Biomarkers of benefit from cetuximab-based therapy in metastatic colorectal cancer: interaction of EGFR ligand expression with RAS/RAF, PIK3CA genotypes

Pentheroudakis, George; Kotoula, Vassiliki; De Roock, Wendy; Kouvatseas, George; Papakostas, Pavlos; Makatsoris, Thomas; Papamichael, Demetris; Xanthakis, Ioannis; Sgouros, Joseph; Televantou, Despina; Kafiri, Georgia; Tsamandas, Athanassios C; Razis, Evangelia; Galani, Eleni; Bafaloukos, Dimitrios; Efstratiou, Ioannis; Bompolaki, Iliada; Pectasides, Dimitrios; Pavlidis, Nicholas; Tejpar, Sabine; Fountzilas, George

doi:10.1186/1471-2407-13-49

Cited by 111Colorectal Cancer Treatments and StudiesLung Cancer Treatments and MutationsHER2/EGFR in Cancer Research

Biomarkers of benefit from cetuximab-based therapy in metastatic colorectal cancer: interaction of EGFR ligand expression with RAS/RAF, PIK3CA genotypes

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Pentheroudakis, George, Kotoula, Vassiliki, De Roock, Wendy, Kouvatseas, George, Papakostas, Pavlos, Makatsoris, Thomas, Papamichael, Demetris, Xanthakis, Ioannis +13 more·2013·BMC Cancer

DOI 10.1186/1471-2407-13-49PMC PMC3599697

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Abstract

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.

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High mRNA levels of either amphiregulin or epiregulin may predict a better response to cetuximab.
“while high mRNA levels of either amphiregulin or epiregulin may predict a better response [21, 116-119]”
From Primary and acquired resistance to EGFR-targeted therapies in colorectal cancer: impact on future treatment strategies (2014) · cites this paper as [119]

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Siena S Sartore-Bianchi A Di Nicolantonio F Balfour J Bardelli A Biomarkers predicting clinical outcome of epidermal growth factor receptor-targeted therapy in metastatic colorectal cancer J Natl Cancer Inst 2009 101 19 1308 1324 10.1093/jnci/djp280 19738166 PMC2758310 · DOI

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Authors: Pentheroudakis, G., Kotoula, V., De Roock, W., Kouvatseas, G., Papakostas, P., Makatsoris, T., Papamichael, D., Xanthakis, I., Sgouros, J., Televantou, D., Kafiri, G., Tsamandas, A. C., Razis, E., Galani, E., Bafaloukos, D., Efstratiou, I., Bompolaki, I., Pectasides, D., Pavlidis, N., Tejpar, S., & Fountzilas, G.
Affiliations: University Hospital of Ioannina (GR)
Aristotle University of Thessaloniki (GR)
Hippocration General Hospital (GR)
University of Patras (GR)
Bank of Cyprus Oncology Center (CY)
Hygeia Hospital (GR)
Metropolitan Hospital (GR)
Papageorgiou General Hospital (GR)
Chania General Hospital ”St. George” (GR)
Ziekenhuis Oost-Limburg (BE)
Corresponding author: Pentheroudakis, George
ORCID: Pentheroudakis, George
Kotoula, Vassiliki
Makatsoris, Thomas
Papamichael, Demetris
Sgouros, Joseph
Razis, Evangelia
Pectasides, Dimitrios
Pavlidis, Nicholas
Tejpar, Sabine
Fountzilas, George
Venue: BMC Cancer
Publisher: Springer Science and Business Media LLC
Published: 2013-02-02
Volume: 13
Issue: 1
Pages: 49-49
ISSN: 1471-2407 (ISSN-L)
DOI: 10.1186/1471-2407-13-49
PMC: PMC3599697
OpenAlex: W2145310954
Cited by: 111
References: 30
Citations by year: 2026: 1 · 2025: 1 · 2024: 3 · 2023: 11 · 2021: 6 · 2020: 5 · 2019: 11 · 2018: 3 · 2017: 5 · 2016: 15 · 2015: 16 · 2014: 25 · 2013: 9
FWCI: 11.59
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by
www.springer.com/tdm (unspecified)
Locations: BMC Cancer (publishedVersion, cc-by)
Europe PMC (PubMed Central) (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
Topics: Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
Keywords: cetuximab, metastatic colorectal cancer, EGFR ligands, amphiregulin, epiregulin, PIK3CA mutation, KRAS mutation, BRAF mutation, RAS/RAF pathway, predictive biomarkers, anti-EGFR therapy response, ephrin-A2, epidermal growth factor, transforming growth factor-alpha, survival, objective response
MeSH terms: Cetuximab, Adenocarcinoma, Adult, Aged, Aged, 80 and over, Antineoplastic Agents, DNA Mutational Analysis, Epidermal Growth Factor, Female, Genotype, Glycoproteins, Humans, Male, Middle Aged, Genes, ras, Retrospective Studies, RNA, Messenger, Biomarkers, Tumor, Colorectal Neoplasms, Genetic Predisposition to Disease, Intercellular Signaling Peptides and Proteins, Proto-Oncogene Proteins B-raf, Phosphatidylinositol 3-Kinase, Antibodies, Monoclonal, Humanized, ErbB Receptors, EGF Family of Proteins, Amphiregulin, Epiregulin

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Biomarkers of benefit from cetuximab-based therapy in metastatic colorectal cancer: interaction of EGFR ligand expression with RAS/RAF, PIK3CA genotypes

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