Abstract
BackgroundThe survival rate of colorectal cancer (CRC) patients carrying wild-type KRAS is significantly increased by combining anti-EGFR monoclonal antibody (mAb) with standard chemotherapy. However, conflicting data exist in both the wild-type KRAS and mutant KRAS groups, which strongly challenge CRC anti-EGFR treatment. Here we conducted a meta-analysis in an effort to provide more reliable information regarding anti-EGFR treatment in CRC patients.MethodsWe searched full reports of randomized clinical trials using Medline, the American Society of Clinical Oncology (ASCO), and the European Society for Medical Oncology (ESMO). Two investigators independently screened the published literature according to our inclusive and exclusive criteria and the relative data were extracted. We used Review Manager 5.2 software to analyze the data.ResultsThe addition of anti-EGFR mAb to standard chemotherapy significantly improved both progression-free survival (PFS) and median overall survival (mOS) in the wild-type KRAS group; hazard ratios (HRs) for PFS and mOS were 0.70 [95% confidence interval (CI), 0.58–0.84] and 0.83 [95% CI, 0.75–0.91], respectively. In sub-analyses of the wild-type KRAS group, when PCR-based assays are employed, PFS and mOS notably increase: the HRs were 0.74 [95% CI, 0.62–0.88] and 0.87 [95% CI, 0.78–0.96], respectively. In sub-analyses of the mutant KRAS group, neither PCR-based assays nor direct sequencing enhance PFS or mOS.ConclusionOur data suggest that PCR-based assays with high sensitivity and specificity allow accurate identification of patients with wild-type KRAS and thus increase PFS and mOS. Furthermore, such assays liberate patients with mutant KRAS from unnecessary drug side effects, and provide them an opportunity to receive appropriate treatment. Thus, establishing a precise standard reference test will substantially optimize CRC-targeted therapies.
Highlights
Over the last two decades, considerable progress regarding the molecular biology of colorectal cancer (CRC) has remarkably increased the biologic therapeutic options [1]
With or without KRAS mutations, addition of anti-epidermal growth factor receptor (EGFR) therapy remarkably improved progression-free survival (PFS) [hazard ratios (HRs) 0.84, P = 0.02] according to a random-effect model (P value for heterogeneity,0.00001)
When we evaluated the data based on KRAS status, we observed a significant improvement in PFS in patients with wild-type status [HR 0.70, P = 0.0001] according to a random-effect model (P value for heterogeneity,0.00001), but not in patients with mutant KRAS [HR 1.06, P = 0.44] according to a randomeffect model (P value for heterogeneity = 0.009)
Summary
Over the last two decades, considerable progress regarding the molecular biology of colorectal cancer (CRC) has remarkably increased the biologic therapeutic options [1]. A key breakthrough was the discovery of two monoclonal antibodies (mAb) targeting epidermal growth factor receptor (EGFR): chimeric immunoglobulin G1 mAb (cetuximab) and a fully humanized immunoglobulin G2 mAb (panitumumab) These antibodies have been found to be very effective in combination with standard chemotherapy or as single therapeutic agents for chemotherapy-resistant metastatic CRC (mCRC) [2,3]. Extensive retrospective studies and phase III trials disclosed that KRAS gene activating mutations are the main negative predictor of mCRC anti-EGFR therapy [8,9,10] Based on these findings, the FDA changed the guidelines to recommend that cetuximab and panitumumab only be given to CRC patients with wild-type KRAS [11]. We conducted a metaanalysis in an effort to provide more reliable information regarding anti-EGFR treatment in CRC patients
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