Malcolm C. Pike, PHD; USC Norris Comprehensive Cancer Center; Innovator Award:

I've been very interested over a long period of time of trying to actually use what we know about hormones to prevent breast cancer. So, I've been around a long time and my colleagues and I - Dr. Brian Henderson and Ron Ross and Leslie Bernstein and Anna Wu - a lot of us were working since the late seventies really and John Casagrande. Since the late seventies, we showed first of all that if a woman took oral contraceptives it was phenomenally protective against cancer of the ovary. So, for example to give you a sort of number you can think of, that if you take oral contraceptives for six years your risk of cancer of the ovary is reduced by half - that's fifty percent for the rest of your life. It's a huge effect; it's like having four babies. So you've been taking oral contraceptives for six years, that's a long time - oh no it isn't. People are sexually active from their teenage years or late teenage years until well for the rest of their life actually, but in fact importantly until menopause. Well that's like thirty years - thirty five years, so using oral contraceptives for six years or seven years that's actually very, very common. And we can see that in the figures for the United States where cancer of the ovary rates are much lower now than they were back in the sixties.

In the early nineteen eighties we also showed, as did other people, that in fact the same effect was true for cancer endometria. So oral contraceptives prevented cancer of the endometria even more then they prevented cancer of the ovary. But, oral contraceptives did not prevent breast cancer. Why didn't it work with breast cancer? Well it didn't work with breast cancer because progestins or progesterone actually causes increased activity in the breast. Whereas it blocks the activity in the endometrium it causes activity in the breast. And so the pill was neither good nor bad for breast cancer but about the same because the amount of hormones that you were getting from the pill, which blocks your own ovary from working, the amount of hormones that you were exposed to from the pill was about the same as what you were blocking from the ovaries. On average you were getting about the same amount of hormones. Our idea was can you actually change the way the composition of the pill is to prevent breast cancer? Oh that's easy to do, just don't take it every morning take a quarter of it every morning - unfortunately it doesn't work if you take a quarter every morning, you ovulate still. So, in the late eighties - early nineties my colleague Darcy Spicer and John Daniels and I, we showed that if in fact you added a third hormone to oral contraceptives you could take a quarter of it and you add another hormone which blocked ovarian function. And we showed that you could make a dramatic change to the breast, you could actually quite clearly down-regulate it and that this would be a way of developing a formal contraception that would prevent breast cancer as well as cancer in the endometrium and the ovary. So we're still working on that whole game. But that was the proposal that we put in for an innovator award, we said look we've got these ideas related to this but we have other ideas that we would like to explore. We were exploring this fixing hormonal contraceptives, we would like to explore two other ideas.

The first was why does having a baby early protect you against breast cancer? We know that in fact certain changes take place in the breast and that having a baby, or rodents happen to have six babies at a time, that it's very protective against breast cancer in the rodent. And actually having multiple babies - one after the other - in women, especially if they have them when they are young, it's very protective against breast cancer and we don't really know why. So we put in a proposal to do animal work with Dr. Chodosh and his group at the University of Pennsylvania. They would study how pregnancy protected rodents against breast cancer and we would see whether the same effects were true in women. So that was the first proposal we put in to investigate that and that's what we are doing currently and a few other people are now doing it as well.

And the second thing we said was one of the biggest risk factors for breast cancer is so-called mammographic density, so when a woman has a mammogram well the reason she has a mammogram is to try and find a tumor. But in fact one of the most useful aspects of mammograms is they can predict whether you are going to get a tumor, and we don't really understand why that is. Its been known for a long time that if you take a mammogram, if you've seen a mammogram, or if you are a woman and you've seen your own mammogram, you know that most of it's grey and some of it's white. Well, your risk of breast cancer is directly proportional to the amount of white, so the more white you've got the more chances you've got of breast cancer. So for example if a woman has more than fifty percent of her mammogram is white and there's another woman who has less than ten percent of her mammogram is white, that's quite common - both situations, the woman who has more than fifty percent white, she's got five times the risk as the woman who has less than ten percent of white. That is a huge effect. So why is that? Well the white stuff is generally its collagen; well collagen doesn't get breast cancer. But it turns out that breast tissue (the stuff that makes milk - real breast tissue, breast epithelium), that actually essentially only exists in the white areas. There isn't any breast tissue or virtually none anywhere else. So it looks like as if the reason that mammographic density - the amount of white - is important is because that actually either represents more breast tissue (which is what I tend to believe) or in fact the collagen and the other cells around the epithelium they actually are doing something to the epithelium to make it more active. So we said we would like to have some support to start investigating this. So I was given the innovator award I think because of my ideas on changing contraception, because they could see that we were thinking out of the box, and I said well the other two big issues that we know so little about is how does pregnancy protect you - can we study it -- and why are mammographic densities so important. And I remember when the note came from the BCRP saying they had awarded me this grant, I was incredibly delighted because I thought now I can just continue to do what I have been doing for a long time which is to think differently from most other people and I was being the beneficiary of the fact that they like thinking outside the box.