Abstract 3990: Imaging molecular alterations during tucatinib response in preclinical models of HER2+ breast cancer

Abstract

Abstract Introduction: Human epidermal growth factor receptor 2 (HER2) is overexpressed in 25% of breast cancers. Tucatinib, a small molecule HER2 inhibitor, was FDA approved for inoperable or metastatic HER2+ breast cancer. As many of these patients have inoperable tumors, there is a need to identify imaging metrics that can characterize response to tucatinib. Positron emission tomography (PET) imaging can quantify changes in the tumor microenvironment that precede changes in tumor size through imaging with radiopharmaceuticals that target proliferation (fluorothymidine, [18F]-FLT), hypoxia (fluoromisonidazole, [18F]-FMISO) and HER2 expression ([89Zr]-Pertuzumab). The goal of this study is to use advanced PET imaging to non-invasively monitor response to tucatinib in HER2+ primary breast cancer and quantify the subsequent tumor microenvironment modulation. Methods: HER2+ cell line (BT474) and patient derived xenograft (BCM 3472) tumor models were engrafted and developed to 270 ± 166.4 mm3 before being enrolled into experiments. Mice were treated with 50 mg/kg tucatinib via PO and were imaged with [18F]-FLT PET (N = 8) on days 0, 3 and 7, [18F]-FMISO PET (N = 6) on days 0, 3 and 7, or [89Zr]-Pertuzumab PET (N = 5) on days 0 and 14. Intratumoral proliferation, hypoxia and HER2 expression were quantified with standardized uptake value (SUV). Following the final imaging timepoint, tumors were excised for immunohistochemistry against Ki-67 (proliferation), pimonidazole (hypoxia), and HER2. A non-parametric T-test was used to assess for significance. Results: Tucatinib treated BT474 and BCM3472 tumors had a 2.07 and 2.63 fold decrease in tumor volume, respectively (p<0.01). Tucatinib treated BT474 and BCM3472 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 change in HER2 expression was observed in tucatinib treated BCM3472 tumors. Conclusion: Tucatinib significantly decreases tumor volume and decreases intratumoral proliferation and hypoxia in both cell-line and patient-derived xenograft models of HER2+ breast cancer. Our data suggests molecular imaging may drive understanding of and predict response to tucatinib therapy. Acknowledgements: Tucatinib was provided by Seagen Inc. Bothell, Washington, USA. Citation Format: Patrick Song, Ameer Mansur, Anna Sorace. Imaging molecular alterations during tucatinib response in preclinical models of HER2+ breast cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3990.