Acquired gene alterations potentially related to resistance to anti-HER2 therapy in HER2-positive metastatic colorectal cancer (mCRC).

• DOI: 10.1200/jco.2025.43.4_suppl.277
• Publication Date: 2025-01-27T14:33:47Z
• Authors: Celine Hoyek; Binbin Zheng-Lin; Angelo Pirozzi; Oluseyi Abidoye; Cody Eslinger; Naoko Iida; Yoshiaki Nakamura; Ryne Ramaker; Mohamad Bassam So...; Christina Wu; Mitesh J. Borad; Daniel H. Ahn; Masafumi Ikeda; Taro Shibuki; Takayuki Yoshino; John H Strickler; Tanios S. Bekaii-...
• Keywords: Acquired resistance

277 Background: While HER2-targeted therapies benefit patients (pts) with advanced HER2-positive mCRC, the development of resistance remains inevitable. This study aims to explore landscape and frequency genetic alterations putatively associated acquired anti-HER2 therapy in mCRC. Methods: In this retrospective-multicenter international involving Mayo Clinic, Duke Cancer Center National Hospital East (Japan), we descriptively compared comprehensive genomic analyses from tissue or blood samples pts CRC pre-treatment post-treatment HER2-targeting agents. Results: A total 36 were included study. 29 (80%) had mCRC as confirmed by immunohistochemistry (IHC) fluorescent situ hybridization (ISH), remaining HER2 amplification detected on . 34/36 (94%) administered their first agent after progressing ≥2 prior lines treatment. The most common regimen was trastuzumab/pertuzumab (50%, 18/36), followed trastuzumab-tyrosine kinase inhibitors (TKIs) (tucatinib neratinib) (30%, 11/36) trastuzumab deruxtecan (14%, 5/36). Putative mechanisms 72% (26/36), while lacked new that might explain therapy, suggesting alternative escape mechanisms. Acquired downstream alternate bypass pathways identified (26/36) pts; commonly RAS/RAF pathway EGFR (34.6%, 9/26 each), 27% (7/26) MET point mutations (mts) amplification; activating muts PI3K/AKT (7/26), CDK12 (60%, 4/7) receptor 3 (8.3%), all whom received trastuzumab-tucatinib L755S, V777L, D769Y, G727A S310F, which are known cause , however, information about tucatinib is not yet available. Other altered AR, RB, NOTCH HRD. Two lost expression NGS post therapy. Conclusions: emergence be part related constitutively activate signaling parallel HER2, bypassing inhibition. Additional histologic studies, deep mutational scanning, larger populations correlative analysis needed validate these findings.