Evaluating treatment response using DW-MRI and DCE-MRI in trastuzumab responsive and resistant HER2-overexpressing human breast cancer xenografts

Jennifer G Whisenant; Anna G Sorace; J Oliver McIntyre; Hakmook Kang; Violeta Sánchez; Mary E Loveless; Thomas E Yankeelov

doi:10.1016/j.tranon.2014.09.011

Evaluating treatment response using DW-MRI and DCE-MRI in trastuzumab responsive and resistant HER2-overexpressing human breast cancer xenografts

Transl Oncol. 2014 Dec;7(6):768-79. doi: 10.1016/j.tranon.2014.09.011.

Authors

Jennifer G Whisenant¹, Anna G Sorace¹, J Oliver McIntyre², Hakmook Kang³, Violeta Sánchez⁴, Mary E Loveless⁵, Thomas E Yankeelov⁶

Affiliations

¹ 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.
² 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.
³ Departments of Biostatistics, Vanderbilt University, 1161 21st Avenue South, Medical Center North, AA-1105, Nashville, TN 37232-2675.
⁴ Departments of Breast Cancer Research Program, Vanderbilt-Ingram Cancer Center, Vanderbilt University, 2220 Pierce Avenue, Nashville, TN 37232-2675.
⁵ Institute of Imaging Science, Vanderbilt University, 1161 21st Avenue South, Medical Center North, AA-1105, Nashville, TN 37232-2675.
⁶ 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; Departments of Physics, Vanderbilt University, 1161 21st Avenue South, Medical Center North, AA-1105, Nashville, TN 37232-2675; Departments of Biomedical Engineering, Vanderbilt University, 1161 21st Avenue South, Medical Center North, AA-1105, Nashville, TN 37232-2675; Departments of Breast Cancer Research Program, Vanderbilt-Ingram Cancer Center, Vanderbilt University, 2220 Pierce Avenue, Nashville, TN 37232-2675. Electronic address: thomas.yankeelov@vanderbilt.edu.

Abstract

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.

Abstract

Grants and funding