Distinct clinical features and outcomes in never-smokers with nonsmall cell lung cancer who harbor EGFR or KRAS mutations or ALK rearrangement

Hye Ryun Kim, Hyo Sup Shim, Jin Haeng Chung, Young Joo Lee, Yun Kyoung Hong, Sun Young Rha, Se Hoon Kim, Sang Jun Ha, Se Kyu Kim, Kyung Young Chung, Ross Soo, Joo Hang Kim, Byoung Chul Cho

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Abstract

BACKGROUND: The objectives of this study were to determine the proportions of major oncogenic alterations and to examine survival in genotype-specific subsets of never-smokers with nonsmall cell lung cancer (NSCLC). METHODS: The authors concurrently analyzed mutations in the epidermal growth factor receptor (EGFR) and v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) genes and investigated anaplastic lymphoma kinase (ALK) gene rearrangements in samples from 229 never-smokers with NSCLC. ALK rearrangements were identified by fluorescent in situ hybridization and were confirmed by immunohistochemistry. Mutations in EGFR (exons 18 to 21) and KRAS (codons 12 and 13) were determined by direct sequencing. RESULTS: Of 229 tumors, the frequency of EGFR mutations, ALK rearrangements, KRAS mutations, and no mutations (wild type [WT]) in any of the 3 genes (WT/WT/WT) was 48%, 8.3%, 3.5%, and 40.2%, respectively. All genetic alterations were mutually exclusive. The median progression-free survival after treatment with EGFR tyrosine kinase inhibitors (TKIs) was 12.8 months, 6.3 months, 2.1 months, and 1.6 months in patients with EGFR mutations, the WT/WT/WT genotype, KRAS mutations, and ALK rearrangements, respectively. In a Cox regression model, the adjusted hazard ratio for the risk of disease progression after treatment with EGFR TKIs was 0.59 (95% confidence interval [CI], 0.40-0.87; P =.008) for patients with EGFR mutations, 4.58 (95% CI, 2.07-10.15; P <.001) for patients with ALK rearrangements, and 4.23 (95% CI, 1.65-10.8; P =.003) for patients with KRAS mutations. Overall survival also differed significantly among genotypes. CONCLUSIONS: To the authors' knowledge, this was the largest comprehensive and concurrent analysis to date of 3 major oncogenic alterations in a cohort of East Asian never-smokers with NSCLC. Because survival outcomes differed among genotypes, and drugs that target specific alterations currently are available, genetic profiling to identify genotype-specific subsets can lead to successful treatment with appropriate kinase inhibitors.

Original languageEnglish
Pages (from-to)729-739
Number of pages11
JournalCancer
Volume118
Issue number3
DOIs
Publication statusPublished - 2012 Feb 1

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Epidermal Growth Factor Receptor
Non-Small Cell Lung Carcinoma
Mutation
Genotype
Confidence Intervals
Protein-Tyrosine Kinases
Survival
anaplastic lymphoma kinase
Gene Rearrangement
Fluorescence In Situ Hybridization
Oncogenes
Proportional Hazards Models
Codon
Sarcoma
Genes
Disease-Free Survival
Disease Progression
Exons
Phosphotransferases
Therapeutics

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Kim, Hye Ryun ; Shim, Hyo Sup ; Chung, Jin Haeng ; Lee, Young Joo ; Hong, Yun Kyoung ; Rha, Sun Young ; Kim, Se Hoon ; Ha, Sang Jun ; Kim, Se Kyu ; Chung, Kyung Young ; Soo, Ross ; Kim, Joo Hang ; Cho, Byoung Chul. / Distinct clinical features and outcomes in never-smokers with nonsmall cell lung cancer who harbor EGFR or KRAS mutations or ALK rearrangement. In: Cancer. 2012 ; Vol. 118, No. 3. pp. 729-739.
@article{8832f12c614f4677bc2f8a7e9b2b3961,
title = "Distinct clinical features and outcomes in never-smokers with nonsmall cell lung cancer who harbor EGFR or KRAS mutations or ALK rearrangement",
abstract = "BACKGROUND: The objectives of this study were to determine the proportions of major oncogenic alterations and to examine survival in genotype-specific subsets of never-smokers with nonsmall cell lung cancer (NSCLC). METHODS: The authors concurrently analyzed mutations in the epidermal growth factor receptor (EGFR) and v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) genes and investigated anaplastic lymphoma kinase (ALK) gene rearrangements in samples from 229 never-smokers with NSCLC. ALK rearrangements were identified by fluorescent in situ hybridization and were confirmed by immunohistochemistry. Mutations in EGFR (exons 18 to 21) and KRAS (codons 12 and 13) were determined by direct sequencing. RESULTS: Of 229 tumors, the frequency of EGFR mutations, ALK rearrangements, KRAS mutations, and no mutations (wild type [WT]) in any of the 3 genes (WT/WT/WT) was 48{\%}, 8.3{\%}, 3.5{\%}, and 40.2{\%}, respectively. All genetic alterations were mutually exclusive. The median progression-free survival after treatment with EGFR tyrosine kinase inhibitors (TKIs) was 12.8 months, 6.3 months, 2.1 months, and 1.6 months in patients with EGFR mutations, the WT/WT/WT genotype, KRAS mutations, and ALK rearrangements, respectively. In a Cox regression model, the adjusted hazard ratio for the risk of disease progression after treatment with EGFR TKIs was 0.59 (95{\%} confidence interval [CI], 0.40-0.87; P =.008) for patients with EGFR mutations, 4.58 (95{\%} CI, 2.07-10.15; P <.001) for patients with ALK rearrangements, and 4.23 (95{\%} CI, 1.65-10.8; P =.003) for patients with KRAS mutations. Overall survival also differed significantly among genotypes. CONCLUSIONS: To the authors' knowledge, this was the largest comprehensive and concurrent analysis to date of 3 major oncogenic alterations in a cohort of East Asian never-smokers with NSCLC. Because survival outcomes differed among genotypes, and drugs that target specific alterations currently are available, genetic profiling to identify genotype-specific subsets can lead to successful treatment with appropriate kinase inhibitors.",
author = "Kim, {Hye Ryun} and Shim, {Hyo Sup} and Chung, {Jin Haeng} and Lee, {Young Joo} and Hong, {Yun Kyoung} and Rha, {Sun Young} and Kim, {Se Hoon} and Ha, {Sang Jun} and Kim, {Se Kyu} and Chung, {Kyung Young} and Ross Soo and Kim, {Joo Hang} and Cho, {Byoung Chul}",
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Distinct clinical features and outcomes in never-smokers with nonsmall cell lung cancer who harbor EGFR or KRAS mutations or ALK rearrangement. / Kim, Hye Ryun; Shim, Hyo Sup; Chung, Jin Haeng; Lee, Young Joo; Hong, Yun Kyoung; Rha, Sun Young; Kim, Se Hoon; Ha, Sang Jun; Kim, Se Kyu; Chung, Kyung Young; Soo, Ross; Kim, Joo Hang; Cho, Byoung Chul.

In: Cancer, Vol. 118, No. 3, 01.02.2012, p. 729-739.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Distinct clinical features and outcomes in never-smokers with nonsmall cell lung cancer who harbor EGFR or KRAS mutations or ALK rearrangement

AU - Kim, Hye Ryun

AU - Shim, Hyo Sup

AU - Chung, Jin Haeng

AU - Lee, Young Joo

AU - Hong, Yun Kyoung

AU - Rha, Sun Young

AU - Kim, Se Hoon

AU - Ha, Sang Jun

AU - Kim, Se Kyu

AU - Chung, Kyung Young

AU - Soo, Ross

AU - Kim, Joo Hang

AU - Cho, Byoung Chul

PY - 2012/2/1

Y1 - 2012/2/1

N2 - BACKGROUND: The objectives of this study were to determine the proportions of major oncogenic alterations and to examine survival in genotype-specific subsets of never-smokers with nonsmall cell lung cancer (NSCLC). METHODS: The authors concurrently analyzed mutations in the epidermal growth factor receptor (EGFR) and v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) genes and investigated anaplastic lymphoma kinase (ALK) gene rearrangements in samples from 229 never-smokers with NSCLC. ALK rearrangements were identified by fluorescent in situ hybridization and were confirmed by immunohistochemistry. Mutations in EGFR (exons 18 to 21) and KRAS (codons 12 and 13) were determined by direct sequencing. RESULTS: Of 229 tumors, the frequency of EGFR mutations, ALK rearrangements, KRAS mutations, and no mutations (wild type [WT]) in any of the 3 genes (WT/WT/WT) was 48%, 8.3%, 3.5%, and 40.2%, respectively. All genetic alterations were mutually exclusive. The median progression-free survival after treatment with EGFR tyrosine kinase inhibitors (TKIs) was 12.8 months, 6.3 months, 2.1 months, and 1.6 months in patients with EGFR mutations, the WT/WT/WT genotype, KRAS mutations, and ALK rearrangements, respectively. In a Cox regression model, the adjusted hazard ratio for the risk of disease progression after treatment with EGFR TKIs was 0.59 (95% confidence interval [CI], 0.40-0.87; P =.008) for patients with EGFR mutations, 4.58 (95% CI, 2.07-10.15; P <.001) for patients with ALK rearrangements, and 4.23 (95% CI, 1.65-10.8; P =.003) for patients with KRAS mutations. Overall survival also differed significantly among genotypes. CONCLUSIONS: To the authors' knowledge, this was the largest comprehensive and concurrent analysis to date of 3 major oncogenic alterations in a cohort of East Asian never-smokers with NSCLC. Because survival outcomes differed among genotypes, and drugs that target specific alterations currently are available, genetic profiling to identify genotype-specific subsets can lead to successful treatment with appropriate kinase inhibitors.

AB - BACKGROUND: The objectives of this study were to determine the proportions of major oncogenic alterations and to examine survival in genotype-specific subsets of never-smokers with nonsmall cell lung cancer (NSCLC). METHODS: The authors concurrently analyzed mutations in the epidermal growth factor receptor (EGFR) and v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) genes and investigated anaplastic lymphoma kinase (ALK) gene rearrangements in samples from 229 never-smokers with NSCLC. ALK rearrangements were identified by fluorescent in situ hybridization and were confirmed by immunohistochemistry. Mutations in EGFR (exons 18 to 21) and KRAS (codons 12 and 13) were determined by direct sequencing. RESULTS: Of 229 tumors, the frequency of EGFR mutations, ALK rearrangements, KRAS mutations, and no mutations (wild type [WT]) in any of the 3 genes (WT/WT/WT) was 48%, 8.3%, 3.5%, and 40.2%, respectively. All genetic alterations were mutually exclusive. The median progression-free survival after treatment with EGFR tyrosine kinase inhibitors (TKIs) was 12.8 months, 6.3 months, 2.1 months, and 1.6 months in patients with EGFR mutations, the WT/WT/WT genotype, KRAS mutations, and ALK rearrangements, respectively. In a Cox regression model, the adjusted hazard ratio for the risk of disease progression after treatment with EGFR TKIs was 0.59 (95% confidence interval [CI], 0.40-0.87; P =.008) for patients with EGFR mutations, 4.58 (95% CI, 2.07-10.15; P <.001) for patients with ALK rearrangements, and 4.23 (95% CI, 1.65-10.8; P =.003) for patients with KRAS mutations. Overall survival also differed significantly among genotypes. CONCLUSIONS: To the authors' knowledge, this was the largest comprehensive and concurrent analysis to date of 3 major oncogenic alterations in a cohort of East Asian never-smokers with NSCLC. Because survival outcomes differed among genotypes, and drugs that target specific alterations currently are available, genetic profiling to identify genotype-specific subsets can lead to successful treatment with appropriate kinase inhibitors.

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