Dataset Information

Molecular Landscape of BRAF-Mutant NSCLC Reveals an Association Between Clonality and Driver Mutations and Identifies Targetable Non-V600 Driver Mutations.

ABSTRACT:

Introduction

Approximately 4% of NSCLC harbor BRAF mutations, and approximately 50% of these are non-V600 mutations. Treatment of tumors harboring non-V600 mutations is challenging because of functional heterogeneity and lack of knowledge regarding their clinical significance and response to targeted agents.

Methods

We conducted an integrative analysis of BRAF non-V600 mutations using genomic profiles of BRAF-mutant NSCLC from the Guardant360 database. BRAF mutations were categorized by clonality and class (1 and 2: RAS-independent; 3: RAS-dependent). Cell viability assays were performed in Ba/F3 models. Drug screens were performed in NSCLC cell lines.

Results

A total of 305 unique BRAF mutations were identified. Missense mutations were most common (276, 90%), and 45% were variants of unknown significance. F468S and N581Y were identified as novel activating mutations. Class 1 to 3 mutations had higher clonality than mutations of unknown class (p < 0.01). Three patients were treated with MEK with or without BRAF inhibitors. Patients harboring G469V and D594G mutations did not respond, whereas a patient with the L597R mutation had a durable response. Trametinib with or without dabrafenib, LXH254, and lifirafenib had more potent inhibition of BRAF non-V600-mutant NSCLC cell lines than other MEK, BRAF, and ERK inhibitors, comparable with the inhibition of BRAF V600E cell line.

Conclusions

In BRAF-mutant NSCLC, clonality is higher in known functional mutations and may allow identification of variants of unknown significance that are more likely to be oncogenic drivers. Our data indicate that certain non-V600 mutations are responsive to MEK and BRAF inhibitors. This integration of genomic profiling and drug sensitivity may guide the treatment for BRAF-mutant NSCLC.

SUBMITTER: Negrao MV

PROVIDER: S-EPMC7529990 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Publications

Molecular Landscape of BRAF-Mutant NSCLC Reveals an Association Between Clonality and Driver Mutations and Identifies Targetable Non-V600 Driver Mutations.

Negrao Marcelo V MV Raymond Victoria M VM Lanman Richard B RB Robichaux Jacqulyne P JP He Junqin J Nilsson Monique B MB Ng Patrick K S PKS Amador Bianca E BE Roarty Emily B EB Nagy Rebecca J RJ Banks Kimberly C KC Zhu Viola W VW Ng Chun C Chae Young Kwang YK Clarke Jeffrey M JM Crawford Jeffrey A JA Meric-Bernstam Funda F Ignatius Ou Sai-Hong SH Gandara David R DR Heymach John V JV Bivona Trever G TG McCoach Caroline E CE

Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 20200613 10

<h4>Introduction</h4>Approximately 4% of NSCLC harbor BRAF mutations, and approximately 50% of these are non-V600 mutations. Treatment of tumors harboring non-V600 mutations is challenging because of functional heterogeneity and lack of knowledge regarding their clinical significance and response to targeted agents.<h4>Methods</h4>We conducted an integrative analysis of BRAF non-V600 mutations using genomic profiles of BRAF-mutant NSCLC from the Guardant360 database. BRAF mutations were categori ...[more]

PMID: 32540409

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Project description:BackgroundGiven advancements in adjuvant treatments for non-small-cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK)-targeted therapies, it is important to consider postoperative targeted therapies for other early-stage oncogene-addicted NSCLC. Exploring baseline outcomes for early-stage NSCLC with these rare mutations is crucial.ObjectivesThis study aims to assess relapse-free survival (RFS) and overall survival (OS) in patients with resected early-stage NSCLC with rare targetable driver mutations.MethodsThis retrospective single-center study identified stage I-III NSCLC patients with rare targetable mutations who underwent curative surgery. Tissue-based molecular profiling identified mutations in KRASG12C, EGFR Exon20, Erb-B2 receptor tyrosine kinase 2 (ERBB2), ALK, ROS1, B-Raf proto-oncogene (BRAF) V600E, mesenchymal-epithelial transition factor (MET) exon14 skipping, and rearranged during transfection (RET). Baseline patient and tumor characteristics, mutation subtype, and TP53 co-mutation were correlated with RFS and OS using Cox regression. The KRASG12C cohort was used as the reference for survival comparisons.ResultsAmong 225 patients, mutations included the following: KRASG12C (n = 101, 45%), MET exon 14 skipping (n = 26, 12%), EGFR Exon 20 (n = 25, 11%), ERBB2 (n = 25, 11%), ALK fusion (n = 16, 7%), ROS1 fusion (n = 14, 6%), BRAF V600E mutation (n = 13, 6%), and RET fusion (n = 5, 2%). Five-year survival probabilities were 76% for stage I, 60% for stage II, and 58% for stage III. RFS was shorter across most mutation subgroups compared to KRASG12C, with ROS1 mutations showing significantly poorer RFS (HR 2.70, p = 0.019). By contrast, all mutation subgroups were associated with better OS than KRASG12C. The incidence of brain metastasis was highest in ERBB2 (22% at 5 years). TP53 co-mutation was associated with significantly worse OS (HR 2.35, p = 0.008).ConclusionWhile RFS was poorer for most mutations compared to KRASG12C, OS generally was better, suggesting a potential role for postoperative targeted therapies. These findings warrant further investigation through prospective studies and clinical trials to optimize adjuvant treatment strategies for patients with early-stage NSCLC harboring rare driver mutations.

Project description:BackgroundResistance to therapy with BRAF kinase inhibitors is associated with reactivation of the mitogen-activated protein kinase (MAPK) pathway. To address this problem, we conducted a phase 1 and 2 trial of combined treatment with dabrafenib, a selective BRAF inhibitor, and trametinib, a selective MAPK kinase (MEK) inhibitor.MethodsIn this open-label study involving 247 patients with metastatic melanoma and BRAF V600 mutations, we evaluated the pharmacokinetic activity and safety of oral dabrafenib (75 or 150 mg twice daily) and trametinib (1, 1.5, or 2 mg daily) in 85 patients and then randomly assigned 162 patients to receive combination therapy with dabrafenib (150 mg) plus trametinib (1 or 2 mg) or dabrafenib monotherapy. The primary end points were the incidence of cutaneous squamous-cell carcinoma, survival free of melanoma progression, and response. Secondary end points were overall survival and pharmacokinetic activity.ResultsDose-limiting toxic effects were infrequently observed in patients receiving combination therapy with 150 mg of dabrafenib and 2 mg of trametinib (combination 150/2). Cutaneous squamous-cell carcinoma was seen in 7% of patients receiving combination 150/2 and in 19% receiving monotherapy (P=0.09), whereas pyrexia was more common in the combination 150/2 group than in the monotherapy group (71% vs. 26%). Median progression-free survival in the combination 150/2 group was 9.4 months, as compared with 5.8 months in the monotherapy group (hazard ratio for progression or death, 0.39; 95% confidence interval, 0.25 to 0.62; P<0.001). The rate of complete or partial response with combination 150/2 therapy was 76%, as compared with 54% with monotherapy (P=0.03).ConclusionsDabrafenib and trametinib were safely combined at full monotherapy doses. The rate of pyrexia was increased with combination therapy, whereas the rate of proliferative skin lesions was nonsignificantly reduced. Progression-free survival was significantly improved. (Funded by GlaxoSmithKline; ClinicalTrials.gov number, NCT01072175.).

Dataset Information

Molecular Landscape of BRAF-Mutant NSCLC Reveals an Association Between Clonality and Driver Mutations and Identifies Targetable Non-V600 Driver Mutations.

Introduction

Methods

Results

Conclusions

Publications

Molecular Landscape of BRAF-Mutant NSCLC Reveals an Association Between Clonality and Driver Mutations and Identifies Targetable Non-V600 Driver Mutations.

Similar Datasets

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