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Gene Expression Database Helps Advance Prostate Cancer Research, GenomeDx Testing Business

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NEW YORK (GenomeWeb) – GenomeDx Biosciences, a urological cancer-focused genetic testing company, this week significantly expanded a data-sharing network that has been instrumental to its growing diagnostics business and has helped researchers better understand the genomic underpinnings of prostate cancer.

GenomeDx markets a test that measures the expression of 22 RNA markers and provides a score denoting the aggressiveness of a patient's prostate cancer. The San Diego and Vancouver, Canada-based company launched the so-called Decipher Genomics Resource Information Database (Decipher GRID) last May, which contains a variety of different data points on patients who have received its test. 

This week, GenomeDx announced that the Glickman Urological and Kidney Institute at Cleveland Clinic, Tulane Cancer Center, Chesapeake Urology, University of Michigan Cancer Center, University of Maryland Medical Center, and Rush University Medical Center had also joined a network of collaborators using Decipher GRID for research. Last year, the Sidney Kimmel Cancer Center at Thomas Jefferson University and Cedars-Sinai Medical Center had announced their participation. 

According to GenomeDx CEO Doug Dolginow, researchers from 55 cancer centers have used the resource to conduct and publish studies on the Decipher test. The database to date contains profiles from more than 10,000 patients who have been analyzed on the prostate cancer classifier, and is clocking 900 new profiles per month.

GenomeDx soft-launched the Decipher test three years ago for cancer patients who've had their prostate surgically removed, and fully commercialized the diagnostic last year. This January, the company began marketing Decipher for prostate cancer patients with localized disease who've had a biopsy. 

While the commercially marketed test only reports on the expression of 22 markers, it uses the Affymetrix GeneChip, which analyzes 1.4 million markers. Decipher GRID contains anonymized tumor RNA expression data on all the markers gauged by the chip, which researchers can study alongside other information on patients' tumors and outcomes, to explore signatures associated with cancer progression or treatment response.

"What's happening with the GRID is that we're using the other markers [on the chip] to generate new signatures, and look at functional pathways to try to have a better understanding of patients' cancers," Robert Den from Sidney Kimmel Medical College at Thomas Jefferson University told GenomeWeb.

All study collaborators and any physician who orders a test receives a report based on Decipher GRID data on additional RNA expression markers linked to cancer on a research-use basis. Researchers who want more detailed information in the database for their clinical investigations have to sign user agreements.

According to Dolginow, Decipher GRID has been enormously beneficial for GenomeDx's business and is advancing knowledge of the biology underlying prostate cancer. "Last year we published two publications a month, and this year we're averaging three publications a month," he told GenomeWeb.

By allowing researchers access to data in Decipher GRID, GenomeDx has been able to expedite the development of its prostate cancer test into new indications. "We get products out that have high performance, but we do it very quickly," Dolginow said, noting that the database was instrumental in the validation of the Decipher prostate cancer tests in the post-operative setting and on biopsy samples.

A few weeks ago, researchers led by Den published the first prospective validation study for the Decipher test in Prostate Cancer and Prostatic Diseases. Den and colleagues concluded in the study — involving more than 2,300 prostate cancer patients tested on Decipher after a radical prostatectomy — that the classifier score correlates with pathologic stage, age, CAPRA score, and pathologic Gleason score, but also provides information beyond these traditional risk factors and assessments. 

The authors noted that 25 percent of patients in the study, who were stage T2, had negative margins, and wouldn't be recommended for post-operative radiation, were deemed to be high risk by Decipher. Meanwhile, 18 percent of patients in the study who were stage T3 or more advanced, had Gleason scores 8-10, and would normally be considered for adjuvant radiation, received low risk scores from Decipher.

"There is a percentage of patients that have discordance that we have seen and known about having followed patients clinically," Den said. "But we never had a way to tell a patient a priori with more certainty how truly aggressive their disease was."

Using available risk assessment tools, urologists have long had to guess the aggressiveness of prostate cancer patients' tumors and figure out whether to give them radiation therapy immediately after a prostatectomy or follow them closely and give salvage radiation if prostate cancer antigen levels start to rise. This is the uncertainty that molecular diagnostic companies like GenomeDx are aiming to resolve.

The American Cancer Society estimates more than 180,000 men will be diagnosed with prostate cancer this year and around 26,000 will die from the disease. Of the men that receive surgery, 50 percent are considered at increased risk for recurrence and metastases based on clinical or pathological risk factors, and current guidelines recommend they get post-operative radiation therapy. While studies have shown that radiation treatment reduces biochemical recurrence, the data also show that half of the men who are closely followed after a prostatectomy don't experience recurrence.  

"The problem is, you have to radiate 56 men to save one man's life," Dolginow said, highlighting that radiation treatment brings with it risks for side effects, including incontinence, impotence, and bladder failure.

Guidelines bodies have extended support for molecular testing for certain prostate cancer patients, recognizing the limitations of current risk assessment modalities. The latest guidelines from the National Comprehensive Cancer Network recommends molecular testing for men with localized disease to reduce uncertainty about disease progression.  

Medicare has agreed to cover a number of molecular tests for prostate cancer, including Decipher. In a decision last year, Medicare said it would cover Decipher when used to identify high-risk prostate cancer patients who can be followed closely and avoid post-surgery radiation treatment. The test is only covered for patients who are considered high risk for recurrence after a radical prostatectomy using traditional parameters, including stage T2 disease with positive surgical margins; pathological stage T3 disease; or rising prostate specific antigen levels from previously undetectable levels.

The latest prospective study on Decipher showed that doctors are largely ordering the test for the patients that fit Medicare coverage criteria. It also revealed that 89 percent of the more than 2,300 patients in the trial received testing at community centers and 11 percent were seen at academic centers. This suggests greater adoption of Decipher within community practices.

Although the majority of cancer patients in the US receive care in the community setting, novel genomic testing approaches aren't as readily used as they are in academic and large cancer centers. This has been the case, Den acknowledged, because it's often unclear what action to take based on the results of a genomic test, or the treatments that a test might point to aren't available outside of an academic center. 

"If you order a test but you don't have a way to bring treatments to bear based on the results, it's not as useful a test," he said. "With this test, because there are previous publications showing how this test can have direct impact on management using conventional treatments, it's easier for the community physicians to understand the value and to bring that value to their patients."

However, guidelines bodies and insurers trying to pinpoint the specific context in which molecular testing benefits prostate cancer patients have noted that the slow progression of the disease is a major challenge for prospective evaluation. Approximately 99 percent of prostate cancer patients are alive five years after diagnosis, and it can take more than 15 years before the cancer recurs, metastasizes, or a patient dies from it.

So, it will take a long time to complete prospective, randomized studies investigating whether molecular tests are better at measuring prostate cancer aggressiveness and can reduce metastasis and extend survival compared to standard risk assessment tools. But this is also where a resource like Decipher GRID can help.

Currently, close to two dozen collaborators have institutional review board approval to use Decipher GRID and are applying anonymized genomic information in their studies. Many of these studies are using registries to longitudinally track patients' disease features, progression, treatments, and side effects.

As an example of the types of investigations being spurred by Decipher GRID, Den highlighted a study he collaborated on, led by Scott Tomlins of the University of Michigan and published last year in European Urology, where researchers analyzed Affymetrix GeneChip expression profiles from more than 1,300 patients who had been tested on GenomeDx's test and identified three distinct molecular subtypes. 

Prostate cancer researchers are working to advance therapeutic strategies for molecularly defined subpopulations in the same way breast cancer patients classified to have estrogen receptor-positive, HER2-positive, or triple-negative disease, undergo different treatment modalities. "We don't yet have that for prostate cancer, but through understanding and characterizing patients into different subtypes the idea is to … be able to give more personalized approaches for a patient," Den said.

He is collaborating with other researchers using Decipher GRID to study markers predicting response to radiation, hormone therapy, and chemotherapy, and they hope to publish data from some of these investigations in the near future.

Meanwhile, bolstered by the database and multiple research collaborations, GenomeDx is aiming to launch one or two new tests a year, and has slated for commercialization a bladder cancer test in 2017. According to GenomeDx, Decipher GRID is the largest RNA expression data repository in prostate cancer, and the company continues to grow the resource to support development of other tests. "We will have the largest cohort of data around bladder cancer, shortly," Dolginow said.

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