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

Nature Reviews Clinical Oncology volume 6, pages 519–527 (2009)Cite this article

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.

Key Points

  • Cetuximab and panitumumab are effective as single agents, and cetuximab is effective in combination with irinotecan, in heavily pretreated patients with chemorefractory metastatic colorectal cancer (mCRC)

  • Cetuximab in combination with standard chemotherapy is also active as first-line therapy in untreated patients with mCRC; however, efficacy of anti-EGFR monoclonal antibodies in mCRC is limited to a subgroup of patients

  • Several potential biomarkers for the optimal selection of patients with mCRC who are candidates for treatment with anti-EGFR drugs have been evaluated

  • Activating mutations in KRAS have been strongly correlated with lack of efficacy of anti-EGFR drugs in mCRC, whereas patients with wild-type KRAS respond to cetuximab or panitumumab monotherapy

  • Combination of cetuximab with standard 5-fluorouracil-based chemotherapy doublets is a valid therapeutic option for the first-line treatment of patients with wild-type KRAS mCRC

  • Determination of KRAS status should be mandatory in all patients with mCRC to help select the most appropriate combinations and/or sequences of molecular targeted drugs and cytotoxic agents

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Figure 1: RAS mediated intracellular signal transduction pathways.

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Acknowledgements

Research projects in the laboratories of F. Ciardiello and N. Normanno are partly supported by Associazione Italiana per la Ricerca sul Cancro (AIRC), Milan, Italy. S. Tejpar and E. Van Cutsem are Senior Clinical Investigators of the Fund for Scientific Research, Flanders. Their work is partly supported by a grant of the Belgian Foundation against Cancer.

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Authors and Affiliations

  1. Cell Biology and Biotherapy Unit, INT-Fondazione Pascale, Naples, Italy,

    Nicola Normanno & Antonella De Luca

  2. Centro di Ricerche Oncologiche di Mercogliano (CROM), INT-Fondazione Pascale, Mercogliano (AV), Italy

    Nicola Normanno & Antonella De Luca

  3. Digestive Oncology Unit, University Hospital Gasthuisberg, Leuven, Belgium

    Sabine Tejpar & Eric Van Cutsem

  4. Division of Medical Oncology, Department of Experimental and Clinical Medicine and Surgery “F. Magrassi and A. Lanzara”, Second University of Naples, Naples, Italy

    Floriana Morgillo & Fortunato Ciardiello

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Correspondence to Fortunato Ciardiello.

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E. Van Cutsem declares he receives grant/research support from Amgen and Merck Serono. F. Ciardiello declares he receives grant/research support from Merck Serono. S. Tejpar declares she receives grant/research support from Merck Serono and Pfizer. The other authors declare no competing interests.

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Normanno, N., Tejpar, S., Morgillo, F. et al. Implications for KRAS status and EGFR-targeted therapies in metastatic CRC. Nat Rev Clin Oncol 6, 519–527 (2009). https://doi.org/10.1038/nrclinonc.2009.111

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