The International Journal of Biological Markers

Receptor tyrosine kinases play a major role in human carcinogenesis. Overexpression of the epidermal growth factor receptor (EGFR) has been associated with poor clinical outcome in several types of cancer. In principle, as with HER2, the EGFR status of a tumor should predict the likelihood of response to EGFR-targeted therapy. However, clinical data have failed to demonstrate a relationship between EGFR expression and response to the EGFR-targeted compounds cetuximab, gefitinib and erlotinib. Recently, patients reported to be EGFR negative have been shown to respond to cetuximab. Possible explanations include methodological failures or most likely heterogeneity and complexity of the mechanisms of EGFR-mediated molecular carcinogenesis. Immunohistochemistry is the most widely used method for measuring EGFR expression; however, its value is limited by lack of methodological standardization. Other approaches to measuring EGFR such as amplification assays are currently being introduced but need further testing before they can enter clinical practice. Mutational analysis seems also fruitful in predicting response to anti-EGFR small molecules. Further work is needed to identify how EGFR contributes to the carcinogenic and metastatic processes.

The epidermal growth factor receptor (EGFR) plays a key role in cancer development and progression in several human malignancies including non-small cell lung cancer (NSCLC). Several strategies aimed at inhibiting the EGFR have been investigated in the last years, including the use of small tyrosine kinase inhibitors (TKIs) directed against the intracellular domain of the receptor and monoclonal antibodies targeting its extracellular portion. Subgroups of patients who are more likely to respond to TKIs have been identified based on both clincal and biological features. Never-smoking history has emerged as the most relevant clinical characteristic predictive of response to TKIs in NSCLC, while presence of drug-sensitive EGFR mutations and EGFR gene gain represent critical biological variables associated with an improved outcome for patients exposed to these agents. Recent studies have highlighted the existence of biological factors involved in intrinsic and acquired resistance to TKIs, including k-ras, HER-2 and EGFR exon 20 mutations. Increasing knowledge of EGFR biology and drug-receptor interactions will allow to identify individuals who are likely to derive a clinical benefit from the proposed targeted therapy, sparing refractory patients expensive and potentially toxic treatment.

Research into the molecular bases of malignant diseases has yielded the development of many novel agents with potential antitumor activity. Evidence for a causative role for the epidermal growth factor receptor (EGFR), which is now regarded as an excellent target for cancer chemotherapy in human cancer, leads to the development of EGFR inhibitors. Two classes of anti-EGFR agents are currently in clinical use: monoclonal antibodies directed at the extracellular domain of the receptor, and the low-molecular-weight receptor tyrosine kinase inhibitors acting intracellularly by competing with adenosine triphosphate for binding to the tyrosine kinase portion of the EGFR. The effect on the receptor interferes with key biological functions including cell cycle arrest, potentiation of apoptosis, inhibition of angiogenesis and cell invasion and metastasis. Cetuximab, a monoclonal antibody, and the receptor tyrosine kinase inhibitors gefitinib and erlotinib are currently approved for the treatment of patients with cancer. New agents with clinical activity are entering the clinic, and new combinatorial approaches are being explored with the aim of improving the potency and pharmacokinetics of EGFR inhibition, to increase the synergistic activity in combination with chemotherapy and overcome resistance to the EGFR inhibitors.

Cetuximab is a chimeric immunoglobulin G1 monoclonal antibody that targets the extracellular domain of the epidermal growth factor receptor (EGFR) with high specificity and affinity. It competitively inhibits endogenous ligand binding and thereby inhibits subsequent EGFR activation. The EGFR signaling pathways regulate cell differentiation, proliferation, migration, angiogenesis and apoptosis, all of which become deregulated in cancer cells. EGFR is an important target for cancer therapy and many studies have demonstrated that cetuximab is active in several types of cancer, particularly colorectal and head and neck cancer. Cetuximab enhances the effects of many standard cytotoxic agents, including irinotecan, and in combination with chemotherapy it can elicit antitumor responses in tumors that previously failed to respond to that chemotherapy. Cetuximab also enhances radiation-induced apoptosis. On the basis of a pivotal European randomized study (the BOND study) and of 2 clinical studies conducted in the USA, cetuximab has been approved in combination with irinotecan for patients affected by EGFR-expressing metastatic colon cancer after failure with irinotecan. There have only been a few small phase II trials on first-line treatment in metastatic colorectal cancer, but the results suggest promising activity of cetuximab together with irinotecan or oxaliplatin. There is some evidence that additive efficacy can be achieved using EGFR inhibitors in combination with vascular endothelial growth factor receptor inhibitors such as bevacizumab. A correlation between response and the main toxicity (acne-like skin reaction) has been observed but is unclear. EGFR status as a specific marker for EGFR inhibitors is controversial. At the moment, EGFR expression does not appear to be a predictive factor for response to EGFR inhibitors.

The epidermal growth factor receptor (EGFR) is frequently overexpressed in a wide range of human tumors; such overexpression often correlates with poor prognosis and worse clinical outcome. It has been demonstrated that the EGFR autocrine pathway plays a crucial role in human cancer since it contributes to a number of highly relevant processes in tumor development and progression, including cell proliferation, regulation of apoptotic cell death, angiogenesis and metastatic spread. For these reasons EGFR is one of the most studied and exploited targets for molecular cancer therapy. Two classes of anti-EGFR agents have entered clinical practice: monoclonal antibodies and small molecules targeting receptor tyrosine kinases. The possibility of combining conventional cytotoxic drugs with agents that specifically interfere with key pathways controlling cancer cell survival, proliferation, invasion and/or metastatic spread has generated wide interest. This could be a promising therapeutic approach for several reasons. First, the occurrence of cross-resistance is infrequent since the cellular targets and mechanisms of action of cytotoxic drugs and EGFR antagonists are different. Second, alterations in the expression and/or activity of genes that regulate mitogenic signals may either cause perturbation of cell growth or affect the sensitivity of cancer cells to conventional chemotherapy and radiotherapy. In fact, EGFR inhibitors have shown activity alone and/or in combination with conventional antitumor treatments.

Cutaneous toxicity is the most evident adverse effect of epidermal growth factor receptor (EGFR) inhibitors because of the specific role played by EGFR in skin biophysiology. Dermatological adverse reactions, mainly folliculocentric, have been widely reported in the literature. However, the mechanism of these reactions is not well defined and their management is still a matter of debate. In this paper keratinocyte differentiation, activation and pathways regulating gene expression are reviewed in order to improve the understanding of adverse skin reactions and obtain success in their management. The authors had the opportunity to treat skin reactions induced by cetuximab in a cohort of patients affected by metastatic colorectal carcinoma. The aims of this clinical approach were to control the signs and symptoms of skin toxicity in order to avoid delay in cancer therapy and to use nondrug agents for the treatment of drug-induced skin reactions.

In the last decade remarkable progress has been made in the treatment of metastatic colorectal cancer due to the introduction of oxaliplatin and irinotecan in clinical practice. The addition of biological agents seems to offer a chance to further enhance the activity of conventional chemotherapy. Cetuximab, a chimeric mouse-human monoclonal antibody targeting the extracellular domain of the epidermal growth factor receptor (EGFR), has shown low but detectable activity when employed in pretreated patients either as a single agent or in combination with irinotecan. Cetuximab in combination with irinotecan has been registered in the USA and Europe for the treatment of patients with metastatic colorectal cancer expressing the EGFR after failure of prior irinotecan-based cytotoxic therapy. The role of cetuximab in first-line therapy is still investigational. Some phase II trials assessing cetuximab plus chemotherapy demonstrated a high objective response rate and promising results in terms of time to progression and overall survival; data from phase III trials are pending. Further studies are needed to investigate the efficacy of cetuximab in combination with conventional chemotherapy in the adjuvant/neoadjuvant setting and to define criteria for a better selection of patients for this type of treatment.

Cetuximab is a monoclonal antibody targeting the transmembrane receptor HER-1 (epidermal growth factor receptor, EGFR). In theory, inhibition of EGFR may influence tumor behavior since the receptor regulates many important tumor cell activities including tumor growth, angiogenesis, and inhibition of the apoptotic response to chemotherapy and radiotherapy. Available experimental data suggest that cetuximab may enhance the activity of chemotherapy and radiotherapy, reverse resistance to some anticancer drugs, and has itself anticancer activity. Early clinical data support the experimental results. This paper reviews the published findings on cetuximab in the treatment of advanced head and neck cancer and points out the future objectives of the clinical research on this drug.

During the last 10 years, the concept of targeted biological therapy for the treatment of cancer has emerged. Targeted agents entered clinical practice only recently, and the first drugs with demonstrated clinical efficacy were mainly inhibitors of the ErbB family of receptors (i.e., EGFR and HER-2), either monoclonal antibodies (MAbs) or tyrosine kinase inhibitors (TKIs). After the proof of concept for the clinical efficacy and tolerability of these selective agents, it was conceived that most tumors will depend on more than one signaling pathway for their growth and survival. As a consequence, different strategies were pursued to inhibit multiple signaling pathways or multiple steps in the same pathway, either by the development of multi-targeted agents or the combination of single targeted drugs. The recent FDA and EMEA approval of sorafenib and sunitinib, both multi-targeted TKIs, marked the coming of age of this new generation of drugs. Now a whole new wave of multi-targeted compounds is moving into clinical trials, raising in the minds of investigators important questions about the best strategies to pursue in their use and many doubts about their differences and the seeming redundancies in the pipelines of pharmaceutical companies. This review will deal with the rationale underlying the multi-targeted approach and with the available clinical experience with multi-targeted agents, especially focusing on molecules with anti-EGFR mechanisms of action.

We report here on the state of our knowledge of the target - namely, the epidermal growth factor (EGF) and its receptor - and the challenges related to the methods of determination of the epidermal growth factor receptor (EGFR) and associated molecular pathways. A critical review of the anti-EGFR therapeutic strategies is also outlined. The chimeric anti-EGFR monoclonal antibody cetuximab has been approved for EGFR-expressing colorectal tumors in patients who progress after irinotecan-based chemotherapy in combination with irinotecan and in squamous cell head and neck carcinomas for patients with locally advanced disease in combination with radiation therapy or after failure of platinum-based chemotherapy in recurrent or metastatic disease (FDA). Cetuximab has the potential to provide an improvement of clinical outcome also in other indications and tumor types, particularly when used as first-line therapy combined with standard chemotherapy for metastatic disease or in the adjuvant setting. Possible strategies to improve the effectiveness of anti-EGFR agents are suggested and include (i) the use of predictive tools capable of making a more rational selection of patients; (ii) the development of standardized predictive biomarkers as surrogates for early monitoring of drug efficacy; and (iii) adequate study design, statistical analysis and proper end points of efficacy to be applied in future prospective trials.