Research Profile - Blood tests versus biopsies: The biomarker breakthrough

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Heart transplant patients often tell Dr. Bruce McManus that if there's one thing they could change about their life following the operation that saved them, it would be to end the biopsies required to make sure their body does not reject their donor organ.

In the first year after a heart transplant, patients undergo about a dozen biopsies. Each time, they have a catheter inserted through a vein in their neck and guided to the heart to take small pieces of the organ, which a pathologist then examines for signs of rejection.

In the second year after the transplant, patients typically need at least a couple of additional biopsies. More testing may be required, using a catheter passed to the main arteries of the heart, to see whether the patient is experiencing chronic rejection, expressed as a thickening of the walls of the arteries in the transplanted organ.

Patients dread the biopsies.

"There's a slight risk to it, and it's fear-evoking, and uncomfortable," says Dr. McManus, a cardiovascular and transplant pathologist and professor at the University of British Columbia.

Getting an accurate diagnosis also depends on the skill of the pathologist involved, and it's not a timely process.

So Dr. McManus and a cross-disciplinary team of researchers at the PROOF Centre of Excellence in Vancouver are doing their best to replace biopsies with a simple blood test.

PROOF stands for Prevention of Organ Failure, and that's Dr. McManus's ultimate goal. The PROOF team is working with public and private-sector partners and health regulators in Canada and the United States to bring to market blood tests that use biomarkers derived from a set of genes and proteins that can diagnose both chronic and acute organ failure and predict who is most likely to experience rejection.

Both chronic rejection, which takes place over time, and acute rejection, which occurs more immediately following a transplant, can damage the new organs as the immune system attacks what it perceives as foreign antigens. If doctors knew immediately that their patients were experiencing rejection, or if they knew they were at high risk of doing so, they could tailor the doses of immune-suppressing drugs that patients receive. Boosting the drugs could prevent damage from occurring; alternatively, patients at lower risk of rejection might be able to take lower doses of the potent pharmaceuticals.

A biomarker is a biological indicator that can be measured to detect or monitor changes in a person's health.

Preventing or treating rejection could save precious vital organs from damage in 10–20% of heart transplant recipients in their first year, and about 10% of kidney patients. That's why the biomarker blood tests are so important, in addition to being a less costly alternative to biopsies, which currently cost about $7500 each time.

"It's about increasing patient comfort, reducing cost, reducing risks and improving the quality of the diagnosis," says Dr. McManus, who is the director of PROOF.

The PROOF professionals include a computation team consisting of biostatisticians, computer scientists and data analysts who analyze patients' blood samples. They have identified unique sets of gene and protein biomarkers that lead to molecular signatures. Those signatures indicate acute or chronic rejection responses in the body – which the blood tests can catch earlier than is possible when relying on biopsies. The PROOF team has also identified biomarker sets that can diagnose and predict organ rejection before it has occurred.

The PROOF team's collaboration with IO Informatics Inc., a California-based firm specializing in software for health-care technology, has benefited both the company and, ultimately, patients, by improving the quality of the software the firm creates to screen biomarkers.

"Scientists from PROOF demanded a new level of flexibility, power and ease-of-use for algorithms that score patient risk relative to biomarker-based classifiers," says Dr. Erich Gombocz, IO Informatics' chief science officer. "We extended our 'ASK' software product to meet these demands and provide more effective biomarker-based patient risk assessment. These efforts significantly improved our ability to deliver improved research and decision support to our customers."

Now Dr. McManus and the PROOF team are midway through international clinical trials that will test the validity of their biomarkers and result in blood tests that are easy to interpret, through an algorithm that reduces the analysis of tens of genes or proteins into a single score. In addition, the PROOF Centre is working with Health Canada and the U.S. Food and Drug Administration to ensure the test is reliable and effective.

PROOF team members are also working with experts on the process of getting the tests reimbursed by provincial health-care plans, and with diagnostic companies and laboratories to get the technology right for the clinical lab setting.

"We're very solution-oriented for patients," Dr. McManus says.

Within two and a half years, Dr. McManus predicts, at least one of these biomarker blood tests will be approved and ready for use in clinics across Canada.

The PROOF team is also working on biomarker tests to distinguish between two types of chronic heart failure – diastolic failure, when the heart can't fill with blood, from systolic failure, when the heart can't pump enough blood. The conditions require different treatments, but are difficult to diagnose without ultrasounds. Blood tests would make it easier for doctors to manage patients even from remote distances where ultrasounds are more difficult to obtain.

Another form of heart failure, called acute heart failure, would also be easier to manage with a biomarker blood test, which PROOF is working on to help doctors decide whether their patients need a mechanical assistive device to treat that condition.

Once Dr. McManus and the PROOF team have brought their first biomarker tests to market, it will be faster and easier to bring the subsequent ones to clinics, he says.

"Every major biomarker study we do makes the likelihood of success in the next one – regardless of disease – more likely," he says.

"It's about increasing patient comfort, reducing cost, reducing risks and improving the quality of the diagnosis."
- Dr. Bruce McManus, University of British Columbia