You can't always get what you want
But if you try sometimes you just might find
You get what you need
--Rolling Stones
For years, we have had many studies that implicated hormone replacement therapy (HRT) with estrogens in increasing the risk of breast cancer in post-menopausal women who took them for relief of menopausal symptoms and other medical problems facing older women.
At the same time, there was a parallel study underway which was evaluating the use of estrogen treatment alone for women who had a prior hysterectomy (combination therapy is used in women who still have their uterus in place, since the progestin has been shown to decrease the risk of uterine cancer which occurs when estrogen alone is given to women with an intact uterus. If the uterus has been removed, then there is no need to give the progestin).
But the investigators noted that there did not appear to be an increased risk of breast cancer in the women who took only estrogens compared to those who took placebos. And, in fact, for some women the risk of breast cancer may have actually been decreased.
There has been substantial criticism of the WHI study for a number of reasons. The practical problem has been that, for many women, hormonal replacement therapy is critical for their general sense of well-being. Doctors and patients alike are confronted with the dilemma of prescribing and/or taking a medication that may be helpful, but has many serious and undesirable side effects.
Over the past couple of years, some researchers have begun reexamining the data, and doctors and patients alike now understand that hormonal therapy should be used at the lowest dose for the shortest time to control menopausal symptoms, and that women need to understand the risks and benefits of the treatment.
The short, the general answer is: no. And that was a surprise.
The study, in brief, recruited almost 11,000 women from ages 50 to 79 who had a prior hysterectomy. One half of the women were assigned to treatment with low dose estrogens, and the other half were given a dummy pill, or placebo.
The women were followed carefully, including scheduled physical exams and mammography. On February 29, 2004 the participants were instructed to stop taking their medications because of the increased stroke risk noted above. 292 women had developed some form of breast cancer by that time.
What was interesting to me was that slightly over half of the women in both groups (including those on the placebo) had stopped their medications for the most part because of perceived or actual side effects caused by the medication (that means that almost 1 out of 5 women taking the dummy pill thought they had side effects from the estrogen, which in fact they were not taking; some of these women may have also had an unsatisfactory response to the placebo, which might have explained the reason they stopped it).
When the entire group of women treated with estrogens and placebos was evaluated, there was no increased risk of breast cancer in the group treated with estrogens compared to the group that received a placebo. There was actually a slight decrease in the number of cancers in the women taking estrogen, and when examined further, most of this decrease was in women with early stage cancers.
Ductal carcinoma in situ (DCIS), a non-invasive and very early form of breast cancer, was also decreased in the women taking estrogen, but lobular carcinoma in situ (LCIS), another less common form of early breast cancer, was not. The implication here is that estrogens may decrease the risk of DCIS which is hormone sensitive, compared to LCIS which is not hormone sensitive.
Then there is the confounding fact noted above that over half of the women who were assigned to estrogen HRT stopped taking their drugs sometime during the study period.
When we normally evaluate research trials, we do it on a basis of what is called “intent to treat analysis.” What this means is that once you are assigned to a treatment group, you are considered part of that treatment group, even if you don’t get the treatment or withdraw from the treatment program at any time.
When the investigators took a look at women who actually took the estrogen treatment for the entire time of the study, and included data for women who stopped taking their estrogen up to six months after they discontinued the medication, they found something very interesting. The estrogen actually reduced the risk of getting breast cancer by 33%!
This is the finding that was not expected, and was very surprising.
The investigators also found that in some groups of women, namely those with a lower
risk score for getting breast cancer, those with no first-degree relative (mother, daughter, sister) with breast cancer, and those who have no history of benign breast disease, there also appeared to be a protective effect with estrogens.
In the post-menopausal women who had no prior hormone use, estrogen alone appeared to decrease their risk of getting breast cancer. This was not the case if the women had previously used hormone therapy prior to entering the study.
Finally, one interesting side note to this study is that the investigators found no evidence that hormone therapy increased the risk of breast cancer more for thinner women than overweight or obese women,
in contrast to the report I wrote yesterday.
Given the fact this is a randomized controlled trial, which is generally considered the highest quality of medical evidence, it appears that the use of estrogens alone in post-menopausal women who have had a hysterectomy not only does not increase the risk of breast cancer, but it may actually decrease the risk in certain circumstances.
There is a price to be paid, however, and that is the increased risk of stroke which was reported previously from this study. And, women who took estrogen had an increase of “call backs” for short-term repeat mammograms because of suspicious findings compared to women who were taking the placebo pills. There was also an increase in the number of breast biopsies in the treated women beginning after 2 years of estrogen HRT.
How does all this fit together with what we currently know about hormonal influences on breast cancer development, prevention and treatment?
I can still recall a discussion with one of my medical school professors around 1970 (he was a surgical oncologist at the University of Pennsylvania) regarding estrogens and breast cancer.
At that time, we faced many of the same questions being asked today regarding the role of estrogens and breast cancer. We didn’t have tamoxifen at that time, and high dose estrogen therapy was a common form of endocrine therapy that we used to treat women with recurrent disease.
And it worked. For some women it worked well for many years. And, when we would stop the therapy because the cancer was progressing, we would occasionally observe the cancer would regress as well. By the same token, if we removed the ovaries of a young woman with metastatic disease, the cancer would regress. Different approaches in different circumstances, and both frequently brought positive results.
The essence of the professor’s comment was that it was the changes in the hormonal environment that explained the role of estrogen with regard to breast cancer. Change the environment by adding or removing estrogen (in those days, by doing an oophorectomy in pre-menopausal or peri-menopausal women), and you can benefit women with breast cancer.
Low and behold, in 2006 after many years of study in a detailed randomized trial, the investigators in this study came to the same conclusion. It is the change in the hormonal environment that explains the benefits of various drugs in preventing recurrent breast cancer, or treating recurrence when it happens. And, as demonstrated by this study, increase the amount of estrogen with medications, and the risk can be reduced.
As the authors note, “These data are consistent with breast cancer cells being susceptible to estrogen fluctuations either above or below that tolerated by normal breast glandular tissues.”
My professor may have been way ahead of his time. Over the years, a substantial amount of expert medical opinion was generated that suggested estrogens were plain bad for women because they increased their risk of breast cancer. Now, the experts are saying change the level in the blood, up or down, and you decrease the risk.
We must never forget that these medications may increase the risk of stroke. But for many women who have had a hysterectomy and who suffer from severe menopausal symptoms, they may now have one less concern to worry about if they make the informed decision to initiate short term hormonal therapy with estrogens.
Which brings me back to the Rolling Stones: It has taken a study of this size and this duration to prove that you don’t always find what you want, but you may get what you need.
Now, maybe there is some satisfaction for those who have questioned the estrogen/breast cancer hypothesis, and comfort for women who may benefit from this medication.
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