Background: 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 EGFRblockade. Methods: We retrospectively investigated the role of PTEN immunoreactivity (IHC) loss and of pAKT IHC both on primary CRC and related mets in predicting the activity of cetuximab plus irinotecan combination treatment in EGFR-positive metastatic CRC patients (pts) pretreated with irinotecan. We defined responders those pts obtaining a complete (CR) or partial (PR) response (RECIST) or SD lasting >6mos provided that were clearly progressed on previous irinotecan-based regimen with a TTP<3 mos (SD6). Results: A total of 102 pts have been evaluated. M/F=60/42, median age=62 (38-78), median number of previous lines of chemotherapy=2 (1-5).We observed a PR or CR in 13 and 1 cases respectively for an overall response rate of 14%. PTEN IHC resulted positive (+), negative (-) or unconclusive (NE) in respectively 49, 36, 11 while pAKT IHC resulted +, - or NE in respectively 35, 52, 9 out 96 primary tumors. On 59 mets PTEN IHC was +, - or NE in 33, 22, 4 cases respectively while pAKT IHC was +, - or NE in 21, 30, 8 cases respectively. PTEN analysis on primaries was concordant in 27 out 45 related mets (60%) while discorded in the others; pAKT results con corded in 30 out 45 (67%) paired samples. PTEN status tested on primaries was not predictive of response nor PFS, neither was pAKT on primaries nor mets. PTEN IHC performed on 55 evaluable mets showed: 1- vs 12+ responders (1 CR + 7 PR + 5 SD6) and 21- vs 21+ not responders (p=0.008). Median PFS in pts with PTEN+ mets was 4.8 vs 3.3 mos in PTEN- (p=0.0045, HR=0.49, 95% CI 0.20-0.74). Conclusions: Loss of PTEN immunoreactivity tested on mets may predict the activity of cetuximab plus irinotecan combination treatment. Further analysis on KRAS mutational status are ongoing. Final data will be presented at the meeting.
Loss of PTEN expression in colorectal cancer (CRC) metastases (METS) predicts lack of activity of cetuximab plus irinotecan treatment
G. MASI;PETRINI, IACOPO;CAMPANI, DANIELA;FALCONE, ALFREDO
2008-01-01
Abstract
Background: 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 EGFRblockade. Methods: We retrospectively investigated the role of PTEN immunoreactivity (IHC) loss and of pAKT IHC both on primary CRC and related mets in predicting the activity of cetuximab plus irinotecan combination treatment in EGFR-positive metastatic CRC patients (pts) pretreated with irinotecan. We defined responders those pts obtaining a complete (CR) or partial (PR) response (RECIST) or SD lasting >6mos provided that were clearly progressed on previous irinotecan-based regimen with a TTP<3 mos (SD6). Results: A total of 102 pts have been evaluated. M/F=60/42, median age=62 (38-78), median number of previous lines of chemotherapy=2 (1-5).We observed a PR or CR in 13 and 1 cases respectively for an overall response rate of 14%. PTEN IHC resulted positive (+), negative (-) or unconclusive (NE) in respectively 49, 36, 11 while pAKT IHC resulted +, - or NE in respectively 35, 52, 9 out 96 primary tumors. On 59 mets PTEN IHC was +, - or NE in 33, 22, 4 cases respectively while pAKT IHC was +, - or NE in 21, 30, 8 cases respectively. PTEN analysis on primaries was concordant in 27 out 45 related mets (60%) while discorded in the others; pAKT results con corded in 30 out 45 (67%) paired samples. PTEN status tested on primaries was not predictive of response nor PFS, neither was pAKT on primaries nor mets. PTEN IHC performed on 55 evaluable mets showed: 1- vs 12+ responders (1 CR + 7 PR + 5 SD6) and 21- vs 21+ not responders (p=0.008). Median PFS in pts with PTEN+ mets was 4.8 vs 3.3 mos in PTEN- (p=0.0045, HR=0.49, 95% CI 0.20-0.74). Conclusions: Loss of PTEN immunoreactivity tested on mets may predict the activity of cetuximab plus irinotecan combination treatment. Further analysis on KRAS mutational status are ongoing. Final data will be presented at the meeting.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
