ESR1 and breast cancer: Third, given that aberrant activation of the PI3K pathway has been implicated in resistance to HER2-targeted therapy64, one might hypothesize that GATA3 mutations may be a mechanism of resistance to HER2-targeted therapy and that MDM2 inhibitors may act synergistically with trastuzumab in ER+/HER2+, GATA3-mutant breast cancers.