Charis Eng: Hello.
Good morning.
Teri asked me to briefly mention some of the tumors that we discussed in June and speak
only about one, although in the small group sessions, we may speak about all of them.
Always show my favorite slide.
We're a little slow, 4,600 years old.
And in June what I spoke about with Marc was MSI analysis and mis-measured [spelled phonetically]
pair protein immunohistochemistry for system X screening of Lynn Syndrome in all [unintelligible]
colorectal cancers on our main campus and the uptake is exceedingly good, at least 80
percent make it to genetics clinics.
We also spoke about a slower implementation of the same types of analysis for Lynn Syndrome
screening for all endometrial cancers because it is a component.
The uptake's a little less, 64 percent, and there are challenges, including unlike colon,
many different pathology labs doing it.
This'll probably be solved when everything will be sent into our central lab.
We also discussed the integration of genetic counselors and now over 25 non-genetic specialty
clinics on our main campus and regional practice.
And a prototype of a family [unintelligible] cancer family history tool.
Today, Kate Nathanson [spelled phonetically] from Penn and I are going to speak about routine
screening for [unintelligible] neuroendocrine tumors and we will look at pheochromacytoma.
We could have picked [unintelligible] cancer, but this one's slightly more exciting as our
prototype.
So pheos [spelled phonetically] come from the adrenal medulla and that means they're
from neural crests.
So neuroendocrine tumors, in general, comes from neural crests.
This one in particular can secrete catecholamines and I don't think I have to tell this group
that if it's not recognized, bad things happen.
This is just a picture, an MRI, to show those who don't quite know where the adrenals are.
And that's an axial view and there's the big purple arrow.
Now paraganglion can be anywhere along the paraganglial [spelled phonetically] chain
and can be sympathetic or parasympathetic.
So this one happens to be in the thorax.
Now we learned in med school the famous 10 percent rule.
Ten percent are genetic or inheritable, 10 percent are bilateral, 10 percent malignant.
Now, we thought this was gospel until we started -- meaning the [unintelligible] we -- started
looking into it and the first genes appeared and doesn't really matter.
Well, so much for the 10 percent rule.
So let me tell you, to fast forward a lot of work probably over the last 10 to 15 years,
many [unintelligible] here and we have a population based registry.
Showed that up to 30 percent, sometimes more, of all fields in paraganglial presentations
have a genetic etiology and those are some, but not all of the known genes.
So many genes, neuroendocrine tumors.
So in theory, this is the ideal, when you go through a germline mutation analysis, I've
added in all the genes, there are actually 10, I didn't even put NF1 [spelled phonetically],
because we have found that in the presence of -- that NF1 pheos do not present unless
they have physical stigmata [spelled phonetically], which, hopefully, we can actually recognize.
And every gene has other features, other tumors or different presentations.
For example, let's take SDHB.
There is a high malignancy rate, depending on who you believe, between 14 and 30 percent,
whereas in some of the others, malignancy is rarely, if ever, seen.
For Rett [spelled phonetically], you have to worry about medullary thyroid cancer, and
so on, so forth.
VHL, renal tumors, SDHB and D, they are renal tumors, so it does effect management.
Well, what have we done?
We have [unintelligible] genetic counselors in endocrinology and endocrine surgery clinics.
In the literature, so if that's all we're [spelled phonetically] done, 10 has a [unintelligible],
so a little bit more systematic.
In the literature, SDHB immunohistochemistry is said to be able to pick up those with germline
SDHB, C and D mutations, but not in the other syndromes that I showed you.
A recent paper also showed this might be true for SDHA.
This is routinely implemented at Penn net [spelled phonetically] and Kate tells me that
the uptake is very, very good.
However, [unintelligible] clinical pathologists, while not slouchers [spelled phonetically],
get very inconsistent results so if you ask them to read SDHB staining, it's all over
the place; it's not correlating any germline mutation.
When we do western blots and I give it to my lab to read and finally it can predict
presence of [unintelligible].
So -- but this needs to be worked out.
It looks like a very reasonable screening tool.
And so, with that, I will stop well within my time.
Eight minutes.
Female Speaker: [inaudible]
Charis Eng: Nope, we speak on each -- we have -- please
add in.
Female Speaker: I will add that we routinely do this at our
practice, so all neuroendocrine, also [unintelligible] patients that come through, get genetic testing
and our mutation positivity rate, a little biased, is 60 percent.
So, it's very, very high rate of positives and clearly effects our, at least at Penn,
the management of patients.
And then have patients who have SDHB mutations, we manage them more aggressively and follow
them, and we now actually, in many cases, our management teams are awaiting [spelled
phonetically] genetic testing results.
So I think that this is a really important area that is really under recognized in the
community as something that really is affecting clinical practice.
Male Speaker: Are there -- what happens if you sequence
the tumors?
Female Speaker: What do you mean what happens?
Male Speaker: I mean can you increase it from 60 percent
to 95 percent?
Female Speaker: So we're -- this is actually inherited mutations
--
Male Speaker: Right.
Female Speaker: So we have not gone back and resequenced the
tumor.
There are actually several issues about them -- I'm sorry, there's several -- Charis can
talk about what her experience is, but this is actually something that we're in the process
of doing.
We've actually got funding to do this, but the PGLs [spelled phonetically] actually tend
to get embolized before they get removed so that it can be very difficult to actually
get decent tissue out to do them.
And then the pheos, obviously, can be relatively small or problematic, but actually, at least
at Penn, we're in the process of collecting fresh frozen tissue.
There are some studies, Charis may talk about that, that have shown these mutations in otherwise
somatic mutations in otherwise germline negative patients.
Charis Eng: Correct, although I'm not sure -- I guess
your question is can we use somatic sequencing to enhance the positivity in the germ line?
One of that's [spelled phonetically] obviously technical issues and we have that too and
poking pheos with a fine needle, of course it's not a good idea; surgeons hate that.
[laughs] We also worry about somatic mutations, although we have looked at that with my collaborator
[unintelligible] and the somatic mutation frequency, meaning, truly, a second somatic
hit, is variable so it could, in fact, fool us as a somatic or [spelled phonetically]
germline.
Female Speaker: This is also a complicated area, just to point
out, because the issue of some of these mutations are imprinted and nobody's actually ever been
able to figure out what the imprinted tissue is, so they clearly only affect susceptibility
when inherited from the father, but no one's determined what the tissue is that's infecting
that, and so it's a complicated sort of somatic issue.
Charis Eng: And that's SDHD, especially.
And A, because they are on the same imprinting.
And that's a very neat little [unintelligible] HMG.
Female Speaker: So could I ask both of you to maybe describe
-- and I should have asked this, and will ask it of all the speakers in this session
-- could you describe what the collaborative opportunities might be for those around the
table and in the room, in terms of maybe expanding or building on your work?
Charis Eng: So, Kate and I and [unintelligible] have started
talking offline [spelled phonetically] before this, so we thought it would be neat to bring
it to a group because these are not exactly common tumors.
We talked as broadly as forming a NATNET [spelled phonetically], N-A-T-N-E-T, for things like
this at a quick, rapid screens, like screening for germline syndromes, studying the uptake
all the way to treatment consortia.
Because by -- I mean, this has been an amazing field from nobody cared about it to we know
all these molecular pathways and lots of pathway directed therapy coming up and, might I say
for people's germline disease, we really should be thinking of prevention.
Female Speaker: And I think actually, there are a lot of [unintelligible],
so [unintelligible] and I actually also, as part of this, put together a group to ACMG
to develop genetic testing guidelines for these patients.
There are no published genetic testing guidelines --
Charis Eng: That's true.
Female Speaker: There are no surveillance guidelines for patients
at risk, and actually one of the issues that we run into and I'm sure both of you run into
is how do you manage these patients after they're diagnosed?
Should it be the same for the different mutations?
So I think there are a lot of opportunities to develop sort of best practice guidelines,
here, in many different venues, and I think what Charis is emphasizing is also multi-institutional
targeted therapy trials for patients with metastatic disease, particularly as many of
them have inherited diseases and inherited mutations.
Male Speaker: The other thing that I just mentioned that
directly relates to the surveillance piece is that Josh Schiffman [spelled phonetically]
at Primary Children's Hospital and Hudson Cancer Institute has, in fact, instituted
a surveillance protocol, particularly for the paraganglioma families and preliminary
results are very encouraging, that in fact there's a high degree of preventability, which,
again, is another one of those gospel axioms that you can't do anything about, that it
appears to be about to get an X through it.
So I think that that would be, you know, definitely something that needs to be considered in the
overall consortium approach and would be a likely collaborator.
Female Speaker: I agree, and that's something that Charis
and I have certainly talked about, and I think the other thing that I know Josh has done
is the implementation of rapid full body MR as a screening tool for patients with these
diseases.
And that's actually something that is very hard to get paid for because of the CPT [spelled
phonetically] codes and something that's actually much quicker, much less, shall we say, invasive
and should be, is in fact, cheaper than this standard screening that we employ.
So I think there are a lot of venues to really translate this and different avenues, which,
larger groups are needed to be able to move this forward.
Charis Eng: Of course, I'm outlining [spelled phonetically]
all of this and it's rarely said, is that we would like to study the true cause/effectiveness
as well, something you guys are very, very good at.