Welcome to our program, Tumor Testing and
the Transformation of Lung Cancer Treatment.
The American Lung Association thanks AstraZeneca,
Bristol-Myers Squibb, Foundation Medicine,
Pfizer, and Merck & Co., Inc. for their generous
support of this program.
I'm Carly Ornstein, a National Director of
Lung Cancer Education at the American Lung Association.
During this conversation, I will be joined
by Dr. Justin Gainor, and Dr. Mark Pool, as
we discuss lung cancer tumor testing, what
it means, and who should be tested.
Dr. Justin Gainor is an Oncologist and Assistant
Professor of Medicine at the Harvard Medical
School, and Massachusetts General Hospital
Cancer Center.
Dr. Mark Pool is an Attending Pathologist
at Rush University Medical Center.
We're also joined by several lung force heroes
in the audience, as well as hundreds joining
us online.
If you're joining us via Facebook Live, you
can post your questions in the comments of
the feed, and hopefully we can answer a few
at the end of our program.
We'll try to address any questions we don't
get to in future resources, so stay tuned.
Let's get started.
Thank you Dr. Gainor and Dr. Pool for joining
us today.
I'd like to start with the definition of some
of the terms that we might be discussing today.
Dr. Gainor, can you help us understand what
tumor testing is and what it means?
Sure.
Broadly speaking, tumor testing refers to
doing additional analysis on a tumor in order
to help physicians guide the best treatment
choices.
Importantly, this is typically done on a biopsy
specimen, or a surgical specimen, so if someone's
already had a surgery.
It doesn't necessarily require additional
procedures.
This is something that has already been obtained
if someone's already had a biopsy.
By and large, what we're gonna be focusing
on throughout much of this discussion is gene testing.
That is, we're looking at the DNA of tumor
cells.
DNA is the building blocks of life, the blueprints.
We're looking for changes in the DNA, and
we call those mutations.
This is particularly important because we
know that certain cancers, and specifically
lung cancers, can have genetic mutations that
help inform how we actually treat them.
Great.
Can you talk a little bit about the types
of mutations, and how they actually work,
what's causing the cancer to grow?
Sure.
Here I use the analogy of a light switch,
for my patients.
For many of the genes that we're looking at,
these are present in normal cells.
When there's a genetic mutation in them, and
at specific points, it changes the function of the
light switch.
Normally these are under control.
Turn it on, it tells the cell to grow.
If you turn the light switch off, it says,
"Stop growing."
The problem with these genetic mutations is
that the change results in the light switch
constantly being on.
It changes the function of that particular
gene.
The cell is constantly being told to grow,
grow, grow.
Now we can take advantage of that therapeutically
by delivering targeted medicines that actually
shut off that signal.
But it's just like a lock and a key.
You have to have the right genetic change,
and pair it with the right therapy.
Do we know what causes these genetic changes?
That's a really interesting question.
Right now, we don't.
We know that there are some characteristic
features of patients who have these particular
genetic alterations.
If we focus on those where we have FDA approved
therapies, we know that by and large, these
occur in patients who have never smoked, or
who have a very light smoking history.
We don't think that these genetic alterations
are actually caused by tobacco exposure.
These could just be simply sporadic events.
In all of the cells in our bodies, cells have
to divide.
When they divide, they have to copy all of
the blueprints from one to two.
You can imagine if I had you copy a book,
letter by letter, you're gonna make mistakes.
Most of those mistakes are inconsequential.
But every once in a while you make a mistake
in the wrong word, and it changes the meaning
of everything entirely.
My sense, even though we don't have direct
proof of this yet, is that that explains a
lot of it.
We're actively looking though, if there are
other causes.
I would emphasize that we don't believe that
these are inherited.
Outside of exceptional circumstances, these
are not things that are passed down from one
person to the other when we're speaking about
lung cancer, and some of the genetic changes
that we're gonna be talking about in lung
cancer.
In other cancers, certainly there can be these
familial relationships.
But the genes that we're gonna be talking
about in lung cancer generally are not passed
down from one person to the other.
Right, that makes sense.
When we're talking about this tumor testing,
which sometimes we call biomarker testing,
or genomic testing, you mentioned that we're
looking for these mutations, or these changes
in the genes.
What else can that testing look for?
This field has changed pretty dramatically
over the last several years.
I use the term targeted therapies, which is
trying to pair a genetic change with a targeted
pill directed at that gene change.
That was really something that evolved beginning
in 2004.
That's when we developed the first targeted
therapies.
In the last five to six years, there's been
a second major paradigm for how we've treated
lung cancer, and that's been using immune
therapies.
These therapies work very differently than
targeted therapies.
These drugs are intended to really boost a
patient's own immune system, and use that
to then attack the cancer.
Unfortunately, the biomarkers or the predictors
that we've had for how those drugs are gonna
work have been a bit more complicated.
We don't have the silver bullet, in terms
of predicting those.
But to date, the best predictor that we've
had is something called PD-L1 expression.
Essentially this is a marker on the surface
of cancer cells that indicates that those
tumor cells are trying to evade your own immune
system.
That's another test that has been crucial
for oncologists and pathologists alike, to
do when someone's been diagnosed with lung
cancer.
Great.
Thanks.
Dr. Pool, you're a pathologist.
I'd like you to speak a little bit about what
your role is in this whole tumor testing process.
Sure.
The pathologist is really the unseen physician
in the lung cancer team.
We take tissue that's removed from some surgical
procedure.
It could be a biopsy, or a surgical resection
of the tumor, and then try to look at it visually,
do simply things like just measuring the tumor,
and then look at it under the microscope to
try to look at different attributes of the
tumor in order to try to put it in a group
of tumors that we know from previous history,
from other patients, how they will behave or,
or how they will respond to certain treatments.
One of the most important things that we do
now with genetic testing is to determine which
is appropriate tissue to send for genetic
testing.
Not only are we taking the tissue and trying
to maximize the information by looking at
it under the microscope, but now we're trying
to select appropriate areas of the tumor,
to determine whether there's even enough tissue
to do this testing, and then making sure that
it's triaged appropriately.
For those of us that don't know exactly what
you're looking at under a microscope, can
you explain it in layman's terms what you're
looking for?
Sure.
Generally there's two or three major types
of lung cancer.
It's not all the same thing.
We can tell these different types of lung
cancer under the microscope.
We generally look at small-cell lung carcinoma,
and then another category is non-small cell.
Out of those, which are most of the cancers,
these are divided into squamous cell carcinomas
and adenocarcinomas.
It's adenocarcinomas, in particular, that
we're really interested in, in relation to
molecular testing.
However now with PD-L1, like Dr. Gainor was
mentioning, we're looking at all the PD-L1
expression on all lung cancers, regardless
of this histological type.
Some of the other things we look at microscopically
are the extent of invasion, and other attributes.
We lump this into tumor staging.
The tumor staging is what's useful to physicians
like Dr. Gainor, in terms of what do we do
next with this patient?
What are the treatment options, and so forth?
Dr. Pool touched on this a little bit, but
Dr. Gainor, I was hoping that you could further
explain which lung cancer patients should
get this type of testing.
It's a good question.
By and large, when we're thinking about using
targeted therapies, when we're thinking about
using immune therapies, these are usually
in the context of people who have metastatic
cancer or stage 4 disease.
That means the cancer has spread past [crosstalk]
the lung.
That means the cancer has spread outside of
the lung.
For cancers that are earlier contained within
the lung, our primary therapies are things
like surgery and radiation.
But when cancers escape outside of the lung,
we generally rely on drug therapies.
That's really where these genetic tests and
this PD-L1 test is most important in that setting.
By drug therapy do you mean targeted therapies
and immunotherapy?
Correct, and even chemotherapy.
And chemotherapy.
Historically, when we've been treating lung
cancer, now 15 years ago, when we talked about
drug therapy it was only chemotherapy.
Now it actually spans many, many different
things.
I think of this as these three big buckets
of targeted medicines, immune medicines and
then traditional chemotherapy.
Great.
Just to recap, when you have a patient, if
the patient has stage 4 lung cancer, which
means it's spread past the lungs, and it's
non-small cell, and non-squamous, those are
the patients that you're really looking at
to see if they had mutations?
That's correct.
According to all of the guidelines, those
are the specific patients that everyone should
be tested in that category.
What about patients that don't fit into that
category?
As you're alluding to, that accounts for most
lung cancers, but there are people who are
outside of that.
There the guidelines suggest that it also
depends on some of the characteristics of
the patient, some of the characteristics of
the tumor itself.
There are also large ongoing efforts in the
United States and elsewhere looking at the
importance of gene testing for these other
tumor types, namely things like squamous cancers.
Because what we know is that the gene changes
for squamous cancers is very different than
non-squamous tumors.
The frequencies of these genetic changes differ.
What we're looking for differs depending on
how they appear visually underneath the microscope.
Would you say the best thing is for a patient
just to talk to their doctor about whether
or not [inaudible] [crosstalk].
Exactly.
This is something that should just be raised.
Is this something that I should have genetic
testing for in order to help guide therapy
for me?
Great.
That covers the testing for mutations.
What about testing for the PD-L1, which you
said could be an indicator of how a patient
might respond to an immunotherapy drug?
This is something that's really changed in
the last two years.
Now, any patient with advanced, and that is
spread outside the lungs, non-small cell lung
cancer should have PD-L1 testing at their
diagnosis.
The levels of PD-L1 will help indicate treatment,
whether or not they might be eligible to be
on an immunotherapy drug.
Correct.
This is something that this field is moving
rapidly.
If you would have asked me this question in
March 2018, I would have given you a different
answer than I am today.
Just speaking to how quickly the field is
moving.
Now the paradigm is that if a patient does
not have a genetic change, so we're not doing
targeted medicines, which is the majority
of patients will not get targeted therapy.
For everyone else, all of those patients for
the most part are going to be getting immunotherapy,
and it's just a matter of whether you're going
to add chemotherapy to that or not.
Okay, interesting.
We use this PD-L1 score to help gage whether
we need to do that.
Great, thanks.
Dr. Pool, can you tell us a little bit about
the different types of tests that are out
there to help reveal if a patient has these
mutations or biomarkers?
Sure.
There's different levels of testing that can
be done.
For the last eight to 10 years, we really
only looked at two or three specific mutations.
The advantage to these was that they could
be done relatively quickly, and lot of different
laboratories could do them.
The disadvantages were that number one, these
were usually done in a sequential manner.
One test was then, and then another test,
and then another.
That consumed not only time, but also valuable
tissue.
With small biopsies, sometimes you run out
of tissue.
We have to have tissue to make the diagnosis
to start with.
More recently, there's a different type of
testing called next-generation sequencing
in which multiple tests can be done on the
tissue at one time.
That's been great because you get all of this
information off of one testing period.
The downsides are that you get a lot of information,
in addition to these most common mutations.
It requires a lot of information support to
sort out which are important, and like Dr.
Gainor mentioned before, there's some changes
that are inconsequential, or we don't really
know what information they mean for the patient.
The other downside is that they usually take
about two to three weeks, and sometimes the
oncologist is seeing the patient before they
have all of this information.
The PD-L1 test is a little bit different.
That's a test that we actually do on slides,
and that we examine microscopically.
We do a procedure called immunohistochemical
staining, where we use antibodies that are
directed against the PD-L1, and then look
for the level of expression in the tissue.
Then we provide a score so that it's useful
for the clinicians to decide whether anti-PD-L1
therapy is appropriate or not.
Great.
PD-L1 is treated a little differently 'cause
you are staining on a slide for it.
That's correct.
Versus how are the mutations looked at, like
under a microscope, a little differently?
Right.
The genetic testing is looking for signals
that indicate whether a change is present
in the DNA or not.
It's not looked at under the microscope.
It's really examined by instruments that detect
whether the signals are present or not.
If the DNA is normal, there would be no signal
that the instrument would read.
If there is a mutation, a change in the DNA,
then a signal would be indicated, and so ...
PART 1 OF 3 ENDS [00:20:04]
... then that would ... A signal would be
indicated.
The instrument and the computer behind the
instrument tabulates all of these changes.
And the results that you get are basically
a list of all of the mutations that may be
present.
As we said, some of these may be significant
and we know about and can link it up with
a current or potential treatment.
Some of them are inconsequential.
And then some of them, we don't really know
what the significance is.
Part of the goal of getting as many patients
or, ideally, all patients tested is to accumulate
this data and then link these patients up
with studies and see what these mutations
really mean because some of them may be significant.
Also, many of them are in very low frequency.
They're less than 1% of all of the patients
that have cancer.
So it's difficult to group these patients
into similar patients because they're so infrequent.
By testing more and more patients, we develop
this database.
Yeah.
That makes sense.
In our next panel discussion later this afternoon,
I think we're going to be talking a little
bit about that and how this data can actually
really help move lung cancer research forward.
Right.
Dr. Gainor, when you get this printout with
everything that a patient has or doesn't have
and a report from the pathologist with their
PD-L1 levels, what's your next step?
How does that impact your treatment choices
for your patient?
In my mind, it's a combination of things going
to the decision making.
Typically a patient will come back into the
office and we'll review it together.
If there's a genetic change in one of four
genes, and we call those EGFR, ALK, ROS1 or
BRAF, these are genes where if they're in
specific places, we have FDA approved therapies,
targeted medicines.
And that is very straightforward because we
know that targeted therapies are the best
therapies for those patients.
And we call those actionable.
Call those actionable.
Okay, because there is a targeted therapy
pill that's linked to treat the mutation.
Those specific mutations.
Yeah.
Okay.
And we have multiple clinical trials where
we've compared giving a targeted medicine
versus historical chemotherapy for most of
those genetic changes, not all, because some
of those are so infrequent you can't do those
big comparisons.
But in all of those studies, the targeted
therapies have always won versus chemotherapy.
They shrink the tumors more commonly, patients
feel better, and they have a better side effect
profile.
For those, very straightforward, we give targeted
therapies.
There's a whole nother group of gene changes
where we know a lot about them.
We know that they are activating, meaning
that the light switch has changed, it's on.
And we know that there are, so far, some effective
preliminary drug data.
These are drugs that have not been approved
yet, they're in active clinical trials, but
the data has been very promising.
For that, I would group things like RET or
something called MET.
Those are examples of where response rates
to targeted medicines have been very, very
high, but we just don't have the regulatory
approvals just yet.
For those patients, I still want to pursue
targeted therapy, but what that looks like
might be a little different because it might
be in the context of a clinical trial.
If we don't have a genetic change or we do
have a genetic change, it's just not something
we can target, we don't have a drug for it,
then we start looking at this PD-L1 score
and we start making a decision of whether
we should just do immunotherapy by itself
or immunotherapy with chemotherapy.
Into that decision making, it's not just the
PD-L1 score, it's also the patient's preferences,
what other medical conditions they have, how
old are they, their functional status.
A lot goes into that decision making.
All right.
The targeted therapy drugs, I'm sure they
each work a little differently based on the
type of mutation, but basically they're just
targeting the mutation instead of generally
killing cancer cells and healthy cells, right?
Correct.
They're targeting the mutated protein.
Right.
Great.
Okay.
When should a patient be retested?
Let's say the patient had their tissue tested
initially before they started any treatment.
When, if ever, is it appropriate for them
to have another test?
I think this is a great question.
And there are lots of layers to this, so I'll
be very interested in your thoughts as well,
Dr. Pool.
The first question I would ask is how comprehensive
was their initial testing?
If this is someone who had one or two gene
tests and they were negative, that might be
someone where you do a more comprehensive
panel, looking to find whether there are alterations
there.
Right.
Maybe they were doing what Dr. Pool was saying.
Maybe it was a few years ago or not, but they
just were looking for EGFR, or they're looking
for ALK-
Correct.
... instead of all of the possibilities.
And some of those mutations now are actionable
that weren't actionable before.
Exactly right.
Exactly right.
Okay.
It is a bit sobering that, despite us knowing
about these gene changes now for a while,
and despite seeing transformative activity
of some of these targeted therapies, even
some of the most basic genetic changes like
EGFR and ALK, rates are not 100%.
We would think that's the case, but they're
not.
Rates of ...
Of testing.
Okay.
Even in the United States, there was a recent
paper from last week was showing that ALK
testing rates were only 60%.
So clearly we need to do better.
That number should be 100%.
So I would ask first, how comprehensive was
their initial testing.
If it wasn't comprehensive, that's something
that you might pursue.
There are various reasons why they may not
have had comprehensive testing.
There may not have been enough tumor biopsy
material.
That might be something that there's a conversation
about.
We might want to get into are there other
tools to test outside of just looking at the
tumor material.
Meaning that when they had a biopsy and tissue
was taken out of their lung, there wasn't
enough to do the testing.
Right.
Right.
There wasn't enough tumor there or it's been
exhausted with other tests.
Okay.
In terms of, say they've had comprehensive
genetic testing and, by and large, if you
have one of these genetic changes like EGFR,
ALK, ROS, these are mutually exclusive.
If you have one, you don't have the other.
I think that's something important to note.
And those don't really change over time.
Those are present in every single cell.
The medical term or the scientific term we
think about is these are clonal.
They are present and generally you don't lose
those genetic changes.
The reason to retest, though, is to see if
there are additional genetic changes on top
of that.
When patients receive a targeted therapy,
say a patient has an EGFR mutation or an ALK
rearrangement, when you treat with a targeted
therapy, over time the tumor can develop resistance
to that targeted therapy.
Commonly, that resistance is through additional
genetic changes in the tumor.
That may be one place where we would want
to repeat genetic analysis.
We wouldn't go back to the first biopsy, though,
because the cancer has changed.
We would actually want to do another biopsy
to see how that tumor has changed.
Again, with the thought process being that
we can potentially change to a different targeted
therapy.
We can use that information to guide our decision
making.
They wouldn't change from EGFR to ALK, but
they might change from EGFR to a mutation
that indicates resistance to an EGFR drug,
right?
Correct.
Correct.
So they can develop another mutation in EGFR-
Another slightly different EGFR mutation that
might mean they'll go on a second type of
EGFR targeted therapy.
Correct.
Okay.
And then my other question is if you were
tested and did not have any of these mutations,
especially the actionable ones, is there any
likelihood that you would then develop one
of those mutations?
Usually not.
Okay.
Many times, we see that there are other genetic
changes in those tumors.
But most of the time these are mutually exclusive.
If you have one, you don't have the other.
Or if you don't have it, you won't have it.
Correct.
Okay.
Now, there are some important caveats there.
I'd want Dr. Pool's input, too.
First you need to actually make sure that
it was a good quality specimen that was actually
tested and you actually have confidence that
you're actually testing the tumor and not
just normal cells around that.
Right.
The other thing is, and I think this is going
to be a question mark as we start using other
forms of gene testing like testing the blood.
There's a newer technology called circulating
tumor DNA where we actually look for these
gene changes not through biopsies, but actually
a sample of the blood.
And looking for very, very rare quantities
of tumor DNA that has been released into the
bloodstream.
And that's a prime example where, just because
it's quote negative, doesn't mean it's truly
not there.
It may be that the tumor just isn't releasing
the DNA into the bloodstream.
So a negative test isn't really negative,
it's more non-diagnostic.
It's something that you may want to repeat
down the road.
Great.
Do you have anything to add, Dr. Pool?
I think the circulating tumor DNA has really
let us off the hook in some respects because
it's very frustrating to run out of tissue
when we want to do these additional tests.
Especially when the patients were initially
diagnosed a few years ago, we didn't get a
complete molecular testing profile done and
they were negative at the time for EGFR or
ALK.
And now they have recurrent disease.
And they undergo a biopsy procedure.
We want to get a diagnosis, we want to get
molecular testing.
And either the sample quality is poor, which
is what we assess the tissue for, or there's
an insufficient quantity of tissue or there's
enough tissue to run some tests, but not all
of them.
Circulating tumor DNA actually is one way
we can get around that and maybe prevent the
patient from undergoing a different procedure.
Sometimes when we discuss these patients with
the team it's decided, yes, we want to go
ahead and do another biopsy procedure or maybe
pursue serum testing.
Okay.
Interesting.
And then what about PD-L1
if a patient wasn't tested?
That's fairly new.
It's quite possible
that you'll be seeing
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00:31:09,590 --> 00:31:113,260
some patients that
weren't tested for that.
Can that test be done at any time on the tissue?
Yes.
Since that tissue is done on tissue that's
been fixed and processed, we can always go
back to tissue that's stored and do that test.
It's not uncommon that we get those requests,
several times a month, to look back in our
archives and pull the tissue out and do the
test on it.
Yeah, I completely agree.
I do think that the utility of that test also
depends where someone is in their disease
course.
I think going back and doing the testing is
very relevant for people who had disease that
was confined to the lungs and they had a surgery
and then, unfortunately, the cancer came back.
That's a place where really then you would
want to test.
If somebody, though, was in a situation where
the cancer had already escaped the lungs and
they've already gotten standard chemotherapy,
that's one place where it's less important
to do that test.
It's very important at the initial diagnosis
and less important after chemotherapy.
And the reasons for that are, in the clinical
trials that were done compared to other forms
of chemotherapy after someone's already had
chemotherapy regardless of whether that test
is positive or negative, immunotherapy is
better than other forms of chemotherapy.
In my mind, if the test isn't going to impact
what I do, I don't do the test.
Right.
That's a good point.
One thing that I did want to touch on because
I've been hearing about it is tumor mutational
burden.
Can you define that a little bit and explain
what that is?
Sure.
It's actually still a term that is in need
of a uniform definition, I would argue.
But intuitively, it's something where, think
about this, the concept of using immune therapy,
the central premise of it, is that cancers
... The more and more genetic mutations that
a cancer develop, so the more and more mutations,
the more and more it begins to look foreign
to the immune system.
If it has one mutation, it's pretty close
to normal self, but if it's got 200 mutations,
it begins to look much more foreign and is
therefore more likely to be recognized by
the immune system.
And destroyed by the immune system.
Okay.
And destroyed by the immune system.
At the most simplistic level, it's really
the total number of mutations in a particular
tumor.
Now there are many different ways to measure
this.
It depends on the total number of genes you're
looking at, so how much DNA you're analyzing,
and what the specific mutations that you're
actually counting.
Right now we're lumping all the mutations
into one bucket, but there are many different
types.
Tumor mutation burden, or TMB for short, is
really just some way to quantify the total
number of mutations in that tumor.
Okay.
Which might give us information about how
that person might respond to immunotherapy?
Correct.
Okay.
This looks like it's an independent marker
from PD-L1.
They provide complimentary information.
And it also is a predictor for responsiveness
to immunotherapy.
Now, it's a much more complicated one, though,
than the standard PD-L1 testing that we've
talked about.
It requires much more of that bio-informatic
support.
Right?
Right.
Patient education is important.
We want to educate patients about genetic
testing, tumor testing, whatever you want
to call it, and the availability of targeted
therapies and immunotherapies.
But really the physicians and the hospitals
need to play a big part in this, too, so that
patients aren't missed when they come in,
especially patients that really should be
tested.
I was hoping that you guys could speak, maybe
starting with Dr. Pool, about what you think
needs to happen to get this testing done more
reflexively on eligible patients when they
see the physician.
I think approaching lung cancer from a multidisciplinary
team approach is how you make sure that you
have pathways in place so that patients don't
get missed.
And if they do get missed or if there's pieces
of the information that the treating physicians
need, that there's communication between the
surgeon, the oncologist, the pathologist to
obtain enough tissue.
To make sure that tissue is appropriately
handled.
And then to communicate those results in a
timely manner so that the oncologist has that
information when they see the patient.
And there's not delays in terms of seeing
the patient but not having all the information
you need and in formulating a plan.
It's also important in that we educate each
other.
I, as a pathologist, I'm learning what the
oncologist needs in terms of what tests they
want, what tests are going to be useful for
the patient.
And I learn from the surgeon some of the technical
issues with getting more tissue or not being
able to get it.
I guess you need to be a little louder.
Go ahead.
I am finished.
It's really just a multidisciplinary team
approach.
Okay.
Great.
Dr. Gainor, do you have any thoughts on how
to get this done more reflexively?
I agree completely.
I think it all boils down to communication.
I do think you'd actually get different answers
if you polled 100 pathologists and 100 oncologists
about what's the best way to do it reflexively.
At our institution, we actually don't do it
reflexively because the oncology community
at my institution actually wants to have some
input into what specific testing is going
to be done in what order.
But that's not uniform.
I think the bottom line is it's important
to get the testing done and really have open
lines of communication between pathologists,
oncologists, surgeons.
Cancer is something that can't be addressed
by one-
PART 2 OF 3 ENDS [00:40:04]
... surgeons.
Cancer is something that can't be addressed
by one single specialty.
It's really teams that come together, and
you really need open lines of communication
to do that.
Right.
That's what, I think, Dr. Pool is meaning
by by multidisciplinary.
Correct.
Lots of different physicians from different
specialties all working together and communicating
so that the patient actually gets what they
need.
Right.
Right.
Okay, great.
So now we're gonna take a few questions from
our audience and try and address some that
we received online.
I have a question.
Nicole Hampton.
I'm with my mother, Cindy Hampton, a Lung
Force Hero in Milwaukee.
My question is, do patients have to be treated
at big hospitals to get this type of testing?
Dr. Gainor?
Yeah, so the answer is no.
This is something that should be done regardless
of where patients actually are getting treated.
Now, the extent of the tumor panels, the gene
panels can vary from institution to institution.
But the core genetic changes with FDA approved
therapies, someone should be getting access
to that regardless of where they're getting
treated.
And do you have any tips for the language
that a patient can use to kind of advocate
for themselves?
So I think we've tried using some of that
language today, which is I've heard about
tumor testing or gene testing and/or what
is my eligibility for using a targeted medicine?
Those are some of the things that I think
a patient or a patient's family would be wholly
appropriate to ask.
And advocating for next generation sequencing,
is that the most comprehensive approach?
It's the most comprehensive approach in at
least bringing it up.
There may be times, though, where it's more
appropriate to do a very rapid test based
upon the clinical situation.
So I think raising the question and then starting
some dialogue about what are the pros and
cons of doing that.
Okay, great.
Good morning.
I'm Cindy Hampton, Milwaukee.
Does insurance cover this testing?
So I can take that one, as well.
In general, insurance does cover genetic testing
if it's done for advanced non-small cell lung
cancer.
And this is something that should be standard
of care.
So regardless of where you're getting care
in the United States, this should be a standard,
and so as such, it's generally covered by
insurance.
Hi Dr. Renee Matthews, lung cancer advocate.
If a patient's never had any testing done,
is it ever too late?
I can take that one.
Most of the time, we can do these tests on
tissue that's already been processed and archived.
So we can always go back to that.
Occasionally, there are some tests that require
fresh tissue, but for the next generation
sequencing, PD-L1, generally we can do that
on tissue that, even if it was obtained years ago.
This is actually a follow-up question I have
to that.
It seems like one of the difficulties with
this is that there needs to be an appropriate
amount of tissue taken at the time of the
biopsy, but a patient might not know that
they have lung cancer at that point, right?
And they certainly might not know to ask about
tumor testing.
Any thoughts on how we can communicate better
with the physicians performing the biopsies
so that they know that this kind of testing
is gonna be coming and they should remove
an appropriate amount?
I think from our team approach, everyone is
aware that we need a certain amount of tissue.
We certainly discuss in tumor boards how much
tissue is needed so the minimal amount of
cells or DNA that's required.
The problem is sometimes the tumor's difficult
to get to or the tumor is associated with
a lot of necrosis, meaning that the tumor
is growing so rapidly that it actually dies,
the tumor cells die themselves.
And so we need viable live tumor cells in
the biopsy material to do this.
So sometimes that's a problem, too, just we
don't know really what the quality of the
tissue will be until we can examine it on
the microscope.
Also, because of lung cancer screening, a
lot more small nodules are being removed with
the idea that maybe they are cancerous.
And so we still go through the same process
of obtaining tissue for molecular testing,
for example, just in case it might be a tumor.
And so we need to have a dialogue with our
labs or with commercial labs that we're sending
these tests out to to make sure that if it's
not tumor that we don't do testing, and if
there is tumor there, we need some kind of
quality assurance that we actually are testing
the tumor cells and not normal cells, like
Dr. Gainor mentioned before.
Do you think there will ever be a time when
a liquid biopsy, like a blood draw or even
saliva, will be able to replace the tissue
biopsy from the lung?
No.
Well, at least for the initial diagnostic
biopsy.
I view liquid biopsies as really complementary,
not a replacement for.
Because what you can't get by a liquid biopsy
is actually the architecture, what do these
cells actually look like.
You're just finding the DNA.
So you can't see this is a small cell lung
cancer, this is a non-small cell, this is
a squamous cancer.
You can't figure that out from a liquid biopsy.
It's one of the principle limitations of it.
And so it can provide complementary information,
though.
So say you already have a diagnosis, but there's
insufficient material to do the comprehensive
gene testing.
You can try to get it via liquid biopsy.
Or if someone is already on a targeted medicine
and is starting to develop resistance and
it's hard to get another biopsy, that's another
place where liquid biopsy would have utility.
And what about, I don't know if this is also
considered liquid biopsy, but taken from their
sputum or the mucus in their lungs?
You mean cells that are in the sputum?
Yeah, like coughing up something that will
have cells in it that will give us information.
Does that have a role?
Sure, we can do molecular testing.
If there's enough cells, those kind of samples
we can do additional testing on PD-L1 and
molecular testing, as well.
The challenge really is, again, getting enough
cells in these samples Sometimes we're making
diagnoses on a handful of cells and feel fortunate
just to be able to say it's cancer or not
cancer.
But the paradigm is evolving past that just
from saying yes, there's cancer, no, there's
cancer to yes, there's cancer, and there's
these additional markers or mutations and
so forth that are very important now in treatment.
This is kind of what we call precision medicine,
figuring out not just the type of cancer you
have, but as much about your cancer as possible
and pairing it with the best treatment possible,
right?
Okay great.
We're gonna take a few questions from our
Facebook audience.
The first question is, how does a patient
know if their tumor has had next generation
sequencing or any type of testing?
I think that's a challenge, especially because
this information may reside in other places,
so for example, sometimes we have patients
referred to our institution, and we don't
really know what testing they've had previously.
So again, it goes back to communicating with
the oncologists or surgeons to find out what
has been done so far so we don't reduplicate
testing.
But also, if testing hasn't been done that
we acquire the appropriate tissue.
This is a question for Dr. Gainor.
I'm hoping that you can clarify a little bit.
We had a question that says, are you saying
that immunotherapy doesn't work after chemotherapy?
No.
No.
So I'm saying it works regardless of whether
or not you have that PD-L1 score.
If you had chemotherapy first?
So, yeah.
So the role of that PD-L1 test, really it's
an imperfect predictor.
So if you take 100 people with lung cancer,
only about 20% will actually respond to immunotherapy.
If you use that PD-L1 test, it actually brings
it up to about 40%.
So it's still not perfect.
And so the role of that PD-L1 test is really
to help you prioritize at point should you
use it.
Well, what point do use the immunotherapy?
At what point to use the immunotherapy.
And part of this is historic in that it reflected
that these drugs were initially approved after
chemotherapy, regardless of whether you had
PD-L1 positive or negative, those drugs were
better than chemotherapy.
So that's why I was saying that after someone's
already had chemotherapy, there's a less of
a need to actually do that testing.
Okay.
Great.
And can you talk a little bit more about the
PD-L1 levels?
What are the ranges, and what do the ranges
mean?
So this, thankfully I would say, we've gotten
some clarity on this point in the last several
years.
It was very complicated around 2014, 2015
because there are multiple of these immunotherapies,
and in each of the different immunotherapies
would use different cutoff.
Even the same drug would use a different cutoff
whether someone had chemotherapy or not.
But fortunately, there have been major efforts,
collaborative efforts between industry, academics
and industry partners trying to harmonize
those efforts and looking at how closely if
you did one PD-L1 test, does it replicate
another one?
So long story short, I think the most clinically
relevant cutoff is 50%.
So 50% of tumor cells expressing PD-L1.
Would that be considered a high level?
That'd be considered high.
Okay.
So if the tumor is less than 1% expressing,
so the tumor cells, less than 1% show this
positive PD-L1 reaction on the stain, we would
call that negative.
And as Dr. Gainor said, if it's more than
50%, we would call that a high expression.
And so anything in between, between 1% and
49%, we call that low expression.
And so we give that information.
It's not just positive or negative, it's really
whether it's high, low or negative.
And depending on that score impacts whether
or not maybe they go on immunotherapy before
or after chemotherapy?
Yeah.
Complicated.
Yeah.
And the bottom line, now because these drugs
were initially all explored second line, meaning
after someone had already received chemotherapy.
Once the drugs were approved there, then they
started being looked at first line.
And so the most relevant thing now is someone
who's newly diagnosed, they haven't received
any therapy, it's going to be immunotherapy,
plus or minus chemotherapy.
Got it.
Plus or minus chemotherapy.
Great.
One more question.
We've talked a little bit about clinical trials.
When might a clinical trial be the right choice
for a patient, specifically around this issue
of tumor testing and immunotherapy and things
like that?
I mean, maybe I'll weigh in.
I am a clinical trialist, that's a lot of
what I do.
And I would say that it depends.
A lot of people have strong feelings when
they hear clinical trial, thinking that oh,
it's just because I've exhausted other options.
And I want to emphasize that that is not the
case.
Even things like phase one studies right now
may be the most appropriate thing to even
start with.
We've been fortunate in the lung cancer world,
where we now have multiple drugs that have
been approved on the basis of a phase one
study.
So phase one studies historically were just
about dose.
But as you start using very targeted, precision
therapies, so you have a biomarker, a test
that can identify group most likely to respond,
and a very targeted medicine, you can see
dramatic activity, even in that phase one
study.
And so now the trend with all of these targeted
therapies is that we're seeing activity in
the phase one.
And so if someone has one of these genetic
changes that is actionable, where we know
a lot about it, but it's not approved yet,
I would argue that for those people, depending
on what the target is, sometimes a clinical
trial may actually the most appropriate very
first therapy.
It really depends.
And this speaks to the fact that sometimes
the regulatory aspects, so getting a drug
approved, commonly lags behind the science.
And so we may know a lot about it.
A classic example right now is [RET].
So this is found in 1%-2% of people with lung
cancer, and we now have several drugs that
have shown responses above 70%.
So marked shrinkage, but those drugs aren't
approved yet.
So if I saw a patient with a RET rearrangement
right now, I would out them on a phase one
clinical trial because the current data has
been so promising.
Great.
Do you have anything to add?
I get these reports myself, and I'm always
to curious to look at them, mainly if it's
one of the big four mutations, fine, but I'm
always interested to see these additional
mutations for which there's phase one trials,
and then that kind of triggers me to start
looking in the literature and see are there
mutation-specific antibodies that we could
maybe do faster or what are some other techniques?
Because these are gonna be escalated once
they're approved and so forth.
So I agree with Dr. Gainor, it's a whole new
world opening up.
Great.
Well, thank you so much for your time today
both of you.
A recording of this video, as well as additional
resources, will be made available at lung.org/tumor-testing-videos.
So that's lung.org/tumor-testing-videos.
And that will be available in the next couple
weeks.
If you're tuning in live, we'll have another
panel discussion with Dr. Gainor, and we'll
also be joined by Dr. Sherri Millis from Foundation
Medicine, and we'll be discussing a little
bit more about the future of this very fast-paced
field.
That discussion's gonna happen at 2 p.m. Eastern,
1 p.m. Central.
So I wanted to thank again AstraZeneca, Bristol-Myers
Squibb, Foundation Medicine, Pfizer and Merck
and Co. Incorporated for their generous support
of this program.
Thank you.
