Exploring tumor heterogeneity: The role of PET/CT with various radiopharmaceuticals in diagnosis and treatment guidance

Cancer development is a multi-step process that undergoes multiple alterations over time. The tumor microenvironment (TME) contains tumor cells and stroma, including blood cells, fibroblasts, and immune cells, which undergo spatial and temporal changes. These changes contribute to tumor heterogeneity, leading to treatment failure and poor prognosis. As we move toward personalized medicine with the approval of targeted and other therapies, identifying tumor heterogeneity is becoming crucial to management. Positron emission tomography/computed tomography (PET/CT) with various radiopharmaceuticals plays an important role in diagnosing and highlighting heterogeneity non-invasively, guiding treatment decisions, and assessing treatment response. Variability in tracer distribution of 18F-fluorodeoxyglucose (FDG) and various radiopharmaceuticals when coupled together can target various tumor characteristics and, therefore, play an important role in diagnosing heterogeneity. Some of the commonly paired radiopharmaceuticals include 18F-FDG with 68Gallium DOTA (1,4,7,10-tetraazacyclododecane-tetraacetic acid) peptide for neuroendocrine tumors, 18F-FDG with 68Ga-prostate specific membrane antigen for prostate cancers, 18F-metafluorobenzylguanidine with 18F-FDG and 68Ga-DOTA peptide for neural crest tumors, and 18F-fluoroestradiol with 18F-FDG for breast cancers. Many other tracers, including 68Ga-fibroblast activation protein inhibitor and labeled integrins, attach to various components on tumor cells and TME and have displayed significantly positive effects in certain tumors. However, their potential role as a biomarker to evaluate tumor heterogeneity and its clinical relevance remains largely uninvestigated.