Early Results From a Ground Breaking Study of Tumour Evolution Identifies Genetic Drivers in NSCLC

Unique study aims to establish models of tumour progression

Data from the first 4 patients analysed in a longitudinal study evaluating the genetic and phenotypic relationships between primary and metastatic tumours were presented at the ESMO 2018 Congress in Munich, Germany. The investigators are working towards establishing a model for tumour progression and the metastatic process, as well as identifying the potential mechanisms that are involved in tumour evolution and the development of therapeutic resistance.

Deep sequencing of sequential patient samples used to plot genetic alterations over the course of NSCLC

Mariam Jamal-Hanjani of the University College London Cancer Institute, Cancer Research UK Lung Cancer Centre of Excellence in London, UK presented findings from the Posthumous Evaluation of Advanced Cancer Environment (PEACE; NCT03004755) study. Dr Jamal-Hanjani and colleagues used a cohort of patients initially enrolled in the TRACERx (NCT01888601) study, which tracks tumour evolution from primary to relapsed disease in non-small cell lung cancer (NSCLC).

The investigators performed multiregional sampling of primary tumours at surgical resection, and metastatic tumours in the post-mortem setting. DNA was extracted from fresh frozen tissue and deep whole-exome sequencing (WES) was done and analysed using bioinformatic tools developed to assess tumour clonal architecture and evolutionary pathways.

PEACE has recruited over 100 patients and captured over 50 tissue harvests to date.

At ESMO 2018 Congress, the results of the preliminary analysis done on the first 4 TRACERx/PEACE patients were presented. This evaluation demonstrated the presence of driver events, including mutations and somatic copy number aberrations, in both early and late evolution, as well as continued tumour diversification that further drives genome instability. The researchers also uncovered different patterns of metastatic seeding using evolutionary phylogenetic analyses, and were able to demonstrate the timing of such events from primary to metastatic disease.

Conclusions

According to the authors, PEACE is a unique study leveraging the true longitudinal sampling in these studies from diagnosis to death. PEACE has the potential to inform understanding of the metastatic process, and to reveal the lethal subclone(s) that are involved in branched tumour evolution. WES data from primary and metastatic tumours in the cohort of patients recruited into both TRACERx and PEACE can help decipher the clonal dynamics and evolutionary trajectory of lung cancer.

Dr Jamal-Hanjani pointed out that data arising from PEACE have already demonstrated implications for tracking disease progression.1 PEACE data have also informed the emergence of drug resistance and the identification of distinct patterns of metastatic spread with potential prognostic implications.

Citations 

  1. Abbosh C, Birkbak NJ, Wilson GA, et al. Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution. Nature. 2017;545(7655):446-451.
  2. 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

Disclosure

The TRACERx and PEACE studies are funded by Cancer Research UK. TRACERx is also funded by UCLH Biomedical Research Council, UCLH Experimental Cancer Medicine Centre and The Rosetrees Trust, and supported by the CR UK Lung Cancer Centre of Excellence, CR UK & UCL Cancer Trials Centre, the Francis Crick Institute and the UCL Cancer Institute.

Reference

LBA11 -Jamal-Hanjani M, Huebner A, McGranahan N, et al.Defining the lethal subclone in metastatic lung cancer.