Clinicopathological predictors of EGFR/KRAS mutational status in primary lung adenocarcinomas

Screening for EGFR and KRAS mutations in patients with lung adenocarcinomas can be used to predict the patient's response to EGFR tyrosine kinase inhibitors, but there is a lack of guidelines for testing in clinical practice. We analyzed the morphological and clinicopathological characteristics, including tumor stage, size, presence of scar, inflammatory response, angiolymphatic and pleural invasion, of 345 surgically treated primary lung adenocarcinomas with respect to their EGFR and KRAS mutational profile and EGFR FISH. EGFR and KRAS mutations were found in 33 (10%) and 78 (23%) of lung adenocarcinomas, respectively, whereas 226 (67%) cases were negative for both mutations. There was a large overlap in the analyzed clinicopathological characteristics among the three study groups. Statistically significant predictors for the presence of EGFR mutations included history of never smoking (OR 5.939; 95% Wald confidence limit 1.662-21.223, P=0.0149), mild lymphocytic host response (OR 4.724; 95% Wald confidence limit 1.33-1.776; P-0.0163), female gender (OR 2.571; 95% Wald confidence limit 1.015-6.511, P=0.0463) and absence of solid growth pattern. Statistically significant predictors for the presence of KRAS mutations included older age (OR 1.034; 95% Wald confidence limit 1.007-1.062, P=0.0132), history of smoking (OR 0.617, 95% Wald confidence limit 0.357-1.066, P=0.0412) and mucinous differentiation. EGFR FISH positivity as defined by the Colorado criteria was a significant predictor of EGFR mutations, with high polysomy as the strongest predictive criteria. Despite statistically significant differences among the study groups and because of the large overlap in the analyzed clinicopathological criteria, none of these could be implemented as the selection criteria for molecular testing in clinical practice. The cost-effectiveness of lung carcinoma mutational testing would be improved by initial determination of KRAS mutational status as negative predictor of the patient's response to EGFR tyrosine kinase inhibitors, followed by EGFR mutational analysis, if necessary. Modern Pathology (2010) 23, 159-168; doi: 10.1038/modpathol.2009.154; published online 23 October 2009