Abbosh, Christopher; (2021) Cell-free DNA in early-stage non-small cell lung cancer. Doctoral thesis (Ph.D), UCL (University College London).

Abstract

Circulating tumour DNA (ctDNA) detection following curative treatment is indicative of Minimal Residual Disease (MRD) in solid tumour-types. In this thesis, I discuss the development, analytical validation, orthogonal validation, and clinical validation of two separate tumour-informed personalised ctDNA enrichment assays designed as MRD detection tools. Through analyses of patient samples from the TRACERx-100 and TRACERx-421 cohorts, I identify clinical predictors of pre-operative ctDNA detection, including non-adenocarcinoma histology and tumour proliferation rate. I explore transcriptomic pathways upregulated in pre-operative ctDNA positive adenocarcinomas and observe that pathways involved in DNA replication and proliferation enrich in preoperative ctDNA positive versus ctDNA negative cases. Additionally, I find that preoperative ctDNA detection in adenocarcinomas lead to poor post-surgical outcomes with a DFS-rate of only 25% at 2 years and a high rate of extra thoracic relapse. I compare ctDNA levels in plasma, to tumour volume and demonstrate a correlation between tumour-size and quantity of ctDNA in peripheral blood. I note that this correlation varies by NSCLC histological subtype. In the post-operative setting I identify that MRD detection could highlight patients destined to relapse from their NSCLC and perform clinically focused analyses integrating imaging data from standard of care surveillance scans with MRD detection data. This work demonstrates that MRD detection can precede abnormal imaging findings on routine post-operative surveillance scans and aid interpretation of the equivocal imaging findings which are common in the NSCLC postoperative setting. Through longitudinal MRD tracking, I explore ctDNA doubling times prior to clinical relapse to gain insight into metastatic tumour growth dynamics in recurrent NSCLC. Finally, I discuss how work from this thesis has informed trial design concepts incorporating ctDNA as an MRD biomarker and reference the MERMAID study, an adjuvant phase III global randomised trial informed by MRD data generated in this study.

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