Negative NKX2-1 (TTF-1) as temporary surrogate marker for treatment selection during EGFR-mutation analysis in patients with non-small-cell lung cancer

J Thorac Oncol. 2012 Oct;7(10):1522-7. doi: 10.1097/JTO.0b013e3182635a91.


Introduction: In the past decade, major progress has been made toward personalized medical treatment of non-small-cell lung cancer (NSCLC) through the discovery of epithelial growth factor receptor (EGFR) mutations. However, mutation analysis takes extra time and additional costs in the diagnostic evaluation of lung cancer patients. It has been hypothesized that EGFR mutations are restricted to terminal respiratory unit -type adenocarcinoma expressing thyroid transcription factor-1 (official symbol NKX2-1) as determined by immunohistochemistry. The aim of the current study is to evaluate the potential of NKX2-1 immunohistochemistry as a prescreening test for EGFR mutation analysis.

Methods: From 2004 to December 2010, 810 consecutive NSCLC tumor specimens were tested for EGFR mutations in a routine diagnostic procedure. Immunohistochemistry for NKX2-1 was performed (clone 8G7G3/1 [Dako]) and the results were compared with tumor EGFR-mutation status and clinicopathological characteristics.

Results: EGFR mutations were detected in 114 specimens (14%). NKX2-1 expression was present in 68%. In the cases with EGFR mutation, NKX2-1 staining was positive in 92%. NKX2-1 immunohistochemical (IHC) staining was significantly associated with the presence of EGFR mutations (p = 5.3×10). NKX2-1 increased the negative predictive value in NSCLC to more than 95%.

Conclusions: In case of a negative NKX2-1 IHC staining, and only if clinically urgent, the high negative predictive value of more than 95% for EGFR mutations is a suitable temporary surrogate marker for the choice of starting with chemotherapy. In case of positive NKX2-1 IHC, the best strategy is to wait for the outcome of EGFR-mutation analysis and then choose the appropriate treatment.

MeSH terms

  • Adenocarcinoma / genetics
  • Adenocarcinoma / metabolism*
  • Adenocarcinoma / pathology
  • Aged
  • Carcinoma, Non-Small-Cell Lung / genetics
  • Carcinoma, Non-Small-Cell Lung / metabolism*
  • Carcinoma, Non-Small-Cell Lung / pathology
  • DNA, Neoplasm / genetics
  • ErbB Receptors / genetics*
  • Female
  • Follow-Up Studies
  • Humans
  • Immunoenzyme Techniques
  • Lung Neoplasms / genetics
  • Lung Neoplasms / metabolism*
  • Lung Neoplasms / pathology
  • Male
  • Middle Aged
  • Mutation / genetics*
  • Neoplasm Staging
  • Nuclear Proteins / metabolism*
  • Patient Selection*
  • Polymerase Chain Reaction
  • Prognosis
  • Thyroid Nuclear Factor 1
  • Transcription Factors / metabolism*


  • DNA, Neoplasm
  • NKX2-1 protein, human
  • Nuclear Proteins
  • Thyroid Nuclear Factor 1
  • Transcription Factors
  • EGFR protein, human
  • ErbB Receptors