New prostate cancer tests mark era of personalized medicine

National Report-A new generation of prostate cancer biomarkers promises to alter the way in which urologists make clinical management decisions. Although some of the tests that rely on these newer biomarkers can be expensive, their use also may be cost saving if the information they provide allows clinicians and patients to make more informed choices about the need for biopsy, re-biopsy, or adjuvant therapies, say leaders in the field.

The newer prostate cancer biomarkers are “one of the most exciting things that has happened in prostate cancer in the last decade or so,” said E. David Crawford, MD, head of urologic oncology and professor of surgery, urology, and radiation oncology at the University of Colorado School of Medicine, Denver. “These markers are personalized medicine. If they had been around 5 years or 10 years ago, we wouldn’t have the problem we have right now [with overdiagnosis and overtreatment].”

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Dr. KleinThe first-generation biomarkers represent “incremental but important steps forward in making more precise judgments about how to manage patients,” said Eric Klein, MD. Although not 100% accurate, the newer biomarkers improve upon the approximately 80% predictive accuracy achieved with the standard nomogram-based approach using prostate-specific antigen (PSA), Gleason grade, and clinical stage to assess prostate cancer aggressiveness, he said.

“We overtreat prostate cancer in this country,” said Dr. Klein, chairman of the Glickman Urological and Kidney Institute at Cleveland Clinic. “Ninety percent of men with newly diagnosed low-grade, Gleason 6 disease get treated when in fact most of them could be watched. My goal for these first-generation assays is to reduce that overtreatment rate by 20%.”

With the use of the newer prostate cancer biomarkers, a patient’s risk category shifts about 20% of the time compared with using the standard risk nomogram as defined by the National Comprehensive Cancer Network, potentially changing the management strategy depending on clinical circumstances.

Solid science behind biomarkers

An understanding of the molecular changes that occur in the pathogenesis of prostate cancer to changes associated with aggressive growth and metastatic potential has fueled the discovery of the newer biomarkers. The changes can be measured at the DNA level where structural rearrangements of DNA, chromosomal translocations, gene fusions (ie, TMPRSS2:ERG fusion), and epigenetic alterations such as DNA methylation within the promoter region of genes can be observed and sometimes measured.

Gene expression changes induced at the RNA level in prostate cancer have also been identified, and are measurable by standard gene expression assays. Dysregulation of regulatory (non-coding) RNAs has been implicated in the initiation and progression of prostate cancer.

“The development of these biomarkers is based on solid science,” Dr. Klein said. “At some level, they all can predict the biologic potential of a tumor by measuring the molecular changes either on a biopsy or on a prostatectomy specimen.”

Actionable results

Dr. ShoreClinical applications of prostate cancer biomarkers include diagnosing patients with the disease, defining the aggressiveness of prostate cancer, identifying patients most likely to benefit from treatment, finding low-risk prostate cancer (thereby sparing some patients from unnecessary intervention), or guiding the selection and intensity of adjuvant therapy in the post-radical prostatectomy setting. To be relevant, the tests that accompany these biomarkers must be shown to achieve their intended goal in prospective clinical utility trials.

The message from Neal D. Shore, MD, director of the Carolina Urologic Research Center in Myrtle Beach, SC, is that clinicians must be aware of the biomarker assays so that they and their patients can make more informed decisions.

“There is information [from biomarkers] that’s actionable now,” he said. “Many of these biomarkers are commercially available. Most of them are in ongoing trials.”

One obstacle to their routine use in practice, he said, is that with the exception of the PSA test, testing for most of the prostate cancer biomarkers lacks a code for reimbursement by the Centers for Medicare & Medicaid Services, and by extension, most third-party payers.

At present, the biomarker list exceeds a dozen and is expanding rapidly as a result of genomic profiling of prostate cancer. The list can be categorized into biomarkers that can help clinicians decide whom to biopsy, those that can help select candidates for re-biopsy, those that can assist in determining whom to treat or manage with active surveillance, and those that can be used to assess therapeutic response, according to Drs. Shore and Crawford.

Deciding when to biopsy

The prostate health index (phi), approved by the FDA in June 2012, is one test that estimates the probability of prostate cancer diagnosis. It combines measurements of free/total PSA (%PSA) and proPSA to arrive at a score. When total PSA is 2.0 to 10.0 ng/mL, using a phi level of 27 for selecting men for biopsy has been shown to decrease the rate of unnecessary biopsies and reduce the rate of overdiagnosis of non-aggressive disease (Clin Chem 2013; 59:306-14).

Prostate cancer antigen 3 (PCA3) is a gene that is highly overexpressed in prostate cancer. The assay to test for PCA3 on messenger RNA from urine is FDA-approved for use in men 50 years or older who have had one or more previous negative biopsies. It also has utility in helping to determine whom to re-biopsy and in following patients who are being managed with active surveillance, Dr. Crawford said. PCA3 has outperformed PSA in predicting low- and intermediate-grade cancer (J Urol Dec. 11, 2013 [Epub ahead of print]).

Deciding when to re-biopsy

Dr. CrawfordDetermining whom to re-biopsy is the indication for which prostate cancer biomarkers “have the most use right now,” he said. Of the 1.2 million prostate biopsies done annually in the United States, about 80% are negative, he noted.

“There’s a need for a test to help us determine who needs to be re-biopsied and who doesn't,” he said. “The one that's getting a lot of attention right now, and rightfully so, is the ConfirmMDx test [MDx Health, Irvine, CA].” It extends the coverage of a biopsy by detecting changes that occur in cells around the cancer from methylation of DNA.

“The test is powered for a negative predictive value, so that if it comes back negative, you have 90+% confidence that no cancer is present,” as determined in a study known as MATLOC (J Urol 2013; 189:1110-6), said Dr. Crawford.

The actionable guidance provided by ConfirmMDx is also cost-effective, he said. When the test was implemented solely on negative biopsies in a managed care plan of 1 million men, the number of repeat biopsies avoided was calculated to save the plan more than $500 per patient (American Health & Drug Benefits 2013; 6:15-24).

Deciding who to treat

Gleason grade is the most widely used tool in assigning prostate cancer grade. It remains a powerful predictor of the aggressiveness of the cancer, “but we know that it doesn’t tell the whole story,” said Dr. Klein. Even low-grade tumors can become metastatic while not all high-grade tumors will.

Prolaris (Myriad Genetics, Salt Lake City, UT) and Oncotype DX (Genomic Health, Redwood City, CA) are molecular tests intended to predict candidates for surveillance. These tests identify molecular markers in prostatectomy specimens that predict for biochemical recurrence, metastasis, or death. An absence of these markers on a biopsy specimen predicts lower risk cancer and therefore a good candidate for surveillance.

“We now have a window, using some of these tests, into the biology of cancer that adds useful, unique, and significant information above and beyond Gleason grade,” Dr. Klein said. “It is possible to measure a molecular marker that is associated with aggressive tumors in tumors that look like they’re low Gleason grade.”

Because prostate cancer is multi-focal, whether or not the absence of a biomarker on a biopsy specimen reflects the biology of the entire prostate is unknown, he said. The genes assayed in Oncotype DX were shown to predict for metastasis or death in both low-grade and high-grade tumors in prostatectomy specimens (J Clin Oncol 2012; 30 [suppl; abstr 4560]).

“At least for Oncotype DX, we can say with some confidence that if the marker is present even in the low-grade tumor that you typically biopsy, you can believe that the prostate harbors some aggressive biology in it somewhere,” Dr. Klein said.

The accuracy of the Genomic Prostate Score (GPS) derived from Oncotype DX in predicting the absence of aggressive features on tumor biopsy approaches 90%, compared with 80% using Gleason grade, clinical stage, and PSA, said Dr. Klein.

How management is influenced

He gave examples of management strategies that were influenced by use of Oncotype DX in his practice. In one case, a patient in his mid-50s had two cores of cancer assigned as Gleason 6 and a PSA level of 6.0 ng/mL, defined as low risk. His GPS predicted with 75% certainty that he had low-risk disease confined to the prostate, making him a candidate for active surveillance. The patient opted instead for treatment, not being satisfied with the odds of low-risk disease.

A 75-year-old patient with an approximate 15-year life expectancy had intermediate-risk disease defined by <1 mm of Gleason 3+4 cancer on biopsy. His GPS revealed a 60% chance of having low-grade cancer, yet the patient insisted on prostatectomy.

“It turned out that he had a large volume of Gleason 8 cancer that was outside his prostate,” said Dr. Klein. “I’m really glad that we treated him.”

In each case, Oncotype DX provided an estimate of risk to the patient on which to base his decision that was more precise than simply indicating “low risk” on the basis of Gleason score and clinical stage.

Decipher (GenomeDx Biosciences, San Diego) is a genomic test that assesses the risk of disease progression after radical prostatectomy. (The Prolaris test is also used post-prostatectomy to estimate risk of recurrence.) Decipher’s utility may lie in selecting men for adjuvant systemic therapy or radiation therapy, said Dr. Crawford. “You can have two patients with positive margins, seminal vesicle invasion, Gleason 7 or 8 grade cancer who look the same pathologically, but one might have a 5% risk of progression [on Decipher] and the other might have a 30% or 40% risk,” he said. The next step is showing that delivering therapy based on the results of this test alters survival.

Imaging techniques as a complement

Advanced imaging modalities may also facilitate risk stratification by accurately identifying tumor size, location, and extent, said Dr. Shore. (Also see, “MRI guiding future of prostate Ca diagnosis")

“With improved sophistication of MRI technologies, specifically multiparametric MRI, which uses diffusion-weighted or contrast-enhanced MRI evaluation, the MRI can potentially assist in helping to decide where to biopsy a lesion,” he said. “Some have argued that some lesions look more aggressive than others on MRI.”UT

Disclosures: Dr. Crawford is an adviser to and a speaker for Genomic Health, MDxHealth, and Myriad Genetics. Dr. Klein is a consultant and has received research support from Genomic Health, Metamark Genetics, and GenomeDx Biosciences. Dr. Shore is a consultant to Genomic Health, MDxHealth, and Myriad Genetics.

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