dc.contributor.advisor |
Print, Cristin |
|
dc.contributor.advisor |
Lasham, Annette |
|
dc.contributor.author |
Fitzgerald, Sandra Joanne |
|
dc.date.accessioned |
2022-02-21T01:15:33Z |
|
dc.date.available |
2022-02-21T01:15:33Z |
|
dc.date.issued |
2021 |
en |
dc.identifier.uri |
https://hdl.handle.net/2292/58288 |
|
dc.description.abstract |
With the increasing global focus on integrating circulating tumour DNA (ctDNA) analysis into routine cancer care, this thesis describes research to develop and evaluate ctDNA analysis in New Zealand. The context of this work is New Zealand’s substantial inequities in cancer patient outcomes and whether these inequities could be addressed using ctDNA analysis.
Several different genomic technologies were used to monitor ctDNA mutations in the blood plasma of 45 advanced melanoma patients. Mutations could be identified by next-generation sequencing (NGS) analysis of cell-free DNA (cfDNA) for 80% of these patients when a bespoke melanoma-specific NGS panel was used. All ctDNA mutations identified using NGS could be validated using custom droplet digital PCR (ddPCR) assays. A detailed comparison between NGS and ddPCR revealed concordance between these technologies and provided reassurance about NGS assay repeatability. 29 stage IV melanoma patients were followed through multiple cycles of immunotherapy to correlate ctDNA mutations in sequential blood samples with the clinical assessment of treatment response. This longitudinal analysis revealed a complex association between ctDNA analysis and the results of clinical imaging. In a subset of patients, ctDNA analysis identified the evolution of potentially actionable sub-clonal mutations. 16 stage III melanoma patients were followed after surgery using the same melanoma-specific NGS panel. This long-term pilot study is still ongoing but suggests that ctDNA analysis is a practical approach to identify both residual disease immediately after surgery and relapse in the longer term.
The utility of ctDNA analysis to detect mutations in other cancer types was then assessed using a larger pan-cancer NGS panel. I first showed that this panel was able to detect all mutations present in a set of standard control samples. I then used this panel to analyse cfDNA samples from patients with five different cancer types, identifying mutations in 78% of these patients. Mutations that appear to have evolved during drug treatment and may be associated with drug resistance were identified in breast cancer patients.
Finally, I assessed the feasibility of collecting blood samples at geographically remote locations for analysis at a central site. Blood was collected into DNA-stabilising collection tubes and stored for one week at room temperature before delayed processing was
conducted. Specific ctDNA mutations detected by NGS in blood collected and stored using this technique had 91% concordance with ctDNA mutations detected using standard blood collection tubes with immediate processing. This suggested that blood collection in geographically remote clinics using DNA-stabilising blood collection tubes would be viable.
Overall, this work demonstrated the utility of ctDNA analysis using a melanoma-specific NGS panel for melanoma patients. Longitudinal ctDNA analysis could detect early patient response or failure to immunotherapy treatment and may also be a feasible approach to monitor for relapse after surgery. These methods appear to have utility in both clinical care and cancer research. A pilot analysis using a larger pan-cancer NGS panel suggested this approach could be used to detect mutations in cfDNA for patients with multiple different cancer types, and may be extended to geographically remote regions of New Zealand by employing DNA-stabilising collection tubes followed by delayed analysis. In instances where the standard protocols for clinical imaging of cancer patients were delayed due to inconsistent service provision, or system-wide challenges such as the COVID-19 pandemic, ctDNA analysis could continue regularly. In this way, ctDNA analysis may be useful to prioritise or triage patients for imaging and other clinical investigations within a stretched health service. While further investigation is required before clinical implementation of liquid biopsy platforms can occur in New Zealand, my research suggests that ctDNA analysis has the potential to help overcome barriers to equitable cancer care. |
|
dc.publisher |
ResearchSpace@Auckland |
en |
dc.relation.ispartof |
PhD Thesis - University of Auckland |
en |
dc.relation.isreferencedby |
UoA |
en |
dc.rights |
Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. |
en |
dc.rights |
Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. |
|
dc.rights.uri |
https://researchspace.auckland.ac.nz/docs/uoa-docs/rights.htm |
en |
dc.rights.uri |
http://creativecommons.org/licenses/by-nc-sa/3.0/nz/ |
|
dc.title |
Plasma genomic biomarkers for New Zealand cancer patients |
|
dc.type |
Thesis |
en |
thesis.degree.discipline |
Molecular Medicine |
|
thesis.degree.grantor |
The University of Auckland |
en |
thesis.degree.level |
Doctoral |
en |
thesis.degree.name |
PhD |
en |
dc.date.updated |
2022-02-14T02:58:56Z |
|
dc.rights.holder |
Copyright: The author |
en |
dc.rights.accessrights |
http://purl.org/eprint/accessRights/OpenAccess |
en |