Individual radiosensitivity reflected by γ-H2AX and 53BP1 foci predicts outcome in PSMA-targeted radioligand therapy

Abstract

Purpose γ-H2AX and 53BP1 are fundamental for cellular DNA damage response (DDR) after radiation exposure and are linked to cell repair, arrest, or apoptosis. We aimed to evaluate whether DDR-markers in peripheral blood lymphocytes (PBLs) may have predictive potential for outcome in metastatic castration-resistant prostate cancer (mCRPC) patients receiving [177Lu]Lu-prostate-specific membrane antigen (PSMA) radioligand therapy (RLT). Methods We prospectively enrolled 20 men with advanced mCRPC scheduled for PSMA-targeted RLT. Prior to the first cycle of [177Lu]Lu-PSMA RLT, all patients underwent [18F]F-PSMA-1007 positron emission tomography (PET)/computed tomography (CT) for assessment of tumor PSMA expression (assessing maximum standardized uptake value (SUVmax) of all tumor lesions). Blood samples were collected prior to, + 1 h after, and + 24 h after administration of [177Lu]Lu-PSMA, and DDR-markers γ-H2AX and 53BP1 were determined in PBLs through immunocytofluorescence. We then tested the predictive performance of DDR-markers relative to clinical and PET-based parameters for progressive disease (PSA-PD) after 2 cycles. In addition, the predictive value for progression-free survival (PSA-PFS, provided as median and 95% confidence interval [CI]) was explored. Results Low baseline 53BP1 and γ-H2AX foci (P = 0.17) tended to predict early PSA-PD, whereas low SUVmax was significantly associated with higher risk for PSA-PD (P = 0.04). In Kaplan–Meier analysis, there was a trend towards prolonged PSA-PFS in patients with higher baseline 53BP1 of 6 months (mo; 95%CI, 4–9 mo) compared to 3 mo in patients with low 53BP1 (95% CI, 2–3 mo; P = 0.12). Comparable results were recorded for higher γ-H2AX expression (6 mo [95% CI, 3–9 mo] relative to 3 mo [95% CI, 2–4 mo] in patients with low γ-H2AX; P = 0.12). SUVmax, however, did not demonstrate predictive value (P = 0.29). Consistently, in univariate Cox-regression analysis, baseline 53BP1 foci demonstrated borderline significance for predicting PSA-PFS under [177Lu]Lu-PSMA RLT (P = 0.05). Conclusion In this prospective study investigating mCRPC patients undergoing [177Lu]Lu-PSMA RLT, low baseline DDR-markers in PBLs tended to predict poor outcome. Although the study group was small and results need further confirmation, these preliminary findings lay the foundation for exploring additive radiosensitizing or treatment intensification in future studies with high-risk individuals scheduled for RLT.

Status of PSMA-targeted radioligand therapy in prostate cancer: current data and future trials

“…Widjaja et al . 48 evaluated DNA damage repair (DDR) markers in peripheral blood lymphocytes (PBLs) to assess if these markers could predict outcome of 177 Lu-PSMA-RLT; this preliminary study showed that low baseline DDR markers in PBLs trended toward poor treatment outcomes. Future studies ideally will be embedded into phase III trials with clinically meaningful endpoints.…”

Effective therapy with Bismuth-212 labeled macroaggregated albumin in orthotopic mouse breast tumor models

“…Therefore, to find out the downstream molecular markers involved in cell death, a DNA damage marker and a cell death marker were evaluated. H2AX phosphorylation (γH2AX) is a well-known marker of an early cellular response to DNA double-strand breaks, and Caspase 3 is a key molecule involved in cell death ( Chen et al, 2022 ; Widjaja et al, 2023 ). In this study, western blot analysis showed that Bi-212-MAA treatment induced H2AX phosphorylation in 4T1-treated cells ( Figure 3A ).…”

“…Further, no change was seen in markers of radioresistance, specifically proteins involved in cell cycle checkpoint control. It is known that increased radiation dose can lead to cell cycle arrest and cell survival, making it critical to find a sensitive dose ( Chan Wah Hak et al, 2022 ; Chen et al, 2022 ; Widjaja et al, 2023 ). Alpha (α)-particle therapy works through direct double-stranded DNA breaks, thus leaving the cell with very few options for resistance and survival.…”

Relevance of Comet Assay and Phosphorylated-Hsp90α in Cancer Patients’ Peripheral Blood Leukocytes as Tools to Assess Cisplatin-based Chemotherapy Clinical Response and Disease Outcome

“…43 A diminished γH2AX response has been associated with increased radiosensitivity or chemosensitivity and poor outcome, so the identification of non-responders' patients may contribute to optimizing and personalizing cancer treatments. 44,45 Another study found no predictive utility for γH2AX and 53BP1 foci determinations regarding the radiotherapy outco-me. 33 The measurement of γH2AX and 53BP1 foci in PBL of patients receiving radioligand therapy may contribute to predicting patients with gastroenteropancreatic neuroendocrine tumors at high risk of early progression.…”