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Alzheimer's and Parkinson's research, HPV Vaccine, BRCA genes

Pfizer announces that it's pulling Alzheimer's and Parkinson's research and the relationship between the HPV vaccine and the need for future smears.

News that the pharmaceutical giant Pfizer has pulled out of research into Alzheimer's and Parkinson's disease is casting doubt over the future of long promised breakthroughs in this area. Mark Porter hears from two leading experts who explain that due to the complexity of the disease the pharmaceutical industry's single agent 'magic bullet' approach needs to change. And while over the last 15 years nearly every trial into new treatments for Alzheimer's has ended in failure, lifestyle and medical prevention are starting to make a difference.

Plus clarity on headlines that women who've had the HPV vaccine to prevent cervical cancer will need far fewer smear tests in future. But how will the national screening programme know for sure who has been vaccinated - and who hasn't? And Margaret McCartney's thoughts on other news that women treated for breast cancer who carry the BRCA1 and BRCA2 mutations that dramatically increase the risk of developing the disease, are just as likely to survive their illness as women who don't.

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28 minutes

Programme Transcript - Inside Health

Downloaded from www.bbc.co.uk/radio4

 

THE ATTACHED TRANSCRIPT WAS TYPED FROM A RECORDING AND NOT COPIED FROM AN ORIGINAL SCRIPT.  BECAUSE OF THE RISK OF MISHEARING AND THE DIFFICULTY IN SOME CASES OF IDENTIFYING INDIVIDUAL SPEAKERS, THE BBC CANNOT VOUCH FOR ITS COMPLETE ACCURACY.

 

 

INSIDE HEALTH – Programme 3.

 

TX:  16.01.18  2100–2130

 

PRESENTER:  MARK PORTER

 

PRODUCER:  FIONA HILL

 

 

Porter

Coming up today:  Smears – we examine claims that women who’ve been given the cervical cancer vaccine will need far fewer smear tests in future.  But how will the national screening programme know for sure who has been vaccinated and who hasn’t?

 

And new research suggesting that women treated for breast cancer, who carry the so-called Angelina Jolie genes, the BRCA mutations, are just as likely to survive as other women with the disease.

 

But first, news that the pharmaceutical giant Pfizer has pulled out of research into neurodegenerative diseases like Alzheimer’s and Parkinson’s, casting doubt over the future of long promised breakthroughs in this area.

 

In reality progress has been worryingly slow, over the last 15 years nearly every trial into new treatments for Alzheimer’s has ended in failure, and Pfizer is unlikely to be the only company to say enough is enough.

 

Roger Barker is Professor of Clinical Neuroscience at the University of Cambridge and currently in New York organising the next World Parkinson’s Congress.  What was his reaction to Pfizer’s announcement?

 

Barker

I was really rather disappointed, to be honest.  The idea of trying to treat chronic degenerative brain diseases – they are such a challenge and there have been a lot of failures in this field, despite large amounts of money being invested.  So, there is a sort of groundswell of feeling that these diseases are really too hard to treat and too difficult and too expensive.  And so, given all of that, a lot of people rather than rise to the challenge have slightly withdrawn.

 

Porter

With the benefit of what we know now, looking back on R&D over the last couple of decades, have we gone down the wrong path or is it just the sheer complexity of the challenge?

 

Barker

I think it’s a bit of both really, to be honest, and I think one of the realisations that people have come up with, I think, in the last 20 odd years, treating these conditions, is firstly, by the time people present clinically their condition has already advanced to quite a major stage and thus you’re trying to treat something which is more advanced than you initially thought and therefore, you’re always chasing after when the disease began and trying to stop a disease which has already gained a momentum.  So, I think there has been a sort of sentiment that we have been going far too late in the disease and I think people have understood that we need to change out strategy on that.  I think there’s also been a slightly naïve view that there will be one pathway, there will be one protein, there’ll be one aspect of the disease which if you critically target it will actually stop the disease and I think that that is simplistic, given the complexity of what goes wrong in all degenerative diseases of the brain – dementia, Alzheimer’s and such like.

 

Porter

Well looking forward now then, how do we change our strategy because we want R&D to continue in this field, we need it?

 

Barker

We’re going to have to get better at diagnosing people earlier.  So, I think the challenge will be can we, using more sensitive measures, pick up with reliable accuracy people who are in the very earliest stages of a process which may not even have any major clinical manifestations but somehow can we pick this up.  If we could pick up people at the very early stage then I think that increases the likelihood that we could stop the disease process from getting a hold in the brain.  The second approach would be actually could we think about trying to use multiply agents to target multiple pathways?  So, could we use combination therapies, rather than just stick with let’s just try one thing and see if it works. 

 

Now, one of the things that people sometimes forget is that the brain probably is extremely good at dealing with the abnormal proteins which ultimately lead to diseases like Alzheimer’s disease and Parkinson’s disease because these proteins are produced all of the time and so one the theories is that, for example, in Parkinson’s disease this protein – alpha-synuclein – what happens is instead of producing it at a certain amount you produce it at just a little bit more.  And over time that little bit more producing that protein eventually leads to clogging up the cell and the cell then dying.  Now, obviously, if it’s that subtle that the difference is, and of course most people with Parkinson’s disease live for 70 years before they develop the disease, then for 70 years your brain has been capable of dealing with that protein.  So, what it would take in order to shift you back to getting rid of the protein, rather than allowing it to accumulate wouldn’t be very much. 

 

So, I think strategically in terms of treatment, probably the changes you have to make within a cell to take it from one that’s diseased to one that’s healthy is relatively subtle and relatively small.  And I therefore feel that if you can use drugs that target little bits of those pathways and slowly tip the balance in favour of clearing the protein more than it’s produced, this could make all of the difference.  And in this respect, there’s a very interesting paper that came out in the autumn of last year, from a group in America, who had been looking at drugs which are used for asthma in the population of Norway and its relationship to Parkinson’s disease and showed that these drugs, these beta-agonist, actually influence how much of this protein you produce.  Now, this is just illustrative of the fact that subtle changes, relatively small changes within several linked pathways in a cell could dramatically change you from getting a disease to living a perfectly healthy long life.

 

Porter

And by beta-agonist, you’re talking about the salbutamol, the Ventolin inhaler, the reliever type drugs that are used by millions of people, it’s a new use for an old drug.

 

Barker

It is, and so this was a very interesting study because basically they did an epidemiological study of everybody in Norway and found that if you took beta-agonist your risk of getting Parkinson disease, I can’t remember the exact figures, was reduced to something like point seven, if you take one as the sort of normal risk.  So, it was a very exciting study, I mean there’s lots of work to still take that forward but I think it just illustrates that something that’s very commonly used, as you say, actually with a bit of thought and a bit of engineering, so you get enough of it into the brain at the right stage, could make all the difference.

 

Porter

The problem is, of course, with reusing existing medication is getting the funding for the trials.  Big pharmaceutical companies are not interested in doing that, there isn’t a lot of payback for them, so it’s dependent on academic bodies and charities etc.

 

Barker

It is, unless of course you start going down the line of combing therapies.  Now obviously, you would have to be able to secure the access to the original agents but not that I work, obviously, in the pharma industry but you could imagine that if you took the Mark Porter capsule, which you had engineered in your lab, which contained a bit of beta agonist, it contained a bit of anti-inflammatory, it contained a bit of creatine, you could imagine that these combination drugs, which have a unique combination, like Coca-Cola, could allow you to have a drug that you could then patent and say well this is, this is my agent for Alzheimer’s disease or dementia take this.  And so, it sounds very old-fashioned and very much of the sort of 19th century, slight quackery, but the scientific basis for it I think would be very sound.  And it would, I think, allow companies to develop therapies using agents which are already out there.

 

Porter

Looking forward from your perspective, knowing what you know, are you hopeful that the future is brighter than perhaps Pfizer’s decision suggests?

 

Barker

I think so, it’s very challenging, as I’ve said, but I think the future does hold great hope really.  I think we need to be clever, we need to be strategic and I think we need to change our mentality around looking for a magic bullet and looking much more for combination therapies, with things are already out there, new interventions and trying to work together to combine those in a very strategic population of patients, probably very early on with the hope that we can make a difference.  So, I feel much more optimistic than big pharma does in this area.

 

Ballard

My name is Clive Ballard, I am a dean of the medical school, I’m Professor of Age Related Diseases at the University of Exeter.

 

I think it’s very disappointing – one of the major pharmaceutical companies pulling out, particularly on the back of other companies also withdrawing from this area over the last five to 10 years.  And I think sometimes that can lead people to feeling that it’s hopeless and there’s nothing that we can actually do.  But I think the important thing is that what’s become very clear is that actually about a 30-35% of the potential risk for Alzheimer’s disease can be modified by sort of medical or lifestyle factors.  And in fact, if you look at the large community studies, epidemiological studies, that have been conducted in Europe, in the UK, in the US over the last sort of 50 years, that tend to assess people every 10 years, although the total number of people with dementia is going up because the population is getting older, within each age band actually less people are developing dementia now than they were 10 years ago, probably somewhere between 10-20% less.  And that seems to be about lifestyle changes but also about better medical management of risk factors in mid-life.

 

Porter

So, to be clear, although the number of people in the UK with dementia is going up because we’ve got an older population, the actual proportion of those older people who develop dementia is starting to fall?

 

Ballard

It’s starting to fall slightly.  And I think there’s opportunity to build on that and to reduce that proportion more.  And I don’t think that will be quite enough to reverse the overall increase in trend because our population is ageing so rapidly but I think it will be a really important part of containing that increase.  So, things like high blood pressure and high cholesterol in people in their 40s and 50s are big risk factors for Alzheimer’s disease and treating those more effectively at that life stage then has a really major impact on preventing Alzheimer’s disease down the line.

 

Porter

So, these are the sorts of interventions that GPs actually, to be honest, have been focusing primarily on cardiovascular health but that’s having a knock-on effect, we think, perhaps on dementia?

 

Ballard

No, absolutely, and I think there’s a very good mantra which is what’s good for the heart is good for the brain and I think really enforcing these types of approaches will make a big difference.  Similarly, the risk factors for diabetes are very similar to the risk factors for dementia.  So again, things that are going to reduce the risk of diabetes, like being the right weight, like having a good diet, will also reduce the risk of dementia.  And I think the other thing that comes out very strongly from these studies is physical exercise.  So, people who are more active, who exercise more regularly again that has an important protective effect.

 

Porter

Professor Clive Ballard, talking to me online from his office in Exeter.  As usual there are links to more information on the Inside Health page of the Radio 4 website, where you can also listen to the programme again.

 

Now to another story that hit the headlines before Christmas while we were off air.

 

News clip

A new study is recommending a major change in the way women are screened for cervical cancer.  It suggests those who’ve been vaccinated against the HPV virus need only have three smear tests during their life, rather than the 12 currently offered.  The vaccine has been given to girls, aged 11 and 13, since 2008. 

 

Porter

The vaccine works by protecting against the strains of the human papilloma virus responsible for most cases of cancer of the cervix.  The research that prompted the recent headlines concluded that vaccinated younger women are likely to need fewer smears in the future.

 

GP, Margaret McCartney, is in our Glasgow studio.  Margaret, remind us what the current smear programme involves.

 

McCartney

Yes, and the age range has been changed slightly recently.  So, every woman aged between 25 and 49 gets an invitation to cervical screening every three years and from the age of 50 to 64, or 71 in Scotland, you get an invitation every five years.

 

Porter

Now this human papilloma virus, HPV, that we’re talking about, this is principally a sexually transmitted infection?

 

McCartney

That’s correct.  There’s a hundred sub-types of HPV but there are several of them that are particularly known to be risky when it comes to the potential to develop future cervical cancer.

 

Porter

And most women will probably be exposed to this virus at some time or other, if left to natural history.

 

McCartney

Oh absolutely, so, we think around about eight out of 10 unvaccinated people will be infected with the virus at some point in their lives.

 

Porter

Now looking at this new study, I mean, first of all, what was your initial reaction to the idea that women might need fewer smears – I mean it’s attractive isn’t it?

 

McCartney

Oh, it’s very attractive and the idea is really that vaccination is a better preventative strategy than cervical screening.  I think that’s a good one because vaccination has the potential to reach more women than cervical screening does.  And catching something even earlier is more attractive than waiting for changes to appear in the cervix.  So, the theory is really good.  And also, there’s been studies done in Scotland that have found that HPV vaccination can reduce very early stages of potential changes that might eventually lead to cervical cancer even in women who are at most high risk because they live in deprivation.  And these are the groups of women who traditionally have lower attendance rates for cervical screening.  So, you can see how that might be a better strategy.  So yes, the idea of it is very attractive, the idea of being able to reduce cervical smears is, I’m sure, an attractive idea for many women.  But the problem for me is that we really need hard real-life evidence and this was a modelling study, it was a theoretical study rather than a real-life study of what would actually happen.

 

Porter

So, by modelling we’re talking about best guestimates about what’s likely to happen based on what we know so far, because we probably won’t know for decades how effective this vaccine has been.

 

McCartney

Well that’s the problem, the data we’ve got so far is that the vaccine seems to work pretty well for 10-12 years and after that we just simply don’t know.  It’s not been around for long enough.  And I think until we’ve got longer term data about how long that vaccine will last for I don’t think we really have sufficient evidence to be able to give good advice to women about how much they can reduce the frequency of cervical screening down by.

 

Porter

Professor Peter Sasieni is Deputy Director of the Centre for Cancer Prevention and one of the lead authors of the new research. Was he happy with the way his findings were portrayed?

 

Sasieni

In general, I was very happy with the way it was portrayed.  I would like to emphasise that we’re not saying that anyone should stop going for screening now.  And I think there were one or two places where there might have been a little bit of uncertainty.  The implication of this research is that the screening programme can change dramatically in the future but any woman who’s invited for screening now should seriously consider that invitation.

 

Porter

And based on your research when is that change likely to happen in terms of reducing the number of screens that women will need?

 

Sasieni

So, I think women who were vaccinated aged 12 probably don’t need to have nearly as much screening and those women would have been born in 1996 and onwards, so it would be a couple more years before we can say that 25-year-olds who have been vaccinated probably don’t need to be screened.

 

Porter

And how do you come up with this, presumably, you’re using a prediction as to their risks of cancer?

 

Sasieni

Yes, so this is a prediction till we consider what happens in our model every six months and the chances of getting an infection and the chances that infection being cleared or causing minor disease and the chance of that progressing.  And then on top of that model of what might happen to an individual woman we then think about what would happen if she was screened at various times and what would happen if she’s vaccinated. 

 

So, the parameters in the model are all based on data that we have observed either in trials or doing other studies but the full history, from age 10 to age 80, we haven’t been able to observe because the vaccine hasn’t been around for that long we can’t be certain that vaccinating a 12-year-old girl is still giving her protection when she’s 40.  But most of the data suggests that the vaccine’s going to work for a very long time.  We have data on how quickly antibody titres over time, so this is one of the things that’s used to look at other vaccines where we do have data about how the potency of the vaccine, if you like, wears off over time and there’s a need for a booster.  But the studies that we have show that even after eight, 10 years the antibody levels are higher than you get from a natural infection.  And in addition, the data seems to show that women are not getting infections eight, 10 years after they’ve been vaccinated.  So, between the two things it looks like this vaccine is going to probably not have a need for a booster.  But if there is a need for a booster in 25-year-olds or something then that I’m sure will be offered to women.

 

Porter

What about the implications for women who are either too old for the vaccine or have chosen not to have it or have missed out, is there any herd immunity here, are we reducing the circulating levels and therefore protecting unvaccinated women?

 

Sasieni

In the past people, at least the public often thought, herd immunity, if they knew about it all, was that if you vaccinated 90% of the population then actually everyone was protected and you’d eliminate the disease.  What’s going on here is that as more and more people are vaccinated, so the chances of other people getting the infection is going to be reduced.  It probably happens because the virus is mostly sexually transmitted and because mostly people don’t have sexual intercourse with people who are a very different age from them.  So, by vaccinating young people there will be very little protection for people currently in their 30s or older.  So that group of people have to continue with screening exactly the same as if there’d been no vaccination programme.  And it is quite likely that the risk in teenagers who are now 16-18 who haven’t been vaccinated, the risk of them getting cervical cancer will be reduced, as a result of the fact that 80-90% of their female peers will have been vaccinated.  So, there will be some effect but we haven’t really allowed for it because it’s going to be quite a while before it’s seen and in the short term, if you haven’t actually been vaccinated, I think you should rely on screening rather than hoping for herd immunity to help.

 

Porter

What about the implications for uptake of the programme, do you think dropping it to three smears, let’s say it goes down to three smears during the life of a woman, we’ve already got a problem with uptake in many parts of the country, do you think this might make it worse, that people might not bother?

 

Sasieni

I think what could make it worse is the success of vaccination in a way, so that people will just thinking of this as a disease.  Already it’s the case that probably you don’t know anyone who’s had cervical cancer, whereas you probably know several women who’ve had breast cancer, for instance.  So, the disease appears to be very rare and it is but that’s thanks to the success of screening.  I think it’s important that invitations are sent out, that we don’t just think oh well, everything’s worked pretty well, we can forget about screening altogether.  I hope that the message will be clear, that screening should be better targeted to those people who really need it the most.  And it’s very important that we are able to tell who has been vaccinated and who hasn’t.  Unfortunately, the records in England are poor, they’re much better in Scotland.

 

Porter

Why are the records so poor in England, I’m surprised at that?

 

Sasieni

Because there is no national record of exactly who’s been vaccinated and who hasn’t.

 

Porter

Professor Peter Sasieni.  And as well as confusion about who has been vaccinated, there are concerns that older women will think they can get away with fewer smears too.  Professor Jack Cuzick is head of the Centre for Cancer Prevention.

 

Cuzick

I’m afraid that’s an issue and it does reflect the fact that there is going to be some confusion.  This would be helped if there was a central registry of exactly who was vaccinated.  So, one of the challenges is actually knowing in a central way which women have been vaccinated and which haven’t.  Of course, they’ll be vaccinated mostly as girls and they may have forgotten exactly what has happened.  Fortunately, the screening programme has a national registry in which we know who’s been screened and that’s how we can invite them back at the appropriate time.  What would make sense would be to link the vaccination activity to that registry so we actually have a national account of who’s been vaccinated and by what vaccine and how many doses, so that when a woman is due for screening the national registry can actually check the vaccine status and adjust the screening invitations accordingly.

 

Porter

Because herein lies the problem, I mean within the next five years we’re going to have two groups of women, aren’t we, we’re going to have women who maybe able to have fewer smears and there’s another group, the older women, who are going to carry on as per normal and we need to be able to tell the difference.

 

Cuzick

Yeah, we’re going to really have three groups.  We’re going to have the older women who will have not been vaccinated and not been approached by the programme to be vaccinated, they could have it done privately.  And then even in the younger women, vaccine coverage isn’t 100%, it’s between 80-90%, so there’ll still be that small proportion of women who haven’t been vaccinated, who are younger.  And knowing who they are is very important.  The other thing is that there is interest in the value of vaccinating older women.  We’ve been trying to set up a trial to look at whether or not we should just go ahead and vaccinate right up to the age of 45, which would simplify that problem a lot.  It does look like there’s going to be substantial benefit but the studies haven’t been done yet.

 

Porter

This lack of connection between who’s had the vaccine and who’s having smears, is that the norm across the world, is that a problem for all countries?

 

Cuzick

Sadly, I think it is.  We’re in a position to get a vaccine registry and we really should, it would improve our ability to screen women appropriately.

 

Porter

Professor Jack Cuzick.

 

Margaret McCartney, so where are we now in terms of the joined-up records that would be necessary to tailor the number of smears to a woman’s needs?

 

McCartney

Well I have to say it’s a bit confusing at first glance.  In Scotland the School Health Programme, which records HPV vaccination, already links in with the Cervical Screening Programme.

 

Porter

So, Scotland comes out of this well.

 

McCartney

Yes, the programme appears to dovetail between the Child Health Programme, which records the HPV vaccination, and then the Cervical Screening Programme for later in life.  In England, Public Health England have told me, that HPV vaccination is recorded on the Child Health Information System, that is then transferred to the GP record and that in turn is pulled into the National Health Applications and Infrastructure System which in turn can speak to the Cervical Screening Programme.

 

Porter

Because it’s slightly complicated, isn’t it, because most of the girls, certainly in my part of the world, will have had their vaccinations done at school.  Some, however, will have had them done at the GP’s surgery and some will have had them done privately, as well, before the vaccine was released on the NHS.  So, we can’t be sure we’ve got everybody whatever way we do it.

 

McCartney

Yeah, this requires pooling of information, sort of very strategically, from one bit to the other without losing any in between in the gaps.  And I think where there are potential gaps that’s always a problem.  What you really want is a system that transfers exactly what’s on – the important bits of one record on to the other without any manual error or allowances for slip.

 

Porter

Databases aside Margaret, to be clear, this idea that women might be able to have three smears or so in the future, that, at the moment, is only a proposal.

 

McCartney

It’s a theoretical possibility.

 

Porter

There’s been no change in practice?

 

McCartney

That’s completely correct.  As we go forward, just now, there’s going to be no change to the cervical screening programme, this is a theoretical research paper which is really useful and interesting but we really need real life long term evidence based trials to tell us if we can safely make changes in the current recommendations.

 

Porter

Thank you, Margaret.  And there is more information on the HPV vaccine, the Cervical Cancer Screening Programme, and the new research about how many smears vaccinated women might need in future on our website.

 

Now, to another form of cancer – breast cancer – and headlines suggesting that women who carry the BRCA1 and BRCA2 mutations, that dramatically increase the risk of developing the disease, are just as likely to survive their illness as women who don’t.  Or, to put it another way, while carrying the mutations increases a woman’s risk of getting breast cancer, they do not affect her chances of surviving it once she does.

 

And the findings piqued Margaret McCartney’s interest.  Here are her thoughts:

 

McCartney

Breast cancer survival unaffected by faulty gene, said BBC News.  The faulty gene is the BRCA1 and 2 mutations which have been known to increase the risk of breast cancer, since it was discovered in the early 1990s.  Only a small minority of women with breast cancer have the BRCA mutations but it is younger women who are particularly affected by it.  After an average of eight years the Lancet study found that women who had been treated for breast cancer and carried the BRCA mutation were just as likely to survive as women who had been treated for breast cancer but didn’t have the mutation. 

 

Why is this important?  One woman described to me how she felt after her treatment for breast cancer knowing that she carried the mutated gene.  She described feeling that her remaining breast was like a timebomb.  Women in this situation may feel an awful dilemma, they are just recovering from treatment for cancer but are then offered further surgery – the removal of the remaining breast tissue and ovaries – because the mutation also raises the risk of cancer in the ovaries.  It sounds logical – preventative surgery capable of stopping cancer before it even has a chance to start – but counterintuitively this study implies that the speedy preventative surgery that is usually on offer for women with this mutation is unlikely to be necessary.  Women are just as likely to be able to delay prophylactic surgery and do just as well. 

 

But actually, this study reveals the immense difficulty of balancing acquired information about ourselves with evidence of what we should do usefully with it.  Some questions in medicine may be perceived as too obvious to be worth asking.  It may seem logical to assume that women with a known risk factor have a worse outlook but this study showed it’s not necessarily the case.  I’m sure there are few perfect clinical trials, this trial might not have been run for long enough to see a benefit from immediate preventative surgery.  However, that’s no excuse, we still need to ensure that what we offer is evidence based and not what we think of as common sense because that doesn’t always play out. 

 

For those women who have had cancer and know they have a BRCA mutation it might have seemed like an obviously good idea to operate on the other breast and ovaries quickly but that incurs physical and psychological risk.  There is also concern that an immediate large operation might adversely affect the immune system when it is needed to deal with the original cancer.  Truly good decisions need reliable information.  We need to ask basic questions and want to be the masters of the information we gather and not be at the mercy of the uncertainty and anxiety thrown up.  It is entirely understandable that women who have had breast cancer and found to have a BRCA mutation have been offered rapid surgery.  But now we have better information we can offer women better choices.  Gathering this takes courage to question what seemed like an obvious answer.  And of course, the other thing that often helps to make better decisions is time, and a study that tells us that breathing space is an offer is very welcome.

 

Porter

Margaret McCartney.  And there are more details of that breast cancer study on our website.

 

Just time to tell you about next week, when I learn how microprocessor enabled knees are transforming the latest prosthetic legs.  And Margaret explores the link between asbestos and mesothelioma in her home city of Glasgow – the mesothelioma capital of the UK.

 

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