Cancer prevention is a great thing to think about, it’s one that we can’t always think about but breast cancer, you yourself said, is the epidemic of the century. Now that’s the starting point, in a way, for the IBIS-1 study results. Can you tell me about the study, what you did very, very briefly?
Yes, the IBIS-1 study began in 1992 and is very mature now in the sense that we have more than 20 years of follow-up in some patients, 16 years median follow-up. It was a trial of Tamoxifen for five years at the standard 20mg dose or matching placebo. High risk patients without breast cancer were entered into this trial and they continued to be followed in a blinded way for this entire period.
So you got women who were volunteers, essentially, because they were high risk and they agreed to take Tamoxifen?
Yes, these were women who had typically a family history of breast cancer and were very concerned about not only their risk but the risk to their daughters and family as well and offered to join the trial to help us learn how best to prevent breast cancer.
Now you’ve got 16 years of follow-up, that’s quite a long time. What have you discovered in that time?
We knew from previous analyses that after about ten years that Tamoxifen was preventing a lot of cancers, about a third of the cancers were actually being prevented, not only in the five years of active treatment but there was what we called a five year carry-over effect that in the next five years we saw a similar sized benefit. What’s new is we now have good evidence from 10-20 years overall and we found that the benefits have continued for another ten years. So in the next ten years we also prevented another 30% of the breast cancers that would have occurred in the placebo population.
Is there a downside to using Tamoxifen for five years though?
All of these drugs, because they reduce the oestrogen levels, produce oestrogen like withdrawal symptoms like the menopause so some women have hot flushes, night sweats, the standard menopausal problems. The specific side effect of Tamoxifen is an increase in endometrial cancer which we saw previously. It’s been known for some time, we reported it in our 8 year follow-up, and what’s new this time is we’ve actually seen some of those cancers have been fatal which we were hoping wasn’t going to be the case but in fact we now have five deaths in the Tamoxifen arm from endometrial cancer and none in the control arm.
Could I ask you a little bit about the hormones going on here? Did the women have to be hormone receptor positive and what about the use of hormone replacement therapy?
This was a study in women without breast cancer so there’s no knowing what kind of cancer they would have developed. One of the decisions that we argued about was whether or not we would allow women to take concurrent hormone replacement therapy. We decided that this was acceptable, as did the other European trials; the American P1 trial decided not to allow this. In retrospect now we’ve seen that in fact the effects of Tamoxifen are very weak when women are also taking hormone replacement therapy and they’re much stronger if they didn’t take hormone replacement therapy at the time they were taking Tamoxifen. So the benefits in women who did not take hormone replacement therapy are instead of 30% they’re 38%, so a substantial increase.
Could you sum up, then, the benefits of using Tamoxifen therapy?
Yes, we’ve shown very clearly now that five years of Tamoxifen has a very long-lasting effect on reducing breast cancer by about 30% overall. A bigger effect was seen in women who did not take hormone replacement therapy where it was almost 40%. The trial is still too immature to actually look at mortality, less than 5% of the women on the trial have died, so it’s going to take us another 5-10 years to really understand if these benefits will translate into a mortality reduction which we have not seen at this stage.
Now, some women will be anxious about possible symptoms with an anti-oestrogen therapy, what would you say to them?
My suggestion is basically women should try it. If they think that they’re at increased risk of breast cancer and know that to be the case it’s always worthwhile giving it a try. If the symptoms are really very difficult or intolerable just simply stop. In fact the symptoms in terms of menopausal symptoms will disappear within a few months. So that should not be a reason to not give it a try, it may be a reason not to continue on.
So could you sum up in a few words what doctors need to know about this to discuss with their patients, whether they’re at high risk and how many of them need to take a drug to prevent a breast cancer?
Yes, the data are quite clear that Tamoxifen does prevent breast cancer but there are some side effects. The reduction is about 30%. Last year we actually showed that the use of an aromatase inhibitor will actually reduce breast cancer incidence by about 50%, probably with fewer side effects, but that’s only for post-menopausal women. So these results are probably particularly important for high risk pre-menopausal women who, of course, because they’re younger have longer to live and this long-term benefit is very, very important for them. We estimate that you only need to treat 22 women to prevent one breast cancer and it may be even better than that for younger pre-menopausal women.
So the very brief take home message is what?
The brief take home message is that Tamoxifen is a very attractive option for high risk pre-menopausal women and they should consider it seriously.