ESTRO38 Congress Report

Radiobiology

3. Targeting TEMPRSS2: ERG fusion to achieve tumour-specific radiosensitisation in prostate cancer (E38-1769) Sabrina Köcher 1 , Burkhard Beyer 2 , Tobias Lange 3 , Lena Nordquist1, Susanne Burdak- Rothkamm 1 , Thorsten Schlomm 2 , Cordula Petersen 4 , Kai Rothkamm 1 , Wael Mansour 1 . 1 University Medical Center Hamburg - Eppendorf UKE, Lab of Radiobiology and Experimental Radiation Oncology, Hamburg, Germany, 2 Prostate Cancer Center- University Medical Hamburg Eppendorf, Martini-Klinik-, Hamburg, Germany, 3 University Medical Center Hamburg-Eppendorf, Institute of Anatomy, Hamburg, Germany, 4 University Medical Center Hamburg - Eppendorf UKE, Department of Radiotherapy and Radiooncology, Hamburg, Germany.

Overview of abstract In prostate cancer (PC), TEMPRSS2:ERG fusion is the most frequent translocation that involves the androgen- responsive gene TMPRSS2 and the ETS-transcription factor ERG, leading to overexpression of ERG. ERG overexpression is reported in about 50% of PC. The current study aimed to determine the impact of ERG status on radiotherapy (RT) response, DNA double-strand break (DSB) repair and ability to radiosensitise PC using PARP inhibitors. What were the three main findings of your research? 1- Cells overexpressing ERG showed a repair switch to PARP1-dependent alternative end joining (EJ). Ex-vivo analyses confirmed the ERG-dependent repair switch to PARP1-EJ in primary PC biopsies, as indicated by a significantly higher number of residual γH2AX/53BP1 foci. 2- ERG fusion was analysed in (i) 14,000 PC patients who underwent radical prostatectomy and (ii) 1,426 PC patients who underwent salvage radiotherapy. A multivariable Cox proportional hazards model did not show any significant impact of ERG status on biochemical recurrence in either cohort. 3- PARP1 inhibition selectively radiosensitised ERG- overexpressing cells and tissues and increased the number of residual γH2AX/53BP1 foci after irradiation.

What impact could your research have? Collectively, these data demonstrate that ERGoverexpression is not a predictive marker for RT response in PC but drives a switch to PARP1-EJ, which in turn enables tumour-specific radiosensitisation by PARP1 inhibition, therefore paving the way to widen the use of PARPi in the clinic. Is this research indicative of a bigger trend in oncology? Radiotherapy (RT) is one of the mainstay treatments for prostate cancer (PC). Despite all technological advances in RT delivery over the recent years, improvements in molecular characterization of PC have not changed clinical practice. Decision-making in RT for PC is still guided by conventional clinical-pathological factors such as PSA-levels and Gleason scores. Local recurrence after RT is thought to occur predominantly in regions bearing higher histological tumour burden. Consequently, PC is still the third-leading cause of cancer-related death in males. Therefore, there is a great need for development of strategies that improve both local control at the tumour site and eradicate occult metastasis in PC patients. Clinically, these findings motivate the combination of PARP inhibitor olaparibwith radiotherapy in ERG-positive PC patients.

Congress report | RADIOBIOLOGY

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