Quantification of Tumor Hypoxia through Unsupervised Modelling of Consumption and Supply Hypoxia MR Imaging in Breast Cancer

Abstract

Simple SummaryHypoxia in solid tumors is common in most solid cancers and is associated with treatment resistance to both chemo- and radiation-therapy. There is also reason to believe that hypoxia is an important determinant of metastic disease. Identifying hypoxia in solid tumors is important in treatment planning and decision making. In 2018 Hompland et al. proposed a method, based on quantifying consumption and supply of oxygen from diffusion weighted magnetic resonance imaging, to estimate the hypoxic fraction of a solid tumor. The method was based on training model parameters on a known hypoxia state in prostate cancer. In the present study we verified the validity of the consumption and supply concept in breast cancer. Furthermore, we developed and validated a new approach to the concept that does not require a ground truth to train the parameters.The purpose of the present study is to investigate if consumption and supply hypoxia (CSH) MR-imaging can depict breast cancer hypoxia, using the CSH-method initially developed for prostate cancer. Furthermore, to develop a generalized pan-cancer application of the CSH-method that doesn’t require a hypoxia reference standard for training the CSH-parameters. In a cohort of 69 breast cancer patients, we generated, based on the principles of intravoxel incoherent motion modelling, images reflecting cellular density (apparent diffusion coefficient; ADC) and vascular density (perfusion fraction; fp). Combinations of the information in these images were compared to a molecular hypoxia score made from gene expression data, aiming to identify a way to apply the CSH-methodology in breast cancer. Attempts to adapt previously proposed models for prostate cancer included direct transfers and model parameter rescaling. A novel approach, based on rescaling ADC and fp data to give more nuanced response in the relevant physiologic range, was also introduced. The new CSH-method was validated in a prostate cancer cohort with known hypoxia status. The proposed CSH-method gave estimates of hypoxia that was strongly correlated to the molecular hypoxia score in breast cancer, and hypoxia as measured in pathology slices stained with pimonidazole in prostate cancer. The generalized approach to CSH-imaging depicted hypoxia in both breast and prostate cancers and requires no model training. It is easy to implement using readily available technology and encourages further investigation of CSH-imaging in other cancer entities and in other settings, with the goal being to overcome hypoxia-induced resistance to treatment.