Targeting Non-V600 Mutations in BRAF: A Single Institution Retrospective Analysis and Review of the Literature

Abstract

Background and objective: While successful treatment paradigms for BRAF V600 mutations have been developed, 10% of BRAF mutations are not at V600 and lack a standard treatment regimen. This study summarizes the current body of knowledge on the treatment of non-V600 mutations and reports a single institution experience.

Methods: We conducted a literature review to summarize relevant preclinical and clinical published data on the response of non-V600 mutations to targeted therapies. We performed a retrospective analysis of INOVA Schar Cancer patients registered in our Molecular Tumor Board database with non-V600 BRAF mutations who were recipients of targeted therapy and assessed their time to next treatment and best response.

Results: Published preclinical and clinical data have demonstrated limiting results in the response of non-V600 mutated cancers to targeted therapies. Response rates were variable for the major classes of BRAF mutations including class II and class III mutations as well as, BRAF fusions. Data collected from our INOVA cohort offered promising results with one patient achieving partial remission and two patients achieving stable disease.

Conclusions: This article reflects the current understanding of targeted therapies in non-V600 mutations. Further large-scale studies separating BRAF mutations based on their mechanism of activation will expand our understanding.

Fig. 1

Classes of BRAF mutations that can result in activation of the MAPK pathway and examples of common mutations in each class. Class I mutations are the most common mutation that result in highly activating monomers. Class II mutations dimerize and moderately increase kinase activity. Class III mutation are kinase dead, but often result in paradoxical activation of CRAF via a feedback loop. BRAF fusions are activating fusions that retain the kinase domain. BRAF inhibitors, MEK inhibitors, and ERK inhibitors are drugs that target within the MAPK pathway [12].

Fig. 2

Computed tomography of the abdomen and pelvis of Case 1 with pancreatic ductal adenocarcinoma before third-line therapy with trametinib and a follow-up scan 224 days into treatment. Infiltrative changes were less apparent surrounding the pancreatic head in the mesentery while on targeted therapy