Measured intrapatient radiomic variability as a predictor of treatment response in multi-metastatic soft tissue sarcoma patients.

Radiomics offers a non-invasive approach to tumor characterization, yet its application in metastatic cancers is limited by intertumor heterogeneity-variability in radiomic phenotypes across lesions within the same patient. We introduce Measured Intrapatient Radiomic Variability (MIRV), a novel metric quantifying heterogeneity using standard-of-care imaging. Applied to 397 metastatic soft-tissue sarcoma patients from the SARC021 trial, MIRV was calculated from pretreatment CT scans using pairwise Euclidean distance and cosine dissimilarity between lesions. Euclidean distance captures absolute differences in radiomic features, while cosine dissimilarity assesses variation in feature patterns independent of magnitude. Higher MIRV correlated with greater variability in tumor-specific response classification and volumetric response, independent of baseline tumor volume. In a subset with liquid biopsy data, MIRV showed a moderate association with ctDNA positivity, suggesting links to molecular heterogeneity. While MIRV was not prognostic for overall survival in the full cohort, higher MIRV was significantly associated with worse survival in leiomyosarcoma patients (n = 165, p = 0.007, FDR = 0.06). These findings establish MIRV as a biomarker for intertumor heterogeneity, with potential to predict mixed treatment responses and guide personalized therapy in metastatic STS. Future studies should assess its relevance across other tumor types and therapeutic settings.