Prostate Cancer (PCa) is the most commonly diagnosed cancer and the second leading cause of cancer related deaths in men. Although measurement of prostate-specific antigen (PSA) has been a cornerstone in follow-up of PCa patients, clinical progression has been reported without a rising PSA in both early-stage and metastatic cases. To date, there are few serological biomarkers that indicate the rate of cellular proliferation which could provide valuable information for monitoring patients and making prognosis. Thymidine kinase 1 (TK1) is a key enzyme in DNA precursor synthesis. The development of immunoassays for TK1 based on antibodies directed against the TK1 "210" epitope enables all serum TK1 forms to be assayed. Aim of the study is to prospectively analyze serum TK1 levels in a cohort of early-stage PCa patients undergoing radical prostatectomy (RP) and, in a second cohort of advanced metastatic PCa, to investigate its possible role as a response biomarker after treatment with androgen deprivation therapy (ADT).
In this prospective study, 150 patients diagnosed with PCa will be enrolled. Based on PCa stage and treatment received, our population will enclose 2 settings of PCa patients: "RP group" and "ADT group". TK1 and total PSA samples will be collected at different follow-up intervals. All patients will be followed in order to detect disease progression.
The development of TK1 immunoassays has made the assay of TK1 more widely available and increased its applicability to solid tumor diseases, as PCa. To date, very few studies have evaluated the utility of serum TK1 in monitoring responses to cancer therapies, and none have analyzed the level of TK1 and its modifications after treatments in patients with early-stage and metastatic PCa.
This study would be the first to analyze serum TK1 levels in a cohort of both early-stage and metastatic PCa patients, aiming to evaluate its potential role in monitoring patients after and during treatments in order to provide information regarding the effects of therapy (prognostic biomarker). Although measurement of total PSA has been a cornerstone in follow-up of PCa patients, progression after treatments is possible without a concomitant rise in PSA level, in both early-stage and advanced cases. To date, there are few serological biomarkers that indicate the rate of cellular proliferation which could provide especially valuable information for monitoring patients and assessing prognosis. TK1 has been shown as a clinically valuable biomarker for the management of hematological malignancies, due to its close association with DNA synthesis and cell proliferation. However, TK1 activity assays may underestimate serum TK1 in subjects with solid tumors limiting its sensitivity. The development of TK1 immunoassays has made the assay of TK1 more widely available and increased its applicability to solid tumor diseases, as PCa. To date, very few studies have evaluated the utility of serum TK1 in monitoring responses to cancer therapies, and none have analyzed the level of TK1 and its modifications after treatments in patients with early-stage and metastatic PCa.
Expected results and clinical practice implications:
- In patients with PCa, we can expect serum TK1 levels related to clinical stage. For instance, subjects with apparently early clinical stage PCa, but with a relatively elevated serum TK1 level at baseline, could hide a higher pathological stage at RP.
- In patients with early-stage PCa with a high serum TK1 level at baseline, we can expect 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.
- In patients with advanced metastatic PCa who will undergo ADT therapy, a high serum TK1 level at baseline, may be associated with a higher likelihood of progression and/or resistance to drugs during the follow-up. This finding may be useful to establish follow-up intervals and guide treatments modalities (i.e. ADT alone versus ADT plus CHT or ADT plus ABI/ENZA).
- In patients with early-stage PCa who will undergo surgery, we can expect a decline in TK1 serum concentrations to near normal concentrations post-operatively; if these data would be confirmed, TK1 serum levels could be used to evaluate local treatment effectiveness. For instance, a post-operative relatively elevated serum TK1 value could be associated with a residual cancer, either micrometastases or residual disease in the prostatic fossa (i.e. positive surgical margins). This finding may be useful to establish follow-up intervals and guide modalities and timing of further treatments (i.e. adjuvant versus salvage RT).
- In patients with PCa, we can expect that timing and magnitude of increase in serum TK1 levels after and during treatments may be related to PCa aggressiveness (i.e. clinical and pathological stage).
- We can expect modifications in serum TK1 levels positively correlate to total PSA changes over time.
- Elevated serum TK1 levels after RP and during ADT may be associated with poorer therapeutic prognosis and clinical outcomes.