Early detection of prostate cancer (PC) is achieved by testing the prostate-specific antigen (PSA) level in blood, yet PSA cannot discriminate benign prostatic hyperplasia (BPH) from PC. Metabolomics is a valuable tool to discover new markers, however, only few studies have evaluated the role of metabolomics in distinguishing benign from PC cases, and none have analyzed modifications of metabolomic profiles on different bio-specimens after surgical treatment in PC patients.
Aim of this study is to prospectively identify a set of polar metabolites that could contribute to a better understanding of the processes involved in the onset and progression of PC.
Primary outcomes:
- Untargeted analysis: to identify a set of polar metabolites that are differentially expressed by BPH and PC cases.
- Targeted analysis: to analyzed changes over the time in sarcosine and carnitine expression in patients with PC submitted to radical prostatectomy (RP).
In this prospective research study, 80 patients will be enrolled.
For untargeted analysis, patients will be distinguished into two groups: BPH (group 1) and PC (group 2). In patients diagnosed with PC (group 2), who will undergo RP as primary treatment, targeted analysis will be also performed. For untargeted analysis, urine samples will be collected; for targeted analysis, urine and serum samples will be collected at baseline (the day before surgery) and at 1-month interval; moreover, prostatic tissue from RP specimens will be analyzed.
Expected results:
- Untargeted analysis: we can expect to find metabolites differently expressed in urine of BPH versus PC cases.
- Targeted analysis: in patients with PC, we can expect to find changes in concentration of metabolites of interest (i.e., sarcosine and carnitine) in both urine and blood samples, and PC tissue. If this data would be confirmed, the role of these metabolites in the onset and progression of PC will be further supported.
Early detection of PC is achieved by testing the PSA level in blood, yet it cannot reliably discriminate BPH or other benign prostatic pathologies from clinically significant forms of PC due to its limited sensitivity and specificity. Metabolomics - by untargeted and targeted approaches - represents a valuable tool to discover markers suitable for tumor early detection, prognostic stratification, and therapy response monitoring. This study would be the first to analyze modifications of metabolomic profiles on different biospecimens (i.e., urine, blood and tissue samples) after surgical treatment (i.e., RP) in PC patients.
Expected results and clinical practice implications:
Untargeted metabolomic analysis:
- we can expect to find metabolites differently expressed in urine of BPH versus PC patients. If this data would be confirmed, metabolites detected in urine could be used as markers able to discriminate between BPH versus PC patients. Indeed, in men with clinical suspicious of PC, specific metabolites could be used as biomarker for the early detection of PC.
- we can expect to find metabolites differently expressed in urine of indolent (i.e., GS 6(3+3)) versus clinically significant (i.e., GS >=7(3+4)) PC patients, reflecting the clinical heterogeneity of PC which is usually observed in clinical practice. If this data would be confirmed, metabolomics of urine could be used as a tool able to guide further diagnostics (e.g., prostate biopsy and the need of further imaging for staging purpose) and treatments (surgery versus radiotherapy versus active surveillance).
- on the other hand, we can expect similar metabolomics profiles expressed by BPH and PC patients with an indolent disease (i.e., GS 6(3+3)) versus men diagnosed with a clinically significant (i.e., GS >=7(3+4)) PC, reflecting the clinical heterogeneity of PC which is usually observed in clinical practice. Indeed, PC is a highly heterogeneous neoplasm with some men presenting an indolent disease and others whose disease is rapidly progressive. A low GS (i.e., GS 6(3+3)) can be associated with a PC low aggressiveness; on the contrary, clinically significant PC cases, and in particular those with a higher GS (i.e., GS >=7(4+3)), show rapid growth and progression, probably sustained by a different metabolic profile. Given this evidence, it could be possible that metabolomics profiles of indolent PC cases could be closer to that of BPH cases. If this data would be confirmed, metabolites detected in urine of PC patients could be used as markers able to guide further diagnostics (e.g., imaging for staging purpose) and treatment modalities (surgery versus radiotherapy versus active surveillance).
Targeted metabolomic analysis:
- in patients with PC, we can expect to find changes in concentration (i.e., elevated levels) of metabolites of interest (i.e., sarcosine and carnitine) in both urine and blood samples. If this data would be confirmed, the role of these metabolites in the onset and progression of PC will be further supported. On the other hand, changes in concentration of metabolites of interest could be detected in either urine or blood, highlighting the best bio-fluid source that could be used for clinical purpose.
- in patients with PC, we can expect to find different concentration of metabolites of interest detected in tumor versus benign prostatic tissues from RP specimens. If this data would be confirmed, the role of these metabolites in the onset and progression of PC will be further supported.
- in patients with PC, we can expect to find a concordance of changes in concentration of metabolites of interest between bio-fluids (i.e., urine and blood samples) and PC tissue. If this data would be confirmed, urine and blood samples could be used to predict the final pathologic aggressiveness (GS) at RP.
- In patients with PC who will undergo surgery, we can expect a decline in metabolites concentrations post-operatively (i.e., 1 month of follow-up); if these data would be confirmed, the role of these metabolites in the onset and progression of PC will be further supported. This finding may be useful to evaluate local treatment effectiveness. For instance, a post-operative elevated value could be associated with a residual cancer, either micrometastases or residual disease in the prostatic fossa. This finding may be useful to establish follow-up intervals and guide modalities and timing of further treatments.
- In patients with PC, we can expect elevated levels of metabolites of interest related to clinical stage. For instance, subjects with apparently early clinical stage PC, but with elevated serum and/or urine metabolites level at baseline, could hide a higher pathological stage at RP, as well as a higher likelihood of progression during the follow-up. This finding may be useful to establish follow-up intervals and guide modalities and timing of further treatments.