biostudies-literatureSmyth LMNCI NIH HHSNational Breast Cancer FoundationNIH198-213https://www.ebi.ac.uk/biostudies/studies/S-EPMC7007377biostudies-literatureUnknown10(2)<i>HER2</i> mutations define a subset of metastatic breast cancers with a unique mechanism of oncogenic addiction to HER2 signaling. We explored activity of the irreversible pan-HER kinase inhibitor neratinib, alone or with fulvestrant, in 81 patients with <i>HER2</i>-mutant metastatic breast cancer. Overall response rate was similar with or without estrogen receptor (ER) blockade. By comparison, progression-free survival and duration of response appeared longer in ER⁺ patients receiving combination therapy, although the study was not designed for direct comparison. Preexistent concurrent activating <i>HER2</i> or <i>HER3</i> alterations were associated with poor treatment outcome. Similarly, acquisition of multiple <i>HER2</i>-activating events, as well as gatekeeper alterationCancer discoveryEfficacy and Determinants of Response to HER Kinase Inhibition in <i>HER2</i>-Mutant Metastatic Breast Cancer.PMC7007377P30 CA016672R01 CA234361P30 CA008748R01 CA190642EC-17-001Scaltriti MBaselga JSamoila ASohn JZimel CSaura CGonzalez-Farre XChandarlapaty SDujka MJhaveri KShapiro GIJuric DPiha-Paul SAArnedos MMau-Sorensen MSmyth LMSelcuklu SDMeric-Bernstam FUlaner GALalani ASBryce RArteaga CLSpanggaard IGorelick ANXu FBrufksy AMCervantes AWon HHBidard FCSchwartzberg LSHyman DMBoni VMayer IAGavrila EIMelcer MMann GMoreno VLanman RBEli LDLu JCai YTaylor BSSchram AMLoi SNagy RJde la Fuente MISolit DBfalseEfficacy and Determinants of Response to HER Kinase Inhibition in <i>HER2</i>-Mutant Metastatic Breast Cancer.<i>HER2</i> mutations define a subset of metastatic breast cancers with a unique mechanism of oncogenic addiction to HER2 signaling. We explored activity of the irreversible pan-HER kinase inhibitor neratinib, alone or with fulvestrant, in 81 patients with <i>HER2</i>-mutant metastatic breast cancer. Overall response rate was similar with or without estrogen receptor (ER) blockade. By comparison, progression-free survival and duration of response appeared longer in ER⁺ patients receiving combination therapy, although the study was not designed for direct comparison. Preexistent concurrent activating <i>HER2</i> or <i>HER3</i> alterations were associated with poor treatment outcome. Similarly, acquisition of multiple <i>HER2</i>-activating events, as well as gatekeeper alteration2020-01-01T00:00:00Z2020 Feb2025-04-19T01:02:18.931Z2020-10-29T12:35:50ZS-EPMC70073773180662710.1158/2159-8290.CD-19-096610.1158/2159-8290.cd-19-0966