Clinical Markers for Prostate Cancer
Project ended 31 March 2019
Dr Antonio Serafin
Title of the project
Clinical markers for prostate cancer.
Prostate cancer screening using prostate-specific antigen (PSA) is controversial due to the very real risk of over-diagnosis and over-treatment as most cancers diagnosed would remain asymptomatic. Urokinase Plasminogen Activator (uPA) and Plasminogen Activator Inhibitor type-1 (PAI-1) have been implicated in tumour aggressiveness and metastatic potential in breast cancer. In view of the relatedness of breast and prostate cancers, and similarities of the invasion process, it was decided to determine the abundance of the markers, urokinase plasminogen activator and its inhibitor in, at first, prostate tissue, and, later, blood samples, using enzyme-linked immunosorbent assay (ELISA) methodology. The project was aimed at developing an assay that would characterise the presence and severity of prostate disease in patients.
We tested the correlation between stage of the disease, age of the patient, and PSA value, with the abundance of the marker protein under investigation. The plan was to move from invasive (tissue) to less invasive (blood) sample collection and to test the robustness of our findings.
The results were “inconclusive”, with no one marker showing consistent prominence. In light of these results, then, we proposed a “Malignancy Index”. Said index was calculated by dividing the product of the concentration of the three markers (PSA, PAI-1 and uPA) by the age of the patient. The abovementioned three markers increase with age (as seen in our research), hence their inclusion in the formula.
The malignancy indices in transurethral resection tissue (TURP), biopsy tissue and blood from prostate cancer patients were, respectively, ~39, ~19, and ~9-fold higher than those obtained from individuals with benign prostatic hyperplasia (BPH), and healthy volunteers.
Urokinase plasminogen activator (uPA) and its inhibitor type 1 (PAI-1) have been implicated in tumour aggressiveness and it’s potential to metastasise, in breast cancer. In view of the relatedness of breast and prostate cancers, and similarities in the invasion process, it was decided, then, to go in search of a noninvasive predictive assay for prostate cancer by determining the abundance of urokinase plasminogen activator and its inhibitor, first in tissue, and, later, in blood samples.
Much has been written about prostate cancer screening using prostate-specific antigen (PSA) and the risk of over-diagnosis and over-treatment, as most cancers diagnosed would remain asymptomatic. Truth be told, the uPA and PAI-1 results across three sample types (prostate resection tissue, needle biopsies and blood samples) in our studies have been disparate.
To address this, a simple but promising malignancy index was proposed to discriminate benign from malignant in prostate tissue and blood samples. The malignancy index was calculated by dividing the product of the concentrations of three popular markers (PSA, PAI-1 and uPA), by patient age. Why age? Our studies have shown that the marker values/concentrations increase with age.
On average, and regardless of age, we found that the malignancy indices in prostate resection tissue, biopsy tissue, and blood samples from prostate cancer (PCa) patients were ~39-, ~19-, and ~9-fold higher than those obtained from individuals with benign prostatic hyperplasia (BPH) or healthy volunteers, respectively. However, it is worth noting that three independent cohorts were used in the resection tissue, biopsy, and blood studies. Ideally, one would have liked paired tissue-and-blood samples from the same patients!
In this final phase, we tested the robustness of our malignancy index in a validation study using fresh blood samples from patients diagnosed with prostate cancer, benign prostatic hyperplasia, and healthy volunteers. The results confirmed earlier findings that the malignancy index does indeed discriminate prostate cancer from non-prostate cancer. The index significantly separated the PCa group from the Control group with values of 0.0701 (n=54), and 0.0007 (n=47), respectively, a factor of 100. The malignancy index value of the small BPH cohort was well placed at 0.0016 (n=20), a factor of 44.
When the earlier study and the validation study data were pooled, the index again significantly separated the PCa group from the Control group with values of 0.0624 (n=125), and 0.0042 (n=110), respectively, a factor of 15. However, the same could not be said of the BPH data since the sample size was well below par (n=20).
We contend that the malignancy index has potential and value, at this preliminary stage, as a prostate cancer biomarker.
Value of the project in the struggle against cancer
The development of a cancer biomarker requires extensive validation and comparison with other applicable (in this case, prostate) biomarkers in a clinical setting. There are currently several PSA derivative assays to improve the utility of PSA.
We proposed a novel malignancy index ** which is seen to be effective in tissue and peripheral blood, to differentiate prostate cancer from non-prostate cancer. Said index came about as a result of the inconsistent data gathered whilst assaying two breast cancer markers, uPA and PAI-1, in prostate tissue and blood samples.
** The malignancy indices in transurethral resection tissue (TURP), biopsy tissue and blood from prostate cancer patients were, respectively, ~39, ~19, and ~9-fold higher than those obtained from individuals with benign prostatic hyperplasia (BPH), and healthy volunteers.
We should like to view this study as a small step in the continuum of prostate cancer patient care.