Association between Polymorphisms in the DNA Repair Genes, XRCC1, APE1, and XPD and Acute Side Effects of Radiotherapy in Breast Cancer Patients

Abstract

Purpose: Several DNA repair gene polymorphisms have been described, which affect DNA repair capacity and modulate cancer susceptibility.We evaluated the association of six polymorphisms in the DNA repair genes: XRCC1 (Arg Asn), with the risk of acute skin reactions following radiotherapy. Design: We conducted a prospective study of 446 female patients with breast cancer who received radiotherapy after breast-conserving surgery. Individual genetic polymorphisms were determined using melting point analysis of sequence-specific hybridization probes. The development of acute skin reactions (moist desquamation) associated with DNA repair gene polymorphisms was modeled using Cox proportional hazards, accounting for cumulative biologically effective radiation dose. Results: Overall, the development of acute toxicity, which presented in 77 patients, was not associated with the genetic variants studied, although the hazard ratios (HR) were generally below 1. Risks were however differential by body mass index. Among normal-weight patients only, both carriers of the APE1 148Glu and the XRCC1 399Gln alleles had decreased risk of acute skin reactions after radiotherapy (HR, 0.49 and 0.51, respectively). The results for XRCC1 were confirmed by haplotype analysis. When considering joint effects, we observed that compared with homozygote carriers of the wild-type allele in both genes, the risk was most strongly reduced in carriers of both APE1148 Glu and XRCC1 399 Gln alleles with normal weight [HR, 0.19; 95% confidence interval (95% CI), 0.06-0.56] but not in those with overweight (HR, 1.39; 95% CI, 0.56-3.45; P interaction = 0.009). Conclusion: The XRCC1399 Gln or APE1 148

Predictive Value of Xrcc1 Gene Polymorphisms for Side Effects in Patients undergoing Whole Breast Radiotherapy: a Meta-analysis

“…The development of acute side effects of grade ≥2c according to the Common Toxicity Criteria of the U.S. NIH or ≥2 according to the CTCAE v3.0 or RTOG was considered to indicate increased sensitivity for acute effects in our study (Chang-Claude et al, 2005;Zhou et al, 2010;Mangoni et al, 2011;Raabe et al, 2012;Terrazzino et al, 2012). The development of late effects of grade ≥2 according to the CTCAE v3.0 or SOMA was considered to indicate increased sensitivity for late effects in our study (Giotopoulos et al, 2007;Chang-Claude et al, 2009;Zschenker et al, 2010;Falvo et al, 2012).…”

“…After application of critical search strategies and exclusion criteria, 11 follow-up studies (Moullan et al, 2003;Chang-Claude et al, 2005;Brem et al, 2006;Giotopoulos et al, 2007;Chang-Claude et al, 2009;Zhou et al, 2010;Zschenker et al, 2010;Mangoni et al, 2011;Falvo et al, 2012;Raabe et al, 2012;Terrazzino et al, 2012) comprising 2199 cases were eligible for the present analysis. The baseline characteristics of the included studies are shown in Table 1.…”

“…Data concerning the predictive value of the XRCC1 Arg399Gln allele with respect to the risk of radiationinduced toxicity in breast cancer patients were available in 10 trials comprising 1929 individuals (Moullan et al, 2003;Chang-Claude et al, 2005;Giotopoulos et al, 2007;Chang-Claude et al, 2009;Zschenker et al, 2010;Zhou et al, 2010;Mangoni et al, 2011;Terrazzino et al, 2012;Falvo et al, 2012;Raabe et al, 2012). No significant association between the 399Gln allele and radiationinduced toxicity was detected in the overall analysis (Table 3).…”

“…Data concerning the predictive value of the 280His allele with respect to radiation-induced toxicity were available from 4 studies covering a total of 1088 individuals (Moullan et al, 2003;Chang-Claude et al, 2005;Chang-Claude et al, 2009;Zschenker et al, 2010). Table 4 shows an association between the 280His ("decreasing" allele) and radiation-induced toxicity relative to the 280Arg allele in studies of patients treated by radiotherapy alone, although these studies used low quality genotyping methods (Figure 3).…”

“…In breast cancer patients treated with radiotherapy after mastectomy or breast-conserving surgery, Andreassen et al observed a significant correlation between the XRCC1 Arg399Gln polymorphism and the risk of subcutaneous fibrosis (Andreassen et al, 2003) but these findings could not be confirmed in a larger subsequent study (Andreassen et al, 2006). Chang-Claude et al (2005) reported that the XRCC1 399Gln allele may be protective against the development of acute side-effects after radiotherapy in a study that included a cohort of 446 normal weight Caucasian breast cancer patients who received radiotherapy after breast-conserving surgery. In contrast, Giotopoulos et al (2007) found an association between the 399Gln allele and an increased risk of developing late side effects.…”