by Elizabeth Newbern

NEW YORK (GenomeWeb) – A recently published study by researchers from New Zealand-based diagnostic firm Pacific Edge and collaborators has shown that the firm's molecular diagnostic test for bladder cancer recurrence, Cxbladder Monitor, outperforms cytoscopy and other commonly used US Food and Drug Administration-approved urine- based tests for bladder cancer monitoring.

The study, published in late April in Urologic Oncology,concluded that the test provides clinicians with a "confirmatory negative adjunct to cystoscopy" or justification to postpone a cystoscopy when monitoring for recurrent bladder cancer in low-risk patients. The paper also follows on the heels of a company-led prospective validation of the assay published in December in the Journal of Urology.

Together, the studies provide compelling evidence regarding the clinical utility of Cxbladder Monitor, which hit the US market as a laboratory-developed test in December 2016 after being launched in New Zealand a year earlier.

Pacific Edge is headquartered in Dunedin and also has a CLIA-certified, CAP-accredited lab facility in Hershey, Pennsylvania, where a 20-person sales team markets its product directly to urologists. The company also has a CLIA laboratory in Dunedin, and has commercial operations in Singapore and Australia.

Cxbladder Monitor is the third of four tests in the company's portfolio of assays bearing the Cxbladder moniker. Cxbladder Detect, which identifies patients showing changes in gene expression for bladder cancer, and Cxbladder Triage, which combines the biomarker genes with known bladder cancer risk factors to help rule out cancer, have been commercially available for several years in New Zealand, and Cxbladder Detect has been available for several years in the US. A fourth assay called Cxbladder Resolve, which is intended to identify patients with high-grade and late-stage disease, launched in New Zealand this past December and is expected to be launched as an LDT in the US later this year. Cxbladder Detect, Triage, and Monitor are also available in Australia and Southeast Asia.

Founded in 2001, the company "spent the first three years of our life building this large gene database with all of these gene expression patterns for cancer," Pacific Edge CEO Dave Darling said. "We were working on [developing markers for] breast cancer, colorectal cancer, endometrial cancer, melanoma, and bladder cancer."

At first the company planned to break into the US market by selling its products through blue chip companies such as Abbott, Roche, and Bayer. However, after several meetings with these companies and a few rounds of clinical research Pacific Edge decided to follow a different path. "At the time Genomic Health and Myriad Genetics were getting underway with this small-to-medium enterprise," Darling said. "They were showing us that there was a model that involved CLIA regulatory approval that would give us the opportunity to regulate our product in a non-FDA compliant environment."

Once the company opened up its CLIA-certified laboratory in Pennsylvania, it began to roll out the Cxbladder portfolio beginning with Detect, which measures five messenger RNA (mRNA) biomarkers (MDK, HOXA13, CDC2, IGFBP5, and CXCR2) to determine the presence or absence of a tumor. The same five mRNA biomarkers are measured in each Cxbladder test, although some of the tests, namely Triage and Monitor, also combine the gene information with different phenotypic markers, such as age, sex, smoking history, and hematuria history.

Each of the tests includes a test tube filled with a proprietary buffer that preserves mRNA in the patient's urine sample. The test tube is then sent to one of the company's laboratories where the samples are run as a multiplexed, PCR-based assay to determine the presence or absence of the mRNA biomarkers. The lab then sends back a report to the patient's urologist with a three-day turnaround time.

Traditionally, patients that present with hematuria, or blood in the urine, are asked to undergo a CT urogram and cystoscopy, where a scope is inserted into the urethra to search for tumors, which is invasive and uncomfortable for the patient, Darling said. Cytology is the gold standard of care the US, but it is often supplemented by FISH or other urine-based diagnostics, all of which have varying levels of sensitivity and specificity. The Cxbladder products offer clinicians another non-invasive diagnostic alternative.

The company focused its initial efforts on bladder cancer because it determined that there was a need for a series of diagnostic tests along the entire clinical pathway from initial detection to recurrence monitoring, Darling said. While bladder cancer is only the ninth most prevalent cancer worldwide and is usually curable, it has an approximate 70 percent recurrence rate.

The high recurrence rate requires a great deal of monitoring after cancer treatment and remission. For patients this can mean somewhere between 12 and 24 follow-up evaluations that include CT scans and additional cystoscopy. "It's a very onerous and burdensome issue for bladder cancer patients," Darling said. Many patients become intolerant of the continual invasive procedures and the costs that they incur, he added.

In the Urologic Oncology study, Cxbladder Monitor demonstrated performance advantages over cytology, the current gold standard for bladder cancer detection, as well as NMP22 ELISA, NMP22 BladderChek, and UroVysion FISH.

Specifically, the researchers collected a total of 1,036 urine samples from 803 patients undergoing surveillance for urothelial carcinoma. Of these, 1,016 samples were directly assessed using Cxbladder Monitor, cytology, NMP22 Bladderchek, and NMP22 ELISA. In addition, they compared data from 157 samples where UroVysion FISH analysis was performed locally. Overall, they found that Cxbladder Monitor outperformed the other three tests with 91 percent sensitivity and a negative predictive value of 96 percent compared to cytology (22 and 87 percent, respectively) NMP22 ELISA (26 and 87 percent), and NMP22 BladderChek (11 and 86 percent).

"When it comes to sending FISH versus NMP22, I don't routinely use [either] of those tests," said Sia Daneshmand, a practicing urologist and director of urologic oncology as the University of Southern California who was not involved in the study but has used the Cxbladder tests. "FISH is accurate to a degree but it often leads to unnecessary workup, particularly of the upper tract, looking for disease that's not present...NMP22 is really not very accurate at all."

Daneshmand noted that with Cxbladder Monitor, he felt confident in the test's negative predictive value. It allows him to tell patients with negative results that there is 98 percent chance that they don't have a tumor and can come back for monitoring in a few months instead of going on the operating table for a cystoscopy.

Similar studies published in BMC Medical Research Methodology and BMC Urology have validated the clinical utility of Pacific Edge's other Cxbladder tests, and the high negative predictive value are the tests' most valuable aspect.

"To me as a clinician, [the negative predictive value] is more reassuring, so to speak," said Scott Owens, a urologist at Urology of Central Pennsylvania who also was not involved in the recent study but has used Cxbladder tests. "You can order [Cxbladder Detect] and you can tell [patients] there is a 96 percent chance that [they] don't have cancer, and we don't have to do any further testing."

Owens also mentioned that Cxbladder Triage is useful for ruling out cancer in high-risk groups, i.e. patients over 50 with persistent blood in the urine for several years. "It's another way for us to manage patients, and I think what you are going to get is better compliance," he said of Triage. "Compliance is a huge issue for some patients now."

Darling said that the urology community has had a very positive response to Pacific Edge's products. "In New Zealand, we have already had our technology adopted into the standard of care, and [by] two large public healthcare providers," he said. He also noted that the company signed a federal supply contract with the US Veterans Administration late last year. Darling declined to release information about the tests' pricing at this time.

While the company's main focus is on the continued success of its Cxbladder products, it is also looking into developing products for melanoma and colorectal cancer.

(Originally published by GenomeWeb on May 04. 2017)