Because activating mutations in PIK3CA, which are commonly associated with resistance to HER2-targeting agents [140-143], induce breast tumor heterogeneity by evoking cell dedifferentiation into multipotent stem-like states and promoting different cell fate switches [144, 145], their selection upon treatment with chemotherapeutic agents or other microenvironmental stresses might drastically accelerate tumor relapse and metastatic progression by altering the initial intrinsic phenotype of cHER2+ BC and generating M-CSC-like states refractory to anti-HER2 therapies [146]. The gene discussed is PIK3CA; the disease is breast cancer.