Biomarkers Predicting Clinical Outcome of Epidermal Growth Factor Receptor–Targeted Therapy in Metastatic Colorectal Cancer

Salvatore Siena; Andrea Sartore-Bianchi; Federica Di Nicolantonio; Julia Balfour; Alberto Bardelli

Disclosures

J Natl Cancer Inst. 2009;101(19):1308-24. 

In This Article

Abstract and Introduction

Abstract

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.

Introduction

The epidermal growth factor receptor (EGFR), a member of the human epidermal growth factor receptor (HER)–erbB family of receptor tyrosine kinases, represents an important target for cancer treatment because its activation stimulates key processes involved in tumor growth and progression, including proliferation, angiogenesis, invasion, and metastasis. The binding of EGF or other ligands to EGFR initiates a mitogenic signaling cascade via several pathways, including the RAS–RAF–mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K)–Akt, and phospholipase Cγ pathways.[1,2] Overexpression of EGFR is found in a range of solid tumor types and has been linked to poorer outcomes.[3,4]

EGFR inhibitors—monoclonal antibodies targeting the extracellular domain and small-molecule tyrosine kinase inhibitors—have expanded the range of treatment options for various solid tumors. EGFR-targeted monoclonal antibodies have been extensively studied in metastatic colorectal cancer (Table 1), whereas tyrosine kinase inhibitors have thus far shown little activity in this setting.[5,6] Cetuximab (ER-K0034, Erbitux, Merck-Serono KgaA, Darmstadt, Germany; ImClone Systems Inc, New York, NY), the first anti-EGFR monoclonal antibody to be approved for clinical use for metastatic colorectal cancer, is a chimeric mouse–human monoclonal antibody that has been evaluated primarily in combination with chemotherapy[7–10] but also as monotherapy.[7,11,12] Panitumumab (ABX-EGF, Vectibix; Amgen Inc, Thousand Oaks, CA), a fully human monoclonal antibody, has shown efficacy as monotherapy in chemotherapy-refractory patients with metastatic colorectal cancer,[13] and ongoing chemotherapy combination trials in earlier lines of treatment have reported acceptable interim safety data.[14,15] In addition, cetuximab and panitumumab have both been evaluated in combination with bevacizumab, a monoclonal antibody targeting the vascular endothelial growth factor (VEGF), plus standard first-line chemotherapy.[16,17] However, increased toxicity and a shorter progression-free interval were observed in the experimental groups compared with the control groups. Thus, the strategy of combining both an EGFR inhibitor and a VEGF inhibitor with chemotherapy appears to be detrimental and is not being pursued further.

Cetuximab and panitumumab appear to have similar efficacy, achieving fairly modest but clinically meaningful objective response rates of approximately 10% when used as monotherapy for chemotherapy-refractory EGFR-expressing metastatic colorectal cancers.[7,11–13,18] However, panitumumab is likely to be less immunogenic than cetuximab because of its fully human composition and, indeed, panitumumab seldom gives rise to severe infusion reactions.[13] Such events may occur in up to 22% of cetuximab-treated patients, depending on geographical region,[19,20] and appear to be commonly associated with preexisting specific IgE antibodies against the oligosaccharide component of the cetuximab molecule, galactose-α-1,3-galactose.[21]

Positive EGFR protein expression, as determined by immunohistochemistry, was initially selected as an entry criterion for studies evaluating EGFR inhibitors on the assumption that sensitivity to such agents was associated with EGFR expression. However, a large body of evidence from patients who were treated with monoclonal antibodies for metastatic colorectal cancer[7,11,13,22,23] or tyrosine kinase inhibitors for other solid tumors[24,25] indicates that this biomarker is poorly associated with response to EGFR inhibitors in the clinical setting. Objective responses have been observed in patients with low or negative, as well as high, EGFR protein expression, as determined by immunohistochemistry. These findings have led to intense research to identify alternative predictive molecular biomarkers that can be used to identify patients who are most likely to benefit from EGFR-targeted treatment. This review discusses progress made toward these ends with a focus on treatment of metastatic colorectal cancer with anti-EGFR monoclonal antibodies.

Literature was identified in PubMed and oncology conference databases by use of the search terms "colorectal cancer" and "molecular markers" and retrieved articles were evaluated by the authors. All fully published clinical data relating to clinical response to treatment with monoclonal antibodies in metastatic colorectal cancer were considered for inclusion, as well as key conference abstracts. Additional searches of the same databases were performed to identify suitable background information.

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