Author Identifier

Lydia Warburton: http://orcid.org/0000-0001-9417-1596  

Date of Award

2025

Document Type

Thesis - ECU Access Only

Publisher

Edith Cowan University

Degree Name

Doctor of Philosophy

School

School of Medical and Health Sciences

First Supervisor

Elin Gray

Second Supervisor

Michael Millward

Third Supervisor

Leslie Calapre

Abstract

In the last decade, significant gains have been made in the understanding of the biology of melanoma, translating to new drugs and improved outcomes for patients with advanced disease. Therapeutics such as BRAF/MEK inhibitors and immune checkpoint inhibitors (ICI) have revolutionised the melanoma treatment landscape. A small proportion of patients treated with these agents achieve durable long-term disease control and survival. However, toxicity can be substantial, and the financial cost of these drugs is significant. Furthermore, optimal duration of therapy is unknown.

As the health budget for anti-cancer drugs in Australia continues to grow, there is an increasing need to identify non-invasive biomarkers that can aid clinicians in making treatment cessation and adjuvant treatment decisions. Safe early cessation of melanoma treatments has the potential to minimise toxicity and reduce clinic visits thereby improving the quality of life for patients and may also potentially translate to a cost savings.

Liquid biopsy, a minimally invasive blood test can access fragments of the tumour deoxyribonucleic acid (DNA), providing information of the tumour genome as well as prognosis, response to therapy and patterns of resistance across various cancer types. Measurement of ctDNA can reveal the presence of residual cancer that was not eradicated by standard treatment, and thus identify patients at high risk of recurrence.

The aim of this PhD project was to determine if measurable ctDNA correlates with minimal residual disease and predicts recurrence in patients in whom there is no radiological measurable disease. First, I undertook a thorough review of the literature surrounding ctDNA as a biomarker in melanoma (Chapter 2), noting the lack of reports regarding ctDNA levels at treatment cessation. This led to the analysis of ctDNA in a cohort of patients who discontinued BRAF inhibitor-targeted therapy upon achieving a complete response (CR). Chapter 3 explores the impact of stopping targeted therapy for patients who achieve a CR, a relatively novel approach at the time of the study. The chapter investigates the potential of ctDNA as a crucial biomarker for determining which patients might maintain their response even after treatment cessation. This study aligns with the broader context of utilizing ctDNA to optimise treatment duration and minimise unnecessary toxicity.

In parallel, we undertook a retrospective study of a cohort of patients at cessation of anti-PD1 monotherapy (N=70) after achieving durable disease control. Chapter 4 further investigates the role of ctDNA in patients who discontinue PD1 inhibitors without disease progression. The study highlights how ctDNA can be a valuable tool in identifying patients at risk of relapse, even when conventional imaging does not show disease progression. This aligns with the theme of utilising ctDNA as a potential guide for making informed decisions about treatment cessation.

For a complete picture of the current treatment landscape, I undertook a retrospective exploratory study to investigate the role of ctDNA in guiding treatment decisions for melanoma patients experiencing high-grade immune-related adverse events (irAEs) while on combination ICIs. The study assessed ctDNA at baseline and at the time of treatment cessation due to toxicity on 34 patients with stage IV melanoma. Chapter 5 demonstrates that the presence of detectable ctDNA at the time of stopping ipilimumab and nivolumab for toxicity is predictive of disease progression. This finding emphasises the importance of monitoring ctDNA levels not only during treatment but also at its cessation, providing a more nuanced approach to managing treatment and anticipating potential relapse.

Finally, the implementation challenges of ctDNA into melanoma clinic (Chapter 6) and the subsequent developments in real-world data regarding therapy cessation are discussed in Chapter 7. The last two chapters review the current knowledge of ctDNA in melanoma, the potential applications and pitfalls limiting its translation for patient care and the current landscape of treatment cessation in advanced melanoma. Our findings underscore how ctDNA can guide treatment decisions, particularly when therapy cessation is being considered. We advocate for using ctDNA to inform personalised treatment plans, aiming to balance the risks and benefits of continuing or stopping therapy, and improve patient management and outcomes.

Access Note

Access to this thesis is embargoed until 12th February 2027 

DOI

10.25958/rf70-db39

Download

Available for download on Friday, February 12, 2027

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