Dr. Vanessa Bianchi

April 1st, 2021
The Impact of Surveillance for Individuals Affected with CMMRD

Hi everybody, before I start, I just want to say a huge thank you to all of you that have joined the webinar today. We are so excited to be able to bring you these new initiatives, one of which is this educational series where we are really hoping to try and present this information to you in a way that is easy to understand, especially for those of you that are not in the medical or academic fields.

So as this is the first of our seminar series, I am open to any suggestions. I think most of you have my contact information already. If you don’t I have provided my e-mail address (vanessa.bianchi@sickkids.ca) here at the bottom of the screen.

Please feel free to send us any feedback, comments, questions, that you have at the end of the talk.

So, I’m going to go into my presentation now and I’m going talk to you today about work that was presented by myself or, sorry, work that was conducted by myself and other members of the replication repair deficiency consortium. Specifically, what I am going to be talking to you about today is the impact of surveillance for individuals that are affected with CMMRD.

Before I get into the actual research, what I actually want to do is give you a brief introduction to the consortium. Those of you who do know me have probably interacted with me before when I have asked if you wanted to register either yourselves, your children or your patients to our registry and to our research studies. But, I think that without being as heavily involved with it as we are, it can be a little confusing to try and understand who we really are, what we are doing with all the information that we are collecting, what the aim of everything that we are doing is, and how you are really playing a role and making an impact.

So, this slide is just a brief overview of the consortium. We work with physicians and genetic counsellors,
patient advocates and families from all over the world. The last time we counted, we were working with people in over 45 different countries. So, when we’re made aware of individuals who may have CMMRD or other replication repair deficiency syndromes, what we do is we register them to our biobank. And when we do that, that allows us to collect things like clinical information which is how I was able to conduct the study that I’m going to talk to you guys about today.

But, we’re also able to collect a number of biological specimens as well. This includes things like blood or available tumour tissue and this allows us to conduct biological research studies with the goal of new discoveries.

I know Dr. Tabori already went into some of the new discoveries that we’ve had over the year, so this is sort of a brief summary of the things that we’re very interested in.

[Slide describing our current research interests. It includes molecular and genetic analysis, functional assays, animal modelling, genetic and epigenetic screens, drug discovery and preclinical testing]

We will look at molecular and genetic analysis of the tumors that we receive. Here, functional assays, what I mean by that is the diagnostic assays. Dr. Tabori was talking about one of the new diagnostic tools that we recently developed, which is a really simple, cheap and robust way of detecting CMMRD in a blood sample.

We’re interested in animal modelling, and what I mean by animal modelling is that we are able to actually see how these tumors are forming, growing, and ways in which we can treat them.

We do genetic and epigenetic screening studies. And of course we’re interested in discovering new drugs and developing new preclinical guidelines that may influence clinical trials that are ongoing.

We do have a few clinical trials that we are working on currently. And as Dr. Tabori already touched on we are interested in managing patients worldwide as much as we possibly can and part of that is surveillance and developing protocols and ways in which we can better our surveillance tactics.

Before I go into some of the research, I just want to give a brief overview into the genetic background of constitutional mismatch repair deficiency syndrome which is abbreviated as CMMRD.

CMMRD is a childhood cancer predisposition syndrome that results from the loss of functional DNA mismatch repair. The mismatch repair complex is composed of these 4 proteins that are listed here and individuals with CMMRD inherit mutations in one of these proteins from both of their parents. Our DNA is composed of 4, they are called nucleic acids or base pairs. I have them simplified here as G, T, A and C. And, this is the genetic code that makes up who we are and makes up all of our DNA. Every time that our DNA is copied, and this happens if an individual is growing for example, if you have an injury and you need to repair and just in order to maintain ourselves as just functioning human beings, as we do have a natural amount of cell turnover. And so, every time the DNA is copied sometimes the wrong base pairs are inserted. For example, maybe a T is inserted instead of a G, and when this happens it is called a mutation.

Individuals that have CMMRD have complete loss of the proofreading mechanism that is involved in DNA so they have complete loss of the mismatch repair complex. The mismatch repair complex will scan the DNA and go in and find a mistake and make sure that it’s corrected. The easiest analogy that I can think of to describe this is if I had you transcribing a document into a software like Microsoft Word. You’re typing, you’re transcribing the document and you may make an error and when you do you have the proofreading mechanism of something like Microsoft Word that will then go in and tell you that you’ve made a mistake and make sure that it’s corrected. This is a very similar mechanism, just in our bodies. In individuals that have CMMRD, this complex is dysfunctional and therefore they have the accumulation of mutations every time their cells divide. This accumulation of mutations is ultimately what predisposes these individuals to getting cancer.

The 3 most common cancer types that we see are brain cancers, gastrointestinal cancers and hematological or blood cancers. Because we know that these individuals are at risk of developing cancers, what we propose is that these individuals undergo routine surveillance.

Here you can see a surveillance protocol that was proposed by our group

This protocol has certain types of tests and examinations that target the 3 main types of tumors that we see in these individuals. So we see brain tumors, we see leukemias and lymphomas, and we also see gastrointestinal cancers. However, we’ve also included extended screenings, like whole body MRI, that can search the body for all tumor types. For those of you who either have CMMRD or if you have children or know individuals that are undergoing surveillance that are affected with CMMRD, you know that this protocol can be very demanding, and it’s primarily been based off of expert opinion. What I mean by expert opinion is that people who are experts in the field got together and designed this protocol, trying to figure out what would be the very best thing that they can think of for the patients.

However, until now, a protocol like this hasn’t been fully tested for its ability to detect cancers early and improve overall survival of individuals that have CMMRD. In the study that I am going to present to you today, this is exactly what we looked at.

So, as I discussed, we had two main questions. First, does surveillance help find tumors early, at stages when they would be more easily treatable? And, secondly, does early detection of these cancers actually improve overall and long-term survival of individuals that have CMMRD?

I’ll talk to you a little bit now about how we did our study and this is where you can really see the consortium come into play. At the time that we started the study, we used all patients that were enrolled in the consortium with a confirmed diagnosis of CMMRD. And we were able to collect information on these patients through a few different avenues.

First, we were able to get clinical information which was provided by the physicians when the patients enrolled in the study and through ongoing follow up with the physicians while managing patient care. What we also did though, was we sent a questionnaire to the physicians at the start of the study in order to get additional information. This is the study that I am going to present to you today

We had a total of 110 patients with CMMRD. 5 of them did not develop cancer during the study and we had enough information on 89 of these patients in order to do a robust analysis of long term survival.

The first thing that we wanted to look at was whether all of these tests and exams that we’re asking these patients to undergo are actually targeting the types of tumors that we’re seeing present in these individuals?

So here you can see, that, if we stratify the tumors, what we see is that the main types of tumors that are already known to occur in individuals with CMMRD were the main types that we also observed. So, we saw brain tumors, gastrointestinal cancers as well as blood cancers.

But what we found was that 10 percent of tumors were actually occurring in other tissues and organs of the body as well. For us, 10 percent was a pretty large fraction. So, what this really told us was that it justified the use of including these extended testings, like whole body MRI for these individuals.

So, now we know that the testing that we are proposing should be able to identify tumors early, and that’s what we went on to look at next. So, in our patients that were undergoing surveillance we wanted to see how many tumors could be detected asymptomatic. What I mean by asymptomatic is that these tumors are found early, before the patient is presenting with any symptoms.

What you can see from the chart here, is that most of the tumors were able to be detected asymptomatic. So 75 percent of the brain tumors, 100 percent of our gastrointestinal cancers and 100 percent of those other tumors, were detected by the surveillance tests and exams that we had proposed. 25 percent of the brain tumors were found when the patient was symptomatic. However, when we went in and looked at these cases specifically, what we found was that these tumors were occurring in individuals where the frequency or the time interval between the screenings that we had proposed was longer than what was recommended.

In contrast, what we saw when we looked at our blood cancers was that only 16 percent of the tumors were able to be captured using the recommended tests that we had proposed. This actually is not a surprising finding. It is known that when it comes to blood cancers, the tests that are currently available are not the best at catching these tumors at the very early or pre-malignant stages. And so really what this information suggests is that more research needs to go into developing new ways to detect blood cancers.

Now, what we know is that the surveillance protocol is able to detect most tumors that are asymptomatic. But, what we don’t know is whether or not this actually impacts the patient and if it actually affects long term survival in these individuals. So, this is what we looked at next.

If you’ve never seen a graph like this before, it may be tricky to interpret. This is called a survival curve, and as the name suggests it represents patient survival. Here, on the axis you can see survival represented as a percentage. And on the axis here you can see time in years. At the point of diagnosis, all patients have a 100 percent survival. Each dip in the curve here, unfortunately represents a patient that has succumbed to the disease.

When we looked at the patients that were a part of our study, what we did was we stratified them based on the level of surveillance that the patients received. Patients were placed in the “Full Surveillance” group if they had received the routine screenings at all of the routine intervals that were recommended. We placed patients in the Partial Surveillance group if they did not receive all of the tests and exams that we had suggested routinely or if they were at intervals longer than what we had proposed. The No Surveillance group was those individuals who did not receive any of the recommended screenings.

If we go back to our graph here and we look at a specific time point, we are going to specifically look at 4 years from the point of diagnosis.

What we can see is that individuals that are undergoing “Full Surveillance” have a significantly increased overall survival in comparison to those individuals that have had “No Surveillance”. This is a difference of around 80 percent compared to 15 percent. What was interesting to us was that individuals that were undergoing “Partial Surveillance” still had a significantly increased overall survival in comparison to those undergoing “No Surveillance”. This was a difference of 55 percent compared to 15.

Before I finish off my talk, I just want to show some real examples of how early tumor detection can save lives. In the images over here you can see a whole body MRI and a brain MRI of a patient with a brain tumor known as a glioblastoma. I have pointed out where the tumor is located, here and here. In this group of individuals, all 10 of them were undergoing routine surveillance and had diagnoses of brain tumors and all 10 of then were long term survivors when their tumors were diagnosed through surveillance.

We saw the same thing for individuals that were undergoing routine gastrointestinal screenings. Here you can see a gastrointestinal cancer. We had 24 patients that were undergoing surveillance. All of the patients were affected before the age of 18. 21 of them had malignant tumors that were diagnosed. All of the patients whose tumors were discovered by surveillance are still alive. This was actually work that was done by Carol Durno and Melyssa Aronson, our genetic counsellor and gastroenterologist for the consortium.

And so just before I finish up, I want to say a huge thank you to everyone who was involved in bringing this study together. Just from our group specifically, Carol, Ayse and Uri played a huge role in getting all of this data and information together. But, what I really want to emphasize is how powerful this global collaboration can be. For such a rare syndrome, having a study with 110 patients really emphasizes just how important this collaboration can be. So, I want to thank all of our collaborators globally, the physicians, genetic counsellors, scientists, staff members and our parent and patient advocates.

And I would be happy to take any questions now.

I think I am going to throw it back to Lucie, she is going to do the question and answer period and then we will continue on. So thank you all very much for listening, I really appreciate that, I hope this was easy to understand and you really enjoyed it.