Blood DNA biomarkers track progression during prostate cancer radioligand therapy

Circulating tumor DNA measurements were associated with progression and survival in a prospective observational study of 78 patients with metastatic castration-resistant prostate cancer receiving tandem actinium-225 and lutetium-177 PSMA-617 therapy. Researchers analyzed 172 longitudinal plasma samples using ultra-low-pass whole-genome sequencing, estimating tumor DNA fraction and identifying genome-wide copy-number alterations linked with treatment outcomes and resistance biology.

Baseline tumor DNA fraction, termed TFx, differed across metastatic disease stages, with a reported p-value of 0.027. During early treatment, dynamic changes in TFx moved in parallel with changes in prostate-specific antigen, indicating that the blood-based measure tracked biological changes during therapy. Because the study was observational, this relationship does not show that TFx caused the observed changes or that using it to guide treatment would improve outcomes.

In Cox proportional hazards models that treated TFx as a time-dependent variable, changes in TFx were associated with a significantly increased risk of progression. The estimated hazard ratio was 4.9, with a wide 95% confidence interval of 1.2 to 20.1 and a p-value of 0.026. The interval indicates considerable statistical uncertainty around the size of the association. The investigators also used unsupervised clustering to divide patients into groups with high and low copy-number alteration burden. These groups were strongly correlated with TFx, with a p-value of 8.09 × 10⁻8, showing that the amount of circulating tumor DNA and the genome-wide pattern of copy-number changes carried related information in this cohort.

Patients in the high copy-number burden group had a median overall survival of 8.3 months, compared with 13.8 months in the low-burden group. Multivariable analysis identified baseline log-transformed prostate-specific antigen and log-transformed alkaline phosphatase as independent predictors of overall survival. These results are associations in a single cohort of 78 patients rather than evidence that copy-number burden caused the survival difference. The modest cohort size and broad confidence interval for the progression estimate also limit how precisely the findings can be applied to individual patients.

Recurrent copy-number alterations affected genes including PTEN, RB1, BRCA2 and ATM. The altered genes and pathways were connected with TP53 signaling, homologous recombination repair and oncogenic signaling. Longitudinal analyses also found that specific amplifications persisted and expanded at progression, providing a genomic view of changes associated with the course of disease. The study supports TFx and copy-number profiling as candidate tools for dynamic monitoring and clinical stratification in metastatic castration-resistant prostate cancer treated with PSMA-targeted radioligand therapy, while further evidence is needed to determine their clinical utility.

Subject of Research: Circulating tumor DNA and copy-number alterations as prognostic biomarkers during PSMA-targeted radioligand therapy for metastatic castration-resistant prostate cancer

Article Title: Prognostic value of circulating tumor DNA and copy-number alterations in patients receiving tandem [225Ac]Ac-/[177Lu]Lu-PSMA-617 therapy for metastatic castration-resistant prostate cancer: a prospective observational study

Article References: Amghar, M., Hielscher, T., Rausch, T., Özgür, H., Bauder-Wüst, U., Rathke, H., Bruchertseifer, F., Morgenstern, A., Roscher, M., Beneš, V., Kratochwil, C., & Benešová-Schäfer, M. (2026). Prognostic value of circulating tumor DNA and copy-number alterations in patients receiving tandem [225Ac]Ac-/[177Lu]Lu-PSMA-617 therapy for metastatic castration-resistant prostate cancer: a prospective observational study. BMC Cancer, 26(1), Article 1038. https://doi.org/10.1186/s12885-026-16791-9

Image Credits: AI Generated

DOI: 10.1186/s12885-026-16791-9

Keywords: circulating tumor DNA, prostate cancer, PSMA radioligand therapy, copy-number alterations, tumor fraction, treatment monitoring, progression risk, overall survival, liquid biopsy, genomic resistance, Prognostic, value