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Intratumoral heterogeneity after targeted therapy in murine cancer models with differing degrees of malignancy
M Gerwing1, E Hoffmann1, C Geyer1
1Clinic of Radiology, University of Münster, Münster, Germany.
Introduction:
Conventional morphologic and volumetric assessment of treatment response is not suitable for adequately assessing responses to targeted cancer therapy. The aim of this study was to evaluate changes in tumor composition after targeted therapy in murine models of breast cancer with differing degrees of malignancy via non-invasive magnetic resonance imaging (MRI).
Materials And Methods:
Mice bearing highly malignant 4T1 tumors or low malignant 67NR tumors were treated with either a combination of two immune checkpoint inhibitors (ICI, anti-PD1 and anti-CTLA-4) or the multi-tyrosine kinase inhibitor sorafenib, following experiments with macrophage-depleting clodronate-loaded liposomes and vessel-stabilizing angiopoietin-1. Mice were imaged on a 9.4 T small animal MRI system with a multiparametric (mp) protocol, comprising T1 and T2 mapping and diffusion-weighted imaging. Tumors were analyzed ex vivo with histology.
Results And Discussions:
All treatments led to an increase in non-viable areas, but therapy-induced intratumoral changes differed between the two tumor models and the different targeted treatments. While ICI treatment led to intratumoral hemorrhage, sorafenib treatment mainly induced intratumoral necrosis. Treated 4T1 tumors showed increasing and extensive areas of necrosis, in comparison to 67NR tumors with only small, but also increasing, necrotic areas. After either of the applied treatments, intratumoral heterogeneity, was increased in both tumor models, and confirmed ex vivo by histology. Apparent diffusion coefficient with subsequent histogram analysis proved to be the most sensitive MRI sequence. In conclusion, mp MRI enables to assess dedicated therapy-related intratumoral changes and may serve as a biomarker for treatment response assessment.
Insights
Multiparametric MRI effectively detects changes in tumor composition after targeted cancer therapy. This advanced imaging technique reveals distinct treatment responses, including necrosis and hemorrhage, aiding in assessing treatment efficacy.
Area of Science:
- Oncology
- Radiology
- Biomedical Imaging
Background:
- Conventional methods for assessing cancer treatment response are insufficient for targeted therapies.
- Targeted cancer therapies require advanced imaging techniques to evaluate treatment efficacy.
- Tumor composition changes are critical indicators of response to targeted cancer treatments.
Purpose of the Study:
- To evaluate intratumoral composition changes in murine breast cancer models after targeted therapy using non-invasive magnetic resonance imaging (MRI).
- To compare the efficacy of immune checkpoint inhibitors (ICI) and sorafenib in altering tumor characteristics.
- To assess the utility of multiparametric MRI in detecting therapy-induced changes in tumors with varying malignancy.
Main Methods:
- Utilized murine models with highly malignant (4T1) and low malignant (67NR) breast tumors.
- Administered treatments including immune checkpoint inhibitors (ICI) and sorafenib.
- Employed a multiparametric (mp) MRI protocol (T1/T2 mapping, diffusion-weighted imaging) on a 9.4 T small animal MRI system.
- Correlated MRI findings with ex vivo histological analysis.
Main Results:
- All treatments increased non-viable tumor areas, with distinct patterns between tumor models and therapies.
- ICI treatment induced intratumoral hemorrhage, while sorafenib primarily caused necrosis.
- Treated 4T1 tumors exhibited extensive necrosis, whereas 67NR tumors showed smaller necrotic areas.
- Intratumoral heterogeneity increased in both models post-treatment, confirmed by histology.
- Apparent diffusion coefficient histogram analysis emerged as the most sensitive MRI metric.
Conclusions:
- Multiparametric MRI can accurately assess therapy-related intratumoral changes.
- mp MRI shows potential as a biomarker for evaluating targeted cancer therapy response.
- Distinct intratumoral changes observed with different targeted treatments highlight the need for tailored imaging assessments.
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