Abstract 3123: Lung cancer evolutionary trajectories in PEACE

Abstract

Abstract Introduction: Studies of cancer evolution have relied on archival tissue surplus to diagnostic requirements from living patients obtained in early stage disease and less commonly relapsed/metastatic disease. PEACE (Posthumous Evaluation of Advanced Cancer Environment) is a national research autopsy study aiming to understand the biological processes driving metastatic disease and cancer evolution. Experimental procedures: Patients recruited into the national TRACERx (TRAcking Cancer Evolution through therapy (Rx)) lung study who subsequently developed metastatic disease were enrolled into PEACE. Here we present a cohort of 15 TRACERx/PEACE patients in whom multi-region tumor sampling was performed at diagnosis +/- relapse and at autopsy. Fresh frozen tissue was subjected to whole-exome sequencing (mean depth 390) and germline DNA from blood was used for reference. Single nucleotide variants (SNVs) were identified using VarScan2 and the subclonal composition of each tumor was inferred using PyClone and used to reconstruct phylogenetic trees. Summary of data: Disease progression was associated with increased genomic complexity. Different patterns of progression occurred; monoclonal/monophyletic, polyclonal/monophyletic and polyclonal/polyphyletic dissemination. Both early and late divergence relative to the last clonal sweep were observed. Putative drivers were found to occur both clonally and subclonally. SNVs and copy number aberrations were used to reconstruct migration patterns. Conclusions: Preliminary analysis in this cohort demonstrates increasing genomic complexity with disease progression and variation in patterns of metastatic dissemination. We are yet to establish the impact of the tumor and immune microenvironment on such patterns as well as clinical presentation and outcome. Ongoing PEACE analysis includes study of the somatic copy number landscape and the characterisation of subclones that seed metastases. Patient & sample characteristicsN (%)Total patients15Median age (IQR)73 (65 - 80)Female sex (%)6 (40%)Histological subtypeAdenocarcinoma7 (47%)Squamous cell carcinoma5 (33%)Large cell carcinoma2 (13%)Adenosquamous carcinoma1 (7%)Treatment receivedRadiotherapy8 (53%)Chemotherapy6 (40%)Immunotherapy5 (33%)Targeted therapy4 (27%)Smoking statusCurrent smoker2 (13%)Ex-smoker12 (80%)Never smoker1 (7%)Total metastases sampled289Median samples per patient (range)19 (5 - 41)Number of samples per patient5-104 (27%)11-205 (33%)>206 (40%)Number of tissue types sampled17 Citation Format: Ariana Huebner, Sonya Hessey, Cristina Naceur-Lombardelli, Mita Akther, Selvaraju Veeriah, Maise Al Bakir, David Moore, Simone Zaccaria, Nicholas McGranahan, Charles Swanton, Mariam Jamal-Hanjani, TRACERx and PEACE consortium. Lung cancer evolutionary trajectories in PEACE [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3123.