Abstract A007: Characterization of the recurrent and parallel evolution of non-small cell lung cancer metastases to the brain

Abstract The majority of cancer deaths result from metastatic spread to other tissues and it has been observed clinically that cancers demonstrate distinct preferences for metastatic sites. While factors like physical proximity and the lymphatic access explain a degree of this site bias, the parallel evolution and molecular etiology of the heterogenous primary disease likely results in subclonal or clonal populations of tumor cells which are well-disposed to some potential metastatic sites and maladapted to others. Clinically, metastases to the brain are of particular interest due to the sensitivity of the brain to disruptions, difficulty in treatment, and particular lethality of spread. Non-small cell lung cancers (NSCLC) have been observed to metastasize to the brain at high prevalence. The features of NSCLC tumors that eventually metastasize to the brain may exhibit shared characteristics dictated by unique evolutionary constraints shaping their progression. Here, we examine a cohort of patients with metastatic NSCLC cancer to the brain whose paired primary-site and metastatic-site tumors have been sequenced. First, we reconstruct the individual evolutionary histories—including an estimate of the divergence timeline—of the primary and metastatic tumors using a Bayesian phylogenetic approach. We then investigate the effect of selection on metastatic spread by examining selection on somatic mutations both in individual tumor lineages and recurrently across the cohort. We further probe the population of mutations constituting neoantigens, as well as the shifts in the endogenous and exogenous mutational processes active in each site. We conclude by identifying specific mutational processes, neoantigen dynamics, and high-effect mutations unique to the metastatic lineage. Citation Format: Nic Fisk, Sarah Goldberg, Jeffrey P. Townsend. Characterization of the recurrent and parallel evolution of non-small cell lung cancer metastases to the brain abstract. In: Proceedings of the AACR Special Conference in Cancer Research: Cancer Evolution: The Dynamics of Progression and Persistence; 2025 Dec 4-6; Albuquerque, NM. Philadelphia (PA): AACR; Cancer Res 2025;85 (23Suppl): Abstract nr A007.