Definitive diagnosis of PCa is traditionally based on histopathological analysis. Nevertheless, due to the multifocal nature of most PCas 
, as the tumor progresses, the static result from a biopsy sample will become even more inadequate to reflect dynamics of tumor evolution and its underlying biological modifications under the selective pressure of cancer therapies. These difficulties can be ascribed to the intrinsic difficulties in obtaining biopsy samples from metastases and to the inability to perform selective genetic tests on biopsy-derived tissue. Furthermore, complications may also arise from the invasive nature of biopsy procedures, which make not all cancer patients eligible for surgery due to their intrinsic fragility.
Nowadays, even with new imaging technologies allowing an increasingly early detection, the diagnosis of oligometastasis is currently based exclusively on traditional radiological investigations. Nevertheless, objective categorization of true oligometastatic patients from the ones with a trend to progress to poly-metastatic patients relies on the profile of the biological behavior of the tumor; for this purpose, a minimally invasive real-time monitoring method could be beneficial for both patients and clinicians. This could avoid expensive treatments with limited clinical benefit and potential associated toxicity or, alternatively, provide a group of oligometastatic patients with curative treatment.
Liquid biopsy has recently emerged as a promising minimally invasive approach allowing to overcome the static bioptic approach and to reflect the dynamic tumor modifications over time, specifically those involving its genomic evolution 
. Through liquid biopsy, different biomarkers, commonly extracted from blood, urine or saliva, can be characterized, including circulating tumor cells (CTCs), circulating cell-free DNA (cfDNA) such as circulating tumor DNA (ctDNA), miRNA and exosomes 
2.2. Circulating Tumor Cells (CTCs)
CTCs are cancer cells originating from macroscopic tumor sites (either primary or metastases) and released into the bloodstream. Here, CTCs could be found as single CTCs or CTC clusters, with the latter being more often associated with a higher metastatic potential 
Since CTCs may reflect the current tumor status, there is a growing interest in identifying genomic alterations in CTCs that could aid the decision workflow in targeted therapies.
A recent study by Gkontela et al. 
provided insights about how CTC clusters intrinsic differences have a direct impact on the DNA methylation status and thus influence important regulatory regions related to cancer proliferation, suggesting that agents disrupting these clusters could suppress spontaneous metastatic formations.
A 2020 study by Faugeroux et al. 
emphasized the potential of CTCs in representing metastases mutational content and tumor diversity that would be otherwise inaccessible. Therefore, by offering real-time monitoring of a constantly evolving disease and detecting potentially critical SNPs via liquid biopsy, CTC sequencing can serve an unmet need for optimal therapy selection and precision medicine.
2.3. Circulating Cell-Free DNA (cfDNA)
cfDNA, or ctDNA, shed from apoptotic and necrotic cells, comprises both genomic and mitochondrial DNA and can be used as a biomarker to characterize the mutational and epigenomic status in advanced solid tumors 
. The ctDNA concentration in plasma was correlated with both tumor size and clinical stage of the malignancy 
. Additionally, the half-life of these molecules is relatively short (1–2 h), which provides real-time insight into the tumor status. Clinical studies showed that healthy individuals present lower cfDNA levels, indicating a relatively simple analysis involving the mere cfDNA quantification as a valuable biomarker 
. The exact measure of cfDNA can be challenging due to the high fragmentation degree and the overall low concentration. The main source of cfDNA is also controversial. In fact, while the serum presents a higher concentration of cfDNA molecules, serum-derived samples are often contaminated by a clotting process, and therefore plasma is actually considered a more valuable cfDNA source despite the lower overall concentration 
As the total cfDNA increases with the tumor growth, it was hypothesized that cfDNA derives directly from living tumor cells and that CTCs could be an alternative cfDNA source 
It was speculated that a better understanding of the determinants of oligometastases could come from molecular studies on the signaling between the primary tumor and its metastatic sites. Exosomes are nanoscale extracellular vesicles that have a role in the exchange of genetic material, implicated in tumor cell growth and invasion, favoring disease dissemination by creating a pro-tumor micro-environment and the creation of premetastatic niches 
By analyzing the exosome proteins derived from PCa cells, the researchers found a high level of molecules stimulating tumor cell migration and metastases, such as the b4 and avb6 integrins, vinculin and the Trop-2 transmembrane glycoprotein 
. In addition, cancer-derived exosomes can promote EMT through miRNAs, which play an important role in the conversion from benign to malignant cancers and in the regulation of the response to docetaxel, such as miR-34 in prostate cancer cells and cell-derived exosomes targeting Bcl-2 
On the basis of these findings, the role of exosomes in the early phases of tumor metastatization seems to make them interesting and worth to be explored biomarkers for future diagnostic approaches in the oligometastatic setting.