Timing and Origins of Local and Distant Metastases in Lung Cancer

Abstract

Introduction: Metastasis is the primary cause of lung cancer-related death. Nevertheless, the underlying molecular mechanisms and evolutionary patterns of lung cancer metastases are still elusive.Methods: We performed whole-exome sequencing for 40 primary tumors (PTs) and 61 metastases from 47 patients with lung cancer, of which 40 patients had paired PTs and metastases. The PT-metastasis genomic divergence, metastatic drivers, timing of metastatic dissemination, and evolutionary origins were analyzed using appropriate statistical tools and mathematical models.Results: There were various degrees of genomic heterogeneity when comparing the paired primary and metastatic lesions or comparing metastases of different sites. Multiple metastasis-selected/enriched genetic alterations were found, such as MYC amplification, NKX2-1 amplification, RICTOR amplification, arm 20p gain, and arm 11p loss, and these results were were also featured in a meta-analysis cross-validated using an independent cohort from Memorial Sloan-Kettering Cancer Center database. To elucidate the metastatic seeding time, we applied a metastatic model and found 61.1% of the tumors were late dissemination, in which the metastatic seeding happened approximately 2.74 years before clinical detection. One exception was lymph

Mutational profiles of primary pulmonary adenocarcinoma and paired brain metastases disclose the importance of KRAS mutations

“…), CNA. pairs, including only 7 brain metastases [11]. The increased frequency of KRAS mutations is not unique to LUAD with brain metastases.…”

Systemic Immune Activation and Responses of Irradiation to Different Metastatic Sites Combined With Immunotherapy in Advanced Non-Small Cell Lung Cancer

“…Studies have revealed that primary metastases had various levels of genomic heterogeneity to distinct tumor migration patterns ( 35 ). Related genes were enriched in different metastatic locations, which would alter tumor microenvironment and related inflammatory cell distribution and finally influence the response to ICIs ( 28 , 29 ). The presence of liver metastases (LMs) is associated with lower prognosis in immunotherapy compared to metastases in other organs ( 36 ).…”

“…Conventional views suggest that SBRT to single-site lesion was enough, but there were recent concerns that question whether multisite therapy was superior to single lesion therapy ( 43 ). Due to the organs’ own specific heterogenetic tumor-associated antigens, multisite SBRT may broadly enhance the outcome of immunotherapy by facilitating more antigen released ( 28 , 44 ). Apart from the number of sites to be verified by prospective clinical trials, the localization of SBRT combined with ICIs also remains unclear.…”

“…Temporal variability and the inter- and intra-tumoral spatial heterogeneity including mutation profiles and tumor immune microenvironment are also found to be different ( 27 ). Studies have revealed the site-specific metastatic timing, indicating that lymph node is susceptible to early metastatic seeding but pleura and some distant sites tend to seed lately ( 28 ). Unique genetic alterations are identified for different metastatic locations, which result in altered molecular pathways and protein expressions, responding to immunotherapy, respectively ( 29 , 30 ).…”

Genomic Evolution of Lung Cancer Metastasis: Current Status and Perspectives

“…For total genetic alterations, Tang et al . [ 9 ] revealed that the overall concordance between primary tumors (PT) and metastatic tumors (MT) was 45.6%, and it ranged from 7.3% to 80.6% per patient. Furthermore, metastatic site‐specific differences were also observed.…”