Moving Beyond Imaging in metastatic castration-resistant prostate cancer: Liquid biopsy cfNA profiling of <i>PTEN-FANCD2-POLQ</i> as molecular signatures of response to 177Lu-PSMA-617.

Abstract

e17050 Background: 177Lu-PSMA-617 radioligand therapy (RLT) has demonstrated efficacy in metastatic castration-resistant prostate cancer (mCRPC), although clinical benefit remains heterogeneous. We hypothesize that loss of PTEN leads to the functional impairment of FANCD2 -mediated high-fidelity DNA damage repair (DDR). In this deficient landscape, mCRPC cells become hyper-dependent on POLQ , which governs the error-prone Microhomology-Mediated End Joining (MMEJ) pathway. This "pathway switching" may sensitize mCRPC cells to RLT-induced DDR. We investigated whether baseline clinical factors and cell-free nucleic acid (cfNA) molecular profiles could refine patient selection and predict biochemical response. Methods: Consecutive mCRPC, PSMA-positive, patients treated with 177Lu-PSMA-617 every 6 weeks, from May to October 2025, were included. Baseline clinical data [Body Mass Index (BMI) Neutrophil-to-Lymphocyte Ratio (NLR), NRS pain scale, and time to CRPC)] were collected. Liquid biopsies were obtained after 3 cycles. Gene expression of PTEN , POLQ , and FANCD2 was quantified via ddPCR from plasma-derived cfNA. Biochemical response (BR) was defined as a ≥50% PSA decline. Results: Among 31 evaluable patients, 16 were responders (R) and 15 non-responders (NR). R showed lower baseline BMI (25.2 vs 26.8 months), NLR (2.6 vs 3.5), and NRS (5 vs 7), with a significantly longer time to CRPC (23 vs 13). Liquid biopsy showed lower median cfDNA levels in R (0.35 vs 1.57 ng/µL). Notably, a distinct DDR signature was associated with BR: R exhibited significantly lower median expression of PTEN (11.74 vs 14.83; p = 0.005) and FANCD2 (2.99 vs 13.65; p = 0.03), while POLQ expression was markedly elevated or uniquely detectable in R (range 0–27.23) compared to NR (0–0.83). This molecular signature suggests that the downregulation of PTEN and FANCD2 induces a homologous recombination deficiency state, providing a compensatory activation of the error-prone POLQ -mediated MMEJ pathway. Conclusions: A cfNA profile characterized by reduced FANCD2/PTEN and increased POLQ expression identifies a "synthetic vulnerability" signature of high genomic instability where the loss of high-fidelity repair mechanisms renders the tumor highly susceptible to RLT. These findings support futher study of PTEN-FANCD2-POLQ axis as predictive biomarker in larger cohorts, and the development of combination strategies targeting the DDR axis.