Oncology Biomarkers persistence, recurrence and therapeutic response.35 Urinary EGF
levels demonstrated a higher sensitivity (57 versus 25%) but lower specificity (66 versus 98%) than urine cytology.35,36
Acidic fibroblast
growth factor (FGF) is a regulatory peptide involved in cell proliferation, differentiation and motility. Chopin et al.37
reported a
72% sensitivity and 91% specificity of urinary levels of FGF in patients with muscle-invasive BCa. Vascular endothelial growth factor (VEGF) expression was associated with poor prognosis in BCa patients. Crew et al.38
and specificity by published studies are 72–97% and 80–100%, respectively.47,48
prediction has been also reported.49
A promising prognostic value of the test for recurrence Nevertheless, to become
clinically relevant further research and technical improvement of the assay are necessary.
Flow Cytometry and Karyometric Analysis
reported significantly elevated levels of urinary VEGF in patients with active BCa, with superior sensitivity and specificity to cytology for diagnosing primary or recurrent BCa.
Urokinase-type Plasminogen Activator and Urokinase-type Plasminogen Activator Receptor
The serine protease urokinase-type plasminogen activator (uPA) and its membrane-bound specific receptor (uPAR) play a key role in tumour cell invasion and metastasis.39
by several proteases and is detectable in plasma and urine as both intact and cleaved soluble forms. A prognostic power of plasma uPA and uPAR levels has been reported.40
Casella et al.41 uPAR is cleaved and released showed that
increased urinary levels of both markers were associated with the risk of recurrence in BCa patients; however, only uPA levels were elevated in patients with abnormal urinary cytology.
Cell-based Urinary Markers Fluorescent In Situ Hybridisation and ImmunoCyt® Test These two FDA-approved tests are indicated for use in conjunction with cytology and cytoscopy as an aid in the management of BCa. The fluorescence in situ hybridisation (FISH; Vysis® UroVysion) technique employs fluorescently labelled DNA probes to detect tumour cells by their chromosomal abnormalities. The probe is composed of fluorescent molecules attached to the pericentromeric regions of chromosomes 3, 7 and 17 and to the 9p21 gene locus. A result is considered positive for cancer when at least five polysomic cells are detected at fluorescence microscopy. The sensitivity ranges from 55 to 98% and the specificity from 56 to 100%.3,42
The ImmunoCyt® assay
detects tumour cells exfoliated in the urine of patients previously diagnosed with BCa using three fluorescent monoclonal antibodies (M344, LDQ10 and 19A21) and immunofluorescence microscopy. A high specificity of about 80% with a high sensitivity, reaching 100% in combination with cytology, has been reported.43,44
Telomerase
Telomerase is an enzyme that adds nucleotide sequence repeats (‘TTAGGG’) to the 3’ end of DNA strands in the telomere regions of chromosomes. Telomerase is not normally expressed in adult somatic cells, but it is present in cancer cells. Several preliminary studies using the Telomeric Repeat Amplification Protocol (TRAP) assay showed excellent results in BCa patients, reporting a higher sensitivity than urine cytology.45,46
in cases of bladder inflammation,46
However, false-positive results have been reported and improvements in the assay
technique are needed in order to allow widespread clinical use.29 Microsatellite Analysis
Microsatellites are polymorphic short tandem DNA repeats. Abnormalities in microsatellites such as microsatellite instability (MSI) and loss of hererozygosity (LOH) are common in tumour cells and can be detected by polymerase chain reaction (PCR). Multiple microsatellite markers are used to increase the sensitivity of the analysis. In the setting of BCa patients, the reported sensitivity
38
Flow and image cytometry detect DNA aneuploidia in exfoliated cells in urine. An aneuploid cell population or a population with a higher S-phase fraction are considered to be markers of malignancy. Flow cytometry demonstrated a sensitivity ranging from 45 to 95% and a specificity from 83 to 100%.50–52
The false-positivity rate, the
inferior sensitivity to cytology and the cost of the equipment are still barriers to the widespread use of these techniques. The Quanticyt karyometric analysis of bladder washings allows for an objective interpretation of nuclear features in light microscopic images. A satisfactory specificity (70.6–93%) has been reported; however, a rather low sensitivity (45.4–59%) and the need to examine relatively large numbers of cells represent major shortcomings of this marker.53
Table 1 summarises a selection of the most promising BCa biomarkers.29,54–84
Prostate Cancer Biomarkers Prostate-specific Antigen
Since its first identification in human tissue by Richard Ablin85 and its
approval by the FDA in 1986, prostate-specific antigen (PSA) has continued to be considered one of the best cancer biomarkers and the cornerstone of prostate cancer (PCa) screening and detection.86,87 However, numerous limitations of total PSA (tPSA) have been well recognised from its introduction into clinical practice. First, the modern supersensitive assays demonstrated that PSA is not prostate-specific and can be detected in other body tissues and fluids. Second, it is well known that PSA is not cancer-specific: its serum concentration also correlates with the growth in prostate volume due to benign prostatic hyperplasia, with patients in the grey zone of 4–10ng/ml having a 25% chance of harbouring a PCa.88
Furthermore, prostatitis and lower
urinary tract infections are common causes of serum PSA increase. Third, a cancer risk of 17% or more still exists under the cut-off level of 4ng/ml originally fixed by Catalona et al., seriously limiting the sensitivity of the marker.89–91
Finally, the benefits of PSA-based
screening are still ambiguous and the first results from two large-scale trials are conflicting.92–94
All of the aforementioned shortcomings
prompted the research of other PCa markers in order to improve tPSA operating characteristics. Below, we discuss the established PCa biomarkers and a selection of the most promising exploratory biomarkers, excluding those that are summarised in Table 2.
Prostate-specific Antigen Derivatives and Isoforms In an effort to increase the specificity of tPSA, several PSA derivatives have been proposed such as PSA velocity (the rate of PSA change over time), PSA doubling time (the time required for PSA to double), PSA density (ratio of PSA level to prostate volume) and age-specific PSA values (different upper limits of normality for different age ranges). These PSA derivatives have many limitations in clinical practice and have not been universally accepted. In the last few years, the percentage of free PSA not linked to plasma proteins (%fPSA) has proved to improve specificity of tPSA and to help selecting patients eligible for needle biopsy.95
Reportedly, %fPSA
would avoid 20% of unnecessary biopsies in the tPSA grey zone and would be a strong predictor of later diagnosis of PCa in men with PSA
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