Precision medicine

By Pat Rich

– the emerging approach of tailoring of medical treatment to the individual characteristics of each patient– is set to transform the delivery of health care.

No less a personage than the president of the United States said as much in his State of the Union address at the beginning of last year when he announced a $215 million initiative in precision medicine.

“I want the country that eliminated polio and mapped the human genome to lead a new era of medicine — one that delivers the right treatment at the right time,” President Barack Obama said.

This is a world – no more than a decade away according to the CEO of – where a person’s genome will be sequenced at birth and used to guide their health care. It is an approach that marries all the big buzzwords in health care today – genomics, big data and the electronic medical record.

In Canada, a well-developed network of academic centres and researchers coordinated through the Canadian Institutes of Health Research (CIHR) and Genome Canada is making this country one of the global leaders in precision medicine research.

In 2012, Genome Canada, with its vision to harness the transformative power of genomics for the benefit of Canadians, funded 17 major, innovative projects (described below) to apply precision medicine to the Canadian health care system. The initiative was a collaboration with CIHR, who co-funded many of the projects.

Last month (March), Science Minister Kirsty Duncan announced a $2 million initiative to create a network of researchers involved in these projects to analyze findings on some of the major ethical and economic issues involved in the approach.

Those issues – which Genome Canada characterizes as GE3LS (Genomics and its Ethical, Environmental, Economic, Legal and Social aspects) – are huge and range from the lack of Canadian legislation protecting against genetic discrimination, to determining the economics of providing tailored genetic testing and treatment to individuals with rare disorders.

Precision medicine was one of the areas highlighted in the report of the Advisory Panel on Healthcare Innovation commissioned by the federal government and released last summer.

Chaired by Dr. David Naylor, former president of the University of Toronto, the panel saw its work released without fanfare by the previous Conservative government, but the report has been reborn under the new Liberal government, which has praised its findings.

The report discusses at length the advances made by precision medicine in recent years.

“A patient with a cancer that has stopped responding to intravenous chemotherapy can now contemplate surprising and truly personalized options, such as oral treatment with a drug used for high blood pressure or a now little-used antibiotic,” the report states.

However, Naylor and his fellow panelists go on to note that “for reducing one’s risk of most common diseases, individualized prevention through precision medicine is a side-show at present …”

The report references work done in Canada in precision medicine and said the panel would be remiss if it did not “applaud the investments in applied genomics and precision medicine research that have been made by CIHR (Canadian Institutes for Health Research), Genome Canada, many other national foundations and grant-making bodies, provincial research agencies and ministries, private industry and other supporters.”

But once again, the report sounds a cautionary note: “Despite these advances, the panel also heard warnings from clinicians, researchers, and healthcare stakeholders that Canada may squander its research investments without a more strategic approach.

“…without a cogent strategy, without the right infrastructure – both biobanks and databanks, without mechanisms to translate successful discoveries into both improved clinical care and exciting new businesses, Canada runs a risk of wasting opportunity and money – and falling even further behind our peers.”

Genome Canada CEO Marc LePage feels his organization and CIHR are doing a good job in coordinating the Canadian research agenda for precision medicine at the national level.

While Canada is in the forefront of nations researching this area, in an interview LePage said the current impact of this approach on the health care system is very limited although there is a “tsunami of new practices” on the way. He mentioned initiatives in BC, Quebec and Ontario as examples of where this process is being accelerated.

LePage noted that not only did Obama boost precision medicine by his announcement last year but he has further promoted the field with his “cancer moonshot” funding announcement this January because of the close association between advances in genomics and cancer detection and treatment.

Given the provincial nature of health care delivery in Canada, LePage said national approaches can only go so far in bringing precision medicine approaches to the bedside.

However, as the field advances, LePage said the Naylor report is correct in identifying the need for a “cogent strategy” to translate advances in precision medicine to clinical applications.

Canada’s doctors are still coming to grips with precision medicine both from a high-level policy perspective and for the immediate impact it will have in doctor’s offices.

At its annual meeting in Halifax last August, the general council of the Canadian Medical Association (CMA) passed four resolutions relating to precision medicine.

In an interview, Dr. Jeff Blackmer, who is VP of medical professionalism for the association, said the association has been “carefully” monitoring developments in precision medicine over the past decade.

“There’s no question that the CMA (Canadian Medical Association) supports these kinds of initiatives,” said Blackmer.

However, he added, “the main area we have been focused on … is direct-to-consumer genetic testing, which for practising physicians right now would be one of their main areas of concern.”

“For the average family physician, who would be the normal front-line person the patient would go to for help in interpreting these tests, it can be very difficult and extremely time-consuming, and we really haven’t put the tools in place to allow them to do that in a meaningful way.”

Blackmer said the CMA is working with geneticists at the Children’s Hospital of Eastern Ontario to develop a formal advocacy plan to bring more standardization to direct-to-consumer genetic tests. The association’s committee on ethics will be looking at this issue at its spring meeting.

LePage said researchers are probably divided about the value of direct-to-consumer genetic testing, especially since companies such as 23andMe have been limited in the type of diagnostic information they are allowed to provide in the U.S.

Cover 2He said the reality of using genetic testing at birth to help guide health care delivery is no more than 10 years away and both he and Dr. Karen Dewar, director of genomics programs for Genome Canada, referenced one of the 17 Genome Canada-funded projects, which is investigating the value of pre-natal testing of maternal blood to obtain information about the fetus.

In talking about innovation, LePage also specifically referenced a new partnership between the Structural Genomics Consortium – a public-private partnership that supports the discovery of new medicines through open access research – and the Montreal Neurological Institute, to test new drugs for neurological diseases.

In discussing the major projects being funded by Genome Canada, Dewar described them as encompassing a number of disease areas and approaches

“Many of them are touching areas where (an alternate, earlier term for precision medicine) are more advanced,” she said, as well as areas where Canada has particular research capacity.

In an interview, Dewar noted that the call for research proposals stipulated that projects have deliverables capable of being translated into cost-effective use in the health care system.

Dewar referenced the newly funded network of the research teams to look at some of the common themes in the precision medicine work and to try and address them.

Dr. Chris McCabe, Capital Health Endowed Chair in Emergency Medicine, at the University of Alberta is co-leading the precision medicine networking project with Dr. François Rousseau of Université Laval.

In an interview, McCabe said he felt there is still time “but not lots of time” to establish frameworks for incorporating genomics into health care delivery.

He identified two areas of precision medicine “that are going to be with us, in volume, relatively quickly”; improved early diagnosis of cancer and appropriate treatments; and testing for rare genetic disorders.

McCabe said he agreed with the Naylor report that for the vast majority of common diseases “you get as much information from a good family history and standard clinical testing as you do from a genetic test.”

For these common conditions, he says, “we’re not in the short-term, going to see a sea-change in how health care is delivered because the information (from genetic testing) is not specific enough to guide current clinical or behavioral decisions.”

“That said, this technology (genetic sequencing) is out there: patients will be presenting with their own sequenced DNA and we need to know how to use that information when it’s clinically actionable.”

The 17 successful projects resulting from the 2012 Large-Scale Applied Research Competition in Genomics and Personalized Health. 

Personalized medicine in the treatment of epilepsy

Every time someone with epilepsy has a seizure there is a risk of brain damage. This is particularly true for children. Unfortunately, today’s anti-epileptic drugs simply don’t work on about one third of patients.  The team will identify genes that are associated with epilepsy and that are predictive of the response to various antiepileptic drugs. This will result in earlier and more effective care and potentially prevent cognitive decline in children.

Biomarkers for pediatric glioblastoma through genomics and epigenomics

A type of incurable brain cancer called high-grade astrocytomas (HGA) is taking the lives of children and young adults. Genome Canada and CIHR-funded researchers have identified mutations in a particular gene in a significant fraction of children and young adults with this brain tumor. These mutations partly explain why this cancer remains unresponsive to treatments.

The team will develop new tools that will help healthcare providers identify these mutations in brain tumors, allowing children to receive the best treatment strategy. Using next-generation genomic technologies, they are looking for potential targets for drug treatment.

Personalized cancer immunotherapy

About half of patients with a hematologic cancer develop resistance to chemotherapy. For these patients, the usual treatment is to transplant bone marrow cells from a healthy donor.  This is known as immunotherapy because immune cells from the donor target tumor cells in the recipient. Unfortunately, there are two problems with this treatment: the effectiveness of the transplanted cells varies widely; and there is the chance of rejection by the patient.  In some cases, the donor cells actually attack the patient―something known as “graft versus host disease” (GVHD).

The team is developing a genetic test that will predict GVHD, leading to safer use of bone marrow transplants. This will also improve immunotherapy by targeting the right immune cells to the right tumor cells, leading to more effective treatment.

IBD Genomic Medicine Consortium (iGenoMed): Translating genetic discoveries into a personalized approach to treating Inflammatory Bowel Diseases

With over 230,000 cases, Canada has among the highest frequency of people in the world with inflammatory bowel diseases (IBD), including Crohn’s and Ulcerative Colitis. While there are a several drugs available on the market to treat IBDs, currently physicians are unable to predict which drug would be most effective for a given patient.

The team will develop tests allowing doctors to match the right drug with the right patient. This will prevent patients from receiving ineffective (and often expensive) medication and improve the quality of patient life. In addition, once the project is fully implemented, it will save the health care system more than $10 million annually by avoiding costly hospitalizations and surgeries.

While the research will focus on two specific drugs, the project is in fact creating a system that will become an even greater asset for a large number of new drugs, which are expected to reach the Canadian market in coming years.

PEGASUS: Personalized Genomics for prenatal Aneuploidy Screening Using maternal blood

Every year in Canada, about 10,000 pregnant women undergo amniocentesis to screen for genetic abnormalities such as Down syndrome. This procedure represents a non-negligible risk and tragically, 70 healthy fetuses are lost due to complications from the procedure. Recently, however, scientists have discovered that fetal DNA present in the mother’s blood can be used to test for genetic abnormalities, and this through a simple blood test.

The team will compare different genomic technologies for their effectiveness to successfully detect genetic abnormalities using the mother’s blood. The goal of the study is to implement the most suitable technology into the Canadian health care system to eventually offer, in the context of standard clinical care, non-invasive prenatal screening to all Canadian women.

Innovative chemogenomic tools to improve outcome in acute myeloid leukemia

Acute myeloid leukemia is a particularly lethal type of cancer among young people, with most dying within two years of being diagnosed.  At the moment, analyzing cancer cell chromosomes is the best way to determine the prognosis for patients.  Unfortunately, about 45 per cent of those tested show no anomalies, leaving doctors with little information to go on. Recent developments in DNA sequencing, however, allow for a more complete analysis of these tumors.

The team will use personalized DNA from patients to determine how they should be treated, based on the specific genetic makeup of their tumors. This will lead to better diagnosis and improved outcomes for patients. They are also developing new models for tracking cancer cells that are left behind after a patient is treated.  These cancer stem cells can multiply over time and lead to a relapse.  This research could lead to new ways of preventing such relapses by providing new insights into the biology of this disease.

Personalized risk stratification for prevention and early detection of breast cancer

Currently, mammography is used to screen for breast cancer in women over 50 years of age.  While screening younger women could have significant benefits in terms of early detection and intervention, it is simply not economical.  What’s needed is a way of identifying those who are most at risk, based on a wide variety of factors.

The team is developing just such a screening program so that women with a high risk of breast cancer will be identified―and tested―sooner. Younger women who are currently missed by age-based screening will have their cancer caught at an earlier stage, leading to better treatment, improved prognosis and lower costs for the healthcare system.

Personalized medicine strategies for molecular diagnostics and targeted therapeutics of cardiovascular diseases

Cardiovascular disease is the leading cause of death and hospitalization in the world. In Canada 80,000 people died in 2010 of cardiovascular disease, which accounts for 35 per cent of all deaths in the country. Currently, 1.3 million Canadians suffer from cardiovascular disease, causing a serious economic burden. The cost is estimated to $22.2 billion per year, which constitutes the highest direct healthcare costs.

The team will be applying their expertise in how genes influence drug efficacy and toxicity to provide guidance to health professionals in the selection and dosing of a specific drug. This will improve patient care, reduce harmful side effects and lower health care costs by reducing the use of ineffective drugs and unnecessary spending by healthcare payers.

Enhanced CARE for RARE genetic diseases in Canada

Gene mutations cause not only well-recognized rare diseases such as muscular dystrophy and cystic fibrosis, but also thousands of other rare disorders.  While individually rare, these disorders are collectively common, affecting one to three percent of the population. It is estimated that as many as half of Canadians with rare disorders are undiagnosed.  The team will use powerful new gene sequencing technologies to identify the genes implicated in many of these rare diseases.

Besides providing important new understanding into human disease, this project will yield other benefits, including:  avoiding invasive procedures, stopping ineffective treatments, developing earlier and better diagnoses, devising more appropriate treatment, and predicting the chances that one of these rare diseases could be passed on to offspring.

Once the disease-causing genes have been identified, researchers will test drugs that are currently on the market to identify those that might be effective against these rare diseases.

Autism spectrum disorders: genomes to outcomes

Genome Canada and CIHR-funded research has already led to some exciting breakthroughs in our understanding of autism spectrum disorder, a complex condition that affects normal brain development, social relationships, communication and behaviour.  Among these breakthroughs is the identification of specific DNA anomalies associated with the illness.  The team is going to the next level, aiming to identify the remaining genetic risk factors.

This ground-breaking work will mark Canada’s contribution to an ambitious international initiative that aims to sequence and analyze the genomes of 10,000 people with autism spectrum disorder.  With a more complete understanding of the genetic elements of autism, doctors will be able to make earlier diagnoses, provide better, more personalized care to patients and reduce the enormous cost autism imposes on our health care system.

Early detection of patients at high risk of esophageal adenocarcinoma

Chronic heartburn can damage the lining of the esophagus, leading to a condition known as “Barrett’s esophagus”. Patients with Barrett’s esophagus have a much higher chance of developing cancer of the esophagus.

Until recently, the only way to diagnose Barrett’s esophagus was through endoscopy—an uncomfortable and time-consuming procedure.  However, a swallowable sponge under development in the United Kingdom allows for quick and painless diagnosis of Barrett’s esophagus in a doctor’s office.  The team aims to supplement this test with genomic technologies, allowing doctors to follow patients over time to identify and treat those progressing to cancer.  Early detection, treatment and even prevention of these cancers could save the healthcare system over $300 million a year.

The microbiota at the intestinal mucosa-immune interface: A gateway for personalized health Inflammatory bowel diseases (IBD), such as Crohn’s disease and ulcerative colitis, are incurable debilitating lifelong diseases that can affect children.  Early detection is critical to avoiding complications and improving their quality of life.  At the moment, however, there is no single test to determine the presence or type of IBD and the tests that exist are very uncomfortable for children.

The team is developing a simple, non-invasive approach to detecting IBD that will also be more cost effective.  Using cutting-edge technology, the scientists will examine intestinal bacteria to develop better ways of identifying IBD and determining its severity.  This work could also lead to new treatment, enhancing the quality of life for children everywhere.

PACE-‘Omics: Personalized, Accessible, Cost-Effective applications of ‘Omics technologies

Personalized medicine should allow doctors to tailor treatment to patients’ biological characteristics.  This should mean better treatments with fewer adverse reactions to drugs and other therapies, which could make for a much more efficient and cost-effective healthcare system. However, current processes for developing and licensing medical technologies are a threat to the realisation of this potential.

The project  will give policymakers and investors the tools they need to make the right investment decisions on technology development, regulatory pathways, cost-effectiveness and benefit to the Canadian health system. The project will develop approaches to properly reflect the views and values of Canadians in making decisions for introducing personalized medicine into cash-strapped healthcare systems. Bringing together experts in health economics, health policy, regulation, commerce, law and ethics, they will provide practical decision-making tools and completed analyses that will lead to informed policy-making. At the same time, by helping to establish the “ground rules” for the development of personalized medicine, the project will make Canada a less risky and more attractive base for developers, thereby supporting economic development in the Canadian life sciences industries.

Personalized treatment of lymphoid cancer: British Columbia as model province

Thanks to new research, scientists can now decode the genetic instructions in both normal and malignant cells. Armed with this information, doctors will soon be able to select the best cancer treatment for each individual. Lymphoid cancers are special because even when they have spread widely in the body they can still be cured. Recent research has shown that genomic sequencing can recognize special lymphoid cancers that are often not cured today but which could be treated more effectively using personally designed treatments.

The research team will apply genetic sequencing to lymphoid cancers—the fourth most common type of cancer. This research could increase the cure rate of several lymphoid cancers by 20 per cent—this means more than forty lives saved annually in BC and upwards of $2.5 million savings to the healthcare system in that province alone, and immeasurable dollars recovered from the ripple-effect of disease impacts such as lost work days and family suffering. This research will use BC as a pilot project to show how to use genomic analysis to cost-effectively cure more cancer patients in a way that can readily be duplicated elsewhere around the world.

Viral and human genetic predictors of response to HIV therapies

The HIV drug “cocktail” has transformed AIDS from a fatal disease to a manageable condition.  Unfortunately, HIV can become resistant to these drugs, leading to the development of fullblown AIDS in the patient and increasing the chances of further transmission of the virus.

The research team will develop a test for drug resistance personalized to an individual’s DNA and the DNA of the virus. Lifetime drug costs for HIV are between $250,000 and $500,000 but there are numerous multipliers of the economic impact of an HIV infection. Nations with high HIV-infection rates see the significance of those impacts on GDP to a point of unsustainability.

The project is also developing real-time surveillance systems for monitoring drug resistance to provide an early warning of geographic or population “hotspots” where resistance rates are highest and the risk of transmission greatest.

Reducing stroke burden with hospital-ready

Andrew Penn's project (Reducing stroke burden with hospital-ready biomarker test for rapid TIA triage) Photo courtesy of Genome Canada
Andrew Penn’s project (Reducing stroke burden with hospital-ready biomarker test for rapid TIA triage) Photo courtesy of Genome Canada

biomarker test for rapid TIA triage

Every year, 50,000 Canadians have a stroke, making it the leading cause of disability in the country.  However, an equal number of people suffer what are called transient ischemic attacks, or TIAs, which, while less serious, can lead to strokes. The problem is that many conditions, including migraines, can present as TIAs, leading to expensive neuroimaging testing. What’s needed is a quick, inexpensive test that would differentiate TIAs from other conditions.

The team is developing just such a test, which will provide results within an hour or so, for a fraction of the cost of imaging. With the results of this test, doctors will know whether to keep patients for further care or send them home. This will reduce unneeded imaging risks and costs as well as prevent TIAs from progressing to a full stroke. Averting just 4,000 strokes would save $210 million per year in direct health care costs. The Heart and Stroke Foundation of Canada will work to ensure that physicians, allied healthcare providers, the public and other stakeholders are aware of the outcomes and clinical impacts of this project.

Clinical implementation and outcomes evaluation of blood-based biomarkers for COPD management

Chronic Obstructive Pulmonary Disease (COPD) damages the airways inside of our lungs, making it difficult to breathe. Patients suffer “lung attacks”, characterized by coughing, breathlessness and a dramatic increase in sputum.  If caught early enough―or better yet, prevented―these lung attacks can be effectively treated with medication. Unfortunately, many of the symptoms of lung attacks can resemble pneumonia, heart attacks or even the flu. Lung attacks reduce patient quality of life and cost the Canadian health care system nearly $4 billion dollars each year in direct and indirect costs.

The team will develop new blood tests that will identify patients at high risk for lung attacks as well as differentiate these attacks from other conditions. This means lung attacks can be prevented or treated earlier than was previously possible.  Ultimately, patients who need preventative drugs will receive them, resulting in fewer attacks, as well as reduced hospitalization and emergency visits.  At the same time, patients at low risk of an attack will be able to avoid unnecessary drugs and their potential side effects.

Pat Rich is an Ottawa-based medical writer.

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