Real-world Study Shows Heterogenous Genomic Landscape of Metastatic LUAD

A real-world study is adding insight into the genomic landscape of metastatic lung adenocarcinomas (LUAD), highlighting the heterogeneity of both metastasis types and within each type.

The study researchers analyzed more than 6000 tumor samples, consisting of nearly 5000 primary tumors and more than 1000 metastases. They found that compared with the primary tumor samples, metastases were associated with a significantly higher mutational burden and chromosomal instability.

Comparing the targetable alterations between the 2 types of samples, the researchers observed that ALK mutations, ALK and ROS1 fusions, and MET copy number gains had a significantly higher presence in metastases. The alterations, wrote the authors, were enriched in metastases to certain organs and tissues, including lymph nodes, the liver, and the brain.

“A previous important large-scale study revealed that tumor mutational burden [TMB] is site specific and that brain metastases harbored the highest mutational burden,” wrote the researchers. “Our observations supported the conclusions. The mean TMB in brain metastases in our cohort was 10.1 mutations/Mb, greater than those of primaries (mean: 6.8) and metastases at any other site (mean: 6.7–8.7).”

The researchers also examined the prevalence of mutations not currently actionable but considered of great interest, finding that TP53, CTNNB1, and ARID1A mutations were significantly more prevalent in metastatic samples.

Analyzing PD-L1 expression in the tumor samples, the researchers found that approximately half of primary tumor samples were PD-L1 positive, with lymph node metastasis accounting for the highest proportion of positive samples.

“Our results further revealed that metastases accumulated more actionable targets and may develop more complicated mechanisms of immune escape as the approximate distance of migration increased,” wrote the researchers. “Specifically, lymph node metastases enriched ALK and ROS1 fusions; liver metastases enriched ALK mutations; while brain metastases enriched ROS1 fusions. The heterogeneity of actionable alterations suggested different feasibility of specific target therapies among different metastasis types, leaving implications for future designs of clinical trials.”

Notably, the researchers found that the prevalence of EGFR mutations decreased in metastases compared with primary tumors. They noted that the finding was unexpected, although they found that various small lung cancer cohorts reported reduced EGFR mutations in metastases.

Reference

Li D, Huang Y, Cai L, et al. Genomic landscape of metastatic lung adenocarcinomas from large-scale clinical sequencing. Neoplasia. 2021;23(12):1204-1212. doi:10.1016/j.neo.2021.10.001