Imaging biomarkers predict response to anti-HER2 (ErbB2) therapy in preclinical models of breast cancer.

Shah C, Miller TW, Wyatt SK, McKinley ET, Olivares MG, Sanchez V, Nolting DD, Buck JR, Zhao P, Ansari MS, Baldwin RM, Gore JC, Schiff R, Arteaga CL, Manning HC
Clin Cancer Res. 2009 15 (14): 4712-21

PMID: 19584166 · PMCID: PMC2819132 · DOI:10.1158/1078-0432.CCR-08-2635

PURPOSE - To evaluate noninvasive imaging methods as predictive biomarkers of response to trastuzumab in mouse models of HER2-overexpressing breast cancer. The correlation between tumor regression and molecular imaging of apoptosis, glucose metabolism, and cellular proliferation was evaluated longitudinally in responding and nonresponding tumor-bearing cohorts.

EXPERIMENTAL DESIGN - Mammary tumors from MMTV/HER2 transgenic female mice were transplanted into syngeneic female mice. BT474 human breast carcinoma cell line xenografts were grown in athymic nude mice. Tumor cell apoptosis (NIR700-Annexin V accumulation), glucose metabolism [2-deoxy-2-[18F]fluoro-d-glucose positron emission tomography ([18F]FDG-PET)], and proliferation [3'-[18F]fluoro-3'-deoxythymidine-PET ([18F]FLT-PET)] were evaluated throughout a biweekly trastuzumab regimen. Imaging metrics were validated by direct measurement of tumor size and immunohistochemical analysis of cleaved caspase-3, phosphorylated AKT, and Ki67.

RESULTS - NIR700-Annexin V accumulated significantly in trastuzumab-treated MMTV/HER2 and BT474 tumors that ultimately regressed but not in nonresponding or vehicle-treated tumors. Uptake of [18F]FDG was not affected by trastuzumab treatment in MMTV/HER2 or BT474 tumors. [18F]FLT-PET imaging predicted trastuzumab response in BT474 tumors but not in MMTV/HER2 tumors, which exhibited modest uptake of [18F]FLT. Close agreement was observed between imaging metrics and immunohistochemical analysis.

CONCLUSIONS - Molecular imaging of apoptosis accurately predicts trastuzumab-induced regression of HER2+ tumors and may warrant clinical exploration to predict early response to neoadjuvant trastuzumab. Trastuzumab does not seem to alter glucose metabolism substantially enough to afford [18F]FDG-PET significant predictive value in this setting. Although promising in one preclinical model, further studies are required to determine the overall value of [18F]FLT-PET as a biomarker of response to trastuzumab in HER2+ breast cancer.

MeSH Terms (25)

Animals Antibodies, Monoclonal Antibodies, Monoclonal, Humanized Antineoplastic Agents Apoptosis Breast Neoplasms Cell Line, Tumor Cell Proliferation Diagnostic Imaging Dideoxynucleosides Female Fluorine Radioisotopes Fluorodeoxyglucose F18 Glucose Humans Mammary Neoplasms, Experimental Mice Mice, Nude Mice, Transgenic Positron-Emission Tomography Prognosis Receptor, ErbB-2 Reproducibility of Results Trastuzumab Xenograft Model Antitumor Assays

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