JCES 01.15 Next Generation Sequencing of Large-Cell Neuroendocrine Carcinoma Reveals an Association of PIK3CA Mutations with Brain Metastases

Large-scale genomic characterization of large-cell neuroendocrine carcinoma (LCNEC) has revealed several putative oncogenic drivers. There are, however, little data to suggest that these alterations have clinical relevance. We performed comprehensive genomic profiling of 68 stage IV LCNECs of the lung (including next-generation sequencing) and analyzed differences in the clinical characteristics of two major LCNECs subtypes: KRAS mutation and PIK3CA mutation. In order to better understand the divergence that might exist between brain metastases and their lung primaries, we performed whole-exome sequencing of paired lung primaries and brain metastases from four lung LCNEC patients. Patients with PIK3CA mutation tumors had aggressive disease marked by worse survival (median OS7.9 vs. 18.6 mo, P = 0.002), higher metastatic burden (> 3 organs 15.2% vs. 4.7%, P = 0.029), and greater incidence of brain metastases (19.0% vs.2.3% in others, P = 0.001). Whole-exome and RNA sequencing on paired brain metastases and primary LCNECs of the lung revealed that LCNEC primaries that gave rise to brain metastases harbored PIK3CA mutation. Significant tumor growth inhibition with GDC0941 was observed exclusively in the LCNEC patient-derived xenograft model that harbored PIK3CA mutation. PIK3CA mutation defines a distinct disease phenotype characterized by brain metastasis in LCNEC of the lung. The result may be relevant for targeted therapy and prophylaxis of NSCLC brain metastases.