Abstract A020: Real-world clinical implications of ctDNA-detected ERBB2 amplification across solid tumors in a precision oncology program

Abstract Background: Liquid biopsies offer a rapid detection of genomic alterations, primarily single-nucleotide variants (SNVs), particularly in patients with metastatic lung or breast cancers. However, less is known about the clinical utility of copy number variations (CNVs), such as ERBB2 amplification, detected via circulating tumor DNA (ctDNA). Given recent tumor-agnostic FDA approval of trastuzumab-deruxtecan, based on HER2 overexpression, as determined by IHC, there is a growing need to understand whether ctDNA-based CNV detection can meaningfully inform treatment decisions. We explored real-world attitudes to ERBB2 amplification detection in ctDNA across diverse tumor types. Methods: We retrospectively analyzed patients (pts) with locally advanced or metastatic solid cancers who underwent a liquid biopsy by FoundationOne Liquid CDx ctDNA assay through the Bergonie Institut Profiling (BIP) program (NCT02534649) at our comprehensive cancer center (Institut Bergonié, France). Descriptive statistics were used to assess the prevalence and clinical handling of ERBB2 amplification. Results: 6072 liquid biopsies were performed between Jan 2021 and May 2025, 90 patients had ERBB2 and/or MET amplification in ctDNA. ERBB2 CNV was identified in 66 pts. The median copy number was 29 (Interquartile Range, IQR 12-46). These were observed in 15 tumor types, most frequently in Gastric/Oesophageal/junction adenocarcinoma (N=12), breast (N=10), bladder (urothelial), and colorectal (N=9 for each). Tissue NGS or FISH confirmed ERBB2 amplification in 44/58 (75.9%), with a median copy number of 32.3 (IQR 13.1-99.2). Of the 34 pts with IHC data, 27 (79%) were HER2 3+. In total, 30 pts received anti-HER2-directed therapies (N=25 in routine care, including off-label use, N=6 in clinical trials (one patient received in both)), including 7 pts without IHC confirmation of HER2 overexpression. In total, 13 patients received trastuzumab-deruxtecan, including 6 off-label per national approvals (breast N=7, gastric N=2, NSCLC N=2, colorectal N=1, endometrial N=1). Conclusions: The ctDNA-detected ERBB2 amplification may reflect true oncogenic addiction and tumoral heterogeneity, and may provide additional arguments for targeted therapy as a therapeutic option, including trastuzumab deruxtecan, either in routine clinical practice or in a clinical trial. Our findings support the incorporation of liquid biopsy CNV data into real-world clinical decisions and early-phase trial enrollment strategies, particularly for patients without accessible tissue. Citation Format: Veronique Debien, Eurydice Angeli, Melissa Alamé, Paul Dubos, Nathan El Ghazzi, Yechan Laizet, Sophie Cousin, Antoine Italiano. Real-world clinical implications of ctDNA-detected ERBB2 amplification across solid tumors in a precision oncology program [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr A020.