Abstract
Targeted therapies 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 patients with advanced melanoma, analyzing 364 samples from 214 patients. Whole exome sequencing (WES) and targeted sequencing of circulating tumor DNA (ctDNA) allowed us to monitor responses to therapy and to identify and then follow mechanisms of resistance. WES of tumors revealed potential hypothesis-driven therapeutic strategies for BRAF wild-type and inhibitor-resistant BRAF-mutant tumors, which were then validated in patient-derived xenografts (PDX). 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 in patients with melanoma. 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.
Highlights
Recent developments have revolutionized melanoma care, most patients still die of their disease
We collected plasma samples from 101 patients with melanoma being treated as part of clinical trials or receiving current standards of clinical care to determine if circulating tumor DNA (ctDNA) analysis can be used to support clinical diagnostics
Our initial studies were retrospective, as in patient 1 who presented with BRAFV600E metastatic melanoma with spread to the lymph nodes and lung (Fig. 1B)
Summary
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. Antibody antagonists of CTLA-4 and PD-1 provide survival benefits in a subset of patients [9,10,11] and even better responses when combined [10, 11]. It is unclear which patients will benefit from these agents, so the identification of biomarkers.
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