PMID- 23374602
OWN - NLM
STAT- MEDLINE
DCOM- 20130828
LR  - 20211021
IS  - 1471-2407 (Electronic)
IS  - 1471-2407 (Linking)
VI  - 13
DP  - 2013 Feb 2
TI  - Biomarkers of benefit from cetuximab-based therapy in metastatic colorectal 
      cancer: interaction of EGFR ligand expression with RAS/RAF, PIK3CA genotypes.
PG  - 49
LID - 10.1186/1471-2407-13-49 [doi]
AB  - 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.
FAU - Pentheroudakis, George
AU  - Pentheroudakis G
AD  - Department of Medical Oncology, Ioannina University Hospital, Ioannina, Greece. 
      gpenther@otenet.gr
FAU - Kotoula, Vassiliki
AU  - Kotoula V
FAU - De Roock, Wendy
AU  - De Roock W
FAU - Kouvatseas, George
AU  - Kouvatseas G
FAU - Papakostas, Pavlos
AU  - Papakostas P
FAU - Makatsoris, Thomas
AU  - Makatsoris T
FAU - Papamichael, Demetris
AU  - Papamichael D
FAU - Xanthakis, Ioannis
AU  - Xanthakis I
FAU - Sgouros, Joseph
AU  - Sgouros J
FAU - Televantou, Despina
AU  - Televantou D
FAU - Kafiri, Georgia
AU  - Kafiri G
FAU - Tsamandas, Athanassios C
AU  - Tsamandas AC
FAU - Razis, Evangelia
AU  - Razis E
FAU - Galani, Eleni
AU  - Galani E
FAU - Bafaloukos, Dimitrios
AU  - Bafaloukos D
FAU - Efstratiou, Ioannis
AU  - Efstratiou I
FAU - Bompolaki, Iliada
AU  - Bompolaki I
FAU - Pectasides, Dimitrios
AU  - Pectasides D
FAU - Pavlidis, Nicholas
AU  - Pavlidis N
FAU - Tejpar, Sabine
AU  - Tejpar S
FAU - Fountzilas, George
AU  - Fountzilas G
LA  - eng
PT  - Journal Article
DEP - 20130202
PL  - England
TA  - BMC Cancer
JT  - BMC cancer
JID - 100967800
RN  - 0 (AREG protein, human)
RN  - 0 (Amphiregulin)
RN  - 0 (Antibodies, Monoclonal, Humanized)
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Biomarkers, Tumor)
RN  - 0 (EGF Family of Proteins)
RN  - 0 (EREG protein, human)
RN  - 0 (Epiregulin)
RN  - 0 (Glycoproteins)
RN  - 0 (Intercellular Signaling Peptides and Proteins)
RN  - 0 (RNA, Messenger)
RN  - 62229-50-9 (Epidermal Growth Factor)
RN  - EC 2.7.1.137 (Phosphatidylinositol 3-Kinase)
RN  - EC 2.7.10.1 (EGFR protein, human)
RN  - EC 2.7.10.1 (ErbB Receptors)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins B-raf)
RN  - PQX0D8J21J (Cetuximab)
SB  - IM
MH  - Adenocarcinoma/drug therapy/*genetics/metabolism/secondary
MH  - Adult
MH  - Aged
MH  - Aged, 80 and over
MH  - Amphiregulin
MH  - Antibodies, Monoclonal, Humanized/*therapeutic use
MH  - Antineoplastic Agents/*therapeutic use
MH  - Biomarkers, Tumor/*metabolism
MH  - Cetuximab
MH  - Colorectal Neoplasms/*drug therapy/genetics/metabolism/secondary
MH  - DNA Mutational Analysis
MH  - EGF Family of Proteins
MH  - Epidermal Growth Factor/metabolism
MH  - Epiregulin
MH  - ErbB Receptors/*metabolism
MH  - Female
MH  - Genes, ras/*genetics
MH  - Genetic Predisposition to Disease
MH  - Genotype
MH  - Glycoproteins/metabolism
MH  - Humans
MH  - Intercellular Signaling Peptides and Proteins/metabolism
MH  - Male
MH  - Middle Aged
MH  - Phosphatidylinositol 3-Kinase/*genetics
MH  - Proto-Oncogene Proteins B-raf/*genetics
MH  - RNA, Messenger/metabolism
MH  - Retrospective Studies
PMC - PMC3599697
EDAT- 2013/02/05 06:00
MHDA- 2013/08/29 06:00
PMCR- 2013/02/02
CRDT- 2013/02/05 06:00
PHST- 2012/09/01 00:00 [received]
PHST- 2013/01/30 00:00 [accepted]
PHST- 2013/02/05 06:00 [entrez]
PHST- 2013/02/05 06:00 [pubmed]
PHST- 2013/08/29 06:00 [medline]
PHST- 2013/02/02 00:00 [pmc-release]
AID - 1471-2407-13-49 [pii]
AID - 10.1186/1471-2407-13-49 [doi]
PST - epublish
SO  - BMC Cancer. 2013 Feb 2;13:49. doi: 10.1186/1471-2407-13-49.