The goal of this study is to non-invasively characterize tucatinib response in HER2 + breast cancer and quantify microenvironment modulation with advanced PET imaging.<h4>Methods</h4>Mice with HER2 + human cell line (BT474) or patient derived xenograft (BCM 3472) tumors were treated with 50 mg/kg tucatinib and enrolled into imaging cohorts: imaged with [<sup>18</sup>F]-FLT-PET on days 0, 3 and 7, [<sup>18</sup>F]-FMISO-PET on days 0, 3 and 7, or [<sup>89</sup>Zr]Zr-Pertuzumab-PET on days 0 and 14. Here, ERBB2 is linked to breast cancer.