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

Authors' Affiliations: ¹ Division of Oncology, Department of Oncology, Azienda USL-6 of Livorno, Livorno, Italy; ² Division of Pharmacology and Chemotherapy, Department of Internal Medicine, University of Pisa, and ³ Division of Oncology, Department of Oncology, Pisa, Italy; ⁴ Department of Medical Oncology, VU University Medical Center, Amsterdam, the Netherlands; and ⁵ Istituto Tumori Toscano, Firenze, Italy

Requests for reprints: Carmelo Tibaldi, U.O. Oncologia Medica, Presidio Ospedaliero, Viale Alfieri, 36, 57100 Livorno, Italy. Phone: 39-0586-223458; Fax: 39-0586-223457; E-mail: tiby{at}katamail.com.

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 Asp³¹²Asn and Lys⁷⁵¹Gln, ERCC1 C118T, and CDA Lys²⁷Gln polymorphisms and response, clinical benefit, toxicity, time to progression (TTP), and overall survival (OS) was estimated using Pearson's ² tests, the Kaplan-Meier method, the log-rank test, and the Cox proportional hazards model.

Results: The CDA Lys²⁷Lys 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 Lys²⁷Lys polymorphism.

Conclusions: Our data suggested the role of CDA Lys²⁷Lys 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 Lys²⁷Lys CDA and offer a potential new tool for treatment optimization.