EGFR methylation and outcome of patients with advanced colorectal cancer treated with cetuximab

Elisa Chiadini, Emanuela Scarpi, Alessandro Passardi, Daniele Calistri, Martina Valgiusti, Luca Saragoni, Wainer Zoli, Dino Amadori, Paola Ulivi

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Targeted therapy of metastatic colorectal cancer (mCRC) with monoclonal antibody anti‑epidermal growth factor receptor (EGFR) agents, such as cetuximab (CTX) or panitumumab, is the treatment strategy of choice in patients characterised by a wild-type (wt) RAS gene status. However, despite selection based on RAS status, a high proportion of patients do not respond to therapy. EGFR methylation has been reported to have a role in predicting the response to anti‑EGFR agents. The present study aimed to evaluate the role of EGFR methylation in association with the clinical outcome of patients with mCRC treated with CTX. In total, 64 patients with mCRC were assessed in the present study. Genomic DNA was extracted from tumoral tissue and EGFR methylation and mutation of the KRAS, BRAF and PIK3CA genes were analysed by pyrosequencing. EGFR expression was assessed by immunohistochemistry. The various alterations were analysed by assessing the objective response rate (ORR), progression free survival (PFS) and overall survival (OS) rates. In total, 42 cases (66%) exhibited >10% EGFR methylation and there was no correlation with EGFR expression. Mean EGFR methylation of 41 and 9% was observed in KRAS-mutated and -wt patients, respectively (P=0.05). Conversely, a high EGFR methylation was observed in BRAF-wt patients with compared with patients possessing the mutated gene (18 vs. 3%, respectively; P=0.07). EGFR methylation was significantly correlated with the OS rate [hazard ratio, 0.98; 95% confidence interval (CI), 0.96‑1.00; P=0.019], but not PFS rate. In patients with a methylation rate 10%, the median OS rate was 7.5 months (95% CI, 4.4‑9.4 months) and 12.0 months (95% CI, 8.7‑13.9 months), respectively (P=0.034). In conclusion, the present study revealed a correlation between EGFR methylation and improved OS rate in patients treated with CTX‑based chemotherapy. The presence of EGFR methylation is inversely correlated with BRAF and PIK3CA mutations, indicating that the prognostic value of gene methylation may be worth verifying in further studies.

Original languageEnglish
Pages (from-to)1432-1438
Number of pages7
JournalOncology Letters
Volume9
Issue number3
DOIs
Publication statusPublished - Mar 1 2015

Fingerprint

Methylation
Colorectal Neoplasms
Survival Rate
Confidence Intervals
Genes
Disease-Free Survival
Cetuximab
Mutation
Growth Factor Receptors
Therapeutics
Immunohistochemistry
Monoclonal Antibodies
Drug Therapy
DNA

Keywords

  • Cetuximab
  • Colorectal cancer
  • Epidermal growth factor receptor
  • Methylation

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

EGFR methylation and outcome of patients with advanced colorectal cancer treated with cetuximab. / Chiadini, Elisa; Scarpi, Emanuela; Passardi, Alessandro; Calistri, Daniele; Valgiusti, Martina; Saragoni, Luca; Zoli, Wainer; Amadori, Dino; Ulivi, Paola.

In: Oncology Letters, Vol. 9, No. 3, 01.03.2015, p. 1432-1438.

Research output: Contribution to journalArticle

Chiadini, Elisa ; Scarpi, Emanuela ; Passardi, Alessandro ; Calistri, Daniele ; Valgiusti, Martina ; Saragoni, Luca ; Zoli, Wainer ; Amadori, Dino ; Ulivi, Paola. / EGFR methylation and outcome of patients with advanced colorectal cancer treated with cetuximab. In: Oncology Letters. 2015 ; Vol. 9, No. 3. pp. 1432-1438.
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AU - Saragoni, Luca

AU - Zoli, Wainer

AU - Amadori, Dino

AU - Ulivi, Paola

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N2 - Targeted therapy of metastatic colorectal cancer (mCRC) with monoclonal antibody anti‑epidermal growth factor receptor (EGFR) agents, such as cetuximab (CTX) or panitumumab, is the treatment strategy of choice in patients characterised by a wild-type (wt) RAS gene status. However, despite selection based on RAS status, a high proportion of patients do not respond to therapy. EGFR methylation has been reported to have a role in predicting the response to anti‑EGFR agents. The present study aimed to evaluate the role of EGFR methylation in association with the clinical outcome of patients with mCRC treated with CTX. In total, 64 patients with mCRC were assessed in the present study. Genomic DNA was extracted from tumoral tissue and EGFR methylation and mutation of the KRAS, BRAF and PIK3CA genes were analysed by pyrosequencing. EGFR expression was assessed by immunohistochemistry. The various alterations were analysed by assessing the objective response rate (ORR), progression free survival (PFS) and overall survival (OS) rates. In total, 42 cases (66%) exhibited >10% EGFR methylation and there was no correlation with EGFR expression. Mean EGFR methylation of 41 and 9% was observed in KRAS-mutated and -wt patients, respectively (P=0.05). Conversely, a high EGFR methylation was observed in BRAF-wt patients with compared with patients possessing the mutated gene (18 vs. 3%, respectively; P=0.07). EGFR methylation was significantly correlated with the OS rate [hazard ratio, 0.98; 95% confidence interval (CI), 0.96‑1.00; P=0.019], but not PFS rate. In patients with a methylation rate 10%, the median OS rate was 7.5 months (95% CI, 4.4‑9.4 months) and 12.0 months (95% CI, 8.7‑13.9 months), respectively (P=0.034). In conclusion, the present study revealed a correlation between EGFR methylation and improved OS rate in patients treated with CTX‑based chemotherapy. The presence of EGFR methylation is inversely correlated with BRAF and PIK3CA mutations, indicating that the prognostic value of gene methylation may be worth verifying in further studies.

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