1. 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.
- Author
-
Ludovini V, Bianconi F, Pistola L, Chiari R, Minotti V, Colella R, Giuffrida D, Tofanetti FR, Siggillino A, Flacco A, Baldelli E, Iacono D, Mameli MG, Cavaliere A, and Crinò L
- 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 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, Female, Follow-Up Studies, Humans, Lung Neoplasms genetics, Lung Neoplasms pathology, Male, Middle Aged, PTEN Phosphohydrolase genetics, Polymerase Chain Reaction, Prognosis, Proto-Oncogene Proteins genetics, Proto-Oncogene Proteins p21(ras), Retrospective Studies, Survival Rate, ras Proteins genetics, Carcinoma, Non-Small-Cell Lung drug therapy, Drug Resistance, Neoplasm, ErbB Receptors genetics, Lung Neoplasms drug therapy, Mutation genetics, Phosphatidylinositol 3-Kinases genetics, Protein Kinase Inhibitors therapeutic use
- Abstract
Background: 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., Patients and Methods: 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., Results: 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)., Conclusion: PIK3CA and KRAS mutations seem to be indicators of resistance and poor survival in patients with NSCLC treated with EGFR-TKIs.
- Published
- 2011
- Full Text
- View/download PDF