TY - JOUR
T1 - Circulating tumor DNA genomics reveal potential mechanisms of resistance to BRAF-targeted therapies in patients with BRAF-mutant metastatic non-small cell lung cancer
AU - Ortiz-Cuaran, Sandra
AU - Mezquita, Laura
AU - Swalduz, Aurelie
AU - Aldea, Mihalea
AU - Mazieres, Julien
AU - Leonce, Camille
AU - Jovelet, Cecile
AU - Pradines, Anne
AU - Avrillon, Virginie
AU - Chumbi Flores, Washington R.
AU - Lacroix, Ludovic
AU - Loriot, Yohann
AU - Westeel, Virginie
AU - Ngo-Camus, Maud
AU - Tissot, Claire
AU - Raynaud, Christine
AU - Gervais, Radj
AU - Brain, Etienne
AU - Monnet, Isabelle
AU - Leprieur, Etienne Giroux
AU - Caramella, Caroline
AU - Oukhatar, Celine Mahier Aït
AU - Hoog-Labouret, Natalie
AU - de Kievit, Frank
AU - Howarth, Karen
AU - Morris, Clive
AU - Green, Emma
AU - Friboulet, Luc
AU - Chabaud, Sylvie
AU - Guichou, Jean François
AU - Perol, Maurice
AU - Besse, Benjamin
AU - Blay, Jean Yves
AU - Saintigny, Pierre
AU - Planchard, David
N1 - Publisher Copyright:
© 2020 American Association for Cancer Research.
PY - 2020/12/1
Y1 - 2020/12/1
N2 - 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 ¼ 208) were collected from BRAF-TT-naïve patients (n ¼ 47), patients nonprogressive under treatment (n ¼ 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.
AB - 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 ¼ 208) were collected from BRAF-TT-naïve patients (n ¼ 47), patients nonprogressive under treatment (n ¼ 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.
UR - http://www.scopus.com/inward/record.url?scp=85092129690&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-20-1037
DO - 10.1158/1078-0432.CCR-20-1037
M3 - Article
C2 - 32859654
AN - SCOPUS:85092129690
SN - 1078-0432
VL - 26
SP - 6242
EP - 6253
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 23
ER -