42P - Investigating the influence of extrachromosomal DNA in the progression of non-small cell lung cancer through the TRACERx and PEACE studies

Background

Various cancer types frequently exhibit numerical and structural chromosome anomalies, including focal amplifications. Focal DNA amplifications represent highly amplified sub-chromosomal regions and can manifest as either intrachromosomal homologous staining regions or extrachromosomal DNA (ecDNA). Unequal segregation of ecDNA during cell division contributes to increased tumour heterogeneity. It has previously been shown that patients with tumours containing ecDNA have a worse clinical outcome compared to patients with other focal amplifications.

Methods

TRACERx is a prospective non-small cell lung cancer cohort study with multi-regional sampling of the primary tumour. In the event of disease progression, patients are recruited to the PEACE autopsy study, which allows extensive sampling in the post-mortem setting. For this study, we have established a cohort that comprises whole genome sequencing data from 122 TRACERx and 12 PEACE autopsy patients. To explore the presence of ecDNA, we utilized Amplicon Architect, a computational tool designed for identifying and characterizing focal amplifications.

Results

In our cohort, ecDNA was observed in 13.1% of lung adenocarcinoma samples and 20.4% of lung squamous carcinoma samples. Overall, the presence of ecDNA in primary tumour samples was associated with poor outcomes and points towards a predictive value of ecDNA regarding patient outcomes (HR = 1.88, p = 0.08). Although ecDNA enrichment in later tumour stages did not reach statistical significance (p = 0.25), patients with ecDNA detected in their primary samples consistently exhibited its presence in subsequent autopsy samples, underscoring the persistent nature of ecDNA throughout tumour evolution. Additionally, we found autopsy samples exhibited the highest mean number of ecDNA detected per sample, surpassing that of relapse and primary samples (p = 0.004).

Conclusions

Overall, longitudinal sampling provided valuable insights into the persistence of ecDNA during tumour progression. Understanding how the presence of ecDNA in metastatic samples might drive the metastatic process and possibly lead to drug resistance will be valuable for potential clinical intervention.

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 and PEACE.

Disclosure

N. Kanu: Financial Interests, Institutional, Funding: AstraZeneca. 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. 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. All other authors have declared no conflicts of interest.