Tumor uptake and tumor/blood ratios for [89Zr]Zr-DFO-trastuzumab-DM1 on microPET/CT images in NOD/SCID mice with human breast cancer xenografts are directly correlated with HER2 expression and response to trastuzumab-DM1

Abstract

IntroductionOur objective was to determine correlations between the tumor uptake and T/B ratios for 89Zr-labeled T-DM1 (89Zr-DFO-T-DM1) in mice with human BC xenografts by microPET/CT and biodistribution studies with HER2 expression and response to treatment with trastuzumab-DM1 (T-DM1). MethodsThe tumor and normal tissue uptake and T/B ratios for 89Zr-DFO-T-DM1 (10 μg; 7.0 MBq) incorporated into a therapeutic dose (60 μg) were determined by microPET/CT and biodistribution studies at 96 h p.i. in NOD/SCID mice with s.c. MDA-MB-231 (5 × 104 HER2/cell), MDA-MB-361 (5 × 105 HER2/cell) and BT-474 (2 × 106 HER2/cell) human BC xenografts. Mice bearing these tumors were treated with T-DM1 (3.6 mg/kg every 3 weeks) and the tumor doubling time estimated by fitting of tumor volume vs. time curves. A tumor doubling time ratio (TDR) was calculated by dividing the doubling time for T-DM1 and normal saline treated control mice. The clonogenic survival (CS) of BC cells with increasing HER2 expression treated for 72 h in vitro with T-DM1 or trastuzumab (0–100 μg/mL) was compared. Correlations were determined between the T/B ratios for 89Zr-DFO-T-DM1 and HER2 expression, TDR and CS, and between CS and TDR. ResultsUptake of 89Zr-DFO-T-DM1 in MDA-MB-231, MDA-MB-361 and BT-474 tumors was 2.4 ± 0.4%ID/g, 6.9 ± 2.2%ID/g and 9.8 ± 1.1%ID/g, respectively. There was a non-linear but direct correlation between the T/B ratios for 89Zr-DFO-T-DM1 and HER2 expression with the T/B ratio ranging from 4.5 ± 0.7 for MDA-MB-231 to 18.2 ± 1.8 for MDA-MB-361 and 35.9 ± 5.1 for BT-474 xenografts. Tumor intensity on microPET/CT images was proportional to HER2 expression. The standard uptake value (SUV) for the tumors on the images was strongly correlated with the T/B ratio in biodistribution studies. There was a direct linear correlation between the T/B ratio for 89Zr-DFO-T-DM1 and TDR, with TDR ranging from 0.9 for MDA-MB-231 to 1.6 for MDA-MB-361 and 2.1 for BT-474 tumors. The cytotoxicity of T-DM1 in vitro on BC cells was dependent on HER2 expression but T-DM1 was more potent than trastuzumab. There was an inverse correlation between the TDR for mice treated with T-DM1 and CS of BC cells exposed in vitro to T-DM1. ConclusionsBased on the direct correlations between the T/B ratio for 89Zr-DFO-T-DM1 by PET and HER2 expression and response to T-DM1, our results suggest that PET with 89Zr-DFO-T-DM1 may predict response of HER2-positive BC to treatment with T-DM1. Advances in knowledge and implications for patient careOur results suggest that PET with 89Zr-DFO-T-DM1 may predict response to treatment with T-DM1 in HER-positive BC.