Background. In oligometastatic prostate cancer (oligo-mPC), metastasis-directed therapy (such as stereotactic body radiotherapy, SBRT) can improve local control and progression free survival. However, a part of oligo-mPC patients present an early biochemical progression (BP) which may develop to a polymetastatic scenario. At present, early clinical predictors of BP after SBRT in oligo-mPC are mostly unknown, and plasma proteomics investigations of oligo-mPC undergoing SBRT are still to be performed.

Aims and study design. The main objectives were to identify a plasma proteomics signature associated to early-BP or distant progression (OLIGO or POLI) in oligo-mPC before SBRT at T0. The identification and relative quantitation of differential plasma proteins in early-BP versus no-BP, dist-prog-OLIGO or dist-prog-POLI versus no-dist-prog were investigated by mass spectrometry-based untargeted Data-dependent (DDA) and Data-independent (DIA) proteomics.

Patients and plasma. Oligo-mPC patients (patients with ≤3 bone or lymph node metastases) undergoing SBRT were enrolled at CRO Institute. Oligo-mPC patients were classified on the basis of biochemical progression free survival (BPFS) after SBRT into "early-BP" (n=7, BPFS

Results. LC-MS/MS identified a total of around 300 and 500 distinct proteins by DDA and DIA approaches, respectively. Plasma protein profiles of early-BP and no-BP differed for some differentially abundant proteins (FDR < 0.01, Score Sequest ≥ 1, |fold change|≥ 2, Padjusted < 0.01 and abundance grouped CV% <30). In particular, early-BP showed a lower abundance of extracellular superoxide dismutase [Cu-Zn] (SOD3), carbonic anhydrase (CA1) and nucleophosmin (NPM1) proteins and an higher abundance of serine/threonine-protein kinase Chk1 (CHEK1). Moreover, dist-prog-OLIGO versus no-dist-prog showed an increase in HLA class I histocompatibility antigen, C alpha chain (HLA-C) and a decrease in complement factor H-related protein 5 (CFHR5), while both dist-prog-OLIGO and POLI versus no-dist-prog were characterized by an increase in cadherin-1 (CDH1) and integrin alpha-6 (ITGA6).

Conclusions and perspectives. This study identified some candidate protein markers associated to early-BP or distant progression in oligo-mPC undergoing SBRT. Their differential abundance will be validated by Western Blotting in the same cohort of patients and by further MS analysis in a verification cohort consisting of newly enrolled patients. By means of the expected results, CRO Aviano may benefit for patient stratification and early identification of oligo-mPC patients early ongoing to BP, who thus represent potential candidate for a more aggressive therapeutic approach.