The late radiotherapy normal tissue injury phenotypes of telangiectasia, fibrosis and atrophy in breast cancer patients have distinct genotype-dependent causes

Abstract

The relationship between late normal tissue radiation injury phenotypes in 167 breast cancer patients treated with radiotherapy and: (i) radiotherapy dose (boost); (ii) an early acute radiation reaction and (iii) genetic background was examined. Patients were genotyped at single nucleotide polymorphisms (SNPs) in eight candidate genes. An early acute reaction to radiation and/or the inheritance of the transforming growth factor-b1 (TGFb1 À509T) SNP contributed to the risk of fibrosis. In contrast, an additional 15 Gy electron boost and/or the inheritance of X-ray repair cross-complementing 1 (XRCC1) (R399Q) SNP contributed to the risk of telangiectasia. Although fibrosis, telangiectasia and atrophy, all contribute to late radiation injury, the data suggest that they have distinct underlying genetic and radiobiological causes. Fibrosis risk is associated with an inflammatory response (an acute reaction and/ or TGFb1), whereas telangiectasia is associated with vascular endothelial cell damage (boost and/or XRCC1). Atrophy is associated with an acute response, but the genetic predisposing factors that determine the risk of an acute response or atrophy have yet to be identified. A combined analysis of two UK breast cancer patient studies shows that 8% of patients are homozygous (TT) for the TGFb1 (C-509T) variant allele and have a 15-fold increased risk of fibrosis following radiotherapy (95% confidence interval: 3.76 -60.3; P ¼ 0.000003) compared with (CC) homozygotes.

No association between SNPs regulating TGF-β1 secretion and late radiotherapy toxicity to the breast: Results from the RAPPER study

“…This large, purpose designed study has been unable to confirm recent reports of significant associations between the TGFB1 (C-509T) SNP and increased risk of radiation fibrosis [20][21][22]. We did not find a significant association between either of the correlated TGFB1 SNPs, L10P (rs1800470) or C-509T (rs1800469), with the development of induration, assessed by the clinician.…”

“…However, these results were not replicated in a further study by the same group [39]. In a combined analysis of two published studies [20,22] of adjuvant radiotherapy to the breast (a total of 236 patients) it was reported that CT heterozygotes for C-509T had a 3-fold increased risk and TT homozygotes had a 15-fold increased risk of fibrosis following radiotherapy compared with CC homozygotes [22].…”

“…The highly significant association of increased induration with breast boost shows that this is a sensitive end-point. We had 99% power to detect a 3-fold increase in incidence of fibrosis or induration for carriers of the T allele of the C-509T SNP, as reported in the combined analysis [22], with a type I error rate of 0.05. It remains possible that these SNPs do influence the development of late toxicity, but with much smaller effect sizes than reported in the previous small studies.…”

“…However, others have not found such associations [19]. Several small studies have reported a correlation between SNPs in the TGFB1 gene and fibrosis, one form of late radiotherapy toxicity, in breast cancer patients [20][21][22]. In addition, a study of prostate cancer patients found significant associations between TGF genotype and certain toxicity end-points [23].…”

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

“…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. Mongani et al (2011) reported that the carriers of the XRCC1-Arg194Trp variant allele in combination with the XRCC1-Arg399Gln wild-type allele had a significant risk of acute radiation-induced skin toxicity.…”