A51
Radiotherapy fraction size sensitivity modulated by DNA repair systems
Navita Somaiah1, Kai Rothkamm3, Frances Daley2, Ann Pearson4, Thomas Helleday1, John Yarnold4
1Radiation Oncology and Biology Institute, Oxford, UK, 2Gray Cancer Institute, Northwood, UK, 3Health Protection Agency, Centre for Radiation, Chemical and Environmental Hazards, Chilton, UK, 4Royal Marsden Hospital and Institute of Cancer Research, Sutton, UK
Background
Molecular processes relevant to fraction size sensitivity include recognition and processing of DNA double strand breaks (DSBs). This study investigates changes in DSB repair capacity in human epidermal basal cells of women undergoing breast radiotherapy to test the hypothesis that longer repair times needed for homologous recombination (HR) explain the low RT fractionation sensitivity of rapidly proliferating tissues.
Materials and Method
Thirty breast cancer patients prescribed 50Gy in 25 fractions of 2Gy over 5weeks to the breast were recruited. 4mm punch biopsies of breast skin were collected as follows:
a) 2hrs after 1st fraction from irradiated and contra-lateral breast.
b) 2hrs after 5th fraction from irradiated breast.
c) 1hr before and 2hr after final fraction from irradiated breast (day 33)
Formalin fixed paraffin embedded sections of epidermis were co-stained by immunohistochemistry/immunofluorescence for β-1Integrin (epidermal stem cell marker), Ki67, RAD51 (marker for HR) and 53BP1 (DSB marker).
Results
The population of β-1 Integrin+Ki67+ cells shows a drop from baseline by day5 of RT followed by a significant increase by day 33 (p=0.001). All cells show 53BP1 foci following RT, but RAD51 foci are present only in a subset of Ki67+ cells. Between day 1 and 33, results from 10 patients show an average 3.9 fold increase (range 2.0 to 7.2, p=0.001) in the fraction of Ki67+ cells carrying RAD51 foci in the basal epidermis.
Conclusions
Accelerated repopulation is associated with an increased adoption of HR. This observation may be relevant to low fractionation sensitivity in rapidly proliferating normal and malignant tissues.
