Proposed mechanisms for acquired resistance include mutations in HER family genes (e.g., HER2L755S, HER3E928G), loss or masking of the HER2 epitope (p95HER2), activation of alternative signaling pathways (e.g., PIK3CA mutations, PTEN loss, cyclin D1-CDK4/6 axis), HER2 heterogeneity, and an immunosuppressive tumor microenvironment (TME) [58,59,60,61,62,63,64]. The gene discussed is ERBB2; the disease is neoplasm.