Analysis of Cell-free DNA (cfDNA) in Men With Elevated PSA Levels
Analysis of Cell-free DNA (cfDNA) in Men With Elevated PSA Levels
This is a multi-centre prospective study in which blood samples will be taken from 1500 male
 patients aged between 21-80 scheduled for prostate biopsy. Analysis of cell-free cancer DNA
 extracted from these samples will be undertaken to determine whether copy number instability
 scores derived from the cfDNA correlates with PSA screening levels and prostate biopsy
 results (i.e. Gleason score) in these patients.
The prostate is the most common site of cancer in men with 240,000 new cases diagnosed
 annually in the United States with approximately 28,000 yearly deaths. Prostate screening
 typically relies on digital rectal exam (DRE) and prostate specific antigen (PSA) levels.
 Limitations of the PSA test include its low sensitivity and low specificity and its inability
 to distinguish between low-grade and high-grade lesions. Recent screening trials suggest that
 PSA-based screening programs result in small or no reduction in mortality, and have
 significant treatment-related adverse events (AEs). Better serum/plasma biomarkers are needed
 to supplement the PSA test in the diagnosis and management of a disease with a multiplicity
 of presentations and clinical outcomes.

 Cancer-derived DNA present in peripheral blood (referred to as cell-free DNA or cfDNA) was
 first reported in 1948, but research into this area remained in a dormant state for over 50
 years. Over the last ten years however, the development of Next Generation Sequencing (NGS)
 using massive parallel arrays has allowed researchers to create a database robust enough to
 distinguish normal genomic from non-diploid cfDNA. In 2008, fetal trisomy of chromosome 21
 was detected by analyzing cfDNA in maternal blood. Since then, the method has been validated
 for trisomy 13, 18, and 21 as a clinical laboratory procedure with remarkable accuracy >99%.
 Recently, cancer derived cfDNA has been demonstrated to recapitulate genomic tumor DNA.
 Current clinical acceptance of the utility of cfDNA in cancer diagnosis has been demonstrated
 in multiple abstracts at the 2014 and 2015 ASCO meetings in Chicago.

 In a recent publication in Clinical Chemistry, researchers at Vanderbilt University,
 Gottingen, Germany, and at the University of Toronto, Canada, analyzed cfDNA in the
 bloodstream from healthy controls as compared to those with clinically diagnosed prostate
 cancer. The results of this study demonstrated that it is possible to distinguish prostate
 cancer from healthy controls without prior knowledge of the genetic signature of the tumors
 and with over three times the sensitivity of the FDA-approved blood test for prostate cancer
 (i.e., prostate-specific antigen (PSA)). The study examined serum from more than 200 subjects
 with prostate cancer and more than 200 controls. The comparative data included PSA levels and
 prostate tissue biopsy grading (referred to as the Gleason score). The technique
 distinguished prostate cancer from normal controls with 84% accuracy and cancer from benign
 hyperplasia and prostatitis with an accuracy of 91%. Because the method quantifies the
 inherent chromosomal instability of cancer and can be followed as a function of time (without
 having to do an invasive tissue biopsy), it is called a "liquid biopsy." This multi-centre
 clinical study will analyze cfDNA from subjects scheduled for prostate biopsy and is designed
 to validate the results obtained in the above-mentioned retrospective study. If validated,
 the prostate cfDNA determination test will provide a non-invasive test to aid in the
 diagnosis of prostate cancer, as well as provide guidance on whether a biopsy should be
 performed.

 With regard to the study procedures used, the study subject will undergo routine venipuncture
 and ~20 millilitres of blood (approximately 2 tablespoons) will be collected. The blood will
 then be processed by the Sponsor's laboratory and sent to the Sponsor's testing facility in
 Gottingen, Germany.
Inclusion Criteria:

 1. Who, in the opinion of the site Investigator, have an abnormal PSA level as measured
 by a CLIA certified laboratory or non-USA equivalent within the last 60 days, and/or

 2. Who, in the opinion of the site Investigator, have an abnormal digital rectal
 examination

 Exclusion Criteria:

 1. Male subjects with active or historical histologically confirmed diagnosis of
 malignancy

 2. Male subjects who have participated in a clinical trial involving an investigational
 drug within the 28 days prior to signing the informed consent form