A Test to Prevent Repeat Prostate Biopsies? Perhaps, if the Bar of 'Clinical Utility' Can Be Met

Evidence-Based Oncology, February 2014, Volume 20, Issue SP2

If a man who has symptoms of prostate cancer but a negative biopsy could use a test to avoid a second biopsy, wouldn’t that test make sense? It might, but it might not. The decision to pay for the test could rest on whether the man’s insurer, which often is Medicare, thinks his doctor will act based solely on the test’s outcome.

This is the world of “clinical utility,” where in recent years, proving a test’s accuracy no longer pushes it past the finish line for payers.

Recent efforts by MDxHealth, based in Hertsal, Belgium, and Irvine, California, to market its ConfirmMDx epigenetic test for prostate cancer—and to gather data to support broader availability— crystallize the competing forces at work in the molecular diagnostic marketplace, as clinical utility has emerged as the new bar for reimbursement.

Why the change? It comes down to a single word: Cost.

In the decade after the sequencing of the human genome, there’s been an explosion in personalized medicine, along with a rapid rise in new cost categories that didn’t exist just a few years ago.1

A March 2012 white paper published by UnitedHealthcare said the payer spent $500 million on genetic and diagnostic testing in 2010, which represented 14% more per person than in 2008. Extrapolating on its own data, United Healthcare pegged the 2010 total for Medicaid and Medicare at $5 billion, or 8% of all national spending on clinical laboratory tests.2

The concept of personalized medicine—matching the right drug to the right patient at the right time—holds out the promise of driving down costs over time, as therapies are used with precision, leaving less waste and fewer side effects. But for a test like ConfirmMDx to save money demands that physicians practice medicine differently, relying on a test instead of a second biopsy.3

As new genetic and biomarker-based tests emerge, not all payers are convinced that physicians are ready for change. The bar of clinical utility requires test makers to prove that their diagnostic tool is the factor that drives decisions, not a belt-and-suspenders add-on that simply gives doctors more information.

Therein lies the conundrum. Beth Davis, senior director of health policy and reimbursement for MDxHealth, said “clinical utility” means showing that a test has value to doctors in real-world settings. And proving that value can be difficult if payers won’t reimburse for the test, because that has the practical effect of making it unavailable to most patients.

Clinical utility, Davis said, “is a big, evolving discussion right now, because it means different things to different people.” Essentially, she said, “You’re measuring physician behavior.”

In the case of ConfirmMDx, the test maker is not only making the clinical argument that the test works, but also the economic argument that it saves money by preventing unnecessary second

and third biopsies. Davis made her case December 4, 2013, at the Philadelphia meeting, Oral Oncolytics, including data that show 700,000 men have repeat biopsies annually because the standard 12-core method can miss a growing cancer3,4 (See Figure).

Used in lieu of repeat biopsies, ConfirmMDx could save $588 per patient on average, or $500,000 a year for a commercial health plan with 1 million members, according to results published in

American Health & Drug Benefits.5 The MDxHealth website has a growing list of commercial plans that reimburse for the test, and it continues to highlight results about the test’s validity.6,7

An Economic and Quality of Life Case

Prostate is the most common cancer among men, except for skin cancer; it is the leading cause of cancer deaths among men behind lung cancer. The American Cancer Society estimated that

238,590 new cases would be diagnosed in 2013, with 29,720 deaths.8

At the same time, the rise of cancer screening with the prostate-specific antigen (PSA) test over the past 20 years means that 2.5 million men who have had prostate cancer are alive today.8

Widespread screening has saved lives but also increased costs and for some, complications. There is increased promotion of a “wait and watch” approach to those tumors that are not aggressive, and questions about the value of PSA testing led the US Preventive Services Task Force (USPSTF) to issue a highly controversial D rating for the popular screening.9 (See Panel Discussion).

Since most prostate cancer diagnoses occur among older men, cost implications of large-scale PSA testing are huge. A study published just this month in Cancer tracked almost 95,000 men in Medicare, aged 66 to 99 years, who had never had prostate cancer, for 3 years.10 Just over half, or 51.2%, had PSA tests during the period, with 2.9% having a biopsy.10

But as the Cancer article noted, 72% of the costs associated with PSA screening came from “downstream biopsy-related procedures,”10 and not from the screening itself; if those costs could be mitigated, discussion over the controversial D rating from the USPSTF might shift from how to not screen to how to limit the number of biopsies that result.

ConfirmMDx still relies on biopsy as what Davis called the “gold standard,” but it recognizes that the standard 12- core method might miss cancerous tissue. ConfirmMDx seeks to confirm the presence of an epigenetic “halo” that exists around a tumor, which might be present even though the cells look normal under a microscope.

The test relies upon DNA methylation, a biochemical process that can alter gene expression as cells divide and result in the silencing of tumor suppressors. When DNA methylation goes awry, unfolding either too quickly or too slowly, cancer can result. This process does not happen all at once; thus, DNA methylation can be used as a readout for a pre-cancerous or cancerous state.

If a patient has a negative biopsy but a positive result with ConfirmMDx, the doctor can either treat as if the patient had a positive pathology result, or limit additional cores to the area of known “hot spots,” reducing costs, discomfort, and side effects, according to Davis. Thus, the ConfirmMDx test can not only limit costs but also improve quality of life.

Epigenetic test results may also help determine how aggressive the prostate cancer is and guide treatment, based on data presented at the American Society of Clinical Oncology Genitourinary

(ASCO GU) Cancers Symposium in San Francisco on January 31, 2014. In the results, low methylation levels corresponded to low Gleason scores11; this is significant because the same material collected at biopsy and used to determine if treatment is needed could also be used to determine if the cancer is aggressive, Davis confirmed.

Given the uproar over the USPSTF rating of D, however, multiple methods are emerging to spot prostate cancer and gauge its aggressiveness. On the detection front, a study published just this

month in Radiology examined the use of multiparametric magnetic resonance (MR) imaging to detect prostate cancers in low-risk patients.12 Not surprisingly, researchers found that MR imaging was more reliable in detecting larger cancers (1 cm3 and Gleason score of 7 or above) than smaller cancers, but was reliable overall.12

ConfirmMDx has competition in the realm of testing for cancer aggressiveness. At the same ASCO GU symposium, Myriad Genetics presented results from the PROCEDE 500 registry study, which measured clinical utility for its cell-cycle progression signature test, marketed as Prolaris. So far, data are available on 294 patients across 15 urology practices, with physicians indicating that test results would lead to a definite or possible change in 32% of cases.13

Emerging Standards for Diagnostic Tests

A discussion of clinical utility appeared in the literature in December 2010, when Bruce Quinn MD, PhD, an influential contributor to discussions of payment reform in Medicare and Medicaid, wrote an article in Clinical Pharmacology and Therapeutics that addressed decision-making frameworks for payers to use when evaluating companion diagnostics.14

Over the course of 2011, the ground shifted for test makers from clinical validity, which asks whether the test correctly measures what it is supposed to measure, to clinical utility, which asks if the test is the critical item that guides or even changes physician behavior.

By 2012, the Baltimore-based Center for Medical Technology Policy (CMTP) began an effort to develop an Effectiveness Guidance Document, or EGD, in the area of molecular diagnostic testing.15 This process, which was supported by leaders in the pharmaceutical and diagnostic testing industries as well as by payers, represented a multi-stakeholder effort to develop criteria for evaluating tests used in personalized medicine.

A report published May 1, 2013, outlines in its executive summary 10 items in the areas of reporting, clinical validity, and clinical utility to be used when evaluating tests, and notes that the very nature of such tests requires innovative payment approaches, including some that must be approved on a case-by-case basis.15


Davis noted that clinical utility is only measured after a diagnostic test is commercially available. “For diagnostics in general, it can sometimes be more difficult to prospectively randomize testing due to variance in practice,” with urology being a good example, she said. The CMTP report, she said, provides a “balanced framework” for creating avenues for reimbursement while evidence of clinical utility is still being developed.


1. Crawford JM, Aspinall MG. The business value and cost-effectiveness of genomic medicine. Personalized Medicine. 2012;9(3):265-286.

2. UnitedHealth Group. Center for Health Reform and Modernization. Working Paper No. 7: Personalized medicine: trends and prospects for the new sciences of genetic testing and molecular diagnostics. http://www.unitedhealthgroup.com/~/media/UHG/PDF/2012/UNH-Working-Paper-7.ashx. Published March 12, 2012. Accessed January 29, 2014.

3. Davis B. ConfirmMDx for Prostate Cancer: An epigenetic assay to reduce unnecessary repeat prostate biopsies. Presented at: Oral Oncolytics; December 4, 2013; Phildelphia, PA.

4. Pinsky PF, Crawford ED, Kramer BS et al. Repeat prostate biopsy in the prostate, lung, colorectal and ovarian cancer screening trial. BJU Int. 2007;99(4):775-779.

5. Aubry W, Lieberthal R, Willis A, Bagley G, Willis SM, Layton A. Budget impact model: epigenetic assay can help avoid unnecessary repeated prostate biopsies and reduce healthcare spending. American Health & Drug Benefits. 2013;6(1):15-24.

6. MDxHealth secures coverage for prostate cancer test with two additional insurance companies [press release]. Irvine, CA, and Herstal, Belgium: MDxHealth Press Releases and Events; December 2, 2013. http://www.mdxhealth.com/news-and-events/press-releases-and-events?detail=1746642. Accessed February 6, 2014.

7. MDxHealth’s ConfirmMDx meets all primary endpoints in blinded US clinical validation study [press release]. Irvine, CA, and Herstal, Belgium: MDxHealth Press Releases and Events; October 7, 2013. http://www.mdxhealth.com/news-and-events/press-releasesand-events?detail=1733659. Accessed February 6, 2014.

8. American Cancer Society. What are the key statistics about prostate cancer? http://www.cancer.org/cancer/prostatecancer/detailedguide/prostate-cancer-key-statistics. Updated August 26,

2013. Accessed January 29, 2014.

9. Moyer VA. Screening for prostate cancer: US Preventive Services Task Force recommendation statement. Ann Intern Med. 2012;157(2):120-134.

10. Ma X, Wang R, Long JB et al. The cost implications of prostate cancer screening in the Medicaid population. Cancer. 2014;120(1):96-120.

11. Van Neste L, Falk J, Lee MC et al. Epigenetic profiling of prostate cancer tissue to identify men with high-risk disease. J Clin Oncol 2014; 32(suppl 4, abstr 197).

12. Kim JY, Kim SH, Kim YH et al. Low-risk prostate cancer: the accuracy of multiparametric MR imaging for detection [published online January 24, 2014]. Radiology. doi:http://dx.doi. org/10.1148/radiol.13130801.

13. Shore N, Concepcion R, Saltzstein D et al. Clinical utility of a biopsy-based cell cycle gene expression assay in localized prostate cancer [published online December 23, 2013]. Curr Med Res Opin. doi:10.1185/03007995.2013.873398.

14. Quinn B. Payers and the assessment of clinical utility for companion diagnostics. Clin Pharmacol Ther. 2010;88(6):751-754.

15. Deverka P, Messner D, Dutta T. Evaluation of clinical validity and clinical utility of actionable molecular diagnostic tests in adult oncology. Center for Medical Technology Policy. www.cmtpnet.

org/effectiveness-guidance-documents/molecular-diagnostics-egd/. Published May 1, 2013. Accessed January 29, 2014.