Jennifer G. Whisenant

Amide proton transfer imaging of the breast at 3 T: Establishing reproducibility and possible feasibility assessing chemotherapy response

Chemical exchange saturation transfer imaging can generate contrast that is sensitive to amide protons associated with proteins and peptides (termed amide proton transfer, APT). In breast cancer, APT contrast may report on underlying changes in microstructural tissue composition. However, to date, there have been no developments or applications of APT chemical exchange saturation transfer to breast cancer. As a result, the aims of this study were to (i) experimentally explore optimal scan parameters for breast chemical exchange saturation transfer near the amide resonance at 3 T, (ii) establish the reliability of APT imaging of healthy fibroglandular tissue, and (iii) demonstrate preliminary results on APT changes in locally advanced breast cancer observed during the course of neoadjuvant chemotherapy. Chemical exchange saturation transfer measurements were experimentally optimized on cross‐linked bovine serum albumin phantoms, and the reliability of APT imaging was assessed in 10 women with no history of breast disease. The mean difference between test–retest APT values was not significantly different from zero, and the individual difference values were not dependent on the average APT value. The 95% confidence interval limits were ±0.70% (α = 0.05), and the repeatability was 1.91. APT measurements were also performed in three women before and after one cycle of chemotherapy. Following therapy, APT increased in the one patient with progressive disease and decreased in the two patients with a partial or complete response. Together, these results suggest that APT imaging may report on treatment response in these patients. Magn Reson Med, 2013.

A quantitative comparison of the influence of individual versus population-derived vascular input functions on dynamic contrast enhanced-MRI in small animals

For quantitative analysis of dynamic contrast enhanced magnetic resonance imaging data, the time course of the concentration of the contrast agent in the blood plasma, or vascular input function (VIF), is required. We compared pharmacokinetic parameters derived using individual and population‐based VIFs in mice for two different contrast agents, gadopentetate dimeglumine and P846. Eleven mice with subcutaneous 4T1 breast cancer xenografts were imaged at 7 T. A precontrast T1 map was acquired along with dynamic T1‐weighted gradient echo images before, during, and after a bolus injection of contrast agent delivered via a syringe pump. Each animals individual VIF and derived population‐averaged VIF were used to extract parameters from the signal‐time curves of tumor tissue at both the region of interest and voxel level. The results indicate that for both contrast agents, Ktrans values estimated using population‐averaged VIF have a high correlation (concordance correlation coefficient > 0.85) with Ktrans values estimated using individual VIF on both a region of interest and voxel level. This work supports the validity of using of a population‐based VIF with a stringent injection protocol in preclinical dynamic contrast enhanced magnetic resonance imaging studies. Magn Reson Med, 2011.

Practical Dynamic Contrast Enhanced MRI in Small Animal Models of Cancer: Data Acquisition, Data Analysis, and Interpretation

Dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) consists of the continuous acquisition of images before, during, and after the injection of a contrast agent. DCE-MRI allows for noninvasive evaluation of tumor parameters related to vascular perfusion and permeability and tissue volume fractions, and is frequently employed in both preclinical and clinical investigations. However, the experimental and analytical subtleties of the technique are not frequently discussed in the literature, nor are its relationships to other commonly used quantitative imaging techniques. This review aims to provide practical information on the development, implementation, and validation of a DCE-MRI study in the context of a preclinical study (though we do frequently refer to clinical studies that are related to these topics).

Assessing the reproducibility of dynamic contrast enhanced magnetic resonance imaging in a murine model of breast cancer

Quantitative dynamic contrast enhanced magnetic resonance imaging estimates parameters related to tissue vascularity and volume fractions; additionally, semiquantitative parameters such as the initial area under the curve can be utilized to describe tissue behavior. The aim of this study was to establish the reproducibility of quantitative and semiquantitative analysis of dynamic contrast enhanced magnetic resonance imaging in a murine model of breast cancer. For each animal, a T1‐weighted, gradient‐echo sequence was used to acquire two sets of dynamic contrast enhanced magnetic resonance imaging data separated by 5 h. Data were acquired at both a 0.05 mm3 (1282, n = 12) and a 0.2 mm3 (642, n = 12) resolution, and analysis was performed using both the Tofts–Kety (to estimate Ktrans and ve) and extended Tofts–Kety (Ktrans, ve, and vp) models. Reproducibility analysis was performed for both the center slice and the total tumor volume for all parameters. For the total volume analysis, the repeatability index for Ktrans is 0.073 min−1 in the standard model analysis and 0.075 min−1 in the extended model analysis at the 1282 acquisition. For the 642 acquisition, the values are 0.089 and 0.063 min−1 for the standard and extended models, respectively. The repeatability index for initial area under the curve was 0.0039 and 0.0042 mM min for the 1282 and 642 acquisitions, respectively. Magn Reson Med, 2013.

Assessing reproducibility of diffusion-weighted magnetic resonance imaging studies in a murine model of HER2+ breast cancer.

BACKGROUND AND PURPOSE The use of diffusion-weighted magnetic resonance imaging (DW-MRI) as a surrogate biomarker of response in preclinical studies is increasing. However, before a biomarker can be reliably employed to assess treatment response, the reproducibility of the technique must be established. There is a paucity of literature that quantifies the reproducibility of DW-MRI in preclinical studies; thus, the purpose of this study was to investigate DW-MRI reproducibility in a murine model of HER2+ breast cancer. MATERIALS AND METHODS Test-Retest DW-MRI scans separated by approximately six hours were acquired from eleven athymic female mice with HER2+ xenografts using a pulsed gradient spin echo diffusion-weighted sequence with three b values [150, 500, and 800s/mm(2)]. Reproducibility was assessed for the mean apparent diffusion coefficient (ADC) from tumor and muscle tissue regions. RESULTS The threshold to reflect a change in tumor physiology in a cohort of mice is defined by the 95% confidence interval (CI), which was±0.0972×10(-3)mm(2)/s (±11.8%) for mean tumor ADC. The repeatability coefficient defines this threshold for an individual mouse, which was±0.273×10(-3)mm(2)/s. The 95% CI and repeatability coefficient for mean ADC of muscle tissue were±0.0949×10(-3)mm(2)/s (±8.30%) and±0.266×10(-3)mm(2)/s, respectively. CONCLUSIONS Mean ADC of tumors is reproducible and appropriate for detecting treatment-induced changes on both an individual and mouse cohort basis.

Correlation of tumor characteristics derived from DCE-MRI and DW-MRI with histology in murine models of breast cancer

The purpose of this work was to determine the relationship between the apparent diffusion coefficient (ADC, from diffusion‐weighted (DW) MRI), the extravascular, extracellular volume fraction (ve, from dynamic contrast‐enhanced (DCE) MRI), and histological measurement of the extracellular space fraction.

Coregistration of ultrasonography and magnetic resonance imaging with a preliminary investigation of the spatial colocalization of vascular endothelial growth factor receptor 2 expression and tumor perfusion in a murine tumor model

We present an ultrasonography (US)-magnetic resonance imaging (MRI) coregistration technique and examine its application in a preliminary multimodal, multiparametric study in a preclinical model of breast cancer. Nine mice were injected with 67NR breast cancer cells and imaged 6 and 9 days later with 4.7 T MRI and high-frequency US. Tumor volumes from each data set were segmented independently by two investigators and coregistered using an iterative closest point algorithm. In addition to anatomic images, vascular endothelial growth factor receptor 2 (VEGFR2) distribution images from the central tumor slice using VEGFR2-targeted ultrasound contrast agent (UCA) and measurements of perfusion and extravascular-extracellular volume fraction using dynamic contrast-enhanced MRI were acquired from five mice for multiparametric coregistration. Parametric maps from each modality were coregistered and examined for spatial correlation. Average registration root mean square (RMS) error was 0.36 ± 0.11 mm, less than approximately two voxels. Segmented volumes were compared between investigators to minimize interobserver variability; the average RMS error was 0.23 ± 0.09 mm. In the preliminary study, VEGFR2-targeted UCA data did not demonstrate direct spatial correlation with magnetic resonance measures of vascular properties. In summary, a method for accurately coregistering small animal US and MRI has been presented that allows for comparison of quantitative metrics provided by the two modalities.

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

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, Ktrans, 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 Ktrans 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.

MR Imaging Biomarkers in Oncology Clinical Trials

The authors discuss eight areas of quantitative MR imaging that are currently used (RECIST, DCE-MR imaging, DSC-MR imaging, diffusion MR imaging) in clinical trials or emerging (CEST, elastography, hyperpolarized MR imaging, multiparameter MR imaging) as promising techniques in diagnosing cancer and assessing or predicting response of cancer to therapy. Illustrative applications of the techniques in the clinical setting are summarized before describing the current limitations of the methods.

Ensartinib (X-396) in ALK-Positive Non–Small Cell Lung Cancer: Results from a First-in-Human Phase I/II, Multicenter Study

Purpose: Evaluate safety and determine the recommended phase II dose (RP2D) of ensartinib (X-396), a potent anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI), and evaluate preliminary pharmacokinetics and antitumor activity in a first-in-human, phase I/II clinical trial primarily in patients with non–small cell lung cancer (NSCLC). Patients and Methods: In dose escalation, ensartinib was administered at doses of 25 to 250 mg once daily in patients with advanced solid tumors; in dose expansion, patients with advanced ALK-positive NSCLC were administered 225 mg once daily. Patients who had received prior ALK TKI(s) and patients with brain metastases were eligible. Results: Thirty-seven patients enrolled in dose escalation, and 60 enrolled in dose expansion. The most common treatment-related toxicities were rash (56%), nausea (36%), pruritus (28%), vomiting (26%), and fatigue (22%); 23% of patients experienced a treatment-related grade 3 to 4 toxicity (primarily rash and pruritus). The maximum tolerated dose was not reached, but the RP2D was chosen as 225 mg based on the frequency of rash observed at 250 mg without improvement in activity. Among the ALK-positive efficacy evaluable patients treated at ≥200 mg, the response rate (RR) was 60%, and median progression-free survival (PFS) was 9.2 months. RR in ALK TKI-naïve patients was 80%, and median PFS was 26.2 months. In patients with prior crizotinib only, the RR was 69% and median PFS was 9.0 months. Responses were also observed in the central nervous system, with an intracranial RR of 64%. Conclusions: Ensartinib was active and generally well tolerated in patients with ALK-positive NSCLC. Clin Cancer Res; 24(12); 2771–9. ©2018 AACR.