Recently, I described the rationale for targeting HER2 mutations in non-small cell lung cancer (NSCLC). Most of our experience with HER2 targeted therapy comes from studies in breast cancer. Now, I'd like to introduce you to BRAF, another novel target in NSCLC that is a central component in cell signalling, growth, and division.

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Most of our current information about BRAF comes from promising studies conducted with BRAF inhibitors in melanoma, a cancer that has been notoriously difficult to treat. Overall, BRAF mutations are one of the most common mutations in human cancers, though in lung cancer we estimate the frequency of BRAF mutations at only 1-3%. We've known for a while that these mutations occur in NSCLC but interest is really just picking up. Why? First, there are several BRAF inhibitors, some of which are showing promise in BRAF-mutated melanoma. Second, we now have more widespread ability to test for BRAF mutations (thanks to the success in melanoma) and to identify patients for clinical trials of BRAF inhibitors.

BRAF, like EGFR and other proteins involved in cancer progression, is part of a pathway that transmits signals from the cell surface to the interior of cell, ultimately leading to cell proliferation or in the case of cancer, progression. MEK is a protein which is downstream of BRAF and one of the key proteins involved in cellular growth and proliferation. MEK inhibitors represent another group of drugs that may be used to target this pathway. While it is still early in the BRAF story, we have learned some valuable lessons by looking at the tumors of patients with NSCLC. In contrast to melanoma, where only one specific mutation is found (called the V600E), in lung cancer, there are multiple different mutations that can occur in BRAF. This makes testing more complicated and expensive because we have to test for multiple mutations. We also are not sure yet if particular mutations will be more likely to predict response to drugs targeting the BRAF pathway. Although the number of patients studied to date has been small, it appears that BRAF mutations are most likely to occur in adenocarcinomas and in former or current smokers. It also appears that BRAF mutations are not found in patients who have KRAS or EGFR mutations. In laboratory studies, cells with BRAF mutations were resistant to EGFR inhibitors.

So what does this mean for lung cancer patients? In melanoma, BRAF inhibitors are showing great promise. We hope that on a molecular level, BRAF mutant lung cancer will behave like BRAF mutant melanoma and that the chance of response to these drugs will be high. The Lung Cancer Mutation Consortium trial tests for multiple BRAF mutations, and clinical trials of BRAF inhibitors will be offered through the consortium. Testing for the V600E mutation is more widely available and may also identify patients who can then be referred for BRAF inhibitor trials. Interestingly, Nexavar (sorafenib), which inhibits multiple targets, also has activity against BRAF (its name of sorafenib refers to this, actually). This drug has shown some promise in patients with KRAS mutations though this drug has not been investigated specifically in a BRAF-mutant patient population. Currently, the idea is to use BRAF inhibitors drugs in second-line or greater patients so previous treatment with chemotherapy will be required to participate. Side effects described so far have been for the most part mild, primarily consisting of fatigue, headaches, decreased appetite and skin changes. Stay tuned: I hope that we will be able to get a large number of patients tested for BRAF and on these clinical trials.