Advisory Committee Chair
Anna Sorace
Advisory Committee Members
Arie Nakhmani
Carlos Cardenas
Jonathan Mcconathy
Mary Kathryn Sewell-Loftin
Document Type
Dissertation
Date of Award
1-1-2025
Degree Name by School
Doctor of Philosophy (PhD) School of Engineering
Abstract
Human epidermal growth factor receptor 2 positive (HER2+) breast cancer is a biologically diverse disease, in which intratumoral heterogeneity plays a significant role in tumor progression. Advanced medical imaging and image processing techniques offer the potential to noninvasively characterize the underlying intratumoral biology. Capturing these complex changes can allow for assessing therapeutic response and eventually guiding personalized therapeutic strategies. This work evaluates single and multiparametric imaging biomarkers to characterize tumor biology, identify treatment-induced changes, and predict response to targeted therapies. First, the utility of 3’-Deoxy-3’-[18F]Fluorothymidine positron emission tomography ([18F]FLT-PET) was assessed as a biomarker of proliferation for monitoring response to combined HER2 and poly-ADP-ribose polymerase (PARP) inhibition. Preclinical studies demonstrated that [18F]FLT-PET detected early changes in cellular proliferation before significant tumor volume alterations. A normalized proliferative threshold was established to isolate proliferative tumor tissue, improving the clinical applicability of proliferation-based response monitoring. Second, a multiparametric PET/MRI-based clustering approach was developed to define physiologically distinct intratumoral habitats. By integrating diffusion weighted (DW)-MRI, dynamic contrast-enhanced (DCE)-MRI, [18F]2-Fluoro-2-deoxy-D-glucose ([18F]FDG), and [18F]FLT-PET data, hierarchical clustering was used to identify treatmentiv induced changes, which include reductions in the volume of hypoxic-treatment responsive zones following trastuzumab therapy. The imaging habitats were found to have significant positive linear correlations with matched histological-based habitat clustering. These findings highlight the potential of multiparametric imaging to capture early response patterns with biological relevance before measurable volumetric changes occur. Finally, [89Zr]Zr-trastuzumab-PET was integrated with DW-MRI to characterize HER2 expression and cellular density in a cohort of metastatic HER2+ breast cancer patients. [89Zr]Zr-trastuzumab-PET uptake was evaluated and reported in normal tissue. Additionally, it was found to be significantly higher in lesions compared to contralateral normal tissue. This multimodal approach improved the predictive performance of HER2- targeted imaging and allowed for intratumoral heterogeneity assessment in brain metastases and lymph node lesions. Multiparametric imaging biomarkers serve as powerful tools for characterizing HER2+ breast cancer. They enable for the characterization of early treatment-induced alterations which can inform on treatment response. The integration of these imagingderived biomarkers into clinical workflows represents a significant step toward enhancing precision oncology and improving patient outcomes for HER2+ breast cancer.
Recommended Citation
Mansur, Ameer, "Evaluating Multiparametric Imaging Biomarkers For Guiding Targeted Therapies In Her2+ Breast Cancer" (2025). All ETDs from UAB. 6867.
https://digitalcommons.library.uab.edu/etd-collection/6867
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