World Oncology Forum 2015
The knock-on effects of breast cancer drugs
Prof V Craig Jordan - University of Texas MD Anderson Cancer Center, Houston, USA
Tamoxifen started off as a failed contraceptive. It was wonderful in rats, none of the rats got pregnant, but when they tried it in humans all of the women got pregnant in the clinical trials. So in the 1960s that wasn’t going anywhere, it went on the shelf and then, by a lucky series of accidents, I was doing a PhD in failed contraceptives and met all of the people at then ICI Pharmaceuticals who had developed ICI 46,474 to be the failed contraceptive. One of them, Dr Arthur Walpole, examined my PhD. I went off to America, had nobody to work with when I was there, phoned up Dr Walpole and said, ‘Why don’t we turn ICI 46,474 into a breast cancer drug, treatment of ER positive breast cancer? And he said, ‘Yes, we’ll do that. We will invest in your laboratory for the next ten years with funds. We will market it, you tell us what to do with it.’ What I came out with was long-term tamoxifen therapy as an adjuvant therapy and the prevention of breast cancer with tamoxifen. So those are laboratory studies that then went into clinical trial very successfully.
Is there a place for tamoxifen in prevention?
Chemoprevention has suddenly become rather controversial. All of the clinical trials that were going on with tamoxifen, now with aromatase inhibitors, clearly have proven that we can prevent a small number of breast cancers in large populations of women if we give those drugs to the large populations of women. Here are the complex difficulties with that: yes, these medicines are FDA approved or they’re available in the United Kingdom to be able to do this but I see that there is a difficulty. I think the difficulty is precision in identifying women who will develop breast cancer. We recruited tens of thousands of women to the trials, the benefits were a few hundred women didn’t get breast cancer. That is good but the collateral damage by having to take a tablet for five or ten years to be able to maybe prevent a disease in your body is a bit complicated as far as I’m concerned. We know compliance is appalling, nobody can keep taking these drugs for a long time. It’s almost like saying we’re going to have an outbreak of strep throat in schools and just on the safe side we’ll give every child in America or Britain antibiotics just in case. We’d never do that, absolutely never do that.
So there has to be a better way. The approved agents are tamoxifen, raloxifene, another agent, and that’s what we really must consider in the future. Having smarter medicine to benefit society in multiple ways.
Is there a way of identifying those women who will have a better response?
This is the holy grail, to be able to say, ‘We give you a blood test. We believe there are breast cancer cells in your body.’ I think that that is the best and worst case scenario. The best case scenario is that we have that test, the worst case scenario, now you, for example, now have the worry of what do I do about that? Do I rush off and have a double mastectomy just in case? We’ve seen that this has been the response to ductal carcinoma in situ where 99% of it will never develop into cancer. But the approach has been very, very radical. There’s a big rethink about the whole way of approaching ductal carcinoma in situ, when to say no to therapy. So those are the decisions that have to be made but there are alternatives using selective oestrogen receptor modulators that now are becoming a reality.
Can you tell us more about this group of drugs that you have been developing?
This is a story that has now gained momentum over time. We came up with an idea because we had some interesting laboratory studies that all didn’t add up. Never before in pharmacology have we found that a compound has been able to switch on some sites in the body and switch off other sites in the body using the same receptor outside the nervous system; never happened before with hormones. So we were giving to our animals tamoxifen or a failed breast cancer drug called keoxifene which we will now call raloxifene, that came out of my lab too. These compounds prevented breast cancer in the animals but they would do things to bone. They would tickle bone into believing it was an oestrogen. They would lower circulating cholesterol. So the same compound, a synthetic compound, was blocking one site but encouraging oestrogen-like effects in another. The way that it could never go back, the really crossing the Rubicon with tamoxifen in reverse, to be able to slow up the development of tamoxifen in chemoprevention was our discovery in the lab that tamoxifen would tickle endometrial cancer into life in a woman’s body and raloxifene wouldn’t.
When tamoxifen could replace one disease, endometrial cancer, for another disease, breast cancer, that really didn’t play well for the female population. So you have to have a different way of doing this and it turned out the raloxifene didn’t do that and we predicted that. So we suggested a new strategy for being able to have chemoprevention but benefits in the clinical community for big diseases like osteoporosis and coronary heart disease. These became the focal point of studies in women probably about 20-30 years ago because that became important. Women’s health became important, women were living longer, those became important issues. So aim at osteoporosis with these compounds, aim at coronary heart disease with these compounds for women, and you prevent breast cancer at the same time. If you can find a compound that doesn’t produce endometrial cancer then you’ve got a winner.
Where are we seeing the biggest gains in breast cancer prevention?
Exactly the follow through with that. Raloxifene approved for the prevention of osteoporosis prevents breast cancer at the same time. The study of tamoxifen and raloxifene, big chemoprevention study run by the National Cancer Institute in the United States with the NSABP got raloxifene approved to be able to prevent breast cancer in high risk women. But it was same song, second verse, with tamoxifen - you needed 10,000 high risk women to have benefits in a few dozen.
The approach for the future, I firmly believe, is really deal with women’s health. Women need support for osteoporosis. This is a problem in the making and putting women on raloxifene or a raloxifene-like compound, will now prevent breast cancer at the same time. This is a proven fact. I did a rough calculation of how much good raloxifene has done treating women for osteoporosis with the benefits against breast cancer and it’s really 20,000 breast cancers do not exist now because raloxifene has stopped them ever being produced. Those women don’t know who they are but we haven’t treated a lot of women for no disease, we’ve treated them for osteoporosis. So that’s a benefit twofold within the healthcare system.
So now we’ve got to tackle the problem of can we develop SERMs further. When I started with the concept of SERMs there was really just tamoxifen and maybe going to be this raloxifene. Now there are five SERMs FDA approved in the United States: tamoxifen, raloxifene, bazedoxifene, ospemifene and the last one, toremifene. Each one of those is playing a role at being able to control breast cancer in its own way. The more penetration into the population there’s going to be of women the more protection there will be for breast cancer. So this is the way of the future; the question is can we spot a SERM that will now provide protection against coronary heart disease, the other big killer of women? Yes, there are compounds on the horizon that have yet to be FDA approved. They were originally approved within the European Union but nobody wished to develop that further. But the time has come to be able to consider one compound called lasofoxifene that has that potential. Here is a molecule, I call it a miracle of molecular biology and medicinal chemistry because raloxifene we use 60mg a day, with lasofoxifene to prevent osteoporosis you use 0.5mg. It’s precision medicine to perfection. The medicinal chemists have been able to discover how to put small quantities in the body and stop it being excreted, that’s the way to do it; very clever stuff. That molecule prevents breast cancer, osteoporosis, coronary heart disease, strokes, no endometrial cancer. All we’ve got to do is invest in the winning compounds for the future of women’s health and that future of women’s health will now prevent breast cancer. These compounds are cheap, efficient and extremely well presented to women to be able to treat multiple diseases and that benefits the healthcare system and the female population.
