Response and Resistance to Trametinib in MAP2K1-Mutant Triple-Negative Melanoma

Krebs, Fanny S.; Moura, Bianca Hocevar de; Missiaglia, Edoardo; Aedo-Lopez, Veronica; Michielin, Olivier; Tsantoulis, Petros; Bisig, Bettina; Trimech, Mounir; Homicsko, Krisztian; Zoete, Vincent

doi:10.3390/ijms24054520

Cited by 3 publications

(3 citation statements)

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“…A small cohort of cases demonstrated mutations in multiple TCGA driver genes (n = 20, 7.9%), and within this subset, a majority harbored mutations in NF1 as well as either BRAF or NRAS (n = 18 of 20, 90%) (Figure 1a). In addition to TCGA driver genes (BRAF, NRAS, NF1), we evaluated recurrent molecular alterations observed in at least 5% of the entire cohort, the majority of which were established oncogenes or tumor suppressors (Figure 1b) [29][30][31][32][33][34][35][36][37][38][39][40][41][42]. Recurrently altered genes included 13), PTPRB (n = 13 or 5%), PREX2 (n = 13 or 5%), and SETD2 (n = 13 or 5%).…”

Section: Molecular Melanoma Groups Display Characteristic Phenotypic ...mentioning

confidence: 99%

“…In addition to TCGA driver genes (BRAF, NRAS, NF1), we evaluated recurrent molecular alterations observed in at least 5% of the entire cohort, the majority of which were established oncogenes or tumor suppressors (Figure 1b) [29][30][31][32][33][34][35][36][37][38][39][40][41][42] NRAS mutations were predominantly Q61 variants regardless of whether the tumors were in the NRAS driver (n = 67/77 or 86%) or co-mutated group (n = 9/14 or 64.3%) (Figure 2b). A total of 67 putative loss of function variants in NF1 were identified, with the majority clustered at the 5 ′ end of the gene, suggesting that the upstream loss of function mutations is enriched in NF1 (Figure 2c).…”

Section: Braf Nras and Nf1 Mutant Melanomas Exhibit Distinct Alterati...mentioning

confidence: 99%

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Targeted DNA Sequencing of Cutaneous Melanoma Identifies Prognostic and Predictive Alterations

Haugh,

Osorio,

Francois

et al. 2024

Cancers

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Background: Cutaneous melanoma (CM) can be molecularly classified into four groups: BRAF mutant, NRAS mutant, NF1 mutant and triple wild-type (TWT) tumors lacking any of these three alterations. In the era of immune checkpoint inhibition (ICI) and targeted molecular therapy, the clinical significance of these groups remains unclear. Here, we integrate targeted DNA sequencing with comprehensive clinical follow-up in CM patients. Methods: This was a retrospective cohort study that assessed clinical and molecular features from patients with localized or metastatic CM who underwent targeted next-generation sequencing as part of routine clinical care. A total of 254 patients with CM who had a CLIA-certified targeted sequencing assay performed on their tumor tissue were included. Results: Of the 254 patients with cutaneous melanoma, 77 were BRAF mutant (30.3%), 77 were NRAS mutant (30.3%), 47 were NF1 mutant (18.5%), 33 were TWT (13.0%) and the remaining 20 (7.9%) carried mutations in multiple driver genes (BRAF/NRAS/NF1 co-mutated). The majority of this co-mutation group carried mutations in NF1 (n = 19 or 90%) with co-occurring mutations in BRAF or NRAS, often with a weaker oncogenic variant. Consistently, NF1 mutant tumors harbored numerous significantly co-altered genes compared to BRAF or NRAS mutant tumors. The majority of TWT tumors (n = 29, 87.9%) harbor a pathogenic mutation within a known Ras/MAPK signaling pathway component. Of the 154 cases with available TMB data, the median TMB was 20 (range 0.7–266 mutations/Mb). A total of 14 cases (9.1%) were classified as having a low TMB (≤5 mutations/Mb), 64 of 154 (41.6%) had an intermediate TMB (>5 and ≤20 mutations/Mb), 40 of 154 (26.0%) had a high TMB (>20 and ≤50 mutations/Mb) and 36 of 154 (23.4%) were classified as having a very high TMB (>50 mutations/Mb). NRAS mutant melanoma demonstrated significantly decreased overall survival on multivariable analysis (HR for death 2.95, 95% CI 1.13–7.69, p = 0.027, log-rank test) compared with other TCGA molecular subgroups. Of the 116 patients in our cohort with available treatment data, 36 received a combination of dual ICI with anti-CTLA4 and anti-PD1 inhibition as first-line therapy. Elevated TMB was associated with significantly longer progression-free survival following dual-agent ICI (HR 0.26, 95% CI 0.07–0.90, p = 0.033, log-rank test). Conclusions: NRAS mutation in CMs correlated with significantly worse overall survival. Elevated TMB was associated with increased progression-free survival for patients treated with a combination of dual ICI, supporting the potential utility of TMB as a predictive biomarker for ICI response in melanoma.

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Section: Molecular Melanoma Groups Display Characteristic Phenotypic ...mentioning

confidence: 99%

Section: Braf Nras and Nf1 Mutant Melanomas Exhibit Distinct Alterati...mentioning

confidence: 99%

Targeted DNA Sequencing of Cutaneous Melanoma Identifies Prognostic and Predictive Alterations

Haugh,

Osorio,

Francois

et al. 2024

Cancers

View full text Add to dashboard Cite

show abstract

“…In addition to TCGA driver genes (BRAF, NRAS, NF1), we evaluated recurrent molecular alterations observed in at least 5% of the entire cohort, the majority of which are established oncogenes or tumor suppressors (Figure 1b). [28][29][30][31][32][33][34][35][36][37][38][39][40][41] Recurrently altered genes included TERT (n=216), CDKN2A/B (n=116) TP53 (n=93),…”

Section: Molecular Melanoma Groups Display Characteristic Phenotypic ...mentioning

confidence: 99%

Targeted DNA Sequencing of Cutaneous Melanoma Identifies Prognostic and Predictive Alterations

Haugh,

Osorio,

Francois

et al. 2024

Preprint

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Importance: Cutaneous melanoma (CM) can be molecularly classified into four groups: BRAF mutant, NRAS mutant, NF1 loss, and triple wild type (TWT) tumors lacking these three alterations, yet their clinical significance remains unclear. Here, we integrate targeted DNA sequencing with comprehensive clinical followup in CM patients. Objective: To explore how molecular features and tumor mutational burden (TMB) impact outcomes in CM patients Design: Retrospective cohort study that assessed clinical and molecular features from patients with CM who underwent targeted next-generation sequencing as part of routine clinical care. Setting: Tertiary referral, comprehensive NCI cancer center from 2013 to 2023. Participants: A total of 254 patients with CM who had a CLIA certified targeted sequencing assay performed on their tumor tissue were included Exposure: A CLIA certified targeted sequencing assay was performed as standard of care on 254 patients with CM treated at a single institution. Main Outcome: NRAS mutation correlated with significantly worse overall survival compared to other TCGA driver groups. Elevated TMB correlated with improved progression-free survival on combination checkpoint inhibition (anti-PD1 plus anti-CTLA4). Results: Of 254 patients with cutaneous melanoma, 77 were BRAF mutant (30.3%), 77 were NRAS mutant (30.3%), 47 were NF1 mutant (18.5%), 33 were TWT (13.0%) and the remaining 20 (7.9%) carried mutations in multiple driver genes (BRAF/NRAS/NF1 co-mutated), most commonly in NF1 (n=19 or 90%). Consistently, NF1 mutant tumors harbored numerous significantly co-altered genes compared to BRAF or NRAS mutant tumors. Most TWT tumors (n=29, 87.9%) harbored a known pathogenic Ras/MAPK mutation. NRAS mutant melanoma demonstrated significantly decreased overall survival (HR for death 2.95, 95% CI 1.13 to 7.69, p=0.027, log rank test). Of the 154 cases with available TMB data, the median TMB was 20 (range 0.7 to 266 mutations/Mb). Elevated TMB was associated with significantly longer progression-free survival following dual agent ICI (HR 0.26, 95% CI 0.07 to 0.90, p=0.033, log-rank test). Conclusions and Relevance: NRAS mutation in CMs correlated with significantly worse overall survival. Elevated TMB was associated with increased progression-free survival for patients treated with combination dual ICI, supporting the potential utility of TMB as a predictive biomarker for ICI response in melanoma.

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Response and Resistance to Trametinib in MAP2K1-Mutant Triple-Negative Melanoma

Cited by 3 publications

References 50 publications

Targeted DNA Sequencing of Cutaneous Melanoma Identifies Prognostic and Predictive Alterations

Targeted DNA Sequencing of Cutaneous Melanoma Identifies Prognostic and Predictive Alterations

Targeted DNA Sequencing of Cutaneous Melanoma Identifies Prognostic and Predictive Alterations

Antineoplastics

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