TRACERx is a multicentre, prospective study recruiting patients with early stage non small cell lung cancer. By leveraging longitudinal CT imaging, patterns and timing of metastatic spread and tumour growth rates can be tracked lesion by lesion. Circulating tumour DNA (ctDNA) in longitudinal plasma samples can be mapped to imaging timepoints to assess their role as a biomarker in monitoring cancer progression and the impact of therapy.
436 imaging scans were reviewed by two clinicians from 50 patients (median 7 scans per patient) with disease relapse post-surgical resection. Volumetric growth dynamics of individual metastatic lesions were tracked on serial images and tumour dimensions contoured using ITK-SNAP. ctDNA levels were detected using patient bespoke multiplex-PCR assay-panels based on tissue exome sequencing tracking 200-600 mutations per patient. For 22 patients we tracked ctDNA in 147 plasma samples (median 8 samples per patient) taken from before primary tumour resection to disease relapse and subsequent progression. Clonal mutations were used to track overall disease burden and subclonal mutation to track lesion-specific metastatic subclones.
56% of patients had intrathoracic only relapse and 44% patients had extrathoracic relapse. Common sites of relapse were lung (30%), lymph node (30%), bone (12%) and brain (5%). ctDNA levels were overlayed with tumour growth rate plots demonstrating that ctDNA fraction does not always track with total volume. For two patients we assessed the subclonal composition of ctDNA, tracking lesions with specific subclones detected at autopsy. Most lesion-specific subclones were absent in ctDNA in both cases, despite encompassing a large fraction of total tumour volume on imaging, suggesting many metastatic lesions do not shed substantial amounts of ctDNA. In contrast subclones from specific sites of disease were overrepresented in ctDNA, suggesting a high rate of shedding.
Large-scale studies with longitudinal imaging, ctDNA tracking and clinical annotation, such as TRACERx, can map the pattern and pace of cancer progression adding further insight into the clinical disease course and mechanisms of spread.
The TRACERx study (NCT01888601) is a prospective observational cohort study and PEACE (NCT03004755) is a national research autopsy programme, both approved by independent research ethics committees (13/LO/1546 and 13/LO/0972/AM05, respectively).
Cancer Research UK.
Cancer Research UK funded TRACERx, Invitae has funded ctDNA research.
A. Hackshaw: Financial Interests, Institutional, Advisory Board, Received fees as a member of Independent Data Monitoring Committee: Roche. C.Z. Abbosh: Financial Interests, Institutional, Invited Speaker: Novartis, Roche, AstraZeneca, BMS; Financial Interests, Institutional, Full or part-time Employment: AstraZeneca; Non-Financial Interests, Institutional, Other, patents issued to detect tumour recurrence (PCT/GB2017/053289): Patent; Non-Financial Interests, Institutional, Other, methods for lung cancer detection (PCT/US2017/028013): Patent; Non-Financial Interests, Institutional, Other, co-inventor to a patent application methods for tumour monitoring GB2114434.0: Patent. A.M. Frankell: Non-Financial Interests, Institutional, Other, co-inventor on a patent application to determine methods and systems for tumour monitoring (GB2114434.0): Patent. C. Swanton: Financial Interests, Personal, Invited Speaker, Activity took place in 2016: Pfizer, Celgene; Financial Interests, Personal, Invited Speaker, October 26th 2020: Novartis; Financial Interests, Personal, Invited Speaker: Roche/Ventana, BMS, AstraZeneca, MSD, Illumina, GlaxoSmithKline; Financial Interests, Personal, Advisory Board, AdBoard - November 12th, 2020: Amgen; Financial Interests, Personal, Advisory Board: Genentech, Sarah Canon Research Institute, Medicxi; Financial Interests, Personal, Advisory Board, Joined October 2020. Also have stock options: Bicycle Therapeutics; Financial Interests, Personal, Advisory Board, Member of the Science Management Committee. Also have stock options: GRAIL; Financial Interests, Personal, Other, Consultancy agreement: Roche Innovation Centre Shanghai; Financial Interests, Personal, Full or part-time Employment, Chief Clinician since October 2017: Cancer Research UK; Financial Interests, Personal, Ownership Interest, Co-Founder of Achilles Therapeutics. Also, have stock options in this company: Achilles Therapeutics; Financial Interests, Personal, Stocks/Shares, Stocks owned until June 2021: GRAIL, ApoGen Biotechnologies; Financial Interests, Personal, Stocks/Shares: Epic Biosciences, Bicycle Therapeutics; Financial Interests, Institutional, Research Grant, Funded RUBICON grant - October 2018 - April 2021: Bristol Myers Squibb; Financial Interests, Institutional, Research Grant, Collaboration in minimal residual disease sequencing technologies: Archer Dx Inc.; Financial Interests, Institutional, Research Grant: Pfizer, Ono Pharmaceutical, Boehringer Ingelheim; Financial Interests, Institutional, Invited Speaker, Chief Investigator for the MeRmaiD1 clinical trial and chair of the steering committee: AstraZeneca; Financial Interests, Institutional, Research Grant, Research Grants from 2015-2019: Roche-Ventana; Financial Interests, Personal, Other, Co-chief investigator: NHS-Galleri Clinical Trial; Non-Financial Interests, Personal, Principal Investigator, Chief Investigator for MeRmaiD1 clinical trial: AstraZeneca; Non-Financial Interests, Personal, Invited Speaker, From 2019: AACR; Non-Financial Interests, Personal, Other, Board of Directors: AACR; Non-Financial Interests, Personal, Advisory Role, EACR Advisory Council member: EACR. M. Jamal-Hanjani: Financial Interests, Institutional, Funding, CRUK Career Establishment Awardee: CRUK; Financial Interests, Institutional, Funding: IASLC, International Lung Cancer Foundation, Lung Cancer Research Foundation, Rosetrees Trust, UKI NETs, NIHR, NIHR UCLH Biomedical Research Centre; Financial Interests, Institutional, Advisory Board: Achilles Therapeutics; Financial Interests, Institutional, Invited Speaker: Astex Pharmaceuticals, Oslo Cancer Clusters; Non-Financial Interests, Institutional, Other, methods for lung cancer detection (PCT/US2017/028013): Patent. All other authors have declared no conflicts of interest.