Abstract
The efficacy of erlotinib treatment for advanced non-small cell lung cancer (NSCLC) is due to its action as an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI). Patients treated with erlotinib experience different drug responses. The effect of germline mutations on therapeutic responses and adverse drug responses (ADRs) to erlotinib in Chinese patients requires elucidation. Sixty Han Chinese advanced non-small cell lung cancer patients received erlotinib monotherapy and, for each participant, 76 candidate genes (related to EGFR signaling, drug metabolism and drug transport pathways) were sequenced and analyzed. The single-nucleotide polymorphisms (SNPs) rs1042640 in UGT1A10, rs1060463, and rs1064796 in CYP4F11, and rs2074900 in CYP4F2 were significantly associated with therapeutic responses to erlotinib. Rs1064796 in CYP4F11 and rs10045685 in UGT3A1 were significantly associated with adverse drug reaction. Moreover, analysis of a validation cohort confirmed the significant association between rs10045685 in UGT3A1 and erlotinib adverse drug response(unadjusted p = 0.015). This study provides comprehensive, systematic analyses of genetic variants associated with responses to erlotinib in Chinese advanced non-small cell lung cancer patients. Newly-identified SNPs may serve as promising markers to predict responses and safety in erlotinib-treated advanced non-small cell lung cancer patients after chemotherapy doublet.
Highlights
Lung cancer is the leading cause of cancer-associated death worldwide (Jemal et al, 2011), of which approximately 85% is classified as non-small cell lung cancer (NSCLC)
epidermal growth factor receptor (EGFR)-TKI treatment for NSCLC have an impressive profile of therapeutic responses and adverse drug responses (ADRs) compared with standard chemotherapies
Rs884225 in EGFR is associated with erlotinib-induced ADR
Summary
Lung cancer is the leading cause of cancer-associated death worldwide (Jemal et al, 2011), of which approximately 85% is classified as non-small cell lung cancer (NSCLC). SNPs Associated With Erlotinib Responses disease or distant metastases, making them ineligible for surgery. In these patients, prognosis for radiotherapy or chemotherapy is unsatisfactory with unfavorable side effects, resulting in a 5year survival rate of less than 17% (Siegel et al, 2013; Canada, 2015). Novel therapeutic strategies developed in NSCLC that target specific genomic mutations have been firmly established and show promising efficacy. Epidermal growth factor receptortyrosine kinase inhibitors (EGFR-TKIs) were developed to treat patients with EGFR somatic activating mutations; they were first discovered to underpin NSCLC responsiveness to gefitinib in 2004 (Lynch et al, 2004; Mayo et al, 2012)
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