Journal Article

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

Conca, Raffaele, Squicciarini, Teresa, Pugliese, Giuseppe, Maccallini, Maria Teresa, Tucci, Marco, Lombardo, Maurizio, Indini, Alice, Pellegrini, Stefania, Queirolo, Paola, Girlando, Salvatore, Caraglia, Francesco, Minisini, Alessandro, De Summa, Simona, Strippoli, Sabino, Spagnolo, Francesco, Vecchio, Michele Del, Troiani, Teresa, Di Tullio, Piergiorgio, Natalicchio, Iole, Costabile, Silvia, Pellegrini, Cristina, Perrone, Fabiana, Macrì, Miriam, Melucci, Elisa, Depenni, Roberta, Scaini, Maria Chiara, Guida, Michele, Brugnara, Sonia, Pinto, Rosamaria, Apollonio, Benedetta, Romano, Luca, Fava, Paolo, Fucci, Livia, Croce, Elena, Senetta, Rebecca, Tanda, Enrica, Quaglino, Pietro

2025

Overview

Background 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. Methods 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. Results 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. Conclusions 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. Highlights The role of BRAF-VAF in predicting response to BRAF/MEK inhibitors therapy in melanoma has not been elucidated yet. In 264 metastatic melanoma patients treated with first-line targeted therapy, high BRAF-VAF values correlated with worse clinical outcomes. This evidence is further strengthened when BRAF-VAF was normalized using neoplastic cellularity (nVAF). BRAF-VAF can be used as predictor of clinical outcomes in metastatic melanoma patients treated with first-line targeted therapy.

• Publisher: BioMed Central,Springer Nature B.V,BMC
• Subject: Adult / Aged / Aged, 80 and over / Alleles / Biomedical and Life Sciences / Biomedicine / Biopsy / BRAF mutation / BRAF/MEK target therapy / Combination strategies / Female / Gene frequency / Gene Frequency - genetics / Humans / Immunotherapy / Kinases / Male / Medicine/Public Health / MEK inhibitors / Melanoma / Melanoma - drug therapy / Melanoma - genetics / Melanoma - pathology / Metastases / Metastasis / Middle Aged / Multivariate analysis / Mutation / Mutation - genetics / Neoplasm Metastasis / Next-generation sequencing / Patients / Protein Kinase Inhibitors - pharmacology / Protein Kinase Inhibitors - therapeutic use / Proto-Oncogene Proteins B-raf - antagonists & inhibitors / Proto-Oncogene Proteins B-raf - genetics / Response rates / Retrospective Studies / Treatment Outcome / Variant allele frequency (VAF)