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INTRODUCTION: Precision oncology has informed cancer care by enabling the discovery and application of diagnostic, prognostic, and/or predictive molecular biomarkers. However, many patients lack actionable biomarkers or fail to respond to biomarker-directed therapies. Patient similarity approaches can leverage comprehensive tumor profiling and prior clinical experiences from large cohorts for decision support, facilitating broader realization of precision oncology insights.METHODS: We developed a deep learning-based modeling framework using real-world clinicogenomic data from a tertiary cancer center to (i) measure patient similarity based on embedded tumor genomic profiles and (ii) evaluate the association of derived patient subgroups and neighborhoods with shared therapeutic outcomes in breast cancer-specific and histology-agnostic pan-cancer settings.RESULTS: The model recovered clinically meaningful patient clusters reflecting both expected and previously unknown therapeutic associations, as well as patient-specific neighborhoods that could inform therapeutic trajectories more often than expected by chance in multiple clinical contexts. Moreover, model utility extended to patients without actionable genomic biomarkers and those with cancer of unknown primary (CUP) diagnoses, where neighborhoods aligned with independently predicted primary cancer type. These neighborhoods could also be examined over time in a continuously learning scenario.CONCLUSION: This similarity-based modeling framework distilled complex molecular and clinical data into concise, context-specific insights that augment clinician judgment, providing a foundation for a real-time learning, patient-centered decision support model in precision oncology.