Correlation of activated AKT and MAPK expression in liver metastases with clinical outcome in colorectal cancer patients receiving irinotecan/cetuximab treatment.

Abstract

449 Background: An aberrant activation of the EGFR downstream signaling pathway via MAP-kinase and Akt could be responsible for resistance to anti-EGFR treatment. We tested the interaction between phosphorylated Akt and MAPK in primary colorectal tumours and corresponding metastases and clinical outcome in terms of response rate (RR), progression free survival (PFS) and overall survival (OS) to identify a group of patients more likely to benefit from EGFR-targeted treatment among those harbouring a K-RAS wild type status. Methods: Seventy-two advanced K-RAS wild type colorectal cancer patients treated with irinotecan-cetuximab were analysed. Primary tumour were available in all cases, whereas paired tumour samples from metastatic sites were available in 37 patients. Phosphorylated Akt and MAPK were analyzed by immunohistochemistry. Results: Akt resulted overexpressed in 31 primary tumours (43%) and 23 metastases (62%), whereas MAPK was over-expressed in 32 primary tumours (44%) and 20 metastases (54%). Akt altered expression in primary tumours correlated with a statistically significant worse median PFS (2.4 months vs. 6.5 months, p= 0.0006) and OS (7.8 months vs. 26.7 months, p < 0.0001), without any significant correlation with RR. No significant correlation could be found between MAPK expression in primary tumours and RR, PFS or OS. In metastases Akt expression correlated with RR (9% vs, 58%, p= 0.004), PFS (2.3 months vs.9.2 months p < 0.0001) and OS (6.1 months vs.26.7 months p < 0.0001). Analogously MAPK expression in metastases correlated with RR (10% vs, 47%, p = 0.002), PFS (2.3 months vs.8.6 months p < 0.0001) and OS (7.8 months vs.26 months p = 0.0004). At multivariate analysis Akt and MAPK status in metastases was able to independently predict PFS. Akt status in metastases independently correlated with RR as well. Conclusions: We suggest that Akt and MAPK expression in metastases may have a relevant role in determining the activity of anti-EGFR treatment strategies. Our observations seem also to indicate that for some molecular determinants of resistance the biological profile in metastases is prominent.