Breast cancer prevention in high-risk post-menopausal women

Prof Jack Cuzick - Queen Mary University of London, London, UK

Thank you. It’s a pleasure to report the long-term follow-up of this study. This is an enormous study with over 200 centres involved across about eighteen different countries. Basically the disclosures are given here. The only thing that’s really relevant is the study was partially funded by AstraZeneca who make anastrozole but they had no involvement in the management, running or decision to publish this data.

We published about six years ago the initial results of anastrozole in prevention and the aim of this study is a particular focus on what happens in the longer term. That original publication was a five year median follow-up and now we’re up to almost eleven years median follow-up, so substantial information about the long-term data. Particularly relevant because tamoxifen has been looked at in prevention and been shown that the 30% reduction you get with tamoxifen for five years is maintained for at least twenty years so that’s a crucial question for the aromatase inhibitors.

The study design was just under 4,000 women, 38-64, randomised one to one to either anastrozole 1mg daily or matching placebo. The first five years they were followed up in clinic while they were given treatment and then the subsequent follow-up was a bit of a mixture depending on the country, clinic visits, questionnaires to the patients and in some cases we were able to supplement that with registry data. So the median follow-up now is 10.9 years on that particular data.

The results are here. Previously we only had half the patients out to five years, this is the full complete data for everyone out to five year follow-up and there was a 60% reduction, 61% reduction, in new breast cancers over that five year period going from 4.6% down to 1.8%. The number needed to treat to prevent one breast cancer in that first five years is 36 which is pretty good.

The new data basically looks more at the long-term follow-up. The effect size was not quite so big although it was not significantly lower. It was a 36% reduction in new cancers in years 5-12, going from 4.4% down to 3.5%. Statistically significant in its own right and, although numerically less than in the active treatment period not significantly so. 

So if you put that all together you end up with a substantial benefit over twelve years of 49%, almost half the breast cancers, were prevented, reducing that from 8.8% down to 5.3%. The number needed to treat with that twelve year follow-up now drops to 29 which is substantially bigger than what we’re seeing with tamoxifen at that stage where you needed 49 patients to prevent one breast cancer. So five years of treatment, remember treatment stops at five years, carries on producing continuing benefits right out to twelve years and follow-up will continue.

A little bit of subgroups. If you looked at the effect of first five years versus after five years there was, as I pointed out, a bigger effect in the first five years but still a significant effect subsequently. The effect was stronger, as we expected, in oestrogen receptor positive cancers but we found a somewhat surprising, although non-significant, effect of even a reduction in oestrogen receptor negative cancers which was actually apparent in both treatment periods, although not significant. So this is going to require further follow-up to see whether there is potentially some effect in cancers which arise as ER negative cancers.

A big effect in DCIS, essentially the precursor lesion to cancer, a 59% reduction overall and it was apparent particularly in the first five years but continued to show up after that period. So a substantial reduction in these early lesions. And although we didn’t have oestrogen receptor assays on all of the DCISs, that’s not routine, the ones for which we did we found a really dramatic, almost 80%, reduction in new cancers and that was equally seen both in the first five years and subsequently.

Adverse events were really reassuring. There was really nothing serious. The mortality data is still too early, it’s 69 deaths in the anastrozole versus 70 in the placebo and only two versus three, one less death in anastrozole but way too early. So we need another ten years of follow up to actually sort out how these dramatic reductions in incidence are going to convert into mortality or not. In terms of other cancers we had expected a reduction in endometrial cancer which we didn’t see because it was so oestrogen dependent. Numbers are small but we found a dramatic reduction in skin cancers, mostly non-melanoma skin cancer, for which we don’t have an understanding but a 40% highly significant result in reduction of those cancers as well.

The other issue is we did look at treatment adherence. Every patient had had the full five years, offered full five years, of treatment and the differences were very, very small. So 77% of the placebo arm continued to take treatments for the full five years and it reduced to 74.6% in anastrozole, so just about 2.5% higher dropout rate. I think that’s what you can attribute to the side effects. We did report in the first result, in the five year period, there were a lot of reported side effects, particularly musculoskeletal events. It was 64% in the treatment arm but 58% in placebo. I think one of the real challenges is that most of these effects which are actually being reported are not treatment related. There’s a very, very high rate of musculoskeletal arthralgias even in the placebo arm, indicating that we have to be very careful to interpret this. In fact, the loss of continued treatment for the five years is really very, very small, just this 2.5%. So that’s an important issue.
No serious late events as well that we’ve seen and also no increase in fractures. The fracture rate was known to be high with oestrogen depletion in the treatment trials. We required a baseline DEXA scan in all the patients and they had to take a bisphosphonate if they were osteoporotic and it was recommended in the osteopenic. No increase in fractures, just a tiny 4%, nowhere near significant increase. So that problem seems to be manageable.

Just in conclusion, anastrozole significantly reduces breast cancer by 49% with a twelve year follow-up. It’s particularly clear in the ER positive but some effect in ER negative which we still don’t understand. The important new data was a substantial 36% reduction seen in the post-treatment period which is still larger than seen for tamoxifen which is about a 30% reduction year on year but it goes out to twenty years. We see a much bigger effect in the first five years and a continuing effect which is larger in the post-treatment period so that’s good news as well. The number needed to treat is only 29 now, that’s after twelve years of follow-up, which is a very respectable number, lower than was seen for tamoxifen, a bigger effect there. No increase in fractures, again baseline DEXA scans were important to identify women who were osteoporotic initially and make sure they got treated. They could still take anastrozole but they needed a bisphosphonate as well to protect against fractures. There were really no major adverse events seen between the treatments. The other cancer effect was very, very similar aside from this reduction in non-melanoma skin cancers. No increase in cardiovascular events, as I said, no increase in fractures. We can find really no serious side effects. Of course, the ones that occur in the first five years are things like musculoskeletal pains. We weren’t able to follow that up properly in the follow-up period but most of those occurred within about a year or two so we don’t expect that we’ve really missed anything serious there.

Mortality data is still immature. There is no effect on breast cancer or other deaths but it’s way too early to make any judgement about that. This highlights the real important need, particularly in prevention studies, to do long-term follow-up. We’ve learned a lot going out to twelve years, another ten years of follow-up will tell us a lot more about the impact on mortality.

So in conclusion these data provide further support for the use of anastrozole in breast cancer prevention in high risk women. It’s been recommended by NICE in the United Kingdom, the National Institute for Clinical Excellence, and the US Preventative Task Force in the United States but it’s not licensed for treatment because the drug is off patent and nobody wants to pay those extreme fees. But it is being used, although not as much as we’d hoped. So thank you very much.