2856 - Biological Response Heterogeneity along the Proton Depth-Dose Curve

M. Musielak^1,2, K. Graczyk¹, M. Liszka³, E. Papalanis⁴, B. Stenerlöw⁴, M. Kruszyna-Mochalska^1,2, T. G. Piotrowski^1,2, W. M. Suchorska^1,2, and J. Malicki^5,6; ¹Department of Medical Physics, Greater Poland Cancer Centre, Poznan, Poland, ²Department of Electroradiology, Poznan University of Medical Sciences, Poznan, Poland, ³The Skandion Clinic, Uppsala, Sweden, ⁴Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden, ⁵Electroradiology Department, Poznan University of Medical Sciences, Poznan, Poland, ⁶Greater Poland Cancer Centre, Poznan, Poland

Purpose/Objective(s): Proton therapy involves the superposition of multiple beams of varying energy levels. The dose delivered to the target is comprised of energy absorbed along the depth-dose curve (DDC) in the regions before, within, and after the Bragg peak. However, the magnitude and quality of the biological effects induced by proton beam radiation are not well-understood. The aim of this study was to evaluate potential variations in the biological response of cancer cells to proton beam radiation along the depth-dose curve. Materials/

Methods: Triple-negative breast cancer cells (MDA-MB-231) were placed in a commercial water tank (320 mm x 370 mm) and irradiated with proton (150 MeV) and photon (6 MV) beams at five points along the depth-dose curve (DDC) before, within, and after the Bragg peak.Radiation doses to the cells were measured with radiographic film. Separate calibration curves were prepared for the proton and photon beams against known doses in the same range. A total dose of 5 Gy was delivered to each of the five locations. Radiobiological response was determined by assessing gene expression (qPCR), the relative level of DNA double-strand breaks (DSB) (?H2AX), and cell survival (clonogenic assay).
Results: The surviving fraction (SF) after proton and photon beam radiation was comparable at four of the five points, except for the location just after the Bragg peak, where proton irradiation resulted in a significantly lower SF value. Compared to photons, proton beam radiation induced a significantly higher ?H2AX level in the MDA-MB-231 cells before and behind the Bragg peak. The number of DNA DSBs caused by proton irradiation increased as the depth increased, suggesting that proton beams are more likely to cause DNA DSBs after the Bragg peak rather than before or within the peak. No statistically significance differences were observed in gene expression of the cells regardless of their location on the curve. Gene expression after proton irradiation was largely homogenous, except for expression of the PRDKC, RAD51 and XRCC1 genes, which increased as a function of greater depth.
Conclusion: In this study, the biological response of cancer cells to proton beam radiation along the dose build-up and fall-off regions was heterogenous, both quantitatively and qualitatively. These findings suggest that biological response of homogeneous proton dose in the target may be heterogeneous, which has clinical implications.