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

Purpose: The limited knowledge on the molecular profile of patients with BRAF -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 BRAF mutations and genomic alterations potentially related to resistance to BRAF-TT, in a large cohort of patients with BRAF -mutant NSCLC.
Experimental Design: This was a prospective study of 78 patients with advanced BRAF -mutant NSCLC, enrolled in 27 centers across France. Blood samples ( n = 208) were collected from BRAF-TT-naïve patients ( n = 47), patients nonprogressive under treatment ( n = 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. In silico structural modeling was used to predict the potential functional effect of the alterations found in ctDNA.
Results: BRAF ^V600E 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 BRAF -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 U2AF1, IDH1 , and CTNNB1 .
Conclusions: ctDNA sequencing is clinically relevant for the detection of BRAF -activating mutations and the identification of alterations potentially related to resistance to BRAF-TT in BRAF -mutant NSCLC.
(©2020 American Association for Cancer Research.)