Abstract
BackgroundK-RAS wild type colorectal tumors show an improved response rate to anti-EGFR monoclonal antibodies. Nevertheless 70% to 40% of these patients still does not seem to benefit from this therapeutic approach. FISH EGFR GCN has been previously demonstrated to correlate with clinical outcome of colorectal cancer treated with anti-EGFR monoclonal antibodies. CISH also seemed able to provide accurate EGFR GCN information with the advantage of a simpler and reproducible technique involving immunohistochemistry and light microscopy. Based on these findings we investigated the correlation between both FISH and CISH EGFR GCN and clinical outcome in K-RAS wild-type colorectal cancer treated with irinotecan-cetuximab.MethodsPatients with advanced K-RAS wild-type, colorectal cancer receiving irinotecan-cetuximab after failure of irinotecan-based chemotherapy were eligible.A cut-off value for EGFR GCN of 2.6 and 2.12 for FISH and CISH respectively was derived from ROC curve analysis.ResultsForty-four patients were available for analysis. We observed a partial remission in 9 (60%) and 2 (9%) cases with a FISH EGFR GCN ≥ 2.6 and < 2.6 respectively (p = 0.002) and in 10 (36%) and 1 (6%) cases with a CISH EGFR GCN ≥ 2.12 and < 2.12 respectively (p = 0.03). Median TTP was 7.7 and 6.4 months in patients showing increased FISH and CISH EGFR GCN whereas it was 2.9 and 3.1 months in those with low FISH and CISH EGFR GCN (p = 0.04 and 0.02 respectively).ConclusionFISH and CISH EGFR GCN may both represent effective tools for a further patients selection in K-RAS wild-type colorectal cancer treated with cetuximab.
Highlights
K-RAS wild type colorectal tumors show an improved response rate to anti-EGFR monoclonal antibodies
fluorescence in situ hybridization (FISH) and chromogenic in situ hybridization (CISH) EGFR gene copy number (GCN) may both represent effective tools for a further patients selection in K-RAS wild-type colorectal cancer treated with cetuximab
Research data from retrospective series have repeatedly demonstrated that a K-RAS mutant status was strictly correlated to clinical resistance to EGFR-targeted monoclonal antibodies [7,8,9,10,11,12]
Summary
K-RAS wild type colorectal tumors show an improved response rate to anti-EGFR monoclonal antibodies. FISH EGFR GCN has been previously demonstrated to correlate with clinical outcome of colorectal cancer treated with anti-EGFR monoclonal antibodies. CISH seemed able to provide accurate EGFR GCN information with the advantage of a simpler and reproducible technique involving immunohistochemistry and light microscopy Based on these findings we investigated the correlation between both FISH and CISH EGFR GCN and clinical outcome in K-RAS wild-type colorectal cancer treated with irinotecan-cetuximab. Published data clearly suggest that a non negligible proportion of patients, ranging from 70% to 40% in different series, does not seem to benefit from the use of anti-EGFR targeted antibodies in the absence of a mutation of the K-RAS gene (i.e. K-RAS wild-type) [7,8,9,10,11,12]
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