Background

High prevalence and low risk of progression have made it difficult to effectively screen and manage prostate cancer. Currently, elevated serum prostate‑specific antigen (PSA) testing is the gold standard screening tool for prostate cancer. Men with a positive PSA test undergo an invasive prostate biopsy to obtain a definitive diagnosis. However, PSA testing has a false positive rate of over 75% and a positive predictive value of approximately 25%.

In the United States alone, 4.7 million men are identified each year as having elevated PSA levels. Of these men, 1.3 million are recommended to undergo biopsy for prostate cancer, resulting in an estimated annual cost of $2.5 billion¹. Approximately two-thirds of men undergoing prostate biopsy have no tumor diagnosed due to the high false positive rates of serum PSA². These unnecessary biopsies come at a substantial cost to the healthcare system while also causing anxiety and trauma in patients. This invasive procedure exposes men to the risk of serious complications, including bleeding, infection, urinary incontinence, and erectile dysfunction.

Thus there is a significant need for a more accurate noninvasive biomarker to improve diagnosis and reduce the number of unnecessary biopsies for prostate cancer. As a result, numerous studies have been conducted to investigate the use of messenger RNA, microRNA, genetic mutations, and prostate‑specific proteins as potential biomarkers. However, prostate cancers typically do not possess many informative biomarkers in these categories.

Instead, aberrant DNA methylation may be a superior substrate for biomarker discovery in early prostate cancer. In contrast to the above cancer‑specific DNA methylation alterations are highly prevalent in prostate cancer³. While research in this area is growing, most research efforts to date have focused broadly on describing the overall epigenetic landscape of prostate cancer. Few studies have validated their results or focused on making methylation‑based classifiers for clinically important outcomes.

Altok, M. et al. Cost and efficacy comparison of five prostate biopsy modalities: a platform for integrating cost into novel-platform comparative research. Prostate Cancer Prostatic Dis. 21:524-532, 2018.
Heijnsdijk, E. A. M. et al. Quality-of-life effects of prostate-specific antigen screening. New Engl. J. Med. 367:595–605, 2012.
Kobayashi Y. et al. DNA methylation profiling reveals novel biomarkers and important roles for DNA methyltransferases in prostate cancer. Genome Res. 21:1017-1027, 2011.

Technology Overview

Queen’s researchers used real‑time methylation‑specific PCR (qMSP) assays targeting 15 DNA methylation alterations which had been validated in multiple previous reports. Each locus was tested individually and in combination with other loci to determine its accuracy as part of a compact multigene biomarker, as multigene biomarkers are superior to single‑gene tests.

The GAS6/GSTP1/HAPLN3 was the best multigene model, showing sensitivity of 94% and specificity of 93% in the validation dataset¹ (Figure 1). The three‑gene model also showed a significant improvement over univariate approaches, as none of the univariate classifiers had both sensitivity and specificity of above 90%.

Figure 1: Performance of Three-Gene Classifier (GAS6/GSTP1/HAPLN3) in Training and Validation Dataset

This degree of sensitivity and specificity would represent a remarkable improvement over the current commercially-available tests (Table 1). For example, the Progensa PCA3 assay is an FDA-approved diagnostic test for use in men over 50 with a previous negative biopsy result. This test has been found to have a sensitivity and specificity as low as 77.5% and 57.1%, respectively². It is also notable that, similar to other commercially‑available tests such as the Prostate Health Index (PHI) and ConfirmMDx, the PCA3 assay is only used after a biopsy has been conducted. While these tests may provide additional clinical insight, they do not reduce the number of unnecessary prostate biopsies.

Table 1: Comparison of Commercially Available Diagnostic and Screening Tests for Prostate Cancer

A highly sensitive and specific urine or blood test could avoid hundreds of thousands of unnecessary biopsies each year. Upon validation of the three‑gene classifier in urine samples, this test could be used to identify a significantly smaller group of men who would be appropriate candidates for biopsy.

Patel, P. G. et al. A three-gene DNA methylation biomarker accurately classifies early stage prostate cancer. Prostate. 79(14):1705-1714, 2019.
Gittelman, M. C. et al. 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. 190:64‑69, 2013.

Benefits

Non‑invasive test with over 90% specificity and sensitivity
Reduction in the number of unnecessary biopsies based on PSA screening

Applications

A non‑invasive diagnostic test for prostate cancer with high specificity and sensitivity
The test could be used to select a significantly smaller population of men who should undergo biopsies

Opportunity

Preclinical Development/seeking exclusive licensee, research collaborator or venture investment.

Prostate Cancer Biomarker Assay

Patents

IP Status

Seeking