Abstract
Metastatic colorectal cancer patients with low epidermal growth factor receptor (EGFR) gene copy number are unlikely to respond to anti-EGFR monoclonal antibody (mAb) treatment. The objective of this study was to investigate EGFR fluorescence in situ hybridization (FISH) patterns of chromosome 7 disomy with efficacy of cetuximab therapy in metastatic colorectal cancer patients. We detected the EGFR FISH patterns and KRAS status in 74 tumors from cetuximab-treated metastatic colorectal cancer patients and analyzed with response rate (RR) and progression-free survival (PFS). One of the 16 (6.25%) patients with chromosome 7 homogeneous disomy (defined as FISH negative) had objective response to cetuximab. A total of 53(76.8%) patients with chromosome 7 pattern of variable ratios of disomy versus polysomy (defined as FISH positive) had a significantly higher RR (37.7% versus 6.25%; P = 0.01), a trend towards longer PFS (4.5 versus 2.9 months; P = 0.07). Among 54 KRAS wild-type patients, EGFR FISH-positive patients had significantly higher RR (51.3% versus 9%; P = 0.01) and longer PFS (5.0 versus 2.3 months; P = 0.02) than EGFR FISH-negative patients. However, among 20 KRAS mutant-type patients, there was no difference in RR (0% versus 0%) and PFS (2.5 versus 3.8 months; P = 0.51) between EGFR FISH-positive and -negative patients. Our results show firstly that patients with EGFR FISH pattern of chromosome 7 disomy have a very low chance to benefit from cetuximab-based therapy. EGFR FISH pattern of chromosome 7 disomy may be as a negative predicative factor for cetuximab response in KRAS wild-type metastatic colorectal cancer patients.
Highlights
It has been shown that the anti-epidermal growth factor receptor monoclonal antibody cetuximab (Erbitux, developed by Merck KGaA) as monotherapy or for combination with chemotherapy can improve responsiveness and prolong survival in patients with metastatic colorectal cancer [1,2,3,4], but only 10% to 20% of patients respond to this agent
We describe the epidermal growth factor receptor (EGFR) fluorescence in situ hybridization (FISH) patterns of chromosome 7 homogeneous disomy, which is the most frequent pattern of nonincreased EGFR gene copy number (GCN) in colorectal cancer and is easy to detect as a negative predicative factor for cetuximab response in KRAS wild-type metastatic colorectal cancer
Recent studies have confirmed that EGFR GCN assessed by FISH can influence the response to anti-EGFR monoclonal antibody (mAb) therapy in metastatic colorectal cancer, methods of tissue processing and EGFR scoring systems were not standardized among these studies [8,9,10,11]
Summary
It has been shown that the anti-epidermal growth factor receptor (anti-EGFR) monoclonal antibody (mAb) cetuximab (Erbitux, developed by Merck KGaA) as monotherapy or for combination with chemotherapy can improve responsiveness and prolong survival in patients with metastatic colorectal cancer [1,2,3,4], but only 10% to 20% of patients respond to this agent. Shown that the presence of a KRAS mutation is a significant predictor of resistance to anti-EGFR mAbs [5,6,7]. Studies have suggested that an increased EGFR gene copy number (GCN) analyzed by the fluorescence in situ hybridization (FISH) technique could be a promising predictor of anti-EGFR mAb therapy in metastatic colorectal cancer [8,9,10,11]. The EGFR FISH pattern of metastatic colorectal cancer is often not homogeneous, and has variable ratios of disomy versus polysomy or amplification. In these situations, the definition of EGFR patterns and the reproducibility of data lead to difficulties in direct comparison and clinical application. Moroni et al reported that chromosome 7 homogeneous disomy is the most frequent
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