Dr Nirupa Murugaesu and Professor Sir Mark Caulfield: Providing tailored care for cancer patients through whole genome sequencing

In this instalment, our guests engage in a compelling discussion
centred around a recently published paper that supports the
integration of whole genome sequencing into standard cancer
care. 


Our guests shed light on the transformative potential of
combining health data with whole genome data. Discover how this
innovative approach empowers doctors to deliver more personalised
and effective care. Our guests delve into the findings of a
landmark national study, unravelling the significance of
identifying inherited cancers for patients and their families.
The episode explores not only the scientific advancements but
also the real-world impact on individuals facing a cancer
diagnosis. 


Our host Naimah Callachand is joined by Dr Nirupa Murugaesu, a
Consultant in medical oncology at Guy's and St Thomas' NHS
Foundation Trust, and the Principal Clinician for Cancer Genomics
and Clinical Studies at Genomics England.  And by Professor
Sir Mark Caulfield, a Professor of Clinical Pharmacology at Queen
Mary University of London, and who previously served as Chief
Scientist for Genomics England and was instrumental in the
delivery of the 100,000 Genomes Project. 


 


"In cancer we were sequencing sections of the tumour and
comparing them to DNA inherited from your mum and dad, and that
comparison allows us to work out what is driving the cancer, what
may be affecting its potential for treatment and how we might
choose treatments for patients.  So this is a real
opportunity to create precision cancer care." 


  


You can download the transcript or read it below.


Naimah: Welcome to the G Word.  What does it mean if we can
test for inherited genes?   


Nirupa: It can influence how their cancer is treated.  So it
means that there may be certain types of therapy that are
available if they have a specific inherited cancer gene, number
one.  It also can impact in terms of preventing further or
other cancers related to those genes, and it may impact the type
of surgery they have, and also the type of overall cancer
treatment.  And then finally, if they have got an inherited
cancer, then, as I mentioned before, it may impact in terms of
testing and screening for their family members. 


Naimah: I'm your host Naimah: Callachand.  Today, I'm
delighted to be joined by Dr Nirupa Murugaesu, who's a consultant
in medical oncology at Guy's and St Thomas' NHS Foundation Trust,
and the principal clinician for cancer genomics and clinical
studies here at Genomics England.  And Professor Sir Mark
Caufield, who's a Professor of Clinical Pharmacology at Queen
Mary University of London, and who previously served as chief
scientist for Genomics England and was instrumental in the
delivery of the 100,000 genomes project.  Today, Mark and
Nirupa are going to discuss key findings from a recent paper
that's just been published in Nature.  If you enjoy today's
podcast, we'd really love your support.  Please like, share
and rate us on wherever you listen to your podcasts.  Now,
let's get into the interview.  So first of all, Mark, I
wondered if you could give me a bit of background on the 100,000
genomes project? 


Mark: So the 100,000 genomes project started in July 2013
following an announcement by the then prime minister, David
Cameron, that the UK would be the first health system in the
world to sequence 100,000 whole genomes, which is as much as you
and I can read of the genetic code.  In the case of cancer,
which we focused on here, in cancer we were sequencing sections
of the tumour and comparing them to DNA inherited from your mum
and dad, and that comparison allows us to work out what is
driving the cancer, what may be affecting its potential for
treatment and how we might choose treatments for patients. 
So this is a real opportunity to create precision cancer
care. 


Naimah: And Nirupa, can you tell me what the 100,000 genomes
project meant for these patients with cancer?  


Nirupa: I think, firstly, we're very grateful for all of the
participants in the programme, because what it's allowed us to do
is to look at the data as a whole, and having all of that
sequencing data alongside clinical information has been
incredibly valuable, it has also developed the infrastructure for
testing.  And really I think for patients with cancer, they
participated in this programme as a research project, and
unusually for a research project these results were returned back
to treating clinicians to clinical teams, if there may have been
a result that would impact or change their management.  But
I think, importantly, what it enabled is the implementation of
standardised cancer testing in the NHS, and really enabling that
for a wider range of patients, not just those that participated
in the project.  And because of patients participating, this
then allowed all of the data to be stored in a single place, and
this has been incredibly valuable for clinical academics and
researchers.   


Naimah: And can I ask what specific types of cancer that were
looked at in 100,000 genomes project?  


Nirupa: Again, the project was set up such that we allowed a
number of different types of cancers to be sequenced and,
therefore, very permissible, because we also wanted to ensure
that some of the less common and rarer cancers were also
sequenced and, as you would expect, more of the common cancers as
well.  In addition, I think the opportunity to sequence
paediatric cancers, as well as haematological malignancies, or
blood cancers, was also key as part of the cancer
programme.  Here, we focus on the solid cancers, but
obviously there was a much wider range of cancers that were
sequenced.   


Naimah: And next, can we move on to talk about the findings of
the study? 


Nirupa: I think, firstly, by undertaking sort of a pan-cancer
analysis, it really gave us an overview of the number of target
and genes that were found to be actionable.  And what I mean
by that is that they have a, well, clinically relevant, and we
can see that in certain cancer types, such as in brain cancers,
in colon cancers, lung cancers, there were within the genome
sequence more than 50% of these cancers had something that was
what we would call actionable.  So there was a mutation in a
gene for which this would influence treatment.  And as we
started to look more across the entire cohort of patients, you
can really get an idea of the fact that the more that we
sequence, and the more comprehensive the testing is, the number
of different types of mutations that we were able to
discover.    


Naimah: And when you mentioned that these findings were
actionable, what does that mean? 


Nirupa: So what that means is that has an impact in how the
patient will be managed and treated.  It may influence,
firstly, the type of surgery they have, it may influence the type
of cancer treatment that they receive.  And all of this, I
suppose, comes back to the point that Mark mentioned, of
precision oncology, so we more precisely treat patients based on
their individual cancers.    


Naimah: And could you give me some examples of maybe some of
these genes that were found in the study that were
actionable? 


Nirupa: Yes, so the types of genes also matter, or the type of
mutations.  So some of them were in known cancer genes, and
if you have, for example, a mutation in lung cancer, in a gene
called the EGFR gene, we know that there are cancer therapies
that can be provided that target specifically this
mutation.  So that's one example, and this is quite well
characterised and understood in oncology care.  But what we
were also able to do with whole genome sequencing, is identify
different types of mutations that are harder to characterise
routinely.  And these are often included things that we call
pan-genomic markers, where we can see what the mutational
landscape is of the cancer, the different patterns of mutations
can be gleaned from this, and often this can then give you an
idea of the underlying biology of the cancer.  But
importantly, in certain types of cancers, such as high grade
serious ovarian cancer, it highlights which patients may have a
particular marker that means they may or may not benefit from a
particular type of therapy.  So in this particular case, the
class of therapy is called PARP inhibitors. 


Naimah: And how did the study compare to other similar stuff
studies in the genomics area? 


Nirupa: That's a really good question, and I think we looked at
this from other large sequencing endeavours, such as the ICGC,
TCGA, so these are big studies where have been whole genomes
sequencing.  Also within the Hartwig Institute in the
Netherlands, they've also undertaken whole genome sequencing for
cancer patients.  And what we were able to identify is that
the patterns of mutations were as expected, we found, you know, a
lot of similarities.  I think the difference, the main
difference is not just identifying the type of mutations across
the different cancers.  But the fact that we were then able
to look at the longitudinal outcome, and correlate some of these
genomic markers with outcomes related to both therapies, as well
as survival impact of having certain mutations in terms of
prognosis.   


Naimah: Mark, do you have something you'd like to add there as
well? 


Mark: Yeah.  So one of the things that we did in the 100,000
genomes project, was to evaluate the best way of measuring the
whole of your or my genetic code.  And we discovered that
very early on that if you expose the tumour to a preservative,
which is called formalin which keeps the tumour preserved, that
actually you could get quite a number of misleading
findings.  And so to address that, the distinctiveness from
former programmes, such as Nirupa mentioned, like the Cancer
Genome Atlas, is that all of the tumours that we studied in this
paper were actually produced under fresh tissue conditions, and
have not been exposed to a preservative.  And that means
that what we have is a really accurate reflection of the
variation within the tumours.  And the other thing about
this particular resource is it's the biggest resource.  We
were able to look at 13,000 people with solid tumours, but we
also had blood cancers and other cancers which also feature of
this paper.   


And a further remarkable thing about this is early on, Nirupa and
the team and I decided that we would longitudinally life-course
follow the patients and by accruing data from multiple sources in
the health system.  So, every attendance at the hospital,
what chemotherapy was had, we've been able in this paper to
recapitulate signatures that clearly show that certain mutations
are harmful.  And many of the findings that we've made are
absolutely, if you look at the survival of patients particularly,
you can see almost identical patterns to those in clinical
trials.  What this means is that by the really rich data set
which is now many billions of clinical data points on these
patients, we can actually look for long-term signals of benefit
and harm that perhaps would not be detected by a clinical trial
that might last for six months or a year.  So this is a
really valuable resource, and the really great thing is we can
use what's called real-world data, which is where we take routine
health data, and we can recapitulate the findings from tightly
controlled clinical trials.  And I think that's quite an
important finding.   


Naimah: That kind of brings me onto the next question, Mark,
where I want to talk about the value and benefit of genomics
sequencing for cancer patients.  I wondered if you could
expand? 


Mark: Well, what we know from one of the genomics medicine
centres which were regional hubs, is that they use the
information that we return, that Nirupa outlined earlier in a
report, for 25% of their patients.  Which means that they
concluded having evaluated that as the clinical team locally,
that there was something the patients could benefit from. 
Now, what we think is this makes the case for certain cancers
being part of the national genomics test directory whole genome
sequencing, but it's still the case that the majority of testing
for cancer is now very large focused panels that are focused on
specific gene features.  But in some measure, this work is
also able to reassure us that those gene features are the right
ones to focus on, so this work has been very useful in that
respect, even where the NHS today cannot make the financial or
clinical case for using whole genomes in specific cancers. 
So I think the programme's made a massive
difference.   


The biggest thing it's done for patients, which Nirupa was very
actively involved in, is it's allowed us to create a national
genomics test directory.  So when we started this, cancer
genomic testing was completely random and would vary from one
postcode to another, one hospital to another.  And what
Nirupa and the cancer team created is a national cancer genomic
test directory, which now means that standard of care, that's the
basis for reimbursement, and it's available across the landscape
of 56 million people.  And given that one in two of us will
have cancer, this is a massive advance.   


Naimah: Yeah, you've really highlighted the impact of having
access to such a large database.  And I just wanted to ask
as well, what are the challenges associated with implementing
routine whole genome sequencing into clinical care? 


Nirupa: I think as with all of these things when implementing
something new within a healthcare system, it requires a level of
education, upskilling and also, as Mark has touched on, how we
handle the tumour tissue, so that it's handled in a
genomic-friendly way to enable the best results if you like,
because we want to ensure that their DNA is not damaged so that
we can get accurate read-outs on the results.  So there are
challenges and there is also cost implications in weighing up the
pros and cons.  And I think what we were able to show, and
by undertaking this sort of pan-cancer analysis, is where there
are those cancer type where there is a real need for whole genome
sequencing, or where it can be justified, because there are a
number of different types of mutations both within the
tumour.  And also from a blood sample that is also taken, so
this is your constitutional DNA, so this is if there is a risk of
an inherited cancer.  So we are able to pull together all of
this information, and obviously that's important, not just for
the patient, and their management, but also for family
members.  So I think really what this shows is that where
you have to identify many of these different types of mutations,
whole genome sequencing enables that through a single
test.  


Naimah: Mark, would you like to add something else there? 


Mark: One thing I think which Nirupa's very much part of, is the
distinctiveness of the Genomics England approach has been to
involve the NHS at every stage.  Now, what that means is we
estimate that at the peak of the 100,000 genomes project, 5,000
frontline NHS staff touched the project at some point in their
working week.  What that does mean is that Nirupa and the
cancer team could realign the cancer tissue handling
pathways.  But it also meant that we were able to upskill
the frontline workforce, such that at the end of the programme,
when we produced a genomic test directory, they were really up
for it because they did not want all the hard work they'd put in
to stop.  And so what we've done is produce the national
test directory within five years of starting, that wasn't a
deliverable for the project, but it was nonetheless obvious to
all of us working in it, including NHS England, that there needed
to be service transformation, and we've managed to effect
it.   


Now, if you look at other settings where perhaps Nirupa and I
might have a research team, we might do it some distance from the
health system, it would be in the health system, but not with the
health system, then it takes between nine and 16 years to get
these things into clinical practice.  And that was achieved
here in five years.  So there is a lesson from this, the
cancer programme particularly, because the cancer programme
testing was very limited when we started, but you can take an
entire workforce on a journey and leave them with the legacy of
an entirely transformed system for patients.  And thankfully
because we got, Nirupa and I, the NHS to agree to reimburse for
the testing directory being used, we have eliminated a lot of
randomness that was in the system previously.  So it's quite
an important advance in that respect, and it really does show in
the beautiful work that Nirupa was describing exactly how you can
use this information to change an entire system.  And the
NHS is not the easiest system to change in the world. 


Naimah: Nirupa, you mentioned the findings show that there was
potentially inherited genes.  Can you tell me what does that
really mean for patients, if we're able to diagnose these
inherited genes sooner in life? 


Nirupa: It can influence how their cancer is treated, so it means
that there may be certain types of therapy that are available if
they have a specific inherited cancer gene, number one.  It
also, can impact in terms of preventing further or other cancers
related to those genes, and it may impact the type of surgery
they have, and also the type of overall cancer treatment. 
And then, finally, if they have got an inherited cancer, then, as
I mentioned before, it may impact in terms of testing and
screening for their family members.  And that's really key
as well, because this means that their cancer can be diagnosed,
if they do develop a cancer, because they're being monitored,
because it's much more targeted, their approach in terms of
screening for a particular type of cancer, they can potentially
have their cancer treated much earlier.  Or even better,
before it becomes what we call an invasive cancer but at the
pre-cancerous stage.  So this has huge implications, and
what we're finding actually with more and more testing – and this
is not just... our study was consistent with other studies that
have been published – is that when you undertake more routine
testing, then you are able to identify this.  It is not
common amongst the population, but in those patients where it is
relevant, it really can impact their care. 


Naimah: Mark, do you have something to add there? 


Mark: Well, I think Nirupa's just highlighted a really important
point.  So to bring that into a little bit more ways of
which people listening to this can relate to it, we have a family
where there was a women who had no family history of breast
cancer, she developed breast cancer, and in the tumour we found
that she had a BRCA 2 mutation.  We also found that she'd
probably acquired that or inherited it, we don't know.  That
for her meant that she could enter the Olympia trial, which was
running at the time, which Nirupa alluded to earlier, was a study
of PARP inhibitors.  But without that genetic makeup she'd
never have got into that trial, and she probably wouldn't have
been tested for BRCA at that time in the NHS because she had no
family history, I think that's probably right,
Nirupa.   


And then there was a family-wide consequence for that, because
she had a brother and son, and she also had a daughter, and the
daughter was under 30 at the time and underwent BRCA testing and
was BRCA 2 positive.  But she has the opportunity now to
enter intensive breast screening from the age of 30, and that's
what's happened.  And her brother, and this is the lady who
had the breast cancer, her brother and her son may be at risk of
prostate cancer, so they can consider testing.  So Nirupa
makes a really important point, that when people have inherited a
previous disposition to cancer, that can have a family-wide
impact.  And one test in one family member can open the
doors to opportunity for others to understand their risk and to
be screened more actively and intensively, hopefully with meaning
that if they do develop cancer it will be detected very early, or
maybe we can just prevent it altogether.    


Naimah: Thanks, Mark, a really good example of the impact that
this testing has had.  I just wanted to touch back on your
point, Mark, that you'd made about real-world data.  And I
wondered actually, Nirupa, if you could kind of explain to me why
it's important to link real-world data to the genomic data? 


Nirupa: Yeah.  So I think the work we've done here really
does emphasise this, because when we refer to real-world data,
we're talking about different types of healthcare data across the
population.  And we had the opportunity to link the genomic
data to a number of key data sets that are curated by the cancer
registry, the national cancer registry database.  And this
includes things like all of the population base systemic
anti-cancer therapy, so we know that for each of the participants
the type of cancer therapy they receive, and also, as Mark has
mentioned previously, the hospital episode.  So when
patients needed to be... we can see their data in terms of
admissions, investigations, and so on.  And these are really
valuable data points, because you get an indication of when
patients may have had to then have further testing, or if there
is a risk of recurrence and importantly survival data, because a
lot of this has been, in terms of a lot of the cancer genes have
been well characterised and tested.   


But what we were able to do here at a pan-cancer level on a large
cohort of patients over a period of time, is to look at if you
had a particular mutation, what is the impact of that in terms of
outcome for a particular cancer type, and even more broadly, on a
pan-cancer level?  And actually, as this type of data
accumulates, I think the real value, and if you've got a larger
number, you know, what is the value for patients who've
participated in this programme going forwards, is that as that
data accumulates and the numbers go up, we are able to then ask
more detailed questions.  What is the impact of a particular
type of mutation, or a particular type of variant within a
gene?  And, importantly, what happens when you get a
different sequence or a combination of genes?  And how does
that impact?  And this, I feel, is the way that we are going
to move more towards precision oncology, because we are beginning
to understand the cancer in more detail, how it is going to
behave, and then try and tailor therapies
accordingly.  


Naimah: And Nirupa, I wondered if you could tell me as well if
the findings from this study have benefited directly those
patients that were involved in the 100,000 genome project? 


Nirupa: It has benefited some of the patients because, as Mark
has mentioned, there are findings that we weren't expecting in
terms of potentially inherited cancers and, therefore, this has
had implications.  The way that the project was set up from
the outset, is that we were obtaining tumour samples from
patients who had not received any previous cancer therapy. 
And what this meant is that this was predominantly in patients,
so they were treatment naïve with early stage disease that were
having surgery to treat their cancers.  And as such, what we
know is that fortunately most of those patients did not require
further therapy, because their cancers were treated successfully
with surgery.  But what it did tell us, and what it's really
highlighted, is the number of important genes that were
identified.  And so whilst it may not have impacted patients
directly, it's enabled us to study the biology of the different
types of cancers, how they behave, along with the longitudinal
clinical data.   


But what it is doing now, is through the national test directory
through the genomic medicine service, is enabling testing for
patients that unfortunately now have more advanced cancers, but
where these genomic findings are more likely to impact directly
in terms of therapy.  So, for instance, as we've mentioned,
the ability to have whole genome sequencing for patients with
high grade serious ovarian cancers, means that this will impact
the type of treatment they have.  And this also was the
tumour type where we found the highest number of patients with
BRCA mutations, so we have a potential inherited risk of a cancer
as well.  So now what we have learnt and the infrastructure
that we have developed has enabled this to have a real impact,
not just for patients in the project now, but wider within the
NHS. 


Naimah: Mark, would you like to add something else there? 


Mark: I think Nirupa's encapsulated it very well.  There
were a range of benefits, so I mentioned earlier that in one
centre 25% we have evidence got a benefit for their treatment for
their cancer in some way shape or form.  So an example to
what there might be is that some people got a medicine they
wouldn't have received from routine care, and that might have
been licensed for the treatment of that tumour, but it wouldn't
have been the first line treatment choice.  Some people got
medicines that they wouldn't have got because we don't normally
associate using that medicine with that cancer, but they had a
signature that showed that they were very likely to
benefit.  Quite high numbers got an opportunity to get into
a clinical trial, which is really important because if you look,
over 50% of global oncology trials now have some kind of
biomarker or diagnostic, or something like this alongside, what
better than to have a comprehensive inventory of the variants and
the cancer, and to be able over time to use that library to
understand better the treatment course of that patient.  And
that's what I think a whole genome adds, rather than the single,
look at a single part of the genetic makeup.  


And then finally, some had lots of mutations, really high rates
of mutations, and maybe they should receive specific advance
therapies, like immunotherapies.  Or alternatively, they had
a feature in their genetic makeup which it looks like they
inherited, as Nirupa absolutely correctly said earlier, these
people need to be followed-up and they need more intensive
screening, because this is how you detect cancer at an earlier
stage.  And the final way people benefited is we could
detect genetic changes in  their DNA that meant that if they
were exposed to certain medicines, they were likely to suffer
harm. And there's a particular, two medicines, 5-fluorouracil
capecitabine, where possibly about 5% of people will need either
a reduced dose or a completely different medicine, because it
will be very harmful.  And so this is about getting the
right medicine to the right patient first time, and getting the
right outcome for that patient downstream.   


And I think, you know, Nirupa's encapsulated it perfectly,
there's a whole range of benefits that the patients can accrue
from this.  And I think we should probably, Nirupa, say that
people were quite cynical when we started, about what it would be
that you would get over and above, for example, the cancer genome
map that's at the international cancer genome consortium. 
And, you know, I'd had leading cancer scientists in Britain say,
"Oh well, we've discovered it all, there's nothing to find
here."  And I think what this paper shows is that's not
entirely true.   


Nirupa: I would agree with that Mark, but I would also probably
add that it highlights the value of having a large data set
alongside that clinical information.  And what we were also
able to do,  is whilst we very much talked about what were
the gene targets that had a direct impact or genomic markers that
impact care now, for which there is an approved therapy. 
What we've also been able to do through this analysis, is
actually highlight the number of mutations that have been
identified for which there is a licence therapy in another cancer
type, but not in that particular cancer type.  And what that
means, is that specially now, as we have more and more
biomarker-driven therapies, I mean, if we look at that compared
to when the project started and now, that has increased
dramatically.  And what that means is then there are sort of
licensed medications that actually can be used in non-licensed
indications via a clinical trial, via these very, you know, these
basket studies which are across cancer types and are actually
based on different types of molecular markers.  And really,
we're able to show this at a pan-cancer level across the 13,000
tumours through the results from whole genome sequencing. 


Naimah: You've both kind of touched on this throughout and, you
know, we've talked about the development of personalised
medicine.  And where do you see the future of cancer
treatment in the next five years?  Maybe, Nirupa, we can go
to you first? 


Nirupa: That's a very good question.  I think and what I
hope is that with more comprehensive and equitable and
standardised testing for patients, especially within the NHS,
that this will enable more personalised and targeted therapy
alongside, you know, systemic chemotherapy.  And as well as
that, better selection of patients that are likely to benefit
from the newer immunotherapies.  And also where sequencing
is very exciting, is that once we begin to understand more about
the individual tumours, you know, going forwards there are a
number of cancer vaccine trials, and the aim of those are to have
specific vaccines that are going to target an individual's
tumour.  So I think in the next five years, this is I think
a very exciting space, I hope so, because we need to keep doing
more in the space for our patients to try and improve therapy and
precision oncology for them. 


Naimah: And Mark, do you have anything to add to that
point? 


Mark: I think Nirupa's right, that there are new therapy
extractions coming on, vaccination's one way.  But I think
that what will become clear is whether we can use any molecular
mechanisms for early detection of cancer.  The battleground
here is that we all too often detect cancer late, when it's
already outside of the organ it originated in and may be spread
in other parts of the body.  It's very hard to effect a
cure, almost impossible in that setting.  But what if we
could detect cancer earlier?  And then what if we could
place a whole genome or detailed molecular characterisation
alongside that?  And then, as Nirupa suggested, give someone
a vaccine tailored to their tumour that would eliminate it. 
The real problem is all too often we detect cancer late, so maybe
some of these new molecular diagnostics, such as cell-free tumour
DNA will usher in an era of early detection.   


And one of the things, and particularly before we did this
project but also up until the beginning of the last decade, there
were very few good biomarkers of cancer that were usable in the
health system.  So we have for the first time opened the
vista of having early detection, if we combine early detection
with detailed molecular characterisation, possibly a whole
genome, possibly another test, then I think we really can usher
in the era of precision medicine.  And so I think Nirupa's
absolutely right, there will be new treatments, there always will
be, but what we have to do is to get detection at an earlier
stage. 


Naimah: We'll wrap up there.  Thank you to our guests, Dr
Nirupa Murugaesu and Professor Sir Mark Caulfield for joining me
today.  If you'd like to hear more about this, please
subscribe to the G Word on your favourite podcast app. 
Thank you for listening.