Negative NKX2-1 (TTF-1) as Temporary Surrogate Marker for Treatment Selection During EGFR-Mutation Analysis in Patients with Non–Small-Cell Lung Cancer

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 −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.