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SMMART is a precision medicine research program focused on understanding the evolution of actionable biology and mechanisms of resistance in human tumors during therapy. This is accomplished through in depth functional, ‘omic and multiscale image analysis of longitudinal samples acquired during treatment. Here we present a case report detailing the insights that can be gained from the comparative analysis of pre- and post-treatment biopsy specimens in a late-stage metastatic breast cancer patient. To understand the molecular evolution of cancer, we interrogated genomics with targeted and whole exome sequencing, transcriptomics with RNA and gene-fusion sequencing, and proteomics with reverse phase protein arrays. To understand cellular organization and architectural changes, we employed multi-scale imaging tools, including scanning electron microscopy (SEM), cyclic immunofluorescence, immune cell profiling with cyclic immunohistochemistry, and traditional pathological assessment. During the course of treatment, we monitored patient response to therapy with clinical imaging, circulating tumor DNA sequencing and cancer protein assessment. Individual assays revealed key aspects of how this individual9s cancer evolved under therapeutic pressure. For example, mutational profiling revealed the patterns of clonal evolution and the acquisition of new genetic driver events. 2D and 3D SEM showed changes in ECM organization, macropinocytosis, mitochondrion size, number and density and number and organization of filopodia-like protrusions. We used a 30-color cyclic immunofluorescence analysis to identify differences in cancer cell proliferation and differentiation state, as well as the composition and organization of infiltrating immune cells. In addition, integrative analyses of multiple data types provided insight into the evolution of actionable biology within this patient9s disease. This included changes in the suitability of the patient for immune checkpoint inhibitors as well as specific tyrosine kinase inhibitors. The comprehensive molecular and architectural characterization of an individual patient9s cancer at multiple time points provides biologically novel and clinically relevant insight into the ways in which cancers become resistant to treatment. Citation Format: Brett Johnson, Jamie Keck, Max Morris, Kiara Siex, Annette Kolodzie, Swapnil Parmar, Jessica Riesterer, Koei Chin, Summer Gibbs, Laura Heiser, Paul Spellman, Kyle Ellrott, Ozgun Babur, Emek Demir, Adam Margolin, Jeremy Goecks, Lisa Coussens, Raymond Bergan, Joe Gray. SMMART: Serial measurements of molecular and architectural responses to therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3296.