DNA-damage response foci in peripheral blood lymphocytes and outcome of PSMA-targeted radioligand therapy

Introduction: Targeted DNA damage response (DDR) depends on complex mechanisms including upregulation of the proteins g-H2AX and 53BP1 which may serve as immunofluorescence markers. We sought to identify the formation and evolution of DDR-foci in peripheral blood lymphocytes (PBLs) following ¹⁷⁷Lu-PSMA radioligand therapy (Lu-PSMA) and hypothesized that DDR-foci are predictive of outcome.

Methods: We prospectively enrolled 35 men (20 RLT-naïve patients; 15 non-RLT-naïve patients) with metastatic castration resistant prostate cancer (mCRPC). All patients underwent ¹⁸F-PSMA-1007 positron emission tomography (PET)/computed tomography (CT) for the assessment of tumor PSMA expression (maximum standardized uptake value (SUV_max) of all tumor lesions). Blood samples were collected prior to, 1h after and 24h after administration of Lu-PSMA. DDR-markers g-H2AX and 53BP1 were determined in PBLs through fluorescence microscopy. Then, we determined the predictive value of DDR-foci and PET-based parameters for early progressive disease (PD, defined as PSA increase >25% and/or PET-based progress according to PPP criteria after 2 cycles) and progression-free survival (PFS).

Results: DDR-foci demonstrated interindividual heterogeneity and showed an early increase 1h after administration of Lu-PSMA (P<0.0001), with a subsequent decrease after 24h (P<0.0001). However, DDR-foci remained elevated compared to baseline (P<0.001). Following 2 cycles, 8/20 (40%) of the RLT-naïve patients progressed. Low baseline DDR-foci [g-H2AX (P=0.037); 53BP1 (P=0.032)] and a low SUV_max (P=0.016) were significantly associated with early PD. DDR-foci 1h and 24h after Lu-PSMA however, were not predictive. Patients with high pretherapeutic 53BP1 foci demonstrated significantly longer PFS (P=0.036). In a multivariate Cox-regression model, pretherapeutic 53BP1 foci emerged as the sole independent predictor for prolonged PFS (Hazard Ratio: 0.25 [95%-CI: 0.07 – 0.898]; P=0.034). Of note, in non-RLT-naïve patients, neither DDR-foci (P≥0.089) nor PET-based SUV_max (P=0.326)were predictive for outcome.

Conclusions: Low baseline DDR-foci in peripheral lymphocytes may reflect a systemically low individual radiosensitivity and thereby serve as an independent predictor of response to Lu-PSMA. These findings might be used to guide additive radiosensitizing or treatment intensification in future studies with high-risk individuals scheduled for Lu-PSMA.