BACKGROUND: A large proportion of colorectal cancer patients does not benefit from the use of anti-epidermal growth factor receptor (EGFR) treatment although in the absence of a mutation of the K-RAS gene. Preliminary observations suggested that HER-3, insulin-like growth factor-1 (IGF-1), nuclear factor-kB (NF-kB) and EGFR gene copy number (GCN) might identify patients not likely to benefit from anti-EGFR therapy. We tested the interaction between HER-3, IGF-1, NF-kB, EGFR GCN and K-RAS mutational analysis to verify the relative ability of these variables to identify a subgroup of patients more likely to benefit from EGFR-targeted treatment among those harbouring a K-RAS wild-type status. PATIENTS AND METHODS: We retrospectively collected tumours from 168 patients with metastatic colorectal cancer treated with irinotecan-cetuximab. K-RAS was assessed with direct sequencing, EGFR amplification was assessed by chromogenic in situ hybridisation (CISH) and HER-3, IGF-1 and NF-kB were assessed by immunohistochemistry. RESULTS: In patients with K-RAS wild-type tumours, the following molecular factors resulted independently associated with response rate: HER-3 [odds ratio (OR) = 4.6, 95\% confidence interval (CI) 1.8-13.6, P = 0.02], IGF-1 (OR = 4.2, 95\% CI 2-10.2, P = 0.003) and EGFR GCN (OR = 4.1, 95\% CI 1.9-26.2, P = 0.04). These factors also independently correlated with overall survival as follows: HER-3 [hazard ratio (HR) = 0.4, 95\% CI 0.28-0.85, P = 0.008], IGF-1 (HR = 0.47, 95\% CI 0.24-0.76, P < 0.0001) and EGFR GCN (HR = 0.59, 95\% CI 0.22-0.89, P = 0.04).Discussion: We believe that our data may help further composing the molecular mosaic of EGFR-resistant tumours. The role of HER-3, IGF-1 and CISH EGFR GCN should be prospectively validated in clinical trials investigating anti-EGFR treatment strategies in colorectal cancer patients.
Analysis of HER-3, insulin growth factor-1, nuclear factor-kB and epidermal growth factor receptor gene copy number in the prediction of clinical outcome for K-RAS wild-type colorectal cancer patients receiving irinotecan-cetuximab / M., Scartozzi; R., Giampieri; E., Maccaroni; A., Mandolesi; L., Giustini; R., Silva; A., Zaniboni; T., Biscotti; S., Biagetti; E., Galizia; F., Loupakis; A., Falcone; I., Bearzi; Cascinu, Stefano. - In: ANNALS OF ONCOLOGY. - ISSN 0923-7534. - 23:7(2012), pp. 1706-1712. [10.1093/annonc/mdr558]
Analysis of HER-3, insulin growth factor-1, nuclear factor-kB and epidermal growth factor receptor gene copy number in the prediction of clinical outcome for K-RAS wild-type colorectal cancer patients receiving irinotecan-cetuximab.
CASCINU, Stefano
2012
Abstract
BACKGROUND: A large proportion of colorectal cancer patients does not benefit from the use of anti-epidermal growth factor receptor (EGFR) treatment although in the absence of a mutation of the K-RAS gene. Preliminary observations suggested that HER-3, insulin-like growth factor-1 (IGF-1), nuclear factor-kB (NF-kB) and EGFR gene copy number (GCN) might identify patients not likely to benefit from anti-EGFR therapy. We tested the interaction between HER-3, IGF-1, NF-kB, EGFR GCN and K-RAS mutational analysis to verify the relative ability of these variables to identify a subgroup of patients more likely to benefit from EGFR-targeted treatment among those harbouring a K-RAS wild-type status. PATIENTS AND METHODS: We retrospectively collected tumours from 168 patients with metastatic colorectal cancer treated with irinotecan-cetuximab. K-RAS was assessed with direct sequencing, EGFR amplification was assessed by chromogenic in situ hybridisation (CISH) and HER-3, IGF-1 and NF-kB were assessed by immunohistochemistry. RESULTS: In patients with K-RAS wild-type tumours, the following molecular factors resulted independently associated with response rate: HER-3 [odds ratio (OR) = 4.6, 95\% confidence interval (CI) 1.8-13.6, P = 0.02], IGF-1 (OR = 4.2, 95\% CI 2-10.2, P = 0.003) and EGFR GCN (OR = 4.1, 95\% CI 1.9-26.2, P = 0.04). These factors also independently correlated with overall survival as follows: HER-3 [hazard ratio (HR) = 0.4, 95\% CI 0.28-0.85, P = 0.008], IGF-1 (HR = 0.47, 95\% CI 0.24-0.76, P < 0.0001) and EGFR GCN (HR = 0.59, 95\% CI 0.22-0.89, P = 0.04).Discussion: We believe that our data may help further composing the molecular mosaic of EGFR-resistant tumours. The role of HER-3, IGF-1 and CISH EGFR GCN should be prospectively validated in clinical trials investigating anti-EGFR treatment strategies in colorectal cancer patients.
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