The mechanisms of secondary resistance mainly involve: cluster of differentiation (CD)44+/CD24− BC stem cells inhibiting the binding of trastuzumab to the extracellular domain of HER2 [21, 22]; signal masking by mucin-1 and mucin-4 [23, 24]; increased insulin-like growth factor I receptor signaling [25, 26]; altered beta-2 adrenergic receptor signaling [27]; blockade of phosphatase and tensin homolog (PETN)/PI3K/Akt signaling [28]; caveolae-mediated endocytosis [29]; cell-cycle changes that influence HER2 signaling [30]. The gene discussed is ERBB2; the disease is breast cancer.