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Frequent Overexpression of HER3 in Brain Metastases from Breast and Lung Cancer
Erwin Tomasich1,2, Ariane Steindl1,2, Christina Paiato1
1Division of Oncology, Department of Medicine I, Medical University of Vienna, Vienna, Austria.
Purpose:
HER3 belongs to a family of receptor tyrosine kinases with oncogenic properties and is targeted by a variety of novel anticancer agents. There is a huge unmet medical need for systemic treatment options in patients with brain metastases (BM). Therefore, we aimed to investigate HER3 expression in BM of breast (BCa) and non-small cell lung cancer (NSCLC) as the basis for future clinical trial design.
Experimental Design:
We analyzed 180 BM samples of breast cancer or NSCLC and 47 corresponding NSCLC extracranial tissue. IHC was performed to evaluate protein expression of HER3, and immune cells based on CD3, CD8, and CD68. To identify dysregulated pathways based on differential DNA methylation patterns, we used Infinium MethylationEPIC microarrays.
Results:
A total of 99/132 (75.0%) of BCa-BM and 35/48 (72.9%) of NSCLC-BM presented with HER3 expression. Among breast cancer, HER2-positive and HER2-low BM showed significantly higher rates of HER3 coexpression than HER2-negative BM (87.1%/85.7% vs. 61.0%, P = 0.004). Among NSCLC, HER3 was more abundantly expressed in BM than in matched extracranial samples (72.9% vs. 41.3%, P = 0.003). No correlation of HER3 expression and intratumoral immune cell density was observed. HER3 expression did not correlate with overall survival from BM diagnosis. Methylation signatures differed according to HER3 status in BCa-BM samples. Pathway analysis revealed subtype-specific differences, such as TrkB and Wnt signaling pathways dysregulated in HER2-positive and triple-negative breast cancer BM, respectively.
Conclusions:
HER3 is highly abundant in BM of breast cancer and NSCLC. Given the promising results of antibody-drug conjugates in extracranial disease, BM-specific trials that target HER3 are warranted. See related commentary by Kabraji and Lin, p. 2961.
Insights
HER3 is highly expressed in brain metastases (BM) from breast cancer and non-small cell lung cancer. This supports HER3-targeted therapies and clinical trials for patients with these challenging brain metastases.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- HER3 (Human Epidermal growth factor Receptor 3) is a receptor tyrosine kinase implicated in cancer.
- Brain metastases (BM) represent a significant clinical challenge with limited systemic treatment options.
- Targeting HER3 is a promising strategy for novel anticancer agents.
Purpose of the Study:
- To investigate HER3 protein expression in brain metastases (BM) from breast cancer (BCa) and non-small cell lung cancer (NSCLC).
- To establish a rationale for designing future clinical trials targeting HER3 in BM.
- To explore potential correlations between HER3 expression, immune cell infiltration, and methylation patterns.
Main Methods:
- Analysis of 180 BM samples from BCa and NSCLC patients.
- Immunohistochemistry (IHC) to assess HER3 protein expression and immune cell markers (CD3, CD8, CD68).
- Infinium MethylationEPIC microarrays to identify DNA methylation patterns and dysregulated pathways.
Main Results:
- High HER3 expression was observed in 75.0% of BCa-BM and 72.9% of NSCLC-BM.
- HER2-positive and HER2-low BCa-BM showed significantly higher HER3 coexpression compared to HER2-negative.
- HER3 expression was significantly higher in NSCLC-BM than in matched extracranial NSCLC samples (72.9% vs. 41.3%).
- No correlation was found between HER3 expression and intratumoral immune cell density or overall survival.
- Distinct methylation signatures and dysregulated pathways (e.g., TrkB, Wnt) were identified based on HER3 status and cancer subtype.
Conclusions:
- HER3 is highly prevalent in brain metastases of breast cancer and non-small cell lung cancer.
- The findings support the development of HER3-targeted antibody-drug conjugates for clinical trials in BM.
- Further research into HER3-driven pathways in specific BM subtypes is warranted.
