Abstract B054: Correspondence between circulating tumor DNA (ctDNA)-based <i>ERBB2</i> amplification and HER2 expression by IHC/ISH across solid tumors: Molecular landscape and diagnostic implications

Abstract RationaleERBB2 amplification (ERBB2amp) is a well-established therapeutic target in several malignancies, including breast and gastric cancers. Currently, HER2 overexpression is diagnosed using immunohistochemistry (IHC) and/or in-situ hybridization (ISH), but these tissue-based methods are invasive and often limited by sample availability. This study aimed to evaluate the concordance between ERBB2amp detected by ctDNA and HER2 overexpression assessed by IHC/ISH, and to describe the associated molecular landscape. Methods We retrospectively analyzed patients with advanced solid tumors enrolled in the STING study who had ERBB2amp identified via ctDNA NGS using the Foundation Medicine assay. All cases were reviewed by a molecular tumor board, which recommended confirmatory HER2 testing by IHC and/or ISH when clinically indicated. HER2 overexpression was defined as IHC 3+ or ISH-positive. Results Among 164 patients with ERBB2amp detected on ctDNA, 103 cases had non-equivocal amplifcation levels (62.8%) and 61 cases (37.2%) had equivocal amplification levels. The median number of ERBB2 copies was 14 [interquartile range 8.0-37.5]. Tumor types included gastric (n=31, 18.9%), lung (n=30, 18.3%) and colorectal cancers (n=18, 11%), among others. Of these, 76 patients (46.3%) underwent confirmatory HER2 testing: 46 by IHC, 23 by ISH and 7 by both modalities. The positive predictive value (PPV) of ctDNA-based ERBB2amp was 78.8% in cases of unequivocal amplifications and 58.3% in equivocal cases, yielding an overall PPV of 72.4%. The most frequently co-altered genes were TP53 (86.6%), and PIK3CA (16.5%). Additional recurrent mutated genes included ARID1A (11.6%), ERBB2 (8.5%), SMARCA4 (4.9%) and ERBB3 (3%). Notably, SWI/SNF complex alterations were disproportionately frequent in bladder (8/15=53%) and lung cancers (12/30=40%) compared to historical datasets. Discussion ctDNA-based detection of ERBB2amp has a high PPV, particularly for unequivocal cases, supporting its utility as a non-invasive diagnostic tool to guide HER2-targeted therapy. The unexpectedly high frequency of SWI/SNF-related alterations in ERBB2amp tumors warrants further investigation into potential interactions and therapeutic vulnerabilities. Citation Format: Felix Blanc-Durand, Damien Vasseur, Alicia Tran-Dien, Alexandre Megherbi, Lodovica Zollo, Kaissa Ouali, Cedric Pobel, Filippo Dall'Ollio, Joana Ribeiro, Sofiane Taleb, Alexander Valent, Antoine Hollebecque, Benjamin Verret, Etienne Rouleau, Antoine Italiano. Correspondence between circulating tumor DNA (ctDNA)-based ERBB2 amplification and HER2 expression by IHC/ISH across solid tumors: Molecular landscape and diagnostic implications [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 B054.