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

PURPOSE

mutations are divided into functional classes distinguished by 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 2 institutions from 2005 to 2017 to determine clinicopathologic characteristics, progression-free survival (PFS) on chemotherapy, and overall survival (OS).

RESULTS

We identified 236 patients with BRAF-mutant NSCLC ( = 107 class I, = 75 class II, and = 54 class III). Patients with class II or III mutations were more likely to have brain metastases ( ≤ 0.01) and coalterations ( ≤ 0.001) than class I. Compared with class I, PFS on chemotherapy was shorter for class II ( = 0.069) and class III ( = 0.034). OS was shorter for class II and III (class I, 40.1 months; class II, 13.9 months; and class III, 15.6 months; I vs. II, < 0.001; I vs. III, = 0.023); however, this difference was driven by fewer extrathoracic 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 3 classes.

CONCLUSIONS

BRAF-mutant NSCLC is a heterogeneous disease that encompasses 3 distinct functional classes. Classes II and III have more 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.