Abstract
BRAF 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. 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). 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 coalterations (P ≤ 0.001) than class I. Compared with 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; and class III, 15.6 months; I vs. II, P < 0.001; I vs. III, P = 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. 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.
Highlights
Non–small cell lung cancer (NSCLC) is a heterogeneous disease composed of an expanding number of biologically distinct and clinically relevant molecular subsets [1, 2]
The distinct biological characteristics of class II and III tumors suggest that classspecific therapies may be necessary to effectively target these molecular subsets
We demonstrate that lung cancers with class II and III BRAF mutations share molecular characteristics and possess unfavorable clinical features that are distinct from class I tumors, including worse overall survival
Summary
Non–small cell lung cancer (NSCLC) is a heterogeneous disease composed of an expanding number of biologically distinct and clinically relevant molecular subsets [1, 2]. Identification of these unique molecular drivers and development of highly effective genotype-specific therapies have transformed the natural history of disease for select subgroups of NSCLC [1]. There is variability in clinical characteristics and the magnitude of benefit from identical therapies among patients with NSCLCs that share a common oncogenic driver [3,4,5]. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).
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