128P - Metastatic migrations in lung cancer: Insights from the PEACE autopsy programme

Background

Limited understanding of the biological processes that govern metastasis hinders its prevention and treatment. Studying the tumour cell populations, or ‘clones’, that seed metastases has potential to reveal characteristics required for metastasis and can be accomplished using DNA sequencing data from patient primary and metastasis samples. However, the accuracy of this approach is contingent on how representative the patient samples are of the often extensive, breadth of metastatic disease. Such sampling is rarely clinically feasible in living patients but can be accomplished in research autopsy programmes, such as PEACE.

Methods

We leveraged high-depth, exome sequencing data from 84 primary tumour regions and 306 metastasis regions collected longitudinally from 21 patients with non-small cell lung cancer (NSCLC) co-enrolled in the TRACERx and PEACE studies to elucidate the genetic features that underpin metastasis. Phylogenies were reconstructed for each tumour such that metastasising clones and their putative driver mutations, copy number profiles, and routes of spread could be examined.

Results

Tracking the timing of genetic alterations from diagnosis through to death, we show that metastasis genomes are characterised by putative driver mutations acquired early in tumour evolution and somatic copy number alterations (SCNAs) accumulated throughout the disease course. We found that chromosomal instability (CIN) influenced not only which clones metastasise, but also where they spread to. Specifically, clones that seeded metastases outside of the thoracic cavity were enriched for SCNAs and whole genome doubling compared to those that seeded metastases within. In addition, 59% of metastases were seeded by clones originating in other metastases, indicating that metastasis-to-metastasis seeding is prevalent in NSCLC. We show that the propensity of a metastasis to seed another metastasis relates to its duration in situ demonstrated on clinical imaging.

Conclusions

This work reveals that metastatic progression in NSCLC is underpinned by complex seeding patterns involving both primary and metastasis clones, and implicates CIN as a key mediator of this process.

Editorial acknowledgement

Clinical trial identification

Legal entity responsible for the study

UCL Clinical Trials Centre.

Funding

CRUK, Rosetrees Trust, Bristol Myers Squibb, Roche.

Disclosure

N. McGranahan: Financial Interests, Institutional, Stocks/Shares: Achilles Therapeutics. 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, Ad Board - 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, Advisory Board, Scientific Advisory Board and Stock options from September 2023: Relay Therapeutics; Financial Interests, Personal, Advisory Board, Member of the Scientific Advisory Board: SAGA Diagnostics; 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, Personal, Stocks/Shares, Stock options: Relay 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; Financial Interests, Personal, Advisory Board, Cancer cachexia research advisory board: Pfizer; 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.