Telangiectasia and subcutaneous fibrosis are the most common late dermatologic side effects observed in response to radiation treatment. Radiotherapy acts on cancer cells largely due to the generation of reactive oxygen species (ROS). ROS also induce normal tissue toxicities. Therefore, we investigated if genetic variation in oxidative stress-related enzymes confers increased susceptibility to late skin complications. Women who received radiotherapy following lumpectomy for breast cancer were followed prospectively for late tissue side effects after initial treatment. Final analysis included 390 patients. Polymorphisms in genes involved in oxidative stress-related mechanisms (GSTA1, GSTM1, GSTT1, GSTP1, MPO, MnSOD, eNOS, CAT) were determined from blood samples by MALDI-TOF. The associations between telangiectasia and genotypes were evaluated by multivariate unconditional logistic regression models. Patients with variant GSTA1 genotypes were at significantly increased risk of telangiectasia (OR 1.86, 95% CI 1.11-3.11). Reduced odds ratios of telangiectasia were noted for women with lower-activity eNOS genotype (OR 0.58, 95% CI 0.36-0.93). Genotype effects were modified by follow-up time, with the highest risk observed after 4 years of radiotherapy for gene polymorphisms in ROS-neutralizing enzymes. Decreased risk with eNOS polymorphisms was significant only among women with less than 4 years of follow-up. All other risk estimates were nonsignificant. Late effects of radiation therapy on skin appear to be modified by variants in genes related to protection from oxidative stress. The application of genomics to outcomes following radiation therapy holds the promise of radiation dose adjustment to improve both cosmetic outcomes and quality of life for breast cancer patients. ' 2007 Wiley-Liss, Inc.Key words: genetic polymorphisms; reactive oxygen species; longterm toxicities; radiation therapy; breast cancer Lumpectomy followed by radiation therapy is an effective treatment for women with early-stage breast cancer and is offered for the purpose of breast conservation and better cosmetic results.
1With recent advances in radiation techniques and computer tomography (CT) dose planning, it is possible to reduce cardiac toxicity due to radiotherapy; however, skin reactions, pain, breast edema and poor cosmetic results remain as health concerns of treated breast cancer patients over time. 2,3 Because of the differences in physiological response of various skin layers to radiation, telangiectasia and subcutaneous fibrosis are among the most common long-term skin side effects of radiation therapy, with higher grade correlated with poor cosmesis. 4 The process of endothelium reconstruction is radiation dosedependent, progresses over months and years and leads to the increase in severity of both telangiectasia and fibrosis.5-7 Besides duration, radiation dose and schedule, 8,9 and other factors such as radiation fields, type of surgery, increased breast size, tamoxifen treatment, chemotherapy, acute skin reactions, age, race...
