ConfirmMDx for Prostate Cancer

The ConfirmMDx for Prostate Cancer testing solution addresses false-negative biopsy concerns, helping urologists:  

  • “Rule-out” otherwise cancer-free men from undergoing unnecessary repeat biopsies and screening procedures, helping to reduce complications, patient anxiety and excessive healthcare expenses associated with these procedures.
  • “Rule-in” high-risk men with a previous negative biopsy result who may be harboring undetected cancer (false-negative biopsy result) and therefore may benefit from a repeat biopsy and potentially treatment.

For men with an initial negative biopsy, independently published clinical studies have shown that the ConfirmMDx test is the most significant, independent predictor of patient outcome relative to other available clinical factors such as age, PSA and DRE results.(1,2)

The Most Significant Predictor of Prostate Cancer Detection on Repeat Biopsy

Most Significant Independent Predictor of PCa Detection on Repeat Biopsy

Incorporating ConfirmMDx for Prostate Cancer into clinical practice can substantially reduce the number of unnecessary repeat biopsies.  ConfirmMDx for Prostate Cancer can aid urologists with patient management decisions regarding the need for repeat biopsy with the identification of low-risk patients testing negative for DNA hypermethylation.  

Background

Prostate cancer is the most frequent cancer in men, with one out of six men being diagnosed during their lifetime. Annually in the U.S. there are: 

  • Approximately 20 million men screened by the Prostate-Specific Antigen (PSA) test
  • Over 1.3 million prostate biopsy procedures
  • 240,000 newly diagnosed prostate cancer cases
  • 29,000 deaths(3-5)

Although prostate cancer remains one of the deadliest cancers in men, its accurate diagnosis and follow-up remain a challenge and come at a considerable cost to the healthcare system. Approximately $4.4 billion is spent annually on screening, diagnosing and staging, and an additional $9.9 billion is spent annually on treatment of these patients, totaling nearly $15 billion per year on prostate cancer in the U.S. alone. Annually, over $4 billion is spent on pharmaceutical treatment for prostate cancer, which is expected to increase to $8.7 billion by 2019.(6-8)

Under the current standard of care, men with a PSA score that is elevated (i.e., ≥ 4.0 ng/ml) or rising and/or abnormal digital rectal exam (DRE) are considered at high risk for cancer and will often be referred for a prostate biopsy to determine if prostate cancer is present.  The standard prostate biopsy procedure takes 10-12 core samples and histopathological review by visual inspection under a microscope remains the gold standard for the diagnosis of prostate cancer.  However, this schema actually samples less than 1% of the entire prostate gland and results in limited histopathological analysis.  Sampling error is an inherent and well-documented issue with false-negative rates (FNR) of prostate biopsy procedures reported as high as 25-35%.(9-17)

Prostate Biopsy Sampling Error

Of the estimated 1.3 million biopsies performed each year, less than a third actually result in a cancer finding, leaving more than 1 million men with a negative biopsy reading but still facing elevated clinical risk factors.  Concerns over inconclusive (i.e. false-negative) biopsy results, coupled with the high rate of clinically significant cancer detected upon repeat biopsy, pose a diagnostic dilemma: 

  •  43% of patients with negative histopathology on initial biopsy will undergo a repeat biopsy, many also continuing on to 3rd and 4th biopsies
  • Repeat biopsies are invasive procedures resulting in increased risk of infection and hospitalization
  • Significant costs associated with unnecessary procedures and associated risks(18-20)

For patients with an initial negative biopsy but with persistently elevated or rising PSA, abnormal DRE or other risk factors, few options are currently available to guide a urologist in determining whether or when an additional biopsy procedure is warranted.  Fear of occult (hidden) prostate cancer leads to additional procedures, leading many men to receive 2nd, 3rd and 4th repeat biopsy procedures to rule-out the presence of cancer.

Epigenetics in Cancer

The use of epigenetic testing for prostate cancer detection using methylation specific PCR (MSP) and cancer-associated epigenetic biomarkers to improve upon histopathology has been well validated in both scientific and clinical studies. DNA methylation, the most common and useful measure of epigenetic abnormality testing, is responsible for the silencing of key tumor suppressor genes. DNA methylation biomarkers associated with prostate cancer have been extensively evaluated and more than 43 studies on the ConfirmMDx genes and technology have been published in peer reviewed, scientific and medical journals.

GSTP1 is the most intensely studied and widely reported epigenetic biomarker associated with prostate cancer diagnosis, encoding the glutathione S-transferase Pi 1 protein involved in detoxification, due to its high sensitivity and specificity.  Complementing GSTP1, methylation of the APC and RASSF1 genes is frequently found in prostate cancer, and these markers have demonstrated a “field effect” aiding in the identification of biopsies with false-negative histopathological results.(1,2,17)

The concept of a field cancerization effect, when first reported in medical literature by Slaughter in 1953, described the changes in tissues surrounding cancer lesions and their association with development of tumors.  Later, the term “field effect” evolved to include molecular changes in adjacent, benign-looking tissues.  The epigenetic field effect is a molecular mechanism whereby cells adjacent to cancer foci can contain DNA methylation changes, which may be indistinguishable by histopathology, but detectable by MSP testing.  The presence of epigenetic field effects associated with prostate cancer has been widely published and is the basis of activity for the ConfirmMDx assay to aid in the detection of occult prostate cancer on previously biopsied, histopathologically negative tissue.(21-27)

Epigenetic Field Effect

Clinical Studies

Analytical Validation

A tissue biopsy-based epigenetic multiplex PCR assay for prostate cancer detection, BMC Urology (2012, 12:16) MDxHealth validation study describes the successful development of the ConfirmMDx multiplex DNA methylation test. In the same study the effect of prostate needle core biopsy sample volume and age of formalin-fixed paraffin-embedded (FFPE) samples was evaluated.  ConfirmMDx can be applied to small biopsy specimens widening clinical applicability, and the age of the FFPE-samples does not have a negative impact on the performance of the test.

Clinical Validation

MATLOC Study. As reported in the Journal of Urology (Volume 189, Issue 3, 1110-1116, 2013), MDxHealth’s MATLOC (Methylation Analysis to Locate Occult Cancer) study demonstrated that ConfirmMDx for Prostate Cancer improved on histopathology alone, by accurately identifying two-thirds of the prostate cancer patients missed in the previous biopsy and correctly identifying approximately two-thirds of the men who could forego a repeat biopsy.  In this study, ConfirmMDx yielded sensitivity of 68%, specificity of 64%, and a NPV of 90% to confirm the absence of cancer in histopathologically negative biopsy cores. This represents a significant improvement over histopathology alone, which yields a NPV of 65% to 75%.

DOCUMENT Study. As reported in the Journal of Urology (Volume 191, Issue 4, E713 - E714, 2014), MDxHealth’s DOCUMENT (Detection of Cancer Using Methylated Events in Negative Tissue) study demonstrated that the ConfirmMDx for Prostate Cancer test is the most significant, independent predictor for prostate cancer detection in a repeat biopsy in a cohort of U.S. men. These findings are consistent with and confirm the results from the earlier European MATLOC study. This blinded, multicenter, confirmatory clinical validation study on 350 PSA-screened men, used the same assay cutoffs applied in the MATLOC study and verified test’s high negative predictive value.  Led by principle investigator Alan Partin, MD, PhD, Professor and Chief of Urology at the James Buchanan Brady Urological Institute at Johns Hopkins School of Medicine. 

Clinical Utility

Reduced Rate of Repeated Prostate Biopsies Observed in ConfirmMDx Clinical Utility Field Study, AM HEALTH DRUG BENEFITS (Volume 7, Issue 3, 129-34, 2014), Wonjo et al reported on the real-world use of the ConfirmMDx assay, demonstrating the test impacts physician behavior.  A total of 5 clinical urology practices that had ordered a minimum of 40 ConfirmMDx tests for patients with previous, cancer-negative biopsies over the course of 18 months participated in the study. A total of 138 patients who were considered at risk for malignancy based on traditional risk factors, but had ConfirmMDx negative test results, were identified and all were included in the analysis. A very low rate of repeat biopsies (4.4%) was observed in the ConfirmMDx negative men, as compared to the 43% rate of repeat biopsy reported in the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial, a large population-based randomized trial designed and sponsored by the National Cancer Institute.  Repeat biopsies had been performed in 6 of the 138 (4.3%) men with a negative assay result, in whom no evidence of cancer was found on histopathology. These positive clinical utility results, which demonstrated a 10-fold reduction in the rate of repeat biopsy as compared to the reported standard of care, served as the basis for ConfirmMDx’s Medicare coverage.

PASCUAL Study is a 600 patient randomized, controlled prospective study to track the clinical utility of the ConfirmMDx assay in U.S. urologic practices for the management of patients with a previous histopathologically cancer-negative biopsy, but clinical risk factors suggesting the need for a repeat biopsy.  The study, initiated in H2 2014, will compare the rate of repeat biopsies under the standard of care to the rate of repeat biopsies in patients managed with ConfirmMDx test results and is expected to demonstrate a similar low rate of repeat biopsy in the ConfirmMDx arm as reported by Wojno et al.  The PASCUAL study, led by Principal Investigator Neal D. Shore, MD, FACS, CPI who serves as Medical Director for the Carolina Urologic Research Center, is expected to be completed in H1 2017. 

Health Economics

Budget Impact Model: Epigenetic Assay Can Help Avoid Unnecessary Repeated Prostate Biopsies and Reduce Healthcare Spending. American Health Drug and Benefits (Volume 6, Issue 1, 15-24, 2013).  In a budget impact model (BIM) developed to evaluate the effect of the ConfirmMDx assay on healthcare spending, the model demonstrates the potential healthcare savings associated with the reduction of repeat biopsies and complications avoided. The BIM compares a standard of care scenario, based upon up-to-date prostate cancer biopsy statistics, procedures and Medicare fee schedules, to a new scenario wherein the ConfirmMDx assay is employed for decisions on repeat biopsy. With a significant reduction in procedures and healthcare costs in the first year of adoption, the model supports the coverage of the ConfirmMDx assay given the clinical and economic benefits. 

In summary, ConfirmMDx for Prostate Cancer is an important diagnostic aid for patient management decisions regarding repeat prostate biopsy on men with histopathologically negative previous biopsy results but considered at risk for occult prostate cancer.  The MSP technology and epigenetic biomarkers have been extensively tested and validated in both retrospective and prospectively designed studies.  The assay provides ease-of-use as it is designed to test residual prostate core biopsy tissues from the previous negative biopsy, eliminating the need and expense associated with return patient visits for specimen acquisition.  The improved clinical performance over histopathology alone provides urologists with actionable information and can aid in the earlier detection of clinically significant cancer while greatly contributing to a reduction of unnecessary, invasive, sometimes harmful and costly repeat biopsies.

References

1. Partin et al.; Clinical Validation of an Epigenetic Assay to Predict Negative Histopathological Results in Repeat Biopsies. Journal of Urology 2014. Doi.org/10.1016/j.juro.2014.04.13.

2. Stewart G et al.: Clinical Utility of an Epigenetic Assay to Detect Occult Prostate Cancer in Histopathologically Negative Biopsies: Results of the MATLOC Study. J. Urol. 2013, 189, 1110-1116.

3. National Cancer Institute. Surveillance, Epidemiology and End Results. 2014 Prostate Cancer Statistics  http://seer.cancer.gov/statfacts/html/prost.html.

4. Ekwueme DU, Stroud LA, Chen Y. Cost analysis of screening for, diagnosing, and staging prostate cancer based on a systematic review of published studies. Prev Chronic Dis. 2007;4:A100. 

5. Mosquera J-M, Mehra R, Regan MM, et al. Prevalence of TMPRSS2-ERG fusion prostate cancer among men undergoing prostate biopsy in the United States. Clin Cancer Res. 2009;15:4706-4711.

6. National Cancer Institute Trends Progress Report-2009/2010 Updated. www.cancer. gov/newscenter/newsfromnci/2010/ProgressReport2010. Accessed November 1, 2012.  

7. Ekwueme DU, Stroud LA, Chen Y. Cost analysis of screening for, diagnosing, and staging prostate cancer based on a systematic review of published studies. Prev Chronic Dis. 2007;4:A100.

8. Merril J. Prostate cancer market snapshot: more than provenge. The Pink Sheet. November 22, 2010. Elsevier Business Intelligence Publications and Products. https://www.pharmamedtechbi.com/publications/the-pink-sheet/72/47/prostate-cancer-market-snapshot-more-then-provenge. Accessed January 29, 2013.

9. Carroll P, Coley C, McLeod D, et al. Prostate-specific antigen best practice policy--part I: early detection and diagnosis of prostate cancer. Urology 2001; 57:217.

10. Brawer MK, Chetner MP, Beatie J, et al. Screening for prostatic carcinoma with prostate specific antigen. J Urol 1992; 147:841.

11. Catalona WJ, Smith DS, Ratliff TL, Basler JW. Detection of organ-confined prostate cancer is increased through prostate-specific antigen-based screening. JAMA 1993; 270:948.

12. Crawford ED, DeAntoni EP, Etzioni R, et al. Serum prostate-specific antigen and digital rectal examination for early detection of prostate cancer in a national community-based program. The Prostate Cancer Education Council. Urology 1996; 47:863.

13. Taneja et al.: The American Urological Association (AUA) Optimal Techniques of Prostate Biopsy and Specimen Handling. 2013.

14. Shen et al.: Three-Dimensional Sonography With Needle Tracking - Role in Diagnosis and Treatment of Prostate Cancer. J. Ultrasound Med. 2008; Jun; 27(6): 895-905.

15. Rabets JC et al.: Prostate cancer detection with office based saturation biopsy in a repeat biopsy population. The Journal of Urology. 2004; Jul; 172(1): 94–97.

16. Kronz JD et al.: Predicting cancer following a diagnosis of high-­‐grade prostatic intraepithelial neoplasia on needle biopsy: data on men with more than one follow-­‐up biopsy. American Journal of Surgical Pathology 2001; Aug 25(8): 1079–1085.

17. Trock BJ et al.: Evaluation of GSTP1 and APC Methylation as Indicators for Repeat Biopsy in a High-risk Cohort of Men with Negative Initial Prostate Biopsies. British Journal of Urology International 2012; July 110(1): 56-62.

18. National Cancer Institute. Surveillance, Epidemiology and End Results. 2014 Prostate Cancer Statistics http://seer.cancer.gov/statfacts/html/prost.html.

19. Pinsky PF, Crawford ED, Kramer BS, et al. Repeat prostate biopsy in the prostate, lung, colorectal and ovarian cancer screening trial. BJU Int. 2007;4:775-779.

20. Mosquera J-M, Mehra R, Regan MM, et al. Prevalence of TMPRSS2-ERG fusion prostate cancer among men undergoing prostate biopsy in the United States. Clin Cancer Res. 2009;15:4706-4711.

21. Slaughter DP et al.: Field cancerization in oral stratified squamous epithelium; clinical implications of multicentric origin. Cancer 1953; Sep; 6(5): 963–8. 

22. Braakhuis BJ et al.: A Genetic Explanation of Slaughter’s Concept of Field Cancerization: Evidence and Clinical Implications. Cancer Res. 2003. Apr 15; 63(8): 1727-30.

23. Van Neste L et al.: The Epigenetic Promise for Prostate Cancer Diagnosis. The Prostate 2011; 1; 72(11): 1248-61.

24. Trujillo KA et al.: Markers of Field Cancerization: Proposed Clinical Applications in Prostate Biopsies. Prostate Cancer 2012; 2012:302894.

25. Henrique R et al.: Epigenetic Heterogeneity of High-Grade Prostatic Prostate Carcinogenesis Intraepithelial Neoplasia: Clues for Clonal Progression in Prostate Carcinogenesis. Mol. Cancer Res. 2006; Jan; 4(1): 1-8.

26. Zhou M et al.: Quantitative GSTP1 Methylation Levels Correlate with Gleason Grade and Tumor Volume in Prostate Needle Biopsies. J. Urol. 2004; Jun; 171 (6PT 1): 2195-8.

27. Mehrotra et al.: Quantitative, Spatial Resolution of the Epigenetic Field Effect in Prostate Cancer. The Prostate 2008; Feb 1; 68(2): 152-60.