%0 Journal Article %A Clemens Kratochwil %A Frederik L. Giesel %A Claus Peter Heussel %A Daniel Kazdal %A Voler Endris %A Cathleen Nientiedt %A Frank Bruchertseifer %A Maximilian Kippenberger %A Hendrik Rathke %A Jonas Leichsenring %A Markus Hohenfellner %A Alfred Morgenstern %A Uwe Haberkorn %A Stefan Duensing %A Albrecht Stenzinger %T Patients resistant against PSMA-targeting alpha-radiation therapy often harbor mutations in DNA-repair associated genes %D 2019 %R 10.2967/jnumed.119.234559 %J Journal of Nuclear Medicine %P jnumed.119.234559 %X Prostate-specific membrane antigen (PSMA) targeting alpha-radiation therapy (TAT) is an emerging treatment modality for metastatic castration-resistant prostate cancer. There is a subgroup of patients with poor response despite sufficient expression of PSMA in their tumors. The aim of this work was to characterize PSMA-TAT non-responding lesions by targeted next-generation sequencing (tNGS). Methods: Out of 60 patients treated with 225Ac-PSMA-617, we identified 10 patients that presented with a poor response despite sufficient tumor-uptake in PSMA-PET/CT. We were able to perform CT-guided biopsies with histologic validation of the non-responding lesions in seven of these non-responding patients. Specimens were analyzed by tNGS interrogating 37 DNA damage-repair associated genes. Results: In the seven tumor samples analyzed, we found a total of 15 whole-gene deletions, deleterious or presumably deleterious mutations affecting TP53 (n = 3); CHEK2 (n = 2), ATM (n = 2); BRCA1, BRCA2, PALB2, MSH2, MSH6, NBN, FANCB and PMS1 (n = 1 each). The average number of deleterious or presumably deleterious mutations was 2.2 (range, 0-6) per patient. In addition, several variants of unknown significance in ATM, BRCA1, MSH2, SLX4, ERCC- and various FANC-genes were detected. Conclusion: Patients with resistance to PSMA-TAT despite PSMA-positivity frequently harbor mutations in DNA-damage-repair and checkpoint genes. While the causal role of these alterations in the patient outcome remains to be determined, our findings encourage future studies combining PSMA-TAT and DNA-damage-repair targeting agents such as Poly(ADP-ribose)-Polymerase inhibitors. %U https://jnm.snmjournals.org/content/jnumed/early/2019/10/10/jnumed.119.234559.full.pdf