity of ctDNA as a prognostic biomarker in cancer of low volume disease. This thesis has therefore explored new methodologies to interrogate the epigenetic profile of ctDNA in breast cancer. When coupled with ctDNA genetic information, a breast cancer ctDNA classifier was derived and tested for its sensitivity and specificity for disease detection in patients with oligometastatic disease. As a result, this work provides a platform for future research to refine the use of combined genomic and epigenomic ctDNA test as a sensitive and specific disease monitoring strategy in high risk early and metastatic breast cancer.