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. 2024 Feb;59(2):575-584.
doi: 10.1002/jmri.28774. Epub 2023 May 23.

Detection of Treatment Response in Triple-Negative Breast Tumors to Paclitaxel Using MRI Cell Size Imaging

Xiaoyu Jiang  1   2 , Eliot T McKinley  3 , Jingping Xie  1   2 , John C Gore  1   2   4   5 , Junzhong Xu  1   2   4   5
Affiliations

Detection of Treatment Response in Triple-Negative Breast Tumors to Paclitaxel Using MRI Cell Size Imaging

Xiaoyu Jiang et al. J Magn Reson Imaging. 2024 Feb.

Abstract

Background: Breast cancer treatment response evaluation using the response evaluation criteria in solid tumors (RECIST) guidelines, based on tumor volume changes, has limitations, prompting interest in novel imaging markers for accurate therapeutic effect determination.

Purpose: To use MRI-measured cell size as a new imaging biomarker for assessing chemotherapy response in breast cancer.

Study type: Longitudinal; animal model.

Study population: Triple-negative human breast cancer cell (MDA-MB-231) pellets (4 groups, n = 7) treated with dimethyl sulfoxide (DMSO) or 10 nM of paclitaxel for 24, 48, and 96 hours, and 29 mice with MDA-MB-231 tumors in right hind limbs treated with paclitaxel (n = 16) or DMSO (n = 13) twice weekly for 3 weeks.

Field strength/sequence: Oscillating gradient spin echo and pulsed gradient spin echo sequences at 4.7 T.

Assessment: MDA-MB-231 cells were analyzed using flowcytometry and light microscopy to assess cell cycle phases and cell size distribution. MDA-MB-231 cell pellets were MR imaged. Mice were imaged weekly, with 9, 6, and 14 being sacrificed for histology after MRI at weeks 1, 2, and 3, respectively. Microstructural parameters of tumors/cell pellets were derived by fitting diffusion MRI data to a biophysical model.

Statistical tests: One-way ANOVA compared cell sizes and MR-derived parameters between treated and control samples. Repeated measures 2-way ANOVA with Bonferroni post-tests compared temporal changes in MR-derived parameters. A P-value <0.05 was considered statistically significant.

Results: In vitro experiments showed that the mean MR-derived cell sizes of paclitaxel-treated cells increased significantly with a 24-hours treatment and decreased (P = 0.06) with a 96-hour treatment. For in vivo xenograft experiments, the paclitaxel-treated tumors showed significant decreases in cell size at later weeks. MRI observations were supported by flowcytometry, light microscopy, and histology.

Data conclusions: MR-derived cell size may characterize the cell shrinkage during treatment-induced apoptosis, and may potentially provide new insights into the assessment of therapeutic response.

Level of evidence: 2 TECHNICAL EFFICACY STAGE: 4.

Keywords: breast cancer; cell size; diffusion time; microstructure imaging; oscillating gradient; paclitaxel; treatment response.

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Figures

Figure 1.
Figure 1.
A. Histograms of the emission light intensity of propidium iodide (PI) labelled non-treated and 10 nM paclitaxel treated MDA-MB-231 for different time points. B. Box-and-whisker plots of the cell size measured by light microscopy for non-treated and 10 nM paclitaxel treated MDA-MB-231. For all the Box-and-whisker plots, the 25th-75th percentiles are blocked by the box, the black and red bands inside the box are the median and mean, respectively, and the whiskers mark the SD. ****P<0.0001 as measured by one-way ANOVA with a FDR (False Discovery Rate) posttest.
Figure 2.
Figure 2.
The MR-derived parameters (mean ± standard deviation) for non-treated and 10 nM paclitaxel-treated MDA-MB-231 cell pellets. The sample size of each cohort is 7. ****P<0.0001 as measured by one-way ANOVA with an FDR (False Discovery Rate) posttest.
Figure 3.
Figure 3.
For in vivo experiments, percentage changes in MR-derived parameters for DMSO- and paclitaxel-treated tumors at week 1, 2, and 3. Group means were compared using repeated measures 2-way analysis of variance with Bonferroni posttests. All the p values were False Discovery Rate (FDR) adjusted.
Figure 4.
Figure 4.
Changes in histology-derived cell sizes for DMSO-treated and paclitaxel-treated tumors at weeks 1, 2, and 3.
Figure 5.
Figure 5.
Correlation (Pearson correlation coefficient = 0.78, p < 0.0001) between MR-derived cell sizes and histology-derived cell sizes for all the tumors. The black line represents the identity, while the red line represents the linear regression.
Figure 6.
Figure 6.
Demonstration of tumor cell mitosis, apoptosis, and necrosis in vivo. Macroscopic examination and high power magnification of DAPI, phosphohistone H3 (PH3), and Na/K-ATPase stained sections of a DMSO-treated tumor, 1-week paclitaxel-treated tumor, and a 3-week paclitaxel-treated tumor.
Figure 7.
Figure 7.
Histology-derived apoptotic + necrotic area fractions (Left) and mitotic cell fractions (Right) for DMSO-treated and paclitaxel-treated tumors at week 1, 2, and 3. Group means were compared using repeated measures 2-way analysis of variance with Bonferroni posttests. All the p values were False Discovery Rate (FDR) adjusted.
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