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Molecular signatures of circulating melanoma cells for monitoring early response to immune checkpoint therapy.

Molecular signatures of circulating melanoma cells for monitoring early response to immune checkpoint therapy.
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Hong X, Sullivan RJ, Kalinich M, Kwan TT, Giobbie-Hurder A, Pan S, LiCausi JA, Milner JD, Nieman LT, Wittner BS, Ho U, Chen T, Kapur R, Lawrence DP, Flaherty KT, Sequist LV, Ramaswamy S, Miyamoto DT, Lawrence M, Toner M, Isselbacher KJ, Maheswaran S, Haber DA,


Hong X, Sullivan RJ, Kalinich M, Kwan TT, Giobbie-Hurder A, Pan S, LiCausi JA, Milner JD, Nieman LT, Wittner BS, Ho U, Chen T, Kapur R, Lawrence DP, Flaherty KT, Sequist LV, Ramaswamy S, Miyamoto DT, Lawrence M, Toner M, Isselbacher KJ, Maheswaran S, Haber DA, (click to view)

Hong X, Sullivan RJ, Kalinich M, Kwan TT, Giobbie-Hurder A, Pan S, LiCausi JA, Milner JD, Nieman LT, Wittner BS, Ho U, Chen T, Kapur R, Lawrence DP, Flaherty KT, Sequist LV, Ramaswamy S, Miyamoto DT, Lawrence M, Toner M, Isselbacher KJ, Maheswaran S, Haber DA,

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Proceedings of the National Academy of Sciences of the United States of America 2018 02 16() pii 10.1073/pnas.1719264115

Abstract

A subset of patients with metastatic melanoma have sustained remissions following treatment with immune checkpoint inhibitors. However, analyses of pretreatment tumor biopsies for markers predictive of response, including PD-1 ligand (PD-L1) expression and mutational burden, are insufficiently precise to guide treatment selection, and clinical radiographic evidence of response on therapy may be delayed, leading to some patients receiving potentially ineffective but toxic therapy. Here, we developed a molecular signature of melanoma circulating tumor cells (CTCs) to quantify early tumor response using blood-based monitoring. A quantitative 19-gene digital RNA signature (CTC score) applied to microfluidically enriched CTCs robustly distinguishes melanoma cells, within a background of blood cells in reconstituted and in patient-derived (= 42) blood specimens. In a prospective cohort of 49 patients treated with immune checkpoint inhibitors, a decrease in CTC score within 7 weeks of therapy correlates with marked improvement in progression-free survival [hazard ratio (HR), 0.17;= 0.008] and overall survival (HR, 0.12;= 0.04). Thus, digital quantitation of melanoma CTC-derived transcripts enables serial noninvasive monitoring of tumor burden, supporting the rational application of immune checkpoint inhibition therapies.

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