Liquid Biopsies May Help Track Resistance to Actinium-225 and Lutetium-177 PSMA Therapy

A prospective study published in BMC Cancer suggests that circulating tumor DNA (ctDNA) could help monitor disease progression and identify signs of resistance during PSMA-targeted radioligand therapy in patients with metastatic castration-resistant prostate cancer (mCRPC).

The study included 78 patients treated with a combination of actinium-225 and lutetium-177 PSMA-617, two radioactive treatments that deliver radiation directly to PSMA-expressing cancer cells. Researchers analyzed 172 blood samples collected during treatment, looking for fragments of DNA released by tumor cells into the bloodstream.

One of the most interesting findings was that changes in circulating tumor DNA closely followed changes in PSA. Patients with higher levels of tumor-derived DNA during treatment faced a substantially greater risk of disease progression, with a reported hazard ratio of 4.9. This suggests that liquid biopsies could provide an additional way to monitor how cancer responds to radioligand treatment.

The researchers also examined copy-number alterations, genetic changes in which sections of DNA are gained or lost. These included changes affecting genes such as PTEN, RB1, BRCA2, and ATM, which are involved in cancer growth, tumor suppression, or DNA repair.

Patients with a greater burden of these genetic alterations had a shorter median overall survival: 8.3 months compared with 13.8 months in patients with fewer alterations. However, the difference was not statistically significant, and the number of alterations did not independently predict survival when other factors were considered.

The study also found that some genetic alterations persisted or became more prominent as the disease progressed. Following these changes over time could help researchers understand how resistant cancer cell populations emerge during treatment.

The greatest potential benefit may lie in combining liquid biopsies with PSA measurements and PSMA PET imaging, providing a more complete picture of treatment response and disease evolution.

The study’s main limitation is its relatively small patient population and the absence of a comparison group. It also remains unclear whether changing treatment based on ctDNA findings would improve outcomes. Still, the results support further investigation of liquid biopsies as tools for monitoring advanced prostate cancer during radioligand therapy.

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