Year: 2011
Type: editorial
Abstract: Since the discovery of BRAF mutations in 2002, the focus of the cancer research community has been on a potential therapeutic relevance of this oncogene in melanoma and other cancers. 1 After the initial disappointment with the results achieved in clinical trials with the first generation RAF proto-oncogene serine/threonine-protein kinase (RAF kinase) inhibitor, sorafenib, the validation of BRAF as a therapeutic target was finally realized with two highly selective RAF kinase inhibitors (PLX4032 and GSK2118436).[2][3][4] However, this supportive evidence comes from uncontrolled, single-arm clinical trials in which it is difficult, if not impossible, to discern a clear survival improvement.As with other oncogene-directed therapies, including small molecule epidermal growth factor receptor inhibitors in epidermal growth factor receptor-mutant non-small-cell lung cancer and KIT inhibitors in KIT-mutated GI stromal tumor, single-agent BRAFtargeted therapy results in high response rates and apparently meaningful disease control in the metastatic setting.5,6 There is little doubt regarding the predictive value of BRAF mutation for response to this therapy.However, there has been a paucity of evidence regarding the prognostic significance of BRAF mutations.Prognostic indicators in the setting of metastatic melanoma are few in number and fail to adequately discriminate between the large subpopulation of patients with an aggressive disease course and the small subpopulation with a relatively indolent natural history.The American Joint Committee on Cancer staging system incorporates two disease characteristics to define sub-stages of metastatic melanoma: extent of metastatic disease, as determined by site, and serum lactate dehydrogenase.7 It is also clear from a recent, large metaanalysis of cooperative group clinical trial populations that Eastern Cooperative Oncology Group performance status is also an important prognostic factor in the metastatic setting, 8 although this factor is not incorporated into American Joint Committee on Cancer staging.Even after combining these three prognostic factors, there is misclassification of patients into poor and favorable prognostic groups.Thus, there is clearly room for significant improvement and is has been hoped that molecular classification would fill this void.BRAF mutations are common in melanoma and testing for their presence is well within the reach of most academic pathology laboratories.But most investigators have assumed that BRAF-mutant melanoma would not have a different clinical course then those tumors that lack a BRAF mutation.At the genetic level, 40% of melanomas that lack a BRAF mutation harbor an NRAS mutation which appears to similarly activate the same signal transduction pathway in which BRAF resides, the so-called mitogen-activated kinase-like protein kinase pathway.9 The complementary roles played by BRAF and
Source: Journal of Clinical Oncology
Author: Keith T. Flaherty
Institution: Massachusetts General Hospital
Language: English
Topic: Melanoma and MAPK Pathways
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W2031807471