Impact of BRAF Mutation Class on Disease Characteristics and Clinical Outcomes in BRAF-Mutant Lung Cancer

Purpose: BRAF mutations are divided into functional classes based on signaling mechanism and kinase activity: V600-mutant kinase-activating monomers (class I), kinase-activating dimers (class II), and kinase-inactivating heterodimers (class III). The relationship between functional class and disease characteristics in BRAF-mutant non-small cell lung cancer (NSCLC) has not been fully explored. Experimental Design: We performed a retrospective analysis of BRAF-mutant NSCLCs treated at two institutions from 2005-2017 to determine clinicopathologic characteristics, progression-free survival (PFS) on chemotherapy, and overall survival (OS). Results: We identified 236 patients with BRAF-mutant NSCLC (n=107 class I, n=75 class II, and n=54 class III). Patients with class II or III mutations were more likely to have brain metastases (p≤0.01) and RAS co-alterations (p≤0.001). Compared to class I, PFS on chemotherapy was shorter for class II (p=0.069) and class III (p=0.034). OS was shorter for class II and III (Class I: 40.1 months, Class II: 13.9 months, Class III: 15.6 months; I vs II: p<0.001, I vs III: p=0.023); however, this difference was driven by fewer extra-thoracic metastases and higher use of targeted therapies in class I patients. When patients treated with targeted therapy and those with thoracic-only metastases were excluded, there was no difference in OS across the three classes. Conclusions: BRAF-mutant NSCLC is a heterogeneous disease that encompasses three distinct functional classes. Classes II and III have aggressive clinical features leading to less favorable outcomes. The distinct biological characteristics of class II and III tumors suggest that class-specific therapies may be necessary to effectively target these molecular subsets.

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