EGFR Protein Expression of KRAS Wild-Type Colorectal Cancer: Predictive Value of the Sidedness for Efficacy of Anti-EGFR Therapy

Uhlyarik, Andrea; Piurkó, Violetta; Vízkeleti, Laura; Pápai, Zs.; Rásó, Erzsébet; Lahm, Erika; Kiss, É; Sikter, Marta; Vachaja, József; Kenessey, István; Tı́már, József

doi:10.1007/s12253-018-00572-2

Cited by 8 publications

(15 citation statements)

References 17 publications

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“…A multivariate analysis indicated that the EGFR protein expression of both the primary as well as the metastatic tissues is not an independent predictor of cetuximab efficacy unlike sidedness, confirming previous reports [17,18]. However, sidedness is not an EGFR-independent factor since it was shown recently that there is a close connection between EGFR protein expression and sidedness [11,19]: the poorly responding right-sided tumors express EGFR at significantly higher levels as compared to those left-sided [11]. Again, this suggests that EGFR protein expression is a negative predictive factor.…”

Section: Discussionsupporting

confidence: 80%

“…Age also turned out to be an independent predictor, but the corresponding relative risk (RR) levels were minimal. It is known that EGFR protein expression is significantly different in the case of left-versus right-sided cancers [11,19]. Therefore, we conducted a subgroup analysis on the OS of left-and right-sided cases based on EGFR-HS using Kaplan-Meyer statistics.…”

Section: Resultsmentioning

confidence: 99%

“…Earlier reports did not find any association between these two parameters [9], but more recently, amplification of EGFR was found to be a positive predictor of efficacy [10]. However, a clearcut association between EGFR-CNV and protein expression cannot be demonstrated [11]. On the other hand, mutations of the extracellular domain of EGFR (at codon 492 or 465) were found to be associated with cetuximab resistance [12,13].…”

Section: Introductionmentioning

confidence: 95%

“…Another study demonstrated that the coexpression of EGFR protein and their ligands, TGFα, EGF, amphiregulin and betacellulin, could be a negative predictor of cetuximab effectiveness in metastatic colorectal cancer [21]. In a previous study, we have observed that RAS wild-type left-sided colorectal cancers are characterized by a lower EGFR protein expression as compared to those right-sided but respond significantly better to various anti-EGFR therapies [11]. This suggests that EGFR protein expression might be another negative predictive factor of anti-EGFR therapies.…”

Section: Introductionmentioning

confidence: 96%

“…Furthermore, it was also recently discovered that left-sided colorectal cancers respond significantly better to anti-EGFR therapies than do right-sided colorectal cancers [17,18]. Data also demonstrated that there is a difference in EGFR protein expression between left-and right-sided colorectal cancers that is independent from the RAS mutation statuses [11,19]. One explanation for this discrepancy is that these agents are used in metastatic diseases and EGFR protein expression of the primary tumor may not accurately reflect the status of the metastatic tissue.…”

Section: Introductionmentioning

confidence: 97%

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EGFR Protein Expression in KRAS Wild-Type Metastatic Colorectal Cancer Is Another Negative Predictive Factor of the Cetuximab Therapy

Uhlyarik

Piurkó

Pápai

et al. 2020

Cancers

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The selection of colorectal cancer patients for anti-epidermal growth factor receptor (EGFR) antibody therapy is based on the determination of their RAS mutation status-a strongly negative predictive factor-since the protein target, EGFR, is not a reliable predictor of therapeutic response. In this study, we revisited the EGFR protein issue using a cohort of 90 patients with KRAS exon2 wild-type colorectal cancer who have been treated with cetuximab therapy. Twenty-nine of these patients had metastatic tissue available for analysis. The level of EGFR protein expression in the patients was determined by immunohistochemistry and evaluated by H-score (HS) methodology. Progression-free survival (PFS) and overall survival (OS) of the patients were determined according to the EGFR-HS ranges of both the primary and metastatic tissues using Kaplan-Meyer statistics. In the case of primary tumors, EGFR scores lower than HS = 200 were associated with significantly longer OS. In the case of metastatic tissues, all levels lower than the EGFR-HS range chosen were associated with significantly longer OS. These results are explained by the fact that metastatic tissues rarely maintained the expression levels of the primary tumors. On the other hand, high EGFR expression levels in either primary tumors or metastatic tissues were associated with multiple metastatic disease. This suggests a negative prognostic role of EGFR expression. However, in a multivariate analysis, one-sidedness remained a strong independent predictive factor of survival. Previous studies demonstrated that the EGFR expression level depends on sidedness. Therefore, a subgroup analysis of the left-and right-sided cases was performed on both primary and metastatic tissues. In the case of metastic tissues, an analysis confirmed a better OS in low EGFR protein-expressing cases than in high EGFR protein-expressing cases. Collectively, these data suggest that EGFR protein expression is another negative predictive factor of the efficacy of cetuximab therapy of KRAS exon2 wild-type colorectal cancer.

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Section: Discussionsupporting

confidence: 80%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 97%

See 3 more Smart Citations

EGFR Protein Expression in KRAS Wild-Type Metastatic Colorectal Cancer Is Another Negative Predictive Factor of the Cetuximab Therapy

Uhlyarik

Piurkó

Pápai

et al. 2020

Cancers

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Novel molecular classification of colorectal cancer and correlation with survival

Mangi

Shaikh

Soria

et al. 2022

Saudi Journal of Biological Sciences

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miRNA-9 Inhibits Proliferation and Migration of Lung Squamous Cell Carcinoma Cells by Regulating NRSF/EGFR

Wang

Leng

et al. 2020

Technol Cancer Res Treat

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Background: To investigate the mechanism of microRNA9 in inhibiting proliferation and migration of lung squamous cell carcinoma cells via neuron-restricted silencing factor/epidermal growth factor receptor. Material and Methods: Detection of microRNA9, neuron-restricted silencing factor, and epidermal growth factor receptor expression levels in lung cancer patients’ tissues and lung cancer cells by Western blotting and quantitative polymerase chain reaction. Detection of cell proliferation by colony formation assay and cell counting kit-8 assay. Detection of cell migration by wound-healing assay and Transwell assay. And detection of the regulatory effect between neuron-restricted silencing factor and epidermal growth factor receptor by Luciferase reporter gene system. Subcutaneous implantation mouse models of NCI-H520 cells were constructed to detect cell proliferation in vivo, and Kaplan–Meier method calculated patient survival. Results: The expression of microRNA9 and epidermal growth factor receptor was higher in lung cancer tissues than in normal lung tissues, while the expression of neuron-restricted silencing factor was lower in lung cancer tissues than in normal lung tissues. MicroRNA9 higher expression was strongly related to tumor size, and TNM stage and predicted showed reduced overall survival in patients with lung cancer. Further loss of function and enhancement experiments revealed that inhibition of microRNA9 could significantly inhibit lung squamous carcinoma cell proliferation and migration. Luciferase reporter assay demonstrated that microRNA9 could bind to NRSF messenger RNA and inhibit its expression, neuron-restricted silencing factor overexpression also exerted inhibitory effects on cell proliferation and migration. Moreover, Luciferase reporter assay showed that neuron-restricted silencing factor downregulate epidermal growth factor receptor expression levels by binding to epidermal growth factor receptor promoter regions, and Pearson’s correlation analysis indicated that the levels of microRNA9 in lung cancer tissues were correlated with neuron-restricted silencing factor and epidermal growth factor receptor. Combined microRNA9 with neuron-restricted silencing factor or epidermal growth factor receptor to predict the prognosis of patients with lung cancer may be more accurate. Conclusion: MicroRNA9 inhibits proliferation and migration of lung squamous cell carcinoma cells by inhibiting neuron-restricted silencing factor/epidermal growth factor receptor axis. MicroRNA9 can be a new prognostic marker and therapeutic target for lung squamous cell carcinoma.

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EGFR Protein Expression of KRAS Wild-Type Colorectal Cancer: Predictive Value of the Sidedness for Efficacy of Anti-EGFR Therapy

Cited by 8 publications

References 17 publications

EGFR Protein Expression in KRAS Wild-Type Metastatic Colorectal Cancer Is Another Negative Predictive Factor of the Cetuximab Therapy

EGFR Protein Expression in KRAS Wild-Type Metastatic Colorectal Cancer Is Another Negative Predictive Factor of the Cetuximab Therapy

Novel molecular classification of colorectal cancer and correlation with survival

miRNA-9 Inhibits Proliferation and Migration of Lung Squamous Cell Carcinoma Cells by Regulating NRSF/EGFR

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