ntroduction: PTEN is a key tumor suppressor that inactivates PI3K, a downstream effector of the EGFR cascade. Mutations resulting in PTEN loss lead to uncontrolled activation of PI3K/AKT signalling pathway that may result in resistance to EGFR-blockade. Methods: We retrospectively investigated the role of PTEN immunoreactivity loss (anti-PTEN antibody clone 17.A, Immunomarkers) both on primary CRC and related mets in predicting the activity of cetuximab plus irinotecan combination treatment in EGFR-positive irinotecan-refractory metastatic CRC patients (pts). Results: As of today 102 pts have been included. M/F=60/42, median age=62 (38- 78), median number of previous lines of chemotherapy=2 (1-5). Among the 100 pts evaluable for response we observed a partial (PR) or a complete response (CR) in 13 and 1 cases respectively for an overall response rate of 14%. PTEN immunostaining resulted positive (+), negative (-) or unconclusive (NE) in respectively 48, 36, 11 out 98 primary tumors. On 57 mets PTEN analysis was +, - or NE in 31, 22, 4 cases respectively. PTEN positivity or negativity on primaries was confirmed on 45 related mts in 27 cases (60%) while 7 (16%) + and 11 (24%) - primaries resulted respectively - and + on mets. PTEN status tested on primary tumor was not significantly predictive of response nor PFS. Defining as responders those pts obtaining a PR or CR (RECIST) or SD lasting >6 mos and clearly progressed on previous irinotecan-based regimen with a TTP<3 mos (5 pts), analysis of PTEN on mets showed: 1- vs 12+ responders and 21- vs 19+ non responders (p=0.008). Median PFS in pts with PTEN+ mets was 4.8 vs 3.3 mos in PTEN- (p= 0.009, HR=0.50, 95% CI 0.23-0.81). Conclusions: Loss of PTEN immunoreactivity tested on mets may predict the activity of cetuximab plus irinotecan combination treatment. Further analysis on KRAS mutational status and p-AKT immunostaining are ongoing. Final data will be presented at the meeting. Supported by A.R.C.O. Foundation

Loss of PTEN expression in colorectal cancer (CRC) metastases (mets) but not in primary tumors predicts lack of activity of cetuximab plus irinotecan treatment

MASI, GIANLUCA;PETRINI, IACOPO;FALCONE, ALFREDO
2008-01-01

Abstract

ntroduction: PTEN is a key tumor suppressor that inactivates PI3K, a downstream effector of the EGFR cascade. Mutations resulting in PTEN loss lead to uncontrolled activation of PI3K/AKT signalling pathway that may result in resistance to EGFR-blockade. Methods: We retrospectively investigated the role of PTEN immunoreactivity loss (anti-PTEN antibody clone 17.A, Immunomarkers) both on primary CRC and related mets in predicting the activity of cetuximab plus irinotecan combination treatment in EGFR-positive irinotecan-refractory metastatic CRC patients (pts). Results: As of today 102 pts have been included. M/F=60/42, median age=62 (38- 78), median number of previous lines of chemotherapy=2 (1-5). Among the 100 pts evaluable for response we observed a partial (PR) or a complete response (CR) in 13 and 1 cases respectively for an overall response rate of 14%. PTEN immunostaining resulted positive (+), negative (-) or unconclusive (NE) in respectively 48, 36, 11 out 98 primary tumors. On 57 mets PTEN analysis was +, - or NE in 31, 22, 4 cases respectively. PTEN positivity or negativity on primaries was confirmed on 45 related mts in 27 cases (60%) while 7 (16%) + and 11 (24%) - primaries resulted respectively - and + on mets. PTEN status tested on primary tumor was not significantly predictive of response nor PFS. Defining as responders those pts obtaining a PR or CR (RECIST) or SD lasting >6 mos and clearly progressed on previous irinotecan-based regimen with a TTP<3 mos (5 pts), analysis of PTEN on mets showed: 1- vs 12+ responders and 21- vs 19+ non responders (p=0.008). Median PFS in pts with PTEN+ mets was 4.8 vs 3.3 mos in PTEN- (p= 0.009, HR=0.50, 95% CI 0.23-0.81). Conclusions: Loss of PTEN immunoreactivity tested on mets may predict the activity of cetuximab plus irinotecan combination treatment. Further analysis on KRAS mutational status and p-AKT immunostaining are ongoing. Final data will be presented at the meeting. Supported by A.R.C.O. Foundation
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11568/820605
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