Correlation of BRAF mutation status in circulating-free DNA and tumor and association with clinical outcome across four BRAFi and MEKi clinical trials
A partir d'échantillons sanguins prélevés sur 836 patients atteints d'un mélanome présentant une mutation V600 du gène BRAF et inclus dans un essai clinique d'évaluation du dabrafénib ou du tramétinib, cette étude analyse les performances d'une méthode de détection des mutations BRAF dans l'ADN libre circulant, puis évalue l'association entre les résultats obtenus par cette méthode et la survie des patients
Purpose: Tumor-derived circulating cell-free DNA (cfDNA) is a potential alternative source from which to derive tumor mutation status. cfDNA data from four clinical studies of dabrafenib or trametinib were analyzed to determine the association between BRAF mutation status in cfDNA and tumor tissue, and the association of BRAF cfDNA mutation status with baseline factors and clinical outcome.
Experimental Design: Patients with BRAF V600 mutation-positive melanoma were enrolled in each study after central confirmation of BRAF status in tumor using a polymerase chain reaction (PCR)-based assay. BRAF mutation status in cfDNA from patient plasma collected at baseline, 732 of 836 (88%) enrolled patients in total, was determined.
Results: BRAF mutations were detectable in cfDNA in 76% and 81% of patients with BRAF V600E/V600K-positive tumors, respectively. Patients negative for BRAF mutations in cfDNA had longer progression-free survival (PFS) and overall survival (OS) in each of the four studies, compared with patients with detectable cfDNA BRAF mutations. The presence of BRAF mutant cfDNA was an independent prognostic factor for PFS after multivariate adjustment for baseline factors in three of four studies. Patients negative for BRAF mutation-positive cfDNA in plasma had higher response rates to dabrafenib and trametinib.
Conclusion: BRAF mutations in cfDNA are detectable in >75% of late-stage melanoma patients with BRAF mutation-positive tumors. The lack of circulating, BRAF mutation-positive cfDNA is clinically significant for metastatic melanoma patients, and may be a prognostic marker for better disease outcome.
Clinical Cancer Research , article en libre accès, 2015