Background: 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. Material and methods: A cohort of MMPs receiving first line BRAFi and MEKi was identified by inspecting dedicated databases of 3 Italian Melanoma Intergroup centers. VAF was determined by next generation sequencing in pre-treatment baseline tissue samples. Correlation between VAF and BRAF copy number variation (CNV) was analysed in an ancillary study by using a training and a validation cohort of melanoma tissue samples and cell lines. Results: Overall, 107 MMPs were included in the study. The VAF cutoff 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. Conclusions: 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.
BRAFV600 variant allele frequency predicts outcome in metastatic melanoma patients treated with BRAF and MEK inhibitors / Mandalà, M., Palmieri, G., Ludovini, V., Baglivo, S., Marasciulo, F., Castiglione, F., Gili, A., Osella Abate, S., Rubatto, M., Senetta, R., Avallone, G., Ribero, S., Romano, L., Pimpinelli, N., de Giorgi, V., Roila, F., Pisano, M., Casula, M., Manca, A., Sini, M.C., et al.. - In: JOURNAL OF THE EUROPEAN ACADEMY OF DERMATOLOGY AND VENEREOLOGY. - ISSN 0926-9959. - (2023). [10.1111/jdv.19281]
BRAFV600 variant allele frequency predicts outcome in metastatic melanoma patients treated with BRAF and MEK inhibitors
Palmieri, GiuseppeConceptualization
;
2023-01-01
Abstract
Background: 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. Material and methods: A cohort of MMPs receiving first line BRAFi and MEKi was identified by inspecting dedicated databases of 3 Italian Melanoma Intergroup centers. VAF was determined by next generation sequencing in pre-treatment baseline tissue samples. Correlation between VAF and BRAF copy number variation (CNV) was analysed in an ancillary study by using a training and a validation cohort of melanoma tissue samples and cell lines. Results: Overall, 107 MMPs were included in the study. The VAF cutoff 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. Conclusions: 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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
