High BRAF variant allele frequency predicts poor outcomes in metastatic melanoma patients treated with BRAF/MEK inhibitors

作者：Michele Guida, Benedetta Apollonio, Luca Romano, Francesco Spagnolo, Pietro Quaglino, Roberta Depenni, Rosamaria Pinto, Teresa Squicciarini, Livia Fucci, P. Di Tullio, Maria Chiara Scaini, Maria Teresa Maccallini, Alice Indini, Teresa Troiani, Iole Natalicchio, S. Brugnara, M. Lombardo, Cristina Pellegrini, Paola Queirolo, Fabiana Perrone, Alessandro Marco Minisini, Marco Tucci, Raffaele Conca, Silvia Costabile, Miriam Macrì, Enrica T. Tanda, Elena Croce, Rebecca Senetta, Paolo Fava, Giuseppe Pugliese, Stefania Pellegrini, Elisa Melucci, Michele Del Vecchio, Francesco Caraglia, Salvatore Girlando, Simona De Summa, Sabino Strippoli, on behalf of the Italian Melanoma Intergroup (IMI) · 发表于：Journal of Translational Medicine · 年份：2025 · DOI：10.1186/s12967-025-07434-x · 被引用次数：1 · 研究领域：Melanoma and MAPK Pathways、Cutaneous Melanoma Detection and Management、NF-κB Signaling Pathways

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. 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. 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 ...