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

Abstract

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 ¼ 0.0149), mild lymphocytic host response (OR 4.724; 95% Wald confidence limit 1.33-1.776; P ¼ 0.0163), female gender (OR 2.571; 95% Wald confidence limit 1.015-6.511, P ¼ 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 ¼ 0.0132), history of smoking (OR 0.617, 95% Wald confidence limit 0.357-1.066, P ¼ 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.

Bronchial-pulmonary adenocarcinoma subtyping relates with different molecular pathways

“…67 Adenocarcinomas diagnosed in women patients were more frequently diagnosed at stages IA and IB reflecting somehow a less aggressive behavior demonstrated also by a lower proliferative index in these stages. Tobacco habits could also explain the activation of different pathways and genetic alterations in these cases.…”

Role of molecular studies in the diagnosis of lung adenocarcinoma

“…18,20 (Figures 1-5) Such adenocarcinomas typically do not have evidence of necrosis and tend to be associated with a minimal host stromal and immune response. 18,21 These adenocarcinomas show an immunophenotype of cells of the terminal reserve unit, with antigen expression characteristic of Clara and Type II alveolar pneumocytes in that the neoplastic cells express cytokeratin 7, but more importantly, thyroid transcription factor 1 (TTF1), surfactant apoprotein, and Napsin A. Adenocarcinomas with extensive mucinous and goblet cell differentiation rarely have EGFR mutations, more commonly demonstrating K-RAS alterations. 21 In the assessment of EGFR mutations, several approaches have been taken.…”

Induction Docetaxel, Cisplatin, and Cetuximab Followed by Concurrent Radiotherapy, Cisplatin, and Cetuximab and Maintenance Cetuximab in Patients With Locally Advanced Head and Neck Cancer

“…17 Positive tumors were considered those with high polysomy (Ն 4 gene copies in Ն 40% of cells) or gene amplification (ratio EGFR gene/chromosome 7 Ͼ two or Ͼ 15 gene copies in Ͼ 10% of cells).…”