Epidermal growth factor receptor (EGFR) mutations are exceptionally rare in thyroid transcription factor
(TTF-1)-negative adenocarcinomas of the lung
Neeta Somaiah1,*, Mary Jo Fidler2,*, Elizabeth Garrett-Mayer3, Amy Wahlquist3, Keisuke Shirai3, Lela Buckingham2, Thomas Hensing4, Philip Bonomi2, and George R. Simon1
1 MD Anderson Cancer Center, Houston TX 77004
2 Rush University Medical Center, Chicago, IL 60612
3 Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425
4 North Shore University Health Systems/University of Chicago, Evanston, IL 60201.
* These authors contributed equally to this article and therefore are co-first authors.
Mary Jo Fidler, email:
Key words: TTF-1, EGFR, NSCLC, adenocarcinoma
Received: June 4, 2014 Accepted: August 3, 2014 Published: August 7, 2014
Background: Approximately 70% of lung adenocarcinomas express TTF-1. EGFR mutations are present in 13-15% of Western adenocarcinoma patients. This paper investigates TTF1 as a predictor of wild type EGFR in lung adenocarcinomas.
Methods: Formalin-fixed paraffin-embedded tumors from lung adenocarcinoma patients were analyzed for EGFR mutations by allele-specific PCR in the ‘pilot cohort’. TTF-1 status was documented as positive or negative. Negative predictive value (NPV) for a range of true prevalence of EGFR mutation (1%-50%) was estimated using Bayesian modeling. The hypothesis was validated in a separate ‘validation’ cohort using the same modeling.
Results: In the pilot cohort (N = 301) two of 224 specimens positive for EGFR mutations had negative TTF-1 expression (sensitivity 99.1%, 95% confidence interval (CI) 96.8-99.9%). Estimated negative predictive values (NPV) for EGFR mutation prevalence rates of 13% and 15% are 99.5% (95% credible interval (CRI) 98.6%-99.9%) and 99.4% (CRI - 98.4%-99.9%). For EGFR mutation rates of 13% and 15%, using validation cohort data (211 patients), the estimated NPVs were 97% (95% CRI 92%-99%) and 96% (95% CRI 91%-99%).
Conclusion: An overwhelming majority of TTF-1 negative adenocarcinomas will be negative for EGFR mutations. This finding allows for earlier initiation of chemotherapy in newly diagnosed TTF-1 negative patients.