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potential, such as the presence of ulceration or mitoses. The genetic characterization
of primary tumors as well as hereditary susceptibility to melanoma opens the door
for tailored pharmacologic therapy. Genetic testing for CDKN2A and CDK4 are
already available. Genetic tests for ARF and MC1R are likely to be available soon
to evaluate an individual’s hereditary risk for developing melanoma.
Several pharmacogenomic-based therapies are in development for melanoma.
However, once melanoma spreads beyond the regional nodes, the lack of validated
molecular targets hampers efforts to individualize therapy. In the past decade, tar-
geted inhibitors have been developed for metastatic melanoma to enable more per-
sonalized therapies of genetically characterized tumors. The identifi cation of
somatic mutations in the gene encoding the serine-threonine protein kinase BRAF
in the majority of melanomas offers an opportunity to test oncogene-targeted ther-
apy for this disease.
Inhibitors of BRAF Mutation for Metastatic Melanoma
Mucosal and acral-lentiginous melanomas, comprising 3 % of all melanomas, fre-
quently harbor activating mutations of c-kit and drugs targeting this mutation seem
to confer similar benefi ts for these types of tumors (Puzanov and Flaherty 2010 ).
V600E mutation of the BRAF serine/threonine kinase is present in >50 % of all
melanomas. The mutation appeared to confer a dependency by the melanoma can-
cer cell on activated signaling through mitogen-activated protein kinase pathway.
The frequency and location of this mutation (>95 % of all BRAF mutations being at
V600 position) suggested its importance in melanoma pathophysiology and poten-
tial as a target for therapy. Vemurafenib (PLX4032, Plexxikon/Roche) is an orally
available inhibitor of mutated BRAF. A phase II clinical trial showed that treatment
of metastatic melanoma with vemurafenib in patients with tumors that carry the
V600E BRAF mutation resulted in complete or partial tumor regression in the
majority of patients (Flaherty et al. 2010 ). A phase III randomized clinical trial
vemurafenib in patients with previously untreated, metastatic melanoma with the
BRAF V600E mutation showed improved survival as compared to those treated
with dacarbazine (Chapman et al. 2011 ). A treatment strategy that combines vemu-
rafenib with Yervoy (Bristol-Myers Squibb), an approved melanoma treatment, will
further improve outcomes for melanoma patients with BRAF mutation. In a phase
III open-label randomized trial, trametinib, as compared with chemotherapy,
improved rates of progression-free and overall survival among patients who had
metastatic melanoma with a BRAF V600E or V600K mutation (Flaherty et al.
2012 ). Quest offers Roche’s Cobas 4800 BRAF V600 Mutation Test that gauges
which melanoma patients have BRAF V600E mutations and may receive treatment
with another skin cancer agent, Zelboraf (vemurafenib). Quest also markets a
Sanger sequencing-based laboratory-developed test for assessing BRAF mutations
in melanoma patients.
In 2013, the FDA approved Tafi nlar (dabrafenib) and Mekinist (trametinib) as
treatments for advanced or unresectable melanoma patients whose tumors harbor
10 Personalized Therapy of Cancer