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When researchers reported recently that a precipitous drop in breast cancer rates might be explained by a corresponding decrease in the use of hormones for menopause, women reacted with shock, anger and, in some cases, profound relief that they had never taken the drugs.
But many also had questions. How certain were scientists that the hormones were responsible? How could stopping hormones have such an immediate and pronounced effect? And how much did scientists really know about the biology of breast cancer and hormones?
The data seemed clear enough. In 2003, after climbing for almost seven decades, the breast cancer rate fell for the first time in the United States, and it fell sharply. Over all, the incidence of newly diagnosed breast cancer dropped 7 percent, and it dropped 15 percent among women with cancers whose growth is fueled by estrogen.
There also was no question that at the same time, women had begun to abandon hormones as a treatment for menopause. In July 2002, a large study, the Women’s Health Initiative, concluded that a popular hormone therapy for menopause, Prempro, made by Wyeth, slightly increased the risk of breast cancer. Within the next six months, prescriptions for Prempro dropped by half.
A connection between hormone use and breast cancer rates did not surprise scientists like Dr. V. Craig Jordan, vice president and scientific director for the medical science division at Fox Chase Cancer Center in Philadelphia. Dr. Jordan is a leader in studying the effects of estrogen-blocking drugs on breast cancer. Among his many awards is this year’s American Cancer Society Award from the American Society for Clinical Oncology for his work on estrogen and the prevention and treatment of breast cancer.
Dr. Jordan’s wife, Dr. Monica Morrow, a breast cancer surgeon, is chairwoman of the surgical oncology department at Fox Chase. Their offices, he says, are across the hall from each other, “so we are together 24 hours a day.”
Q. Prempro, the combination drug that many women took for menopause symptoms, contains both estrogen and progestins. And the findings from the Women’s Health Initiative study suggested that estrogen alone has only a tiny effect, if any, on breast cancer risk. So which is the bad actor, progestins or estrogen? Or is it both hormones combined?
A. We’ve known for 30 years that estrogen can directly cause the growth of breast cells and of endometrial cells. Estrogen is fuel for the fire. But progesterone seems to do different things in different places in a woman’s body. In the uterus, it stops the growth of the endometrium and makes it ready for implanting a fertilized egg. In breast cancer, estrogen causes a doubling of cancer cells every 36 hours. Soon, the growing tumor ball needs to increase its blood supply because cells in the middle are not getting enough food and oxygen. Progesterone seems to cause other cells, stromal cells, to gather around the ball of cancer cells and play a supporting role. Stromal cells are the woman’s own cells that researchers now think may be specifically selected to build an architecture and send out signals for more blood supply, more fuel.
Q. That seems to be an unusual arrangement. Why would progesterone act on stromal cells in the breast?
A. When a woman is pregnant, her breasts are much larger and her estrogen and progesterone levels are huge. Progesterone is sending out signals that provide a skeleton to build the breasts.
Q. Was it a surprise to learn that estrogen and progestins can cause breast cancer?
A. We’ve known there is a cause and effect with hormones and breast cancer since 1896. If a woman is premenopausal and she has breast cancer and you take out her ovaries, the tumors decrease in size. Not all the tumors — if you took 100 women who were premenopausal and took their ovaries out, 35 percent would have a response. And you could get a dramatic response. A tumor that was the size of a walnut could shrink in six months to the size of a pinhead. It turned out that the tumors that responded contained estrogen receptors. This became cause and effect — the estrogen receptor was the mechanism that estrogen used to stimulate tumors to grow. If there was no estrogen receptor, taking away estrogen didn’t do anything at all.
Q. Did taking away estrogen ever make a breast cancer go away completely?
A. This is the basic difficulty. We were dealing with advanced breast cancer, and what we saw was that we could get complete remissions in 4 or 5 percent of the women. In the majority of women, the remission would last for one to two years. Taking away estrogen slowed things down, it reversed the process, but it did not cure.
Q. Do you agree with the latest analysis indicating that breast cancer is declining because so many women stopped taking Prempro and other menopausal hormones?
A. Throughout the 1990s, physicians were recommending that menopausal women take hormone replacement therapy. What happens is that you increased the rate of breast cancer in the whole country. And it shifted the epidemiology. We have seen an increase in the percentage of estrogen-receptor-positive tumors in the 1990s and in the beginning of the 2000s, so that now 70 percent of tumors are estrogen-receptor positive.
This was, if you like, consistent. Everything was ticking in. The Women’s Health Initiative and the Million Women Study in Britain really said: “Here’s a controlled series of studies comparing taking nothing with taking hormone replacement therapy. How many cancers were there at the end of the day?”
The Women’s Health Initiative found a 23 percent increase in breast cancer; the Million Women Study found a 100 percent increase. Those studies were highly publicized and women stopped taking hormones. Now the breast cancer rates are going down. Now tumors you would have detected are not being detected. There is no proof the tumors will ever go away, but you can’t detect them. And it is possible that many subclinical cancer cells may never grow inside a woman’s breast if she has no estrogen around to fuel that fire.
Q. If a woman has a tumor that is undetectable because she did not take menopausal hormones, will it eventually grow anyway and turn into a cancer that can be seen on a mammogram?
A. We don’t know. What we have learned from the tamoxifen clinical trial is that tamoxifen, which blocks estrogen, did a fantastic job. The cancer rate in the group taking tamoxifen dropped by 50 percent. Tamoxifen prevented the development of breast cancers that were early stage, and it also stopped cells from progressing to breast cancer.
Q. Some people suggest that the real problem was that the hormones women were taking were artificial or were given in artificial ways. Prempro, for example, gets its estrogen from pregnant mares. Some say other hormone preparations, for example, so-called bioidentical hormones, would be safe. Do you agree?
A. We’ve been talking about women’s ovaries producing estrogen and progesterone. When a woman enters menopause, hormone levels drop dramatically. The longer you bathe a woman’s breasts in these hormones, the more likely she will have cancer. If you start menstruating early, if you have two extra years of estrogen in your body, bathing your breasts in that fuel is a risk factor for breast cancer. If you start menopause late, if your periods go on for an extra four or five years, that is a risk. The longer you have menstrual cycles, the higher your probability of breast cancer. And that is with natural hormones, the ones in your body.
Q. What about birth control pills? Do they increase the risk of breast cancer?
A. We have had testing of birth control pills in huge groups of women since the 1950s, and there really is no evidence of a significant rise in breast cancer risk. What we do know is that oral contraceptives reproduce the messages in the brain to stop a woman from ovulating. You are bathing a woman’s body with artificial hormones, but normally she would be bathing her own body with estrogen and progesterone. You don’t have women getting endometrial cancer, and oral contraceptives reduce the risk of getting ovarian cancer by 50 percent. It is one of the few things we know of that reduces the risk of ovarian cancer.
Q. What about chemicals in the environment, like DDT or chemicals in plastics, that can mimic estrogen. Could they be causing breast cancer?
A. There are a group of compounds like DDT that are byproducts of industry and are in our environment. They can affect cells in the laboratory and can affect the reproduction of animals, but in really huge doses. There is an effect, but does it cause an increase in cancer? I personally don’t believe that is the case. I don’t think there is enough around to do that. A pinch of estrogen in the environment is very small compared to the gallons in a woman’s body.
Q. What should women do now? Should they ever take menopausal hormones?
A. The value of hormone therapy for women with extremely severe menopausal symptoms is well established, and women, in consultation with their doctors, should consider using it for only a few months to alleviate severe symptoms. The main concern is using the drugs for many years to prevent osteoporosis. They can reduce the risk of hip fractures, but there are now many different alternatives for women to maintain bone density, such as bisphosphonates or raloxifene. Hormone replacement therapy should only be considered after all other options have failed.
