Whisenant Jennifer G, Sorace Anna G, McIntyre J Oliver, Kang Hakmook, Sánchez Violeta, Loveless Mary E, Yankeelov Thomas E
Institute of Imaging Science, Vanderbilt University, 1161 21st Avenue South, Medical Center North, AA-1105, Nashville, TN 37232-2675; Departments of Radiology and Radiological Sciences, Vanderbilt University, 1161 21st Avenue South, Medical Center North, AA-1105, Nashville, TN 37232-2675.
Institute of Imaging Science, Vanderbilt University, 1161 21st Avenue South, Medical Center North, AA-1105, Nashville, TN 37232-2675; Departments of Radiology and Radiological Sciences, Vanderbilt University, 1161 21st Avenue South, Medical Center North, AA-1105, Nashville, TN 37232-2675; Departments of Cancer Biology, Vanderbilt University, 1161 21st Avenue South, Medical Center North, AA-1105, Nashville, TN 37232-2675.
Transl Oncol. 2014 Dec;7(6):768-79. doi: 10.1016/j.tranon.2014.09.011.
We report longitudinal diffusion-weighted magnetic resonance imaging (DW-MRI) and dynamic contrast enhanced (DCE)-MRI (7 T) studies designed to identify functional changes, prior to volume changes, in trastuzumab-sensitive and resistant HER2+ breast cancer xenografts. Athymic mice (N = 33) were subcutaneously implanted with trastuzumab-sensitive (BT474) or trastuzumab-resistant (HR6) breast cancer cells. Tumor-bearing animals were distributed into four groups: BT474 treated and control, HR6 treated and control. DW- and DCE-MRI were conducted at baseline, day 1, and day 4; trastuzumab (10 mg/kg) or saline was administered at baseline and day 3. Animals were sacrificed on day 4 and tumors resected for histology. Voxel-based DW- and DCE-MRI analyses were performed to generate parametric maps of ADC, K(trans), and ve. On day 1, no differences in tumor size were observed between any of the groups. On day 4, significant differences in tumor size were observed between treated vs. control BT474, treated BT474 vs. treated HR6, and treated vs. control HR6 (P < .0001). On day 1, ve was significantly higher in the BT474 treated group compared to BT474 control (P = .002) and HR6 treated (P = .004). On day 4, ve and K(trans) were significantly higher in the treated BT474 tumors compared to BT474 controls (P = .0007, P = .02, respectively). A significant decrease in Ki67 staining reinforced response in the BT474 treated group compared to BT474 controls (P = .02). This work demonstrated that quantitative MRI biomarkers have the sensitivity to differentiate treatment response in HER2+ tumors prior to changes in tumor size.
我们报告了纵向扩散加权磁共振成像（DW-MRI）和动态对比增强（DCE）-MRI（7T）研究，旨在识别曲妥珠单抗敏感和耐药的HER2+乳腺癌异种移植瘤在体积变化之前的功能变化。无胸腺小鼠（N = 33）皮下植入曲妥珠单抗敏感（BT474）或曲妥珠单抗耐药（HR6）乳腺癌细胞。荷瘤动物分为四组：BT474治疗组和对照组、HR6治疗组和对照组。在基线、第1天和第4天进行DW-MRI和DCE-MRI检查；在基线和第3天给予曲妥珠单抗（10mg/kg）或生理盐水。在第4天处死动物，切除肿瘤进行组织学检查。进行基于体素的DW-MRI和DCE-MRI分析以生成表观扩散系数（ADC）、容积转运常数（K(trans)）和血管外细胞外容积分数（ve）的参数图。在第1天，任何组之间均未观察到肿瘤大小的差异。在第4天，治疗的BT474与对照BT474、治疗的BT474与治疗的HR6以及治疗的与对照的HR6之间观察到肿瘤大小的显著差异（P <.0001）。在第1天，与BT474对照组（P =.002）和HR6治疗组（P =.004）相比，BT474治疗组的ve显著更高。在第4天，与BT474对照组相比，治疗的BT474肿瘤中的ve和K(trans)显著更高（分别为P =.0007，P =.02）。与BT474对照组相比，BT474治疗组中Ki67染色的显著降低增强了反应（P =.02）。这项工作表明，定量MRI生物标志物在肿瘤大小改变之前对区分HER2+肿瘤的治疗反应具有敏感性。
