By Gregory A. Hosler, M.D., Ph.D. and Kathleen M. Murphy, Ph.D.
Background and Clinical Significance
Patients with metastatic melanoma have a poor prognosis with few therapeutic options. Dacarbazine is the only FDA approved chemotherapeutic agent for advanced stage melanoma and results in an unsatisfactory median survival of only six months following initiation of treatment. As melanoma is not one single disease, targeting molecular defects specific to individual tumors potentially offers a better therapeutic strategy.
Approximately 50% of cutaneous melanomas carry a mutation in the BRAF gene that leads to activation of cell signaling for growth and division. The vast majority of these mutations occur at amino acid position 600, the most common of which results in the V600E amino acid substitution. Some studies suggest that melanomas with the BRAF V600E mutation are more aggressive and are less sensitive to chemotherapy.
Vemurafenib (PLX4032) is a small molecule inhibitor that targets mutated BRAF. A recent study published in the New England Journal of Medicine compared the use of vemurafenib and dacarbazine in patients with previously untreated metastatic melanoma (Stage IIIC or Stage IV) containing the BRAF V600E mutation. The results of their Phase III trial demonstrated a 63% reduction in the risk of death and a 74% reduction in the risk of disease progression as compared with dacarbazine. The response rate with vemurafenib was 48% compared with 5% for dacarbazine. Therefore, patients with advanced melanoma harboring the BRAF V600E mutation may benefit from specific inhibitor therapy.
The Assay Performed at ProPath:
- At ProPath®, all tissues submitted for analysis are reviewed by our expert pathologists to ensure adequacy for testing, and to identify the area of tissue most suitable for analysis. This reduces the risk for false negative results due to testing of inappropriate areas of tissue.
- Our assay uses pyrosequencing technology, which has a better limit of detection (approximately 5%) compared to standard Sanger sequencing (approximately 20%), further reducing the risk for false negative results.
- This assay is performed on formalin-fixed paraffin-embedded tumor specimens.
- Turnaround time is 3-6 days from the time the specimen arrives in the laboratory.
- Chapman PB et al. Improved Survival with Vemurafenib in Melanoma with BRAF V600E mutation. N Engl J Med 2011 (June 5 Epub).
- Flaherty KT, et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med 2010;363:809.
- Arkenau H-T, et al. Targeting BRAF for patients with melanoma. Br J Cancer 2011;104:392.