Clinical impact and biological characterization of breast cancer-related brain metastases: focus on gene expression profiling

Background: Despite the clinical impact of breast cancer (BC) brain metastases (BMs), their biological complexity remains poorly understood. We here evaluate the genomic profile of BCBMs and compare it with paired primary BC samples to characterize biological changes during brain metastasization and their clinical impact in a retrospective real-world cohort. Methods: Expression of 758 genes (BC360 Panel, nCounter), hormone receptor (HR) status and HER2 status were evaluated in BCBMs and matched primary BCs. Intrinsic subtyping was determined using PAM50 subtype predictor. Gene expression/PAM50 signature and OS correlations were analyzed using Cox-models. Median overall survival (OS) was calculated with Kaplan-Meier method. A False Discovery Rate corrected paired two-class SAM identified genes expression changes between paired BC and BMs samples. Results: Seventy-five BCBM samples from 74 patients were analyzed: 30.7% HR+/HER2-, 41.3% HER2+, 28.0% HR-/HER2-. Intrinsic subtype was 36.0% Basal-like, 48.0% HER2-enriched, 14.7% Luminal B, 1.3% Normal-like; among HR+/HER2- BCs, 26.1% were Basal-like and 26.1% HER2-enriched. PAM50 basal-like signature was associated with worse OS overall (p=0.014) and within the HR+/HER2- subgroup (p=0.024). Among 21 primary BCs analyzed, 45% of Basal-like, 100% of Normal-like and 50% of Luminal-A shifted towards the HER2-enriched subtype in matched BMs. 388 genes were differentially expressed in BMs compared to primary BC, including genes involved in survival and migration (e.g. FGFR4), HER2-amplicon (e.g. ERBB2) and endocrine response (e.g. ESR1, PGR). Conclusions: Non-luminal intrinsic subtypes are prevalent in BCBMs and basal-like genomic features are associated with worse survival. Recurrent gene expression modifications with potential therapeutic implications were observed in BCBMs.