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Intrinsic Subtype Switching and Acquired ERBB2/HER2 Amplifications and Mutations in Breast Cancer Brain Metastases
Nolan Priedigkeit1, Ryan J Hartmaier2, Yijing Chen3
1Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania2Women's Cancer Research Center, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania3Magee-Women's Research Institute, Magee-Women's Research Hospital of University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania4Medical Scientist Training Program, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
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 < .001).
Conclusions And Relevance:
Breast cancer BrM commonly acquire alterations in clinically actionable genes, with metastasis-acquired ERBB2/HER2 alterations in approximately 20% of ERBB2/HER2-negative cases. These observations have immediate clinical implications for patients with ERBB2/HER2-negative breast cancer and support comprehensive profiling of metastases to inform clinical care.
Insights
Breast cancer brain metastases (BrM) often acquire actionable gene alterations, particularly ERBB2/HER2 changes in ERBB2/HER2-negative cases. Comprehensive metastasis profiling is crucial for guiding treatment decisions in BrM patients.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Limited therapeutic options exist for patients with breast cancer brain metastases (BrM).
- Understanding molecular alterations in BrM is key to identifying actionable metastatic dependencies.
Purpose of the Study:
- To investigate intrinsic subtype differences between primary breast tumors and matched BrM.
- To identify clinically actionable alterations acquired in BrM.
Main Methods:
- Analysis of 20 matched primary breast cancer and BrM samples.
- Inclusion of two validation cohorts: a published dataset (17 cases) and a larger cohort (7884 tumors).
- Assessment of gene expression changes, PAM50 subtypes, and ERBB2/HER2 DNA gains.
Main Results:
- 17 of 20 BrM retained the primary tumor's PAM50 subtype.
- 17 of 20 BrM showed expression changes in actionable genes, including FGFR4 gains and ESR1 loss.
- ERBB2/HER2 alterations (gain, amplification, mutation) were observed in 35% of BrM, with a significant enrichment in BrM compared to local disease (24% vs 13%).
- Approximately 20% of initially ERBB2/HER2-negative cases acquired ERBB2/HER2 alterations in BrM.
Conclusions:
- Breast cancer brain metastases frequently acquire alterations in clinically actionable genes.
- Metastasis-acquired ERBB2/HER2 alterations occur in about 20% of ERBB2/HER2-negative cases.
- Comprehensive molecular profiling of metastases is recommended to inform clinical care for BrM patients.
