Chronix Uses cfDNA to Change Screening for Common Cancers

Molecular testing firm Chronix Biomedical (Germany and San Jose, Calif.) has set out to change the face of cancer diagnostics on several fronts. Its Second Opinion line of tests is currently available in Europe to improve the accuracy of existing screening methods for prostate cancer and breast cancer. Additionally, the company is currently validating both a pan-cancer screening test, One Test, and an organ transplant rejection test, all based on the principles of utilizing circulating cell-free DNA (cfDNA) as an early sign of changing cellular dynamics in the body.

DTET recently spoke with Howard Urnovitz, Ph.D., the CEO and co-founder of Chronix about the company's plans to commercialize the tests in the United States.

Your Second Opinion cfDNA-based tests initially target two common cancers— breast and prostate. Why target these cancers as an initial strategy?
Chronix Biomedical chose to start with prostate and breast cancer because we saw the trend of negative reports about the current screening tests of PSA and mammograms. These two early screening tests both have low accuracy leading to many misdiagnoses. We believe by adding a blood genetic test to the screening protocol we can increase the accuracy of the current test practices and reverse the trend back to supporting early detection.

Tell us about the role Second Opinion tests can play in routine clinical decision making as supplementary tests.
We built these as laboratory-developed tests (LDTs). Our Second Opinion laboratory report indicates whether a patient's cfDNA matches the cancer fingerprints in our database. One section of the report summarizes the exact regions on the human chromosome where a patient's cfDNA may or may not correlate with the database. In another section, the report gives an overall copy number instability (CNI) score on whether a sample is outside the range of 97 percent of our healthy control database. These additional data points, along with clinical history and other laboratory results, assist physicians in making important medical decisions.

Some physicians are using the Second Opinion test for surveillance of men with elevated PSAs under "wait and watch." Men with elevated PSAs, but no Second Opinion correlation, can be regularly monitored to see if any cancer fingerprints ever appear. Second Opinion can limit the number of cancer-free individuals going for unnecessary tissue biopsies.

The Second Opinion testing also addresses the significant level of overtreatment of prostate cancers that are indolent or slow-growing. Indolent prostate cancer is usually not a threat to a man's lifespan or health. Second Opinion provides a quantitative and qualitative report on whether the amount of cfDNA is increasing in the blood and whether the pattern of the cancer fingerprints is changing, suggesting that the tumor is changing.

What is the economic case for using Second Opinion tests?
Approximately one million prostate biopsies in the United States are false positives. If the prostate biopsy costs between $1,500 and $2,000, we are wasting up to $2 billion a year in unnecessary biopsies. The costs are much higher if you add in the ancillary costs of complications from infection, incontinence, or erectile dysfunction as a consequence of unnecessary biopsies. We estimate that our testing protocol will cost less than $2 billion a year and therefore lower the costs to the health care system, while minimizing the anxiety associated with biopsy procedures.

Chronix has stated that its cancer biomarkers relate to the "earliest" signs of genomic instability and are present, regardless of the cell of origin. Does this signal the potential for a future pan-cancer screening test using cfDNA?
Chronix Biomedical is currently in multiple discussions to conduct large validation and economic health studies on its One Test. Our design goal is for one blood test for the 17 types of cancer that cause the highest economic burden to the health care system. Currently, we have completed studies on samples from 11 different types of cancer and were successful in detecting cancer cfDNA in all 11 cancer types. We are expanding the test to include 17 cancers in our evaluation study.

We don't believe the evidence supports the notion that cancer is a disease defined by single nucleotide polymorphisms. Cancer is a disease of CNIs. We are the only company we know of that is reporting on CNI scores and genomic positions. Our evaluation study will be testing 500 samples of each cancer plus matching controls for 17 cancers. We are looking at a 17,000-person validation study to generate the data. We anticipate no lower than 90 percent accuracy for most cancers. We will submit the One Test data to the U.S. Food and Drug Administration (FDA) and work as hard and quickly as we can to obtain approval.

You say you will submit the One Test to the FDA for approval. Please explain Chronix's regulatory strategy.
We will have to obtain FDA clearance because the test is informing an individual for the first time they may have a specific cancer. Previously, I successfully completed a 26,000-person FDA clinical study for a urine test for HIV. I know what it takes to undertake big studies that have big implications. For AIDS testing, when you are telling somebody for the first time they have HIV, those are serious medical claims that need to have the support from FDA clinical trials. I believe that informing an individual that they may have a specific life-threating cancer would also require similar FDA clinical trials.

One thing particularly interesting about Chronix is its interest in applying cfDNAbased technology outside of oncology. Can you tell us about the development of the cfDNA test for transplantation rejection?
We continue to conduct validation studies of our organ transplant efficacy tests. We published the first results from our heart and kidney transplant studies. Our multicenter trial in liver transplantation has been completed and the manuscript is in preparation. The performance of a test for the detection cfDNA from cells of a transplanted liver that is being rejected by a patient is highly superior with an area under the curve (AUC) of about 97 percent, compared to conventional liver testing such as aminotransferases, bilirubin and gamma-glutamyl transferase, which showed AUCs between 0.79 and 0.90. Our plan is to finish our validation studies on liver, heart and kidney and seek regulatory approvals.

This is a very different technology from our cancer testing next-generation technology. Professors Schütz and Oellerich had been studying transplant biomarkers for two decades, before joining with Chronix Biomedical. Our team came up with a way to combine a panel of primers so that within minutes we can determine which cfDNA biomarkers are organ-specific and which markers are host. It is clearly more powerful than currently used markers. Our test allows a physician to know whether an organ is being rejected at the earliest time point possible, giving the highest probability for success in not losing the transplanted organ. The Chronix test is clearly more effective in treating a patient than currently used markers.

How important are economic trials to driving commercial adoption and reimbursement for liquid biopsy tests? What are your commercialization plans in the United States?
Large prospective studies with key opinion leaders are necessary to show clinical utility with the goal of becoming a standard of care and obtaining reimbursement. Chronix expects to conclude its Second Opinion prostate cancer evaluation study on 1,500 men with elevated PSA in 2016. We will use this data to offer the test as an LDT in the United States from a CLIA-certified lab. The company will work with health care insurers to obtain reimbursement for the test.

After ASCO this year, we will begin validation studies on our One Test for cancer. We are actively raising additional funds for the One Test study, which we estimate, will cost $50 million and take 4 years to complete.

Chronix is a pioneer in cfDNA diagnostics. We were the first to match cell-free nucleic acids with the human genome in a paper published in 1998. In 2008, we were the first to publish that we could use next-generation sequencing as a liquid biopsy for cfDNA using an animal model. In 2010, we confirmed its utility as a liquid biopsy for breast and prostate cancer cfDNA.

Early detection of cancer is essential because it is easier to put out a match than a forest fire. Cancer diagnostics need to create more early-stage success stories and decrease the cost of continuing care from $120 billion to a more sustainable number. I believe we can reach these objectives with the use of Chronix Biomedical technology.