Background: PTEN is a major negative regulator of the PI3K/AKT signalling pathway that may results in resistance to EGFR-blockade. The present study aimed to assess the role of PTEN and other potential predictive factors in relation to cetuximab-based treatment in advanced colorectal cancer. Methods: Both primary and metastatic sites of fifty patients were retrospectively analyzed for PTEN loss at the gene and protein levels by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) respectively, for PAKT (IHC), EGFR (FISH) and KRAS mutations. We defined responders those patients who obtained a partial response (PR) or a stable disease (SD). Results: Eighty percent (40/50) of the patients received ‡3 lines of chemotherapy. Thirty-six patients were treated with cetuximab and irinotecan and 14 with cetuximab and oxaliplatin. Twelve patients (24%) experienced PR, fourteen (28%) SD and twenty-four (48%) a progressive disease (PD). Seventy-two percent (36/50) of the patients with skin rash showed a higher response rate (88% vs 12%; p<0.05), progression free survival (PFS) (6.5 months vs 2.1; p<0.005) and overall survival (OS) (12.7 months vs 2.9; p<0.005). Five out of the 43 evaluable primary tumours (12%) and 4/24 (17%) of the metastases were PTEN negative. PTEN IHC tested on primaries was not predictive of response, while loss of PTEN expression on metastases was negatively associated with response (pd 100% in PTEN negative cases vs 30% in PTEN positive; p<0.05), PFS (2.0 months vs 4.1; p<0.05) and OS (2.9 months vs 14.2; p<0.001). KRAS mutations were assessed in 47/50 cases: 8/47 (17%) of the cases were mutated and of these only one (12%) experienced a PR. pAKT was not predictive of response nor pfs and os, neither was EGFR. Conclusions: a correlation between response to cetuximab-based therapy and the EGFR pathway has been reported. A possible functional interaction of PTEN activity with EGFR tyrosine kinase signalling and potential role for PTEN in the antitumour activity of cetuximab could be hypothesized.

PTEN EXPRESSION IN ADVANCED COLORECTAL CANCER TREATED WITH CETUXIMAB

RUZZO, ANNAMARIA;
2009

Abstract

Background: PTEN is a major negative regulator of the PI3K/AKT signalling pathway that may results in resistance to EGFR-blockade. The present study aimed to assess the role of PTEN and other potential predictive factors in relation to cetuximab-based treatment in advanced colorectal cancer. Methods: Both primary and metastatic sites of fifty patients were retrospectively analyzed for PTEN loss at the gene and protein levels by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) respectively, for PAKT (IHC), EGFR (FISH) and KRAS mutations. We defined responders those patients who obtained a partial response (PR) or a stable disease (SD). Results: Eighty percent (40/50) of the patients received ‡3 lines of chemotherapy. Thirty-six patients were treated with cetuximab and irinotecan and 14 with cetuximab and oxaliplatin. Twelve patients (24%) experienced PR, fourteen (28%) SD and twenty-four (48%) a progressive disease (PD). Seventy-two percent (36/50) of the patients with skin rash showed a higher response rate (88% vs 12%; p<0.05), progression free survival (PFS) (6.5 months vs 2.1; p<0.005) and overall survival (OS) (12.7 months vs 2.9; p<0.005). Five out of the 43 evaluable primary tumours (12%) and 4/24 (17%) of the metastases were PTEN negative. PTEN IHC tested on primaries was not predictive of response, while loss of PTEN expression on metastases was negatively associated with response (pd 100% in PTEN negative cases vs 30% in PTEN positive; p<0.05), PFS (2.0 months vs 4.1; p<0.05) and OS (2.9 months vs 14.2; p<0.001). KRAS mutations were assessed in 47/50 cases: 8/47 (17%) of the cases were mutated and of these only one (12%) experienced a PR. pAKT was not predictive of response nor pfs and os, neither was EGFR. Conclusions: a correlation between response to cetuximab-based therapy and the EGFR pathway has been reported. A possible functional interaction of PTEN activity with EGFR tyrosine kinase signalling and potential role for PTEN in the antitumour activity of cetuximab could be hypothesized.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11576/2303297
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