DOI: 10.1111/jdv.19281 ISSN: 0926-9959

BRAFV600 variant allele frequency predicts outcome in metastatic melanoma patients treated with BRAF and MEK inhibitors

Mario Mandalà, Giuseppe Palmieri, Vienna Ludovini, Sara Baglivo, Francesca Marasciulo, Francesca Castiglione, Alessio Gili, Simona Osella Abate, Marco Rubatto, Rebecca Senetta, Gianluca Avallone, Simone Ribero, Luca Romano, Nicola Pimpinelli, Vincenzo de Giorgi, Fausto Roila, Marina Pisano, Milena Casula, Antonella Manca, Maria Cristina Sini, Daniela Massi, Pietro Quaglino,
  • Infectious Diseases
  • Dermatology



The prognostic impact of variant allele frequency (VAF) on clinical outcome in BRAFV600 mutated metastatic melanoma patients (MMPs) receiving BRAF (BRAFi) and MEK inhibitors (MEKi) is unclear.

Materials and Methods

A cohort of MMPs receiving first line BRAFi and MEKi was identified by inspecting dedicated databases of three Italian Melanoma Intergroup centres. VAF was determined by next generation sequencing in pre‐treatment baseline tissue samples. Correlation between VAF and BRAF copy number variation was analysed in an ancillary study by using a training and a validation cohort of melanoma tissue samples and cell lines.


Overall, 107 MMPs were included in the study. The VAF cut‐off determined by ROC curve was 41.3%. At multivariate analysis, progression‐free survival (PFS) was significantly shorter in patients with M1c/M1d [HR 2.25 (95% CI 1.41–3.6, p < 0.01)], in those with VAF >41.3% [HR 1.62 (95% CI 1.04–2.54, p < 0.05)] and in those with ECOG PS ≥1 [HR 1.82 (95% CI 1.15–2.88, p < 0.05)]. Overall survival (OS) was significantly shorter in patients with M1c/M1d [HR 2.01 (95% CI 1.25–3.25, p < 0.01)]. Furthermore, OS was shorter in patients with VAF >41.3% [HR 1.46 (95% CI 0.93–2.29, p = 0.06)] and in patients with ECOG PS ≥1 [HR 1.52 (95% CI 0.94–2.87, p = 0.14)]. BRAF gene amplification was found in 11% and 7% of samples in the training and validation cohort, respectively.


High VAF is an independent poor prognostic factor in MMP receiving BRAFi and MEKi. High VAF and BRAF amplification coexist in 7%–11% of patients.

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