The Prognostic Value of BRAF , C-KIT , and NRAS Mutations in Melanoma Patients With Brain Metastases

Sperduto, Paul W.; Jiang, Wen; Brown, Paul D.; Braunstein, Steve; Sneed, Penny K.; Wattson, Daniel A.; Shih, Helen A.; Bangdiwala, Ananta S; Shanley, Ryan; Lockney, Natalie A.; Beal, Kathryn; Lou, Emil; Amatruda, Thomas T.; Sperduto, William; Kirkpatrick, John P.; Yeh, Norman; Gaspar, Laurie E.; Molitoris, Jason K.; Masucci, Laura; Roberge, David; Yu, James B.; Chiang, Veronica; Mehta, Minesh P.

doi:10.1016/j.ijrobp.2017.03.030

Cited by 63 publications

(51 citation statements)

References 44 publications

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“…Thus, it may be expected that it is hard to find a uniform molecular pattern associated with a given metastatic phenotype. The challenge is greatly aggravated by the known intertumor heterogeneity (38) as well as the plasticity of tumor cells in general (5) and of melanoma cells (16,39). The challenge of inter-tumor heterogeneity underlying divergent clinical manifestations of different tumors belonging to the same histological type as well as distinct responses of such tumors to therapy is addressed by current precision medicine approaches (35,40).…”

Section: Discussionmentioning

confidence: 99%

“…To draw general statements on the molecular events sustaining the development of metastasis proves to be a very challenging task, sometimes associated with apparently contradicting conclusions. Remarkably, genetic traits of melanoma cells also hardly correlate with survival or with the time from primary diagnosis to the detection of brain metastasis (5). Thus, the absence or presence of certain mutations in key molecules such as BRAF, NRAS or KIT is not directly related to the capability of melanoma cells to colonize the brain (5).…”

Section: Graphical Abstractmentioning

confidence: 99%

“…Remarkably, genetic traits of melanoma cells also hardly correlate with survival or with the time from primary diagnosis to the detection of brain metastasis (5). Thus, the absence or presence of certain mutations in key molecules such as BRAF, NRAS or KIT is not directly related to the capability of melanoma cells to colonize the brain (5). This was our motivation to apply post-genomic techniques searching for molecular patterns potentially associated with brain metastasis which might also support the functional understanding of accompanying drug resistance properties.…”

Section: Graphical Abstractmentioning

confidence: 99%

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The Challenge of Classifying Metastatic Cell Properties by Molecular Profiling Exemplified with Cutaneous Melanoma Cells and Their Cerebral Metastasis from Patient Derived Mouse Xenografts

Neuditschko

Janker²,

Niederstaetter³

et al. 2020

Molecular & Cellular Proteomics

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The prediction of metastatic properties from molecular analyses still poses a major challenge. Here we aimed at the classification of metastasis-related cell properties by proteome profiling making use of cutaneous and brain-metastasizing variants from single melanomas sharing the same genetic ancestry. Previous experiments demonstrated that cultured cells derived from these xenografted variants maintain a stable phenotype associated with a differential metastatic behavior: The brain metastasizing variants produce more spontaneous micro-metastases than the corresponding cutaneous variants. Four corresponding pairs of cutaneous and metastatic cells were obtained from four individual patients, resulting in eight cell-lines presently investigated. Label free proteome profiling revealed significant differences between corresponding pairs of cutaneous and cerebellar metastases from the same patient. Indeed, each brain metastasizing variant expressed several apparently metastasis-associated proteomic alterations as compared with the corresponding cutaneous variant. Among the differentially expressed proteins we identified cell adhesion molecules, immune regulators, epithelial to mesenchymal transition markers, stem cell markers, redox regulators and cytokines. Similar results were observed regarding eicosanoids, considered relevant for metastasis, such as PGE2 and 12-HETE. Multiparametric morphological analysis of cells also revealed no characteristic alterations associated with the cutaneous and brain metastasis variants. However, no correct classification regarding metastatic potential was yet possible with the present data. We thus concluded that molecular profiling is able to classify cells according to known functional categories but is not yet able to predict relevant cell properties emerging from networks consisting of many interconnected molecules. The presently observed broad diversity of molecular patterns, irrespective of restricting to one tumor type and two main classes of metastasis, highlights the important need to develop meta-analysis strategies to predict cell properties from molecular profiling data. Such base knowledge will greatly support future individualized precision medicine approaches.

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Section: Discussionmentioning

confidence: 99%

Section: Graphical Abstractmentioning

confidence: 99%

Section: Graphical Abstractmentioning

confidence: 99%

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The Challenge of Classifying Metastatic Cell Properties by Molecular Profiling Exemplified with Cutaneous Melanoma Cells and Their Cerebral Metastasis from Patient Derived Mouse Xenografts

Neuditschko

Janker²,

Niederstaetter³

et al. 2020

Molecular & Cellular Proteomics

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“…The initial investigation identified the KPS and the number of BM as the unique factors with significant influence on the survival outcomes. Its recently published multi-institutional update involved 823 malignant melanoma patients with BM [15]. In this refined index, namely the 'melanoma molecular-GPA (Melanoma mol-GPA)', the molecular markers were also investigated for their impact on results.…”

Section: Disease-specific Graded Prognostic Assessmentmentioning

confidence: 99%

“…Presentation with BM indicates an adverse prognostic condition with expected survival duration of usually less than a year, yet the prognosis of BM patients may differ broadly due to multiple factors; including the age, performance status, total number and volume of the metastatic lesion(s), treatment modality utilized against the BM, extracranial disease status, and histology of the primary malignancy. Various tumor-specific molecular factors, pathologic biomarkers, and driver mutations have also demonstrated significant prognostic utility in BM of lung-, breast-, hepatocellular carcinomas, and malignant melanomas [13][14][15][16][17]. In past investigations, numerous researchers have blended these identified factors in various manners and created prognostic scoring systems to accurately anticipate the survival of BM patients and to properly guide their treatments in an ideal way.…”

Section: Introductionmentioning

confidence: 99%

Common Prognostic Scoring Systems for Patients Presenting with Brain Metastases

Küçük¹,

Pehlivan²,

Sezen³

et al. 2020

COR

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Brain metastases (BM) of various primaries merely remain the most prevalent type of intracranial tumors, and approximately 25% of all cancer patients are diagnosed with this poor prognostic disease condition somewhere during their treatment course. Contingent upon the general wellbeing status of the potential patient, currently available major treatment options typically include palliative radiotherapy, chemotherapy, and best supportive care. Various published studies have convincingly shown the likelihood to stratify BM patients into particular prognostic gatherings according to the conceivable combinations of multiple patients- and tumor-related characteristics; namely the prognostic scoring systems, which might be useful in the accurate prediction of survival, and thusly, the appropriate choice of the best-fit treatment alternative. In this present article, we meant to review the pros and cons of the as of now accessible and broadly acknowledged prognostic scoring systems for BMs and their clinical values.

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Molecular Features of Resected Melanoma Brain Metastases, Clinical Outcomes, and Responses to Immunotherapy

Vasudevan,

Delley,

Chen

et al. 2023

JAMA Netw Open

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ImportanceCentral 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.ObjectiveTo evaluate how bulk and single-cell genomic features of melanoma brain metastases are associated with clinical outcome and treatment response.Design, Setting, and ParticipantsThis 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.ExposureA 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 MeasuresThe 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.ResultsTo 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 &lt; .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 &lt; .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 RelevanceThis 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.

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The Prognostic Value of BRAF , C-KIT , and NRAS Mutations in Melanoma Patients With Brain Metastases

Abstract: For melanoma patients with brain metastases, BRAF-positive patients survive longer than BRAF-negative patients and overall survival has improved from 1985-2005 to 2006-2015.

Cited by 63 publications

References 44 publications

The Challenge of Classifying Metastatic Cell Properties by Molecular Profiling Exemplified with Cutaneous Melanoma Cells and Their Cerebral Metastasis from Patient Derived Mouse Xenografts

The Challenge of Classifying Metastatic Cell Properties by Molecular Profiling Exemplified with Cutaneous Melanoma Cells and Their Cerebral Metastasis from Patient Derived Mouse Xenografts

Common Prognostic Scoring Systems for Patients Presenting with Brain Metastases

Molecular Features of Resected Melanoma Brain Metastases, Clinical Outcomes, and Responses to Immunotherapy

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