PT  - JOURNAL ARTICLE
AU  - Clemens Kratochwil
AU  - Frederik L. Giesel
AU  - Claus-Peter Heussel
AU  - Daniel Kazdal
AU  - Volker Endris
AU  - Cathleen Nientiedt
AU  - Frank Bruchertseifer
AU  - Maximilian Kippenberger
AU  - Hendrik Rathke
AU  - Jonas Leichsenring
AU  - Markus Hohenfellner
AU  - Alfred Morgenstern
AU  - Uwe Haberkorn
AU  - Stefan Duensing
AU  - Albrecht Stenzinger
TI  - Patients Resistant Against PSMA-Targeting α-Radiation Therapy Often Harbor Mutations in DNA Damage-Repair–Associated Genes
AID  - 10.2967/jnumed.119.234559
DP  - 2020 May 01
TA  - Journal of Nuclear Medicine
PG  - 683--688
VI  - 61
IP  - 5
4099  - http://jnm.snmjournals.org/content/61/5/683.short
4100  - http://jnm.snmjournals.org/content/61/5/683.full
SO  - J Nucl Med2020 May 01; 61
AB  - 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.