1322MO - 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 and patterns of metastatic spread on a lesion-by-lesion level. In this study, we investigated the role of ctDNA as a biomarker in monitoring tumour growth in 102 metastatic lung cancer patients enrolled in the TRACERx study, tracking volumetric dynamics of 341 metastases.

Methods

Patients were categorised based on total volume growth rate: Slow >100mm3/day, Stable <100mm3/day and Rapid >600mm3/day. Individual metastases within patients were categorised into ‘High’ and ‘Low’ growth rate based on the median growth rate for all lesions across the cohort. In addition, RNAseq data from 122 regions belonging to 44 metastases mapped to imaging at autopsy were analysed in 13 patients enrolled in the PEACE study. For 28 patients, ctDNA was used to track 200 clonal or subclonal mutations in 214 plasma samples to assess total disease burden and metastatic subclones.

Results

Growth rate correlated with number of lesions at relapse and overall survival (OS). Median OS was 55.0, 25.4 and 8.5 months for Slow, Stable and Rapid classes respectively (p<0.001). Gene set enrichment analysis demonstrated enrichment in signalling pathways associated with cell proliferation when comparing the gene expression patterns between ‘high’ and ‘low’ growth rate lesions. Early postsurgical ctDNA detection was associated with higher ctDNA shedding at disease relapse. Total ctDNA tracked with tumour volume in the post-relapse setting, and patients with extrathoracic relapse showed higher ctDNA shedding. For eight patients in the PEACE cohort, we assessed the subclonal composition of ctDNA, tracking lesions with specific subclones detected at autopsy. These subclones were mapped to metastatic lesions measured on imaging. ctDNA subclonal fraction tracked with changes in tumour volume upon treatment response and subsequent progression. For all eight patients’ lesion-specific subclones could be detected from day 1 post-surgery prior to detection by radiological imaging.

Conclusions

Our results demonstrate that ctDNA can accurately reproduce observed patterns of metastatic growth on imaging, suggesting it can be used in the detection and monitoring of metastatic disease.

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).

Editorial acknowledgement

Legal entity responsible for the study

Cancer Research UK.

Funding

Cancer Research UK.

Disclosure

A. Hackshaw: Financial Interests, Institutional, Advisory Role: Roche. C.Z. Abbosh: Financial Interests, Institutional, Full or part-time Employment: AstraZeneca; Financial Interests, Institutional, Invited Speaker: AstraZeneca, Bristol Myers Squibb; Financial Interests, Personal, Other, PCT/GB2017/053289: Patent Application; Financial Interests, Personal, Other, PCT/US2017/028013: Patent Application; Financial Interests, Personal, Other, PCT/EP2022/077987: Patent Application. A.M. Frankell: Financial Interests, 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, Principal Investigator, Chief Investigator for MeRmaiD 1and 2 clinical trials: AstraZeneca; Non-Financial Interests, Member of Board of Directors, From 2019-2022: AACR; Non-Financial Interests, Other, Board of Directors: AACR; Non-Financial Interests, 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, Advisory Role, Scientific Advisory Board and Steering Committee member: Achilles Therapeutics; 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.