Implications for KRAS status and EGFR-targeted therapies in metastatic CRC

Normanno, Nicola; Tejpar, Sabine; Morgillo, Floriana; De Luca, Antonella; Van Cutsem, Eric; Ciardiello, Fortunato

doi:10.1038/nrclinonc.2009.111

Cited by 436Colorectal Cancer Treatments and StudiesLung Cancer Treatments and MutationsHER2/EGFR in Cancer Research

Implications for KRAS status and EGFR-targeted therapies in metastatic CRC

Normanno, Nicola, Tejpar, Sabine, Morgillo, Floriana, De Luca, Antonella, Van Cutsem, Eric, Ciardiello, Fortunato·2009·Nature Reviews Clinical Oncology

DOI 10.1038/nrclinonc.2009.111

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Abstract

EGFR regulates cancer-cell proliferation, apoptosis and tumor-induced neoangiogenesis, and has been validated as a relevant therapeutic target in several human cancers, including metastatic colorectal cancer (mCRC). The anti-EGFR monoclonal antibodies cetuximab and panitumumab are available for the treatment of patients with mCRC. Although EGFR is expressed in approximately 85% of patients with mCRC, the clinical efficacy of treatment with anti-EGFR antibodies is limited to a subset of patients. A series of potential biomarkers that could be useful in predicting response to EGFR inhibitors has been investigated. In patients with mCRC, activating mutations within KRAS can predict resistance to anti-EGFR monoclonal antibodies. Activating mutations in KRAS, which could result in EGFR-independent intracellular signal transduction activation, are found in approximately 35-40% of patients with mCRC. These mutations are almost exclusively detected in codons 12 and 13 of exon 2. KRAS mutations have been significantly associated with lack of response to cetuximab or panitumumab therapy in patients with mCRC, which suggests that EGFR-independent, constitutive activation of the RAS signaling pathway could impair response to anti-EGFR drugs. We summarize the experimental and clinical evidence supporting the use of KRAS testing for the optimal selection of patients with mCRC to be treated with anti-EGFR monoclonal antibodies.

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RAS mutations play a critical role in treatment selection and prognosis of metastatic colorectal cancer.
“It is known that RAS mutations, which are one of the first molecular parameters examined in patients diagnosed with mCRC, play a critical role in the selection of treatment and prognosis of the disease.”
From RAS Mutations in Advanced Colorectal Cancer: Mechanisms, Clinical Implications, and Novel Therapeutic Approaches (2025) · cites this paper as [1]
RAS mutations, predominantly KRAS and NRAS, are detected in approximately 40-45% of metastatic colorectal cancer cases.
“specifically KRAS and NRAS, which are detected in approximately 40–45% of mCRC cases”
From RAS Mutations in Advanced Colorectal Cancer: Mechanisms, Clinical Implications, and Novel Therapeutic Approaches (2025) · cites this paper as [1]

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Self-citation
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Authors: Normanno, N., Tejpar, S., Morgillo, F., De Luca, A., Van Cutsem, E., & Ciardiello, F.
Affiliations: Istituto Nazionale Tumori IRCCS "Fondazione G. Pascale" (IT)
Universitair Ziekenhuis Leuven (BE)
University of Campania "Luigi Vanvitelli" (IT)
Corresponding author: Ciardiello, Fortunato
ORCID: Normanno, Nicola
Tejpar, Sabine
Morgillo, Floriana
Ciardiello, Fortunato
Venue: Nature Reviews Clinical Oncology
Publisher: Springer Science and Business Media LLC
Published: 2009-07-28
Volume: 6
Issue: 9
Pages: 519-527
ISSN: 1759-4774 (ISSN-L)
1759-4782
DOI: 10.1038/nrclinonc.2009.111
OpenAlex: W2038624343
Cited by: 436
References: 62
Citations by year: 2026: 7 · 2025: 15 · 2024: 22 · 2023: 19 · 2022: 18 · 2021: 21 · 2020: 20 · 2019: 20 · 2018: 18 · 2017: 25 · 2016: 34 · 2015: 33 · 2014: 40 · 2013: 31 · 2012: 45
FWCI: 3.30
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
Locations: Nature Reviews Clinical Oncology (publishedVersion)
PubMed (publishedVersion)
Archivio Istituzionale della Ricerca - Università degli Studi della Campania "Luigi Vanvitelli" (submittedVersion)
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: KRAS mutation, anti-EGFR therapy, metastatic colorectal cancer, cetuximab, panitumumab, anti-EGFR monoclonal antibody, predictive biomarkers, Ras signaling, treatment resistance, patient selection, irinotecan
MeSH terms: Cetuximab, Panitumumab, Amino Acid Sequence, Antibodies, Monoclonal, Antineoplastic Agents, Aspartic Acid, Base Sequence, Codon, Exons, Humans, Molecular Sequence Data, Neoplasm Metastasis, Genes, ras, Biomarkers, Tumor, Valine, Colorectal Neoplasms, Signal Transduction, Point Mutation, Patient Selection, ras Proteins, Drug Resistance, Neoplasm, Amino Acid Substitution, Antibodies, Monoclonal, Humanized, ErbB Receptors

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Implications for KRAS status and EGFR-targeted therapies in metastatic CRC

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