The Rebirth of Genetic Testing in Ontario

By Patricia Thangaraj

Genetic testing in Ontario has undergone a “rebirth.” These changes make the eligibility criteria for cancer patients, survivors and previvors in this province less restrictive when it comes to the eligibility criteria, which means that hereditary cancer patients, survivors and previvors having better access to genetic testing.

This was revealed by Medical Geneticist and Medical Director, Genetics and Cancer Early Detection, Princess Margaret Cancer Centre, Dr. Raymond Kim who delivered a presentation on entitled “Who Else Is Out There? The Ontario Hereditary Cancer Research Network” as part of a 2022 webinar series hosted by the Women’s College Hospital.

Dr. Kim said that hereditary cancer patients serve as a valuable asset in helping geneticists like himself develop clinical trials specifically targeting these group of patients and their families.

“I have advocated that these patients are Ontario’s golden opportunity in solving the cancer puzzle. Hereditary cancers accounts for approximately 10 percent of all cancers. They have a unique lifecycle with various checkpoints of opportunity. As you watch these patients’ journeys, you can see that they are born with this genetic change. We colloquially call them previvors in the lay press.”

Commonly referred to as previvors, he explained that even though these persons usually do not have cancer at this point in time, they have a genetic mutation, that makes them more susceptible to developing cancer and therefore, geneticists would conduct intensive surveillance including imaging of the breasts to help them identify the risk factors of these persons.

“They are otherwise very healthy. Right? They don’t have cancer. But because they are born with that genetic change, they undergo intensive surveillance, often with imaging of the breasts. Some organs don’t get any imaging such as the ovaries or if you have a mutation in a different gene, you may have an endoscopy or images of your brain and spine.”

The aim here is to detect the cancer in its early stages as this presents the best chances for oncologists to treat the cancer. Unfortunately, many of these patients would go on to develop a second cancer, whether it be in the same organ or a different organ.

“Hopefully the surveillance detects the cancer early. Many patients unfortunately do develop cancer. They undergo some precision cancer therapy based on their genetic change, ultimately, hopefully, survive that cancer and have the imaging resume at the following checkpoint. Many times they undergo a second cancer, whether it be in the same organ or a different organ in their body and it is because that genetic change is present in their entire body.”

With more than a hundred genes with different types of genotypes and precision cancer therapies that explicitly target those genetic changes, these hereditary cancer families are instrumental in helping geneticists develop research aimed at early cancer detection, prevention, precision therapy and gene discovery, explained the Medical Geneticist.

“Now, over a hundred genes with different types of genotype specific surveillance are currently known and they are receptor precision cancer therapies that are based on that specific genetic change. However, due to this lifecycle and the various checkpoints, we believe that these families are very valuable in informing us in early cancer detection, prevention, precision therapy and gene discovery.”

The Rebirth of Genetic Testing

Recent changes that have been made in the genetic testing landscape in Ontario helps geneticists move one step closer towards this goal. This previous genetic testing guidelines were developed more than two decades ago. These outdated guidelines did not take into account changes that have been made over the last 20 years with respect to new genes and/or new interpretations of different types of results.

These updated guidelines would be especially useful for BRCA1 and BRCA2 carriers. About two decades ago, there was very little gene sequencing available for persons in Ontario. Flashforward to 10 years later where gene panel testing became popular in the medical research field, but persons with these genetic mutations had their results sent overseas because gene sequencing was not being done in labs across Ontario at the time.

“So after much advocacy, lobbying and reviewing, genetic testing in Ontario has had a rebirth. For those who know, BRCA1 and BRCA2 genetic testing occurred at the turn of the century, which was approximately over 20 years ago and at that time, bits and pieces of the BRCA gene and BRCA1 and BRCA2 gene were being sequenced in different areas of the province. 10 to 15 years later, gene panel testing became vogue and that was being sent out of the country because most of the academic labs and hospital labs in Ontario were not sequencing those genes.”

This is when Cancer Care Ontario became involved and reviewed the current guidelines and came up with an updated gene list for patients in Ontario that included 76 genes. This list, which came on stream on April 1st, ensures that the testing criteria for cancer patients is more all-encompassing, which would result in more cancer patients in this province gaining access to genetic testing because they now meet the criteria.

“And then Cancer Care Ontario stepped in and reviewed the current state and met with many stakeholders to come up with a gene list that would be available for Ontario patients and be done in Ontario labs. And this is just a snapshot of the 76 genes that are available in the eight provincially funded labs as of April 1st…And the testing criteria has changed to be more liberal and less restrictive, hopefully allowing people to have access to these genetic changes and in genetic testing.”

The new gene list includes the gene mutations that people often hear about such as BRCA1 and BRCA2, but it also includes other genes that geneticists have taken a growing interest in such as PALB2.

“And the 19 genes that are covered in a hereditary breast and ovarian cancer panel are encompassed here and importantly include prostate cancer as an indication for patients to have genetic testing. The usual suspects are here such as BRCA1 and BRCA2. A gene of interest for the group here would be PALB2, a partner and localizer of BRCA2, which is an emerging cancer risk gene approaching that of the BRCA1 and BRCA2, so equally as important, but not as common and other genetic mutations are detectable in the genes listed here TP53, CDH1 etc.”

These guidelines, especially as it relates to breast and ovarian cancer, would be updated every six months to one year to ensure that the gene panel and the respective criteria that geneticists are working with is the most updated version.

Another change that has emerged from these updated guidelines is that the age for breast cancer patients to be eligible for testing has increased from under 35 years of age to under 45 years of age regardless of their family history, said Dr. Kim.

Furthermore, they added gene mutations associated with cancers that were not previously included in the list in Ontario such as patients with pancreatic cancer, the Medical Geneticist stated.

“So specifically for hereditary breast and ovarian cancer, these genetic testing guidelines are updated initially every six months and probably annually to make sure we’ve got the right gene panel and to make sure we have the right criteria. They are listed here. Some of the changes that occurred over this iteration include that it used to be only breast cancer patients under 35 would get genetic testing. Now in fact it has increased to breast cancer patients under 45 irrespective of your family history, in particular triple-negative breast cancer associated with BRCA is also highlighted as a criteria. Invasive epithelial, ovarian cancer and also peritoneal cancer. Prostate cancer is on the list too and pancreatic cancer is on the list too. Previously, they were not even eligible for in province genetic testing for the lab.

Another area that would help geneticists develop more targeted therapies for BRCA carriers and their families is personalized medicine. Homologous recombination plays a critical role in patients with BRCA gene mutations.

“So I wanted to take a brief moment and talk about personalized medicine as they relate to patients who have an inherited genetic change in many of the different genes that we have talked about in the previous slide. So in a BRCA patient, that pathway that is affected in these patients is called homologous recombination. And I am a Geneticist and it is interesting that the gene mutations involved in hereditary cancer, are involved in keeping the integrity of the genetic material in the body pristine.”

Homologous recombination is a highly accurate DNA repair mechanism. Several homologous recombination genes are established cancer susceptibility genes, which have clinically actionable pathogenic variants. BRCA1 and BRCA2 germline pathogenic variants are linked with breast and ovarian cancer, explained the Head of the Provincial Genetics Program at Ontario Health.

“So in homologous recombination, the body is consistently having DNA damages from various sources and they have various types of mechanisms to fix that. Homologous recombination is one of them. It uses the double strand of DNA, there is a sense strand and an anti-sense strand and mother nature has engineered it this way so that when damage occurs, you can use a homologous strand to try to repair some of the DNA damage. And this is where BRCA1 and BRCA2 actually works. If there is a mistake, it looks at the homologous chromosome and then tries to repair it.”

However, if it is not possible to repair the damages, then patients have another option known as base excision repair, which is a cellular mechanism that can also help to repair DNA damages throughout the cell cycle, explained the Princess Margaret Cancer Centre Medical Director.

“If you are not able to repair it though, you can undergo another mechanism. It’s called base excision repair and why am I talking about base excision repair in the context of homologous recombination – it is in fact that a drug targeting that pathway, which actually allows patients to have a specific treatment. So by targeting a backup pathway, that these patients who have a BRCA deficiency or BRCA problem try to use. If you block that pathway too and those patients can’t use that pathway to repair the DNA, that would cause the cell to die, which is what we want in cancer cells.”

He stated that this is built on their knowledge on the genetic changes occurring in hereditary cancer patient families and they have already seen positive outcomes with BRCA gene mutation carriers.

“So homologous recombination cells have a problem with repairing their DNA. They try to repair it using base excision repair, which is what a PARP inhibitor also affects, and then the cell can’t survive. So basically that is a complicated scientific way to say that because we know of these genetic changes in these families, we are able to look inside the cell and try to figure out what drugs are going to target those specific pathways and that is a big success in the BRCA space.”

Potential Targeted Therapies

The Ontario Hereditary Cancer Research Network Leader and Principal Investigator said that there are drugs that are used to treat other diseases that can help treat cancer patients as well. Nuclear Factor (NF) Kappa-B is an important signaling pathway involved in pathogenesis and the treatment of cancers.

This biology is mirrored in osteoporosis and clinicians have discovered that a drug known as denosumab can help to prevent or delay cancer, Dr. Kim said.

“Similarly in the BRCA1 carriers particularly, there is another pathway of growth that these patients use in their breast tissue specifically and it is called the NF Kappa B pathway or rank ligand pathway and interestingly, that biology is mirrored in osteoporosis. And there is actually an osteoporosis drug that also regulates this pathway. So serendipitously, you know the researchers have found that using this osteoporosis drug may prevent cancer in these patients and that is denosumab…and it is a drug that can potentially prevent or delay cancer particularly in the breast.”

There is also a clinical trial currently underway by the Canadian Cancer Trials Group that looks at the role that aspirin can play in preventing ovarian cancer in patients with BRCA gene mutations, said the Princess Margaret Cancer Centre Medical Director.

“There is another ongoing clinical trial by the CCTG – the Canadian Cancer Trials Group – that is looking at the role of aspirin is decreasing the likelihood of ovarian cancer in BRCA carriers and the idea is that aspirin prevents inflammation and that inflammation leads to a lot of cell growth leading to cancer. So there is an ongoing clinical trial called OV.25, where the investigators here are looking for patients who are BRCA carriers and administering aspirin to see if it decreases the ovarian cancer risk.”

Another drug that could be used to prevent cancer are the messenger ribonucleic acid (mRNA) vaccines. The benefits of these vaccines, which have been used with COVID-19, is that different types of these vaccines can be manufactured very quickly. There are also the HPV vaccine and the hepatitis vaccine, said Dr. Kim.

“So the mRNA vaccination community is looking at, ‘well maybe we can come up with a cancer vaccine.’ There are vaccines known to prevent cancer, particularly such as HPV vaccination, hepatitis vaccination as it relates to liver cancer. So vaccinating patients does have a role in cancer prevention, and particularly in the hereditary cancer patients, they are using those well-known cellular pathways or scientific discoveries to really engineer vaccines because of the mRNA technology allows them to be very nimble, and we know that there are a few ongoing trials of BRCA patients receiving mRNA vaccinations and lynch syndrome patients who have hereditary colon cancer to receive vaccines to see if it delays a cancer onset and a lot of them use it to boost that immune system. In the cancer surveillance, the immune system has to clear out cancer cells.”

Obstacles in Genetic Testing In Ontario

However, in spite of the improvements in genetic testing and Canada having a universal health care system, there are still obstacles that hereditary cancer patients face in Ontario. Dr. Kim explained that one of these issues is that there is no unified registry or network where these carriers can interact with one another on a clinical or scientific basis.

He said that such a registry is needed because Ontario is a big province and patients see different doctors in different clinics, making the need for a cancer genetics network even more beneficial.

“Ontario is a big province geographically and clinically, patients are seen in different clinics. Despite us having a publicly funded health care system, where we now have genetic testing that is uniform – 76 genes across the different labs irrespective of where we live – carriers still face some barriers. They see different genetic clinicians, they see different family doctors, and there is no unified registry or network for Ontario hereditary cancer syndrome carriers to interact with each other on a clinical or scientific basis.”

The lack of surveillance guidelines and the inequitable access to research and other areas of expertise for those hereditary cancer patients living in rural areas of Ontario compared to those living in urban areas of Ontario are other hinderances for these persons, said Dr. Kim.

Another barrier is familial cascade testing is not fully exploited, which makes it more difficult for geneticists to be able to identify other family members of hereditary cancer patients who are at risk and intervene early, explained the Princess Margaret Cancer Centre Medical Director.

“So there is a lack of standardization of surveillance guidelines, there is inequitable access to research and expertise and for us in the genetics community, we see that familial cascade testing is underutilized, meaning that there is lost opportunity because genetic testing for a cancer patient, yes, it’s great for them, but the real opportunity for us in the genetics community is to identify those other family members at risk and intervene very early where we can actually prevent cancer from actually happening.”

He said that it is equally important to figure out the perspective of the patient. Here their goal was to find out what would be helpful for patients and their family members in an inherited cancer genetic variant, which has the potential to increase their chances of developing cancer.

Accessing Health Care Services: Rural Ontario Versus Urban Ontario

He stated that a perfect example of the inequitable access to health care services can be seen in the differences for patients in rural Ontario compared to urban Ontario. For example, BRCA1 carriers living in rural Ontario may not have the same access to research; in some cases, there may not even have access to the medical equipment used to detect cancers and/or they may not even have a family doctor because the one that they were seeing may have left.

“So this is the disparity and conundrum and barriers can be best illustrated with a case example of a newly identified BRCA1 carrier in a community hospital living in rural Ontario, where high-risk screening and awareness of this fairly well-known genetic condition is limited. They are only able to access highly specialized screening through MRI and mammography, but maybe they don’t have an MRI machine that is close to them or maybe they don’t have a mammogram that is close to them. Maybe they don’t even have a family doctor because their family doctor just left.”

This means that these carriers have to travel just to gain access for required treatment such as a mastectomy while the lack of a unified network means that they cannot share their concerns with other carriers, Dr. Kim said.

“So these are barriers in Ontario that are real. They may have to travel to have that mastectomy, which is recommended in some individuals who have that gene mutation and they have limited access to research and carriers have a great thirst for knowledge and enthusiasm to be involved in pushing the boundaries of our knowledge in their condition. ”

Some of these persons may also be patients at a rural hospital where there is no research and no partnerships with hospitals in urban Ontario where such research is being carried out, he stated.

“They may be involved in a community hospital that doesn’t know where research is available and there may be limited research agreements between those hospitals to larger academic centres that allow us to enroll these patients. So really a challenge for a patient here.”

However, in an urban hospital, these carriers have access to some of the best radiologists, researchers, medical equipment and other things, which results in prevention, early detection and treatment options, said the Medical Geneticist.

“This is a contrast to a newly identified PALB2 carrier that may be identified in the large research enterprise here at Women’s College Hospital. They have access to high-risk screening; many radiologists, who have expertise in interpreting subtle changes in MRIs; the right sequences are requested; follow-up ultrasounds; follow-up mammograms are ordered on a protocolized basis; the support of the genetics clinic; and oncologists; and the fertility clinics – an entire comprehensive program is available here and access to research programs and clinical trials within the hospital are available.”

Yes another obstacle relates to the lack of province wide data on cancer risks and no standardized screening guidelines in Ontario for PALB2 patients and previvors, he stated.

“However, despite this, there is limited data on an aggregate scale across the province on cancer risks and there are no standardized Ontario screening guidelines and surgical recommendations for all hereditary cancer patients and particularly for PALB2, where unlike BRCA1 and BRCA2, these guidelines are available. PALB2, it is an evolving target and the data is always emerging because these carriers are actually much harder to ascertain and reside less frequently when we do the genetic testing.”

Ontario Genetics Stakeholders Uniting for Cancer Research

The Chair of the CCMG Canada-Wide Cancer Genetics and Genomics (C2G2) Community of Practice said that those in the genetics community recognized this, which is why they partnered with the Ontario Institute for Cancer Research and shortly before COVID-19 hit, they were able to have an in-person think tank on February 10, 2020, where many of the top notch geneticists participated and agreed that they should work together to make cancer genetics and the lives of their cancer patients better by developing a program and research network that can enroll patients.

It is called the Ontario Hereditary Cancer Research Network and under this initiative, which is being funded by the Ontario Institute for Cancer Research over a five year period to the tune of 4.5 million, doctors would use the information collected from persons with hereditary cancer syndrome to deepen their knowledge of the biology prevention, early detection and treatment of all cancers, said the Princess Margaret Cancer Centre Medical Director.

The goals are to identify all hereditary cancer carriers in Ontario, engage the community on the database development, populate the OHCRN database, develop surveillance guidelines and enable genomics and gene discovery for the patients that they enroll, Dr. Kim added.

Some of the big names involved in this network include the Familial Breast Cancer Research Unit at the Women’s College Hospital, experts in the breast cancer landscape; the Familiar GI Cancer Registry led by Zane Cohen and Steven Gallinger; the Pediatrics Cancer Genetics Program, led by David Malkin and the Ontario Familial Breast Cancer Registry at Mount Sinai led by Irene Andrulis, he said.

It is hoped that this network would result in numerous advancements when it comes to clinical trials for hereditary cancer patients and their families, said the Medical Geneticist.

“But there are other genes that are not captured in these research registries and many patients that are otherwise left orphaned and we at the Ontario Hereditary Cancer Research Network wanted to find a mechanism to be gene agnostic, but all-encompassing when it comes to hereditary cancer.”


Who else is out there? The Ontario Hereditary Cancer Research Network


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