[Frontiers in Bioscience 16, 116-130, January 1, 2011]

Influence of polymorphisms on EGFR targeted therapy in non-small-cell lung cancer

Elisa Giovannetti1, Lale Erdem1, Efnan Olcay1, Leticia G Leon1,2, Godefridus J. Peters1

1Department Medical Oncology, VU University Medical Center, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands, 2Instituto Universitario de Bio-Organica Antonio Gonzalez (IUBO-AG), Universidad de La Laguna, C/Astrofísico Francisco Sanchez 2, 38206 La Laguna, Spain

TABLE OF CONTENTS

1. Abstract
2. Introduction
2.1. EGFR pathway
2.2. EGFR targeted therapy
2.2.1. Tyrosine kinase inhibitors (TKIs)
2.2.2. Monoclonal antibodies
3. Polymorphisms
3.1. Polymorphisms affecting EGFR-TKIs
3.1.1. Clinical outcome
3.1.2. Toxicity
3.2. Polymorphisms affecting anti-EGFR antibodies
3.2.1. Clinical outcome
3.2.2. Toxicity
4. Conclusions
5. Acknowledgement
6. References

1. ABSTRACT

Non-small-cell-lung cancer (NSCLC) is the leading cause of cancer-related deaths. However, chemotherapy has reached a therapeutic plateau and deals with significant toxicity. Novel anticancer treatments to neutralize specific molecules or genes involved in cancer development ("targeted-therapy") are being developed to reduce side-effects and improve outcome. The epidermal-growth-factor receptor (EGFR) is over-expressed in NSCLC and emerged as an attractive target. Two classes of anti-EGFR agents (tyrosine-kinase-inhibitors and monoclonal antibodies) have shown clinical activity, depending on EGFR mutations and expression. However, clinical outcome, including tolerability, can not always be explained by these biomarkers. Thus, the identification of novel biomarkers is a viable area of research. Germline polymorphisms can be easily assessed, and polymorphisms in EGFR, AKT1 and ABCG2 have been correlated with outcome and toxicity in NSCLC patients given anti-EGFR therapies. However, there is lack of unanimity in findings, influenced by differences in study design/analysis, and the prognostic/predictive role of these polymorphisms needs to be evaluated within prospective studies. Finally, there is a critical need to conduct more studies on the relation of genotype with drug concentration/activity.