Conventional chemotherapeutic regimens have limited impact against most solid tumors and deal with significant
toxicity. During the last years novel anticancer treatments targeting specific molecules or genes involved in cancer
development are being developed to improve outcome and reduce side-effects. In particular several tyrosine-kinase inhibitors
(TKIs, gefitinib, erlotinib, sorafenib and sunitinib) have been approved for the treatment of different solid tumors.
Their clinical activity has been related to different clinical and biological parameters, such as the EGFR-activating mutations
for gefitinib and erlotinib. However, not all clinical outcomes, including tolerability, are explained, and the identification/
validation of novel biomarkers is a viable area of research. Germline polymorphisms can be easily assessed in
blood samples, and polymorphisms in EGFR, AKT1 and ABCG2 have been correlated with outcome and toxicity in lung
cancer patients given EGFR-TKIs therapies. However, there are several controversial findings, influenced by differences
in study design/analysis, while the prognostic/predictive role of these polymorphisms still needs to be evaluated within
prospective studies. More studies on the relationship of the genotype with drug pharmacokinetics and mechanism of action
are also warranted. All these studies, as well as further development and application of novel technologies to decipher
genetic alterations, might contribute to the validation of selected polymorphisms as molecular markers predictive of drug
activity and help in the selection of TKIs best suited to the individual patient.
Keywords: Tyrosine kinase inhibitors, gefitinib, erlotinib, sorafenib, sunitinib, polymorphisms, outcome, toxicity
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