IMPAKT Breast Cancer Conference 2013

Long-term effectiveness of SERMs for preventing breast cancer

Prof Jack Cuzick - Wolfson Institute of Preventive Medicine, London, UK

We’ve collected all of the studies together, and the first studies began in 1986, studies that have looked at these drugs called SERMs, selective oestrogen receptor modulators, and their role in preventing breast cancer. Tamoxifen is one of them and it’s the only one that’s actually used to treat breast cancer and it gave us our first lead because when using it to prevent recurrence of breast cancer we discovered that it also prevented new tumours in the opposite breast. That led me some years ago to actually suggest that we should actually look at it in prevention. So there have been now four major prevention trials doing that. It’s absolutely proven now; the reduction overall is about 40%.

So you can treat well women with Tamoxifen and they don’t get breast cancer?

Well they get less breast cancers, reduced by 40%.

Why hasn’t it gone into general practice?

I think there have been a number of reluctant things. The cardiologists have recognised for a long time that if you treat somebody before they get disease you’re going to have a bigger effect than waiting for them to get disease. So if you went to your doctor with high cholesterol and he said, “Come back in a year and we’ll see if you’ve had a heart attack,” you wouldn’t be very pleased. In fact that’s what we do in breast cancer – high risk women simply get screened more often and they wait for the cancers to occur. So this is the idea to bring this paradigm of preventing breast cancer to the cancer field.

What can you tell us about Raloxifene?

Raloxifene actually started out as a drug for osteoporosis and in a large trial in which women with osteoporosis were being treated to prevent bone fractures it was discovered that in fact they also had a reduction in breast cancer. So that was identified and further studies were conducted with breast cancer as the primary endpoint and it was discovered it also had a major effect on preventing breast cancer.

Which other SERMs have been included?

There are two new ones, well fairly new now, one called lasofoxifene and one called arzoxifene. Again they both started out as osteoporosis drugs and the trials were in women with osteoporosis trying to prevent fractures and again they showed very big effects on breast cancer reduction. We got all the trialists together to give us their individual patient data and we put all of this together into one big overview of all of these studies to get an overall estimate of the benefits and the risks of these different drugs. We found that there was a large reduction in breast cancer, it was 38% overall. It occurred not only during the five years of active treatment but continued for five years after that. So we’ve done a ten year follow-up on all of these studies now.

Which categories of patients will these SERMs be targeted towards?

These SERMs only work for what are called oestrogen receptor positive breast cancer. This is about 70-80% of breast cancer, depending on age, and they reduce that by a little over 50%.

How do you select the high risk patients?

Selecting high risk is still something where we need to do more work but the major factors are family history – a mother or a sister with breast cancer below the age of 50 or two breast cancers in the family. The other factors that are important and established are women with benign breast lumps that have abnormal features: atypical hyperplasia, globular carcinoma in situ and probably the most important factor, but not currently used very much, is breast density which can be seen on a mammogram.

How many cancers do you think could be prevented worldwide?

Worldwide now there are estimated to be more than 1.4 million cases of breast cancer. In the top 10% of the population we probably have about 20% of those so that’s a little over a quarter of a million cases per year that we could find in this high risk group that might be suitable for Tamoxifen or a SERM.

What are the risks?

Two major side effects which are both fairly rare are thromboembolic disease, blood clots, and the risk is approximately doubled, about an 80% increase. That’s about the same as hormone replacement therapy so it is the most serious side effect and we estimate that, for example, in a thousand women that took one of these drugs for five years you would have about six extra cases. The other concern, which is actually mixed, it’s really only seen clearly with Tamoxifen, is endometrial cancer. Again that’s a little more than doubled with Tamoxifen but it’s quite rare and I think doctors have become much more aware that any abnormal bleeding in women with Tamoxifen needs immediate investigation. These cases have generally all been found very early where you can treat them with just a hysterectomy and nothing additional.

What are the clinical implications?

I think there’s clear evidence that this is a winner in terms of prevention. It’s particularly appropriate, Tamoxifen, for premenopausal women because you don’t have the endometrial cancer risk. We estimate that if you took high risk women with roughly double the average risk, in every one thousand women over a ten year period we would prevent about twenty breast cancers, there would be about three extra endometrial cancers and about six extra thromboembolic events. So the cancers are clearly the most serious of those events and the effect sizes are larger so it’s clearly a winner.

Are newer SERMs as effective and are they likely to be licensed?

The newer SERMs sadly are not being promoted for breast cancer prevention. Of them lasofoxifene appeared to have the best profile because not only did it prevent a little bit more breast cancer, about 50%, but it also had a beneficial effect on fractures, which it was designed for, but also heart disease and strokes. So if you could get a preventative agent that would actually affect a range of diseases, this is particularly important in the general population or well women.

What should ordinary doctors be doing?

I think we need to raise the profile of the fact that cancer is a preventable disease, just like the cardiologists have done. People now consider high blood pressure, high cholesterol, to be a disease, in fact all it is is a risk factor. We have the similar risk factors for breast cancer and we should begin to treat them as well. So the first thing is I think we need regulatory approval for these drugs. Sadly they’re all virtually out of patent now so the companies aren’t inclined to go through the process of regulatory approval. In the UK now the NICE committee, the National Institute for Clinical Excellence, has now recommended that either raloxifene or Tamoxifen be considered for high risk women, so that’s a very positive step in the right direction and hopefully will provide the stimulus and the confidence for doctors to begin to use this more. The next step, though, is to actually begin to educate GPs and the population in general that breast cancer is a potentially preventable disease and we really should put more effort on doing that.

Should doctors think of using Tamoxifen and other SERMs?

I believe they should. They should identify women who have had a strong family history of breast cancer, who have had a benign lump or even those that have very dense breasts and discuss with them the options. But I think the benefits do outweigh the risks for most of these women.