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BRAF V600E Mutation Positive Malignant Melanoma

Posted on August 07 2013

BRAF V600E Mutation Positive Malignant Melanoma
Case Study

A recently published phase 3 clinical trial demonstrates that a novel melanoma therapy targeted to the BRAF V600E gene mutation has significant therapeutic efficacy against BRAF V600E mutated melanomas. The BRAF V600E mutation is present in 30-60% of cutaneous melanomas.

Vemurafenib, a drug with specific inhibitory activity against the BRAF V600E mutated kinase, demonstrates superior overall and progression-free survival compared to dacarbazine in patients with previously untreated, metastatic BRAF V600E mutation-positive melanoma.

Oncologists can now consider vemurafenib therapy for high stage melanoma patients who are positive for BRAF V600E gene mutation.

By coincidence, a separate unrelated publication released ahead of print at the same time by the NEJM describes successful treatment of metastatic melanoma with a different, novel therapy, ipilimunab, a monoclonal antibody drug that activates anti-tumor T cell activity by blocking cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4). And thirdly, a June issue of JAMA reports successful use of Gleevec® in treating c-kit amplified malignant melanoma. Among a subset of patients with c-kit amplified melanomas, 16% had a significant response to Gleevec.

These are striking therapeutic developments. Monoclonal anti-CTLA-4 therapy is arguably a modern extrapolation of longstanding attempts to treat melanoma by immune modulation. In contrast, vemurafenib and Gleevec represent targeted therapies directed towards measurable melanoma genotypes, those containing the BRAF V600E mutation or c-kit amplification, both of which require laboratory testing for drug eligibility.

History

A 61 year-old female with known history of malignant melanoma developed a right pleural effusion and underwent pleural biopsy.

Microscopic Findings: 

Routine histologic sections demonstrate sheets of mitotically active, loosely cohesive malignant cells with open chromatin, single prominent nucleoli, and abundant pale eosinophillic cytoplasm.

Fig 1. Frequent mitoses
Frequent mitoses

Fig 2. Mart-1 (+)

Fig 3. S100 protein (+)
Fig 4. Calretinin (-)

Special Studies

Molecular
The incidence of the BRAF V600E mutation in metastatic melanoma is approximately 45% and the presence of this mutation is highly predictive of improved rates of overall and progression-free survival in patients with previously untreated melanoma who received the BRAF kinase inhibitor vemurafenib (PLX4032).

Fig 5. BRAF mutation analysis was performed using the TrimGen Mutector™ II BRAF kit (TrimGen Corporation Sparks MD).

References: 

Chapman, et al. (2011). Improved survival inMelanoma with BRAF V600E mutation. NEJM; 364:2507-2516

Flaherty K et al.(2010). Inhibition of mutated, activated BRAF in Metastatic Melanoma  NEJM; 363:809-819

 


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