Sir Peter MacCallum Department of Oncology - Theses

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Type: PhD thesis × Subject: breast cancer × Subject: ctDNA ×

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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.
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    Circulating tumour DNA analysis for personalised care in breast cancer
    Zivanovic, Andjelija ( 2020)
    Phenotypic diversity of breast cancers poses insurmountable challenges in the treatment of this lethal disease. Recent advances in next generation sequencing have led to unprecedented insight into the genomic landscape underlying breast tumours. This has resulted in burgeoning development of targeted treatments and predictive biomarkers, several of which have recently demonstrated clinical activity. However, key challenges hinder optimal application. On the background of extensive molecular heterogeneity, most biomarkers represent minority patient subpopulations, hampering clinical development. Furthermore, considerable genomic evolution of breast tumours impacts accuracy of genomic characterisation that is thus far heavily reliant on the sequencing of non-contemporaneous and invasive tumour tissue biopsies. Finally, stratification to genomically-matched targeted therapies also fails to fulfil the extent of its promise. In many cases relentless tumour growth remains unperturbed, while in others resistance ultimately develops. Crucially, molecular mechanisms underlying resistance remain poorly understood, while follow-on treatment options are often poorly defined. Central to the promise of personalised medicine is the robust and accurate characterisation of the tumour genome. Minimal invasiveness and convenience of circulating tumour DNA (ctDNA) analysis, with ability to detect tumour genomic aberrations from a blood draw, highly recommends this approach. Recent technological advances have paved the way to a range of clinical applications, with evolving potential for ctDNA analysis to address the continuum of challenges posed to precision medicine throughout patient management. Toward this end, extensive clinical development is required, while prevailing technological hurdles need to be addressed. This thesis explores a multi-faceted and rigorous approach towards the integration of ctDNA analysis in the management of breast cancer patients. Firstly, the development and validation of multiple assays (allele-specific and NGS-based) tailored to breast cancers, enabled comprehensive genomic analysis with in-built flexibility to be readily applicable to a variety of clinical scenarios. Subsequent establishment of a prospective ctDNA-based molecular profiling program across a large cohort of metastatic breast cancer (mBC) patients demonstrated feasibility of real-time analysis in the clinical setting across a range of genomic targets of variable abundance. Importantly, integration of longitudinal testing in this program throughout patient management demonstrated capacity for ctDNA analysis to reflect genomic evolution in real-time to optimise precision-guided patient management. Finally, exploratory longitudinal ctDNA analysis for the study of resistance mechanisms to CDK4/6i, constituting a novel class of targeted compounds for breast cancer, highlights established and novel resistance markers. Indeed, this study also serves to demonstrate a workable framework for ctDNA analysis as a highly effective approach for the de novo elucidation of resistance mechanisms to novel targeted agents that is relevant across cancer types.