Background: Despite the clinical impact of breast cancer (BC) brain metastases (BMs), their biological complexity remains poorly understood. We evaluated the genomic profile of BCBMs and compared it with paired primary BC samples to characterize biological changes during brain metastasization and their clinical impact in a retrospective real-world cohort. Materials and methods: Expression of 758 genes (BC360 Panel, nCounter), hormone receptor (HR) status, and human epidermal growth factor receptor type 2 (HER2) status were evaluated in BCBMs and matched primary BCs. Intrinsic subtyping was determined using the PAM50 subtype predictor. Gene expression/PAM50 signature and overall survival (OS) correlations were analyzed using Cox models. Median OS was calculated using the Kaplan–Meier method. A false discovery rate-corrected paired two-class SAM identified gene expression changes between paired BC and BM samples. Results: Seventy-five BCBM samples from 74 patients were analyzed: 30.7% HR-positive/HER2-negative, 41.3% HER2-positive, and 28.0% HR-negative/HER2-negative. Intrinsic subtype was 36.0% basal-like, 48.0% HER2-enriched, 14.7% luminal B, and 1.3% normal-like; among HR-positive/HER2-negative 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-positive/HER2-negative subgroup (P = 0.024). Among 21 primary BCs analyzed, 45% of basal-like, 100% of normal-like, and 50% of luminal A shifted toward the HER2-enriched subtype in matched BMs. Three hundred and eighty-eight genes were differentially expressed in BMs compared with 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.
Gene expression profiling in a retrospective real-world cohort of breast cancer brain metastases and paired primary tumors identifies biological changes with potential therapeutic implications
Griguolo, G;Dieci, M V;Bottosso, M;Miglietta, F;Zanconato, F;Schiavi, F;Fassan, M;Dei Tos, A P;Guarneri, V
2025
Abstract
Background: Despite the clinical impact of breast cancer (BC) brain metastases (BMs), their biological complexity remains poorly understood. We evaluated the genomic profile of BCBMs and compared it with paired primary BC samples to characterize biological changes during brain metastasization and their clinical impact in a retrospective real-world cohort. Materials and methods: Expression of 758 genes (BC360 Panel, nCounter), hormone receptor (HR) status, and human epidermal growth factor receptor type 2 (HER2) status were evaluated in BCBMs and matched primary BCs. Intrinsic subtyping was determined using the PAM50 subtype predictor. Gene expression/PAM50 signature and overall survival (OS) correlations were analyzed using Cox models. Median OS was calculated using the Kaplan–Meier method. A false discovery rate-corrected paired two-class SAM identified gene expression changes between paired BC and BM samples. Results: Seventy-five BCBM samples from 74 patients were analyzed: 30.7% HR-positive/HER2-negative, 41.3% HER2-positive, and 28.0% HR-negative/HER2-negative. Intrinsic subtype was 36.0% basal-like, 48.0% HER2-enriched, 14.7% luminal B, and 1.3% normal-like; among HR-positive/HER2-negative 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-positive/HER2-negative subgroup (P = 0.024). Among 21 primary BCs analyzed, 45% of basal-like, 100% of normal-like, and 50% of luminal A shifted toward the HER2-enriched subtype in matched BMs. Three hundred and eighty-eight genes were differentially expressed in BMs compared with 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.
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