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Ref Type Journal Article
PMID (32859654)
Authors Ortiz-Cuaran S, Mezquita L, Swalduz A, Aldea M, Mazieres J, Leonce C, Jovelet C, Pradines A, Avrillon V, Chumbi Flores WR, Lacroix L, Loriot Y, Westeel V, Ngo-Camus M, Tissot C, Raynaud C, Gervais R, Brain E, Monnet I, Giroux Leprieur E, Caramella C, Mahier-Aït Oukhatar C, Hoog-Labouret N, de Kievit F, Howarth K, Morris C, Green E, Friboulet L, Chabaud S, Guichou JF, Perol M, Besse B, Blay JY, Saintigny P, Planchard D
Title Circulating Tumor DNA Genomics Reveal Potential Mechanisms of Resistance to BRAF-Targeted Therapies in Patients with BRAF-Mutant Metastatic Non-Small Cell Lung Cancer.
Journal Clinical cancer research : an official journal of the American Association for Cancer Research
Vol 26
Issue 23
Date 2020 Dec 01
URL
Abstract Text 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.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.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.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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
FGFR2 A553D missense unknown FGFR2 A553D lies within the protein kinase domain of the Ffgr2 protein (UniProt.org). A553D has been predicted to affect the protein stability of Fgfr2 by structural modeling (PMID: 32859654), but has not been biochemically characterized and therefore, its effect on Fgfr2 protein function is unknown (PubMed, Apr 2022).
PTEN R14K missense no effect - predicted PTEN R14K lies within the phosphatase tensin-type domain of the Pten protein (UniProt.org). R14K results in altered subcellular localization, but results in phosphatase activity similar to that of wild-type Pten in culture (PMID: 25875300), and has been predicted to have no effect on protein stability by structural modeling (PMID: 32859654), and therefore, is predicted to have no effect on Pten protein function.
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
BRAF V600E PIK3CA E545K lung non-small cell carcinoma predicted - sensitive Vemurafenib Case Reports/Case Series Actionable In a clinical study, Zelboraf (vemurafenib) treatment resulted in stable disease for 6.4 months in a non-small cell lung cancer patient harboring BRAF V600E, tested in tissue and plasma, and PIK3CA E545K, tested in plasma only (PMID: 32859654). 32859654
BRAF V600E FGFR2 A553D lung non-small cell carcinoma predicted - sensitive Vemurafenib Case Reports/Case Series Actionable In a clinical study, Zelboraf (vemurafenib) treatment resulted in stable disease for 3.3 months in a non-small cell lung cancer patient harboring BRAF V600E, tested in tissue and plasma, and FGFR2 A553D, tested in plasma only (PMID: 32859654). 32859654