9584 Background: Lung carcinomas are most often diagnosed at stage IV, with metastases, which contribute to 90% of deaths of patients. Enormous efforts have been made in previous studies in seek of underlying mechanisms and treatments that prevent or cure metastases. However, few comprehensive conclusions have been drawn on organ-specific genomic landscapes and molecular dependencies of lung cancer metastases, largely due to limited sample sizes. Methods: We employed massive targeted next generation sequencing (NGS) with a panel covering 425 cancer-related genes on 10409 samples from 8619 patients with lung cancer, including 8479 from primary tumors and 1930 from metastases to the brain, liver, pleura, bones, and lymph nodes. We investigated single nucleotide variants (SNVs), copy number variants (CNVs), structural variations (SVs), mutational signatures, and other genomic characteristics at all primary and metastatic sites. With data of primary-metastatic tumor pairs, we also examined genomic evolutionary patterns. Results: Our data revealed that metastases harbored more instable and complicated genomes. Most SNVs (5/6), CNVs (41/47), and SVs (2/3) that showed significant differences of prevalence between primary tumors (PTs) and metastases (MTs) were MT-enriched. Among them, we identified a novel MT-enriched event, PTK2 amplification (2.33 folds), as well as known ones including mutations of TP53, ARID1A, and BRCA1 (1.23, 1.74, and 2.29 folds) , and amplifications of MYC, RICTOR, and EGFR (2.04, 2.15, and 1.59 folds). In addition, almost all actionable CNV alterations (6/7) showed higher frequencies in MTs. ALK fusions and EGFR mutations, which indicate distinct target therapies, exhibited opposite preference in MTs and PTs, respectively. We also identified MT site-specificity of alterations, such as NF2, TSC2, and LRP1B mutations enriched in the brain, BRAF and GNAS mutations absent in the liver, and APOBEC-associated mutational signatures enriched in lymph nodes. Moreover, we unraveled organ-specific patterns of genomic evolutionary trajectories in metastatic diseases. Conclusions: The genomic profile and evolutionary pattern of metastatic lung cancer differed from that of primary tumors. The identification of site-specific characteristics that may have empowered directional metastasis, such as NF2, TSC2, and LRP1B mutations in the brain and APOBEC-associated mutational signatures in lymph nodes, may guide personalized disease management, design of clinical trials, and/or discovery of therapeutic targets for metastatic lung cancer at different body regions.
Patients with Metastatic Lung Cancer and Oncologists’ Views on Achievement of Treatment Goals and Making the Right Treatment Decision: A Prospective Multicenter Study
