Clinical, pathologic, and biologic features associated with BRAF mutations in non-small cell lung cancer

Stephanie Cardarella, Atsuko Ogino, Mizuki Nishino, Mohit Butaney, Jeanne Shen, Christine Lydon, Beow Y. Yeap, Lynette M. Sholl, Bruce E. Johnson, Pasi A. Jänne

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Abstract

Purpose: BRAF mutations are found in a subset of non-small cell lung cancers (NSCLC). We examined the clinical characteristics and treatment outcomes of patients with NSCLC harboring BRAF mutations. Experimental Design: Using DNA sequencing, we successfully screened 883 patients with NSCLC for BRAF mutations between July 1, 2009 and July 16, 2012. Baseline characteristics and treatment outcomes were compared between patients with and without BRAF mutations. Wild-type controls consisted of patients with NSCLC without a somatic alteration in BRAF, KRAS, EGFR, and ALK. In vitro studies assessed the biologic properties of selected non-V600E BRAF mutations identified from patients with NSCLC. Results: Of 883 tumors screened, 36 (4%) harbored BRAF mutations (V600E, 18; non-V600E, 18) and 257 were wild-type for BRAF, EGFR, KRAS, and ALK negative. Twenty-nine of 36 patients with BRAF mutations were smokers. There were no distinguishing clinical features between BRAF-mutant and wildtype patients. Patients with advanced NSCLC with BRAF mutations and wild-type tumors showed similar response rates and progression-free survival (PFS) to platinum-based combination chemotherapy and no difference in overall survival. Within the BRAF cohort, patients with V600E-mutated tumors had a shorter PFS to platinum-based chemotherapy compared with those with non-V600E mutations, although this did not reach statistical significance (4.1 vs. 8.9 months; P = 0.297). We identified five BRAF mutations not previously reported in NSCLC; two of five were associated with increased BRAF kinase activity. Conclusions: BRAF mutations occur in 4% of NSCLCs and half are non-V600E. Prospective trials are ongoing to validate BRAF as a therapeutic target in NSCLC.

Original languageEnglish (US)
Pages (from-to)4532-4540
Number of pages9
JournalClinical Cancer Research
Volume19
Issue number16
DOIs
StatePublished - Aug 15 2013

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Non-Small Cell Lung Carcinoma
Mutation
Platinum
Disease-Free Survival
Proto-Oncogene Proteins B-raf
Neoplasms
Combination Drug Therapy
DNA Sequence Analysis
Research Design
Drug Therapy
Survival

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Clinical, pathologic, and biologic features associated with BRAF mutations in non-small cell lung cancer. / Cardarella, Stephanie; Ogino, Atsuko; Nishino, Mizuki; Butaney, Mohit; Shen, Jeanne; Lydon, Christine; Yeap, Beow Y.; Sholl, Lynette M.; Johnson, Bruce E.; Jänne, Pasi A.

In: Clinical Cancer Research, Vol. 19, No. 16, 15.08.2013, p. 4532-4540.

Research output: Contribution to journalArticle

Cardarella, S, Ogino, A, Nishino, M, Butaney, M, Shen, J, Lydon, C, Yeap, BY, Sholl, LM, Johnson, BE & Jänne, PA 2013, 'Clinical, pathologic, and biologic features associated with BRAF mutations in non-small cell lung cancer', Clinical Cancer Research, vol. 19, no. 16, pp. 4532-4540. https://doi.org/10.1158/1078-0432.CCR-13-0657
Cardarella, Stephanie ; Ogino, Atsuko ; Nishino, Mizuki ; Butaney, Mohit ; Shen, Jeanne ; Lydon, Christine ; Yeap, Beow Y. ; Sholl, Lynette M. ; Johnson, Bruce E. ; Jänne, Pasi A. / Clinical, pathologic, and biologic features associated with BRAF mutations in non-small cell lung cancer. In: Clinical Cancer Research. 2013 ; Vol. 19, No. 16. pp. 4532-4540.
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AU - Cardarella, Stephanie

AU - Ogino, Atsuko

AU - Nishino, Mizuki

AU - Butaney, Mohit

AU - Shen, Jeanne

AU - Lydon, Christine

AU - Yeap, Beow Y.

AU - Sholl, Lynette M.

AU - Johnson, Bruce E.

AU - Jänne, Pasi A.

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Y1 - 2013/8/15

N2 - Purpose: BRAF mutations are found in a subset of non-small cell lung cancers (NSCLC). We examined the clinical characteristics and treatment outcomes of patients with NSCLC harboring BRAF mutations. Experimental Design: Using DNA sequencing, we successfully screened 883 patients with NSCLC for BRAF mutations between July 1, 2009 and July 16, 2012. Baseline characteristics and treatment outcomes were compared between patients with and without BRAF mutations. Wild-type controls consisted of patients with NSCLC without a somatic alteration in BRAF, KRAS, EGFR, and ALK. In vitro studies assessed the biologic properties of selected non-V600E BRAF mutations identified from patients with NSCLC. Results: Of 883 tumors screened, 36 (4%) harbored BRAF mutations (V600E, 18; non-V600E, 18) and 257 were wild-type for BRAF, EGFR, KRAS, and ALK negative. Twenty-nine of 36 patients with BRAF mutations were smokers. There were no distinguishing clinical features between BRAF-mutant and wildtype patients. Patients with advanced NSCLC with BRAF mutations and wild-type tumors showed similar response rates and progression-free survival (PFS) to platinum-based combination chemotherapy and no difference in overall survival. Within the BRAF cohort, patients with V600E-mutated tumors had a shorter PFS to platinum-based chemotherapy compared with those with non-V600E mutations, although this did not reach statistical significance (4.1 vs. 8.9 months; P = 0.297). We identified five BRAF mutations not previously reported in NSCLC; two of five were associated with increased BRAF kinase activity. Conclusions: BRAF mutations occur in 4% of NSCLCs and half are non-V600E. Prospective trials are ongoing to validate BRAF as a therapeutic target in NSCLC.

AB - Purpose: BRAF mutations are found in a subset of non-small cell lung cancers (NSCLC). We examined the clinical characteristics and treatment outcomes of patients with NSCLC harboring BRAF mutations. Experimental Design: Using DNA sequencing, we successfully screened 883 patients with NSCLC for BRAF mutations between July 1, 2009 and July 16, 2012. Baseline characteristics and treatment outcomes were compared between patients with and without BRAF mutations. Wild-type controls consisted of patients with NSCLC without a somatic alteration in BRAF, KRAS, EGFR, and ALK. In vitro studies assessed the biologic properties of selected non-V600E BRAF mutations identified from patients with NSCLC. Results: Of 883 tumors screened, 36 (4%) harbored BRAF mutations (V600E, 18; non-V600E, 18) and 257 were wild-type for BRAF, EGFR, KRAS, and ALK negative. Twenty-nine of 36 patients with BRAF mutations were smokers. There were no distinguishing clinical features between BRAF-mutant and wildtype patients. Patients with advanced NSCLC with BRAF mutations and wild-type tumors showed similar response rates and progression-free survival (PFS) to platinum-based combination chemotherapy and no difference in overall survival. Within the BRAF cohort, patients with V600E-mutated tumors had a shorter PFS to platinum-based chemotherapy compared with those with non-V600E mutations, although this did not reach statistical significance (4.1 vs. 8.9 months; P = 0.297). We identified five BRAF mutations not previously reported in NSCLC; two of five were associated with increased BRAF kinase activity. Conclusions: BRAF mutations occur in 4% of NSCLCs and half are non-V600E. Prospective trials are ongoing to validate BRAF as a therapeutic target in NSCLC.

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