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

Cappuzzo, F.; Magrini, Elisabetta; Bartolini, S.; Ceresoli, G.; Rossi, E.; Ludovini, V.; Gregorc, V.; Ligorio, C.; Cancellieri, A.; Damiani, Stefania; Spreafico, A.; Paties, C. T.; Lombardo, L.; Calandri, C.; Bellezza, G.; Crinò, L.

Purpose: Aim of this trial was to evaluate correlation between P-AKT/P-MAPK status and gefitinib activity in terms of Response Rate (RR) and Time to Progression (TTP) in Non-Small Cell Lung Cancer (NSCLC) patients. Patients and methods: Consecutive patients with NSCLC progressing or relapsing with standard therapy received gefitinib at a daily dose of 250 mg given until disease progression, unacceptable toxicity or refusal. Tumor tissue specimens obtained at the time of primary diagnosis were collected to determine P-AKT/P-MAPK status by immunohistochemistry. Results: One hundred-six NSCLC patients were enrolled onto the study in three Italian Institutions, and 103 were evaluable for P-AKT/P-MAPK status. P-AKT was positive in 51 (49.5%) and negative in 52 (50.5%) patients. P-MAPK resulted positive (2+/3+) in 23 (22.3%) and negative (0/1+) in 80 (77.7%). P-AKT positive status resulted significantly related to female gender (P<0.001), smoking history (P<0.05), and bronchioloalveolar histology (P<0.05). Compared to the P-AKT negative group, P-AKT positive patients had better RR (26.1% versus 3.9%, P=0.003), disease control rate (60.9% versus 23.5%, P<0.001), and significantly longer TTP (5.5 versus 2.8 months, P=0.004). No difference was observed in patients P-MAPK 0/1+ versus 2+/3 in terms of RR, disease control rate and TTP. The multivariate analysis showed that P-AKT positive status resulted in a significant reduction of disease progression risk (HR: 0.66, CI 95%:0.40-1.10). Conclusions: Gefitinib therapy resulted more active in P-AKT positive patients. The role of loss of PTEN and the impact of previous therapies on PI3K-AKT pathway activation should be addressed in further prospective trials.

Titolo:	AKT phosphorylation and gefitinib efficacy in patients with advanced non-small cell lung cancer
Autore/i:	F. Cappuzzo; MAGRINI, ELISABETTA; S. Bartolini; G. Ceresoli; E. Rossi; V. Ludovini; V. Gregorc; C. Ligorio; A. Cancellieri; DAMIANI, STEFANIA; A. Spreafico; C. T. Paties; L. Lombardo; C. Calandri; G. Bellezza; L. Crinò
Autore/i Unibo:	F. Cappuzzo MAGRINI, ELISABETTA S. Bartolini G. Ceresoli E. Rossi V. Ludovini V. Gregorc C. Ligorio A. Cancellieri DAMIANI, STEFANIA A. Spreafico C. T. Paties L. Lombardo C. Calandri G. Bellezza L. Crinò mostra contributor esterni nascondi contributor esterni
Anno:	2004
Rivista:	JOURNAL OF THE NATIONAL CANCER INSTITUTE
Abstract:	Purpose: Aim of this trial was to evaluate correlation between P-AKT/P-MAPK status and gefitinib activity in terms of Response Rate (RR) and Time to Progression (TTP) in Non-Small Cell Lung Cancer (NSCLC) patients. Patients and methods: Consecutive patients with NSCLC progressing or relapsing with standard therapy received gefitinib at a daily dose of 250 mg given until disease progression, unacceptable toxicity or refusal. Tumor tissue specimens obtained at the time of primary diagnosis were collected to determine P-AKT/P-MAPK status by immunohistochemistry. Results: One hundred-six NSCLC patients were enrolled onto the study in three Italian Institutions, and 103 were evaluable for P-AKT/P-MAPK status. P-AKT was positive in 51 (49.5%) and negative in 52 (50.5%) patients. P-MAPK resulted positive (2+/3+) in 23 (22.3%) and negative (0/1+) in 80 (77.7%). P-AKT positive status resulted significantly related to female gender (P<0.001), smoking history (P<0.05), and bronchioloalveolar histology (P<0.05). Compared to the P-AKT negative group, P-AKT positive patients had better RR (26.1% versus 3.9%, P=0.003), disease control rate (60.9% versus 23.5%, P<0.001), and significantly longer TTP (5.5 versus 2.8 months, P=0.004). No difference was observed in patients P-MAPK 0/1+ versus 2+/3 in terms of RR, disease control rate and TTP. The multivariate analysis showed that P-AKT positive status resulted in a significant reduction of disease progression risk (HR: 0.66, CI 95%:0.40-1.10). Conclusions: Gefitinib therapy resulted more active in P-AKT positive patients. The role of loss of PTEN and the impact of previous therapies on PI3K-AKT pathway activation should be addressed in further prospective trials.
Data prodotto definitivo in UGOV:	2005-10-10 14:08:36
Appare nelle tipologie:	1.01 Articolo in rivista

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