TRACERx – TRAcking non-small cell lung Cancer Evolution through therapy (Rx)
Session type: Proffered paper sessions
1UCL Cancer Institute
TRACERx (TRAcking non-small cell lung Cancer Evolution through therapy (Rx)) is a prospective longitudinal cohort study exploring the relationship between intratumour heterogeneity and clinical outcome, the clonal nature of known therapeutic targets and the drivers of intratumour heterogeneity in early stage non-small cell lung cancer (NSCLC). Multiregion high-depth whole-exome sequencing was performed on 100 prospectively collected early stage IA-IIIA NSCLC tumours, comprising of 327 tumour regions, resected prior to systemic therapy in the TRACERx study to define evolutionary histories and obtain a census of clonal and subclonal events. Widespread intratumour heterogeneity was observed at both the mutation and copy number level. Targetable mutations in EGFR, MET and BRAF were almost always clonal, as were mutations in TP53. Positive selection was pervasive during branched tumour growth, and subclonal driver alterations were found in 75% of tumours and were common in PIK3CA, NF1 and genes involved in chromatin modification and DNA repair. Genome doubling and ongoing dynamic chromosomal instability (CIN) were identified as drivers of intratumour heterogeneity resulting in mirrored subclonal allelic imbalance (MSAI) within distinct tumour subclones and parallel evolution of driver copy number events, including amplifications of CDK4, FOXA1, and BCL11A. Consistent with the importance of dynamic CIN, elevated copy number heterogeneity was associated with increased risk of disease recurrence or death (HR=4.9, P<0.00044). Multiregion sequencing provides a census for drug target prioritization in NSCLC based on clonal status. Ongoing CIN, corroborated by MSAI, dynamically alters the cancer genomic landscape fuelling parallel evolution, intratumour heterogeneity and increasing the risk of relapse.