期刊论文详细信息
BMC Cancer
Biomarkers of benefit from cetuximab-based therapy in metastatic colorectal cancer: interaction of EGFR ligand expression with RAS/RAF, PIK3CA genotypes
George Pentheroudakis4  Vassiliki Kotoula12  Wendy De Roock2  George Kouvatseas7  Pavlos Papakostas9  Thomas Makatsoris14  Demetris Papamichael13  Ioannis Xanthakis8  Joseph Sgouros6  Despina Televantou12  Georgia Kafiri10  Athanassios C Tsamandas3  Evangelia Razis17  Eleni Galani1  Dimitrios Bafaloukos16  Ioannis Efstratiou15  Iliada Bompolaki11  Dimitrios Pectasides5  Nicholas Pavlidis4  Sabine Tejpar2  George Fountzilas8 
[1] Second Department of Medical Oncology, “Metropolitan” Hospital, Piraeus, Greece
[2] Department of Oncology, Ziekenhuis Oost-Limburg, Genk, Belgium
[3] Department of Pathology, University Hospital, University of Patras Medical School, Patras, Greece
[4] Department of Medical Oncology, Ioannina University Hospital, Ioannina, Greece
[5] Oncology Section, Second Department of Internal Medicine, “Hippokration” Hospital, Athens, Greece
[6] Third Department of Medical Oncology, “Agii Anargiri” Cancer Hospital, Athens, Greece
[7] Health Data Specialists Ltd, Athens, Greece
[8] Department of Medical Oncology, “Papageorgiou” Hospital, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece
[9] Department of Medical Oncology, “Hippokration” Hospital, Athens, Greece
[10] Department of Pathology, Ippokration Hospital, Athens, Greece
[11] Oncology Department, General Hospital of Chania, Crete, Greece
[12] Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece
[13] Bank of Cyprus Oncology Center, Nicosia, Cyprus
[14] Division of Oncology, Department of Medicine, University Hospital, University of Patras Medical School, Patras, Greece
[15] Department of Pathology, “Papageorgiou” Hospital, Thessaloniki, Greece
[16] First Department of Medical Oncology, “Metropolitan” Hospital, Piraeus, Greece
[17] Third Department of Medical Oncology, “Hygeia” Hospital, Athens, Greece
关键词: Biomarkers;    PI3K gene mutations;    BRAF;    KRAS;    EGFR ligands;    Epidermal growth factor receptor;    Cetuximab;   
Others  :  1079941
DOI  :  10.1186/1471-2407-13-49
 received in 2012-09-01, accepted in 2013-01-30,  发布年份 2013
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【 摘 要 】

Background

More than half of patients with KRAS-wild type advanced colorectal cancer (CRC) fail anti-EGFR monoclonal antibodies. We studied EGFR-axis messenger RNA (mRNA) expression and RAS, RAF, PIK3CA mutations in order to identify additional biomarkers of cetuximab efficacy.

Methods

Previously genotyped (KRAS, NRAS, BRAF, PIK3CA mutations) formalin-fixed paraffin-embedded tumour biopsies of 226 cetuximab-treated CRC patients (1st to 3rd line therapy) were assessed for mRNA expression of epidermal growth factor receptor (EGFR) and its ligands EGF, Transofrming Growth Factor-a (TGFA), Amphiregulin (AREG) and Epiregulin (EREG) with real time quantitative PCR. Mutations were detected in 72 (31.9%) tumours for KRAS, in 6 (2.65%) for BRAF, in 7 (3.1%) for NRAS and in 37 (16.4%) for PIK3CA.

Results

Only PIK3CA mutations occasionally coexisted with other gene mutations. In univariate analysis, prognostic significance for survival ( from metastases until death) was seen for BRAF mutations (Hazard Ratio HR 8.1, 95% CI 3.4-19), codon 12-only KRAS mutations (HR 1.62, 95% CI 1.1-2.4), high AREG mRNA expression only in KRAS wild type CRC (HR 0.47, 95% CI 0.3-0.7) and high EREG mRNA expression irrespective of KRAS mutation status (HR 0.45, 95% CI 0.28-0.7). EREG tumoural mRNA expression was significantly associated with a 2.26-fold increased likelihood of objective response to cetuximab therapy (RECIST 1.1). In multivariate analysis, favourable predictive factors were high AREG mRNA in KRAS wild type tumours, high EREG mRNA, low Ephrin A2 receptor mRNA. Cetuximab-treated patients with AREG-low KRAS wild type CRC fared very poorly, their survival being similar to KRAS mutant CRC. Patients with KRAS codon 13 or other non-codon 12 mutations had a median survival (30 months, 95% CI 20–35) similar to that of patients with KRAS wild-type (median survival 29 months, 95% CI 25–35), in contrast to patients with KRAS codon 12 mutations who fared worse (median survival 19 months, 95% CI 15–26).

Conclusions

BRAF and codon 12 KRAS mutations predict for adverse outcome of CRC patients receiving cetuximab. AREG mRNA reflects EGFR signalling in KRAS wild type tumours, predicting for cetuximab efficacy when high and failure when low. EREG may have a prognostic role independent of KRAS mutation.

【 授权许可】

   
2013 Pentheroudakis et al; licensee BioMed Central Ltd.

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