ESTRO 2021 Abstract Book

S296

ESTRO 2021

Conclusion This study demonstrated that variations in mpMRI data in GBM patients do not affect the ability to generate consistent dose prescriptions when MRI-derived TP modelling is used in combination with dose-mapping techniques.

Proffered papers: Proffered papers 23: Radiation response and biomarkers

OC-0399 Co-occurrence of APOBEC3B and Homologous Recombination Deficiency is Rare in Breast Cancer P. Span 1 , M. Jarvis 2 , J. Martens 3 , R. Harris 2 , P. Roelofs 1 1 Radboud university medical center, Radiation Oncology, Nijmegen, The Netherlands; 2 Institute for Molecular Virology, Center for Genome Engineering, University of Minnesota, Department of Biochemistry, Molecular Biology and Biophysics, Masonic Cancer Center, Minneapolis, USA; 3 Erasmus MC Cancer Institute, Erasmus University Medical Center, Department of Medical Oncology, Rotterdam, The Netherlands Purpose or Objective In many cancer subtypes, including breast cancer, defects in the DNA-damage repair genes such as BRCA1/2 give rise to homologous recombination deficiency (HRD) and an associated HRD mutation signature. Tumors with HRD are generally more sensitive to DNA damaging agents and ionizing radiation (IR). Furthermore, cytosine deamination has been shown to be catalyzed by activity of the DNA cytosine deaminase APOBEC3B (A3B). The ability of A3B to convert DNA cytosine nucleobases into uracils has been shown to induce C-to-T transitions and C-to-G transversions, inducing an APOBEC mutation signature found in a large proportion of breast cancers. The radiosensitivity of HRD breast cancer (e.g. BRCA1 mutated patients) is well established, but the association of A3B signatures with radiosensitivity is unclear. Materials and Methods The (co)occurrence of HRD and A3B signatures was assessed in several breast cancer cohorts. In patients that did not receive adjuvant systemic treatment, the predictive value of A3B expression was established by comparing outcome in patients with or without radiotherapy as part ofd their primary treatment. Overexpression, knockdown and/or pharmacological inhibition of HR (BRCA, RAD51) or A3B was performed in severa; breast cancer cell lines and its effect analysed using colony formation assays. Results In breast cancer patients A3B expression was associated with survival only in patients receiving IR as part of their primary treatment. Interestingly however, we found that breast cancer patients with tumors with prominent APOBEC mutation signatures only rarely show signs of HRD, and vice versa , indicating a mutually exclusive phenotype ( Fig. 1 ). This prompted us to further investigate whether co-existence of these two mutation processes influences (tumor) cell viability in vitro . Unexpectantly, RNAi-mediated knockdown of BRCA1 , thereby inducing HRD, did not impact the clonal survival of normal breast epithelial cells during overexpression of A3B, indicating that A3B alone may be tolerated in the near-absence of BRCA1 ( Fig. 2A ). However, while chemical inhibition of HR using the RAD51 inhibitor B02 potently enhanced the effects of ionizing radiation on breast cancer cells, this effect was absent in their A3B-depleted counterparts, indicating that the combination of A3B expression and HRD is specifically lethal when combined with IR ( Fig. 2B ). Indeed, we found that in the aforementioned patient cohorts those tumors that carried both the APOBEC and HRD mutation signatures responded exceptionally well to clinical DNA-damaging approaches ( Fig. 2c ), indicating the vulnerability of these tumors to exposure to DNA-damage.