High relative biologic effectiveness of carbon ion radiation on induction of rat mammary carcinoma and its lack of H-ras and Tp53 mutations.

Purpose The high relative biologic effectiveness (RBE) of high-linear energy transfer (LET) heavy-ion radiation has enabled powerful radiotherapy. The potential risk of later onset of secondary cancers, however, has not been adequately studied. We undertook the present study to clarify the RBE of therapeutic carbon ion radiation and molecular changes that occur in the rat mammary cancer model. Methods and Materials We observed 7–8-week-old rats (ACI, F344, Wistar, and Sprague-Dawley) until 1 year of age after irradiation (0.05–2 Gy) with either 290 MeV/u carbon ions with a spread out Bragg peak (LET 40–90 keV/μm) generated from the Heavy-Ion Medical Accelerator in Chiba or 137 Cs γ-rays. Results Carbon ions significantly induced mammary carcinomas in Sprague-Dawley rats but less so in other strains. The dose–effect relationship for carcinoma incidence in the Sprague-Dawley rats was concave downward, providing an RBE of 2 at a typical therapeutic dose per fraction. In contrast, ∼10 should be considered for radiation protection at low doses. Immunohistochemically, 14 of 18 carcinomas were positive for estrogen receptor α. All carcinomas examined were free of common H- ras and Tp53 mutations. Importantly, lung metastasis (7%) was characteristic of carbon ion–irradiated rats. Conclusions We found clear genetic variability in the susceptibility to carbon ion–induced mammary carcinomas. The high RBE for carbon ion radiation further supports the importance of precise dose localization in radiotherapy. Common point mutations in H- ras and Tp53 were not involved in carbon ion induction of rat mammary carcinomas.