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Intrinsic Subtype Switching and Acquired ERBB2/HER2 Amplifications and Mutations in Breast Cancer Brain Metastases.


ABSTRACT: Importance:Patients with breast cancer (BrCa) brain metastases (BrM) have limited therapeutic options. A better understanding of molecular alterations acquired in BrM could identify clinically actionable metastatic dependencies. Objective:To determine whether there are intrinsic subtype differences between primary tumors and matched BrM and to uncover BrM-acquired alterations that are clinically actionable. Design, Setting, and Participants:In total, 20 cases of primary breast cancer tissue and resected BrM (10 estrogen receptor [ER]-negative and 10 ER-positive) from 2 academic institutions were included. Eligible cases in the discovery cohort harbored patient-matched primary breast cancer tissue and resected BrM. Given the rarity of patient-matched samples, no exclusion criteria were enacted. Two validation sequencing cohorts were used-a published data set of 17 patient-matched cases of BrM and a cohort of 7884 BrCa tumors enriched for metastatic samples. Main Outcomes and Measures:Brain metastases expression changes in 127 genes within BrCa signatures, PAM50 assignments, and ERBB2/HER2 DNA-level gains. Results:Overall, 17 of 20 BrM retained the PAM50 subtype of the primary BrCa. Despite this concordance, 17 of 20 BrM harbored expression changes (<2-fold or >2-fold) in clinically actionable genes including gains of FGFR4 (n?=?6 [30%]), FLT1 (n?=?4 [20%]), AURKA (n?=?2 [10%]) and loss of ESR1 expression (n?=?9 [45%]). The most recurrent expression gain was ERBB2/HER2, which showed a greater than 2-fold expression increase in 7 of 20 BrM (35%). Three of these 7 cases were ERBB2/HER2-negative out of 13 ERBB2/HER2-negative in the primary BrCa cohort and became immunohistochemical positive (3+) in the paired BrM with metastasis-specific amplification of the ERBB2/HER2 locus. In an independent data set, 2 of 9 (22.2%) ERBB2/HER2-negative BrCa switched to ERBB2/HER2-positive with 1 BrM acquiring ERBB2/HER2 amplification and the other showing metastatic enrichment of the activating V777L ERBB2/HER2 mutation. An expanded cohort revealed that ERBB2/HER2 amplification and/or mutation frequency was unchanged between local disease and metastases across all sites; however, a significant enrichment was appreciated for BrM (13% local vs 24% BrM; P?

SUBMITTER: Priedigkeit N 

PROVIDER: S-EPMC5508875 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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<h4>Importance</h4>Patients with breast cancer (BrCa) brain metastases (BrM) have limited therapeutic options. A better understanding of molecular alterations acquired in BrM could identify clinically actionable metastatic dependencies.<h4>Objective</h4>To determine whether there are intrinsic subtype differences between primary tumors and matched BrM and to uncover BrM-acquired alterations that are clinically actionable.<h4>Design, setting, and participants</h4>In total, 20 cases of primary bre  ...[more]

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