Pro-Neuropeptide Y Emerges as a Circulating Biomarker for Poor Prognosis in Prostate Cancer
Key Insights
Plasma pro-NPY levels measured via a validated sandwich immunoassay were significantly higher in prostate cancer (search) patients with poor outcomes across two independent cohorts.
Patients in the 90th percentile of pro-NPY levels experienced disproportionately high rates of metastasis and prostate cancer (search)-specific mortality, while those in the 10th percentile rarely had adverse events.
Pro-NPY provided independent prognostic information beyond PSA, and combining both markers improved metastasis prediction (AUC 0.85 vs. 0.80 for PSA alone).
A new study published in Nature identifies pro-neuropeptide Y (search) (pro-NPY) as a circulating biomarker capable of predicting poor clinical outcomes in prostate cancer (search) (PCa), offering prognostic value that extends beyond current standard markers such as prostate-specific antigen (search) (PSA).
Researchers quantified plasma pro-NPY levels using a custom-developed sandwich immunoassay (SIA) in two independent patient cohorts. The assay, developed in collaboration with the Affinity Proteomics Unit at Science for Life Laboratory (search) in Stockholm, used an anti–pro-NPY capture antibody (HPA045572) and an anti-NPY detection antibody, demonstrating a dynamic range of 1 pg/ml to 100 ng/ml with a coefficient of variation below 10%.
Pro-NPY Levels and Clinical Outcomes
In cohort 1, comprising 796 men investigated for suspected PCa, patients diagnosed with PCa at blood sampling had significantly higher pro-NPY levels than those who remained disease-free (median 0.0970 vs. 0.0872 ng/ml, p = 0.007). Among those diagnosed at sampling, high pro-NPY levels in the fourth quartile (Q4) were associated with significantly shorter metastasis-free survival (Q4 vs. Q1-3, p = 0.027, M1 cases excluded) and shorter PCa-specific survival (p = 0.009).
Notably, patients in the 90th percentile (≥ 0.199 ng/ml) experienced the poorest outcomes, while no metastases or PCa deaths were observed among patients in the 10th percentile (< 0.0142 ng/ml). Sensitivity analyses excluding samples below the lower limit of quantification confirmed these findings.
Independent Prognostic Value Beyond PSA
In multivariate Cox regression models, higher pro-NPY levels were independently associated with increased risk of metastasis (HR 2.7, CI 1.1–6.4, p < 0.05) and PCa-specific death (HR 3.3, CI 1.4–7.4, p < 0.01), after adjusting for PSA levels, patient age, and sample storage time.
ROC analyses demonstrated that pro-NPY and PSA individually predicted metastasis within 10 years (AUC 0.66 and 0.80, respectively; p < 0.001), while the combined model significantly improved performance (AUC 0.85, p < 0.001), outperforming PSA alone (p = 0.011). In men with PSA levels below 10 µg/l, pro-NPY predicted metastasis (AUC 0.69, p = 0.026), whereas PSA alone did not.
Validation in an Independent Cohort
Cohort 2 validated these findings in 92 patients with samples collected at diagnosis and approximately three months after primary treatment initiation. At baseline, patients with M1 disease had significantly higher pro-NPY levels than non-metastatic cases (median 0.346 vs. 0.186 ng/ml, p = 0.016). High pro-NPY (Q4) was again associated with shorter metastasis-free survival (p = 0.017), PCa-specific survival (p < 0.001), and overall survival (p = 0.013).
Normalization by Androgen-Deprivation Therapy
A key mechanistic insight emerged from the observation that elevated pre-treatment pro-NPY levels normalized approximately three months after initiation of androgen-deprivation therapy (ADT). Patients receiving neoadjuvant ADT plus radiotherapy or continuous ADT showed elevated pre-treatment levels that decreased after therapy, whereas levels in men treated with radical prostatectomy remained unchanged. This suggests that tumor NPY expression is regulated by androgens, potentially through AR-regulated NPY expression or AR-stimulated TMPRSS2-ERG fusion gene expression driving NPY production.
Clinical Implications and Limitations
The authors note that patients with very high pro-NPY levels might have benefited from high-risk classification and intensified therapy, while low levels could support conservative management. However, the study has limitations, including the absence of matched tumor samples to correlate tumor NPY expression with plasma levels, and uncertainty about whether elevated plasma pro-NPY reflects increased levels of biologically active NPY. Additionally, sampling was performed before PSMA-PET was implemented as a staging tool, introducing possible biases in baseline characteristics.
The researchers emphasize that factors such as sympathetic activation, feeding status, obesity, psychiatric disorders, and cardiovascular disease may influence plasma NPY variability, underscoring the need for strictly standardized sampling protocols when interpreting pro-NPY levels in clinical practice.