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Annals of Oncology Advance Access published online on January 11, 2006
Annals of Oncology, doi:10.1093/annonc/mdj135
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© 2006 European Society for Medical Oncology
Received October 19, 2005
Revised November 30, 2005
Accepted December 5, 2005

original article

Polymorphisms in DNA repair genes modulate survival in cisplatin/gemcitabine-treated non-small-cell lung cancer patients

R. de las Peñas 1, M. Sanchez-Ronco 2, V. Alberola 3, M. Taron 4, C. Camps 5, R. Garcia-Carbonero 6, B. Massuti 7, C. Queralt 4, M. Botia 4, R. Garcia-Gomez 8, D. Isla 9, M. Cobo 10, M. Santarpia 11, F. Cecere 12, P. Mendez 4, J. J. Sanchez 2, R. Rosell 4 *, and on behalf of the Spanish Lung Cancer Group

1 Hospital Provincial de Castellón, Castellón, Spain
2 Universidad Autónoma de Madrid, Madrid, Spain
3 Hospital Arnau de Vilanova, Valencia, Spain
4 Institut Catala d'Oncologia, Badalona, Barcelona, Spain
5 Hospital General Universitario de Valencia, Valencia, Spain
6 Hospital Severo Ochoa, Madrid, Spain
7 Hospital General de Alicante, Alicante, Spain
8 Hospital Universitario Gregorio Marañon, Madrid, Spain
9 Hospital Clínico Universitario Lozano Blesa, Zaragoza, Spain
10 Hospital Carlos Haya, Malaga, Spain
11 Institut Catala d'Oncologia, Badalona, Barcelona, Spain; University of Messina, Messina, Italy
12 Institut Catala d'Oncologia, Badalona, Barcelona, Spain; Regina Elena Institute for Cancer Research, Rome, Italy

* To whom correspondence should be addressed.
R. Rosell, E-mail: rrosell{at}ico.scs.es


  Abstract

Background: Impaired DNA repair capacity may favorably affect survival in cisplatin/gemcitabine-treated non-small-cell lung cancer (NSCLC) patients. We investigated the association of survival with genetic polymorphisms in X-ray repair cross-complementing group 1 and group 3 (XRCC3), xeroderma pigmentosum group D (XPD), excision repair cross-complementing group 1, ligase IV, ribonucleotide reductase, TP53, cyclooxygenase-2, interleukin-6, peroxisome proliferator-activated receptor {gamma}, epidermal growth factor, methylene-tetra-hydrofolate reductase and methionine synthase.

Patients and methods: One hundred and thirty-five stage IV or IIIB (with malignant pleural effusion) NSCLC patients treated with cisplatin/gemcitabine from different hospitals of the Spanish Lung Cancer Group were genotyped for 14 different polymorphisms in 13 genes. Polymorphisms were detected by the TaqMan method, using genomic DNA extracted from baseline blood samples.

Results: Median survival was significantly increased in patients harboring XRCC3 241 MetMet: 16 months versus 10 months for patients with ThrMet and 14 months for those with ThrThr (P = 0.01). The risk of death ratio was significantly lower for MetMet than for ThrMet patients (hazard ratio, 0.43; P = 0.01). In the multivariate Cox model, XRCC3 241 remained an independent prognostic factor (hazard ratio: XRCC3 241 MetMet, 0.44; P = 0.01), and XPD 751 and XRCC1 399 also emerged as significant prognostic factors (hazard ratios: XPD 751 LysGln, 0.46, P = 0.03; XRCC1 399 ArgGln, 0.61, P = 0.04). No other association was observed between genotype and survival.

Conclusion: XRCC3 241 MetMet is an independent determinant of favorable survival in NSCLC patients treated with cisplatin/gemcitabine. A simple molecular assay to determine the XRCC3 241 genotype can be useful for customizing chemotherapy.

Keywords: cisplatin; DNA repair genes; gemcitabine; non-small-cell lung cancer; polymorphisms; XRCC3.
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