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

Abstract

e20552 Background: Clonality is an intrinsic phenomenon of disease evolution, with specific clones conferring increased aggressiveness and apparent tropism towards certain metastatic sites. In this analysis, we sought to evaluate the different divergent and unique mutational patterns present in brain metastases. Methods: A retrospective cohort study was undertaken to include patients diagnosed with EGFR-mutated lung adenocarcinoma who either presented with brain metastases upon diagnosis or experienced progression to this site. All patients underwent three NGS-based genomic profiling assessments. The initial two analyses involved tissue samples from the primary and predominant brain lesions, while the third utilized either liquid biopsy or tissue from an extracranial lesion. Treatment for all patients consisted of Osimertinib and Stereotactic radiosurgery following the evaluation of brain lesions. Results: The analysis comprised 30 patients; 22 (73%) were female, with a median age of 55 years. Nearly all patients, except one (97%), had a history of smoking, while the remaining individual was a lifelong non-smoker. Central nervous system (CNS) involvement was noted in 27 patients (90%) at diagnosis, with three experiencing subsequent compromise during disease progression. The median number of brain lesions was 2 (range 1-3). Regarding molecular characteristics, 14 patients (46%) exhibited exon 19 deletions, while the remainder had an L858R mutation. The most frequently mutated gene in the primary lesions was TP53, accounting for 15 cases (50%), followed by RBM10 in 7 patients (23%), with 3 instances of co-occurrence with TP53, as well as STK11 (n=2, 6%), GNAS (n=4, 13%), and RB1 (n=1, 3%). The mean tumor mutational burden (TMB) in the primary lesion was 3.2 mutations per megabase (mut/Mb), compared to 8.5 mut/Mb in the brain metastasis. Notably, all patients exhibited increased TMB between the primary and CNS lesions. Additionally, EGFR mutations were lost in 9 patients (30%), with an almost equal distribution among Exon 19 and L858R mutations. Regarding co-mutations in brain metastases, alterations in PIK3CA/PTEN/AKT were present in 11 cases (36%). Other observed mutations included BRAF V600E (n=1, 3%), non-V600 BRAF mutations (n=3, 10%), and RB1 (n=4, 13%). Interestingly, amplifications across various genes were observed in 19 patients (63%). Upon systemic disease progression, MET amplification was detected in 5 cases (15%), while small cell transformation occurred in 2 (7%). PIK3CA mutations, initially identified solely in brain metastases, re-emerged in systemic disease in 4 cases (13%), along with a V600E mutation in one patient (3%). Conclusions: The molecular features observed in brain metastases differ from those of primary tumors. Results indicate that certain brain metastasis clones can also result in systemic progressions.