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Background <p>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.</p> Methods <p>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 &gt; 30% tumor cellularity were included in the study. The impact of BRAF variant allele frequency (BRAF-VAF) on clinical treatment outcomes was analyzed.</p> Results <p>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 &gt; 44.05% showed a significantly lower PFS (median PFS: 10 months, 95% CI: 7–13 months), compared to patients with BRAF-VAF &lt; 44.05% (median PFS: 13 months, 95% CI: 12–21 months). Moreover, patients with higher VAF (&gt; 45.1%) experienced a lower OS (median OS: 26 months, 95% CI: 19–38 months), compared with patients with VAF &lt; 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.</p> Conclusions <p>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.</p>

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

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  • 发表日期：

    2025年12月17日

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  • Michele Guida,
  • Benedetta Apollonio,
  • Luca Romano,
  • Francesco Spagnolo,
  • Pietro Quaglino,
  • Roberta Depenni,
  • Rosamaria Pinto,
  • Teresa Squicciarini,
  • Livia Fucci,
  • Piergiorgio Di Tullio,
  • Maria Chiara Scaini,
  • Maria Teresa Maccallini,
  • Alice Indini,
  • Teresa Troiani,
  • Iole Natalicchio,
  • Sonia Brugnara,
  • Maurizio Lombardo,
  • Cristina Pellegrini,
  • Paola Queirolo,
  • Fabiana Perrone,
  • Alessandro Minisini,
  • Marco Tucci,
  • Raffaele Conca,
  • Silvia Costabile,
  • Miriam Macrì,
  • Enrica 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

摘要

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.