Will we ever be able to ‘pop a pill’ to stop cancer developing? In our latest expert interview, we talked with Professor Jack Cuzick about the concept of preventive therapy for cancer, and in particular, his work on breast cancer prevention.
Cancer Research UK: When did the idea of preventive therapy for cancer really start to gain ground?
Jack Cuzick: The first major observation that really gave impetus to this idea was the fact that when we were looking at the use of tamoxifen to treat breast cancer, the trials showed a benefit of reducing recurrences of current breast cancers but – very excitingly – also showed that new cancers in the opposite breast (‘contralateral’ breast cancers) were also being reduced substantially.
Breast cancer is kind of unusual in the sense that you have a second breast in which you can learn about drugs that you use for treatment to tell you something about prevention.
That work occurred in the early 1980s. In 1986 we put together a prevention statement about the real need to run clinical trials of tamoxifen as a drug for the prevention of breast cancer in women at higher than average risk of disease.
Cancer Research UK: What kind of research led on from that work?
Jack Cuzick: This led eventually to four large prevention trials in which tamoxifen was compared to placebo in high-risk women who didn’t have breast cancer.
There was initially a lot of reticence about using these drugs in prevention due to concerns about potential side effects. So it took a long time – originally we did a pilot study with Trevor Powles at the Marsden, which was going to be 200 patients.
But because of all the concerns, it got extended, and that eventually became a study of 2,500 patients, so it was more than a pilot study!
And it was not until 1992 that in fact the national trial started. Our IBIS I trial started, the Italian trial started, and in North America their P1 Trial started. So it took about 7 years from the original proposal and pilot data to get these trials running.
Cancer Research UK: Moving on to today, what are the hot topics or big trials that are going on at the moment?
Jack Cuzick: The data from tamoxifen – the prevention trials – are pretty mature. And in fact the data that came out were almost exactly what we would have predicted from the treatment trial: that the effect on new contralateral tumours was almost exactly the same as the effect on new tumours for women who didn’t have breast cancer in the first place.
The new drugs now that have essentially replaced tamoxifen for treating postmenopausal breast cancer are the aromatase inhibitors such as anastrozole. We saw a much bigger effect on new tumours than tamoxifen had in that setting, so that’s led us to want to look at the aromatase inhibitors to see if they’re going to be effective in primary prevention in high-risk women.
And we’re doing a trial called IBIS II to evaluate that. The trial is ongoing and will recruit hopefully 4,000 high-risk women to either get anastrozole or placebo for 5 years.
Read about promising early results with another aromatase inhibitor called exemestane.
Watch a video about IBIS-II:
Cancer Research UK: Why is it that a woman who goes into the clinic today and is seen to be at ‘high-risk’ is not given a preventive drug such as tamoxifen?
Jack Cuzick: We don’t have any infrastructure in this country for actually thinking about chemoprevention of cancer of any sort. The cardiologists sorted this out a long time ago – it’s now standard to look at blood pressure and to give anti-hypertensive drugs to individuals with high blood pressure, and also to measure cholesterol and to give statins to lower cholesterol in those patients. That idea has not percolated very solidly into cancer.
So the thought that a clinician may look at somebody and say “you’re at high risk of a particular cancer, so we’d like to do something active to reduce that risk” is not widely accepted. We don’t have an infrastructure, GPs aren’t prepared to do it.
The optimal place to spend a little time talking to women is in the breast screening programme. At the moment the breast screening programme has no resource, and are very reluctant, to do that, so we need to find additional resource.
Cancer Research UK: And is it anything to do with the fact that we don’t have a way of pinpointing which ‘high-risk’ women would benefit from the drugs that are available?
Jack Cuzick: I think that there are really two aspects, particularly when you have drugs that have some side effects. First of all, identifying a high-risk population where the benefits are actually going to be greatest, so the side effects are less important. Secondly, identifying an agent that is effective in that population.
In breast cancer there is work to be done in both areas.
So we have tamoxifen as a treatment, which is fairly effective and reduces risk by about 40 per cent. There are some side effects – they’re not major, but we’d like to reduce them more.
With the aromatase inhibitors it looks like we might get a 70 per cent reduction with a better side effect profile – but not perfect. So there are still side effects, particularly the effects that essentially make women feel like they’ve had a menopause.
But being able to identify high-risk women where the risk-benefit ratio is particularly attractive is a real challenge and really important, and we’re developing more knowledge about who is at high risk. For instance, we’ve always known that women with a family history are at high risk. And one of the new factors that’s becoming clear – one of the strongest factors – is actually breast density.
Looking at the mammogram – looking at the amount of opaque white tissue on the mammogram – gives a pretty good indicator of who’s at high risk and who isn’t. And this is actually stronger in terms of the overall population value than anything else we have, so we should be using that more.
Cancer Research UK: Thinking of the future, what is the ideal world scenario for women with breast cancer and cancer preventive therapy?
Jack Cuzick: I think that we really should focus on the cancer screening programmes as an ideal way of providing information. Ultimately we need to get GPs more educated. Women now go for screening about the age of 47 – which is just about the right age to be thinking about preventive therapy.
And I think one of the most attractive approaches is to put a bit more resources into the screening programme, where you could begin to identity women who are at high risk and tell them what their options are. Not of course insist on anything – there are lots of options, including changes in lifestyle and – for the very high-risk women – preventive drugs.
Cancer Research UK: How do you see cancer preventive therapies fitting in with other risk reduction strategies such as stopping people smoking, maintaining a healthy body weight, etc.
Jack Cuzick: Well if we focus on breast cancer, there are three clear options: one is to minimise or avoid use of hormone-replacement therapy, which does increase the risk of breast cancer. The other two relate to avoiding obesity and keeping physical activity up – which we know is important, but it’s a real challenge to learn how to encourage these things, particularly in high-risk women.
And we know that the effects of these behaviours, although important, on a population level are not enormous, maybe a 20 percent reduction in risk. So there is still going to be a high-risk population that would benefit from drugs.
Again, the cardiologists have sorted this out, in the sense that they recommend that a healthy diet and physical activity is good for everybody, but even with that there are going to be people with hypertension and high cholesterol levels, and they benefit in addition by taking drugs.
I think that same model and idea works for breast cancer as well.
Cancer Research UK: What single research publication has most excited you recently?
Jack Cuzick: One of the things that came as a bit of a surprise – and we’re very actively pursuing now – is the publication from Peter Rothwell and colleagues about the fact that aspirin when taken regularly for a period of 5 years or longer appears to lead to about a 20 percent reduction in cancer overall – not just one type, but many types. The major effects seem to be in colorectal cancer, oesophageal cancer and maybe stomach cancer, but also some effects for other cancers as well.
I think this is really exciting, and we’re very actively looking at how this might be implemented – whether low dose is enough, what age you should start, whether the effects are as clear in women as they are in men, etc.
But something as simple as a daily low-dose aspirin could produce a 20 percent reduction in all deaths from cancer would be a huge step forward.
Cancer Research UK: So why is it that we’re not all being told to take aspirin on a daily basis to reduce cancer risk?
Jack Cuzick: Like all drugs, aspirin does have some side effects. The biggest concern with aspirin is gastrointestinal bleeding, and that’s been one of the issues where, when the benefits were only thought to be heart disease, they seemed to be pretty evenly balanced with the increased risk of GI bleeds.
Now with the additional benefit of cancer, the balance may be much more favourable, but again it is a concern, and one of the things that will be important if we are going to try and pursue this will be to identify who’s at high risk of bleeding so that those people would not be offered aspirin. Instead we’d offer to people where the benefits clearly outweigh the side effects.
Cancer Research UK: Finally, what inspired you to work in the cancer field in the first place?
Jack Cuzick: It’s actually a long story – a long journey – for me. I started out as a pure mathematician, and liked doing mathematical problems, but always had the feeling that the most interesting mathematics was mathematics that dealt with issues ‘outside’ of mathematics – that is, real problems. In the last century that was physics, and now it’s more computing and medicine.
The most exciting, interesting areas in which new mathematical discoveries are being made are very much in medicine, in terms of analysing new data.
So it’s been a gradual shift, going from doing pure mathematics to more applied mathematics. My thesis was in ‘theoretical probability theory’, then I started teaching statistics, and then moved into working in clinical trials
I’ve now moved into epidemiology and prevention, but still doing some mathematics along with that.
Interview conducted by Olly Childs, June 2011