The Changing Epidemiology of HPV and Cervical Cancer (Gordon Lecture)

The Changing Epidemiology of HPV and Cervical Cancer (Gordon Lecture)


Good afternoon and welcome to the 2017
Robert S Gordon lecture in epidemiology My name is David Murray I’m the
Associate Director for prevention and Director of the Office of Disease
Prevention and I’m very pleased to Represent Dr. Collins today
and introduce our speaker before I do that I wanted to let everyone know that
there will be time for questions after the Gordon lecture presentation and we
have microphones set up in the two aisles for those who want to ask
questions I would also like to invite everyone to join me at a reception for
our ODP early sage investigators and our Gordon lecture winner in the NIH library
after the presentation today just across the hall on my left the Robert S Gordon
jr. lecture is awarded each year to a scientist who has made major
contributions for research training in the field of Epidemiology or in the
conduct of clinical trials the Gordon lecture award recipient is selected
based on the recommendation of the NIH epidemiology and clinical trials
interest group this is the 23rd year that the Office of Disease Prevention
has sponsored the Gordon lecture award the list of prominent scientists who
previously received this award can be found on our offices website prevention
NIH gov the Gordon lecture was established in tribute to Robert S
Gordon jr. for his dedication to the field of Epidemiology and his
distinguished service to NIH over the course of 30 years Dr. Gordon served in
numerous senior senior leadership positions including Special Assistant to
the Director and Chief Advisor for clinical practice and research he was an
early organizer of efforts to address the emerging problem of HIV and AIDS and it became a key coordinator for AIDS research for the first 10 years of his
service to NIH Dr. Gordon made important contributions to policy and management
issues regarding epidemiology clinical trials and the health effects of
environmental hazards today’s this year’s winner and today’s speaker is Dr.
Mark Schiffman he received his MD from the University of Pennsylvania and an mph
and epidemiology from the Johns Hopkins School of Hygiene and public health he’s
currently a senior investigator at the or Cancer Institute in the division of
Cancer Epidemiology and genetics Dr. Schiffman joined NCI is a staff fellow
in 1983 and in 1996 was appointed chief of the clinical genetics branch sorry of
appointed chief of the interdisciplinary study section of the environmental
epidemiology branch he joined the clinical genetics branch in October 2009
to study intensively why HPV is such a powerful carcinogenic exposure akin to
an acquired genetic trait with high penetrance for a cancer phenotype Dr.
Schiffman’s primary research interest is to clarify the natural history of human
peplum papilloma virus infection in relation to risk of cervical cancer and
to apply the insights gained towards improving the screening for in
management of women at increased risk of cervical cancer Dr. Schiffman’s goal has
been to mitigate the morbidity mortality related to cervical cancer which is a
leading cause of malignancy among women worldwide he’s directed one of the
premier HPV cervical cancer research programs in the world he has employed an interdisciplinary research strategy which has involved collaborations
between experts in public health clinical medicine molecular biology
biology genetics vaccine development all grounded in state-of-the-art
epidemiologic principles and methods his research has altered cervical cancer
screening and prevention both in the US and abroad particularly in the
developing world his work on the four stage cervical cancer carcinogenesis
model was viewed by many as implausible when it was first proposed and
unfortunately that seems altogether too common with important scientific
progress that people don’t make much of it at first or don’t believe it I’m
reminded of the presentation by Cox on his survival ship model years ago but
his model Dr. Schiffman’s model has been bolstered by extensive research data
from multiple settings is now widely accepted the model is the basis for
rethinking our approach to cervical cancer screening and treatment so I’m
very pleased to introduce Dr. Schiffman who’s present patient today is not yet on the screen but it is the changing epidemiology of
HPV and cervical cancer from etiology to validation to prevention methods to
dissemination please join me in welcoming the 2017 Robert S Gordon jr.
lecture Award recipient Dr. Mark Schiffman hello this is a great thrill for me as a
first-year fellow I think I gave a talk in here and my legs were shaking and I
was I have to talk on something and I remember just being incredibly fearful
that an MD MPH coming to the great NIH would have nothing to contribute here
and now I realized I look out and there’s friends all around and this is
my home so thank you very much and that is my
wife by the way who I’ve slipped in to the Internet so I figure minimum this is
wasting $30,000 in lost productivity and I actually actively encourage
multitasking and anything you want to do so after a brief introduction I want to
give it my best I was trying to think what is worth so much time from so many
people so I’m going to talk about the highlights of the three phases of
cervical HPV epidemiology that I’ve explored and a few important lessons
I’ve learned spending my entire working life at NIH if anyone wants a scholarly
talk then please just look at The Lancet seminar we did in 2007 which is still
true showing that we didn’t make too many mistakes then but for a more
up-to-date thing we just put out in Nature Reviews disease primer and that’s
that would give you more details I went to med school to be an
epidemiologist not the other way around Paul’s Foley was my mentor at Penn I had wanted to do epidemiology since I was an anthro major and I wanted to do good and
I liked statistics like most people didn’t so I spent a year in West Africa
studying justice myiasis I worked for APHA the office of international health
I went to the Public Health Service Office of Public Health at Park Lawn and
then I applied to Johns Hopkins to do a PhD in international health and was
turned down I met with the Dean and he said you’re a bossy guy I can tell that
you’re a bossy guy and you have a lot of things you want to achieve and right now
MDS control international health and most of the world and I’m not letting
you into my program you’d be unhappy which really resented that and but I
went to med school ultimately wanting to be an epidemiologist the whole time
which was an odd way to address I kept saying what’s the evidence for this
we’re doing so many tests what’s the chance of being a false positive and
other things that led to in different grades while I was in medical so then I
did an internship and I wanted it up get an mph but everything had been shut down all the preventive medicine things have been shut down by the current
administration and but there was the Public Health Service at the training
program and that was my last hope of getting an mph paid for you’re starting
to have kids and so these guys actually hired me and
two of them were in the audience and I thank them for that because I don’t know
what I would have been I had also applied to be a family doc and an ER doc
at the time and that’s was the reason I’m here
and I’ve never left so I’ve only known Dr. Gordon I don’t know how many other
people actually knew dr. Gordon at all just how many people here knew have I
can’t really tell but he would lecture sometimes and then convene this epi
training program and I want to say that he taught me an important lesson in that
sometimes he would fall asleep while we were lecturing while we were giving our
little talks he seemed a little bit disengaged sometimes and I contributed
to his age which is younger he died at 59 younger than I am now and
then I realized he never complained never said anything but he was dying a
cancer and when I found that out it was like damn you know this guy is really
dedicated because he knows he’s dying and he’s still coming to these to hear
these kids talk and I thank him for that lesson and for his dedication and what
he taught me so I studied one thing for 30 years
despite advice from senior investigators that I should switch it out I remember I
started with four things and I decided to study HPV because what I wanted to do was make impact I consider myself a preventive medicine doctor and a
scientist but I want impact so I have gotten variety through focus and what
that means is I’ve been doing exactly the same thing in the same place for
30-some year thirty almost 35 years but it’s like a microscope you focus down
first you look at the tissue then you do low mag and you see certain things if
you get high magnification you start to see cellular features you go to electron
microscopy all of a sudden you’re looking at viral structure and if you do
special stains you get more insight and what I found as as we click down to a
greater and greater understanding of cervical cancer in HPV whole new vistas
open up it really is like different different field different field and
there’s the richness of a continuing story that I’m tremendously interested
in and also the sense that each time we’re rediscovering a level of detail
that will of course I’ll never get to the end of now I know now that we’re
down to the individual isolated whole genome and there’s a whole new world out there that’s redefining a lot of what we thought we knew I realized there’s no
end to it and but I remember what seemed org well I think dr. javelin actually
told me once he wasn’t an investigator working late into his 70s or something
in radiation I asked him what keeps you going all these years that you’re still
working when you could retire and he said find us find something you’re
interested in make it your own be curious and do it as if you don’t even
care if you’re paid and I found that and I’m sticking with it until until they
carry me up so I want to talk about the distinct phases of HPV epidemiology
which has changed around me as we learn more and more first we were faced after
our house and discovered the connection with the natural history of HPV and
cervical carcinogenesis we did etiology then we use some of those biomarkers and started to make them into methods of prevention and then we enter the trying
to actually get people to use those methods and that’s dissemination
implementation and all with the goal of global cervical cancer control because
my heart is an international health so idealogy and Natural History I remember
being so excited as we were learning this story that I didn’t even know what
city I was in we’d be on a bus at some meeting and we’d be like each year had
some discovery that was making it more more profoundly interesting and the tea
the group it was swelling from five just the first meeting – now there’s
thousands of people who come these meetings we were so excited we was like
where am i what – you know it’s just like we just learned this we just
learned that what a wonderful thrill it’s been to get a sense of a team that
was exploring that together but what I learned is that no one remembers who
discovered what even ten years later you can like that tribute to the first
person who wrote it but forget it if you want Fame Dr. Fraumeni will be
remembered I personally think he should be remembered as much for the thousands of things that he did through creating dceg and creating that space for so many
people without demanding to be attributed for any of them so I’d wonder
actually you have to ask him sometime what he considers this greater
achievement has scientific or his enabling achievements but that’s that’s
I’m not going to like put through it who discovered what because it’s been a team
effort as epidemiology or always is so my bias though is that we look for a
signal in the midst of noise and we specialize in error as classification
randomness and we don’t try to control things in a kind of experimental way
we’re trying to see the signal come through in an inductive reasoning
setting so I first heard it from doctoral Lilienfeld who was my mentor at
Hopkins he was very crusty and he was ill himself but I remember him saying
epidemiology of the butcher shop don’t pretend you’re using a scalpel and he
had a way of wanting to simplify simplify and make sure the measurements were right rather than and with big data coming maybe that’s not as true but it
is true that carcinogenesis is so subtle that we have to minimize error we have
to minimize error or the signal will be lost in the complexity of what we’re
trying to study and that’s been the reason and I always say it comes
back to the two-by-two table almost every measurement even if it’s
biochemical starts as a visual continuous measurement so even if it’s a
machine telling you yes or no it started as some kind of blot coming
up as darker light or whatever it’s always a continuum and then we chop it
into categories and eventually we chop it into yes no exposed not exposed some way prospectively or cross-sectionally or or
in some kind of case control fashion but after zur Hausen found DNA from novel
HPV and two cancers which gave him the Nobel Prize in the early 1980s I spent
about five years just trying to measure HPV in all its aspects and it was really
hard to get it right so much so that Bob Hoover when he was mentoring me towards tenure had trouble finding a paper that was ETL logic or in any way not just a
methods paper because all I was doing was trying to figure out how to measure
without error and I consider that is incredibly productive and maybe hard to
imagine being able to get funded now which worries me when we do a raise with you know multiplexing on a million individual tests on a strip and each one
has its AR structure that we’re ignoring the pretending doesn’t exist because I
spent time with one thing measuring HPV how to measure it so we could do valid
analytic studies and setting up cohorts and I made a lot of mistakes and I
wasted a lot of money and I still survived which is another thing that I
hope people can still get a chance to do these days is have your early studies
flow so I was looking at HPV and disease endpoints because I was trying to get
both the columns in the rows right and we through this discovered we were doing awesome methodological work as my friend Arthur shot skin and we were getting
together and all we did was rediscover really something about the etiologic
fraction of a causal pathway an easy way to remember it the etiologic
fraction of a disease that’s caused by a pathway is equal to the sensitivity of
that biomarker indicating that thing which is a over a plus C times a
correction factor 1 minus 1 over the relative risk and the thing that was
interesting is it almost always starts with a somebody sees a disease and
season exposure says maybe these are related and then you can go and start
looking at B start doing comparisons but often it’s useful just to do a case
series and see how many of the disease people have that marker because that’s
the upper bound of how important that factor is for causation and we have a
because we are looking very poorly at it it’s pretty low HPV was not very commonly found you needed a chunk of tissue and you how to
do southern blot and whatever but it kept rising as we got better and better
methods and then we kept finding new new types so if the etiologic fraction keeps
rising as you reduce miss classification you’re on to something
it’s exactly the opposite of the well-known thing that if you have random
miss classification effects it will drive you to the null same thing can use
the bootstrap upward if you’re really are reducing random error and you’re
getting stronger and stronger associations that’s a clue that you’re
on the hunt to something that’s big I’ve always thought of that in terms of
nutritional epi but if we could measure lifetime nutritional patterns
effectively we would see small effects grow enormous but it’s really hard to
measure time dependent covariance and variables effectively with single
measurements so reducing this classification became my
obsession first reproducibility because if it’s you can’t do it over and over
again get the same answer or if different people do it and they get
different answers then you’re in trouble and then accuracy of according to a
reference standard and to do this I had to accept the role which was not easy
for me as an arrogant individual which hopefully I’m less so now to be a
perpetual novice I have to go to people and say how do you measure this or how
do you do this lab thing or how do you do colposcopy how do you do
cytopathology how do you do histopathology and I had to continually
admit ignorance and start over again and I’m still doing that I still was doing
that with genomics and I’m still having to admit that in order to grow as a
scientist you have to be a perpetual full full or at least the knife to and
admit that in order to grow so I just asked like what’s the cervix what are we
talking about what is the cervix I I just try to keep asking simple questions
as Bob once that he was taught who’s the cases who’s the controls ask simple
questions ask simple questions the answers are to be profound so it turns
out the cervix is just not a tissue the bottom third of the uterus sticks out
into the vagina but and it’s not even just a ring of susceptible tissue that’s
particularly prone to carcinogenesis when HPV infected but it as Nico ven
Simpson and I have been examining it has a topology it’s it’s enormous compared
to the virus and so the virus virus clones are on the figment of each other
they are ignorant of each other unless they collide and on the same cervix you
have an entire two to three dimensional kind of thing where you can have an HPV
but an HPV normal CIN 1c on Tuesday on three different grades of severity of
Intrepid co2 disease and rather than being a point it can be typify its complexes can be the cervix itself so now at the same
time HPV okay it’s a small 8 KB DNA double-stranded episome old virus okay
not very many genes only couple genes turns out it’s incredible evolutionary
story with my friend Ravi Burke we looked at the HPV s which are currently
over 200 known HPD’s and what we found in what was my favorite paper ever which
was rejected five times because of that because I loved it that there was a
particular evolutionary clade in the Alpha genus that has evolved for some
reason to be carcinogenic as as its lifestyle where all the different clades
have different some just evade and don’t do anything some make warts it’s the
wart virus papilloma means work but around HPV 16 and it’s related alpha 9
types almost all are carcinogenic and alpha 7 which is HPV 18 counts for
almost most of the others and this is all evolutionarily tightly related and
for some reason they cook they evolved this style of an extremely vigorous e6 2
oncogenes e6 and e7 that kill kill they interact with RB in p53 and they do a
fantastic job of keeping the cell alive just like the movie aliens they keep the
epithelium alive so that the virus can grow keep growing so even if damaged or
mutated the epithelium lives and it’s a perfect setup for the ablation and so we
thought we were really at the end of things when we realized that there were
these types that were so specifically evolved we weren’t even close to done
so turns out at the same time I was trying to figure out how do people
classify disease so through some really great people Bob Herman and Diane Solomon here but I still miss incredibly she retired I
can’t believe she retired she took a library of knowledge of pathology away
with her when she retired happily she’s happy retired I can’t believe it
because I still want her around so but there were all these classification
systems mild dysplasia moderate dysplasia every everybody had their own
scale and then Ralph Richard cervical intraepithelial neoplasia 132 33 the CIN
3 subsuming carcinoma in situ all of these are bunk you know none of
them really are anything more than biomarkers in fact the notion they’ve
been basically people who invented them that said that they don’t no longer true
but they’ve become time-honored pathology names and therefore we don’t
realize they’re just biomarkers even histopathology of precursor lesions just
a nominal biomarker that has something to do with prediction of risk of
neoplasia and Papanicolaou had it right all he did was one two three four five
chance of it being cancer and that’s what these really armor just chance of
being cancer but they were trying to do a diagnosis that was more precise and it
became made into a disease so someone say I have CIN 2 I have asked us
cytology uncertain cytology and they would act as if they had been diagnosed
when in fact what we’ve learned is well there’s no reason to go one-third
two-thirds three-thirds why not force no their people wanted the histopathology
certainty and that’s still prevalent in the way a lot of people think in terms
of trial design in fact it’s very hard to be bunk that once it’s made into
disease we’re used to the history pathologist
telling us the anatomic reciprocal pathologist telling us what it was and
in this case it wasn’t very accurate in fact as I’ll say later I’ll say it now
CIN 2 doesn’t really exist so these are categories that are just arbitrary and
in continuum so to get to what really is HPD and cervical carcinogenesis you have
one of the oncogenic HPD’s there’s about a dozen that can cause cervical cancer
but that doesn’t mean they have the same strength 16 is much more carcinogenic
than any others almost we there’s an old rule one-third one-third one-third if
you have a low-grade lesion one-third are going to persist one-third they’ll
go away one-third will progress that just had to do with mis classification
they couldn’t tell the different types apart and you get it down to an HPV type
level what really happens is of 100 HPV infections the time zero they rapidly
within months most of them are gone and then it slows down but this curve is
really steep and then it levels off and then slowly you start to see pre cancer
which here is to find a CIN 3 in this study and then it’s it’s something
magical about the basement membrane said it can invade that’s it’s a powerful
contact inhibitor and in epithelium and so it phases pre-cancer looking like
cancer but not invading and then it circumferentially grows and at some
point additional mutations that permit invasion are slowly accumulated or
quickly if you’re someone’s very unlucky and there’s invasion but invasion takes
place over decades so most of the sojourn time is spent as a pre cancer
which allows pap smear programs to work because pap smears finally catch
something severe enough to treat in a very slow process that lasts usually
decades now what we were finding was as we
increased the number of HPV s that we related cervical cancer it turned out
that all the theories about the ones that cervical cancers that didn’t have
HPV no HPV this there were all kinds of theories and talks given about what they
were they pried primary mutations in this or that’ they were somatic this or
that and it was very interesting to watch those theories be strained as
seeing shrunk and shrunk and shrunk and a kept getting bigger and bigger bigger
until virtually we found that 95 plus percent of cervical cancers had HPV of
one of these types and in fact that whole group didn’t exist so we have very
few cervical cancers that don’t have HPV of one of those types and so we have an
a unique opportunity of a major cancer that’s almost a single necessary cause
and that’s been really really important and hopefully will have something to do
eventually with eradication or come or control at least of cervical cancer so
each of these stages has a very characteristic age peak just like if you
have warts on your feet they used to happen when kids got into middle school
and they had showers together and then you get plantar warts just type one HPV
one or little kids who get digital warts on fingers that’s you know HPV 2 and 26
there’s their characteristic timings and for sexually transmitted HPV that’s
there’s a peak with onset of sexual activity that then declines in terms of
incidence pretty much everywhere whereas then there’s a second peak of those that
don’t lose it and that’s pre cancer and then there’s eventual to grow out slow
the plateaus or drops or goes up but it cancer itself and these 3 peeps if you
really believe in them lead the way with this model that this is the real model
of things that are undeniable the real transition states to logical prevention
primary prevention just stop people from getting HPV and you’ll prevent cancer or
get rid of all the pre cancers and you get you’ll get rid of cancer and if you
believe those things that have some pretty radical notions that we’ll talk
about later about how we should go about getting rid of cervical cancer as fast
as possible okay so that’s the natural history in a real rapid blur so this is
Sholem lock holder it was a dearly missed friend who died a couple years
ago but without companion for 25 years in these explorations and was teaching
us how to translate of the very best and strongest associations into clinical
tests and so it’s only rarely that a biomarker is strong enough Association
strong enough to merit considering it for anything clinical but if use in
medicine or public health is the goal we see the lab usually or the clinician
that person who discovers a as the accelerator and epidemiology invariably
becomes very dour and we’re the steering wheel or even the brake saying hold on
you know this is not really strong enough to marry clinical use but this is
where epidemiology is the strongest they you have to come through up in order to
talk about clinical utility you need epidemiology and most biomarkers fails
tests so the default conclusion if you really want to be grandiose is that we
are standoff on the bridge and chaos of too many tests right the consumer coming
at us and we’re saying you shall not pass without suddenly thing would be
grandiose and think that we really are that effect
but but basically things have to come through population translational science
to prove themselves on the other hand say something really does prove itself
like HPV testing there’s fierce inertia usually against changing a familiar
clinical reference standard so when you’re kind of to plant a reference
standard like CIN 2 3 for the FDA or for somebody else and say that instead you
have molecular measurements that are providing a test that’s better than the
reference standard that are even in the histologic standard I say let whoever’s
without conflict of interest cast first stone what I mean by that is almost all
committees exclude anyone whose work with these tests from the committee’s
but clinicians and photo pathologists are considered physicians and therefore
without conflict of interest or in fact what we’re basically saying is we need
fewer gynecologists we need less screening we need less annual exams and
of course the people most impacted is we need less psychopathology and so I say
we everyone has a point of view and when big things are shifting cn2 is an
example of an endpoint that just needs to go away as being thought of as
something and that makes people very angry because they’ve spent their life
trying to distinguish what’s CIN 2 what c 9 and 3 how bad is something and it
turns out that it’s virtually impossible to make those distinctions so a lot of
what we’ve done is to question all biomarkers including our own and even if
it’s clinically established make sure that they aren’t thought of as disease
if someone has one of these an abnormal pap smear is not disease its
asymptomatic entirely it’s a predictor variable and everything
is a predictor variable and the other thing that we’re trying to change is
we’re trying to change the view of what makes a good test it’s been based in FDA
clearance and every other venue as sensitivity specificity and derived
there Abel’s such as ROC curves a area under
the curve but that may be yielding and showing would sake rightfully so too
does the tests correctly assign what should happen to the person in other
words a good test correctly assigns what the action should be and that’s
switching from the columns of an 2×2 table to the rows and to issues of
absolute risk in counting up absolute risk numbers and also it because we
can’t do we can’t afford the randomized clinical trials on everything it’s
shifting to learning how to use big data because you need really big data to look
at a lot of these issues so we’re finding that we have to be very careful
because we have to when we’re doing these kind of trials which are
prospective trials realize there aren’t cancer we’re not following to cancer so
CI 3 is not a perfect surrogate endpoint and we actually called one type
carcinogenic and it’s not and it takes 10 years to get rid of a test and once
one company uses that test every other company wants to also have that type in
their test and my friend Phil and I have tried for years they get rid of the
mistake I made at that ir committee by using CIN 3 prospectively as a surrogate
endpoint incorrectly 66 is a type that causes Santry but not invasive cancer
and yet it’s in every test kit and even the ones that being planned now will
have it and hundreds of thousands will be told they have a carcinogenic HPV and they done what if this thing just came on what does that mean no no okay so we now have all these tests we’ve been developing just an embarrassment of
riches of tests we have cytology with HPV testing we have using them both
we have low resource settings high resource settings we actually divide it
more finely than that and the problem is it is so complicated that there’s so
many algorithms now and different plight people making algorithms that we can’t
keep up so we are moving towards a different kind of dissemination of
vaccinations and HPV screening policy and trying to wonder how far do we go as
NIH scientists we don’t make guidelines clinical groups make guidelines we talk
about risk and so we’ve made the decision that we we provide the risk
estimates other groups provide the decision about what they mean because
they’re often value judgments so the principle that a lot of us were most
CACI a lot have promulgated is equal management of equal risk doesn’t matter
what tests you use but a certain risk means a certain kind of what you should
do as you get increasingly severely at risk for cancer there’s more that you
should do and we’re putting out tables like this instead of algorithms that if
your risk is really high no matter how it got there you do something like
immediate colposcopy or even treatment all the way down to discharge or
whatever depending on risk and that involves massive risk matrices risk
calculations that we are undertaking with all the approved tests and all the
combinations of approved tests and risk factors and so we’re moving from
algorithms to apps and young clinicians appear to be very comfortable with
lookup apps it’s not a calculator it’s just an enormous risk matrix that the
put into the electronic electrical electronic medical record or on a phone
app can tell you’ve given this and this and this and this and this and this
history and whatever here’s the recommended guideline and then if you
push a button here’s why here’s the risk and then if you push another button and
here’s the educational note and that is very different than it the old way which
was you get this test result here’s what you do but the test result sort of
disappears and the inside disappears and a simplified recommendation comes out
which was considered a loss of locus control for clinicians but the young
ones seem to be used to it because there’s so much information now that
they realize they have they can’t carry it all around in their head so we’re
just one voice at the table once we get to disseminating something like this so
what I learned we may think that we understand risk better than other people
we’re just we’re just one voice we need to do much better discussing risk about
the social aspects of risk tolerance decisions about risk and unless we do
that we’ll be just scientific voices that are ignored so we spend a lot of
time trying to learn how to explain what we do better but without crossing the
line to pretending in any way that we’re in charge what the decisions are one
society make tolerate a certain trade-off between a few cancers and
efficiency others or can’t afford to not whereas in the United States were very
risk intolerant and we may do a lot more in terms of interventions I wanted to
finish with a sense of the future and then try to get interactive I’m much
more comfortable talking to people than I am talking out people so I welcome any
any discussion here or in the future by email or whatever say we really really
wanted to get rid of cervical cancer we weren’t just saying we wanted to or
discussing it but we it was absolutely imperative to us each one of us to get
rid of it there are faster ways than what we are
doing and I want to give credit to Doug Doug Lowy is a humble and interested
scientist and I you know really AM credibly grateful that I could call my
friend over the many many years because he’s in the HPV field and I’m sure that he agrees that the real high impact is dropping
incidence and mortality of cervical cancer not just having the promise that
we’re about to do it and advancing fundamental understanding of
carcinogenesis those are those are what we really want to do and what we want to
do is do them as fast as possible and so instead of this model where we prove
that a vaccine works which is currently a two dose HPV prophylactic vaccine that
he helped invent and give it the forceps starts and then wait all those years for
cancer to be invariably prevented and then screen people which is a very
difficult several times every three years or whatever there’s a theory
coming HPV faster popularized by cha via Bosch and Nature Reviews in which we
take faith in what Amy Kremer and Alan until this time we’re doing right now
which is a trial of one dose vaccine one dose of HPV vaccine lasts at least five
to seven years it appears and if you can consider this epidemic of HPV
acquisition as any kind of epidemic and if you do campaign and if you just give
it to everybody one just I’m thinking back to all the
time I’ve spent in Africa – ibadan – places that I’ve sat and I can’t even
see across the street where Julie and I were trying to walk across the street
together and lost each other in the crowd you know if you really want to get
go to a place like I was just in Addis Ababa and I was looking around saying
programs are going to be really hard to institute here we need campaign
something where you go around you do something once and that we’ve been
successful in very poor places doing that so if we combine one dose back team and know that the last five to seven years at least we don’t know how long it
will last and that’s the big trial that we’re doing now to make sure we’re right
but while that is being confirmed and that’s dub division to do that trial
with gates if we if we start planning for a screening of everybody that
overlaps that HPV vaccination of the entire epidemic curve we have something
called HPV faster which means you wipe out the first peak the only people who
don’t get benefit or those who have active infection at that moment those
people you pick up on an HPV screening test and you manage and treat them if
you can motivate donors big donors to get excited about the notion of doing
something definitive about one of the worst cancers one of the leading cancers
in the world the first leading cancer in women in lots of very poor places it
might reenergize the donor community if they think they can actually take
something out rather than just institute a program that has to last decades and
that’s the vision the vision is to now get screening tests and HPV vaccination
together and then to start seriously taking a very very common infection
leading to a common cancer and eliminating it or at least controlling
it severely and that’s sort of the hope of what we’re working on now and that’s
Doug’s vision I believe so it in the end it’s all about people I want to thank
Dr. Fran meanie who I spent most of my career working under for creating BCG I
can see early believe that it’s spawn things that he taken no credit for but
have been incredibly I mean thousands and thousands of things that he’s
responsible for biogenic moving in some direction of a whole world of genetics
and I want to really thank Peggy and mark green in particular because it
turns out that everything comes together mark was the first one with Peggy to
realize that when I was coming as an epidemiologist and talking about
absolute risk or positive predictive value that’s the same as penetrance and
when they were studying rare family syndromic clinical genetics that those
were pointing out places and cascades growth or growth control pathways which
are really hard to find if you just go if you just go and you just try to find
them as candidate or if you try to intuit them they were pointing out
entire pathways each family each syndromic thing was now leading to an X
on the kind of exploration of the whole spectrum of that mutation that that
critical point and what it and what it does and and how its modified and how
there’s whole there’s people with lesser risk it’s a tip of the iceberg to
discover critical points that lead to carcinogenesis and we I think we had a
common vision that we wanted to study strong effects and we wanted to study
things that clinical impact and their understanding my desire to move that to
the clinical genetics branch studying HPV took some site visits to and
pleading to even convince people made sense but they saw it immediately and I
want to especially thank them for enabling the second part of my career
thanks very much thank you very much for that
presentation we have microphones in the aisles encourage you to step up and ask
questions we’re available here for a bit to try to answer or challenges I love I
like we don’t sometimes I think we don’t argue enough anymore because we’re
afraid of hurting each other’s feelings but in the grand British tradition it’s
just good good science to argue about things not personal so please as someone who did a residency in pathology back in in the 80s we had to go through the
psychology pap smears and things and it metamorphosed into the bethesda system but i think what you’re looking at isn’t necessarily specific to the cervix we
have the same problem as I learned further on with thyroid psychology
whereas in particular a follicular thyroid cancer is a very difficult
entity to classify which is also a need perhaps the same type of treatment as
you did here with the cervix in the top and Niccolo no yeah the Bethesda system was a tremendous advance but it was just on the way to recognizing that the real
action was at the molecular level and so even the Bethesda system eventually
yields because it’s a microscopic diagnosis of a molecular process and the
best way to look at a molecular process was molecularly so I think more and more
we just have to do the first thing which is reproducibility get the best experts
in the world who are absolutely certain they’re the expert in their area and
compare them and when they disagree they can’t just say well you know you know
whatever then there’s I’m sure that disagreement
spawns discussion about the reality of any category I think if you look at the
whole field of psychology or psychopathology you’ll find those type
of controversies in many different organs and so that might be a fruitful
a direction for individuals looking for this type of really willing you need
humility and cooperation from your colleagues and a sense of humor like Bob
Sherman had about the process because people get pissed off and you know when
you challenge experts from around the world so you you need those people who
want the greater truth and I’ve tried to get epidemiologists all of us to have a
day where we all do our modeling on one data set and prove that we don’t know
what we’re doing but no one never agree with me – we with the place to look
would be the follicular carcinoma of the thyroid the psychology that you’d be
interested in that thank you there are two I think multivalent vaccines
available for HPV so are they good enough for preventing HPV into cancer
that’s that’s the vision that God is carrying forward which is the work of
Amy Kremer and Allen Hill design which is a very large randomized trial of the
Gardasil 9 and cervix of on allowed to say names and then seeing do they in
fact last 5 to 7 years in their protection at one dose and that trials ongoing now in collaboration with the Gates
Foundation my guess is from our preliminary data
yes absolutely we’re going to find they are good enough for the kind of strategy
we talked about not for lifelong immunity but plenty long enough to wipe
out an epidemic of HPV and to reduce it to a less common or uncommon infection
so you think you might not need fuck that injection you’re saying only 5 to
70 years again I’m sorry you do not need lifetime durability you might not even
need 10 to 20-year durability if you’re only going about trying to crush
cervical cancer now we haven’t talked about cancer and then we haven’t talked
about a lot of other things but for the purpose of getting rid of cervical
cancer as soon as possible I’m sure that we can do it to the
campaign and about five to seven years of durability so things like your learns
of the cervical cancer it did also true for HPV induced oral cancer oral cancer
is a whole other perfect in this annual here someone else expert I’ll leave is M
different different different epidemiology learned a great deal about
the differences and it might be is a different story so I’m not extending to that thank you other questions I want to thank everyone for coming today I encourage you to come over to
the library we’re going to have a reception immediately after you can say
hello to all of our speakers and ask additional questions there thank

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