Breast cancer, Tamoxifen, Estrogen

Estrogen Vindication, Part 3: The Tamoxifen Connection and Hormone Therapy

By Devaki Lindsey Berkson, DC

All three parts of this article are posted with appendices and references online at www.townsendletter.com.

Medical practitioners thought tamoxifen worked because it was an anti-estrogen. But tamoxifen works in a wide variety of anti-cancer mechanisms, not just by tamping down estrogen. In fact, tamoxifen can often raise estrogen levels. Of the 20 studies between 1980 and 2008 that showed estrogen was not only safe for breast cancer patients but was also protective, only the HABITS study found an increased risk of recurrence in breast cancer patients on HRT. This risk only occurred if the women were on tamoxifen, which “blocked” the action of estrogen.

Tamoxifen

A major argument that estrogen causes or promotes breast cancer is that tamoxifen helps to reduce or retard the growth of ER positive breast cancer by competitively blocking the binding of estrogen to the estrogen receptor on breast cancer cells. Several lines of research, according to correspondence with Dr. Avrum Bluming, a California oncologist and co-author of Estrogen Matters, dispute this belief.

• When tamoxifen is given to premenopausal women, their natural estrogen levels increase up to five-fold.

• This rise in estrogen should block any competitive binding of tamoxifen, yet it doesn’t. Tamoxifen’s protective effect against breast cancer works as well in premenopausal as postmenopausal women.

• Approximately 40% of ER+ patients fail to respond to tamoxifen.

• Cancer is “growth out of control” worsened by “growth factors.” Tamoxifen inhibits growth factor stimulatory effects involved in breast cancer even in the absence of estrogen, pointing a finger at initiators of breast cancer other than estrogen.

• Estrogen added to tamoxifen can help make tamoxifen work better. After treatment with tamoxifen, some breast cancer cells acquire the ability to proliferate. These cells become “resistant” to the protective action of tamoxifen. But when low doses of estrogen are then given, this helps cancer cells die (apoptosis). Estrogen therapy helps breast cancer cells overcome tamoxifen resistance by adding estrogen.

• Tamoxifen has also been shown to have a therapeutic effect on ER negative breast cancer cells, both in laboratory studies and in human patients, pointing to other cancer protective effects of tamoxifen than affecting estrogen receptors.

In summary, tamoxifen works through a protective number of portals that have nothing to do with the estrogen receptors. Exactly how tamoxifen protects against breast cancer isn’t completely known. But it’s inaccurate to say tamoxifen mainly works as an anti-estrogen, and thus estrogen is the main driver of breast cancer.

In 1980, Torbin Palshof from Copenhagen, Denmark, published the results of a study comparing adjuvant estrogen with adjuvant tamoxifen in the management of patients with treated breast cancer. From 1975 to 1978, 387 patients who were admitted to three breast cancer clinics in Copenhagen entered the study. Subjects were women younger than 70 years of age, with T1 to T4, N0 to N3, M0 breast cancers. There could be no history of previous or concomitant malignancy. Treatment involved simple mastectomy without routine axillary dissection and postoperative irradiation. Two weeks after surgery, patients were randomized to double-blind endocrine therapy for two years.

After a median duration of observation of three years, 91 recurrences were observed.

The investigators concluded that despite the limited number of patients and time of observation, a marked effect of tamoxifen on recurrence rate was observed in postmenopausal patients as well as:

• An even higher reduction in the rate of recurrence was achieved when estrogen was added to the tamoxifen therapy.

• ER assay positivity did not correlate adversely with prognosis among patients treated with estrogen.

• There were no recurrences among the ER-positive patients who received adjuvant estrogen therapy.

DES vs. Tamoxifen

Dr. JoAnn Manson, one of the lead researchers on the WHI, has come around to looking at estrogen in a new way. Dr. Manson said the breast protective effects seen in the estrogen-only arm in the WHI was probably due to estrogen’s alter ego ability to act like tamoxifen. But tamoxifen is an anti-estrogen. How can an estrogen act like an anti-estrogen? Oy veh.

To answer this question, we have to go back to DES (diethylstilbestrol), the most powerful synthetic and pharmaceutical estrogen ever invented, fifty times more powerful than our own naturally made estrogen. Sir Charles Dodds, the same doctor and scientist who invented plastics (which are also estrogenic), created it.

DES was given to many millions of pregnant women for 36 years. It was outlawed in 1971 when it was finally proven to be the most powerful endocrine-disrupting and cancer-causing drug even invented. It is now labeled a Class-1 carcinogen, never to be used during pregnancy. But it was the preferred method of treating metastatic breast cancer in the 1960s and 1970s. Metastatic cancer is when cancer cells have spread from the initial primary tumor out into other parts of the body. This is diagnosed as a life-threatening stage 4 cancer.

How can that be? The original studies showed it shrank tumors in many women with breast cancer. DES was so effective that it was described as making tumors dissolve in 30% of women treated with it.

Craig Jordan, PhD, (credited with getting tamoxifen recognized as a breast cancer treatment and now working on hormone therapies for breast cancer patients so they don’t miss out on a higher quality of life), said, “Large tumors would just melt away, but you needed sledgehammer doses to do it—50 times more than a woman would normally have in her body.” Thus, DES was used until tamoxifen was found to work as well—not better, but with less adverse effects; DES was being linked to other nasty things. When the Mayo Clinic’s 1981 head-to-head comparison of tamoxifen with DES showed similar response rates—and far fewer adverse responses in tamoxifen users—breast oncologists switched en masse to the newer agent. By that time, DES had also gained a reputation for producing a rare vaginal tumor cancer in the daughters of women who used DES to sustain their pregnancy.

The longer-term follow-up studies were rather mind-bending. The Mayo Clinic ran a follow-up analysis of one of its older studies comparing DES treatment to tamoxifen treatment on breast cancer patients. This follow-up study showed that some breast cancer patients treated with DES actually lived longer compared to those treated with tamoxifen. How? The Mayo Clinic researchers were able to show that estrogens, given at the right time (and the “timing” is a big part of this deal) can deliver signals to breast cancer cells to instruct them to “die.” This is exactly what Dr. Jordan had been talking about.

Sometimes robust estrogens, like DES, can make breast cancer cells that were not responsive to drugs like tamoxifen start to respond. A Norwegian study published in 2001 showed that half of 32 breast cancer patients who had become resistant to tamoxifen or other endocrine therapies, once treated with high-dose DES then became responsive to the endocrine therapies. This meant that a woman who had become non-responsive to tamoxifen or an anti-aromatase inhibitor could be rebooted to once again respond to them by the use of a powerful estrogen.

The natural next question was: Could a woman’s own home-grown estrogen be protective like DES, too? The answer was yes.

Matthew Ellis, MD, PhD, director of the breast cancer program at Washington University in St. Louis, answered this question and published his results. Dr. Ellis showed that giving both high-dose natural estrogen (30 mg/day) or low-dose estrogen (6 mg/day) to women with metastatic breast cancer, who had failed aromatase inhibitors, helped effectively kill breast cancer cells. These women were given oral estradiol, identical to the active form of estrogen inside a women’s body. The estradiol shrank tumors in 30% of the women. The adverse side effects from the estrogen therapy, especially the lower dose, were less toxic than from chemo, and certainly less costly.

It always boggles my mind when some women come to me after working with other doctors trying to find the right HRT dosage but getting no or bad results on high dosages of estrogen. Why? You just learned. High dosages of estrogen “turn off” the estrogen receptor. They are not to be regularly used as hormone therapies, but rather cancer therapies.

Interest in DES rekindled following the 1999 long-term follow-up of the original Mayo Clinic study that showed patients treated with DES had increased survival compared to tamoxifen-treated patients. Then, in 2001, a Norwegian study of 32 breast cancer patients who had become resistant to endocrine therapy showed that almost half of the participants responded to high-dose DES.

We are not recommending DES to treat cancer but rather showing that estrogenic compounds can be cancer killing and protective.

Breast Cancer Risk and Hormone Therapy: The Science

In 1990, Darcey Spicer from the Kenneth Norris Jr. Comprehensive Cancer Center, USC Medical School, Los Angeles, said: “While there is a general belief that hormone replacement therapy will increase the risk of recurrence of breast cancer, there are, in fact, no data to support this notion.”

A very thorough review of the research up to 1994 from cancer doctors at Rush-Presbyterian-St. Luke’s Medical Center in Chicago, and colleagues in the Breast Cancer Committees of the Eastern Cooperative Oncology group, wrote: “A major concern over prescribing ERT for women with a history of breast cancer is that dormant tumor cells might be activated. There is surprisingly little clinical information to substantiate such concern.”

Up to 20 scientific human studies published in peer review, most of them taking place at prestigious cancer institutes, have shown that breast cancer patients given prescriptive estrogen therapy (most of the time as Premarin or estradiol), in studies lasting an average of two to five years, had the following:

• Statistically significant “less” risk of breast cancer recurrence.

• Quite a number of these studies also demonstrated less risk of death from breast cancers.

• In a number of these studies, breast cancer patients had less risk of dying prematurely from a wide range of non-cancer issues, called “all-cause mortality.” (See the Appendix for details on the human trials.)

Yet many doctors are still reluctant to recommend hormonal therapies, especially to high-risk women—such as those with breast cancer or close family members with history of breast cancer.

Pelin Batur, MD, an internist at the Cleveland Clinic, published a review of 15 studies totaling 1,416 breast cancer survivors using hormonal therapies (most started two to four years post diagnosis) compared to 1,998 not using HRT. The women were followed for three years and findings showed the following:

• Women on hormones had a 10% reduced risk of recurrence of breast cancer.

• There was a slightly significant decreased risk of mortality from cancer and all-causes at a seven-year follow-up.

• Protection of estrogen continues after stopping therapies, as was stated in the re-analysis 19-year follow-up study headed by Dr. Chlebowski.

The Stockholm study was similar in size to the HABITS study. This was a prospective and randomized trial, with 188 women randomized to HRT and 190 not given hormones. There was no difference in the rate of new breast cancers, which held up over a 10-year follow-up.

A variety of scientists like Dr. LaCroix started to refer to the WHI as the first randomized trial to give evidence that if you give healthy women estrogen therapy within 10 years from the initiation of their menopause, or to post-menopausal women without a uterus, this reduced the risk of getting breast cancer.

Two other researchers agreed. Dr. Craig Jordan, the estrogen and cancer scientist who put tamoxifen on the cancer map, and Leslie Ford, MD, associate director for clinic research at the National Cancer Institute’s Division of Cancer Prevention, wrote an article called “Clinical Paradoxical Effect of Estrogen on Breast Cancer Risk.” This research showed that sometimes estrogens not only prevent breast cancer, they also cause breast cancer cells to die. The ability of estrogen to do this seems to be activated by a period of lack of estrogen exposure (menopause or anti-estrogen therapy) and then re-exposure to estrogen. The absence of estrogen and then re-exposure retriggers breast cancer cells to die in some women. Dr. Jordan commented on this rebooting of response to endocrine therapies by estrogen: “After five years of anti-estrogen therapy, a switch takes place inside breast cancer cells which makes them resistant to these anti-estrogen agents. When estrogen is then used, it triggers breast cancer cell death, not growth.”

Dr. Jordan is a big fan of estrogen. Presently he is a cancer director at the renowned MD Anderson Medical Center, researching safe estrogen therapies for breast cancer patients (meaning patentable).

So, research is showing that estrogens help prevent breast cancer in some women, help eradicate sleeping breast cancer cells, and help some women become responsive once again to breast cancer therapy that had stopped working.

The Benefits of Estrogen

By the early 1990s, researchers had summarized the benefits of estrogen therapies and documented them in the medical literature.

Estrogen controls menopausal symptoms.

If given early, it helps prevent strokes and bone loss and fractures for many years, even after discontinuation.

Estrogen significantly reduces the risk of heart disease,

Significantly reduces the risk of fracture (Framingham study showed a 50% drop in osteoporosis-hip fracture),

Significantly decreases risk colorectal cancer, and

Significantly reduces the risk of cognitive decline and Alzheimer’s disease. The Cache County studies (which had the bad karma to come out only months after the WHI and was not noticed) showed that if women had been on 10 years of estrogen therapies, they had a 30 to 50% reduction in incidence of AD.

Estrogen has now been found to have hundreds of other pleotropic effects, such as helping epigenetics and protecting mitochondria (our energy organelles) from damage, so it helps in maintaining the energy production needed for a positive lifestyle effort.

Estrogen helps maintain volume, plasticity, and protection from injury of the hippocampus, where memories live in the brain.

Now we see that estrogen protects against breast cancer in a woman who has not yet had it and even in those that already have. To age without individualized hormonal support is to age at the speed of an accelerating bullet, while hormonal therapies allow us to live younger longer and healthier.

Vindication

Let 2020 be the year that estrogen is vindicated.

I had breast cancer 26 years ago and have been on estrogen and other hormone therapies for 21 years now. I would not be the person, physician, or author that I am if I were not on hormones. I am passionate about passing this information forward.

I get email after email from women all over the world saying that their doctor will not prescribe estrogen for them. I hope this article makes it possible for more women to enjoy the benefits of this hormone.

This article is written for women to hand to their doctors or for doctors to feel vindicated (and safe) about prescribing hormones.

All three parts of this article are posted with appendices and references online at www.townsendletter.com.