361 - Predictive Role of Tumor Fraction and Copy Number Alteration Burden in mCRPC Patients Receiving Tandem Actinium-Lutetium Radionuclide Therapy
Presenter(s)
M. Amghar1, T. Rausch2, T. Hielscher1, H. Ozgur2, U. Bauder-Wüst1, H. Rathke3,4, M. Roscher1, F. Bruchertseifer5, A. Morgenstern5, V. Benes2, C. Kratochwil6, and M. Benešová-Schäfer1; 1DKFZ, Heidelberg, Germany, 2EMBL, Heidelberg, Germany, 3Cantonal Hospital Grisons, Chur, Switzerland, Chur, Switzerland, 4Department of Nuclear Medicine, University Hospital, Heidelberg, Germany, 5Institute for Transuranium Elements, Karlsruhe, Germany, 6Department of Nuclear Medicine, University Hospital Heidelberg, Heidelberg, Germany
Purpose/Objective(s): First clinical experiences employing PSMA (prostate-specific membrane antigen) with the alpha particle-emitting radionuclide actinium-225 (225Ac) exhibited astonishing responses in metastasized castration-resistant prostate cancer (mCRPC) patients. To address the toxicities associated with its stand-alone administration, a tandem approach combining [225Ac]Ac-PSMA-617 and [177Lu]Lu-PSMA-617 (actinium-lutetium) has been developed as an optimized strategy, balancing treatment efficacy while reducing adverse effects. This study explores circulating tumor DNA (ctDNA) analysis, specifically tumor fraction (TFx) estimation via ichorCNA, as a biomarker to track treatment response and resistance in mCRPC patients receiving tandem actinium-lutetium therapy. By integrating clinical data with whole genome sequencing, we aim to decode resistance mechanisms and relapse patterns hidden in ctDNA, paving the way for personalized treatment strategies.
Materials/Methods: Within the framework of ethical approval (S-882/2020), this study involved collecting blood samples from mCRPC patients scheduled bimonthly [225Ac]Ac-PSMA-617/[177Lu]Lu-PSMA-617 cycles. Circulating free DNA (cfDNA) was extracted and prepared for ultra-low-pass whole genome sequencing (ULP-WGS), with a depth of 5x. The study employed ichorCNA algorithm via R (version 3.3.1) for analyzing the sequencing data, which estimates genome-wide copy number alterations (CNA) and TFx from the sparse sequencing data.
Results: This study examined a cohort of 78 patients with mCRPC undergoing actinium-lutetium treatment, with a median age of 75.5 years (range: 55–91 years). Pairwise analysis of TFx and PSA across treatment cycles revealed a strong correlation, with both markers showing significant changes during treatment. However, TFx, unlike prostate-specific antigen (PSA), effectively distinguished between metastatic stages (p = 0.027), highlighting its potential as a more precise biomarker for disease burden. A Cox hazards model indicated that higher pre-treatment TFx levels were associated with a 5-fold increased risk of relapse in the subsequent treatment cycle (p = 0.0259). Hierarchical clustering of logR values for CNA across the whole genome identified two distinct patient clusters: Cluster 1, with lower TFx values and a low CNV burden, and Cluster 2, with higher TFx values and an increased CNV burden (p = 8.09e-08). Survival analysis showed that patients with a lower CNV burden had a longer median survival (13.8 vs. 8.3 months, log-rank p = 0.112) suggesting CNV burden as a potential prognostic factor in mCRPC.
Conclusion: This study highlights the potential of ctDNA analysis, specifically TFx estimation, as a valuable biomarker for tracking treatment response and disease progression in mCRPC patients receiving tandem actinium-lutetium therapy.