Impact of ABCG2 polymorphisms on the clinical outcome and toxicity of gefitinib in non-small-cell lung cancer patients

• Published in: Pharmacogenomics Vol. 12; no. 2; pp. 159 - 170
• Main Authors: Lemos, Clara, Giovannetti, Elisa, Zucali, Paolo A, Assaraf, Yehuda G, Scheffer, George L, van der Straaten, Tahar, D'Incecco, Armida, Falcone, Alfredo, Guchelaar, Henk-Jan, Danesi, Romano, Santoro, Armando, Giaccone, Giuseppe, Tibaldi, Carmelo, Peters, Godefridus J
• Format: Journal Article
• Language: English
• Published: England Future Medicine Ltd 01.02.2011
• Subjects: Antineoplastic Agents - adverse effects; Antineoplastic Agents - therapeutic use; ATP Binding Cassette Transporter, Subfamily G, Member 2; ATP-Binding Cassette Transporters - genetics; ATP-binding protein; Carcinoma, Non-Small-Cell Lung - drug therapy; Clinical outcomes; Complications and side effects; Diagnosis; Diarrhea; Diarrhea - chemically induced; Diarrhea - genetics; Dosage and administration; Drug therapy; Female; Gefitinib; Gene polymorphism; Genetic polymorphisms; Genome-Wide Association Study; Genotype; Haplotypes; Haplotypes - drug effects; Humans; Identification and classification; Lung cancer; Lung cancer, Non-small cell; Lung Neoplasms - drug therapy; Male; Middle Aged; Neoplasm Proteins - genetics; Pharmacogenetics; Polymorphism, Genetic - genetics; Precision Medicine; Quinazolines - adverse effects; Quinazolines - therapeutic use; Survival; Toxicity; Treatment Outcome; Tumors; Netherlands
• ISSN: 1462-2416; 1744-8042
• DOI: 10.2217/pgs.10.172

The current study investigates whether or not functional polymorphisms in the ATP-binding cassette transporter gene ABCG2 might affect gefitinib activity and/or toxicity in non-small-cell lung cancer (NSCLC) patients. Towards this end, ABCG2 polymorphisms and expression were assessed in DNA and tumors from 94 NSCLC patients treated with gefitinib, whereas their associations with toxicity/response and time-to-progression/overall survival were evaluated using Pearson-χ(2) and log-rank-test, respectively. Patients carrying an ABCG2 -15622T/T genotype or harboring at least one TT copy in the ABCG2 (1143C/T, -15622C/T) haplotype developed significantly more grade 2/3 diarrhea (p < 0.01). No associations were found between polymorphisms and outcome. Consistently, ABCG2 protein levels in tumors were not significantly different between patients harboring different ABCG2 variants. The ABCG2 -15622C/T polymorphism and ABCG2 (1143C/T, -15622C/T) haplotype resulted in a gefitinib-dependent, moderate-to-severe diarrhea suggesting that these pharmacogenetic markers should be considered to optimize NSCLC treatment.