Imaging biomarkers predict response to anti-HER2 (ErbB2) therapy in preclinical models of breast cancer.
Imaging biomarkers predict response to anti-HER2 (ErbB2) therapy in preclinical models of breast cancer.
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DOI：
10.1158/1078-0432.ccr-08-2635
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发表时间：
2009-07-15
期刊：
影响因子：
--
通讯作者：
Manning HC
中科院分区：
文献类型：
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作者：
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
在HER2过表达乳腺癌的小鼠模型中，评价非侵入性成像方法作为曲妥珠单抗反应的预测生物标志物。在有反应和无反应的荷瘤队列中，纵向评估肿瘤消退与细胞凋亡、葡萄糖代谢和细胞增殖的分子成像的相关性。将MMTV/HER2转基因雌性小鼠的乳腺肿瘤移植到同基因雌性小鼠体内。将人乳腺癌细胞株BT474移植于裸鼠体内。肿瘤细胞凋亡(NIR700-Annexin-V蓄积)、葡萄糖代谢([18F]FDG-PET)和增殖([18F]Flt-PET)在两周曲妥珠单抗方案中被评估。通过直接测量肿瘤大小和裂解caspase-3、磷酸化AKT(p-AKT)和Ki67的免疫组织化学(IHC)分析来验证成像指标。NIR700-Annexin-V在曲妥珠单抗治疗的MMTV/HER2和BT474肿瘤中显著积聚，这些肿瘤最终消退，但在无反应或赋形剂治疗的肿瘤中没有。曲妥珠单抗治疗不影响MMTV/HER2或BT474肿瘤对[18F]FDG的摄取。[18F]Flt PET成像可预测BT474肿瘤中曲妥珠单抗的反应，但不能预测MMTV/HER2肿瘤中的曲妥珠单抗反应，后者表现出对[18F]Flt的适度摄取。在成像指标和IHC分析之间观察到了密切的一致性。细胞凋亡的分子成像准确地预测了曲妥珠单抗诱导的HER2(+)肿瘤的消退，并可能值得临床探索以预测新辅助曲妥珠单抗的早期反应。在这种情况下，曲妥珠单抗似乎不能显著改变葡萄糖代谢，不足以提供[18F]FDG-PET显着的预测价值。虽然在一个临床前模型中很有希望，但还需要进一步的研究来确定[18F]Flt-PET作为曲妥珠单抗治疗HER2+乳腺癌的生物标记物的整体价值。
To evaluate non-invasive 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 non-responding tumor-bearing cohorts. 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 ([18F]FDG-PET), and proliferation ([18F]FLT-PET) were evaluated throughout a bi-weekly trastuzumab regimen. Imaging metrics were validated by direct measurement of tumor size and immunohistochemical (IHC) analysis of cleaved caspase-3, phosphorylated AKT (p-AKT) and Ki67. NIR700-Annexin-V accumulated significantly in trastuzumab-treated MMTV/HER2 and BT474 tumors that ultimately regressed, but not in non-responding 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 IHC analysis. 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 appear 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.