Dr. Anton Titov, MD.: Professor Lippman, you created the first model of hormone-dependent human breast cancer, and you've been at the forefront of hormone breast cancer treatment ever since. Could you please give a high-level overview of the history and the presence of breast cancer treatment with hormone therapies? Sure, it's been appreciated for about 300 years that hormones played some role in breast cancer. There were epidemiology studies in Verona, Italy, in the 17th century. Can you believe it? They showed a difference in the incidence of breast cancer amongst nuns compared to women who weren't in nunneries. And the person making this observation correctly attributed this to some sort of use of the breasts. The first classical way people think of people understanding endocrine therapy was done in the late 19th century, when someone first thought that perhaps removing the ovaries might have a beneficial effect on breast cancer. And that turned out to be exactly the case in a small series of women who had their ovaries removed. These were obviously premenopausal women. Some of them showed enormous objective responses to removal of ovaries. It was very, very gratifying result. Dr. Marc Lippman, MD.: But the real science of this took many, many, many years to uncover because people didn't know how hormones worked. Not only did they not know how hormones worked, but they weren't able to even measure them. The concentrations of hormones required the invention in the early 1960s a radioimmunoassay and radioreceptor essay. And suddenly, endocrinology became a science. Suddenly, it was possible to measure incredibly low concentrations of all kinds of steroid and peptide hormones. Hormone feedback loops became clear. And it became very, very easy to understand that breast cancer was a hormone-dependent illness. It became appreciated, of course, that at puberty, a girl's estrogen levels rise, and she developed breasts. And it was appreciated shortly after that that if you gave a man estrogens, he would grow breasts. And of course, the outstanding, though perhaps subtle observation about this is that. If, for example, I gave you, Dr. Titov, if I gave you estrogens, you would grow breasts. Dr. Marc Lippman, MD.: But you wouldn't turn into a breast. You would have limits on growth. And that's exactly what happens to women. At puberty, they develop breasts. Their breasts, even though they bathe in estrogens for the next seven or eight decades of their lives, breasts don't particularly change. Breast Cancer remembers that phenotype some of the time. Breast Cancer remembers this responsiveness to estrogens. Except when you give a breast cancer estrogens, it has forgotten how to stop growing. So it continues to grow and spread as long as it's stimulated with estrogens. And therefore, it became clear in the 1940s, originally, that you could scientifically develop endocrine therapies for women involving the removal of ovaries. Of course, as I mentioned, in the adrenal glands, you have to substitute back glucocorticoids because they're essential for life. Dr. Marc Lippman, MD.: But the adrenals are the source indirectly of estrogens which can stimulate the breast. And for many years, it was popular and very successful to remove the pituitary. They did hypophysectomy, which also by removing gonadotropins and ACTH would result in falls of hormone levels and regressions of breast cancer. The major advances in the 70s, and 80s, were to learn how to do these things without ablative surgery. Drugs such as what was commonly referred to as anti-estrogens were developed. There are several of those drugs, interfering with estrogen action. And when given to the right women, anti-estrogens result in breast cancer regression. It's also a clear story that for almost all oncology, as things start to work in the more advanced disease settings for women with metastatic cancer, the same therapies can be advanced to earlier stages of cancer. And this is exactly what happened with endocrine therapy of breast cancer. It was first used for patients with metastatic cancer. Then very imaginatively hormones were used to prevent recurrences of the breast cancer, when women had their primary breast cancer treated by mastectomy or lumpectomy. And those clinical trials, which are still being analyzed now 30 and 40 years later, resulted in profound improvements in survival. And in fact, many women were cured who would have otherwise died. And the single greatest advance, single greatest advance unquestionably, in the treatment of breast cancer, which has resulted in extraordinary falls in mortality rate, has been the adroit use of either hormone therapy or, in some cases, chemotherapy to treat women at the time of their local therapy. Then breast cancer has not overtly spread to the rest of the body. And more recently, it's become clear that these endocrine therapies can prevent breast cancer. Though these treatments aren't used as widely as they should be, in my opinion. You can prevent 60 to 75% of all breast cancer in women by treating them for five years with therapies that interfere with their estrogen hormone levels. The data are unequivocal and very compelling. Dr. Marc Lippman, MD.: But unfortunately, these therapies aren't as widely used as they should be.