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Review: Beyond KRAS: perspectives on new potential markers of intrinsic and acquired resistance to epidermal growth factor receptor inhibitors in metastatic colorectal cancer

Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Department of Oncology, Transplants and New Technologies in Medicine, University of Pisa, Italy, fotiosloupakis@ gmail.com

Chiara Cremolini

Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Department of Oncology, Transplants and New Technologies in Medicine, University of Pisa, Italy, . Unit of Medical Oncology, Livorno, Italy

Gabriella Fontanini

Gabriella Fontanini Division of Pathology, Department of Surgery, University of Pisa, Italy, Unit of Medical Oncology, Livorno, Italy

Irene Stasi

Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Department of Oncology, Transplants and New Technologies in Medicine, University of Pisa, Italy, Unit of Medical Oncology, Livorno, Italy

Lisa Salvatore

Chiara Cremolini Lisa Salvatore Irene Stasi Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Department of Oncology, Transplants and New Technologies in Medicine, University of Pisa, Italy, Unit of Medical Oncology, Livorno, Italy

Alfredo Falcone

Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Department of Oncology, Transplants and New Technologies in Medicine, University of Pisa, Italy,a.falcone{at}med.unipi.it

The monoclonal antibodies cetuximab and panitumumab, directed against the epidermal growth factor receptor (EGFR), are licensed for the treatment of KRAS wild-type metastatic colorectal cancer (mCRC). Such ‘molecular restriction’ derived from post-hoc analyses of randomized trials and from other retrospective series all indicate how tumors bearing KRAS (v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog) mutations are resistant to EGFR inhibition. Even if highly sensitive for nonresponse, KRAS testing is not very specific. In fact, a limited but still considerable proportion of KRAS wild-type patients rapidly progress on treatment with an EGFR inhibitor. New potential molecular determinants of benefit from such treatment are under investigation and may further refine the selection of patients. Pharmacogenomic analyses and translational studies are also ongoing for exploring the field of acquired resistance to anti-EGFRs, since all patients eventually progress. New biological data are awaited for optimizing the use of molecular agents in colorectal cancer and for identifying promising targets that could allow to better understand and, potentially, overcome mechanisms of primary or secondary resistance to EGFR inhibitors.

Key Words: colorectal cancer • epidermal growth factor receptor • cetuximab • panitumumab • predictive factors

This version was published on November 1, 2009

Therapeutic Advances in Medical Oncology, Vol. 1, No. 3, 167-181 (2009)
DOI: 10.1177/1758834009348984


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