Targeted and immunotherapies have transformed melanoma care, extending median survival from ~9 to over 25 months but nevertheless, most patients still die of their disease. The aim of precision medicine is to tailor care for individual patients and improve outcomes. To this end we developed protocols to facilitate individualized treatment decisions for advanced melanoma patients, analyzing 364 samples from 214 patients. Whole exome sequencing (WES) and targeted sequencing of circulating tumor

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... A (ctDNA) allowed us to monitor responses to therapy and to identify and then follow mechanisms of resistance. WES of tumors revealed potential hypothesisdriven therapeutic strategies for BRAF wild-type and inhibitor-resistant BRAF mutant tumors, which were then validated in patient-derived xenografts (PDXs). We also developed circulating tumor cell-derived xenografts (CDX) as an alternative to PDXs when tumors were inaccessible or difficult to biopsy. Thus, we describe a powerful technology platform for precision medicine of melanoma patients. SIGNIFICANCE Although recent developments have revolutionized melanoma care, most patients still die of their disease. To improve melanoma outcomes further, we developed a powerful precision medicine platform to monitor patient responses, and to identify and validate hypothesis-driven therapies for patients who do not respond, or who develop resistance to current treatments.