6O - Insights into tumour dissemination and progression using longitudinal imaging and ctDNA in the TRACERx lung cancer study

Background

Longitudinal imaging and circulating tumour DNA (ctDNA) can map tumour growth on a lesion level. We investigated the role of ctDNA as a biomarker in monitoring tumour growth in 103 patients with metastatic lung cancer enrolled in the TRACERx study, tracking volumetric dynamics of 456 metastases.

Methods

Total volume growth rate (TVGR) was calculated using CT imaging performed between disease relapse and death. 31 patients had whole exome sequencing of 153 tumour regions sampled at surgery. For 14 patients enrolled in the PEACE study, RNAseq from 129 regions of 48 metastases visible on imaging prior to death and subsequently sampled at autopsy were analysed. In 28 patients, ctDNA was used to track 200 tumour-specific mutations in 214 plasma samples to assess tumour burden and detect metastatic subclones.

Results

TVGR correlated with worse overall survival. Extrathoracic and intrathoracic soft tissue lesions had the highest growth rates whilst bone and lung the lowest (Kruskal-Wallis p < 0.0001). Gene set enrichment analysis demonstrated enrichment in the expression of cell proliferation signalling pathways in ‘high’ growth rate lesions. Subclonal genome doubling (GD) in the primary tumour associated with higher TVGR when compared with tumours with clonal or no GD. Early postsurgical ctDNA detection associated with higher TVGR and more metastatic lesions at relapse. ctDNA tracked with tumour burden and patients with extrathoracic relapse showed higher ctDNA shedding. In eight patients we used subclonal metastatic mutations found at autopsy, and tracked in ctDNA, to determine the contribution of different metastatic sites to ctDNA shedding throughout the clinical disease course. ctDNA subclonal fraction tracked with changes in lesion volumes upon disease progression and for patient CRUK410 the seeding subclone leading to a brain metastasis could be detected from day 1 post-surgery, 884 days before radiological detection.

Conclusions

Distinct genomic features in the primary tumour such as subclonal genome doubling may predict for rapid tumour growth at disease relapse. ctDNA can accurately reproduce patterns of radiological disease progression, supporting its use in the detection and monitoring of metastatic disease.

Editorial acknowledgement

Clinical trial identification

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).

Legal entity responsible for the study

Cancer Research UK.

Funding

Cancer Research UK funded TRACERx, Invitae has funded ctDNA research.

Disclosure

A. Hackshaw: Financial Interests, Institutional, Advisory Board, data monitoring committee member: Roche. C.Z. Abbosh: Financial Interests, Institutional, Other, honoraria and employment: AstraZeneca; Financial Interests, Institutional, Invited Speaker: Bristol Myers Squibb; Other, Personal, Other, PCT/GB2017/053289: Patent; Other, Personal, Other, PCT/US2017/ 028013: Patent; Other, Personal, Invited Speaker, PCT/EP2022/ 077987: Patent. A.M. Frankell: Other, Personal, Other, PCT/EP2022/ 077987: Patent application. 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, GSK; Financial Interests, Personal, Advisory Board, AdBoard - November 12th, 2020: Amgen; Financial Interests, Personal, Advisory Board, Current - since 2018: Genentech; Financial Interests, Personal, Advisory Board: Sarah Canon Research Institute; Financial Interests, Personal, Advisory Board, Joined October 2020. Also have stock options: Bicycle Therapeutics; Financial Interests, Personal, Other, Consultancy: Medicxi; Financial Interests, Personal, Advisory Board, Member of the Science Advisory Board. Also had stock options until June 2021: GRAIL; Financial Interests, Personal, Other, Consultancy agreement: Roche Innovation Centre Shanghai; Financial Interests, Personal, Advisory Board, 29 November - 1 December 2022: Novartis; Financial Interests, Personal, Invited Speaker, Oncology Collective - 2nd Nov - 4 Nov 2022 - Atlanta, USA: Roche; Financial Interests, Personal, Advisory Board, ctDNA advisory Board - 24th March 2023: AstraZeneca; Financial Interests, Personal, Invited Speaker, Pfizer Oncology 'Leading the revolution for the future: Pfizer; 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, Boehringer Ingelheim; Financial Interests, Institutional, Invited Speaker, Chief Investigator for the MeRmaiD 1and 2 clinical trials and chair of the steering committee: AstraZeneca; Financial Interests, Institutional, Research Grant, Research grant from Oct 2019 - July 2023 - Genetics of CIN and SCNAs for Targeted Discovery (SCEPTRE): Ono Pharmaceutical; Financial Interests, Institutional, Research Grant, Research Grants from 2015: Roche; Financial Interests, Personal, Other, Co-chief investigator: NHS-Galleri Clinical Trial; Financial Interests, Institutional, Research Grant, from October 2022: Personalis; Non-Financial Interests, Personal, Principal Investigator, Chief Investigator for MeRmaiD 1and 2 clinical trials: AstraZeneca; Non-Financial Interests, Personal, Member of Board of Directors, From 2019-2022: 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, Personal, Invited Speaker, Invited speaker honorarium: Oslo Cancer Cluster, Astex Pharmaceutical; Financial Interests, Personal, Invited Speaker, Speaker honorarium: Pfizer, Bristol Myers Squibb; Non-Financial Interests, Personal, Advisory Role, Scientific Advisory Board and Steering Committee member: Achilles Therapeutics; Other, Personal, Other, I am named as co-inventor on patent PCT/US2017/028013 relating to methods for lung cancer detection: Patent. All other authors have declared no conflicts of interest.