ERBB2 and neoplasm: In contrast, AI resistance—which affects over 20% of early-stage and most metastatic cases—is driven by both intrinsic (e.g., upregulation of FGFR, ERBB2, IGF1R, PI3K-AKT-mTOR, MAPK signaling) and extrinsic factors, including interactions with the tumor microenvironment (34).