DNA damage response (DDR) and repair kinetics predict treatment response in patients receiving Lu-177-DOTA-TATE peptide receptor radionuclide therapy for advanced gastro-entero-pancreatic neuroendocrine tumors

Ziel/Aim The tumor supressor P53-binding protein 1 (53BP1) and the phosphorylated H2A histone family member X (yH2AX) are crucial factors in the DNA damage response (DDR) to radiation-induced double-strand breaks (DSBs). We investigated their usefulness for prediction of hematotoxicity, and treatment response.

Methodik/Methods A prospective analysis of DDR and repair kinetics was performed in 20 patients with advanced gastro-entero-pancreatic neuroendocrine tumors undergoing Lu-177-DOTA-TATE peptide receptor radionuclide therapy (PRRT). The DSB markers 53BP1 and yH2AX were evaluated in peripheral blood lymphocytes (PBLs) of patients at −1h, + 1h and +24h after administration of Lu-177-DOTA-TATE. Toxicity was evaluated using standard haematology. Tumor burden was determined using Ga-68-DOTA-TATE PET/CT before enrollment and every 1-2 cycles thereafter. Therapy response was assessed using RECIST 1.1, including its volumetric modification.

Ergebnisse/Results DDR (e.g, yH2AX foci per cell at 1h p.i., +4 % to +200 %) and repair kinetics (e.g., change in yH2AX foci per cell between 1 and 24h p.i., −37 % to +52 %) were heterogeneous among patients. Hematotoxicity was associated with DSB markers (e.g., increase in 53BP1⁺ cells at 1h vs. decrease in thrombocyte counts, r = −0.45, P = 0.046). Intermediate-term change in individual tumor burden was inversely correlated with early change in DSB marker-positive PBLs between BL and 1h (yH2AX: r = −0.56, P = 0.01; 53BP1: r = −0.48, P = 0.04) and BL and 24h (yH2AX: r = −0.60, P = 0.007; 53BP1: r = −0.66, P = 0.002). Patients developing new metastases under PRRT more often showed a distinct kinetic pattern with an absence of DSB marker decrease at 24 h (yH2AX: P = 0.003; 53BP1: P = 0.03).

Schlussfolgerungen/Conclusions DDR and repair kinetics in PBLs of patients receiving PRRT are heterogeneous. Beyond prediction of hematotoxicity, these parameters may hold promise for prediction of treatment response and risk of progression by elucidating individual DNA damage response properties.