Abstract 468: BRAF mutation analysis in cell free tumoral DNA (cfDNA) of melanoma patients: results from the prospective study GEM1304 (Spanish Melanoma Group)
Authors: Gonzalez Cao Maria , Manzano Jose Luis , Soriano Virtudes , Puertolas Teresa , Soria Ainara , Mayo Clara , Magem Margarita , Molina Miguel Angel , Montagut Clara , Muñoz Eva , Rodriguez Delvys , Perez Elizabeth , Garcia Almudena , Cortes Javier , Jordana Nuria , Rodon Jordi , Karachaliou Niki , Rosell Rafael 
Published: July 2016

Abstract
Backgroud: Tumor-derived circulating cell-free DNA (cfDNA) is a dynamic source for determination of tumor mutation status. We have previously demonstrated the prognostic value of BRAFV600 mutation status in pretreatment cfDNA (BRAF pre-cfDNA) in advanced melanoma patients (p) treated with BRAF inhibitors (median overall survival [OS] 7 months [m] vs 22m for BRAF pre-cfDNA positive and negative p, respectively p = 0.017)1. Based on these results, the Spanish Melanoma Group conducted a prospective study in 13 centers to determine the prognostic value of BRAFV600 mutation in pre-cfDNA, the change in mutation status at time of first evaluation (BRAF early-cfDNA), and the correlation of BRAF cfDNA dynamics with clinical evolution (GEM1304) (ClinicalTrials.gov Identifier: NCT01960634).
Methods: One hundred and fifty nine plasma and serum samples from 66 stage IV BRAF mutant melanoma p were collected before and during treatment, until disease progression.
A quantitative 5’-nuclease PCR based assay was used to determine BRAFV600 mutation status in cfDNA.
Results: Most p were stage M1c (62%), treated with BRAF inhibitors (53%), and not previously treated (67%). BRAF pre-cfDNA was positive in 42 p (64%). Median OS was 6.4 m (95% CI: 10.9-23.6) and 17 m (95% CI: 3.5-9.2) for p with positive and negative BRAF pre-cfDNA, respectively (p = 0.06). Significant differences in OS were observed according to BRAF early-cfDNA negativization: 4.7 m (95%CI: 1.2-8.1) in those with persistence of BRAF in cfDNA (12 p), not reached (NR) in p with BRAF early-cfDNA negativization (11 p), and 22 m (95%CI:0.6-43.9) in those who continued to be negative (17 p) (p&lt;0.001). Median progression free survival (PFS) was 3.4 m (95% CI: 2.1-4.6), 16.8 m (95% CI: 6.9-26.8) and 15.3 (95%CI: 1.1-29.6), respectively (p&lt;0.001). There were also significant differences according to BRAF early-cfDNA among p treated with BRAF inhibitors: in p with persistence of BRAF in cfDNA (8p), median OS was 4.7 m (95% CI:16-7.8), NR for those with BRAF early-cfDNA negativization (9p), and 22 m (95%CI: 7.9-36.6) for those who continued to be negative (8 p) (p&lt;0.001). Median PFS was 3.6 m (95% CI: 2.2-5.1), 16.9 m (95% CI: 6.9-26.9) and 18 m (95% CI: 0.6-35.3), respectively (p = 0.001). In those p with serial samples taken during treatment, BRAF mutation disappeared from cfDNA in all cases who responded (18). Those with persistence of mutation during follow up had rapid progression and death (10). BRAF mutation had relapsed in cfDNA at time of progression in 6/15 cases.
Conclusions: Patients with early negativization of BRAFV600 in cfDNA have excellent prognosis, at least as good as those with negative BRAF in pre-cfDNA.
González-Cao et al. Mel Res 2015; 25:486
Citation Format: Maria Gonzalez Cao, Jose Luis Manzano, Virtudes Soriano, Teresa Puertolas, Ainara Soria, Clara Mayo, Margarita Magem, Miguel Angel Molina, Clara Montagut, Eva Muñoz, Delvys Rodriguez, Elizabeth Perez, Almudena Garcia, Javier Cortes, Nuria Jordana, Jordi Rodon, Niki Karachaliou, Rafael Rosell. BRAF mutation analysis in cell free tumoral DNA (cfDNA) of melanoma patients: results from the prospective study GEM1304 (Spanish Melanoma Group). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 468.