title: Genetic predictors of long-term toxicities after radiation therapy for breast cancer.
abstract: 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.
authors.affiliation: Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY 14263, USA. nataliya.kuptsova@roswellpark.org
authors.forename: Nataliya
authors.initials: N
authors.lastname: Kuptsova
authors.forename: Jenny
authors.initials: J
authors.lastname: Chang-Claude
authors.forename: Silke
authors.initials: S
authors.lastname: Kropp
authors.forename: Irmgard
authors.initials: I
authors.lastname: Helmbold
authors.forename: Peter
authors.initials: P
authors.lastname: Schmezer
authors.forename: Dietrich
authors.initials: D
authors.lastname: von Fournier
authors.forename: Wulf
authors.initials: W
authors.lastname: Haase
authors.forename: Marie Luise
authors.initials: ML
authors.lastname: Sautter-Bihl
authors.forename: Frederik
authors.initials: F
authors.lastname: Wenz
authors.forename: Kenan
authors.initials: K
authors.lastname: Onel
authors.forename: Christine B
authors.initials: CB
authors.lastname: Ambrosone
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001943:Breast Neoplasms / Q000235:genetics* / Q000532:radiotherapy; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008875:Middle Aged; D018384:Oxidative Stress / Q000235:genetics; D011110:Polymorphism, Genetic; D011878:Radiotherapy / Q000009:adverse effects*; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization