Abstract
BackgroundEpidermal growth factor receptor gene copy number (EGFR GCN) has been heavily investigated as a potential predictive biomarker for the treatment of metastatic colorectal cancer (mCRC) with anti-EGFR monoclonal antibodies (MAbs). The objective of this study was to systematically review current evidences on this issue.MethodsPubMed, EMBASE, The Cochrane Library, Chinese Biomedical Literature Database, Wanfang Data, and the conference abstracts of American Society of Clinical Oncology and European Society of Medical Oncology were comprehensively searched. Studies that reported the objective response rate (ORR), progression-free survival, and/or overall survival of mCRC patients treated with anti-EGFR MAbs, stratified by EGFR GCN status, were included. The effect measures for binary outcome (response) and time-to-event outcomes (progression-free survival and overall survival) were risk difference and hazard ratio, respectively. Statistical heterogeneity among the studies was assessed by the Cochran’s Q-test and the I2 statistic. If appropriate, a quantitative synthesis of data from different studies would be conducted with a random-effects model.ResultsNineteen eligible studies were identified. The criteria for increased EGFR GCN (GCN+) were highly inconsistent across different studies. The prevalence of GCN + ranged from 6.9% to 88.9%, and the difference in ORR between patients with GCN + and those with non-increased EGFR GCN (GCN-) varied from −28% to 84%. Because of the significant heterogeneity, no quantitative synthesis of data was performed. There was a general trend towards higher ORR in patients with GCN+. The difference in ORRs between patients with GCN + and those with GCN- was even greater in KRAS wild-type patients, while in KRAS mutated patients the difference often did not exist. Almost all patients with EGFR amplification responded to the treatment. However, the prevalence of EGFR amplification was generally low. Incomplete data on progression-free survival and overall survival seemingly supported the findings on ORR.ConclusionsAlthough increased EGFR GCN is generally associated with a better outcome of anti-EGFR MAbs treatment, especially among patients with wild-type KRAS, the clinical utility of this biomarker for selecting recipients of anti-EGFR MAbs would be severely limited by the heterogeneous scoring system and the poor reproducibility of EGFR GCN enumeration due to technical reasons.
Highlights
Epidermal growth factor receptor gene copy number (EGFR GCN) has been heavily investigated as a potential predictive biomarker for the treatment of metastatic colorectal cancer with anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (MAbs)
Three studies were conducted in KRAS wild-type patients only [16,31,32], and another eight studies reported the data on KRAS wild-type and mutant patients separately [14,18,19,22,24,25,26,28], providing us the opportunity to examine the impact of KRAS status on the predictive power of GCN+
The anti-EGFR MAb administered, the response criteria, and the assay for EGFR GCN quantification were generally consistent across different studies
Summary
Epidermal growth factor receptor gene copy number (EGFR GCN) has been heavily investigated as a potential predictive biomarker for the treatment of metastatic colorectal cancer (mCRC) with anti-EGFR monoclonal antibodies (MAbs). Colorectal cancer (CRC) is the third most common malignant disease and the fourth leading cause of cancerrelated deaths worldwide [1]. The chimeric IgG1 cetuximab and the fully humanized IgG2 panitumumab, two monoclonal antibodies (MAbs) targeted at epidermal growth factor receptor (EGFR), were found effective in combination with chemotherapy or as a single agent for the treatment of chemotherapy-resistant mCRC [4,5,6]. The tumor response rate increased by anti-EGFR MAbs was only 10%-20%, whether it be used as the 1st- or 2nd-line treatment [4,6,7,8,9]. As antiEGFR MAbs were associated with significant increase in toxicities [5] and costs [10], it is important to identify the responsive patients for treatment and prevent nonresponsive ones from exposure to unnecessary treatment
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