title: Correlation between the radiation responses of fibroblasts cultured from individual patients and the risk of late reaction after breast radiotherapy.
abstract: Late normal tissue toxicity varies widely between patients and limits breast radiotherapy dose. Here we aimed to determine its relationship to DNA damage responses of fibroblast cultures from individual patients. Thirty-five breast cancer patients, with minimal or marked breast changes after breast-conserving therapy consented to receive a 4 Gy test irradiation to a small skin field of the left buttock and have punch biopsies taken from irradiated and unirradiated skin. Early-passage fibroblast cultures were established by outgrowth and irradiated in vitro with 0 or 4 Gy. 53BP1 foci, p53 and p21/CDKN1A were detected by immunofluorescence microscopy. Residual 53BP1 foci counts 24 h after in vitro irradiation were significantly higher in fibroblasts from RT-sensitive versus RT-resistant patients. Furthermore, significantly larger fractions of p53- but not p21/CDKN1A-positive fibroblasts were found in cultures from RT-sensitive patients without in vitro irradiation, and 2 h and 6 d post-irradiation. Exploratory analysis showed a stronger p53 response 2 h after irradiation of fibroblasts established from patients with severe reaction. These results associate the radiation response of fibroblasts with late reaction of the breast after RT and suggest a correlation with severity.
authors.affiliation: Public Health England, Centre for Radiation, Chemical and Environmental Hazards, Chilton, UK.
authors.forename: Otilia
authors.initials: O
authors.lastname: Nuta
authors.affiliation: Division of Radiotherapy and Imaging, Institute of Cancer Research, London, UK.
authors.forename: Navita
authors.initials: N
authors.lastname: Somaiah
authors.affiliation: Division of Radiotherapy and Imaging, Institute of Cancer Research, London, UK.
authors.forename: Sue
authors.initials: S
authors.lastname: Boyle
authors.affiliation: Public Health England, Centre for Radiation, Chemical and Environmental Hazards, Chilton, UK; National Cancer Centre, Singapore Duke-NUS Graduate Medical School, 11 Hospital Drive, Singapore, 169610.
authors.forename: Melvin Lee Kiang
authors.initials: ML
authors.lastname: Chua
authors.affiliation: Division of Radiotherapy and Imaging, Institute of Cancer Research, London, UK.
authors.forename: Lone
authors.initials: L
authors.lastname: Gothard
authors.affiliation: Division of Radiotherapy and Imaging, Institute of Cancer Research, London, UK.
authors.forename: John
authors.initials: J
authors.lastname: Yarnold
authors.affiliation: Public Health England, Centre for Radiation, Chemical and Environmental Hazards, Chilton, UK; Department of Radiotherapy and Radiation Oncology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany.
authors.forename: Kai
authors.initials: K
authors.lastname: Rothkamm
authors.affiliation: Department of Radiation Oncology, Universitaetsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany. Electronic address: carsten.herskind@medma.uni-heidelberg.de.
authors.forename: Carsten
authors.initials: C
authors.lastname: Herskind
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D002478:Cells, Cultured; D053903:DNA Breaks, Double-Stranded; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects*; D006801:Humans; D008856:Microscopy, Fluorescence; D008875:Middle Aged; D011832:Radiation Injuries / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D011836:Radiation Tolerance; D016032:Randomized Controlled Trials as Topic; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53
keywords: 53BP1; Breast cancer; Double-strand breaks; Individual radiosensitivity; Normal-tissue reaction; p53