Circulating Tumor DNA Genomics Reveal Potential Mechanisms of Resistance to BRAF-Targeted Therapies in Patients with <i>BRAF</i>-Mutant Metastatic Non-Small Cell Lung Cancer.

Abstract

The limited knowledge on the molecular profile of patients with <i>BRAF</i>-mutant non-small cell lung cancer (NSCLC) who progress under BRAF-targeted therapies (BRAF-TT) has hampered the development of subsequent therapeutic strategies for these patients. Here, we evaluated the clinical utility of circulating tumor DNA (ctDNA)-targeted sequencing to identify canonical <i>BRAF</i> mutations and genomic alterations potentially related to resistance to BRAF-TT, in a large cohort of patients with <i>BRAF</i>-mutant NSCLC. This was a prospective study of 78 patients with advanced <i>BRAF</i>-mutant NSCLC, enrolled in 27 centers across France. Blood samples (<i>n</i> = 208) were collected from BRAF-TT-naïve patients (<i>n</i> = 47), patients nonprogressive under treatment (<i>n</i> = 115), or patients at disease progression (PD) to BRAF-TT (24/46 on BRAF monotherapy and 22/46 on BRAF/MEK combination therapy). ctDNA sequencing was performed using InVisionFirst-Lung. <i>In silico</i> structural modeling was used to predict the potential functional effect of the alterations found in ctDNA. <i>BRAF^V600E</i> ctDNA was detected in 74% of BRAF-TT-naïve patients, where alterations in genes related with the MAPK and PI3K pathways, signal transducers, and protein kinases were identified in 29% of the samples. ctDNA positivity at the first radiographic evaluation under treatment, as well as <i>BRAF</i>-mutant ctDNA positivity at PD were associated with poor survival. Potential drivers of resistance to either BRAF-TT monotherapy or BRAF/MEK combination were identified in 46% of patients and these included activating mutations in effectors of the MAPK and PI3K pathways, as well as alterations in <i>U2AF1, IDH1</i>, and <i>CTNNB1</i>. ctDNA sequencing is clinically relevant for the detection of <i>BRAF</i>-activating mutations and the identification of alterations potentially related to resistance to BRAF-TT in <i>BRAF</i>-mutant NSCLC.