Nick Mulcahy

May 22, 2014

ORLANDO, Florida — A commercially available prostate cancer test (Prolaris, Myriad Genetics) has been "validated" in its ability to predict disease-specific death in the largest study of its kind, according to a presentation here at the American Urological Association (AUA) 2014 Annual Scientific Meeting.

The 46-gene test is marketed as a molecular prognostic tool that assesses the aggressiveness of an individual patient's cancer.

The study showed that the test can differentiate men at higher risk for death from prostate cancer from those at lower risk.

But the usefulness of Prolaris — and genetic tests like it — is unclear because it has not yet been demonstrated that it actually improves outcomes, said a number of experts interviewed by Medscape Medical News.

For instance, the Prolaris test can indicate that a 60-year-old man with a Gleason score of 7 has a greater risk for metastasis and death than a similarly aged man with the same Gleason score, explained Stephen Jones, MD, from the Department of Urology at the Cleveland Clinic, who was not part of the study.

"That may be accurate, but what is the impact on actual outcomes? We don't know," he told Medscape Medical News. "The impact on outcomes is the part that is not validated."

The study assessed data on 761 men from the United Kingdom who had prostate cancer diagnosed with needle biopsy from 1990 to 2004 and who were "conservatively managed" with watchful waiting. Definitive treatment was provided at the onset of symptoms.

The primary end point of the study was disease-specific mortality (18%), and the median follow-up was 9.5 years, said lead author Jack Cuzick, PhD, from the Wolfson Institute of Preventive Medicine in London, United Kingdom.

Tumor tissue from this prospective cohort was later retrospectively analyzed with the Prolaris test. Thus, the researchers were able to associate outcomes with test scores.

The results indicate that for each 1 unit increase in Prolaris score, patients had approximately twice the risk of dying from prostate cancer over 10 years.

Table. 10-Year Death Rate by Polaris Score

Prolaris Score 10-Year Death Rate, %
<0.0 7
0.0–1.0 15
1.1–2.0 36
>2.0 59

 

Overall, the test scores are "highly predictive" of disease-specific mortality (P = 3.9 × 1021), according to the study authors.

However, Dr. Jones questioned the time period used in the study and the population. The data may or may not "apply to a contemporary group of patients in a different geography — for instance, the United States in 2014. We don't know," he said.

An official from Myriad discounted that compliant.

 
Prostate cancer is prostate cancer.
 

"Prostate cancer is prostate cancer," chief medical officer Michael Brawer, MD, told Medscape Medical News. He also said that most of the men in the study were followed from 2002 onward, making it "contemporary."

"You could never do this study in the United States," said Dr. Brawer. The event rate would probably not have been substantial enough in an American population, where patients are managed more aggressively, he explained.

Dr. Jones and another expert not involved with the study, Michael Blute, MD, both believe that more studies are needed.

Widespread adoption of genetic tests would be "a major paradigm shift in the management of men with newly diagnosed prostate cancer," said Dr. Blute, who is chief of the Department of Urology at the Massachusetts General Hospital in Boston.

"The test needs to show consistency in a clinical setting," Dr. Blute told Medscape Medical News. He said he would like to see prospective multi-institutional clinical trials to reproduce the results in the United States.

Do not expect Myriad to run such trials, said Dr. Brawer, citing expense. Furthermore, current data provide prognostic information beyond that of standard clinical measures, and are, as such, very valuable, he explained.

 
A test like this is sorely needed.
 

Dr. Blute is not opposed to Prolaris or other genetic tests. "A test like this is sorely needed," he said, but too many questions about "clinical utility" remain.

Dr. Jones agreed: "It's important that we continue to investigate all of these tests to determine if they are going to give meaningful and actionable information."

The AUA and other organizations need to provide direction, suggested Dr. Blute. "Leadership in urology needs to come to the fore. How are we going to handle tests like this?" he asked.

"We don't want the marketing to get out in front of the science. We have seen that in medicine before," Dr. Blute added.

But the marketing has begun for these genetic tests, which include Prolaris, Decipher (GenomeDx), and the Oncotype DX (Genomic Health). And they are expensive, say experts.

"Their cost is substantial," said Laurence Klotz, MD, from the division of urology at the University of Toronto, who was not involved with the study, but who answered questions about genetic testing during an AUA press briefing.

The list cost for Prolaris is $3400 and for Oncotype DX is around $4000.

Prolaris "is an expensive test," Dr. Brawer acknowledged. But he cited a study that found that the test "changes management in two-thirds of patients" (Curr Med Res Opin. 2014;30:1025-1031).

Cost-effectiveness studies are forthcoming. The savings from preventing under- and overtreatment in some men needs to be assessed when discussing cost, he said.

Marginal Utility?

Dr. Brawer believes that this validation study and 9 other studies of Prolaris are solid evidence of its usefulness. The test should be used in patients who clinicians believe are in need of "more precision in arriving at a risk assessment," he said.

"I can't tell you a patient group with a constellation of clinicopathologic features where the test won't have an impact," he added. "There is no cut point."

In other words, most men with newly diagnosed prostate cancer are candidates for genetic testing.

However, Dr. Klotz, who is a pioneer in the use of active surveillance in low-risk men, sees genetic testing differently.

 
The tests look very promising.
 

"The tests look very promising," he offered. However, "the number of patients who are really going to benefit [from genetic tests] is probably fairly small."

Dr. Klotz suggested that the swath of men in need of the test might be limited because there is only so much room for improvement in the death rate of low-risk prostate cancer, which is the majority of disease.

"The question is how useful these [tests] are going to be, because the marginal utility is to reduce mortality from 1.5% or 2% to close to 0% — it's probably never going to absolutely zero," he said. These data come from a long-term study of a Toronto cohort presented by Dr. Klotz at the 2014 annual congress of the European Association of Urology, as reported by Medscape Medical News.

In other words, men with low-risk disease already have a very low rate of death from prostate cancer at a median follow-up of 10 years, even without genetic testing.

However, Dr. Brawer pointed out that 40% of the men in the Toronto cohort went onto receive definitive treatment. "You want to do the right treatment at the right time," he said.

Dr. Klotz further said that data on the Oncotype DX test indicate that only about 10% of men with very-low-risk disease and 20% of men with low-risk disease, by standard clinical measures, have a subsequent genomic score that puts them at higher risk for worse disease. The Polaris test gives "similar results," he added.

"That may be a way of identifying the bad actors," he noted.

Over the next decade or so, the urology community will learn how best to use the tests, said Dr. Klotz. Prognostic tests will also need to be integrated with MRI, which is now a "very, very valuable tool" for diagnosing and monitoring prostate cancer.

The study had no funding source disclosed. Dr. Jones, Dr. Blute, Dr. Klotz have no financial disclosures. Dr. Brawer is an employee of Myriad Genetics.

American Urological Association (AUA) 2014 Annual Scientific Meeting: Abstract MP79-17. Presented May 20, 2014.

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