High BRAF variant allele frequency predicts poor outcomes in metastatic melanoma patients treated with BRAF/MEK inhibitors.
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Guida Michele, Apollonio Benedetta, Romano Luca, Spagnolo Francesco, Quaglino Pietro, Depenni Roberta, Pinto Rosamaria, Squicciarini Teresa, Fucci Livia, Di Tullio Piergiorgio, Scaini Maria Chiara, Maccallini Maria Teresa, Indini Alice, Troiani Teresa, Natalicchio Iole, Brugnara Sonia, Lombardo Maurizio, Pellegrini Cristina, Queirolo Paola, Perrone Fabiana, Minisini Alessandro, Tucci Marco, Conca Raffaele, Costabile Silvia, Macrì Miriam, Tanda Enrica, Croce Elena, Senetta Rebecca, Fava Paolo, Pugliese Giuseppe, Pellegrini Stefania, Melucci Elisa, Vecchio Michele Del, Caraglia Francesco, Girlando Salvatore, De Summa Simona, Strippoli Sabino, Italian Melanoma Intergroup (IMI)
Аннотация
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.