Circulating Tumor DNA Genomics Reveal Potential Mechanisms of Resistance to BRAF-Targeted Therapies in Patients withBRAF-Mutant Metastatic Non–Small Cell Lung Cancer
- 1 December 2020
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Clinical Cancer Research
- Vol. 26 (23), 6242-6253
- https://doi.org/10.1158/1078-0432.ccr-20-1037
Abstract
Purpose: The limited knowledge on the molecular profile of BRAF-mutant non-small cell lung cancer (NSCLC) patients 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 ctDNA targeted sequencing to identify canonical BRAF mutations and genomic alterations potentially related to resistance to BRAF-TT, in a large cohort of BRAF-mutant NSCLC patients. Experimental Design: Prospective study of 78 advanced BRAF-mutant NSCLC patients, enrolled in 27 centers across France. Blood samples (n=208) were collected from BRAF-TT-naïve patients (n=47), non-progressive under treatment (n=115) or at disease progression (PD) to BRAF-TT (24/46 on BRAF-monotherapy; 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: BRAFV600E 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% 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% patients and 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.Keywords
Other Versions
Funding Information
- Fondation ARC (PJA 2017-1206573)
- INCa DGOS (INCa-DGOS-Inserm_12563)
- Agence national de la recherche (ANR-10-BINF-03-03)
- University Hospital of Toulouse (DC-2011-1382, AC-2013-1984, CNIL 1727608)
This publication has 67 references indexed in Scilit:
- Tumor Genetic Analyses of Patients with Metastatic Melanoma Treated with the BRAF Inhibitor Dabrafenib (GSK2118436)Clinical Cancer Research, 2013
- Genotype-Dependent Sensitivity of Uveal Melanoma Cell Lines to Inhibition of B-Raf, MEK, and Akt Kinases: Rationale for Personalized TherapyInvestigative Ophthalmology & Visual Science, 2011
- Dissecting Therapeutic Resistance to RAF Inhibition in Melanoma by Tumor Genomic ProfilingJournal of Clinical Oncology, 2011
- Clinical Characteristics of Patients With Lung Adenocarcinomas Harboring BRAF MutationsJournal of Clinical Oncology, 2011
- PTEN Loss Confers BRAF Inhibitor Resistance to Melanoma Cells through the Suppression of BIM ExpressionCancer Research, 2011
- Acquired Resistance to BRAF Inhibitors Mediated by a RAF Kinase Switch in Melanoma Can Be Overcome by Cotargeting MEK and IGF-1R/PI3KCancer Cell, 2010
- Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulationNature, 2010
- The activating mutation R201C in GNAS promotes intestinal tumourigenesis in ApcMin/+ mice through activation of Wnt and ERK1/2 MAPK pathwaysOncogene, 2010
- Differential sensitivity of melanoma cell lines with BRAF V600E mutation to the specific Raf inhibitor PLX4032Journal of Translational Medicine, 2010
- A Chromatin-Mediated Reversible Drug-Tolerant State in Cancer Cell SubpopulationsCell, 2010