Dr. Gerald Falchook and colleagues at MD Anderson Cancer Center provided the first report of a GIST patient responding to a BRAF inhibitor.  The BRAF gene is frequently mutated in melanoma and BRAF inhibitors provide one of the most important therapies available for melanoma patients. BRAF mutations are rare in GIST however, making up about 13% of patients with wildtype GIST (which is itself about 10-15% of all GISTs). Wildtype GIST is basically a diagnosis of exclusion; patients that have neither a KIT nor PDGFRA mutation are classified as wildtype GIST. At the current time, this includes patients that have a BRAF mutation and patients that have mutations that affect the SDH protein (this causes pediatric-like GIST). The wildtype GIST classification may change in the future as it becomes apparent that some of these patients have identifiable mutations that suggest which therapies might or might not work.

BRAF mutations were first reported in 2008 in GIST patients by Agaram et al., from Memorial Sloan-Kettering Cancer Center. BRAF mutations have been found in GIST patients that have never had Gleevec (as a primary mutation) as well as in a patient with a PDGFRA mutation that eventually became resistant to Gleevec (as a secondary mutation).

Most GIST patients respond to Gleevec and other KIT inhibitors (or PDGFRA inhibitors in some cases), because KIT or PDGFRA is the most important mutation; it’s the primary driver of their cancer. Melanoma patients respond to BRAF inhibitors for the same reason, because BRAF is the most important mutation for their cancer; it’s the driver mutation. These driver mutations are not the only mutation in these patients, but they are the most important ones. What had previously been unknown regarding GIST patients with BRAF mutations was whether these mutations were the driver mutations; were they so important that BRAF inhibitors would work? The report of a response from MD Anderson appears to provide proof of concept that they are.

In melanoma, one concern has been that responses are typically not as long-lasting as in GIST. This has spurred a search into mechanisms of resistance. One promising approach is combining BRAF inhibitors with MEK inhibitors.  The response of the BRAF/GIST patient reported by MD Anderson was about 8 months; this is also shorter than the typical GIST response of 2 years or more.

The question of how to treat the rare BRAF mutations that occur in cancers other than melanoma (such as GIST), is one of concern, since it is often difficult to conduct clinical trials for such rare mutations. Fortunately for GIST patients, mutational analysis to test for BRAF and other rare mutations in GIST is clinically available from Knight Diagnostic Laboratories with a new 23 gene GIST panel. The GIST patient treated at MD Anderson was in a clinical trial that used the drug dabrafenib (GSK2118436). At least one BRAF inhibitor, Zelboraf, has already been approved for melanoma.

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Jerry Call
Author: Jerry Call