Circulating Tumor DNA Genomics Reveal Potential Mechanisms of Resistance to BRAF-Targeted Therapies in Patients with BRAF -Mutant Metastatic Non–Small Cell Lung Cancer - CNRS - Centre national de la recherche scientifique Accéder directement au contenu
Article Dans Une Revue Clinical Cancer Research Année : 2020

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

Laura Mezquita
  • Fonction : Auteur
Mihalea Aldea
  • Fonction : Auteur
Julien Mazieres
Cecile Jovelet
  • Fonction : Auteur
Anne Pradines
Virginie Avrillon
  • Fonction : Auteur
Washington Chumbi Flores
  • Fonction : Auteur
Ludovic Lacroix
Yohann Loriot
  • Fonction : Auteur
Virginie Westeel
  • Fonction : Auteur
Maud Ngo-Camus
  • Fonction : Auteur
Claire Tissot
  • Fonction : Auteur
Christine Raynaud
  • Fonction : Auteur
Radj Gervais
  • Fonction : Auteur
Etienne Brain
Isabelle Monnet
  • Fonction : Auteur
Etienne Giroux Leprieur
  • Fonction : Auteur
Caroline Caramella
  • Fonction : Auteur
Celine Mahier-Aït Oukhatar
  • Fonction : Auteur
Natalie Hoog-Labouret
  • Fonction : Auteur
Frank de Kievit
  • Fonction : Auteur
Karen Howarth
  • Fonction : Auteur
Clive Morris
  • Fonction : Auteur
Emma Green
  • Fonction : Auteur
Luc Friboulet
Sylvie Chabaud
  • Fonction : Auteur
Jean-François Guichou
  • Fonction : Auteur
Benjamin Besse
  • Fonction : Auteur
David Planchard
  • Fonction : Auteur

Résumé

Abstract 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: 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% 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.

Dates et versions

hal-03851856 , version 1 (14-11-2022)

Identifiants

Citer

Sandra Ortiz-Cuaran, Laura Mezquita, Aurélie Swalduz, Mihalea Aldea, Julien Mazieres, et al.. Circulating Tumor DNA Genomics Reveal Potential Mechanisms of Resistance to BRAF-Targeted Therapies in Patients with BRAF -Mutant Metastatic Non–Small Cell Lung Cancer. Clinical Cancer Research, 2020, 26 (23), pp.6242-6253. ⟨10.1158/1078-0432.CCR-20-1037⟩. ⟨hal-03851856⟩
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