Molecular and clonal evolution of primary lesions vs. brain metastasis in EGFR-mutated NSCLC: a retrospective cohort study.

Clonality is an intrinsic phenomenon of disease evolution, with specific clones conferring increased aggressiveness. We aimed to evaluated the different divergent and unique mutational patterns in brain metastases (BM). This retrospective cohort study included patients with epidermal growth factor receptor (EGFR)-mutated lung adenocarcinoma and BM. All the patients underwent three next-generation sequencing (NGS)-based genomic profiling assessments. Two analyses involved tissue samples from the lung and brain lesions, whereas the third utilized either liquid or tissue biopsy. Treatment consisted of Osimertinib and Stereotactic radiosurgery. Thirty patients were included (73% female). Central nervous system (CNS) involvement was noted in 90% of the patients at diagnosis, with a median of two BM. 46% exhibited Ex19del, while the remainder had an L858R mutation. The most frequently co-mutated gene in primary lesions was TP53 (50%), followed by RBM10. All patients showed an increase in tumor mutational burden (TMB) from the primary lung lesions to the CNS metastases, rising from a median of 3.2 to 8.5 mut/Mb. Additionally, 30% of the EGFR mutations were lost. Regarding co-mutations in BM, alterations in PIK3CA/PTEN/AKT at 36%, BRAF (11%), and RB1 (13%) were presented. MET amplification was detected in 15% of cases upon systemic disease progression, while small cell transformation occurred in 7%. PIK3CA and BRAF mutations, initially found solely in BM, re-emerged in systemic disease in 16% of the cases. The molecular features of BM differ from those of the primary tumor. These results indicate that specific brain metastatic clones can also result in systemic progression.