Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.784747
Title: Cancer patient stratification by next generation sequencing of circulating tumour DNA : taking the next steps towards implementation in the clinic
Author: Openshaw, Mark
ISNI:       0000 0004 7970 2936
Awarding Body: University of Leicester
Current Institution: University of Leicester
Date of Award: 2019
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Abstract:
Recent advances in next generation sequencing (NGS) have allowed significant improvement in the sensitivity of detection of the tumour derived fraction of cell free DNA termed circulating tumour DNA (ctDNA). This thesis investigated the clinical application of ctDNA in serial plasma samples from breast cancer and gastroesophageal adenocarcinoma (GOA) patients undergoing palliative and curative treatment. Additionally, evaluation of tumour and ctDNA whole exome sequencing (WES) was completed on serial samples from one breast cancer patient. Targeted NGS was used to detect tumour specific mutations. The same technology and commercial/designed droplet digital assays were used to detect ctDNA. WES was undertaken in Spain and the resultant sequencing data analysed in-house. Ampliseq™ NGS detected ctDNA in 9 of 13 patients with metastatic breast cancer (69.2%). Detected mutations tracked disease progression and response. Oncomine™ NGS detected ctDNA in 5 out of 10 patients with pre and post neoadjuvant chemotherapy plasma samples. Two ctDNA positive patients relapsed, while none of the 5 ctDNA negative patients relapsed. WES of ctDNA was successfully undertaken. Mutations detected from ctDNA WES overlapped with WES of the primary and relapsed tumours. Key tumour mutations could be identified in ctDNA including ongoing mutational changes caused by tumour evolution. ctDNA was detected in a cohort of 44 patients with GOA. Nine of 13 (69.2%) metastatic patients with a detectable tumour mutation had detectable ctDNA. ctDNA levels tracked disease response and high levels of ctDNA at diagnosis of metastatic disease predicted short survival. Seven of 19 patients (36.8%) treated with curative intent that had a detectable tumour mutation had detectable ctDNA. Three patients had detectable ctDNA post surgery, two of whom relapsed during follow-up. Detection of ctDNA at any time prior to relapse predicted poor relapse free survival (HR 21.6, CI 2.5-185.5, p=0.005). This thesis demonstrates the potential clinical utility of ctDNA in both breast cancer and GOA and shows an emerging role for the use of ctDNA WES.
Supervisor: Thomas, Anne ; Shaw, Jacqui Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.784747  DOI: Not available
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