Clemens Kratochwil1, Frederik L Giesel2, Claus-Peter Heussel3, Daniel Kazdal4, Volker Endris4, Cathleen Nientiedt5,6, Frank Bruchertseifer7, Maximilian Kippenberger6, Hendrik Rathke2, Jonas Leichsenring4, Markus Hohenfellner8, Alfred Morgenstern7, Uwe Haberkorn2,9, Stefan Duensing6,8, Albrecht Stenzinger4. 1. Department of Nuclear Medicine, Heidelberg University Hospital, Heidelberg, Germany clemens.kratochwil@med.uni-heidelberg.de. 2. Department of Nuclear Medicine, Heidelberg University Hospital, Heidelberg, Germany. 3. Thorax Centre, Department of Interventional and Diagnostic Radiology, Heidelberg University Hospital, Heidelberg, Germany. 4. Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany. 5. Department of Medical Oncology, National Center for Tumor Diseases, Heidelberg, Germany. 6. Section of Molecular Urooncology, Department of Urology, Heidelberg University Hospital, Heidelberg, Germany. 7. Directorate for Nuclear Safety and Security, European Commission-Joint Research Centre, Karlsruhe, Germany. 8. Department of Urology, Heidelberg University Hospital, Heidelberg, Germany; and. 9. Clinical Cooperation Unit Nuclear Medicine, German Cancer Research Center, Heidelberg, Germany.
Abstract
Prostate-specific membrane antigen (PSMA)-targeting α-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-nonresponding lesions by targeted next-generation sequencing. Methods: Of 60 patients treated with 225Ac-PSMA-617, we identified 10 patients who 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 nonresponding lesions in 7 of these nonresponding patients. Specimens were analyzed by targeted next-generation sequencing interrogating 37 DNA damage-repair-associated genes. Results: In the 7 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), and 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. Although 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.
Prostate-specific membrane antigen (PSMA)-targeting α-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-nonresponding lesions by targeted next-generation sequencing. Methods: Of 60 patients treated with 225Ac-PSMA-617, we identified 10 patients who 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 nonresponding lesions in 7 of these nonresponding patients. Specimens were analyzed by targeted next-generation sequencing interrogating 37 DNA damage-repair-associated genes. Results: In the 7 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), and 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. Although 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.
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