biostudies-literatureGuida MMinistero della Salute1407https://www.ebi.ac.uk/biostudies/studies/S-EPMC12713232biostudies-literatureUnknown23(1)<h4>Background</h4>BRAF/MEK inhibitors have improved the outcome in metastatic melanoma (MM) patients harboring a BRAF mutation, but no biomarker predictive of response has been identified.<h4>Methods</h4>We conducted a retrospective analysis on 264 MM patients that had received first-line targeted therapy with BRAF/MEK inhibitors. Next-generation sequencing (NGS) was performed on tissue biopsies, and samples with > 30% tumor cellularity were included in the study. The impact of BRAF variant allele frequency (BRAF-VAF) on clinical treatment outcomes was analyzed.<h4>Results</h4>BRAF-VAF was dichotomized using two approaches. (1) The "surv_cutpoint" function identified two different cut-off for progression-free survival (PFS: 44.05%) and overall survival (OS:45.1%). Patients with BRAF-VAF > 44.05% showed a significantly lower PFS (median PFS: 10 months, 95% CI: 7-13 months), compared to patients with BRAF-VAF < 44.05% (median PFS: 13 months, 95% CI: 12-21 months). Moreover, patients with higher VAF (> 45.1%) experienced a lower OS (median OS: 26 months, 95% CI: 19-38 months), compared with patients with VAF < 45.1% (median OS: 29 months, 95% CI: 29-51 months). (2) The ROC analysis significantly predicted PFS but not OS. BRAF-VAF normalized with neoplastic cellularity (nVAF) showed a strong association with both PFS, and OS compared to BRAF-VAF alone. nVAF also emerged as an independent predictor for PFS in the multivariate analysis (HR: 3.88, 95% CI: 1.84-8.20), with a higher nVAF score associated with a 3.88-fold increased risk of progression.<h4>Conclusions</h4>Our study demonstrated the role of the BRAF-VAF as predictor of response in MM patients treated with BRAF/MEK inhibitors. Moreover, VAF normalization predicts PFS better than BRAF-VAF alone.Journal of translational medicineHigh BRAF variant allele frequency predicts poor outcomes in metastatic melanoma patients treated with BRAF/MEK inhibitors.PMC12713232Ricerca Corrente 2025Perrone FPinto RSquicciarini TQueirolo PPellegrini SStrippoli SApollonio BCroce EConca RDe Summa SPellegrini CMelucci ELombardo MFucci LDepenni RTroiani TCaraglia FRomano LTucci MBrugnara SVecchio MDDi Tullio PIndini AQuaglino PScaini MCSenetta RCostabile STanda EGuida MNatalicchio ISpagnolo FItalian Melanoma Intergroup (IMI)Fava PMaccallini MTMinisini APugliese GMacri MGirlando SfalseHigh BRAF variant allele frequency predicts poor outcomes in metastatic melanoma patients treated with BRAF/MEK inhibitors.<h4>Background</h4>BRAF/MEK inhibitors have improved the outcome in metastatic melanoma (MM) patients harboring a BRAF mutation, but no biomarker predictive of response has been identified.<h4>Methods</h4>We conducted a retrospective analysis on 264 MM patients that had received first-line targeted therapy with BRAF/MEK inhibitors. Next-generation sequencing (NGS) was performed on tissue biopsies, and samples with > 30% tumor cellularity were included in the study. The impact of BRAF variant allele frequency (BRAF-VAF) on clinical treatment outcomes was analyzed.<h4>Results</h4>BRAF-VAF was dichotomized using two approaches. (1) The "surv_cutpoint" function identified two different cut-off for progression-free survival (PFS: 44.05%) and overall survival (OS:45.1%). Patients with BRAF-VAF > 44.05% showed a significantly lower PFS (median PFS: 10 months, 95% CI: 7-13 months), compared to patients with BRAF-VAF < 44.05% (median PFS: 13 months, 95% CI: 12-21 months). Moreover, patients with higher VAF (> 45.1%) experienced a lower OS (median OS: 26 months, 95% CI: 19-38 months), compared with patients with VAF < 45.1% (median OS: 29 months, 95% CI: 29-51 months). (2) The ROC analysis significantly predicted PFS but not OS. BRAF-VAF normalized with neoplastic cellularity (nVAF) showed a strong association with both PFS, and OS compared to BRAF-VAF alone. nVAF also emerged as an independent predictor for PFS in the multivariate analysis (HR: 3.88, 95% CI: 1.84-8.20), with a higher nVAF score associated with a 3.88-fold increased risk of progression.<h4>Conclusions</h4>Our study demonstrated the role of the BRAF-VAF as predictor of response in MM patients treated with BRAF/MEK inhibitors. Moreover, VAF normalization predicts PFS better than BRAF-VAF alone.2025-01-01T00:00:00Z2025 Dec2026-06-06T05:08:07.096Z2026-05-26T03:12:12.668ZS-EPMC127132324140829510.1186/s12967-025-07434-x