XPD and XRCC1 genetic polymorphisms are associated with overall survival (OS) in advanced non-small cell lung cancer (NSCLC) patients treated with platinum chemotherapy

Category: Prognostic Factors

Authors: S. Gurubhagavatula, G. Liu, S. Park, W. Zhou, L. Su, J. C. Wain, T. J. Lynch, D. S. Neuberg, D. C. Christiani; Massachusetts General Hospital, Boston, MA; Harvard School of Public Health, Boston, MA

Abstract: 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 inter-individual differences in OS after therapy with platinum agents for NSCLC. We evaluated 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 using PCR-RFLP. Median age was 58 (32-77) years; 53% were males; there were 86 deaths. 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). Median follow-up period was 63.9 months. Stage was not associated with any genotypes. Increasing numbers of either XPD or XRCC1 variant alleles were associated with shorter OS (p=0.003 and p=0.07, respectively, by logrank test). Similarly, when we compared combinations of variant genotypes across both polymorphisms, we found that a greater number of variant alleles was associated with decreasing MST (p=0.009, logrank). These polymorphisms independently predicted OS even after taking into account stage and performance status (PS). Genetic polymorphisms in XPD and XRCC1 may be key prognostic factors in platinum-treated NSCLC patients.

Genetic polymorphism		n	MST (mos)	Logrank test	Hazard Ratio (95% CI)*
XPD Asp312Asn	Asp/Asp**	50	16.3	p=0.003	1.0 (reference)
	Asp/Asn	41	15.2		1.36 (0.97-1.90)
	Asn/Asn	12	6.6		1.84 (1.31-2.58)
XRCC1 Arg399Gln	Arg/Arg**	51	17.3	p=0.07	1.0 (reference)
	Arg/Gln	42	11.4		1.45 (1.03-2.05)
	Gln/Gln	10	7.7		2.11 (1.49-2.98)
Combined	0 variants***	26	20.4	p=0.009	1.0 (reference)
	1 variant allele	40	16.6		1.41 (1.11-1.80)
	2 variant alleles	24	11.0		1.99 (1.56-2.53)
	3 variant alleles	13	6.8		2.80 (2.20-3.57)

*by Cox proportional hazards model adjusted for stage and PS;
**homozygous wildtype;
***double homozygous wildtype