While Myriad Genetics, Inc, touts recent studies on the predictive value of its Prolaris test for prostate cancer, the biggest news may be yet to come: as Evidence-Based Oncology went to press, CMS was weighing whether the test merits reimbursement.1
Prolaris, which came on the market in 2010,2 is a 46-gene test designed to gauge the aggressiveness of prostate cancer in individual patients, based on the expression of cell cycle regulator genes. Unlike the prostate-specific antigen (PSA), which offers a snapshot of the cancer on a given day, Prolaris promises a window into the future, assigning a score that increases along with the risk of progression.
Myriad’s CMS filing is “the most comprehensive dossier for a molecular diagnostic test ever,” said Ronald Rogers, a spokesman for the company. However, as Evidence-Based Oncology reported in May, standards of reimbursement for diagnostic tests are still in flux, especially when CMS must pay.3 Thus, CMS’ decision on Prolaris will be watched closely across the diagnostic testing industry.
Evidence-Based Oncology made multiple attempts to seek comment from CMS, but the agency did not respond.
Myriad Presents Results
On May 20, 2014, Myriad presented a new round of results at the annual meeting of the American Urological Association (AUA) in Orlando, Florida. The most important data came from a study of 761 men in the United Kingdom whose cancer was conservatively managed after they were diagnosed by needle biopsy. Patients were followed for an average of 9.5 years, with prostate cancer death as the primary end point. Tumor samples from these patients were later evaluated with the Prolaris test. Results showed that for each 1-unit increase in the Prolaris score, patients’ risk of dying from prostate cancer doubled.4
“This is the largest study of its kind,” said Michael Brawer, MD, vice president of medical affairs for Myriad. Before these results, he said, “There have never been any publications involving patients who were managed conservatively, with death as the end point.”
The prospect of better information on how an individual’s prostate cancer will act is compelling in light of the controversy in the United States over who should get PSA tests and how often. The AUA was among the groups that pushed back in May 2012, when the US Preventive Services Task Force (USPSTF) issued a recommendation of “D” for PSA tests. USPSTF had responded to concerns about overtesting and high downstream costs from treatment of cancers that posed little risk. However, many were incredulous at the USPSTF rating and said the problem was overtreatment, not screening. As reported in Evidence-Based Oncology in February, the journal Cancer published results in January that found 72% of the “cost” associated with the PSA test came in the aftermath, not from the test itself.5
The AUA responded with its own guidelines to target PSA screening in men aged 55 to 69 years. In March, the National Comprehensive Cancer Network (NCCN) updated its screening criteria, with testing to start as early as age 45 years and repeated at intervals, depending on results and a patient’s risk factors.6 But so far, while some physicians strongly support biomarker use, both AUA and NCCN guidelines are more cautious, with a focus on PSA screening.
Recent updates of AUA guidelines speak to biomarkers generally but not to a Prolaris-type test specifically. The 2013 update on detection of prostate cancer states, “Future studies of the genetic and epigenetic basis of disease development and progression may provide biomarkers and/or panels of biomarkers with improved specificity when compared to PSA. When available, risk assessment tools combining multiple predictors will need to be evaluated in carefully designed trials to be generalizable to the population in which they would be used.”7
The recently updated guideline on treatment of castration-resistant prostate cancer states, “One of the glaring deficiencies in prostate cancer drug development, by comparison to several other solid tumors, has been the lack of predictive biomarkers to help better personalize therapy. This is especially important if we are to optimize risk/benefit, particularly given that a significant percentage of patients do not benefit or have small benefits from current FDA approved agents.”8
The NCCN’s 2011 task force report on biomarkers offered little enthusiasm for prostate cancer tests.9 Multiple studies have appeared since then, including reports on Prolaris and ConfirmMDx, a test by MDxHealth designed to avoid repeat biopsies. But payers offer reimbursement based on “clinical utility,”5 and when prognostic tests are described as an “adjunct” to decision making, coverage may be denied. This happened recently with Blue Cross and Blue Shield of Alabama, which described testing for the PCA3 biomarker as “investigational.”10
Comparison to Gleason Score
The 2011 NCCN report said, “In prostate cancer, Gleason score remains the single most prognostic feature of localized cancer. Although many molecular assays have also been found to be associated with prognosis in prostate cancer, none are in broad use, because most offer little to no independent prognostic information over Gleason sum, and thus lack clinical utility.”9
Myriad’s AUA presentations addressed this directly. The company reported results that compare the results of Prolaris with the Gleason score in a study of 230 men who had scores of either 4+3 or 3+4.4 Gleason scores, which are determined by a pathologist, range from 2 to 10 and represent the sum of 2 evaluations of cancer cells on a scale of 1 to 5. The first number characterizes the appearance of cells in the primary tumor, while the other score describes the secondary pattern in other cancer cells. Sometimes, Gleason scores are “upgraded” based on what pathologists find in a cancerous tissue after a radical prostatectomy.
This study asked how well Prolaris predicted biochemical recurrence (BCR) compared with the Gleason score. There was no difference in BCR based strictly on Gleason score; however, Prolaris more accurately predicted BCR prior to upgrading. According to Myriad, this means if the Prolaris test is performed right after a biopsy, the true risk of progression can be known earlier, leading to better initial decisions about treatment.4
The Clinical Utility Question
The AUA presentations followed the March publication of the PROCEDE 500 study,11 which found that 65% of physicians changed their initial treatment plans for prostate cancer patients based on Prolaris results. Of the 305 patients in the study, 122 saw their treatment plans scaled back, while 76 experienced a more aggressive treatment plan after their doctors viewed the results.
These findings address “clinical utility,” or whether a test makes the difference in guiding treatment decisions. Clinical utility, not validity, is now the benchmark insurers use to decide whether to
pay for molecular tests.5 Overall, the study reported a 50% reduction in surgical interventions and a 30% reduction in radiation treatment.10 Myriad’s case for CMS reimbursement, which was updated in March, is based largely on these results, which the company says show that the test more than pays for itself by preventing unnecessary care. A press release anticipates a ruling from CMS “by the end of June 2014,” but Rogers said the agency is not required to respond to Myriad’s filing at that time.1
Among clinicians, Prolaris has received high-profile praise from some of the most prolific researchers in prostate cancer, as well as skepticism from others about its value. E. David Crawford, MD, was the lead author on the clinical utility results reported in March,10 and is head of the Section on Urologic Oncology at the University of Colorado. Crawford called the test “a game changer for urologists, because it adds meaningful new prognostic information in terms of risk assessment.”11
In the April issue of Current Medical Research Opinion, Neal D. Shore, MD, FACS, and director of the Carolina Urologic Research Center, was lead author on an article reporting a survey of urologists who have used the test. Results found that the Prolaris scores differed with expectations 55% of the time.12 “The data suggest that the test would have the net effect of shifting patients from more aggressive treatment to more conservative treatment,” the study said. But during the AUA meeting in May, leading clinicians not connected with these studies had questions about their significance. Stephen Jones, MD, from the Department of Urology at the Cleveland Clinic, told Medscape Medical News, “What is the impact on actual outcomes? We don’t know,” he said. “The impact on the outcomes is the part that is not validated.” Jones was among prostate cancer clinicians who told Medscape that the jury is still out on such tests.13
Lack of Consensus About Payment
Disagreement among scientists is cited by payers in decision making. The Blue Cross decision in Alabama, for example, cited NCCN’s language that biomarkers should not be used as first-line therapy to “increase the specificity” of decisions.10 Prolaris costs $34002; a competing test, Oncotype DX, reportedly costs $4000.11 While some payers have raised alarms about cost, molecular testing companies have told Evidence-Based Oncology that without reimbursement, it’s difficult to gather the clinical utility data that so many seek.4 A review article on diagnostic tests by David A. Santori and Daniel W. Chain, which appeared around the time of the AUA meeting, did not mention cost per se, but advised clinicians to evaluate clinical utility and said tests should be “used with caution.”14
The authors noted that unlike the PSA, which is designed primarily to detect cancer, “The current focus of (prostate cancer) biomarker research is to find markers for aggressive disease.
However, there is no consensus on the definition of aggressiveness.” The only standard is the NCCN guideline of a Gleason score of 8, although they note that most doctors will view a score of 7 as aggressive.12 Testing companies, frustrated by inconsistency in reimbursement decisions nationwide, are fighting back. This spring, the California Clinical Laboratory Association sued over Medicare’s denial of coverage for several tests.3
In an e-mail, Myriad’s Rogers said the company believes CMS categories for reimbursement are clear: analytical validity, clinical validity, and clinical utility. However, he said, “The levels of evidence needed to support each of these categories is subjective and open to interpretation, making the process somewhat unpredictable.” Myriad believes that well-designed retrospective studies are “appropriate” for demonstrating clinical validity and utility. Others want to see prospective studies, but the company said this is not always practical.
Clinicians may disagree on whether the evidence is in, but even the skeptics say a test such as Prolaris would help doctors and patients. Said Michael Blute, MD, chief of urology at Massachusetts General Hospital, “A test like this is sorely needed.”13 References
1. Myriad publishes clinical utility study for Prolaris: Myriad updates dossier for Medicare reimbursement [press release]. Salt Lake City, UT: Globe Newswire; March 3, 2014. http://investor.myriad.com/releasedetail.cfm?ReleaseID=829482.
2. Myriad launches Prolaris: first diagnostic test to predict prostate cancer recurrence [press release]. Salt Lake City, UT: Globe Newsire; March 2, 2010. http://investor.myriad.com/releasedetail.cfm?releaseid=448383.
3. Caffrey MK. When science outpaces payers: reimbursement in molecular diagnostics. Am J Manag Care. 2014;20(SP7):SP234-SP236.
4. Prolaris predicts prostate cancer mortality risk in biopsy study [press release]. Salt Lake City, UT: Globe Newswire; May 20, 2014. http://files.shareholder.com/downloads/MYGN/3154717975x0x756185/bd1ef370-452a-4dc6-ac99-94e425d62431/MYGN_News_2014_5_20_General.pdf.
5. Caffrey MK. A test to prevent repeat prostate cancer biopsies? perhaps, if the bar of “clinical utility” can be met. Am J Manag Care. 2014;(SP2):SP30-SP31.
6. Caffrey MK. New NCCN prostate cancer screening guidelines aim for middle ground. Am J Manag Care. 2014:20(SP7):SP210, SP212.
7. American Urological Association. Detection of cancer. http://www.auanet.org/education/guidelines/prostate-cancer-detection.cfm. Published April 2013. Accessed June 24, 2014.
8. American Urological Association. Castrationresistant prostate cancer. http://www.auanet.org/education/guidelines/castration-resistantprostate-cancer.cfm. Published April 2014. Accessed June 24, 2014.
9. Febbo PG, Ladanvi M, Aldape KD, et al. NCCN Task Force report: evaluating the clinical utility of tumor markers in oncology. J Natl Compr Canc Netw. 2011;9(suppl 5):S1-S32.
10. Gene-based tests for screening, detection, and/or management of prostate cancer. Blue Cross Blue Shield of Alabama website. https://www.bcbsal.org/providers/policies/final/534.pdf. Published April 2014. Accessed June 18, 2014.
11. Crawford ED, Scholz MC, Kar AJ, et al. Cell cycle progression score and treatment decisions in prostate cancer: results from an ongoing registry. Curr Med Res Opin. 2014;30(6):1025-1031.
12. Shore N, Concepcion R, Saltzstein D, et al. Clinical utility of a biopsy-based cell cycle gene expression assay in localized prostate cancer. Curr Med Res Opin. 2014;30(4):547-553.
13. Mulcahy N. Gene test for prostate cancer validated: triumph or worry? Medscape Medical news. http://www.medscape.com/viewarticle/825578. Published May 22, 2014. Accessed June 17, 2014.
14. Santori DA, Chan DW. Biomarkers in prostate cancer: what’s new? Curr Opin Oncol. 2014; 26(3):259-264.