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- Title
Molecular Features of Resected Melanoma Brain Metastases, Clinical Outcomes, and Responses to Immunotherapy.
- Authors
Vasudevan, Harish N.; Delley, Cyrille; Chen, William C.; Mirchia, Kanish; Pan, Sixuan; Shukla, Poojan; Aabedi, Alex A.; Nguyen, Minh P.; Morshed, Ramin A.; Young, Jacob S.; Boreta, Lauren; Fogh, Shannon E.; Nakamura, Jean L.; Theodosopoulos, Philip V.; Phillips, Joanna; Hervey-Jumper, Shawn L.; Daras, Mariza; Pike, Luke; Aghi, Manish K.; Tsai, Katy
- Abstract
Key Points: Question: What is the translational importance of alteration status in the treatment of melanoma brain metastases? Findings: In this cohort study of 94 patients with resected melanoma brain metastases that underwent targeted DNA sequencing, BRAF V600E variant lesions were associated with worse intracranial progression-free survival and overall survival. Single-cell sequencing showed that BRAF V600E variant brain metastases harbored fewer immune cell types; immunotherapy was associated with improved outcomes for patients with BRAF wildtype but not BRAF V600E variant brain metastases. Meaning: This study suggests that, for patients with melanoma brain metastases, BRAF status may be an important molecular biomarker to guide systemic therapy selection. Importance: Central nervous system (CNS)–penetrant 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. Objective: To evaluate how bulk and single-cell genomic features of melanoma brain metastases are associated with clinical outcome and treatment response. Design, Setting, and Participants: 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. Exposure: A Clinical Laboratory Improvement Amendments–certified targeted sequencing assay was used to analyze tumor resection specimens, with a focus on BRAF V600E alteration. For frozen pathologic specimens from CNS treatment-naive patients undergoing surgical resection, commercial single nuclear RNA sequencing approaches were used. Main Outcomes and Measures: 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. Results: 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 BRAF alteration testing showed worse median intracranial PFS (BRAF variant: 3.6 months [IQR, 0.1-30.6 months]; BRAF wildtype: 11.0 months [IQR, 0.8-81.5 months]; P <.001) and OS (BRAF variant: 9.8 months [IQR, 2.5-69.4 months]; BRAF wildtype: 23.2 months [IQR, 1.1-102.5 months]; P =.005; log-rank test) in BRAF V600E variant tumors. Multivariable Cox proportional hazards regression analysis revealed that BRAF V600E status was an independent variable significantly associated with both PFS (hazard ratio [HR], 2.65; 95% CI, 1.54-4.57; P <.001) and OS (HR, 1.96; 95% CI, 1.08-3.55; P =.03). For the 45 patients with resected melanoma brain metastases undergoing targeted DNA sequencing, molecular classification recapitulated The Cancer Genome Atlas groups (NRAS variant, BRAF variant, NF1 variant, and triple wildtype) with no subtype enrichment within the brain metastasis cohort. On a molecular level, BRAF V600E variant lesions were found to have a significantly decreased tumor mutation burden. Moreover, single nuclear RNA sequencing of treatment-naive BRAF V600E variant (n = 3) brain metastases compared with BRAF wildtype (n = 3) brain metastases revealed increased immune cell populations in BRAF wildtype tumors (mean [SD], 11% [4.1%] vs 3% [1.6%] CD45-positive cells; P =.04). Survival analysis of postoperative immunotherapy responses by BRAF status revealed that BRAF 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]; P =.001; log-rank test) while BRAF 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]; P =.81; log-rank test) were not. Conclusions and Relevance: This molecular analysis of patients with resected melanoma brain metastases found that BRAF V600E alteration is an important translational biomarker associated with worse clinical outcomes, differential microenvironmental composition, and benefit from immunotherapy. Patients with BRAF V600E variant melanoma brain metastases may thus benefit from alternative CNS-penetrant systemic regimens. This cohort study evaluates how bulk and single-cell genomic features of melanoma brain metastases are associated with clinical outcome and treatment response.
- Subjects
MELANOMA treatment; BRAIN; DNA; SEQUENCE analysis; MELANOMA; METASTASIS; RNA; TREATMENT effectiveness; GENOMICS; DESCRIPTIVE statistics; RESEARCH funding; T cells; IMMUNOTHERAPY; LONGITUDINAL method
- Publication
JAMA Network Open, 2023, Vol 6, Issue 8, pe2329186
- ISSN
2574-3805
- Publication type
Article
- DOI
10.1001/jamanetworkopen.2023.29186