Is It Good or Bad to Find a BRAF Mutation

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. 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). 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. 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. 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, 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. The complementary roles played by BRAF and NRAS in melanoma are hinted at by their mutual exclusivity. Even in melanomas that lack a BRAF or NRAS mutation, there is ample evidence that the mitogen activated kinase-like protein kinase pathway is constitutively activated in the vast majority of cases. In other words, this signal transduction pathway appears to be central to melanoma biology and, therefore, one might not expect the activation of a particular component of the pathway to be associated with a difference in outcome. In this issue of Journal of Clinical Oncology, Long et al report, for the first time, on a consecutive series of patients with genetically characterized metastatic melanoma. Others have reported retrospective associations between BRAF mutations and various clinical and histopathologic features of melanoma. However, such cohorts could not meaningfully interrogate the prognostic significance of BRAF mutations. Importantly, Long et al confirmed the overall prevalence of BRAF mutations in the metastatic population and previously reported associations between BRAF mutation and young age at diagnosis with melanoma as well as site of primary melanoma. Theirs is the first analysis to investigate the prognostic significance of BRAF mutation as compared with site of metastatic disease, lactate dehydrogenase, and Eastern Cooperative Oncology Group performance status. There were no associations between these established prognostic factors and BRAF mutation. But the presence of a BRAF mutation was strongly associated with inferior survival in the metastatic setting. Interestingly, this finding was not paralleled by a difference in disease-free survival after the diagnosis of primary melanoma, though the selection of this metastatic patient cohort was not ideally suited for making such a connection. Although it is too early to say that a definitive prognostic marker has been uncovered in BRAF, there are several important implications for these findings that have already impacted the melanoma research and treatment communities. These results effectively rule out the possibility that BRAF might be a favorable prognostic marker. Thus, the emerging results from single-arm clinical trials with BRAF inhibitors in patients whose tumors harbor BRAF mutations can appropriately be embraced as evidence of clinical benefit in this notoriously aggressive disease. It is important to keep in mind that the mere association between the presence of BRAF mutation and poor survival does not allow conclusions regarding causality. Nonetheless, these data may have broader implications regarding our understanding of tumor biology descendent from so-called driver oncogenes such as BRAF. An exploratory analysis performed by Long et al suggests that BRAF-targeted therapy may obviate the more aggressive tumor biology conferred by JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L S VOLUME 29 NUMBER 10 APRIL 1 2011