ERBB2 and neoplasm: Specifically, the genomic locus of HER2 is amplified which is detected clinically at the DNA level and informs the clinician to start HER2-targeted therapy, but PIK3CA also acquires a mutation in the kinase domain; this kinase mutation renders the protein constitutively active which circumvents the need for continuous signaling from HER2, causing downregulation of HER2 expression at the mRNA level and the protein level, thereby making the tumor refractory to HER2-targeted therapy.