Advanced PET/MRI to quantify heterogeneity of HER2 and vasculature in HER2+ breast-to-brain metastasis prior to combination targeted and radiotherapy - Project Summary The overall goal of this proposal is to integrate advanced molecular imaging of HER2 expression and vascularity to assess treatment response to radiation following quantification of targeted HER2 bioavailability and heterogeneity in HER2+ breast-to-brain metastasis. HER2+ breast cancer has a higher incidence of brain metastases compared to other breast cancer subtypes. Patients with HER2+ breast cancer are 2-4 times more likely to develop metastases to the central nervous system compared to HER2-negative patients. Quantitative imaging provides the opportunity to evaluate intratumoral subregions of variable response and discordance of underlying biology between metastatic tumors. Furthermore, molecular imaging of HER2 with [89Zr]trastuzumab-position emission tomography (PET) with simultaneous quantification of vascular perfusion (Ktrans) from dynamic contrast enhanced (DCE)- magnetic resonance imaging (MRI) provides an opportunity be able to noninvasively quantify the spatial delivery of trastuzumab into brain lesions prior to radiation and systemic targeted therapy. New preliminary results reveal that trastuzumab can increase vascular delivery and decrease hypoxia in preclinical models of breast cancer, which can be longitudinally monitored by advanced imaging techniques and improve effects of radiation and chemotherapy. Furthermore, noninvasive imaging using [89Zr]trastuzumab-PET in HER2+ breast cancer has shown us that we can assess inter- and intra- tumoral heterogeneity in both preclinical and clinical cancer. In preclinical models of HER2+ primary disease, HER2 heterogeneity and expression correlate with response to cytotoxic therapies. The overarching hypothesis is that advanced imaging with PET/MRI can characterize underlying initial conditions in the tumor microenvironment on a personalized basis to provide biological evidence of intratumoral heterogeneity and delivery of systemic targeted therapies, providing surrogate information to predict treatment response to combination therapies in HER2+ breast-to-brain metastasis. To test this hypothesis, we’ve identified the following specific aims: 1) Quantify HER2+ expression and vasculature to assess bioavailability of trastuzumab in patients with HER2+ breast-to-brain metastasis and 2) Quantify intratumoral heterogeneity of brain lesions and discordance of HER2 heterogeneity in metastatic lesions in patients with HER2+ breast-to-brain metastasis. This translational approach to personalize, guide, and predict response to combination treatments in HER2+ breast- to-brain metastasis will provide an advanced, and noninvasive approach to improve patient outcomes in a patient population with dire need of improved treatment strategies.
