Genomic, Transcriptomic, and Proteomic Profiling of Metastatic Breast Cancer.

Abstract

Metastatic breast cancer (MBC) is not curable and there is a growing interest in personalized therapy options. Here we report molecular profiling of MBC focusing on molecular evolution in actionable alterations. Sixty-two patients with MBC were included. An analysis of DNA, RNA, and functional proteomics was done, and matched primary and metastatic tumors were compared when feasible. Targeted exome sequencing of 41 tumors identified common alterations in <i>TP53</i> (21; 51%) and <i>PIK3CA</i> (20; 49%), as well as alterations in several emerging biomarkers such as <i>NF1</i> mutations/deletions (6; 15%), <i>PTEN</i> mutations (4; 10%), and <i>ARID1A</i> mutations/deletions (6; 15%). Among 27 hormone receptor-positive patients, we identified <i>MDM2</i> amplifications (3; 11%), <i>FGFR1</i> amplifications (5; 19%), <i>ATM</i> mutations (2; 7%), and <i>ESR1</i> mutations (4; 15%). In 10 patients with matched primary and metastatic tumors that underwent targeted exome sequencing, discordances in actionable alterations were common, including <i>NF1</i> loss in 3 patients, loss of <i>PIK3CA</i> mutation in 1 patient, and acquired <i>ESR1</i> mutations in 3 patients. RNA sequencing in matched samples confirmed loss of NF1 expression with genomic <i>NF1</i> loss. Among 33 patients with matched primary and metastatic samples that underwent RNA profiling, 14 actionable genes were differentially expressed, including antibody-drug conjugate targets LIV-1 and B7-H3. Molecular profiling in MBC reveals multiple common as well as less frequent but potentially actionable alterations. Genomic and transcriptional profiling demonstrates intertumoral heterogeneity and potential evolution of actionable targets with tumor progression. Further work is needed to optimize testing and integrated analysis for treatment selection.