LiFE – An International Consortium Approach to Researching a Rare Cancer Syndrome Webinar

LiFE – An International Consortium Approach to Researching a Rare Cancer Syndrome Webinar


Jennifer: Welcome and thank you for joining
us today for the webinar on LiFE, an International Consortium Approach to Researching a Rare
Cancer Syndrome. My name is Jennifer Leidenberger, and I will
be your Web-Ex host. Before we get started, I’d like to make
a few comments. All lines have been muted upon entry and will
remain muted for the duration of the webinar. Please submit your questions throughout the
presentation in the chat panel and select host or all panelists from the dropdown. We will ask them on your behalf during the
Q&A portion of the webinar. You’ll see a link in the chat box shortly
if you need live closed captioning, and I’d also like to note that this webinar is being
recorded. And now I’d like to turn it over to Nonniekaye
to introduce our speakers. Nonniekaye: Thank you, Jennifer. Again, my name is Nonniekaye Shelburne. I’m a program director with the Epidemiology
and Genomics Research Program and also the NCA liaison to the Li-Fraumeni Exploration
Consortium, which we’ll refer to as LiFE throughout the presentation. Li-Fraumeni Syndrome is rare. It’s an inherited cancer syndrome requiring
collaborative science to address many of the needs of the growing population. The LiFE Consortium was established in 2011
to foster communication among Li-Fraumeni Syndrome investigators and to promote collaborative
multi-site research to improve our understanding of Li-Fraumeni Syndrome and clinical care. Recognizing the benefit of data coordinating
centers as a tool for collaborative cancer epidemiology research, our program here at
NCI piloted a data coordinating center contract in 2014. The goal of the contract was to demonstrate
data pooling, harmonization, management, distribution, and public and secure access through a collaborative
process across cancer epidemiology consortia, and we chose one focused on rare cancer for
which LiFE was selected. During 2014 and 2015 the LiFE consortia investigators
and the Maryland-based contractor Enterprise Science Computing, or ESAC for short, created
the data coordinating center. Once fully operational, the data coordinating
center was transferred from the contractor to the consortia, and the City of Hope received
that data coordinating center in 2016 and has been managing it since. It is my privilege to have Dr. Jeffrey Weitzel
and Miss Sharon Sand from the City of Hope here with us today to discuss the Li-Fraumeni
Data Coordinating Center work to date, including challenges, successes, outcomes, and practical
tips for running and housing a rare cancer data coordinating center. Dr. Jeffrey Weitzel is a physician and a researcher
in clinical cancer genomics, working with populations at increased risk for developing
cancer because of family history or personal risk factors. He’s been a member of the City of Hope team
since 1996 and is expanding the reach of low-cost genetic screening materials as well as training
the doctors and nurses in underserved populations in Peru, Colombia, and Mexico. Dr. Weitzel is a founding member of the Li-Fraumeni
Exploration Consortium. We also have Sharon Sand with us. She is a highly experienced clinical research
administrator and supervises the research core staff in the Clinical Cancer Genomics
Division at City of Hope. She is administrator of the Clinical Cancer
Genomics Community Research Network, managing clinical data, pedigrees, and DNA samples
from the multi-country initiative. Miss Sand was vital to the development of
the Li-Fraumeni Data Coordinating Center, and as a member of the technical working group
has been the lead coordinator of the LiFE Consortium database since it was transferred
to City of Hope in 2016. At this time I’ll turn the presentation
over to Dr. Weitzel and Miss Sand. Jeff: Thank you very much and thank you for
that warm introduction. So can you see to share my desktop? There we go. Now go ahead and go into presentation mode. I just want to confirm that you guys can see
our screen. Nonniekaye: We can. Thank you. Jeff: Perfect. All right. Great. Well, again this is — when we were asked
to do this, Sharon and I were delighted. This is a labor of love, as really all good
science is I think, and we’ll tell the story both a little bit of a story about the syndrome
but really the big story about how do people come together to work on such an important
area. So we’re, as mentioned, at the City of Hope
out here in Los Angeles. We’re just into the end of our gloating
season in terms of weather, but it’s nice 280 days a year. So we can’t argue. So let me go forward and just go to the next
slide. So first off, who were Li and Fraumeni? So, Frederick Li and Joseph Fraumen, Jr.,
many of you know about this, and for those of you who are aficionados and really know
about this, but it was really extraordinary science. It was the science of observation. Really, they said boy, there’s a cluster
of cancers here that is more than we expected, Rhabdomyosarcoma in children: epidemiologic
study and identification of a familial cancer syndrome. And it was 1969 so that was 50 years ago and
in the JNCI, and it was really identification of a syndrome. Now Fred worked from Boston at the Dana Farber
Cancer Institute but was a member of the NCI. He passed away in 2015 after a long and really
amazing illustrious career. I’ve had the great honor and look forward
to that honor many times over of meeting with Dr. Fraumeni, Jr. We’ve seen him, and I know they just had
a seminar at the AARC which was commemorating the syndrome. And so I’m really, really delighted to be
involved in this and really honored to be a part of the program. So as a chronology though and for a rare disorder
and especially one that involves counting on perhaps two hands or two hands and two
feet the number of cases, let’s talk about what the syndrome looks like first. So this is actually from the ASCO Core Curriculum
looking at teaching about Li-Fraumeni Syndrome, and as you can see, it’s an autosomal dominant
syndrome, although we know now it’s associated with p53, but that wasn’t always the case. And breast cancer was one of the manifestations
that I would see as an adult oncologist, but really with soft tissue sarcomas and osteosarcomas
in children, brain tumors in children and adults. Leukemia was thought to be an important part
of the syndrome but really was made into a secondary characteristic many years later. So the core cancers as they’re called, brain
tumors, especially choroid plexus tumors in childhood; sarcomas, especially rhabdoid and
lipo sarcomas; specifically certain types of sarcomas with known translocations and
things like that are not part of the syndrome; adrenal cortical carcinoma with a susceptibility
window during childhood, the major manifestation often being hirsutism. So you have to be adept at understanding this. Breast cancer is here. Obviously covering every tissue in the body,
all the scary stuff like the brain tumors, and things like that. And if a woman gets to adulthood, we’re
talking about breast cancer. And these are the youngest onset breast cancers
I’ve ever seen. So not uncommon at all for a woman to have
breast cancer in her twenties or early thirties. Men are carriers as well as women. So this is autosomal on chromosome 17. But I think the penetrance is less [unintelligible]
are some of the things we still need to understand. Now what about the ontogeny and how we learned
about this? So yeah, 1969 was the first observation. And then look at this. You’re getting a paper on cancer research
in 1988 on 24 families. That was the entire base they’re working
with. Fred Li was the lead author here. Joseph Fraumeni, Jr., the second author. John Mulvihill, a geneticist who’s been
doing this for a long time, one of the earliest people doing it. Margaret Tucker later focused more on melanoma. But this is a really strong crew at the NCI
that really is the founders in my mind of familiar cancer care. Then look at this. A few years later a follow-up study of the
same 24 families with my dear friend and colleague, Judy Garber, as the lead author, and this
was around the time of her training or finishing of her training and being engaged in the syndrome,
and she worked very closely with Fred Li who was at the Farber. It wasn’t until 1990 that gent p53 was connected
then to this syndrome. So this was really an interesting time. I will share with you that that was when I
was a third-year med-on chem-on fellow just finishing my fellowship, and it was things
like p53 being linked to Li-Fraumeni Syndrome that if you remember 1990 was the year that
BRCA1 was localized to chromosome 17. These were exciting, exciting times, and they
still are today, but it really changed my life and the directions I went. How do you recognize this beyond the pedigree
that I showed you? And so there are some would call the Chompret
criteria, which really sort of picked out the key features, very early onset cancers,
breast cancers under a certain age, sarcomas, and then tried to sort of do a calculated
sensitivity for how do you know who to do testing on because frankly testing was very
expensive and in fact wasn’t even available commercially until interestingly it was the
City of Hope Molecular Diagnostic Laboratory then under the direction of Steve Summer who
started it. He was somewhat of a maven in p53 research
himself. And so City of Hope was one of the first places
to offer commercial testing in the mid-2000s, so around 2005. I’ll talk about some of that data. But here we are now 50 years from the initial
definition of the syndrome. And by the way, the Chompret criteria looked
at Li-Fraumeni [unintelligible]. So what was the syndromic definition versus
who all should be referred? For 40 years form the discovery of the tumor
protein and 30 years form the association of TP53 with Li-Fraumeni Syndrome. So these are kind of interesting decades in
terms of our timing for having this webinar today and for talking about a consortium focused
on this disease. So this was our paper from 2009, which was
a summary of the 500 or so cases who were referred for single gene testing for p53,
and one of the things about this table and this is what our contribution was at that
time, was to sort of put it if you have a core cancer under a certain age, what’s
the likelihood that you would have a p53 mutation? It was sort of mirroring the BRCA criteria
at the time. But one of the things that came from this
paper was that we saw that for women under 30 with breast cancer who were BRCA negative,
that that alone had a yield of about 7 percent for having a p53 pathogen variant. And that was then incorporated in the NCCN
guideline. And so more women got access to testing and
really the recognition of it as a cause of early onset breast cancer even if you didn’t
see the childhood cancers. The first glimpse, if you will, that there
might be some differences in the phenotypes across families. The second was it really did focus on the
fact that we didn’t find the p53 mutation in anybody who didn’t have at least one
of the core cancers at a young age. So those were two things. Now that’s reinforced. This is just another way of looking at the
data that we had from our paper. Again, 91 of 500 individuals had a mutation,
and you can see the distribution of the cancers among those who were carriers. So in most [unintelligible] cancers in the
series, but it was really focusing on the core cancers as sort of a dogma to be thinking
about when we’re thinking about the syndrome. This is a paper from the French [unintelligible]. The French have also one of the largest experiences,
but if you look here, this is from a paper in 2015 and you’ll notice that all the N,
the total N of individuals that they were following at that point were 132 kids and
219 adults. Okay. So this is an entire country’s consortium
looking at p53, and look at the limited numbers. But what I wanted to highlight here was for
the childhood presentation, the core cancers, exactly what I just recited for you, and for
the adult presentation we’re talking about the breast cancers and the soft tissue sarcomas. And then lung cancer interestingly is one
of the — among the common adult cancers, that’s one of the more common ones. And you’ll see the others here. Colorectal also comes in and often at a very
early onset. So this is worked on at Dana Farber. [unintelligible] published on this and the
idea that we do screen for colon cancer starting in their twenties for these individuals. But nonetheless, the syndrome and its phenotypic
features have remained remarkably durable over time. So what was going on up to that point? So we had multiple investigators working on
Li-Fraumeni, this very rare syndrome, each with their own research registry. They were relatively small numbers of patients. I showed you the two papers that were on 24
families. Most of our collaborations were one on one
or one in a few collaborators. These are wonderful people. I am just so honored to be, you know, around
with Louise Strong, David Malcon [phonetic], Judy Garber, all the folks that are really
well-known in this realm. Great friendships, good collegial relationships,
but no formal agreement on common interests and a mission. We have limited genomic tools and testing
was expansive and there were limited commercial testing options. City of Hope was the only lab that offered
single-gene testing for quite a long time until the era of multigene panels started
to kick in around 2013. With regard to advocacy there are grateful
patient advocacy at the local level. So David’s got folks, [unintelligible] got
folks who are really grateful and so, so essential but not really organized in a way that was
going to be systemic. So that was the genesis of the consortium. The first genesis meeting, which was in 2010
on the campus at the National Cancer Institute. I was again honored to be there to be part
of that group. And what was unique about this, and I don’t
wasn’t anyone to underestimate the importance and the power of this. We didn’t do it with the intent that we
were going to be a bunch of poohbahs and academics and that this is the way of the world, but
we brought with us and invited and fully embraced our partners who are our patients. And so I had some of my patients who were
there. And by the way, because these families are
so rare, and they gravitate to centers of excellence, I share families with Judy, I
share families with Kate Nathanson at UPenn, I share families with the folks at the NCI
with Dr. Savage and others. So we all had some families there, and they
built up an advocacy group, a lay organization at the same time as we grew up as a consortium. And the idea was that we were joined at the
hip from the start where they could help with fundraising and awareness and they keep our
feet to the fire with the burning clinical questions that need to be answered desperately
for their families. And I got to tell you, we listen to patients
all the time, and I could watch and cry at many of the talks and how heartfelt they were. And we never lose touch with that. I think one of the privileges of being in
the prevention realm is we’re dealing with the future and how we prevent cancer, and
I’ve always felt privileged to be there, but I am moved today and there’s nothing
more sincere and authentic than what their real experiences are. So this was the marriage. That paper that I cited here, Phuong Mai led
the paper. Phuong trained us, was at the NCI when she
wrote this up for our group. You can see all the authors there really reflect
the folks of the day who are some of the leaders in this realm and have been involved in p53
for a long time and obviously it was really an honor to have the other founders there. But either way, the point was that at the
end of this paper — most people don’t see it — there was a two page statement or resolution
of what we were. By the way, the acronym, Li-Fraumeni Consortium,
I like to say we did one paper on referral guidelines, but I really haven’t been [unintelligible]
at p53 like my colleagues like Judy and [unintelligible] and some of these real lions of that field,
but I did come up with the acronym. I’ll take credit for it, and I put a little
lightbulb on the top of the I. And so I couldn’t think of a better acronym
for something that is so forward-looking and prevention oriented than life, and it honored
the founders. And oftentimes they have to be really strained
to make an acronym. This one fell together, and I put a little
lightbulb you’ll see it on the emblem — on the top of the I as a symbol of really bright
light and also illuminating ideas. But you can read through this. I believe this will be available as a recording. But it was really talking about the fact that
we’re multidisciplinary. So many people involved, [unintelligible]
resources. We’re talking to psychologists, researchers,
genetic counselors, especially genetic counselors, and other members of this community. We want to combat and understand this disorder,
and our goal is to eliminate suffering. That you can put on any medical mantra, but
really here these families do suffer. We recognize the complexity. We acknowledge that no single institution
— and the rarity. And again this goes to the Rare Diseases Webinar
concept here that when you have a rare disorder, you have to collaborate. Collaborate, collaborate, collaborate and
put your, you know, eggs in the same basket if you want sample size and to be able to
give some effective and reproducible work. So no single institution can do it. To really benefit patients, we need to understand
and work together. So we want to pool ideas, resources, and energy
as a most effective means. Therefore, the consortium. And further, we wanted to reflect the hope
and belief that cancers ultimately associated with LFS are in many cases manageable, increasingly
curable, and ultimately preventable. It goes on. I actually cut out a few paragraphs. This is a two-page manifesto. But LiFE will work to understand the mechanisms
of this order, predict individual cancer risk, detect cancers at their earliest stage and
most treatable stage, develop new therapeutic strategies, and support affected patients
and their families, and it will operate in partnership with the LFSA, the Li-Fraumeni
Syndrome Association, and other advocacy groups and international organizations and funding
agencies to deliver on our promise. So this is really, again, a unique concept
of putting together the consortium of academics with the group of the lay individuals who
will be the fire under our feet and the light on our lamp to help us not lose the way on
the way. And so again I’m really honored to be part
of that, and it’s at this point that I’m going to transfer the control to Sharon and
she’ll talk a little bit about sort of the nuts and bolts of who’s involved, what were
the first iterations in the database, and then some transitions that were unique to
our experience at the City of Hope. Sharon? Sharon: Well hello there. I’m honored to be with you here today and
to share our experience with you about establishing the data coordinating center here at City
of Hope and also being part of the initial startup of the data coordinating center. So the participating cites include these initially
and it’s actually continuing to grow pretty rapidly right now. But we have [unintelligible] from Brazil,
who’s been involved from the beginning; Garrett Evans from the U.K.; Judy Garber from
the Dana Farber; Tim Nichols at St. Jude; Dr. Kratz [phonetic] from Germany; and then
Dr. Savage from NIH; Louise Strong from MD Anderson; and Josh Schiffman from University
of Utah; and David [unintelligible], who is in Canada, the Hospital for Sick Children. So this was the initial steering committee
as it was set up, and it has been evolving a little bit, and we’ll talk about that
a little bit later. So as Nonniekaye mentioned, the NCI contracted
with Enterprise Science and Computing or ESAC as we refer to them, to develop the LiFE Data
Coordinating Center as a model. They developed and documented the DCC development
for LiFE. They did this with input from the steering
committee and also the technical working group which [unintelligible] primarily with clinical
research administrators such as myself from each of the principal investigator sites. And at the end of
that two-year period a technical paper was drafted. So then once that process had been completed,
it was time to turn over the Data Coordinating Center to one of the steering committee sites,
and that ended up being the City of Hope. So we took it over. And the Li-Fraumeni Association, which is
the advocacy group started in parallel with LiFE, provided partial funding for a coordinator,
which really helped to get us going. So in the first iteration of the Data Coordinating
Center database setup ESAC established this fairly elaborate system that would take data
from each of the participating sites in like an Excel format and load that data, validate
it, and harmonize it. At that point it would go into the database,
and reports would be automatically generated through a system that was a dynamic system
and could be seen via a website by the PIs and administrators but also in limited fashion
by public users. And the reason for this was so that people
could see what was going on with LiFE and also so that other researchers who were not
part of the steering committee and were part of LiFE could see the type of data that was
available for research and could submit proposals and query the steering committee as to whether
they could use the data for research. So this is one of the pages that was part
of that dynamic database demonstration. And with the great representation of the data,
a little bit challenged with data harmonization, which is what the technical working group
was working on, and I’ll show you an example of one of the challenges later. We had so many different sites collecting
basically the same information but all in slightly different ways. And then within the website and in the database,
we were able to see the data in several different ways, both by genetic status, by the type
of cancer that was represented in families and by sites, and [unintelligible] were available
by different types of cancer and genetics data. So now we have the database has been growing
fairly quickly and we have assembled nearly about 1,169 TP53 carriers in over 513 families. So this is the representation of the cases
that are TP53 positive and then by age at first diagnosis. And you can see here the early childhood cancers
followed by later childhood, early adult, and then later adulthood cancers. Then we have the data separated by positive
for TP53, negative for TP53, and then variants of uncertain significance. The negatives are important for us to be able
to understand the penetrance and variability within families as well as the probability
calculations that can be done with calculating for TP53. Variants of uncertain significance are those
variants that show up in TP53 but we don’t know whether they’re cancer causing, and
important work is being done in this area to adjudicate whether those are truly positive
or truly negative. So this is just a quick representation of
data assembled by site, and this is continuing to grow. As we’ve recently transitioned our database,
we’ve been able to increase these numbers both in terms of numbers by site and also
the numbers of sites that are contributing. And then this is a breakdown of the cases
by — or the families by country. So primarily in the US but then followed by
Brazil, the U.K., and then several others. This is the representation of the cases broken
down by positive cases both affected and unaffected. Affected means they have cancer and the unaffected
means they don’t have cancer. And we’re able to do probability studies
with this data because we have probability and penetrance studies because we have the
age for each of the individuals. So we can see if they’re, you know, age
30 and haven’t gotten cancer, age 50 and haven’t gotten cancer and have the TP53
variant. So for race and ethnicity, the vast majority
is white followed by a fairly significant representation of Hispanic. Then the other categories are not as well
represented, but we’re anticipating that with the growth of both the sites and then
as well as increase in numbers from especially the sites that have more diversity, we’ll
be able to increase this diversity. So for the logistics we have a monthly steering
committee meeting that’s done by phone, and it includes the LFSA leaders as well. So the advocacy group is represented on those
calls. We also have semiannual — so every two years
we have a LiFE and LFSA meeting, and those are great meetings which include the researchers
where we have steering committee meetings but also the families. So educational events and sessions for the
families in conjunction with the researchers. So in terms of logistics, we have review of
research proposals and implementation of data use agreements. We’re just getting started with this and
we’re pretty excited that we’re able to provide research data for collaborating sites
who have proposed ideas. And because of this impetus, the database
has continued to grow both in depth and breadth. Data transfer agreements are set up with each
site before any data is collected, and then the data collection begins. So some observations and limitations. So although with the setup at ESAC, the summary
statistics and graphics were very aesthetically pleasing — it’s a beautiful website and
a way to present the data so that people can see it — the visit statistics were not exciting
and we didn’t unfortunately generate much in the way of research proposals. So we also were not getting new data from
the member sites because so much of the effort was put into establishing the logistics of
that process. So we also had the challenge of adding additional
fields. So once the data dictionary was set, it was
difficult to add those additional fields when the focus was on the data harmonization. The data dictionary was set up at ESAC with
the steering committee and the technical working group at the beginning, and we’ve been able
to expand that recently. So the variant level data was not included
initially, but we’ve been able to add that and correct data for most of the sites on
the variant level data for each of their cases recently. We also added breast cancer hormone receptor
status, so ER, PR, HER2 data that was recently added as well, and that was in direct response
to a research proposal that was looking at TP53 cases and hormone receptor status based
on TP53 status. In the original database it was quite complete,
but there was only categorical or limited family history data and no pedigree. So no family history representation. The steering committee decided to transfer
the data to a pedigree-level relational database, and the reason they did that was because they
wanted to be able to view the pedigree-level data. We wanted to be able to include the specific
TP53 variant data. And we also wanted to be able to give sites
access to their data for submission and also for updates. So by doing this, we were able to create better
user operability on our side and ability to add and revise data fields as we realized
if they were too constraining or not broad enough. And then we also expanded the phenotypic data. And the reason we were able to do this was
because we’ve been coordinating the Clinical Cancer Genomics Community Research Network
for over 20 years and using the progeny relational pedigree database for that consortium pretty
much the entire time. And that consortium is 45 sites across the
U.S. and in Latin America with over 25,000 pedigrees and DNA data. We also used the same backbone to coordinate
another consortium [unintelligible], which is another international consortium. So some of the challenges that we’ve had
at the Data Coordinating Center, one is funding. While we have had very generous funding from
the Li-Fraumeni Syndrome Association, it does not cover all the costs that we have for managing
the database and coordinating the data transfer and updates and all of that, including the
informatics person, the administrator, and the clinical research assistant. Another challenge has been defining roles,
the membership of LiFE and the steering committee because it was very clear who that was when
it started, but it is starting to evolve a little bit and we want to make room for new
folks and make sure that it’s clear which people are in which role. The data dictionary has been a little bit
of a challenge. We’ve been working on refining that, clarifying
that, and then also expanding that. Data harmonization, which I’ll show you
an example of in a minute, has been challenging because there’s so many different ways of
representing a specific cancer or even a genetic variant might be in two different types of
nomenclature. And then with an international consortium,
there’s been some barriers with some data transfer agreements, legal types of issues
from different organizations and mostly from international sites. So also the timing of the steering committee
phone conferences, we have to make it when everybody’s awake, and somehow we manage
to do that. So for data harmonization this is just a quick
example of a very small part of the data. So sarcoma is listed here as what we’ve
mapped, and these are the types of data that were submitted. So all sarcoma but slightly different in terms
of how they’re worded. And then osteosarcoma, all of these down here,
we had to realize that these are all osteosarcoma and then map them so that we can categorize
them into a reasonable number of categories. So lessons learned. It’s important to define everything as much
as possible up front but to continue to be flexible, to do that going forward as well. And this is especially important for the data
dictionary but also to plan for the research proposals including what the authorship rules
will be if research proposals are granted. And then we talked about flexibility to add
more fields. That’s important as you — like we did,
we got the research proposal that had data we didn’t have collected, but by being fairly
nimble, we were able to collect that additional data. And then a plan for funding. It’s important to have sustainability and
continuity plans to be able to continue the coordination. And then data submission timing and method. So it’s pretty straightforward to collect
the first cases, but then what do you do when somebody has an update to their case? How do you know what’s new data and how
do you identify and/or collate that data into the existing data and then how do you add
new data for new cases or new individuals in a pedigree? Now I’ll hand it back to Dr. Weitzel here. Great. So actually the key ingredient on that last
list is Sharon Sand. So no, people like Sharon. So smart, critical, analytical. You have people like me and Judy Garber biting
off way more than we can chew sort of, you know, we give ourselves the glad-handed title
of visionary, but really we’re just scattered. So Sharon and people like Sharon help to give
us alignment. Alec Savantis [phonetic] is the one who’s
helping to organize our steering committee calls and so we really rely on folks to help
us with that structure, but you need leadership and you need structure and both of those are
going to be important for your success down the line. So now I want to talk about if we had this
consortium 10 years ago and it was a well-organized data coordinating center, well supported,
again when it comes to that data coordinating center role that we took on, it was really
like that infamous movie where they have everybody in a line in the Army and they say whoever
wants to do this, step forward and everybody else steps back. So we were like the last one standing, but
we were willing to take action. We thought it was important and we knew there
would be some bridging to get to where we need to be. So one of the first things that we wanted
to talk about was how does this consortium help advance our science and so I want to
give you just a few quick examples. It’s still very early in the running because
we are really just really hitting the ground in terms of our establishment. But first off, it was a wonderful amazing
study by Vilani [phonetic] and Wahl, and this is David Malkin’s group in Toronto. And we were all waiting for a prospective
study of a highly regimented surveillance regimen that had an outcome related to survival,
and that was because really it was just watchful waiting for most kids. We didn’t even want to know whether they
were carriers, just if they started bleeding or had a lump, you did something. So that was not a way to live. But now we know that whole-body MRI, rigorous
screening for biochemical science of adrenal cortical carcinoma, et cetera, actually has
a role. So where is the LiFE Consortium? That was their work. They had been doing this for some time and
it was their study that then stimulated a lot of other [unintelligible]. So the NCI, the lead program over at MD Anderson,
that’s Dr. Strong’s group. We were following the same protocol, albeit
unfunded, but probably the same protocol. And so what happened in some of our steering
committee calls is we were able to put together all of the, if you will, thought leaders in
this realm and this paper was born from that, which is a meta-analysis or a series of about
four papers that came out demonstrating the yield of whole-body MRI and in part catalyzing
the integration of whole-body MRI as an insurable care for individuals with Li-Fraumeni syndrome
with regard to the NCCN guideline. So you can see on this list of authors for
this meta analysis we had maybe 20 cases in. This put together all the other cases that
had their own separate funded studies. They got published separately and then this
was our meta-analysis and this was really a product. If you look on there, all the people who are
on the steering committee are there, Sharon Savage, Tom’s one of my colleagues, David
Malcom is there, Josh Schiffman, Garrett Evans, all of us are here. So this was I think really I consider it a
product of the consortium even though it didn’t use the database per se. We also had our own databases, but I want
to bring that out. This is really important translational stuff. And then the second thing is that one of the
first projects that we did as part of a consortium, we published in 2012 [unintelligible] et al,
this top line, under the banner of LiFE Consortium but really for the database even had the data
deposited in it and validated. And this was hey, let’s look at breast cancer
because in two previous studies, 2010 and 2012 from this group had 9 and 30 cases respectively. So we’re talking really small numbers, but
we want to say what’s the snapshot of breast cancer in this context, and strikingly it
was HER2/neu positive. So it’s triple positive as compared to triple
negative. So that’s what our paper said, and this
table is actually from our paper that we published in 2012. This was a LiFE Consortium effort, but look
at the number, 32 cases, okay. And at that point this is the world’s literature
was 71 cases of breast cancer that had been immunophenotype to be able to know that this
seems to be a dominant phenotype compared to the reported population. Well, one of our first formal concepts that’s
been submitted to the committee, approved by the committee required us to go up and
get new data, the receptor data, but we’re able to do this again. So data recently organized for the new project
proposal, which is made up of Andy [unintelligible] and Christina Fortuno [phonetic] in Australia
was that they’re able to get data striking out 196 cases of the 502 that are in the database,
and this is on relatively short order with no money. Okay. So we’re not giving anybody any money to
go back to their database or go back to the medical record and collect this data, but
this is out of the commitment to this mission that we have. But look at that, 196 compared to the 71 from
before. So this means we can do this science and we
can do it better. We will get some solid data out of this. This will be a joint publication that will
remember the members who have to sort out those rules yet but already with an N of 196
I’s a very reasonable study. They intend to use that phenotype if they
confirm the phenotype to the carriers, to help adjudicate — they’re working on a
model [unintelligible] in P53 so that they can use a predictive model that allows to
take the phenotype like if it’s HER2 DR positive is that predictive, they can incorporate
that in the model. So there’s a translational element to this,
not just the recognition that it’s HER2 positive, but that if that actually predicts
the likelihood of that mutation or that variant was pathogenic, that will just forward too. Another project that is just getting off the
ground which we’re really excited about and it’s been going for a while. This was published by [unintelligible] at
the Dana Farber. Judy Garber is the senior author. And this was in partnership not with LiFE
Consortium but rather with Amber [phonetic] Genetics, but what they published in JMCI
this past year was that [unintelligible] while we pick up P53 mutations on multigene panels,
especially when they’re qualified for something else that I’m going to talk to you about,
they seem to have a little bit of a different phenotype from what they’re showing here. This is from the paper. It was that the age of diagnosis was pushed. This is single-gene testing compared to multigene
testing. Single gene versus multigene. So you can see that there’s a slight [unintelligible]
onset if you weren’t looking for Li-Fraumeni Syndrome. So it must mean that the phenotype has expanded
a bit. So that’s one important observation. Another observation was from our own group
where I’m starting to get P53s on multigene panel tests where I just flat-out didn’t
believe. Fifty-eight-year-olds with ER positive HER2
negative breast cancer. I just wasn’t convinced. I convinced the lab to work with us and we
found out that when you look at certain parameters, in this case low [unintelligible] so in other
words the P53 was there. It was a bona fide analytic finding, but it
didn’t look like a regular kind of a case from a phenotype perspective. And the [unintelligible] was less than the
50/50 you expect for [unintelligible]. It turns out that most of these are what we
call apparent [unintelligible] expansion and essentially analytically correct. It’s in the blood, but it wasn’t in the
constitution of the individual. And most of those when we did confirmatory
testing, meaning we looked at other tissues, we showed that 96 percent of the time it was
not in the other tissues. Therefore, at the least it’s mosaic, and
at the most it’s most likely [unintelligible]. So putting those two studies together, all
of the P53s coming out of the door we have to be careful about when the multigene panel
and the phenotype doesn’t fit. So how do we do studies to understand the
phenotype and penetrance? So we now have to qualify these folks. So we have an R01 that we wrote using our
collaboration with the group, and the title is Precision Approaches to Refining TP53-associated
Cancer Risk. This will assemble the largest cohort of TP53
carriers. We’ve embraced the consortium, so the LiFE
Consortium, but in addition reached out to Geisinger, reached out to O’Ryan [phonetic],
reached out to other sources of these testing processes because — and all of the commercial
labs. So all of the major commercial labs have agreed
to collaborate by at least referring these families to us via their provider so that
we can then do secondary [unintelligible] within these families to do — our goal is
to accrue at least two to three persons per family in addition to the propend to do segregation
analyses, and we have Chris Amos as one of our co PIs. So it’s Dr. Garber, myself, and Chris Amos,
all of us representing the Li-Fraumeni Consortium, and one of the key things is that this is
funded. It’s got a nice score for the R01. So, you know, from your mouth to God’s ears. We’ll hope that it will be funded this summer
when the council meets. But the idea is to determine the prevalence
and clinical implications of [unintelligible] expansion. So what does it mean if you have [unintelligible]? It could be good news you don’t have Li-Fraumeni
Syndrome, bad news you might be at risk for leukemia. So we’re going to figure that out from a
prospective perspective. But once we have a cohort that’s adequately
sized, we expect to be able to help define penetrance with narrow [unintelligible] intervals
as well as modifiers. So we’ll be looking at [unintelligible]
and polygenic risk scores as modifiers of TP53-associted risks. Why is there such a variation of these phenotypes? And at the end of this, this data is all going
to be incorporated in the database and will then be available to the larger community
for studies. And remember, all these consortia, the goal
is future studies, not just the present. So we’ll do our shameless pitch already,
which is for anybody in the consortium, you know, P53s, we need to collaborate. Anybody who’s got P53, we’d love to have
them in the consortium. Any one of the consortium members can enroll
these patients and they can then be part of this. If you have a large number of these patients,
we’re not necessarily a revolving door, but we’re an open door to having people
coming in who have some skin in the game and want to be part of our group. So this is all collegial. It’s not fixed in stone. Here is the contact information for our group. So the lifedcc, that’s at Cityofhope.org. That will get to Alec or Sharon or one of
us. The contact for the Li Fraumeni Syndrome Organization. So you want help with your families, you want
help to help your families find resources and to share what they are experiencing because
as we have our annual meetings we haven’t had them — we didn’t talk about that yet,
but we had the meeting in D.C., had a meeting in [unintelligible] Boston, we had a meeting
in Ohio, our last meeting was in Toronto last spring, and the next meeting is going to be
in Boston in I believe the fall or summer of 2020. So we’re looking very much forward to that
next meeting, but during those meetings we have an LFSA meeting and the main consortium
meeting. So these are two ways in which we do it. The other sense is if you propose a concept,
expect that we want you to include some measure of support for the data coordinating center. We gave up on just support for our consortium
but rather support for projects that each incrementally help to support the Data Coordinating
Center because we really have one-half of [unintelligible] available to us for this. The rest is all donated at this point. But I think it’s going to be worthwhile,
and I think it’s going to be really exciting. And that’s the end of our presentation. I want to thank you all very much for your
attention. If you sat in through the whole thing, we
hope that it was stimulating and that you’ll use this for inspiring your work with other
rare disorders. Do we need to change the bouncing ball? Oh, Jennifer, you already took it. Jennifer: No. I already took it back from you guys. Thank you so much for the presentation. It was great. I know we do have a few questions coming in. I do want to remind our audience please submit
your questions using the chat or a Q&A box and select all panelists or hosts and our
moderator will ask them on our behalf. So, Nonniekaye, I’ll pass it over to you. Nonniekaye: Thank you. Jeff and Sharon, one question that came in
was you mentioned that several patients that have rare cancers do go to various cancer
centers for assessment and treatment, and you mentioned that that was a problem and
something you noted within the Li-Fraumeni Group. When you were creating the Data Coordinating
Center, how did you identify those patients to make sure you didn’t count them twice? Jeff: Yeah. So that’s a great question, and to be honest,
there’s not a formal process yet. What we know is that what it is is Judy sends
them to me, I would send one back to Judy. So it was more colleague to colleague because
if the patient brings their medical records, we know who else is in the field and so we
recognize that or that their extended family had members in different cities, and we would
refer actively to those folks that we know because they need specialized care. That’s an informal approach. A formal approach, which we believe is now
enabled is by using a pedigree-based program, we can both look at okay, we have two pedigrees
that have been submitted. We can look for overlap and there will be
[unintelligible] ways for us to do that. The second way to do that is we did not originally
have variant level data because from the perspective at least one of our contributing centers,
their [unintelligible] thought that a variant because it’s such a rare syndrome, would
identify the family. Now that we have more than 1,000 people, that’s
not so much the worry. The pedigrees still are to some extent, but
they’re private. They’re in our setting. So we can match by variant. And then among those with the same variant,
we can look at the pedigree and look for structural similarity. Our projects will include or do include genetic
counselors. So Kathy Schneider and the group and others
at Dana Farber. We’ve got our group who’s going to have
[unintelligible]. So we will actively curate by looking at pedigree
structure and looking at the specific variant. I think that’s the best we can do. Nonniekaye: Thank you very much. Jeff: That’s short of ancestry informative
markers and identity. One of the things we’ll do with the project
when it is funded is we will get all the [unintelligible] and they’ll have a whole genome wide association
backbone clearly to establish identity from that. Okay. Nonniekaye: Thank you. Another question, you mentioned a technical
paper being drafted. Is that paper accessible and what does it
include? Jeff: That’s a great question. I mean that was originally drafted, as you
know, by the folks at ESAC with our team. It went through at least one round of review
at one place. Now that we’ve changed the database, we’ve
changed the focus of the paper a little bit [unintelligible]. It is being submitted. So as soon as that’s available, we’ll
put on the website perhaps links to the appropriate literature. So hopefully we’ll have a growing bibliography
to share with folks. That’s the other thing is giving back to
the community, making sure that in our new website design by the way, I don’t know
if you mentioned it, Sharon, but with Jen Perry, who is one of the leaders at the LFSA,
president of the LFSA, we’re hoping to maybe cohabitate the two websites. So have the web presence, the external-facing
web presence really a stone’s throw, a sister to the LFSA site so that — because we really
want to continue to cultivate that interrelationship between the advocacy organization and the
academic folks. Nonniekaye: Thank you. Another question. There is a lot of standardization work going
on in HL7 within the genomics work group to be able to use data directly from the electronic
health record to limit harmonization efforts and increase productivity. Have you looked into this to improve data? Jeff: So that’s a great question. HL7 is basically for those of you who are
— and again I only know enough to be dangerous here. I’m just a physician. Which is a communication tool. Basically it’s a health language HL7 tool
that basically allows us to move things. For example, you can take the Surgeon General’s
Family History website and patients can enter family history into that website, create their
own pedigree, and there’s a backdoor way to take an HL7 translator and move that actually
into a pedigree drawing program. So just to give you one example. This is something when I talked to Kevin Hughes
about this when he was developing his Hughes Risk [unintelligible] software. So absolutely we’re thinking about that
in our own world because as I started our own consortium, which aren’t just P53, it’s
all cancer genetics, we’ve been doing data mining in our EMR for some time for patients
who are enrolled in our registry, gave us permission to get followed data. And so we need to do more of that. There are HL7 connections that are already
made between family history forms in our [unintelligible] database and things like that. So yeah, the whole point is to try and make
it interoperable. At our own center we’re hoping to integrate,
for example, progeny or a pedigree drawing program in the EMR for the whole institution
because nobody takes adequate pedigrees outside of the genetic counselors who we all work
with or those of us if we had any tincture of time. So I think HL7 is one of the programming languages
that are translating languages. It will be very helpful, but we are working
on doing data mining to get that because that’s the way of the world, right. It’s the big data, the data mining. But this is a rare disorder. I will make one caveat, one comment. Brad Coffee [phonetic], who’s at Myriad
and has done some work presented at the American Society [unintelligible] meeting, pointed
out that even 50 percent [unintelligible] fraction P53s could still be false. And so he did this by looking at nomad. So nomad is one of those publicly available
databases, and there’s two papers out there that suggest that we just didn’t appreciate
how common P53 was. No. We just didn’t appreciate that there were
false positives in the database and it is still rare, albeit worldwide you get enough
to work with. So we think that there’s conflation in the
current population databases regarding P53 because this is a rare syndrome. How can they be unaffected at 80? They did the other experiment with a gene
probe ASXL1. It’s a [unintelligible] gene that’s involved
in leukemia or if it’s inherited as a germline trait, it’s a profound developmental disorder. They don’t live long. Well, it was frequent in the nomad database,
and we’re certain that reflects again confounding of epidemiology by these sorts of things. Nonniekaye: All right. Next question. We’ve established an international consortium
in retinoblastoma and second cancer research last year. It proved difficult to have all legal counsel
agree on the contracts, such as data sharing, data transfer, data use agreement. What are your tips for speeding this process
along? Sharon: So ESAC started the process and in
conjunction with NCI, and we had to redo all of the data transfer agreements so that they
were between City of Hope and the sites. We had, you know, our lead role team in our
office of [unintelligible] was able to successfully do that. We didn’t have too many hiccups. Jeff: Yeah. So that’s a constant problem. We’ll tell you it’s a constant problem. Internationally it was a challenge. So for example for the Brazilians there was
a rule that we weren’t aware of that the PI, essentially the protocol goes with a PI. So if a PI leaves an institution, it’s not
the institution that represents for that protocol. So that as an interesting quirk. We worked it out because they’re good people
and they’re going to work it out and we have now two people in Brazil, one representing
the old database who is the new person and one representing [unintelligible]. So there’s things you have to work out. And as busy clinician scientists, it’s no
small task to get this stuff through legal. Half the time we don’t even know who those
folks are. And you want to develop a close relationship
with your tech transfer guy. They can be your advocate. Don’t look at them as the enemy. They’re just doing their job. It is a barrier-oriented process. And I’ll tell you that even one of our major
anchor tenants in the current consortium still hasn’t completed their DUA. Every time it’s oh, we’re going to get
a new coordinator or oh, they just changed the lawyer. So I’m sympathetic. Nonniekaye: And I will add the National Cancer
Institute does have transfer and use agreements that can be used as templates, and that was
the starting point for this project and the various centers did have some minor changes,
but it was a good way to start. So should anyone on the call be interested,
you can give us an email and we can connect you with that. We’re at time, but I just wanted to end
with this one last question to you guys. It was how can institutions not yet part of
the LiFE Consortium join? Jeff: Okay. So the last slide we had, sort of the contact
information for this, we are not the steering committee. We are the custodians, you know, the custodians
of the galaxy here in terms of the database, but please reach out to that email address,
which I believe was [email protected] We organized the monthly steering committee
meetings. We just had somebody, for example, from UPenn
join, but we do expect that there will be some substantial clinical contribution they
can make or that we’ll suggest that they fold in with one of the others and collaborate
with somebody who’s already in. They’ll still be recognized as being part
of the group, but please reach out to us with queries and some sort of a snapshot of what
is it that you have in hand or expect to have in terms of wanting to participate. We’re delighted. We will make it as transparent as possible. We hope to have the new web presence up as
well in the not too distant future to be able to make it clear, but that’s the thing,
just reach out. We’re really, like I said, we’re an open
door in that regard. We need everybody to do this for rare disorders. Nonniekaye: Great. Thank you so much to both of you for your
great presentation and to our audience for some great questions that came through. As a reminder, this webinar is recorded and
it will be posted within the next week or so. So please continue to check back on the rare
cancers website as well as any upcoming events that we’ll be having later this fall. So thank you, everybody. [END OF FILE]

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