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Originally published as JCO Early Release 10.1200/JCO.2004.08.067 on June 1 2004

Journal of Clinical Oncology, Vol 22, No 13 (July 1), 2004: pp. 2594-2601
© 2004 American Society of Clinical Oncology.
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XPD and XRCC1 Genetic Polymorphisms Are Prognostic Factors in Advanced Non—Small-Cell Lung Cancer Patients Treated With Platinum Chemotherapy

Sarada Gurubhagavatula, Geoffrey Liu, Sohee Park, Wei Zhou, Li Su, John C. Wain, Thomas J. Lynch, Donna S. Neuberg, David C. Christiani

From the Departments of Medicine and Surgery, Massachusetts General Hospital; the Departments of Environmental Health, Epidemiology, and Biostatistics, Harvard School of Public Health; and the Dana-Farber/Harvard Cancer Center, Boston, MA

Address reprint requests to David C. Christiani, MD, Department of Environmental Health, Harvard School of Public Health, 665 Huntington Ave, Boston, MA 02115; e-mail: dchristi{at}hsph.harvard.edu

PURPOSE: Platinum agents cause DNA cross-linking and oxidative damage. Genetic polymorphisms of DNA repair genes are associated with differential DNA repair activity and may explain interindividual differences in overall survival after therapy with platinum agents for non–small-cell lung cancer (NSCLC).

METHODS: We used polymerase chain reaction–restriction fragment length polymorphism to evaluate genetic polymorphisms of the XPD (Asp312Asn) and XRCC1 (Arg399Gln) DNA repair genes in 103 patients with stage III (54%) and IV (46%) NSCLC treated with platinum-based chemotherapy.

RESULTS: Median age was 58 years (range, 32 to 77 years), 49% were females, and there were 86 deaths. Median follow-up period was 61.9 months. Median survival time (MST) was 14.9 months; by stage, MST was 28.6 months (IIIA), 16.0 months (IIIB), and 9.3 months (IV). Genotypes were not associated with stage. Increasing numbers of either XPD or XRCC1 variant alleles were associated with shorter overall survival (P = .003 and P = .07, respectively, by log-rank test). Similarly, when we compared combinations of variant alleles across both polymorphisms, we found that a greater number of variant alleles was associated with decreasing overall survival (P = .009, log-rank test). These polymorphisms independently predicted overall survival even after taking into account stage, performance status, and chemotherapy regimen.

CONCLUSION: Genetic polymorphisms in XPD and XRCC1 may be important prognostic factors in platinum-treated patients with advanced NSCLC.

D.C.C. was supported by National Institutes of Health (NIH) grants CA092824, CA74386, and CA90578; S.G. was supported by an NIH grant (5T32 CA71345-07) in Cancer Biology; G.L. was supported by a Doris Duke C.S. Award and a DF/HCC Lung Cancer Clinician Scientist Development Award.

This study was initially presented in the Pharmacogenomics and Cancer Therapy oral presentation session at the 39th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 31-June 3, 2003.

Authors' disclosures of potential conflicts of interest are found at the end of this article.


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