Akt phosphorylation and gefitinib efficacy in patients with advanced non-small-cell lung cancer

Abstract

Background: Gefitinib, a specific epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, has activity against approximately 10 % of unselected non–small-cell lung cancer (NSCLC) patients. Phosphatidylinositol 3-kinase (PI3K)/Akt and Ras/Raf/mitogen-activated protein kinase (MAPK), the two main EGFR-signaling pathways, mediate EGFR effects on proliferation and survival. Because activation of these pathways is dependent on the phosphor-ylation status of the components, we evaluated the associa-tion between phosphorylation status of Akt (P-Akt) and MAPK (P-MAPK) and gefitinib activity in patients with advanced NSCLC. Methods: Consecutive patients (n 106) with NSCLC who had progressed or relapsed on standard therapy received gefitinib (250 mg/day) until disease pro-gression, unacceptable toxicity, or patient refusal. P-Akt and P-MAPK positivity was determined with immunohistochem-istry using tumor tissues obtained before any anticancer treatment. Association of P-Akt and time to progression was determined by univariable and multivariable analyses. All statistical tests were two-sided. Results: Of the 103 evaluable patients, 51 (49.5%) had tumors that were positive for P-Akt, and 23 (22.3%) had tumors that were positive for P-MAPK. P-Akt–positivity status was statistically signifi-cantly associated with being female (P<.001), with never-smoking history (P .004), and with bronchioloalveolar carcinoma histology (P .034). Compared with patients whose tumors were negative for P-Akt, patients whose tu-mors were positive for P-Akt had a better response rate (26.1 % versus 3.9%; P .003), disease control rate (60.9% versus 23.5%; P<.001), and time to progression (5.5 versus 2.8 months; P .004). Response rate, disease control rate, and time to progression did not differ according to P-MAPK status. The multivariable analysis showed that P-Akt posi-tivity was associated with a reduced risk of disease progres-sion (hazard ratio 0.58, 95 % confidence interval 0.35 t