Modelling the HPRT-gene mutation induction of particle beams: systematic in vitro data collection, analysis and microdosimetric kinetic model implementation

Objective. Since the early years, particle therapy treatments have been associated with concerns for late toxicities, especially secondary cancer risk (SCR). Nowadays, this concern is related to patients for whom long- term survival is expected (e.g. breast cancer, lymphoma, paediatrics). In the aim to contribute to this research, we present a dedicated statistical and modelling analysis aiming at improving our understanding of the RBE for mutation induction (RBE(M) over tilde) for different particle species. Approach. We built a new database based on a systematic collection of RBE data for mutation assays of the gene encoding for the purine salvage enzyme hypoxanthine-guanine phosphoribosyltransferase from literature (105 entries, distributed among 3 cell lines and 16 particle species). The data were employed to perform statistical and modelling analysis. For the latter, we adapted the microdosimetric kinetic model (MKM) to describe the mutagenesis in analogy to lethal lesion induction.Main results. Correlation analysis between RBE for survival (RBES) and RBE(M) over tilde reveals significant correlation between these two quantities (rho= 0.86,p< 0.05). The correlation gets stronger when looking at subsets of data based on cell line and particle species. We also show that the MKM can be successfully employed to describe RBE<(M)over tilde>,obtaining comparably good agreement with the experimental data. Remarkably, to improve the agreement with experimental data the MKM requires, consistently in all the analysed cases, a reduced domain size for the description of mutation induction compared to that adopted for survival.Significance. We were able to show that RBES and RBE(M) over tilde are strongly related quantities. We also showed for the first time that the MKM could be successfully applied to the description of mutation induction, representing an endpoint different from the more traditional cell killing. In analogy to the RBES,RBE(M) over tilde can be implemented into treatment planning system evaluations.

Automated summary

This study investigates the concerns of late toxicities, particularly secondary cancer risk, associated with particle therapy treatments. Through statistical and modeling analysis, the study reveals a strong correlation between the relative biological effectiveness (RBE) for mutation induction and the RBE for survival. The study also introduces the successful application of the microdosimetric kinetic model (MKM) in describing mutation induction, providing a new approach for treatment planning system evaluations.