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), 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; 714 rMBC). Single-nucleotide variants, copy number variations and tumor mutational burden (TMB) in treatment-naive dnMBC primary tumors were compared to 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 vs. rMBC (21.1% vs. 0%, p=0.0005, q=0.111). Mutations in KMTD2, SETD2 and PIK3CA were more prevalent, and TP53 and BRCA1 less prevalent, in primary HR+/HER2- tumors of dnMBC vs. 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.