|Title:||Genetic modifiers of progression-free survival in never-smoking lung adenocarcinoma patients treated with first-line tyrosine kinase inhibitors||Authors:||Chang I.-S.
|Issue Date:||2017||Publisher:||American Thoracic Society||Journal Volume:||195||Journal Issue:||5||Start page/Pages:||663-673||Source:||American Journal of Respiratory and Critical Care Medicine||Abstract:||
Rationale: Patients with non-small cell lung cancer (NSCLC) with mutated epidermal growth factor receptor (EGFR) are relatively sensitive to EGFR-tyrosine kinase inhibitor (TKI) treatment and have longer progression-free survival (PFS) when treated with EGFR-TKI compared with platinum-based chemotherapy. However, many patientswith advanced NSCLCwho have mutated EGFR do not respond to first-line EGFR-TKI treatment and still have shorter PFS. Objectives: The aim of this study was to identify genetic variants associated with PFS among patients with lung adenocarcinoma who were treated with first-line EGFR-TKIs. Methods: A genome-wide association study on PFS was performed in never-smoking women diagnosed with lung adenocarcinoma and who were treated with first-line EGFR-TKIs (n = 128). Significant single-nucleotide polymorphisms (SNPs) were selected for follow-up association analysis (n = 198) and for replication assay in another independent cohort (n = 153). Measurements and Main Results: We identified SNPs at 4q12 associated with PFS at genome-wide significance (P,1028) andwith an estimated hazard ratio of more than 4. This association was also replicated in a larger but similar cohort and in an independent NSCLC cohort. Follow-up functional analyses showed that these SNPs were associated with the expression ofEGFR,whichencodes theTKI target, and with a nearby gene neuromedin-U, which encodes a G protein-coupled receptor ligand known to be involved in the progression of NSCLC. Considering these as possible prognostic biomarkers for the treatment of patients with late-stage lung cancer, we found that these SNPs were not associated with EGFR mutation status or with polymorphism of the Bcl2-interacting mediator of cell death gene. Conclusions: Genetic variants in 4q12 merit further investigation to assess their potential as pharmacogenomic predictors for and to understand the biology underlying its influence on PFS in patients treated with TKI therapy. Copyright ? 2017 by the American Thoracic Society.
|ISSN:||1073-449X||DOI:||10.1164/rccm.201602-0300OC||SDG/Keyword:||carboplatin; cisplatin; docetaxel; epidermal growth factor receptor; erlotinib; gefitinib; gemcitabine; guanine nucleotide binding protein; neuromedin U; paclitaxel; vinorelbine tartrate; epidermal growth factor receptor; protein kinase inhibitor; adult; aged; Article; cancer combination chemotherapy; cancer survival; cell death; cohort analysis; controlled study; female; follow up; gene expression; genetic association; genetic association study; genetic variability; genome-wide association study; human; lung adenocarcinoma; major clinical study; male; molecularly targeted therapy; priority journal; progression free survival; protein expression; single nucleotide polymorphism; Carcinoma, Non-Small-Cell Lung; disease free survival; genetics; Lung Neoplasms; middle aged; procedures; very elderly; young adult; Adult; Aged; Aged, 80 and over; Carcinoma, Non-Small-Cell Lung; Disease-Free Survival; Female; Follow-Up Studies; Genome-Wide Association Study; Humans; Lung Neoplasms; Male; Middle Aged; Polymorphism, Single Nucleotide; Protein Kinase Inhibitors; Receptor, Epidermal Growth Factor; Young Adult
|Appears in Collections:||腫瘤醫學研究所|
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