In primary HER2+ breast cancer, continuously activating PI3K mutations play an inhibitory role to inhibit the expression and activation of HER2 and other RTKs; meanwhile, in advanced HER2+ cases, long‐term anti‐HER2 treatment resulted in the enrichment of PI3K mutant clones which eventually led to the failure of anti‐ HER2 therapy. The gene discussed is PIK3CA; the disease is breast cancer.