dc.contributor.advisor | Turner N | |
dc.contributor.author | Kingston, B | |
dc.contributor.editor | Turner, N | |
dc.date.accessioned | 2022-10-26T09:36:17Z | |
dc.date.available | 2022-10-26T09:36:17Z | |
dc.date.issued | 2022-10-17 | |
dc.identifier.citation | 2022 | en_US |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/5550 | |
dc.description.abstract | Circulating tumour DNA (ctDNA) analysis shows great potential both as an approach to understand the evolution of advanced breast cancer (ABC) and as a clinical tool to assist in ABC management. ctDNA analysis has not yet entered routine clinical practice, and important questions remain around the validity and applications of the approach.
The objectives of this work were to:
- validate the approach of ctDNA analysis
- establish the landscape of ABC according to ctDNA analysis
- utilise ctDNA analysis to identify biomarkers of response and resistance to therapy
ctDNA isolated from plasma samples from the plasmaMATCH trial underwent digital PCR and targeted sequencing. DNA extracted from paired tissues underwent targeted sequencing. A putative resistance mechanism was further investigated using transient transfection.
Two orthogonal ctDNA analysis techniques demonstrated a high level of agreement for targetable mutation status (kappa values 0.89 to 0.93). Sensitivity of ctDNA-assessed gene mutation status was high compared to the gold-standard tissue-based sequencing (88.2% to 96.8%), with specificity lower (40.0% to 98.5%), likely secondary to biological factors such as tumour heterogeneity and temporal mutation acquisition.
The landscape and clonal architecture of ABC was defined through analysis of a large cohort of patients (n=800). Significant and novel findings were identified in gene mutation patterns including dual PIK3CA mutagenesis, MAPK pathway and ESR1 co-mutation, and APOBBEC mutagenesis, which both enhances our understanding of the evolution of ABC and has prognostic and predictive relevance for patients on subsequent targeted therapy.
ctDNA analysis also revealed a novel putative resistance mechanism to fulvestrant, ESR1 p.F404. Transient transfection data supported the role of this mutation in fulvestrant resistance, and suggested alternative treatment strategies in patients with this mutation which may prolong survival.
These findings enhance our understanding of ABC, and support the use of ctDNA analysis as a research and clinical tool. | |
dc.language.iso | eng | en_US |
dc.publisher | Institute of Cancer Research (University Of London) | en_US |
dc.rights.uri | https://www.rioxx.net/licenses/all-rights-reserved | en_US |
dc.title | Circulating tumour DNA analysis in advanced breast cancer | en_US |
dc.type | Thesis or Dissertation | |
dcterms.accessRights | Public | |
dc.date.updated | 2022-10-26T09:34:46Z | |
rioxxterms.version | AO | en_US |
rioxxterms.licenseref.uri | https://www.rioxx.net/licenses/all-rights-reserved | en_US |
rioxxterms.licenseref.startdate | 2022-10-17 | |
rioxxterms.type | Thesis | en_US |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Breast Cancer Research | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Breast Cancer Research/Molecular Oncology | |
pubs.organisational-group | /ICR/Students | |
pubs.organisational-group | /ICR/Students/PhD and MPhil | |
pubs.organisational-group | /ICR/Students/PhD and MPhil/17/18 Starting Cohort | |
icr.researchteam | Molecular Oncology | en_US |
dc.contributor.icrauthor | Kingston, Belinda | |
uketdterms.institution | Institute of Cancer Research | |
uketdterms.qualificationlevel | Doctoral | |
uketdterms.qualificationname | Ph.D | |
icr.provenance | Deposited by Mr Barry Jenkins (impersonating Dr Belinda Kingston) on 2022-10-26. Deposit type is initial. No. of files: 1. Files: B Kingston PhD thesis.pdf | |
dc.type.qualificationlevel | Doctoral | |
dc.type.qualificationname | Ph.D | |