ESTRO 38 Abstract book

S309 ESTRO 38

target volume (CTV), for LEMI- and MKM-RBE computations, were criteria to assess target dose. Selected ACC and SC included patients presenting a tumor relapse at follow-up. Recurrences were retrospectively contoured on the follow-up MR scan corresponding to first diagnosis. The relapse location, with respect to CTV and spared OARs, and relative dose distributions in the two RBE systems were analyzed. Results The MKM-D RBE analysis showed that prescription dose conversion factors correctly acted on median CTV D RBE , but allowed the generation of low and high MKM-D RBE regions (figure 1a-b) linked to the steeper MKM-RBE variation along the beam path. Location of inhomogeneities was related to tumor volume, beam number and configuration. The average MKM-D RBE reduction at 95% of CTV ranged from 8% to 2% of the expected value, for the lower and higher fraction doses, respectively. ACC and SC relapses were mainly (38% ACC and 25% SC) related to poor CTV coverage due to OARs sparing to a MKM-D RBE significantly lower than expected (figure 1c). No clear evidence was found of a cause-effect relation between low MKM-D RBE to 95% of CTV and loss of tumor control.

Radiotherapy, Center of Oncology- University Medical Center Hamburg-Eppendorf UKE, Hamburg, Germany Purpose or Objective Breast cancer comprises a heterogeneous group of tumors of whom 20% are categorized as triple-negative (TNBC). A specific tumor therapy for this subgroup is still lacking. Important biological characteristics and potential therapeutic targets of TNBC include a basal-like and mesenchymal so called stem-cell phenotype and a defect in the DNA repair pathway Homologous Recombination (HR), which feeds the observed elevated chromosomal instability (CIN) in these tumors. This project aims to develop treatment intensification strategies based on the simultaneous exploitation of the HR-deficiency and the stem-like phenotype, using specific inhibitors such as ATR, CHK1, RAD51, and PARP1 in combination with irradiation. Material and Methods The investigations were performed in three TNBC cell lines MDA-MB-231 which metastasize systemically (WT), into the brain (BR) or into the bone marrow (SA) and their respective radiation resistant subclones selected by repeated irradiation (10x4Gy). Luminal MCF7 cells served as controls. Expression of HR-related and stem-like factors was determined and DNA repair in general (53BP1) as well as HR functionality (RAD51 foci formation, MMC-sensitivity and plasmid reporter assay) was analyzed. Replication processes were examined by using the DNA fiber assay and migration assays were also performed. Radiosensitizing effect of several HR and S-phase specific inhibitors were analyzed by colony assay and correlated with expression profiles of stem cell markers and DNA repair proteins in the METABRIC database. Results A significantly increased expression of the stem cell markers ALDH1, ZEB1 and Vimentin was observed in all four radioresistant sublines, both on single cell basis and in Western blots. This led to an increased activation of ALDH1 in the Aldeflour assay in all investigated clonal subpopulations. After irradiation, survival in the clonal subpopulation was significantly increased compared to the original cell line. In accordance with this, the radioresistant subclones showed a lower number of 53-BP1 foci, indicating improved DNA repair. Also HR capacity seem to be improved. This is confirmed by a significantly stronger activation of the Intra-S phase control point, with an increased activation of CHK1.This results in a distinct radiosensitization after CHK1i; the most radioresistant cell line was most strongly sensitized (EF=3) and also showed up in DNA replication processes: the higher the EF the stronger the inhibitory effect on DNA replication. The effect of other inhibitors on radiosensitivity is currently being investigated. A second promising target is RAD51, because a METABRIC analysis (952 TNBCs) showed that both, RAD51 and CHK1 are differentially expressed according to their degree of chromosomal instability. Conclusion In conclusion the results presented here show that DNA repair and a stem-like phenotype are closely intertwined in determining resistance to tumor therapy of TNBCs with high CIN.

Conclusion The use of a MKM system, as a starting point for LEMI optimization, could reduce CTV dose inhomogeneities and their potential impact on tumor local control and patient toxicity (figure 1d). D RBE deviations between LEMI and MKM plans were significantly higher in regions where steep dose gradients were applied to spare OARs, than in the target region. New constraints are currently being defined for optic pathways, brainstem and rectum at CNAO to improve target coverage with no expected increase in tissue complications. (1) Molinelli S. et al. Radiotherapy and Oncology 120 (2016). OC-0590 Avoidance of DNA replication stress by functional HR leads to radioresistance in stem cell-like TNBC K. Borgmann 1 , M. Felix 1 , E. Anna Maria 1 , B. Saskia 1 , H. Linda 2 , P. Claudia 2 , D. Anna 2 , W. Sabine 3 , W. Harriet 4 , R. Kai 1 , P. Cordula 5 1 Laboratory of Radiobiology & Experimental Radiooncology, Department of Radiotherapy- Center of Oncology- University Medical Center Hamburg - Eppendorf UKE, Hamburg, Germany ; 2 Institute of Radiooncology- OncoRay- National Center for Radiation Research in Oncology-, Faculty of Medicine and University Hospital Carl Gustav Carus- Technische Universität Dresden- Helmholtz-Zentrum Dresden - Rossendorf, Dresden, Germany ; 3 Institute of Biochemistry, University Medical Center Hamburg- Eppendorf UKE, Hamburg, Germany; 4 Department of Tumor Biology, University Medical Center Hamburg- Eppendorf UKE, Hamburg, Germany; 5 Department of

Proffered Papers: CL 11: Proffered papers : Breast

OC-0591 Response after MR-guided single dose ablative preoperative partial breast irradiation J. Vasmel 1 , R. Charaghvandi 1 , A. Houweling 1 , M. Philippens 1 , C. Vreuls 2 , P. Van Diest 2 , G. Van Leeuwen 3 , J. Van Gorp 4 , A. Witkamp 5 , C. Van der Pol 5 , R. Koelemij 6 , A. Doeksen 6 , M. Sier 7 , T. Van Dalen 8 , E. Van der Wall 9 , W. Veldhuis 10 , M. Hobbelink 11 , A. Kirby 12 , H. Verkooijen 13 , D. Van den Bongard 1