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There is level I evidence that breast cancers are significantly more sensitive to fraction size than previously thought, so that small fractions spare the cancer as much as the dose-limiting normal tissues. In skin, sensitivity to fraction size is associated with the proliferative status of cells in the basal epidermis, which are more sensitive to fraction size during the first 3 weeks of radiotherapy (RT) than during weeks 4 and 5. This study exploits RT-induced proliferation in human epidermis as a model of human cancer to investigate changes in DNA double-strand break (DSB) repair pathways postulated to determine RT fractionation sensitivity.
Thirty patients prescribed 50 Gy/25 fractions over 5 weeks to the breast after tumour excision of early breast cancer were recruited. Then 4 mm punch biopsies of breast skin were collected 2 hours after the first fraction from irradiated and contralateral breast, and 2 hours after the fifth fraction and 1 hour before and 2 hours after the final fraction from irradiated breast. Formalin-fixed paraffin-embedded sections of epidermis were co-stained for β1-integrin (epidermal stem cells), Ki67 (proliferation), 53BP1 (DSBs), RAD51 (homologous recombination), cyclin A (S-G2 phase) and p21 (cell cycle arrest).
The population of β1-integrin+Ki67+ cells shows a drop from baseline by day 5 of RT, followed by a significant increase by day 33 (P = 0.001). All epidermal cells show 53BP1 foci following RT, but RAD51 foci are present only in a subset of Ki67-expressing cells. Between days 1 and 33, there is a fourfold increase (P = 0.001) in the fraction of Ki67+ cells carrying RAD51 foci in the basal epidermis. This correlates with the observation that more basal cells are in the S/G2 phase of the cell cycle by week 5.
Accelerated proliferation in the epidermis at the end of a 5-week course of fractionated RT is associated with an increased adoption of homologous recombination for repairing DSBs. Adoption of homologous recombination, with its high fidelity, offers a mechanism explaining loss of fractionation sensitivity in rapidly proliferating normal (and malignant) cells.