title: EGFRmethylation and outcome of patients with advanced colorectal cancer treated with cetuximab.
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)RASgene status. However, despite selection based onRASstatus, a high proportion of patients do not respond to therapy.EGFRmethylation has been reported to have a role in predicting the response to anti-EGFR agents. The present study aimed to evaluate the role ofEGFRmethylation 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 andEGFRmethylation and mutation of theKRAS,BRAFandPIK3CAgenes 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. MeanEGFRmethylation of 41 and 9% was observed inKRAS-mutated and -wt patients, respectively (P=0.05). Conversely, a highEGFRmethylation was observed inBRAF-wt patients with compared with patients possessing the mutated gene (18 vs. 3%, respectively; P=0.07).EGFRmethylation 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 and >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 betweenEGFRmethylation and improved OS rate in patients treated with CTX-based chemotherapy. The presence ofEGFRmethylation is inversely correlated withBRAFandPIK3CAmutations, indicating that the prognostic value of gene methylation may be worth verifying in further studies.
authors: Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy.
authors: Elisa
authors: E
authors: Chiadini
authors: Unit of Biostatistics and Clinical Trials, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy.
authors: Emanuela
authors: E
authors: Scarpi
authors: Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy.
authors: Alessandro
authors: A
authors: Passardi
authors: Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy.
authors: Daniele
authors: D
authors: Calistri
authors: Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy.
authors: Martina
authors: M
authors: Valgiusti
authors: Pathology Unit, Morgagni-Pierantoni Hospital, Forlì, Italy.
authors: Luca
authors: L
authors: Saragoni
authors: Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy.
authors: Wainer
authors: W
authors: Zoli
authors: Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy.
authors: Dino
authors: D
authors: Amadori
authors: Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy.
authors: Paola
authors: P
authors: Ulivi
keywords: cetuximab; colorectal cancer; epidermal growth factor receptor; methylation