The conventional wisdom is that estrogen causes breast cancer. If you want to grow breast cancer cells in a petri dish, you need to add estrogen. And if a postmenopausal woman has an estrogen receptor positive (ER+) tumor you treat it with an aromatase inhibitor, which blocks estrogen production in the breast. So, when researchers looked at what happened to the women in the Women’s Health Initiative study who had had a hysterectomy and who were randomized to get either estrogen or a placebo, the results should have been a slam dunk: increased breast cancer in those on estrogen!
But no! An article published online yesterday in the Lancet Oncology showed that the women in the WHI study who took estrogen alone for about five years had a lower risk of developing breast cancer than the women who were on a placebo. What? Why? In sum it’s complicated.
First a little background. When women enrolled in the WHI, a large randomized placebo-controlled study designed to measure the benefits and risks of menopausal hormone therapy, they were divided into two groups. One group was composed of women who still had their uterus and who would be given estrogen and a progestin or a placebo. The second group was composed of women who no longer had a uterus, and who were given either estrogen alone or a placebo. (The progestin is given to reduce the risk of uterine cancer.)
As you may recall, in July 2002, researchers stopped the part of the WHI study investigating the benefits and risks of estrogen and a progestin after an interim analysis indicated that the risks of this therapy outweighed any benefits it had to offer. But the estrogen-only arm of the study kept going. It wasn’t stopped until 2004, when an interim analysis showed that the women receiving estrogen were more likely to have a stroke than those on the placebo. At that time, the women had been on estrogen for a median of 5.9 years.
When the study was stopped, the researchers asked the women if they would agree to be in a follow-up study, and 7,645 agreed. These women have now been followed for a median of 11.8 years. And as the researchers just reported, what they found took them by surprise. In terms of risk, the women who had taken estrogen were still more likely to have a stroke than those who had been on the placebo. But on the positive side, the women without a family history of breast cancer or benign breast disease also had less breast cancer!
How is this possible, after we’ve had so many studies that have shown that women with higher estrogen levels are at increased risk of developing breast cancer as well as observational studies that showed a higher breast cancer rate in women on estrogen alone? I think that part of the problem is that we’ve oversimplified how estrogen works. We’ve made women think estrogen is always bad. But the reality is that estrogen does not act like gasoline to the fire! In fact, back in the 1980s before we used chemotherapy as much as we do now, metastatic breast cancer was treated with DES, which is an estrogen, and Megace, which is a progestin and both were about as good as tamoxifen.
So, what is the story? The real answer is that we don’t know. One theory is that the cancer cells can adapt to lower levels of estrogen. So, if a woman has been treated for breast cancer by removing estrogen (having her ovaries out, for example) and then has a recurrence, you could then treat her with estrogen, because the cancer cells that had learned to grow when surrounded by low levels of estrogen might be overwhelmed if there were now high levels. In other words, once the cancer cells have adjusted to their environment, we need to make them uncomfortable, and stop growing, by changing up their local environment or neighborhood. This is supported by many doctor’s first-hand experience of seeing a woman whose tumor progresses on a high dose of estrogen stop growing or shrink after the estrogen is stopped.
Another theory is that Premarin, which is the drug the women in the estrogen alone arm of the study received, may itself be a factor. The drug is made from pregnant horse urine, and it contains a variety of estrogens, some of which may act more like tamoxifen and block the receptor. This would mean that we should not assume that bio-identical hormones would offer the same benefit.
Should we give women estrogen alone after menopause to prevent breast cancer? The answer is probably not. For one, this study showed that the decrease in cancers only occurred in the women who were at low risk of developing breast cancer to begin with. And for those who are high risk, tamoxifen and raloxifene are better choices.
However, it does mean that if you are not at high risk for breast cancer, have had a hysterectomy, and are looking to relieve some of your menopausal symptoms, you can use estrogen alone for up to five years knowing that it won’t increase your breast cancer risk. (Still, don’t forget that the estrogen alone study was found to increase the risk of stroke.)
Finally, all of us doctors, scientists, and women need to come to terms with the fact that the relationship between estrogen, menopause, and breast cancer is far from simple. Like all relationships . . . it’s complicated!