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Employing Digital Droplet PCR to Detect BRAF V600E Mutations in Formalin-fixed Paraffin-embedded Reference Standard Cell Lines
Published on: October 8, 2015
Targeting the BRAF V600E mutation in multiple myeloma
Mindaugas Andrulis1, Nicola Lehners, David Capper
1Department of General Pathology, Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.
Abstract:
In multiple myeloma, there has been little progress in the specific therapeutic targeting of oncogenic mutations. Whole-genome sequencing data have recently revealed that a subset of patients carry an activating mutation (V600E) in the BRAF kinase. To uncover the clinical relevance of this mutation in multiple myeloma, we correlated the mutation status in primary tumor samples from 379 patients with myeloma with disease outcome. We found a significantly higher incidence of extramedullary disease and a shorter overall survival in mutation carriers when compared with controls. Most importantly, we report on a patient with confirmed BRAF V600E mutation and relapsed myeloma with extensive extramedullary disease, refractory to all approved therapeutic options, who has rapidly and durably responded to low doses of the mutation-specific BRAF inhibitor vermurafenib. Collectively, we provide evidence for the development of the BRAF V600E mutation in the context of clonal evolution and describe the prognostic and therapeutic relevance of this targetable mutation.
Insights
Activating BRAF V600E mutations in multiple myeloma are linked to worse outcomes. A patient with refractory disease showed durable response to BRAF inhibitor vermurafenib, highlighting a new therapeutic target.
Area of Science:
- Oncology
- Genetics
- Pharmacology
Background:
- Limited progress in targeted therapies for multiple myeloma.
- Recent whole-genome sequencing identified BRAF V600E mutations in a subset of patients.
Purpose of the Study:
- To investigate the clinical relevance of BRAF V600E mutations in multiple myeloma.
- To assess the prognostic and therapeutic impact of this mutation.
Main Methods:
- Correlation of BRAF V600E mutation status with disease outcome in 379 myeloma patients.
- Whole-genome sequencing of primary tumor samples.
- Case study of a patient with relapsed myeloma treated with vermurafenib.
Main Results:
- BRAF V600E mutation carriers showed a higher incidence of extramedullary disease and shorter overall survival.
- A patient with refractory, relapsed myeloma and BRAF V600E mutation achieved rapid, durable response to vermurafenib.
- Evidence for BRAF V600E mutation development during clonal evolution.
Conclusions:
- BRAF V600E mutation has prognostic significance in multiple myeloma.
- BRAF V600E is a targetable mutation, offering a potential therapeutic strategy for a subset of patients.
- Targeted inhibition with BRAF inhibitors like vermurafenib shows promise in refractory myeloma.
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