Abstract PR04: Genomic characterization of brain metastases reveals branched evolution and metastasis-specific mutations

Abstract

Abstract Background: Brain metastases are associated with a dismal prognosis. There is a limited understanding of the oncogenic alterations harbored by brain metastases and whether these are shared with their primary tumors. Our objectives were to (1) elucidate the evolutionary patterns leading to brain metastases and (2) identify whether brain metastases are genetically distinct from their primary tumors and other distal metastatic sites. Methods: We performed whole-exome sequencing of 104 matched brain metastases, primary tumors and normal tissue, including 7 cases with spatially and temporally separated brain metastasis sites and 8 cases with additional extracranial disease sites, including regional lymph nodes, and distal metastases. We developed novel computational tools to perform an integrative analysis of somatic mutations and copy-number alterations. This analysis allowed us to estimate the clonal architecture of the primary and metastases, and to reconstruct a phylogenetic tree relating the subclones from each patient. Results: In all related cancer samples, we observed branched evolution, where all metastatic and primary sites shared a common ancestor yet continued to evolve independently. In 53% of cases, we found clinically actionable driver alterations in the brain metastases that were not detectable in the matched primary-tumor sample. In contrast, spatially and temporally separated brain metastasis sites were more genetically homogenous and shared nearly all driver alterations detected. Extracranial metastases and regional lymph nodes were highly divergent from brain metastases. Several clinically actionable pathways were enriched in brain metastases. Conclusions: These observations demonstrate that brain metastasis tissue provides an opportunity to identify clinically important driver alterations that may be undetected in single samples of primary tumors, regional lymph nodes, or extracranial metastases. Genetic divergence between primary tumors and brain metastases may underlie some of the difficulties encountered with the combined treatment of systemic disease and brain metastases in patients. When clinically feasible, genomic characterization of brain metastasis tissue should be considered when selecting therapeutic agents for patients with brain metastases. Citation Format: Priscilla K. Brastianos, Scott L. Carter, Sandro Santagata, Daniel Cahill, Amaro Taylor-Weiner, Robert T. Jones, Eliezer Van Allen, Peleg Horowitz, Keith L. Ligon, William T. Curry, Ian F. Dunn, Paul Van Hummelen, Matthew Meyerson, Levi Garraway, Josep Tabernero, Joan Seoane, Stacey Gabriel, Eric S. Lander, Rameen Beroukhim, Tracy T. Batchelor, Jose Baselga, David N. Louis, William C. Hahn, Gad Getz. Genomic characterization of brain metastases reveals branched evolution and metastasis-specific mutations. [abstract]. In: Proceedings of the AACR Special Conference: Advances in Brain Cancer Research; May 27-30, 2015; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2015;75(23 Suppl):Abstract nr PR04.