Optical imaging markers of breast cancer treatment response and resistance

Abstract

Breast cancer is currently projected to affect 1 in 8 women in the US over the course of their lifetime with more than 40,000 deaths in 2022. While there has been significant improvement in patient outcomes, the ongoing challenge of highly heterogeneous breast cancer responses to therapeutics, combined with the increasing array of agents and dosing regimens, highlights the importance of tools that can assist oncologists in monitoring and adapting regimens to improve outcomes. Non-invasive imaging modalities can provide valuable prognostic feedback by longitudinally tracking the functional and metabolic characteristic of tumors. This work focuses on a platform of three imaging modalities to investigate breast cancer response and progression in different models of different length scales from humans to mice to 3D spheroids. This dissertation will highlight two Diffuse Optical Imaging (DOI) techniques: Diffuse Optical Spectroscopic Imaging (DOSI) and Spatial Frequency Domain Imaging (SFDI) and a microscopy technique: Fluorescence Lifetime Imaging Microscopy (FLIM). The preclinical setting, and in particular, in vitro models provide the unique advantage of controlling for biological heterogeneity compared to the clinical setting. In this setting, FLIM can measure the autofluorescence of key enzymatic metabolites and quantify levels of oxidative phosphorylation (OXPHOS) compared to glycolysis. A preliminary study demonstrated that FLIM could discriminate between non-invasive vs invasive breast cancer spheroids embedded in collagen and the metabolic profile was modulated by the density of the collagen. DOI techniques utilize near-infrared light to probe tissue and can quantify the optical absorption and scattering of tissue. These optical properties can be used to determine hemodynamic and cellular growth information about tissue and tumors. SFDI can provide widefield optical properties of tumors with a penetration depth of several millimeters making it the ideal imaging modality for tracking murine breast tumors. A major advantage of utilizing a murine breast cancer model is being able to study tumors in a living organism while controlling for both subject and tumor diversity. A study was conducted that confirmed SFDI derived optical scattering served as a prognostic biomarker to discriminate between a paired immunoresponsive and immunoresistant murine breast cancer model. Finally, DOSI is a clinical instrument that can provide point optical properties with a depth sensitivity of a few centimeters making this the ideal instrument for monitoring breast tumors in breast cancer patients. A large, multi-center clinical trial demonstrated that a large tumor oxyhemoglobin increase is a strong prognostic biomarker of treatment response as soon as the first day after treatment onset and the manifestation of the biomarker strongly depending on the specific treatment regimen the patients received. In summary, this dissertation demonstrates the rich diversity of information that can be discovered through these imaging techniques. These multiscale imaging modalities can provide a translational platform for discoveries to move from cells to animal and ultimately validation in humans.2023-07-16T00:00:00