Journal of the National Cancer Institute Advance Access originally published online on September 8, 2009
JNCI Journal of the National Cancer Institute 2009 101(19):1308-1324; doi:10.1093/jnci/djp280
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Biomarkers Predicting Clinical Outcome of Epidermal Growth Factor Receptor–Targeted Therapy in Metastatic Colorectal Cancer
Affiliations of authors: The Falck Division of Medical Oncology, Department of Oncology, Ospedale Niguarda Ca’ Granda, Milan, Italy (SS, AS-B); Laboratory of Molecular Genetics, Institute for Cancer Research and Treatment, University of Torino Medical School, Turin, Italy (FDN, AB); Kilconquhar, Fife, Scotland (JB); Fondazione Italiana Ricerca Cancro Institute of Molecular Oncology, Milan, Italy (AB)
Correspondence to: Salvatore Siena, MD, The Falck Division of Medical Oncology, Ospedale Niguarda Ca’ Granda, Piazza Ospedale Maggiore 3, 20162 Milan, Italy (e-mail: salvatore.siena{at}ospedaleniguarda.it); Alberto Bardelli, PhD, Laboratory of Molecular Genetics, Institute for Cancer Research and Treatment, University of Torino Medical School, Strada Provinciale 142, Km 3.95, 10060 Candiolo, Turin, Italy (e-mail: a.bardelli{at}unito.it).
The monoclonal antibodies panitumumab and cetuximab that target the epidermal growth factor receptor (EGFR) have expanded the range of treatment options for metastatic colorectal cancer. Initial evaluation of these agents as monotherapy in patients with EGFR-expressing chemotherapy-refractory tumors yielded response rates of approximately 10%. The realization that detection of positive EGFR expression by immunostaining does not reliably predict clinical outcome of EGFR-targeted treatment has led to an intense search for alternative predictive biomarkers. Oncogenic activation of signaling pathways downstream of the EGFR, such as mutation of KRAS, BRAF, or PIK3CA oncogenes, or inactivation of the PTEN tumor suppressor gene is central to the progression of colorectal cancer. Tumor KRAS mutations, which may be present in 35%–45% of patients with colorectal cancer, have emerged as an important predictive marker of resistance to panitumumab or cetuximab treatment. In addition, among colorectal tumors carrying wild-type KRAS, mutation of BRAF or PIK3CA or loss of PTEN expression may be associated with resistance to EGFR-targeted monoclonal antibody treatment, although these additional biomarkers require further validation before incorporation into clinical practice. Additional knowledge of the molecular basis for sensitivity or resistance to EGFR-targeted monoclonal antibodies will allow the development of new treatment algorithms to identify patients who are most likely to respond to treatment and could also provide rationale for combining therapies to overcome primary resistance. The use of KRAS mutations as a selection biomarker for anti-EGFR monoclonal antibody (eg, panitumumab or cetuximab) treatment is the first major step toward individualized treatment for patients with metastatic colorectal cancer.
Manuscript received November 21, 2008; revised July 17, 2009; accepted July 24, 2009.
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J Natl Cancer Inst 2009 101: 1293.