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Arginine methylation of EGFR: a new biomarker for predicting resistance to anti-EGFR treatment.

ABSTRACT: Arginine methylation of the epidermal growth factor receptor (meEGFR) increases the binding affinity of EGFR ligands and is reported to have a role in predicting response to anti-EGFR agents. This study investigated the predictive impact of meEGFR in metastatic colorectal cancer (mCRC) patients treated with anti-EGFR agents. Two patient cohorts were evaluated. Cohort 1 consisted of mCRC patients with documented disease progression following anti-EGFR treatment. Circulating tumor cells (CTCs) were isolated and distinguished based on CD45^- and Epcam⁺. Cohort 2 consisted of formalin fixed paraffin-embedded (FFPE) blocks from a prospective cohort. meEGFR in both cohorts was identified by positive staining for me-R198/200 EGFR signal. CTCs were identified in 30 out of 47 cases in cohort 1. Of those 30, meEGFR-CTCs were identified in 19 cases. Mean total meEGFR-CTCs counts was 2.3 (range 0-30) cells per 7.5 ml. There was no association between meEGFR-CTCs and clinic-pathological-molecular features. In RAS^wt/BRAF^wt patients with high levels of meEGFR-CTCs ratio (? 0.23) had significantly inferior PFS with anti-EGFR treatment (HR = 3.4, 95% CI 1.5-7.9, P = 0.004). By contrast, high levels of meEGFR in the untreated tumor tissues had no correlation with anti-EGFR treatment duration in cohort 2. Therefore, meEGFR-CTCs may have the potential to serve as a "liquid biopsy" biomarker to predict anti-EGFR treatment efficacy.

SUBMITTER: Korphaisarn K

PROVIDER: S-EPMC5752698 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Arginine methylation of EGFR: a new biomarker for predicting resistance to anti-EGFR treatment.

Korphaisarn Krittiya K Chou Chao-Kai CK Xia Wei-Ya WY Clarke Callisia N CN Katkhuda Riham R Davis Jennifer S JS Raghav Kanwal Ps KP Liao Hsin-Wei HW Wu Ji-Yuan JY Menter David G DG Maru Dipen M DM Hung Mien-Chie MC Kopetz Scott S

American journal of cancer research 20171201 12

Arginine methylation of the epidermal growth factor receptor (meEGFR) increases the binding affinity of EGFR ligands and is reported to have a role in predicting response to anti-EGFR agents. This study investigated the predictive impact of meEGFR in metastatic colorectal cancer (mCRC) patients treated with anti-EGFR agents. Two patient cohorts were evaluated. Cohort 1 consisted of mCRC patients with documented disease progression following anti-EGFR treatment. Circulating tumor cells (CTCs) wer ...[more]

PMID: 29312811

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Project description:Carcinoembryonic antigen (CEA) is the most widely used tumor marker in metastatic colorectal cancer (mCRC). However, its potential as a predictive marker of progression in mCRC during systemic chemotherapy, particularly in patients receiving monoclonal antibodies as a combination therapy, has remained of interest. Herein, we investigated whether CEA changes could predict disease progression and clinical outcomes in patients with mCRC cotreated with systemic chemotherapy and/or biologic agents. A total of 1261 patients with mCRC undergoing a first-line systemic treatment were included in this retrospective study. We analyzed the optimal cut-off value for CEA changes to predict progression at the first response evaluation by the treatment arm (chemotherapy alone, chemotherapy plus anti-vascular endothelial growth factor (VEGF) monoclonal antibody [mAb], and chemotherapy plus anti-epidermal growth factor receptor [EGFR] mAb). These cut-off values were then used to predict overall survival (OS) and progression-free survival (PFS). When stratified by their treatment arm, 891 (70.6%), 266 (21.0%), and 104 (8.2%) of the study patients were included in the chemotherapy alone-, anti-VEGF mAb, and anti-EGFR mAb groups, respectively. The optimal CEA cut-off values were 16.5% and 38.9% increase in the whole cohort and anti-EGFR mAb group, respectively, and these values showed high sensitivity and specificity for predicting disease progression. The patients in the entire population and anti-EGFR mAb group with CEA changes below these cut-off values showed significantly better OS and PFS outcomes compared those whose changes were above cut-off values. Among the patients with mCRC treated with anti-VEGF mAb, no associations were found between OS or PFS outcomes and CEA changes. CEA is potentially a good surrogate marker for predicting disease progression and survival outcomes in patients with mCRC receiving first-line systemic chemotherapy alone or chemotherapy with anti-EGFR mAb, whereas it is less effective in those treated with anti-VEGF mAb.

Project description: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.

Dataset Information

Arginine methylation of EGFR: a new biomarker for predicting resistance to anti-EGFR treatment.

Publications

Arginine methylation of EGFR: a new biomarker for predicting resistance to anti-EGFR treatment.

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