Genomic Characterization of de novo Metastatic Breast Cancer

Purpose: In contrast to recurrence after initial diagnosis of stage I-III breast cancer (recurrent metastatic breast cancer (rMBC)j, de novo metastatic breast cancer (dnMBC) represents a unique setting to elucidate metastatic drivers in the absence of treatment selection. We present the genomic landscape of dnMBC and association with overall survival (OS). Experimental Design: Targeted DNA sequencing (OncoPanel) was prospectively performed on either primary or metastatic tumors from 926 patients (212 dnMBC and 714 rMBC). Single-nucleotide variants, copy-number variations, and tumor mutational burden (TMB) in treatment-naive dnMBC primary tumors were compared with primary tumors in patients who ultimately developed rMBC, and correlated with OS across all dnMBC. Results: When comparing primary tumors by subtype, MYB amplification was enriched in triple-negative dnMBC versus rMBC (21.1% vs. 0%, P = 0.0005, q = 0.111). Mutations in KMTD2, SETD2, and PIK3CA were more prevalent, and TP53 and BRCAI less prevalent, in primary HR+/HER2(-) tumors of dnMBC versus rMBC, though not significant after multiple comparison adjustment Alterations associated with shorter OS in dnMBC included TP53 (wild-type: 79.7 months; altered: 44.2 months; P = 0.008, q = 0.107), MYC (79.7 vs. 23.3 months; P = 0.0003, q = 0.011), and cell-cycle (122.7 vs. 54.9 months; P = 0.034, q -= 0.245) pathway genes. High TMB correlated with better OS in triple-negative dnMBC (P = 0.041). Conclusions: Genomic differences between treatment-naive dnMBC and primary tumors of patients who developed rMBC may provide insight into mechanisms underlying metastatic potential and differential therapeutic sensitivity in dnMBC. Alterations associated with poor OS in dnMBC highlight the need for novel approaches to overcome potential intrinsic resistance to current treatments.

Automated summary

The study compared the genomic landscapes of de novo metastatic breast cancer (dnMBC) with recurrent metastatic breast cancer (rMBC) and found MYB amplification was enriched in triple-negative dnMBC. Mutations in specific genes were more prevalent in dnMBC, and alterations associated with shorter overall survival were identified. High tumor mutational burden correlated with better overall survival in triple-negative dnMBC, suggesting potential implications for therapeutic strategies.