期刊
CLINICAL CANCER RESEARCH
卷 23, 期 12, 页码 3168-3180出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-17-0270
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资金
- Melanoma Research Alliance
- Bloombergsimilar toKimmel Institute for Cancer Immunotherapy
- Barney Family Foundation
- Moving for Melanoma of Delaware
- Laverna Hahn Charitable Trust
- National Cancer Institute [R01 CA142779, 5T32 CA193145, R01 CA179991, P30-CA008748]
- MSKCCTROT Fellowship
- Starr Cancer Consortium
- Pershing Square Sohn Cancer Research Foundation
- Immunogenomics and Precision Oncology Platform
- Marie-Josee and Henry R. Kravis Center for Molecular Oncology
Purpose: To explore factors associated with response and resistance to anti-PD-1 therapy, we analyzed multiple disease sites at autopsy in a patient with widely metastatic melanoma who had a heterogeneous response. Materials and Methods: Twenty-six melanoma specimens (four premortem, 22 postmortem) were subjected to whole exome sequencing. Candidate immunologic markers and gene expression were assessed in 10 cutaneous metastases showing response or progression during therapy. Results: The melanoma was driven by biallelic inactivation of NF1. All lesions had highly concordant mutational profiles and copy number alterations, indicating linear clonal evolution. Expression of candidate immunologic markers was similar in responding and progressing lesions. However, progressing cutaneous metastases were associated with overexpression of genes associated with extracellular matrix and neutrophil function. Conclusions: Although mutational and immunologic differences have been proposed as the primary determinants of heterogeneous response/resistance to targeted therapies and immunotherapies, respectively, differential lesional gene expression profiles may also dictate anti-PD-1 outcomes. (C) 2017 AACR. See related commentary by Wilmott et al., p. 2921
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