OncoPROSTATE Dx (OncoPROSTATE) is an innovative, non-invasive, accurate, and cost-effective already validated test to help in Prostate Cancer diagnosis as well as confirmatory diagnostic ―as an adjunct to suspicious image procedures findings, in order to reduce the number of unnecessary tissue biopsies that patients have to undergo―, with potentially uses for screening, prognosis and recurrence monitoring.
OncoPROSTATE is based on a score calculation that it is obtained from several Biomarkers of the patient (mainly Tumor Markers but also patient’s clinical information).
Tumor Markers are parameters released by tumor cells, which enter the bloodstream or other biological fluids and are useful for the diagnosis, prognosis and treatment monitoring.
Most Tumor Markers are not specific to any type of cancer and the differences between benign and malignant diseases are quantitative (for example, patients with epithelial tumors tend to have significantly higher levels of these Tumor Markers than patients without malignancy).
There are now more than 20 well known parameters that are widely regarded as Tumor Markers such as PSA ―related to Prostate Cancer―, CA 15.3 ―related to Breast Cancer―, CA 125 and HE4 ―both related to Ovarian Cancer―, CEA and CA 19.9 ―both related to different gastrointestinal cancers (Colorectal, Gastric and Pancreatic Cancer)―, or NSE and ProGRP ―both related to in Lung Cancer―.
However, there are a variety of factors that can affect the accuracy of Tumor Markers by increasing its levels without malignancy presence. The main reason are benign diseases, among others, such as technical interferences.
In this sense, the Spanish Society of Clinical Biochemistry and Molecular Pathology, Cancer Biomarker Commission established the Barcelona Criteria, 4 criteria that help to correctly distinguish and value Tumor Markers results and reduce False Positives (FP):
- Tumor Markers Serum concentrations.
- Discard benign pathology by the exclusion of main source False Positive results.
- Follow-up if Tumor Markers moderate results (Grey Zone/Undetermined).
- Technical interference.
Statistical measurements in diagnostic tests
Unfortunately, the use of Tumor Markers in routine presents also other problems such as low Sensitivity in early stages, or nonexistence of any specific Tumor Marker for each malignant tumor. However, the combination of 2 or more Tumor Markers has a better outcome, especially in advanced stages.
In this regard, the combination of several Tumor Markers ―as well as the inclusion of patient history information in the equations―, using complex algorithms with multiple variables, results in higher Sensitivity and Specificity: that is what we have christened Multi-Biomarker Disease Activity Algorithm (MBDAA).
The Sensitivity of a diagnostic test is the percentage of actual positives that are correctly identified, and Specificity is the proportion of true negatives that are correctly classified. Both variables are closely linked together and give an idea of the accuracy of a test.
A test that correctly identifies all true positive as positive, but has many false negatives would have a Sensitivity of 100%, but low Specificity. For example, Sensitivity measures the number of cancerous tumors that are correctly identified as cancerous, whereas Specificity measures how many benign tumors are correctly identified as benign. A high Sensitivity means fewer cancers diagnosed as benign and high Specificity means fewer benign tumors diagnosed as cancerous.
Besides, the positive predictive value (PPV) is the number of true positives correctly identified on total real positive. A test with many false positives will have a low VPP. Moreover, the negative predictive value (NPV) is the number of true negatives correctly identified on the total actual negative. A high NPV value means that very few true positives were incorrectly identified as negative.
All these different values can be plotted together in a graphic that it is known as Receiving Operator Curve (ROC), where better results are displayed with curves that tends to come near to the upper left corner of the image (where 100% Sensitivity and 100% Specificity are reached).
Receiving Operator Curves (ROC)
The ROC curve of OncoPROSTATE test ―based on the combined count of Total PSA, Free PSA (fPSA), p2PSA and hK2 Tumor Markers; over expression of Post-DRE PCA3 and T2:ERG genes; comorbidities; and other patient’s data from 3.725 patients―, throws a really interesting diagnostic capabilities: 81.7% Sensitivity and 98.2% Specificity.
How does it work
As all Bioprognos’ MBDAA tests, OncoPROSTATE test is available online once access is granted through our secure Cloud Platform. As a Cloud solution, it is designed to be used in a Software as a Service (SaaS) basis, that means, no installation, no periodically patch upgrades, low TCO (Total Cost of Ownership) and no maintenance.
In this way, doctors or lab technicians only should fill the form with values obtained previously from patients (Personal data, Comorbidities and Serum and Urine Tumor Marker values), and click on Submit button in order to obtain the risk score of having Prostate Cancer.
To facilitate work, doctors can download and fill the Order Form for OncoPROSTATE in a quick and an easy way ―with all required data for a best risk calculation already detailed―.
After doctors entered the patient’s data, OncoPROSTATE test presents the results in a separate screen that can be converted to a PDF document in order to be downloaded or sent by email.
The report includes two main sections: Patient Information and Outcome. In the first one, all patient data entered previously is showed as record. The second one includes: Results, indicating whether Tumor Marker levels are within normal range or not; Risk, with a score bar showing the probability of having Prostate Cancer; Comments, that are created dynamically to help doctors and healthcare professionals to understand ―in an easy way―, how to detect False Positives (FP), such as levels of Tumor Markers that would suspect the presence of Cancer, but when considering other variables together ―Race, Age and Comorbidities information―, do not correspond with malignant diseases; and finally, Conclusions, with recommendations suggesting to retest patient in 1 year (for Low Risk), or in 4 weeks (for Moderate Risk, that is, these cases in which Tumor Marker levels are higher than normality but there is not quite clear to be High Risk.
Please note that final report is oriented to healthcare professionals only ―not to patients―, because it was designed as “a tool to help healthcare professionals in Prostate Cancer diagnostic”, and in this way it is been certified by obtaining the CE DECLARATION OF CONFORMITY (Medical Device Directive 93/42/EEC, Class I, rule 12).
CE Declaration of Conformity
Since April 20th, 2017 (when version 1.0 was released), OncoPROSTATE test has the CE Declaration of Conformity that certifies it has been assessed to meet high safety, health, and environmental protection requirements.
This declaration also certifies that OncoPROSTATE test can be sold throughout the European Economic Area (EEA) without restrictions.
Besides, there are two main benefits CE marking brings to businesses and consumers within the EEA:
- Businesses know that products bearing the CE marking can be traded in the EEA.
- Consumers enjoy the same level of health, safety, and environmental protection throughout the entire EEA.
Uses and purposes for OncoPROSTATE test
OncoPROSTATE test has been developed for:
- Aid in diagnostic assessments for high-risk patients (men older than 50 years with PSA blood levels higher than 4 ng/mL).
- Confirm or discard malignancy from results obtained previously with other tests, such as Computed Tomography (CT) Scan or Magnetic Resonance Imaging (MRI) findings thanks higher Sensitivity and Specificity than imaging procedures.
- Help doctors predict the cancer’s behaviour and response to treatment, as well as a person’s chance of recovery.
- Guide treatment decisions (such as decide whether to add or immunotherapy after surgery and/or radiation therapy), therapy monitoring (doctors may use changes in the presence or amount of one or more Tumor Markers to assess how the cancer is responding to treatment) and predict or monitor for recurrence (looking for changes in the amount of a Tumor Marker may be part of their follow-up care plan and may help detect a recurrence sooner than other methods).
Other tests in the market
Different methods for early diagnosis have been developed, including the use of the PSA Tumor Marker, but the results are not satisfactory, since this marker has a low Sensitivity in the early stages while offering a high proportion of false positives (FP) in all aged men.
PSA has well-defined roles in prostate cancer including diagnosis, staging, planning of and response to treatment. However, clinicians must remember that PSA is organ rather than tumour-specific.
Further, age-adjusted levels of PSA and free/total ratios only help guide clinicians and still require investigation. For example, the role of free/total PSA (carcinoma has more PSA bound) in the setting of a raised PSA may only prevent biopsies being done once one is satisfied that there is no carcinoma. Also, performing a digital rectal exam at a different time to the PSA test may be advisable to avoid a falsely elevated result.
As more patients request and clinicians order measurement of serum PSA, results outside the normal range (0–4 ng/mL) will increasingly be found. Clinicians must place a raised PSA in context, or there is a danger of creating anxiety and assuming cancer is the diagnosis. This has often occurred where PSA levels are just above normal, but is probably important in the context of any level. The absolute cut-off point used to determine the need to evaluate a patient for prostate cancer by biopsy is not clear and detection rates for a PSA level between 2.5–4.0 ng/mL have been found to be similar (around 30%) to those for the PSA range of 4.0–10.0 ng/mL. This indicates that 2–2.5 ng/mL may be a more appropriate cut-off point than 4.0 ng/mL. Against this, some have suggested that serum PSA may be more related to Benign Prostatic Hyperplasia (BPH) than cancer in the modern era and that there is an urgent need for serum markers that more accurately reflect malignancy.
In recent years, the valuation levels of other novel Tumor Markers, basically PSA isoforms such as p2PSA or Intact PSA (iPSA), offers greater sensitivity for these early stages, and greater specificity, but still not quite good.
Another interesting Tumor Marker is hK2, which although it belongs to the same family of serum proteases that PSA ―sharing up to 80% of its amino acid sequences―, it seems to differentiate such better between benignity (Benign Prostatic Hyperplasia or Prostatitis, among others) and malignancy than the PSA itself.
Besides, the Prostate Cancer Antigen 3 (PCA3) is a gene that expresses a non-coding RNA that it is only expressed in human prostate tissue, and highly overexpressed in Prostate Cancer (up to 60 or 100 times in Prostate Cancer cells than in normal prostate cells), so because of its restricted expression profile, the PCA3 RNA is useful as a Tumor Marker, but unfortunately, used independently ―as shows its stand alone curve―, does not have enough performance.
In this way, Opko Health (Nasdaq: OPK), an American biotech company, have developed the 4K Score to also help physicians make the right treatment decisions for patients with enlarged prostate gland or high PSA levels and avoid unnecessary prostate biopsies.
The 4K Score is based in 4 kallikrein found in urine, such as Total PSA, Free PSA (fPSA), Intact PSA (iPSA) and hK2, and the global performance is greater than PSA, but still not significant, as we have demonstrated with our own Algorithm (see comparision curves below).
Finally, superposed ROC curves for Total PSA Test, hK2, PCA3 as well as 4K Score, that also include the one for OncoPROSTATE test.
Based on Publications
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