Future Prospects

Clinical trials with Iressa and other EGFR-targeted drugs (e.g. erlotinib/ Tarceva and cetuximab/Erbitux) have clearly demonstrated that this new approach to cancer therapy is of great benefit for some patients (Grunwald and Hidalgo 2003). However, it is equally clear that some patients in an un-selected population with, for example, advanced NSCLC, do not derive significant benefits from treatment with this class of drugs. Unlike the case of breast cancer patients, where trastuzumab (Herceptin) treatment is determined by the presence or absence of overexpression of ErbB2, the very small number of clinical studies on linkage between tumour EGFR expression and response to EGFR-targeted therapies have so far failed to establish any correlation. Currently, the best indicator of response to gefitinib is symptom improvement, which typically occurs early during the course of treatment and is associated with tumour response, time to progression and overall survival (Cella et al. 2003). A huge challenge for the future is to identify either pathological or mechanism-based biomarkers which accurately predict the likelihood of therapeutic benefit from treatment with EGFR inhibitors. Formidable intellectual and technical barriers must be surmounted to achieve this objective. For example, to what extent would a complete knowledge of the expression or activity levels of all signal transducers, downstream of or linked to EGFR, help in patient stratification, and how might the best quantitative methods for putative biomarker measurement be defined and applied in the routine pathology laboratory setting? Measurement of EGFR expression by IHC presents major problems for routine application, since there is no consensus on methods for tumour sampling, storage, preparation and analysis. Many translational science laboratories are focussing their attention on the use of IHC methods to measure activated receptors [e.g. phosphorylated (p) EGFR and other ErbBs] and key downstream mediators like pMAPK and pAKT, as well as putative endpoints of drug action, like changes in cell cycle status (eg p27KIP1), proliferative rate (eg Ki67/Mib1) and apoptosis (eg Tunel) in Iressa-treated patients (Albanell et al. 2001, 2002; Cappuzzo et al. 2003; Daneshmand et al. 2003; Mukohara et al. 2003; Rojo et al. 2003). Because of the inaccessibility to diagnostic biopsy sampling of many tumours, and the cost and complexity of biomarker analyses, the age of targeted drug treatment tailored to the (individual) tumour remains elusive. In immediate practical terms, the fact that Iressa is generally well tolerated means that there is no reason to exclude patients from treatment. Furthermore, as symptom improvement and tumour response generally occur soon after the start of treatment (IDEAL trials), the patients who do benefit from Iressa treatment will be rapidly identified.

In the longer term, the application of oncogenomic and/or proteomic analysis to tumour diagnostic samples may open a realistic prospect for individually targeted treatment. Important pilot studies in Iressa-treated xeno-graft models (Zembutsu et al. 2003) and patient samples have begun (Natale et al. 2003), and the increasing availability and use of frozen tumour tissue microarrays (Fejzo and Slamon 2001) hold great promise for the future.

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