Molecular imaging of tucatinib-induced cellular and TME changes in preclinical models of HER2 + breast cancer.

INTRODUCTION: Tucatinib, a small molecule HER2 inhibitor, was approved in inoperable or metastatic HER2 + breast cancer. As many patients have tumors in challenging surgical locations, there is a need for imaging metrics to characterize tucatinib response and microenvironment impact. Molecular imaging can be used to quantify dynamic molecular changes that precede tumor size alterations and can target proliferation (fluorothymidine, [(18)F]-FLT), hypoxia (fluoromisonidazole, [(18)F]-FMISO) and HER2 expression ([(89)Zr]-Pertuzumab) with positron emission tomography (PET) imaging. The goal of this study is to non-invasively characterize tucatinib response in HER2 + breast cancer and quantify microenvironment modulation with advanced PET imaging. METHODS: 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 [(18)F]-FLT-PET on days 0, 3 and 7, [(18)F]-FMISO-PET on days 0, 3 and 7, or [(89)Zr]Zr-Pertuzumab-PET on days 0 and 14. Proliferation, hypoxia and HER2 expression were quantified with standardized uptake value. A Mann-Whitney U Test assessed significance between groups. RESULTS: Tucatinib-treated human cell line and PDX tumors had significantly decreased hypoxia and proliferation relative to control tumors (p < 0.05). Tucatinib-treated BT474 tumors had significantly decreased HER2 expression (p < 0.05); however, no significant HER2 change was observed in BCM3472 tumors. CONCLUSION: Tucatinib significantly decreases intratumoral proliferation and hypoxia in both cell-line and patient-derived xenograft models of HER2 + breast cancer, which can be longitudinally quantified with PET imaging. Our data suggests molecular imaging may improve understanding and prediction of tucatinib response.