title: Polymorphisms to predict outcome to the tyrosine kinase inhibitors gefitinib, erlotinib, sorafenib and sunitinib.
abstract: 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.
authors.affiliation: Dept. of Medical Oncology, VU University Medical Center, Cancer Center Amsterdam, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands.
authors.forename: Lale
authors.initials: L
authors.lastname: Erdem
authors.forename: Elisa
authors.initials: E
authors.lastname: Giovannetti
authors.forename: Leticia G
authors.initials: LG
authors.lastname: Leon
authors.forename: Richard
authors.initials: R
authors.lastname: Honeywell
authors.forename: Godefridus J
authors.initials: GJ
authors.lastname: Peters
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D066246:ErbB Receptors / Q000235:genetics; D000069347:Erlotinib Hydrochloride; D000077156:Gefitinib; D018095:Germ-Line Mutation; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D058990:Molecular Targeted Therapy; D009363:Neoplasm Proteins / Q000235:genetics; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D009536:Niacinamide / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D010671:Phenylurea Compounds / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D011110:Polymorphism, Genetic; D011237:Predictive Value of Tests; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics; D011758:Pyrroles / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D011799:Quinazolines / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D000077157:Sorafenib; D000077210:Sunitinib; D016896:Treatment Outcome
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D007211:Indoles; D009363:Neoplasm Proteins; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D011799:Quinazolines; D009536:Niacinamide; D000077157:Sorafenib; D000069347:Erlotinib Hydrochloride; C512478:EGFR protein, human; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt; D000077156:Gefitinib; D000077210:Sunitinib