GM4: American Society of Clinical Oncology – WIlliam Pao


William Pao:
Can you hear me okay? I want to thank the organizers for inviting me to speak today,
and Dr. Swain for sharing the podium. So, a lot of discussion today about point of decision
— point-of-care decision support, so I’m just going to give you an example of what
we’ve done at Vanderbilt, just as a representative example of what can be done. So many of you may know that cancer has been,
for more than 100 years, really described from where it came from on the body, as well
as what it looks like under the microscope, but we know, really, that at the genetic level,
many cancers can differ, especially in terms of what is so-called the driver mutation,
i.e., the mutation that not only induces tumor genesis, but then is required for that tumor
cell to survive. And so, classically, melanoma, for example, has been described where it comes
from on the skin, but now we know from tumor profiling at Vanderbilt, for example, and
elsewhere, that there’s really multiple subsets that are clinically relevant. At Vanderbilt, we’ve initiated routine tumor
testing. We’ve tested over 2,100 specimens, and, again, a large fraction of these patient’s
tumors will have specific driver mutations that are potentially actionable with targeted
therapies today. And, as a result of the genotyping, 61 percent of those patients have gone on
to a clinical trial, specifically in melanoma, a big comparison to the 3 percent nationally
that go on. So the reason I think I’m talking to you today
is because there’s a huge knowledge gap, even in the oncology world, as to what to do with
all these mutations. We build gene panels that only we’re testing for about 40 to 60
mutations, and even then some fellows and staff at our — at Vanderbilt were having
difficulty deciding what to do with those specific mutations. A lot of people have talked
about this, but, essentially, there are surveys that reveal a disconnect in the understanding
of and communication about genetic mutation testing among health care professionals and
cancer patients. And so one of the things we did was first
to get rid of the old electronic medical record for reporting gene mutation testing. As many
of you may know, most — in many hospitals, there is a scanned .pdf from the molecular
pathology lab that goes into a chart. It’s very hard to find that report. It’s also hard
to see where the result is. And the challenge for us was, really, how do you start to report
multiple mutations in multiple genes at the same time, and whose role is to curate all
that knowledge? And there’s no clinical trial information or therapeutic implications for
the results. And so at Vanderbilt we actually control our
own medical records, called StarPanel, so we can adapt it. And in conjunction with Mia
Levy, a very talented biomedical informaticist, we’ve essentially put into the chart the results
of genetic testing of our patients. Here, in particular, is what we call a dashboard
or a whiteboard, where we can see by patient the exact mutations that were tested for in
this specific melanoma panel. And then we put a lot of thought into saying what does
a clinician really want? Do they just want to know positive or negative? So you can see
a yellow result is positive and a gray result is negative. If you really want to know the
exact mutation, you hover over the yellow, and then it gives you specifically all the
different kinds of mutations that you looked for. And you can see that a clinician at the
point of care with five minutes to see his or her patient could get very confused, especially
at the genomic level, of the significance of all these mutations. Now, again, I’m also a practicing oncologist.
I know that you have five minutes sometimes to go see your patient. You want to just look
it up and be able to discuss it in an intelligent manner. So within the chart, if you forgot
what V600 is, you can just click on that, and it takes you to My Cancer Genome, which
is a freely available website designed to enable a genetically-informed approach to
cancer medicine. Now, at this particular website, you can see in very brief detail. We wrote
it — or the mantra is that clinicians should be able to catch up on all the information
within five minutes. It will tell you, for example, the location of the mutation, the
frequency of that mutation in melanoma, the frequency of the specific V600E mutation among
BRAF mutant melanomas, and then the implications for targeted therapy. In addition, you can then — what we’re most
excited about is that it can help you find clinical trials, and so if you click on the
clinical trials tab, it will take you to BRAF mutation-directed melanoma clinical trials,
not only at Vanderbilt within our own system, but also in Tennessee, in the United States,
and internationally. What Dr. Levy did was to download all of clinicaltrials.gov, and
then using natural language processing and machine learning, used gene names to search
that and annotate it so that you can search the trials by gene status. And then if you
click on, specifically, for example, that number, it will take you to the clinical trial
that is being done at Vanderbilt, and you can check the eligibility. You can click on
the United States and it will tell you which sites around the world — in the United States,
particularly, have trials directed towards BRAF mutant melanoma, and then you’ll take
— click on the specific site, and it will take you to nciclinicaltrials.gov. So, again, this is a website that’s designed
to enable a genetically-informed approach to cancer medicine called My Cancer Genome.
We currently cover 17 cancers, 25 genes, and 289 disease-gene-variant relationships. We
also have clinical trial search, where you can search 36,000 cancer trials, 135 cancer
diagnoses, and 437 cancer genes as defined by COSMIC, which is the Catalog of Somatic
Mutations in Cancer run by the Sanger. We want to be the COSMIC for clinicians, which
is essentially not available, except through this website, currently, in the world. We also built something called DIRECT, which
is the DNA-Mutation Inventory to Refine and Enhance Canter Treatment. We started with
EGF receptor mutations in lung cancer, and basically looked at all the papers since 2005,
and have more than 1,000 patients in the database with 188 different kinds of EGF receptor mutations.
Again, as a person who was involved in the discovery of EGFR mutations, I used to get
emails all over — every week from people: “I have my patient’s tumor genotype, it has
this mutation, what am I supposed to do?” Well, now they can just go to DIRECT, and
then they can find out the significance of that particular mutation in EGF receptor.
And we hope to expand that out. And, actually, we think there should be a national or international
effort with this kind of database so that we can actually keep track of all these rare
mutations. We also built the Internet’s only complete
list of targeted therapeutics, which you can easily access on the website, and there are
other educational things on the website as well. Right now, this is a worldwide collaboration.
It’s basically based on philanthropy and grants. We have 49 contributors from 18 institutions
and eight countries, and we now, starting in about — we started in January of 2011,
and we’re now more than — we now have more than 2,000 site users per week, according
to Google Analytics, from 134 countries around the world and all 52 U.S. territories. And then this slide is just to show you that
it’s a huge collaborative effort. We do have a lot of people at Vanderbilt, but our contributors
are from all over the world, and we ask experts throughout the world to help contribute on
their specific disease and gene variants and mutations. Thanks. Teri Manolio:
Great. All right. Thank you very much. So we have questions for our oncology colleagues.
I think Marc is going to start off. Marc Williams:
Thank you. One comment related to the aggregation of data. Again, we got a great example in
oncology of how this can work, and that’s the Children’s Oncology Group that, you know,
for a variety of reasons, we’re faced with the challenges of rare tumors, and made the
decision from the get-go to aggregate data, and the number of children that are on trials
approaches 100 percent, and so it’s — in some ways I don’t think we’ll be able to scroll
back and begin something like that, but it’s certainly a worthy goal. The question I have for you, Bill, is tell
me a little bit more about the outcome measures that you’re using to determine the impact
and effectiveness of the MCG program. William Pao:
Yeah, that’s a great question. Right now all we have is a user survey that people can ask
us questions or give recommendations, et cetera. We had multiple survey requests. Right now
the content is written for physicians, by physicians, and physician scientists, but
we’ve had a lot of requests to translate it into patient-centric information. We’ve also
had, and I’ll get to your detailed question, but we’ve also had requests to translate it
into French, German, and then other medical institutes wanting to link to us and/or suck
in the content so that they can report their outcomes. In terms of actually whether it’s influencing
patient care, we have not measured that specifically. Right now we’re trying to help clinicians
and oncologists really use the genetic information. We know patients are getting their tumors
tested. The bulk of mutations that are tested for include, like, V600E, or actionable ones,
like an EGF receptor, where people do know what to do, but there are some rare ones where
we don’t have — there’s no evidence as we’ve been discussing in terms of the guidelines. Marc Williams:
In terms — Sandra Swain:
And I think the reason, you know, I wanted him to present it, too, is because we would
like an ASCO to include these kind of things, because our cancer link, one of the main goals
is looking at outcomes for all these patients who are treated, you know, not just with genomic
information, but information in general. Marc Williams:
Yeah, and then one specific question or point. You mentioned that 65 percent of your Vanderbilt
patients are on trial. How much of that is attributable to this, or was that just a cultural
thing that pre-dated this? William Pao:
Yes. So some of that involves the fact that, for example, melanoma, we have lots of trials
that are genome-directed, and so I think there’s a huge referral bias for patients to come
and get specific care for their specific mutation. We have trials for all the different subsets
of melanoma, for example. Teri Manolio:
Great. I’m wondering when you work with these cancer genomes, are you getting more information
than the candidate genes, or are you really just focusing on the driver mutations in cancer? William Pao:
Yeah, so, right now, at least at Vanderbilt, we’re just focusing on the driver mutations,
but we know there’s, as other people have talked about, there’s going to be large groups
of people who are doing exomes or genomes, et cetera. Right now the website is only designed
to help you with a single mutation, and a single gene, and a single gene disease variant,
so I think the next frontier will be how do you deal with multiple mutations? However,
there are companies that many of you may know, for example, like Foundation Medicine, which
profiles more than 200 cancer genes, full exomes, including multiple fusions, et cetera,
and they give much more extensive reports, some of which our clinicians still have trouble
interpreting if they’re not necessarily pathway-oriented in terms of cancer biology. Teri Manolio:
Yeah, one thing that you’ll probably be struggling with as well as everyone is how do you deal
with the mutations that you find that are not really into oncology? So, you know, you’re
dealing with the cancer, but then there are all those other findings, and so have you
run across any of those yet or are you making plans to deal with other subspecialties? You
want to describe that? William Pao:
Sure. Well, in cancer — at Vanderbilt we’re only testing for known variants, but, obviously,
everyone’s moving toward full exome or finding variants of unknown significance. Right now,
as Dr. Swain alluded to, at least in cancer you can say there’s a mutation for which there’s
an FDA-approved drug and has an indication in that specific disease. Then you may get
a mutation, like V600E in a colon cancer, for which there’s no FDA approval, but which
there’s FDA approval in a different cancer, and then — and you can move on down the chain.
You know, that’s a mutation of clinical significance, but not necessarily in that disease. Then
you move on to variants of unknown significance, et cetera. I think a lot of us are wrestling
with that fact. I was just reading the Science paper coming over about how you can also re-identify
patients [laughs] by all of that data, and I think we all have to grapple with that as
we move towards these large databases. Teri Manolio:
Great. Gene. Eugene Passamani:
For Dr. Swain, it seems to me relative to the other subspecialties of medicine, you
really have a challenging task, because you’re having to put this all together as tons of
data rolls in. Are there lessons learned about how you’ve done that that could inform what
other people are going to try to do and get ready for it before it hits? Sandra Swain:
Well, I think the cancer link is the lesson learned, and we are just still — we’re continuing
to learn lessons and the prototype is just being rolled out. So we definitely will and
we plan to publish a paper on it on the issues. It’s not been easy, as you can imagine, using
all different electronic medical records, trying to get it all together, getting, you
know, from my institution, for example, which is MedStar, the lawyers are not excited, would
be an understatement, about giving information to a company to anonymize. That’s a huge problem
right there, the HIPAA issues. So there are a lot of things that we will have to look
at and we’ve worked with, but the plus is that at least 130,000 patient’s data is there,
so the precedent will have been shown, and hopefully in seeing that and seeing that we
can show outcomes and that we can show benefit, quality, looking at value and things like
that, others will see that and actually agree. Marc Williams:
Yeah, so I think that that’s a really important point and something that I think we should
highlight as we think about how to address some of these issues. And this has come up
at other meetings, is the concept of the trusted broker or the safe harbor, and what role could
perhaps the policy shop of genome develop relating to defining those types of safe harbors
where we could do this very important job of aggregating data. Sandra Swain:
I think that would be terrific, really important. William Pao:
Can I comment? Sandra Swain:
Yeah. William Pao:
Quick comment on that. In terms of our DIRECT database, the DNA-mutation Inventory to Refine
and Enhance Cancer Treatment, you would be surprised about how many barriers there are
in terms of getting the mutation status from, for example, trials, from cooperative group
trials, et cetera. Originally we wanted to make that database easily searchable by anyone,
but then because groups would give us data that had already been published but had not
necessarily been published with the fine mutation data in detail, they didn’t want that sharable.
So we had to basically make it that you ask us a question, what is your specific mutation
of interest, and then we would give the result back. And, for example, companies are also very
reluctant to share that information, et cetera. It would be good to have an honest broker
in the middle that could get all that information. Sandra Swain:
I think the other thing that’s really interesting, if you actually talk to patients, they’re
very much for this, so they’re the least of the obstacle, you know, in getting this done,
and I think it’s important in this kind of setting, too, as we go forward in talking
about guidelines that patient advocates really be involved, because they are our advocates.
They want this done. They want quicker therapies and all of that. Teri Manolio:
Great idea. Jonas, please. Jonas Almeida:
[unintelligible] exactly that our initiatives like PatientsLikeMe, some help pushing for
this to happen? Sandra Swain:
Patients pushing for what we’re doing specifically? Jonas Almeida:
Yeah, so, initiatives like PatientsLikeMe, for instance. Sandra Swain:
Yeah, I don’t know that specifically, but I know the patients really, you know, in looking
at different surveys and all, have been very willing to do this, and they’re not pushing
us specifically, but I think that they will definitely be great advocates for it because
it helps them in the long run. You know, you have metastatic cancer, you’re not cured in
most situations. So, they all know that and are very happy to contribute, and I think
we just need to educate people, patients even more about it, and make sure that the, you
know, data is not used inappropriately. Teri Manolio:
Great. Other comments? Super. Well, this has been wonderful. Thank you so much. Our next
topic — Marc Williams:
We should thank our — thank our speakers. Teri Manolio:
We should thank our speakers. [applause] Marc reminds me that my manners aren’t glued
too closely to me [laughs], so he sits next to me instead. So, in terms of lunch, we had
asked them to provide it a little bit early in case we ended early. I don’t think they’re
quite ready yet, but it should be out there momentarily. It will be just to the side here.
We are having a working lunch, so really we need you to get your lunch and bring it back
in, and with the size of this group, it’s going to take the full amount of time to get
it back in. So we will reconvene here at 1:10, hearing from the Heart Association. Thank
you.

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