89Zr]-Pertuzumab PET Imaging Reveals Paclitaxel Treatment Efficacy Is Positively Correlated with HER2 Expression in Human Breast Cancer Xenograft Mouse Models.

Yun Lu,Ameer Mansur,Patrick N Song,Benjamin M Larimer,Katherine A Heinzman,Adriana V F Massicano,Suzanne E Lapi,Anna G Sorace,Meng Li

doi:10.3390/molecules26061568

Yun Lu, Ameer Mansur + Show 7 more

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https://doi.org/10.3390/molecules26061568

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Abstract

Paclitaxel (PTX) treatment efficacy varies in breast cancer, yet the underlying mechanism for variable response remains unclear. This study evaluates whether human epidermal growth factor receptor 2 (HER2) expression level utilizing advanced molecular positron emission tomography (PET) imaging is correlated with PTX treatment efficacy in preclinical mouse models of HER2+ breast cancer. HER2 positive (BT474, MDA-MB-361), or HER2 negative (MDA-MB-231) breast cancer cells were subcutaneously injected into athymic nude mice and PTX (15 mg/kg) was administrated. In vivo HER2 expression was quantified through [89Zr]-pertuzumab PET/CT imaging. PTX treatment response was quantified by [18F]-fluorodeoxyglucose ([18F]-FDG) PET/CT imaging. Spearman’s correlation, Kendall’s tau, Kolmogorov–Smirnov test, and ANOVA were used for statistical analysis. [89Zr]-pertuzumab mean standard uptake values (SUVmean) of BT474 tumors were 4.9 ± 1.5, MDA-MB-361 tumors were 1.4 ± 0.2, and MDA-MB-231 (HER2−) tumors were 1.1 ± 0.4. [18F]-FDG SUVmean changes were negatively correlated with [89Zr]-pertuzumab SUVmean (r = −0.5887, p = 0.0030). The baseline [18F]-FDG SUVmean was negatively correlated with initial [89Zr]-pertuzumab SUVmean (r = −0.6852, p = 0.0002). This study shows PTX treatment efficacy is positively correlated with HER2 expression level in human breast cancer mouse models. Molecular imaging provides a non-invasive approach to quantify biological interactions, which will help in identifying chemotherapy responders and potentially enhance clinical decision-making.

Highlights

Breast cancer is the most common cancer in women [1], with 10–15% overexpressing the human epidermal growth factor receptor 2 (HER2) [2]
We examine the relationship between HER2 expression and tumor heterogeneity with PTX treatment efficacy in controlled xenografted human breast cancer models: BT474, MDA-MB-361, MDA-MB-231 (HER2−) tumors with molecular imaging
Paclitaxel is commonly used in HER2+ breast cancer patients; the relationship between HER2 expression and PTX efficacy has remained unclear

Summary

Introduction

Breast cancer is the most common cancer in women [1], with 10–15% overexpressing the human epidermal growth factor receptor 2 (HER2) [2]. The HER2 receptor ( called Neu), a member of the epidermal growth factor receptor family EGFR/ErbB, is a transmembrane glycoprotein with tyrosine kinase activity [3,4]. This receptor regulates both proliferation and differentiation of epithelial cells, and breast cancer with overexpressed HER2 tends to have increased proliferation, increased disease recurrence, and poorer survival compared to HER2− breast cancers [5]. PTX is part of standard-of-care for HER2+ breast cancer patients; the association between HER2 and PTX treatment efficacy remains surprisingly unclear, with controversial results in both in vitro and in vivo preclinical studies [11]. We utilized controlled in vivo preclinical experiments to quantify the relationship of HER2 expression and PTX response to therapy

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