Why do we need biomarker tests for prostate cancer diagnosis?
Current challenges in prostate cancer diagnosis
Today, the decision to biopsy depends mainly on PSA and DRE. However, because PSA has a low specificity for (high-grade) cancer, many man are diagnosed with clinically insignificant cancer. In turn, this may lead to (over)treatment of insignificant disease. Moreover, many men have a negative biopsy and are unnecessarily exposed to anxiety, pain and potential complications related to biopsy .
One of the major challenges is how to identify men who need a biopsy and, more specifically, those who harbour an increased risk of having clinically significant prostate cancer. Finding these men is essential as they will mostly benefit from earlier diagnosis and treatment. It is also important to reduce the number of unnecessary invasive biopsies in men without (clinically significant) cancer.
Biomarker tests: the answer to the challenges in prostate cancer diagnosis
Biomarker tests help to improve the early diagnosis of clinically significant prostate cancer. This is because they can identify men at risk of harbouring clinically significant cancer who need a biopsy, and who may benefit from earlier diagnosis and treatment. Men at low risk of having clinically significant cancer can be spared an unnecessary biopsy and associated risk of anxiety, pain and complications. Ideally, a diagnostic biomarker test has no or a very low risk of missing clinically significant cancer when the test result is negative.
- To identify men at increased risk of harbouring clinically significant cancer who may benefit from earlier diagnosis and treatment
- To avoid the risk of missing the detection of clinically significant cancer in case of a negative test result
- To avoid the number of unnecessary biopsies with associated complications and costs
Biomarker tests and their use
From the early 1990s, there has been an increasing interest in diagnostic biomarker tests. The old generation tests, such as PCA3 and the Prostate Health Index (PHI), generally only consist of molecular biomarkers. They usually predict overall prostate cancer on biopsy although some studies suggest that PCA3 and PHI correlate with features of prostate cancer significance.
The new generation tests evolved to specifically predicting clinically significant prostate cancer. These tests, including the 4Kscore, ConfirmMDx, and SelectMDx, are usually risk scores including both biomarkers and clinical information (e.g. age, PSA level, DRE outcome).
Diagnostic biomarker tests can help to find men at risk of harbouring (clinically significant) cancer in need for a biopsy. They can be used to decide who needs an initial biopsy and who not. Moreover, biomarker tests can aid to identify men in need for a repeat biopsy. These men had a prior negative biopsy but remain suspicious of having prostate cancer.
Biomarker tests compared
When a diagnostic biomarker test is negative and a biopsy is not performed, the risk of missing (clinically significant) cancer should be as low as possible. This is described by the negative predictive value (NPV): the proportion of men with a negative test result that do not have the disease. The NPV value of a biomarker test therefore needs to be as high as possible.
New generation biomarker tests have a very high NPV (95-98%). This means that they have a minimal risk of missing clinically significant cancer (2-5%) when a biopsy is not performed. In comparison, old generation biomarker tests have a much lower NPV (67-92%). This leads to a higher risk of missing cancer (8-33%).
So far, diagnostic biomarkers have not been directly compared in randomised trials. However, an indirect comparison suggests that SelectMDx has the best outcome: a very high accuracy of finding clinically significant cancer with only a 5% risk of missing significant cancer in case of a negative test result (see table).
What is SelectMDx?
SelectMDx is a diagnostic test that helps distinguish men at increased risk for significant prostate cancer from those at very low risk. SelectMDx can help you find men needing a biopsy.
SelectMDx is a non-invasive, urine-based test that measures the expression of 2 mRNA cancer-related biomarkers (HOXC6 and DLX1). This is combined with age, PSA density and DRE into a risk score.
SelectMDx is CE-marked and available in most EMEA countries and the USA.
Benefits of SelectMDx
- SelectMDx identifies men at high risk of having clinically significant cancer. These men may benefit from earlier diagnosis and treatment
- SelectMDx has a very high NPV of 95-98%. This means that if the test is negative, the patient can be 95-98% sure that he doesn’t have aggressive prostate cancer [2,3]. The risk of missing high-grade (ISUP grade ≥ 2 [Gleason score ≥7]) prostate cancer is only 2-5%. This provides reassurance for your patients.
- SelectMDx has a very high predictive accuracy for high-grade prostate cancer (AUC 0.85), which was significantly better than the PCPT risk calculator (AUC 0.76; P=0.001) 
- SelectMDx is a non-invasive, urine-based test
Clinical utility of SelectMDx
SelectMDx helps distinguish men with a high likelihood for high-grade prostate cancer upon biopsy from men at very low risk (with a 95-98% NPV).
- Men at high risk may benefit from biopsy, early detection and treatment.
- Men at very low risk may avoid unnecessary invasive biopsies and the associated risk of anxiety, pain and complications.
How to use SelectMDx?
Instructions for use
Follow 12 simple steps:
- Perform a DRE (3 strokes per lobe) to mobilise the prostate cancer cells and exosomes towards the urethra. Apply enough pressure to slightly depress the prostate surface (it is not intended to be a prostate massage).
- Collect first voided urine immediately following the DRE. Use the UrNCollect device provided in your SelectMDx Urine Collection kit
- Remove the UrNCollect Funnel and Tube from the box
- Place the Tube upright on a flat surface and unscrew the cap (do not throw away the cap as it will be used later)
- Hold the Funnel upright and screw on the Tube
- Instruct the patient to point the spout of the device towards the toilet and urinate into the Funnel; the patient should continue urinating until the bladder is completely empty
- Unscrew the Tube from the Funnel. Gently tab floater against the inside of the Tube
- Firmly screw the cap onto the Tube
- Place the barcode label on the Tube and Test Requisition Form
- Place the Tube into the Safety bag
- Place the sealed Safety bag with the Test Requisition Form in the SelectMDx Urine Collection kit
- Ship the box at ambient temperature as soon as possible after collection (it must reach the laboratory of MDxHealth BV within 5 days of collection)
Discover the physician's brochure
SelectMDx should be performed only when serum PSA has been determined less than 6 months ago.
SelectMDx should be performed only after 3 months in men who had:
- a prostate biopsy
- a transurethral resection of the prostate (TURP)
SelectMDx should be interpreted with caution in men:
- taking 5α-reductase inhibitors (e.g. Proscar®, Avodart®)
- having a urinary tract infection
The urine sample cannot be collected from a catheter.
SelectMDx is not influenced by prostatitis and Benign Prostatic Hyperplasia (BPH).
SelectMDx patient report
The patient report indicates the likelihood of detecting prostate cancer in the biopsy, including the probability of high-grade (Gleason score ≥7) prostate cancer.
Development and validation of SelectMDx
SelectMDx was developed and validated in a prospective, multicenter study .
Before biopsy, post-DRE urine was collected and mRNA levels of several biomarkers were measured. The combination of HOXC6 and DLX1 had the highest predictive accuracy (AUC 0.76) for high-grade prostate cancer (ISUP grade ≥ 2 [Gleason score ≥7]). From a previous study, it was also shown that these biomarkers have a higher predictive accuracy for high-grade prostate cancer than PCA3 .
Subsequently, logistic regression models were developed and validated combining the biomarkers with clinical variables.
SelectMDx was further optimized and validated in a prospective, multicenter study in men scheduled for initial biopsy . The optimised model included: urinary HOX6 and DLX1 mRNA levels, age, DRE outcomes and PSA density. SelectMDx had a very high predictive accuracy (AUC 0.85) for high-grade prostate cancer, which was significantly better than the Prostate Cancer Prevention Trial (PCPT) risk calculator (AUC 0.76; P=0.001). SelectMDx had a high NPV of 95% which means that the risk of missing high-grade cancer in case of a negative test is only 5%.
- Loeb S, Vellekoop A, Ahmed HU, et al. Systematic review of complications of prostate biopsy. Eur Urol 2013;64:876-92.
- Van Neste L, Hendriks RJ, Dijkstra S, et al. Detection of high-grade prostate cancer using a urinary molecular biomarker-based risk score. Eur Urol 2016;70:740-8.
- Haese A, Trooskens G, Steyaert S, et al. Multicenter optimization and validation of a 2-gene mRNA urine test for detection of clinically significant prostate cancer before initial prostate biopsy. J Urol 2019;202:256-63.
- 4Kscore Test Characteristics, available at http://4kscore.com/wp-content/uploads/2016/09/Interpreting-your-Results.pdf (last accessed May 2017)
- Parekh DJ, Punnen S, Sjoberg DD, et al. A multi-institutional prospective trial in the USA confirms that the 4Kscore accurately identifies men with high-grade prostate cancer. Eur Urol 2015;68:464-70.
- Van Neste L, Partin AW, Stewart GD, et al. Risk score predicts high-grade prostate cancer in DNA-methylation positive, histopathologically negative biopsies. Prostate 2016;76:1078-87.
- Gittelman M, Hertzman B, Bailen J, et al. PROGENSA®PCA3 molecular urine test as a predictor of repeat prostate biopsy outcome in men with previous negative biopsies: a prospective multicenter clinical study. J Urol 2013;190:64-9.
- Wei JT, Feng Z, Partin AW, et al. Can urinary PCA3 supplement PSA in the early detection of prostate cancer? J Clin Oncol 2014;32:4066-72.
- Haese A, de la Taille A, Van Poppel H, et al. Clinical utility of the PCA3 urine assay in European men scheduled for repeat biopsy. Eur Urol 2008;54:1081-8.
- de la Calle C, Patil D, Wei JT, et al. Multicenter evaluation of the prostate health index to detect aggressive prostate cancer in biopsy naive men. J Urol 2015;194:65-72.
- Filella X, Giménez N. Evaluation of [-2] proPSA and Prostate Health Index (phi) for the detection of prostate cancer: a systematic review and meta-analysis. Clin Chem Lab Med 2013;51:729-39.
- Leyten GHJM, Hessels D, Smit FP, et al. Identification of a candidate gene panel for the early diagnosis of prostate cancer. Clin Cancer Res 2015;21:3061-70.