Correlation of BRAF Mutation Status in Circulating-Free DNA and Tumor and Association with Clinical Outcome across Four BRAFi and MEKi Clinical Trials
Autor: | Patricia Haney, Michelle Casey, Keith T. Flaherty, Anne O'Hagan, Ademi Santiago-Walker, Dirk Schadendorf, Vicki L. Goodman, Axel Hauschild, Jeffrey J. Legos, Richard F. Kefford, Robert C. Gagnon, Patrick Hwu, Jolly Mazumdar, Anne-Marie Martin, Georgina V. Long, Jennifer Carver |
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Rok vydání: | 2016 |
Předmět: |
Male
Proto-Oncogene Proteins B-raf 0301 basic medicine Cancer Research endocrine system diseases Medizin Kaplan-Meier Estimate Biology medicine.disease_cause 03 medical and health sciences 0302 clinical medicine Neoplasms Antineoplastic Combined Chemotherapy Protocols medicine Humans Molecular Targeted Therapy Codon skin and connective tissue diseases Protein Kinase Inhibitors neoplasms Trametinib Clinical Trials as Topic Mutation Melanoma MEK inhibitor Cancer Dabrafenib DNA Neoplasm Prognosis medicine.disease digestive system diseases Clinical trial enzymes and coenzymes (carbohydrates) Treatment Outcome 030104 developmental biology Amino Acid Substitution Oncology Circulating free DNA 030220 oncology & carcinogenesis Cancer research Female Mitogen-Activated Protein Kinases medicine.drug |
Zdroj: | Clinical Cancer Research. 22:567-574 |
ISSN: | 1557-3265 1078-0432 |
Popis: | 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 the BRAF inhibitor (BRAFi) dabrafenib or the MEK inhibitor (MEKi) 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 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 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. Conclusions: 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. Clin Cancer Res; 22(3); 567–74. ©2015 AACR. |
Databáze: | OpenAIRE |
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