6258 - Defining the lethal subclone in metastatic lung cancer

Background

The PEACE study aims to study the genetic and phenotypic relationships between primary and metastatic tumours to establish a model for tumour progression, the metastatic process and potential mechanisms involved in therapeutic resistance and tumour evolution.

Methods

In a cohort of patients initially recruited into the lung TRACERx study (NCT01888601), multiregion sampling was performed at each site of metastasis, DNA was extracted from fresh frozen tissue and deep whole-exome sequencing (WES) was subsequently performed and analysed using bioinformatic tools developed to assess tumour clonal architecture (Jamal-Hanjani M, Wilson GA, McGranahan N, et al. Tracking the Evolution of Non-Small-Cell Lung Cancer. N Engl J Med. 2017;376(22):2109-2121).

Results

Preliminary analysis of the first four TRACERx/PEACE patients has demonstrated the presence of driver events, including mutations and somatic copy number aberrations, in both early and late evolution, continued tumour diversification driving genome instability, and different patterns of metastatic seeding. Using evolutionary phylogenetic analyses, the timing of such events is demonstrated from primary to metastatic disease.

Conclusions

PEACE has the potential to inform our understanding of the metastatic process and to reveal the lethal subclone (s) that are involved in branched tumour evolution. The study has recruited over 100 patients and involved over 50 tissue harvests to date. Data arising from PEACE has already demonstrated implications for tracking disease progression (Abbosh C, Birkbak NJ, Wilson GA, et al. Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution. Nature. 2017;545(7655):446-451), the emergence of drug resistance and identifying distinct patterns of metastatic spread with prognostic implications (Turajlic S, Xu H, Litchfield K, et al. Tracking Cancer Evolution Reveals Constrained Routes to Metastases: TRACERx Renal. Cell. 2018;173(3):581–594.e12). WES data from primary and metastatic tumours in this cohort of patients recruited into both TRACERx and PEACE can help decipher the clonal dynamics and evolutionary trajectory of lung cancer. This is a unique study leveraging the true longitudinal sampling in these studies from diagnosis to death.

Clinical trial identification

PEACE (PosthumousEvaluation of Advanced Cancer Environment, NCT03004755)

Editorial Acknowledgement