My last post discussed one of the two papers I thought were notably in the October 2012 Journal of Thoracic Oncology. Here's my take on the other paper by Vincentin et al (J Thorac Oncol 2012;7:1522-1527). NK2 homeobox 1 is the "proper" name that we pathologists more affectionately call "TTF-1." NKX2-1 is normally expressed in type 2 pneumocytes and non-ciliated bronchiolar epithelial cells and has been shown to play an active role in sustaining lung adenocarcinoma. Since NKX2-1 is found in about 95% of lung adenocarcinomas with EGFR mutations, the authors studied whether NKX2-1 IHC staining is a useful provisional marker for guiding EGFR-TKI therapy in advanced stage lung adenocarcinoma while EGFR mutation analysis is being completed.
This is a large study including 810 consecutive NSCLC tumor specimens referred for routine diagnostic EGFR mutation testing. While one may debate the ultimate practicality of this study with respect to it's purpose, what recommends it to me is that the study population more closely mirrors what a general pathologist encounters in routine practice. The study includes biopsies (N=594), resections (N=162), and cytology specimens (N=54) and the overall incidence of EGFR mutations was 14%. It is important to note that the authors used the TTF-1 8G7G3/1 antibody clone for IHC testing. There are substantial differences between the different antibody clones for TTF-1 that have been recently noted in the literature and it is important to take note of this detail when analyzing articles that test NKX2-1 or determining the best antibody to use in your lab.
Results and Authors' Conclusions
NKX2-1 was evaluable in 98% of cases and was positive in 68%, negative in 32%. NKX2-1 positive immunostaining showed a strong correlation with EGFR mutations: in the EGFR-mutated cases, NKX2-1 was positive in 92% and negative in 8%. The probability of absent of EGFR mutation in all adenocarcinomas is 80%; in NKX2-1-negative adenocarcinomas that probability rises to 96%. The authors found a negative predictive value of negative NKX2-1 IHC for EGFR mutation to be >95%.
The authors conclude that if treatment is clinically urgent, the NPV of NKX2-1 expression is appropriate to use as a surrogate marker to choose conventional chemotherapy as starting treatment pending EGFR mutation analysis. The PPV of NKX2-1 is not sufficient to warrent adding an EGFR-TKI. Also, the result of NKX2-1 is not specific enough to exclude a specimen from EGFR-mutation analysis.
My take-aways
While the clinical situation in which NKX2-1 testing would influence an urgent treatment decision may uncommon, I think it is important to note this paper because when it does occur, the pathologist can play a vital role in assisting the clinician determine the management for such a patient. If one is following the diagnostic algorithm from the 2011 IASLC guidelines, one would not routinely test either histologically diagnostic adenocarcinomas or squamous cell carcinomas for NKX2-1 (TTF-1). Another point is that the SPT24 clone for TTF-1 is a more sensitive antibody for TTF-1/NKX2-1 (a point that the authors make as well) and, therefore, one would expect the percentage of NKX2-1-negative cases to be fewer and the NPV to be higher. Finally, the authors used direct sequencing of EGFR exons 19-21, followed by HRM screening, and PCR-sequencing for identifying EGFR mutations; another methodology could influence the denominator of EGFR-mutated cases and, thus, the predictive value of NKX2-1 IHC testing.
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