Abstract Introduction: Amid a surging trend in patient engagement in cancer research and the broader cultural shift toward self-advocacy and technology adaptation in healthcare, this study reports findings from a patient-partnered project investigating the mechanistic underpinnings of metastatic uveal melanoma (UM) progression. Methods: The patient consented voluntarily on IRB-approved protocols under PRISM, a patient-centered research program overseen by The Rare Cancer Research Foundation. Sample collection, processing and distribution for advanced testing was done in collaboration with multiple academic treatment centers and empowered by Pattern.org biologistics and biobanking services. Advanced molecular diagnostic testing was performed on samples collected over a 2 year period from multiple lesion locations, including longitudinal WES/RNA-seq, proteomics, multiplexIF staining, and organoid drug testing. Response to treatment was monitored using longitudinal PET/CT imaging with individual lesion tracking using Mint Medical software, and minimal residual disease monitoring using SignateraTM cell-free DNA testing. All clinical and research data was integrated into the Pattern.org Data Commons (PDC) for downstream analysis. Results: This patient presented with metastatic UM, initial sequencing revealed germline POT1 (Arg363) and somatic GNAQ (Q20P) and BAP1 (E398, LOF) genetic alterations. Organoid-based drug screening results did not reveal any obvious drug sensitivities to targeted treatment options. The patient experienced disease stabilization with minimal toxicity for 6 months while receiving Pembro/Ipi and an endogenous T Cell therapy. During the course of stable disease, longitudinal sequencing revealed consistent genetic alterations across timepoints and multiple lesion samples. Upon disease progression, defined by increased volumetric measurements in tumor size and increased circulating tumor cfDNA, a new EZH2 (Y641H) variant was identified using WES. Differential variant calling and gene expression analysis collected from samples before and after disease progression highlighted potential resistant mechanisms to immune-based therapies. Further, a comparative study on the tumor microenvironment using multiplex IF staining sheds additional insight into the complexities of UM metastasis and disease progression. Conclusion: This patient-driven study utilizing multi-omic disease characterization and longitudinal monitoring illuminates immune therapy resistance mechanisms and tumor microenvironment complexities in UM metastasis. Citation Format: Amber Smith, Ben Kamphaus, Katie Campbell, Robin Kageyama, Benjamin G. Vincent, Christopher Heery, Christine N. Spencer, Marshall Thompson. Patient-driven multi-omic longitudinal research study reveals novel insights into uveal melanoma progression abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2514.
Smith et al. (Fri,) studied this question.