Genomic and transcriptomic evaluation of primary and recurrent luminal B-like breast cancer

BACKGROUND: Luminal B-like breast cancer (LBBC) constitutes approximately 40% of breast cancer cases and carries a higher risk of recurrence and poorer prognosis than luminal A-like disease. This study aimed to investigate the molecular alterations between primary and recurrent LBBC tumors, elucidate the drivers of LBBC recurrence and identify potential therapeutic targets. MATERIALS AND METHODS: We performed DNA sequencing using a custom-designed panel covering 769 cancer-related genes and RNA sequencing (RNA-seq) on 15 LBBC patients (49 samples: 15 primary tumors, 21 recurrent lesions and 15 blood samples; six patients had two recurrent lesions each). Of these, 13 had paired-end DNA sequencing data and five had paired-end RNA-seq data (three of whom also had DNA data). Molecular features altered in recurrent tumors were compared with their corresponding primary tumors, focusing on gene mutations, copy number alterations, tumor heterogeneity, gene expression, pathways, and immune cell composition. Molecular features associated with LBBC recurrence were further identified. RESULTS: The majority of gene mutations and copy number alterations are primarily established in the primary tumor and persist through recurrence. TP53 and PIK3CA were the most frequently altered genes in both primary and recurrent tumors, whereas mutations in EGFR and GNAS emerged in recurrent tumors. Upregulated pathways in recurrences included cell cycle checkpoints, DNA replication, and antigen processing-cross-presentation. Compared with primary tumors, recurrent tumors exhibited an increased abundance of T cells in the tumor microenvironment. Furthermore, higher mutant-allele tumor heterogeneity (MATH) scores in primary tumors were associated with worse recurrence-free survival in exploratory unadjusted analysis (P = 0.032). CONCLUSIONS: Our study reveals the genomic and transcriptomic evolution of LBBC recurrence, suggesting that most drivers are established in the primary tumor. Acquired mutations or alterations warrant further investigation as potential therapeutic targets and MATH scores may represent a candidate biomarker associated with LBBC recurrence.