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NPJ Genom Med. 2017;2. pii: 10. doi: 10.1038/s41525-017-0013-8. Epub 2017 Apr 7.

Genomic and immune heterogeneity are associated with differential responses to therapy in melanoma.

Author information

1
Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA.
2
Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA.
3
Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA.
4
Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA.
5
Department of Pathology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA.
6
Department of Stem Cell Transplantation, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA.
7
Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA.
8
Department of Cancer Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA.
9
Department of Biostatistics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA.
10
Department of Diagnostic Radiology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA.
11
Department of Immunology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA.
12
Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA.

Abstract

Appreciation for genomic and immune heterogeneity in cancer has grown though the relationship of these factors to treatment response has not been thoroughly elucidated. To better understand this, we studied a large cohort of melanoma patients treated with targeted therapy or immune checkpoint blockade (n = 60). Heterogeneity in therapeutic responses via radiologic assessment was observed in the majority of patients. Synchronous melanoma metastases were analyzed via deep genomic and immune profiling, and revealed substantial genomic and immune heterogeneity in all patients studied, with considerable diversity in T cell frequency, and few shared T cell clones (<8% on average) across the cohort. Variables related to treatment response were identified via these approaches and through novel radiomic assessment. These data yield insight into differential therapeutic responses to targeted therapy and immune checkpoint blockade in melanoma, and have key translational implications in the age of precision medicine.

Conflict of interest statement

COMPETING INTERESTS J.A.W. has honoraria from speakers’ bureau of Dava Oncology, and is an advisory board member for GlaxoSmithKline and Roche/Genentech. Z.A.C. is an employee of MedImmune and owns stock or options in AstraZeneca. M.A.D. is an advisory board member for GlaxoSmithKline, Roche/Genentech, Novartis and Sanofi-Aventis, and has received research support from GlaxoSmithKline, Roche/Genentech, Sanofi-Aventis, Oncothyreon, Myriad, and AstraZeneca. J.E.G. is on the advisory board of Merck, and receives royalties from Mercator Therapeutics. S.P.P. has honoraria from speakers’ bureau of Dava Oncology, Merck and Bristol-Myers Squibb, and is an advisory board member for Amgen and Roche/Genentech. P.H. serves on the advisory board of Lion Biotechnologies and Immatics US. R.N.A. has received research support from Merck, Novartis and Bristol-Myers Squibb. I.I.W. receives honoraria from Genentech/Roche, Ventana, GlaxoSmithKline, Celgene, Bristol-Myers Squibb, Synta Pharmaceuticals, Boehringer Ingelheim, Medscape, Clovis, AstraZeneca and Pfizer, and research support from Genentech/Roche, Oncoplex, and HGT. P.S. is a consultant for Bristol-Myers Squibb, Jounce Therapeutics, Helsinn, and GlaxoSmithKline as well as a stockholder from Jounce Therapeutics. J.P.A. is a consultant and stockholder for Jounce Therapeutics, receives royalties from Bristol-Myers Squibb, and has intellectual property with Bristol-Myers Squibb and Merck. The other authors declare that they have no competing interests.

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