Phosphoinositide-3-Kinase Catalytic Alpha and KRAS Mutations are Important Predictors of Resistance to Therapy with Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Patients with Advanced Non-small Cell Lung Cancer

• Published in: Journal of thoracic oncology Vol. 6; no. 4; pp. 707 - 715
• Main Authors: Ludovini, Vienna, Bianconi, Fortunato, Pistola, Lorenza, Chiari, Rita, Minotti, Vincenzo, Colella, Renato, Giuffrida, Dario, Tofanetti, Francesca Romana, Siggillino, Annamaria, Flacco, Antonella, Baldelli, Elisa, Iacono, Daniela, Mameli, Maria Grazia, Cavaliere, Antonio, Crinò, Lucio
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.04.2011; International Association for the Study of Lung Cancer
• Subjects: Adenocarcinoma - drug therapy; Adenocarcinoma - genetics; Adenocarcinoma - secondary; Adenocarcinoma, Bronchiolo-Alveolar - drug therapy; Adenocarcinoma, Bronchiolo-Alveolar - genetics; Adenocarcinoma, Bronchiolo-Alveolar - secondary; Adult; Aged; Aged, 80 and over; Carcinoma, Large Cell - drug therapy; Carcinoma, Large Cell - genetics; Carcinoma, Large Cell - secondary; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - secondary; Carcinoma, Squamous Cell - drug therapy; Carcinoma, Squamous Cell - genetics; Carcinoma, Squamous Cell - secondary; Class I Phosphatidylinositol 3-Kinases; DNA, Neoplasm - genetics; Drug Resistance, Neoplasm; EGFR; Female; Follow-Up Studies; Humans; KRAS mutations; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lung Neoplasms - pathology; Male; Middle Aged; Mutation - genetics; NSCLC; Phosphatidylinositol 3-Kinases - genetics; PI3KCA; Polymerase Chain Reaction; Prognosis; Protein Kinase Inhibitors - therapeutic use; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins p21(ras); PTEN Phosphohydrolase - genetics; ras Proteins - genetics; Receptor, Epidermal Growth Factor - genetics; Response to EGFR TKIs; Retrospective Studies; Survival; Survival Rate; KRAS mutations; NSCLC; Survival; EGFR; Response to EGFR TKIs; PI3KCA
• ISSN: 1556-0864; 1556-1380
• DOI: 10.1097/JTO.0b013e31820a3a6b

Specific mutations of the epidermal growth factor receptor (EGFR) gene are predictive for favorable response to tyrosine kinase inhibitors (TKIs) and are associated with a good prognosis. In contrast, Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation has been shown to predict poor response to such therapy. Nevertheless, tumor that initially responds to EGFR-TKIs almost inevitably becomes resistant later. Other mechanisms of resistance to EGFR inhibitors could involve activating mutations of the other main EGFR effector pathway, i.e., the phosphoinositide-3-kinase/phosphate and tensin homologue deleted from chromosome 10 (PTEN)/alpha serine/threonine protein kinase (AKT) pathway. The aim of this study was to investigate the role of phosphoinositide-3-kinase catalytic alpha (PIK3CA), EGFR, and KRAS gene mutations in predicting response and survival in patients with non-small cell lung cancer (NSCLC) treated with EGFR-TKIs. A total of 166 patients with advanced NSCLC treated with EGFR-TKI with available archival tissue specimens were included. PIK3CA, EGFR, and KRAS mutations were analyzed using polymerase chain reaction-based sequencing. EGFR mutation was detected in 25.3% of patients, PIK3CA mutation in 4.1%, and KRAS mutation in 6.7%. PIK3CA mutation correlated with shorter median time to progression (TTP) (p = 0.01) and worse overall survival (OS) (p < 0.001). EGFR mutation (p < 0.0001) correlated with favorable response to TKIs treatment and longer TTP (p < 0.0001). KRAS mutation correlated with progressive disease (p = 0.05) and shorter median TTP (p = 0.003) but not with OS. Cox multivariate analysis including histology and performance status showed that PIK3CA mutation was an independent factor to predict worse OS (p = 0.0001) and shorter TTP (p = 0.03), while KRAS mutation to predict shorter TTP (p = 0.01). PIK3CA and KRAS mutations seem to be indicators of resistance and poor survival in patients with NSCLC treated with EGFR-TKIs.