Quantitative characterization of tumor heterogeneity in breast cancer in vivo




Syed, Anum Kamal

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Tumor heterogeneity provides a major challenge for the clinical treatment of breast cancer and is associated with poor patient prognosis and treatment failure. Heterogeneity of the tumor microenvironment and cancer cell phenotypes can result in nonuniform drug delivery and varying tumor response. The purpose of this dissertation is to develop novel methods for the quantitative characterization of tumor heterogeneity using noninvasive imaging, and then employ these methods to measure longitudinal changes in intratumoral heterogeneity in response to treatment. This objective is addressed in three parts. First, in a murine xenograft model of HER2+ breast cancer, we quantify temporal alterations of vascular, cellular, and hypoxic heterogeneity in response to the HER2 targeted therapy, trastuzumab. The results indicate that trastuzumab induces longitudinal increases in cellular and vascular heterogeneity, and longitudinal decreases hypoxic heterogeneity. Second, using multiparametric MRI data, we identify physiologically-distinct tumor habitats in two preclinical models of breast cancer, and measure the changes in tumor composition over time, in response to targeted or cytotoxic therapy. We identify tumor habitats associated with treatment response in both models of breast cancer and provide biological validation of the identified habitats using immunohistochemistry. Finally, in an effort to elucidate intertumoral heterogeneity, we utilize tumor habitats to classify HER2+ xenograft tumors into two tumor imaging phenotypes at baseline and measure the longitudinal response of each phenotype to targeted and cytotoxic therapies. The two tumor phenotypes progress and respond to therapeutic intervention differently, as one phenotype demonstrates more “therapy-sensitive” behavior, with significant decreases in tumor volume and increases in low-vascularity low-cellularity habitats in response to treatment. Overall, our results offer a novel methodology to quantify the spatiotemporal alterations in intratumoral heterogeneity in response to therapeutic intervention using clinically-translatable imaging technologies.


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