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 biological effectiveness (RBE) of high linear energy transfer (LET) heavy-ion radiation has enabled powerful radiotherapy. The potential risk for later onset of secondary cancers, however, has not been adequately studied. We undertook the present study to clarify the RBE of therapeuticcarbon ion radiation and molecular changes that occur in the rat mammary cancer model. Methods and Materials: Seven- to eight-week-old rats (ACI, F344, Wistar and Sprague-Dawley) were observed until one year of age following irradiation (0.05-2 Gy) with either 290 MeV/u carbon ions with a spread-out Bragg peak (LET 40-90 keV/um) generated from the Heavy-Ion Medical Accelerator in Chiba (HIMAC) or 137Cs gamma-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 Sprague-Dawley rats was concave downward, providing an RBE of 2 at a typical therapeutic dose per fraction, whereas ~10 should be considered for radiation protection at low doses. Immunohistochemically, 14 of 18 carcinomas were positive for estrogen receptor alpha. 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 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