Human epidermal growth factor receptor 2/3 (HER2/HER3) expression in higher-grade meningioma.

Abstract

e14063 Background: Meningiomas are the most frequently diagnosed primary central nervous system (CNS) tumors in adults. Although most meningiomas can be cured by resection, higher-grade lesions (CNS WHO grades 2 & 3) tend to recur, with limited systemic treatment options after exhaustion of local therapies. Antibody drug conjugates (ADCs) targeting human epidermal growth factor receptors 2 and 3 HER2/HER3) have shown remarkable clinical activity in solid tumors including breast cancer brain metastases and are under investigation in various malignancies. Methods: 64 patients with WHO grade 2 (atypical) and 3 (anaplastic) meningioma have been included. DNA methylation analysis has been performed using Illumina EPIC methylation arrays. Panel sequencing for NF2, PIK3CA, SMO, ARID1A, ARID1B, KLF4, SUFU, TERT promotor, and TRAF7 has been executed applying the Illumina NextSeq 500 platform. HER2 and HER3 expression was evaluated by immunohistochemical analysis using PATHWAY HER2 (4B5, Roche) and HER3 #12708 (Cell Signaling) antibodies on a Ventana Benchmark Ultra staining system. Results: In total, 44/64 (68.8%) patients with WHO grade 2 and 20/64 (31.2%) patients with WHO grade 3 meningioma were included. Median age at surgery was 60 years (range: 19-83), and 37/64 (57.8%) patients were female. DNA methylation classes according to the Molecular Neuropathology classifier were benign-1 in 10 (15.6%), benign-2 in 10 (15.6%), benign-3 in 4 (6.3%), intermediate-A in 26 (40.6%), intermediate-B in 4 (6.3%), and malignant in 10 (15.6%) out of 64 tumors. Weak membranous HER2 expression was observed in 1/64 (1.6%) tumor, which was categorized as WHO grade 3/intermediate-B meningioma characterized by infiltration of adjacent bone and fat tissue as well as positive Ki-67 staining of up to 39% of cells. Similarly, only one sample (1.6%) was HER3-positive which was diagnosed as WHO grade 2 tumor of methylation class benign-2, showing meningothelial morphology with elevated mitotic activity and a mutation in TRAF7. The single HER2+ as well as the HER3+ sample were from two distinct female patients. Conclusions: In our cohort, HER2 and HER3 were only infrequently expressed in a small subset of samples of different WHO grade, methylation class, and genetic background. Exploration of further targets of ADCs which are approved or under investigation in other tumors is currently ongoing.