This is a long one, dear readers, so get yourselves a fresh cup of coffee.
Early this week, one of the presenters at this year’s San Antonio Breast Cancer Symposium made a media splash with the results of his research study, headlined, Estrogen Alone is Effective for Reducing Breast Cancer Risk. Dr. Joseph Ragaz, of the University of British Columbia, Vancouver, and his colleagues reviewed and reinterpreted data from the Women’s Health Initiative (WHI) hormone replacement therapy trials. Starting in 1991, the Women’s Health Initiative was a “15-year research program to address the most common causes of death, disability and poor quality of life in postmenopausal women — cardiovascular disease, cancer, and osteoporosis.” Many studies were compiled and published from this long-term initiative, including the one which brought about its early cessation. Among the various study trials conducted by the Womens’ Health Initiative, was a group of women who received either Premarin, a form of HRT that includes estrogen and progesterone, or a placebo. After five-and-a half years, the entire initiative was infamously terminated early because of an increase of breast cancer among the study participants who took Premarin. Because of the dramatic decrease in the use of this form of HRT which followed, and the subsequent drop in breast cancer incidence among menopausal women over the next several years, the conclusion was that HRT caused breast cancer. What Dr. Ragaz and his team did was to take another look at a different group of study participants, those who had taken manufactured estrogen alone. And he found that, in fact, these women had a lower incidence of breast cancer, leading to the conclusion that exogenous, or synthetic, estrogen (as opposed to endogenous, or natural, estrogen we produce in our bodies) may in fact prevent breast cancer.
Among my survivor friends and readers of my blog’s Facebook page, where I posted the above news, reaction understandably ranged from disbelief to cautious hope to utter confusion. My own response was a bit of cautious hope mixed with a large dose of the usual skepticism with which I regard any research study results that sound too good to be true, or which run counter to most of the research conclusions that have been previously published on a given topic. So, when I heard about Dr. Ragaz and his study, I tried, as is my wont, to find the full text of the study itself. But since it hasn’t been published in a journal yet, I did not succeed. Instead, I found an abstract of the study issued by the American Association for Cancer Research, which provided more details than the write-ups in the scientific and medical news media. And I read it word for word, and grew steadily underwhelmed and increasingly frustrated by the omission of several salient details. However, without the full study text, it is impossible to interpret the results in any truly meaningful way. When they are published, which I’m sure they will be soon, then we might be able to judge their full implications. Maybe.
In a nutshell, this is what I got out of the AACR press release. A woman who enters menopause with her uterus and ovaries intact, and who considers HRT, is not given estrogen alone, without progesterone, because the uterus needs progesterone to stay healthy. The women who took estrogen alone in Dr. Ragaz’s analysis were women who’d each had her uterus removed by surgical hysterectomy. So, they didn’t need the protection of progesterone. These were the women who had a significantly reduced breast cancer risk. One of the things I could not confirm was whether any of these women still had their ovaries, and whether all of them were in full and official menopause — meaning no menstruation for a full year — or if some of them were still pre-menopausal or perimenopausal.
In any event, for those of us who like to live dangerously and keep our reproductive organs, it’s back to the drawing board. In my cynical moments, I can foresee legions of that special group of over-eager oncologists, who equate natural estrogen with the plague, now recommending that the best thing we can all do for ourselves is to have everything yanked out when we’re 45, and take synthetic estrogen for the rest of our lives. Great. Then we can all have bilateral mastectomies, skip the reconstructive surgery, take up body building, and turn ourselves into men while we’re at it.
Many of you could write your own primer about breast cancer and hormone receptivity. If you are one of those readers, feel free to skip down to the next section of this post. Otherwise, bear with me as I provide a little crash course on the subject.
First, a little blog history. I have previously attempted in this blog to tackle, directly and indirectly, various aspects of the almighty hormone and its relationship to the roulette wheel of breast cancer prognostication. Here’s a couple of these posts:
Just yesterday, I listened to a radio interview with no less a person than Dr. Marissa Weiss, breast cancer oncologist and founder of breastcancer.org, who talked about her own recent treatment for early breast cancer and, among other things, outlined her perspective on the role of hormones in breast cancer incidence and prevention. Her treatment involved surgery, with no subsequent radiation or chemotherapy, because, as she explained, it was determined that the most effective follow-up treatment for her was long-term hormone therapy.
After we each hear the shocking, life-altering news that our biopsy is positive for breast cancer, one of the next things we discuss with our doctors is whether our tumor is ER or PR positive. Cancer tumors infamously behave like living entities unto themselves, a little like parasites, a little like germs, and as such, they do their best to keep themselves alive and growing. Many types of breast cancer cells have cell receptors that can pluck the estrogen (ER) or progesterone (PR) that circulates in our bodies in order to feed themselves. Pathologists count whether and how many of these types of cells are present in our excised tumor tissue, to help determine treatment strategies.
The big trade-off.
It’s logical that one way to get cancer cells to die and stop multiplying is to cut off their supply of these hormones. Two types of chemicals that can accomplish this are SERM’s and Aromatase Inhibitors. SERM’s are Selective Estrogen Receptor Modulators, which means that they act to prevent certain cells from being able to suck up estrogen molecules that may be in their vicinity. Tamoxifen is a SERM. So is Evista, a drug developed to treat osteoporosis, which has been found to have some preventative effects for breast cancer as well. SERM’s are clever chemicals. Because they do their work selectively, they are able to keep estrogen away from breast tissue while allowing it to be used to maintain our bone integrity. There are a lot of medicines that are clever in the way that SERM’s are, Selective Serotonin Reuptake Inhibitors being another group of such drugs that are effective in treating depression.
Tamoxifen was a tremendous breakthrough when it was first developed and maintained its place as the gold standard for tumor shrinkage and prevention for many years. Like any other drug, however, it has its side effects, because it’s not perfect in its cleverness. It would be perfect if it only targeted the estrogen receptors on the cancer cells themselves, but it’s not that smart. Estrogen is produced in many areas of the body, including our adrenal glands, our ovaries, our fat cells, our brains, and in men’s testicles. So, tamoxifen also keeps estrogen from being soaked up by these other cells that help keep us feeling hale and healthy. And this inhibition can thereby cause our brains to feel foggy, our moods to spiral like a roller coaster, our joints to ache, our temperature to rise, and our skin, hair and other tissue to dry up or behave abnormally. It can also lead to ovarian cysts and even cancer. [Tamoxifen side effects]
In recent years, another group of drugs has been developed to tackle breast cancer cells that use estrogen. These drugs are called Aromatase Inhibitors. Aromatase is an enzyme produced in our bodies which helps us manufacture estrogen. AI’s inhibit the action of aromatase, thereby preventing our bodies from making any estrogen. While there has been ample research demonstrating that this action gives AI’s a statistical edge over tamoxifen in preventing breast cancer recurrence, it can also lead to even fiercer incidence of many of the above side effects, plus another one, which is to promote bone thinning and osteoporosis. This latter side effect can lead to very serious consequences, especially in women at risk for developing bone metastases, and doctors have scrambled to counteract the problem by also prescribing bone-building drugs like Zometa, which is a bisphosphanate, a class of drugs that includes its more well-known member, Fosamax. [See Bare Bones & Hormones, II for a further discussion of osteoporosis.]
Estrogen, Friend or Foe Revisited
And now for a personal announcement of one of my great pet-peeves when it comes to research and the media: spin! It’s in the nature of media that we receive news about important issues in the form of sound bytes and hyperbole. If we pick which media outlets we read or listen to, we can acquaint ourselves with more in-depth information, but it can take a long time, sometimes days, sometimes months or years, before we actually get the whole story. And, conspiracy theorizing aside, sometimes we never get the whole story. Physicians and other health care clinicians who are doing their level best to stay informed about relevant research are not immune to this problem. While we may have access to the full text of research studies that are published in peer-review journals, we may not, despite our professional education, be as adept as we could be at interpreting study results. I have said elsewhere that one of the most edifying classes I ever took was a statistics class that was taught by one of the statisticians involved with the Framingham Heart Study, another ground-breaking longitudinal study initiative. From her, I learned not only what tools are used to manipulate and even skew research data, but to maintain therefore a healthy dollop of skepticism when contemplating the published results of any research study. Even though peer-review is supposed to weed out imperfect and poorly-designed studies before publication, a lot of dross can sneak through.
Just this past May, the Journal of the American Medical Association published some research about research. Dr. Isabelle Boutron and her team examined the occurrence of spin in the interpretation and reporting of study results. Study authors, she found, “have many opportunities to consciously or subconsciously shape the impression of their results for readers, that is, to add “spin” to their scientific report. Spin can be defined as specific reporting that could distort the interpretation of results and mislead readers. The use of spin in scientific writing can result from ignorance of the scientific issue, unconscious bias, or willful intent to deceive.” Well, isn’t that special??
Intentional or unwitting, spun research finds its way into the media, which then frequently adds more, even if it’s only by virtue of inadequate or incomplete reportage. There also seems to be a proportional relationship between the newsworthiness of the research topic and the amount of media spin heaped upon it. So, is it any wonder that Dr. Ragaz — remember him?? — and his research would be spun to a degree that has made many of us dizzy?
The degree of our vertigo may only reflect the complexity of the subject. Just last year, the National Comprehensive Cancer Network acknowledged this complexity by publishing its NCCN Task Force Report: Estrogen Receptor and Progesterone Receptor Testing in Breast Cancer by Immunohistochemistry, in PDF form, in order to provide oncologists and cancer clinicians an opportunity to wade through and understand the often conflicting research evidence upon which they need to make decisions about hormones and breast cancer. If you had read this report before September 14th of this year, you could have taken the test at the end and submitted it to the NCCN to receive continuing ed credit. Presumably, the NCCN will feel it incumbent to publish a revised version, if it hasn’t already. In any event, the conclusion of the Report is that the determination of hormone-receptivity in breast cancer tumors is still a useful tool in planning the treatment and prevention of breast cancer. But that the standard lab test for ER/PR receptivity can yield high false-negative results, necessitating that clinical expertise in the laboratory be diligently monitored. One can only hope that the research upon which this report is based was itself devoid of spin.
There are many more implications to this entire discussion that I can possibly get into in this already over-long post. Back to Dr. Ragaz. I certainly don’t intend to cast aspersions upon him or his study. Indeed, Dr. Ragaz himself said in the AACR press release that, “further research is warranted to […] understand the estrogen mechanisms that support the prevention of human breast cancer.” Here, here. In the meantime, we can only wait and hope.
Please click on the post title or the comment link below to post a response.