{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,25]],"date-time":"2026-10-25T13:22:01Z","timestamp":1792934521574,"version":"4.5.0"},"reference-count":15,"publisher":"American Medical Association (AMA)","issue":"8","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Netw Open"],"abstract":"\n Importance<\/jats:title>\n Central nervous system (CNS)\u2013penetrant systemic therapies have significantly advanced care for patients with melanoma brain metastases. However, improved understanding of the molecular landscape and microenvironment of these lesions is needed to both optimize patient selection and advance treatment approaches.<\/jats:p>\n <\/jats:sec>\n \n Objective<\/jats:title>\n To evaluate how bulk and single-cell genomic features of melanoma brain metastases are associated with clinical outcome and treatment response.<\/jats:p>\n <\/jats:sec>\n \n Design, Setting, and Participants<\/jats:title>\n This cohort study analyzed bulk DNA sequencing and single nuclear RNA-sequencing data from resected melanoma brain metastases and included 94 consecutive patients with a histopathologically confirmed diagnosis of melanoma brain metastasis who underwent surgical resection at a single National Comprehensive Cancer Network cancer center in San Francisco, California, from January 1, 2009, to December 31, 2022.<\/jats:p>\n <\/jats:sec>\n \n Exposure<\/jats:title>\n \n A Clinical Laboratory Improvement Amendments\u2013certified targeted sequencing assay was used to analyze tumor resection specimens, with a focus on\n BRAF<\/jats:italic>\n V600E alteration. For frozen pathologic specimens from CNS treatment-naive patients undergoing surgical resection, commercial single nuclear RNA sequencing approaches were used.\n <\/jats:p>\n <\/jats:sec>\n \n Main Outcomes and Measures<\/jats:title>\n The primary outcome was overall survival (OS). Secondary outcomes included CNS progression-free survival (PFS), microenvironmental composition with decreased T-cell and macrophage populations, and responses to immunotherapy.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n To correlate molecular status with clinical outcome, Kaplan-Meier survival analysis of 94 consecutive patients (median age, 64 years [range, 24-82 years]; 70 men [74%]) with targeted\n BRAF<\/jats:italic>\n alteration testing showed worse median intracranial PFS (\n BRAF<\/jats:italic>\n variant: 3.6 months [IQR, 0.1-30.6 months];\n BRAF<\/jats:italic>\n wildtype: 11.0 months [IQR, 0.8-81.5 months];\n P<\/jats:italic>\n \u2009&amp;lt;\u2009.001) and OS (\n BRAF<\/jats:italic>\n variant: 9.8 months [IQR, 2.5-69.4 months];\n BRAF<\/jats:italic>\n wildtype: 23.2 months [IQR, 1.1-102.5 months];\n P<\/jats:italic>\n \u2009=\u2009.005; log-rank test) in\n BRAF<\/jats:italic>\n V600E variant tumors. Multivariable Cox proportional hazards regression analysis revealed that\n BRAF<\/jats:italic>\n V600E status was an independent variable significantly associated with both PFS (hazard ratio [HR], 2.65; 95% CI, 1.54-4.57;\n P<\/jats:italic>\n \u2009&amp;lt;\u2009.001) and OS (HR, 1.96; 95% CI, 1.08-3.55;\n P<\/jats:italic>\n \u2009=\u2009.03). For the 45 patients with resected melanoma brain metastases undergoing targeted DNA sequencing, molecular classification recapitulated The Cancer Genome Atlas groups (\n NRAS<\/jats:italic>\n variant,\n BRAF<\/jats:italic>\n variant,\n NF1<\/jats:italic>\n variant, and triple wildtype) with no subtype enrichment within the brain metastasis cohort. On a molecular level,\n BRAF<\/jats:italic>\n V600E variant lesions were found to have a significantly decreased tumor mutation burden. Moreover, single nuclear RNA sequencing of treatment-naive\n BRAF<\/jats:italic>\n V600E variant (n\u2009=\u20093) brain metastases compared with\n BRAF<\/jats:italic>\n wildtype (n\u2009=\u20093) brain metastases revealed increased immune cell populations in\n BRAF<\/jats:italic>\n wildtype tumors (mean [SD], 11% [4.1%] vs 3% [1.6%] CD45-positive cells;\n P<\/jats:italic>\n \u2009=\u2009.04). Survival analysis of postoperative immunotherapy responses by\n BRAF<\/jats:italic>\n status revealed that\n BRAF<\/jats:italic>\n wildtype lesions were associated with a response to checkpoint inhibition (median OS: with immunotherapy, undefined; without immunotherapy, 13.0 months [range, 1.1-61.7 months];\n P<\/jats:italic>\n \u2009=\u2009.001; log-rank test) while\n BRAF<\/jats:italic>\n variant lesions (median OS: with immunotherapy, 9.8 months [range, 2.9-39.8 months]; without immunotherapy, 9.5 months [range, 2.5-67.2 months];\n P<\/jats:italic>\n \u2009=\u2009.81; log-rank test) were not.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions and Relevance<\/jats:title>\n \n This molecular analysis of patients with resected melanoma brain metastases found that\n BRAF<\/jats:italic>\n V600E alteration is an important translational biomarker associated with worse clinical outcomes, differential microenvironmental composition, and benefit from immunotherapy. Patients with\n BRAF<\/jats:italic>\n V600E variant melanoma brain metastases may thus benefit from alternative CNS-penetrant systemic regimens.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1001\/jamanetworkopen.2023.29186","type":"journal-article","created":{"date-parts":[[2023,8,17]],"date-time":"2023-08-17T11:09:12Z","timestamp":1692270552000},"page":"e2329186","source":"Crossref","is-referenced-by-count":17,"title":["Molecular Features of Resected Melanoma Brain Metastases, Clinical Outcomes, and Responses to Immunotherapy"],"prefix":"10.1001","volume":"6","author":[{"given":"Harish N.","family":"Vasudevan","sequence":"first","affiliation":[{"name":"Department of Radiation Oncology, University of California, San Francisco"},{"name":"Department of Neurological Surgery, University of California, San Francisco"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cyrille","family":"Delley","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, University of California, San Francisco"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William C.","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, University of California, San Francisco"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kanish","family":"Mirchia","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of California, San Francisco"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sixuan","family":"Pan","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, University of California, San Francisco"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Poojan","family":"Shukla","sequence":"additional","affiliation":[{"name":"Department of Neurological Surgery, University of California, San Francisco"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alex 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California, San Francisco"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David R.","family":"Raleigh","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, University of California, San Francisco"},{"name":"Department of Neurological Surgery, University of California, San Francisco"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steve E.","family":"Braunstein","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, University of California, San Francisco"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam R.","family":"Abate","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, University of California, San Francisco"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"10","published-online":{"date-parts":[[2023,8,17]]},"reference":[{"key":"zoi230844r1","author":"Long","year":"2018","journal-title":"Lancet 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