Correlation of CDA, ERCC1, and XPD Polymorphisms with Response and Survival in Gemcitabine/Cisplatin–Treated Advanced Non–Small Cell Lung Cancer Patients

• Published in: Clinical cancer research 2008-03, Vol.14 (6), p.1797-1803
• Main Authors: TIBALDI, Carmelo, GIOVANNETTI, Elisa, PETERS, Godefridus J, FALCONE, Alfredo, DANESI, Romano, MEY, Enricovasile Valentina, LAAN, Adrie C, NANNIZZI, Sara, DI MARSICO, Roberta, ANTONUZZO, Andrea, ORLANDINI, Cinzia, RICCIARDI, Simona, DELTACCA, Mario
• Format: Article
• Language: English
• Subjects: Adult; Aged; Antineoplastic agents; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Biological and medical sciences; Carcinoma, Non-Small-Cell Lung - diagnosis; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - mortality; cisplatin; Cisplatin - administration & dosage; cytidine deaminase; Cytidine Deaminase - genetics; Cytidine Deaminase - metabolism; Deoxycytidine - administration & dosage; Deoxycytidine - analogs & derivatives; Disease Progression; DNA-Binding Proteins - genetics; Endonucleases - genetics; Female; gemcitabine; Humans; Lung Neoplasms - diagnosis; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lung Neoplasms - mortality; Male; Medical sciences; Middle Aged; NSCLC; Pharmacology. Drug treatments; Pneumology; Polymorphism, Single Nucleotide; polymorphisms; Prognosis; Retrospective Studies; Survival Analysis; Treatment Outcome; Tumors of the respiratory system and mediastinum; Xeroderma Pigmentosum Group D Protein - genetics
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-07-1364

Purpose: Selecting patients according to key genetic characteristics may help to tailor chemotherapy and optimize the treatment in non–small cell lung cancer (NSCLC). Polymorphisms at the xeroderma pigmentosum group D ( XPD ), excision repair cross-complementing 1 ( ERCC1 ), and cytidine deaminase ( CDA ) genes have been associated with alterations in enzymatic activity and may change sensitivity to the widely used cisplatin-gemcitabine regimen. Experimental Design: Analyses of CDA, XPD , and ERCC1 polymorphisms were done on blood samples of 65 chemotherapy-naïve, advanced NSCLC patients treated with cisplatin-gemcitabine. Furthermore, CDA enzymatic activity was evaluated by high-performance liquid chromatography analysis. Association between XPD Asp 312 Asn and Lys 751 Gln, ERCC1 C 118 T , and CDA Lys 27 Gln polymorphisms and response, clinical benefit, toxicity, time to progression (TTP), and overall survival (OS) was estimated using Pearson's χ 2 tests, the Kaplan-Meier method, the log-rank test, and the Cox proportional hazards model. Results: The CDA Lys 27 Lys polymorphism significantly correlated with better clinical benefit ( P = 0.04) and grade ≥3 neutropenia and thrombocytopenia, as well as with longer TTP and OS ( P = 0.006 and P = 0.002, respectively), whereas no significant associations were found among ERCC1 and XPD polymorphisms and both response and clinical outcome. Finally, the enzymatic activity assay showed a significant lower mean in subjects harboring the CDA Lys 27 Lys polymorphism. Conclusions: Our data suggested the role of CDA Lys 27 Lys polymorphism as a possible predictive marker of activity, toxicity, TTP, and OS in advanced NSCLC patients treated with cisplatin and gemcitabine. These results may be explained by the lower enzymatic activity associated with the Lys 27 Lys CDA and offer a potential new tool for treatment optimization.