Femara, Tamoxifen, and Other Topics: Breast Cancer News and Reviews

Breast Cancer…Questions, Answers, and Recent Research

by John R. Lee, M.D.

Breast Cancer and Femara

Q: I am 61 years of age. I had surgery for breast cancer 5 years ago, followed by radiation treatments. My oncologist put me on tamoxifen for 5 years. I had many side effects including violent headaches, high glucose levels, dizziness, weight gain, etc. Now I am on Femara, and the side effects are as bad as with tamoxifen. I read two of your books and immediately started the progesterone cream. Should I continue to take the Femara in parallel with the progesterone?

A: Femara (letrozole) is an aromatase inhibitor, which primarily blocks the conversion of androgens to estrogens. As I've explained in my books, the ovaries and adrenal glands of postmenopausal women produce the hormone androstenedione, which is converted to estrogen in fat cells by the aromatase enzyme. This is why many postmenopausal women, particularly those who carry some fat, don't need supplemental estrogen.

Letrozole inhibits the aromatase, thereby inhibiting this avenue of estrogen production. Letrozole appears to work about as well as tamoxifen for treating breast cancer, at least in the short term, but like tamoxifen it s only one piece of the breast cancer puzzle. It doesn't address the underlying issues of DNA damage and lack of progesterone and, as you say, like tamoxifen it has a lot of undesirable side effects. In my opinion, progesterone alone opposes the undesirable effects of estrogen very effectively, and if onocologists understood this they would be prescribing progesterone for their breast cancer patients instead of tamoxifen and Femara.

Bone Density and the Risk of Breast Cancer

Q: What did you think of that article in the Journal of the National Cancer Institute stating that women with the greatest bone density had the highest risk factor for developing breast cancer? I would expect that their bones are dense because of progesterone activity. Thus I would have expected that their risk of estrogen dominance is lower. What do you make of the study?

A: This effect is probably due to the fact that the more fat a woman has on her body, the more estrogen she makes. Progesterone stimulates bone building, and estrogen slows bone loss, so they work together. Women who have more unopposed estrogen will have less bone loss, but their risk of breast cancer will increase. The solution to this is of course to use progesterone cream to balance the estrogen effect and reduce or eliminate the risk of breast cancer. And, it's always healthier to lose that extra weight if you are obese.

The BRCA2 Gene and Progesterone

There’s exciting news on the breast cancer front that I wanted to share with you this month, because it sheds more light on the type of breast cancer associated with mutations in the BRCA2 genes. In our book, What Your Doctor May Not Tell You About Breast Cancer (written with Dr. David Zava and newsletter editor Virginia Hopkins) we didn’t say much about BRCA2 because we weren’t entirely sure how closely its underlying mechanisms were related to other types of breast cancer. These genetic defects tend to run in families, and at least double the risk of breast cancer.

Now there’s news from researchers at the Netherlands Cancer Institute, published in the November issue of Nature Genetics, that loss of the tumor suppressor gene p53 plays a pivotal role in BRCA2 cancer. Researchers generated mice with mutations in BRCA2, p53 or both. Those mice with mutations in both genes developed frequent mammary tumors, but those with mutations in BRCA2 only developed them much later.

Those of you who have read my books and newsletters know that progesterone specifically up-regulates or activates the p53 gene, which is one of the ways that it helps prevent cancer. This research suggests that at least one of the underlying mechanisms of BRCA2 breast cancer is likely to be progesterone deficiency.

New Research on Progesterone and Its Effects on Cells

Lin VC, Eng AS, Effect of progesterone on the invasive properties and tumor growth of progesterone receptor-transfected breast cancer cells MDA-MB-231, Clin Cancer Res 2001 Sep;7(9):2880-6.

Lin, Eng et al report that previous studies showed that progesterone inhibits cell growth and induces remarkable focal adhesions in cells. Their study showed that progesterone causes increased resistance to trypsin digestion and increased cell attachment to extracellular matrix proteins.

Their study also showed that progesterone strongly down-regulated gene expression of urokinase plaminogen activator. These and other findings lead to the conclusion that progesterone protects against estrogen-induced breast cancer. In those cases of progesterone receptor-negative cells, they postulate that activation of progesterone-mediated pathways may achieve similar therapeutic effects.

This study adds to the accumulating evidence that progesterone protects against breast cancer.

New Research on Tamoxifen and Breast Cancer

The Fred Hutchinson Cancer Center released study results in the Journal of the National Cancer Institute (July 2001) showing that women taking tamoxifen for treatment of first breast cancer are more likely to develop estrogen receptor-negative tumors in the other breast. These tumors are particularly aggressive and difficult to treat with conventional medicine.

The study looked at 9,000 women who survived breast cancer, about half of whom were being treated with tamoxifen. Some 27 percent of the tamoxifen group had estrogen receptor-negative tumors in the other breast, while only 4 percent of the tamoxifen-free group developed estrogen-negative tumors.

It’s frustrating to me that this huge study didn’t look more closely at the relationship between progesterone receptors and tamoxifen. Estrogen and progesterone are dependent upon each other for keeping their respective receptors active. In other words, estrogen is needed to maintain progesterone receptors, and progesterone is needed to maintain estrogen receptors. Thus, a drug like tamoxifen that blocks estrogen would be likely to severely down-regulate progesterone receptors, which would in turn down-regulate estrogen receptors, which would of course create a hormone receptor-negative milieu in the breasts.

The researchers said that this study should not discourage women from using tamoxifen, but to me it’s just one more reason to run from it. Tamoxifen also increases the risk of uterine cancer, blood clots and eye problems, and its benefits don’t last beyond about three to five years.

You can read more details about hormone receptors and tamoxifen in our book, What Your Doctor May Not Tell You About Breast Cancer.

Eating Meat and Eggs Does Not Increase Breast Cancer Risk

During the 90s, much ado was made about a possible link between eating saturated fat and increased breast cancer risk. In most of the research, consumption of hydrogenated oils (trans fatty acids) was never accounted for or if it was, it was not published. As time passed, this link was discounted, primarily because of the weakness of the studies, so I was glad to see evidence showing that breast cancer is not associated with meat or egg consumption.

Eggs are one of the healthiest foods you can eat, and hormone-free meat supplies valuable high quality protein. The researchers are associated with the famous Nurse's Health Study in Boston, and examined data on diet and breast cancer. The 88,647 women included in the data had been followed for 18 years, with 5 assessments of diet and nutrient intake. During the follow-up period, 4,107 women developed invasive breast cancer. Those who ate the most animal protein had a two percent higher risk of breast cancer, while those who ate the most red meat had a 7 percent lower risk of breast cancer, and those who ate the most meat of all kinds had an 11 percent lower risk of breast cancer.

Lobular Breast Cancer Rates Skyrocketing

The incidence of lobular breast cancer more than doubled between 1987 and 1999, according to a study from the Fred Hutchinson Cancer Research Center in Seattle. The incidence of invasive ductal carcinoma, which is more common, remained stable during the same time period, and the rate of mixed ductal-lobular carcinoma nearly doubled. Lobular carcinoma is the type of breast cancer most frequently associated with the use of PremPro.

Pregnancy Hormones and Breast Cancer

Critique of the report in SCIENCE NEWS, March 6, 1999, concerning a rat test by S. Nandi in the Proceedings of the National Academy of Sciences, March 2.

Hypothesis:
Pregnancy early in adulthood appears to reduce a woman's lifelong risk of breast cancer. If so, could short-term hormonal supplementation that simulates pregnancy do the same?

The theory is that breasts not fully matured are more vulnerable to breast cancer. During pregnancy, hormone levels rise and complete the maturation of breast structures known as terminal end buds. This might be the mechanism for breast cancer protection occurs.

Test Design
The rats chosen for the test were of a special strain. In these rats, exposure to a potent carcinogen at age 7-weeks normally resulted in a 90-100% incidence of breast cancer within 9 months. In this test, two weeks after exposure to the carcinogen, each rat was treated with one of several agents that cause the maturation (or differentiation) of breast duct terminal end buds. Some rats were given the drug perphenazine, others were given capsule implants that dispensed estradiol (without estriol), progesterone, or both for 3 weeks in doses that simulated pregnancy. Outcome was determined by the incidence of breast cancer 9 months later.

Comment
This test used estradiol and not estriol. In humans, estriol concentrations are higher during pregnancy than at any other time in a woman's life. Also, the nature of this special strain of rats may not be similar to any human situation. When interviewed by phone, the author conceded this point, stating that this test may have no relevance to humans. He also indicated that previous tests showed that progesterone provided excellent protection against breast cancer in similar rats if the progesterone were given prior to the exposure to the carcinogen. In the present test, the hormones were given after the carcinogen was administered.

Results
In rats given perphenazine (a drug that promotes breast lobule development), breast cancer incidence reduced from 90% to just under 75%.

In rats given both estrogen and progesterone, breast cancer incidence plummeted to 4-11%.

Comment
Lobule development (end-bud differentiation) is probably not the sole or main reason for the hormones breast cancer protection.

When only estrogen was given, breast cancer incidence rose to 38%.

When only progesterone was given (two weeks after exposure to the carcinogen), breast cancer incidence rose to 100% and the rats developed multiple breast tumors, more than that found in untreated rats.

Comment
Before any conclusion can be drawn from these results, it is important to consider the following facts concerning hormone balance. When the ratio of estrogen:progesterone tilts in favor of estrogen, estrogen receptors are down-regulated and progesterone receptors increase in number. These rats were not deficient in progesterone, as happens often in humans during the premenopausal years. Therefore, the increase in progesterone receptors may well have enhanced the available progesterone effect. When the estrogen:progesterone ratio tilts excessively in favor of progesterone, progesterone receptors are down-regulated and estrogen receptor sensitivity is up-regulated. This is seen repeatedly in perimenopausal women with hot flushes that respond well to normal physiologic doses of progesterone. Administration of progesterone up-regulates estrogen receptors and the hot flushes are controlled by the resumption of estrogen effect despite no increase in estrogen concentrations. In this test by Nandi, the rats were not deficient in estrogen, they were merely overdosed with progesterone. This is not what happens in human pregnancy, or in good clinical practice.

The concept of balance is as important (or more so) than the concentration of any individual factor alone. In humans, tests of hormone concentrations in breast tissue and the cancer cell receptor status clearly show that almost all cases of breast cancer demonstrate a high estrogen:progesterone ratio. In some cases, the women had received excessive supplemental estrogen, and, in others, their progesterone levels were abnormally low.

Rats are convenient test animals but their relevance to humans is often not clear. This test showed that, in these rodents, pregnancy levels of estrogen and progesterone together did, indeed, provide protection against one particular carcinogen. That is the good news. The information that progesterone given before the exposure to the carcinogen provided good protection against its carcinogenic effect is also good news. Individual carcinogens differ in their mechanism of action. It is not clear from this report that the carcinogen used is one to which humans are normally exposed. The progesterone excess, as created in this test, is not one that occurs normally in humans. Further, it is not one that I would recommend in supplementing progesterone to women. The point of supplementing hormones is to create hormone balance.

Whatever implications one might draw from this test may be more relevant to the practice of some physicians who prescribe abnormally large doses of progesterone, far exceeding progesterone levels of normal ovulating women. Higher dosing schedules may be necessary during early pregnancy in women with luteal phase failure but, there again, the purpose is to create the balance that should exist between estrogen and progesterone of the normal pregnancy state.

Critique of a Study About HRT and Breast Cancer

By John R. Lee, M.D.

"Hormone replacement therapy and risk of breast cancer with favorable histology,"
Gapstur SM, Morrow M, Sellers T, JAMA 9 June 1999; 281: 2091-2097

According to recent news reports, this study, sponsored by the Iowa Women's Health Study, showed that most breast cancer was not associated with HRT use. This comes as some surprise since other studies have implicated HRT with an increased risk of breast cancer. As the authors report, a combined analysis of 51 previous studies show a 35% increase in breast cancer risk from >5 years use of HRT. It is important, therefore, to read the present study with care.

In this study, breast cancer was divided into 20 cell types and then further divided into four groups; 1) ductal cell type in situ, 2) invasive – favorable histologic subtype, 3) invasive – ductal and/or lobular carcinoma, and 4) other types excluded from analysis. This last category included lobular carcinoma in situ, inflammatory carcinoma, malignant neoplasm, adenocarcinoma, schirrous adenocarcinoma, unspecified carcinoma, and other rare types, comprising 99 cases out of the total of 1,520 breast cancer cases occurring in the at-risk cohort of 37,105 women.

In all, 4% of the study population developed breast cancer. 77% of the cancers were invasive lobular or ductal tumors, 12% were ductal carcinoma in situ, and 5% were invasive carcinoma with favorable histology. The remaining 7% were excluded from analysis.

Of the three major categories analyzed, ductal carcinoma in situ dominated group 1 (121 of 168 cancers), mucinous adenocarcinoma dominated group 2 (37 of 82 cancers), and infiltrating ductal carcinoma dominated group 3 (999 of 1,164 cancers). The risk of breast cancer relative to HRT was most obvious in group 2, the so-called "favorable" group of invasive histologic cancers.

When analyzed in terms of past versus current HRT use, the relative risk of cancer follows:

According to these results, one might conclude that short-term use of HRT was much more dangerous than longer term HRT in Group 2 cancers, and possibly also in group 3 cancers. However, according to the graph figure on page 2096, the RR’s for current use in Group 2 cancers is reversed, showing the relative risk in group 2 was highest for >5 years use of HRT, and intermediate for <5 years use of HRT. Perhaps there is a misprint in table 4. The written text on page 2096 iterates the table RR’s.

There are a number of weaknesses in this study. HRT is not defined and there may well be difference in cancer risk among different HRT formulations. For example, estradiol may be more dangerous than estrone and horse estrogens (such as Premarin); or, some progestins may be protective and others not so.

The hypothesis that different cancer cell types connote different cancer risk may be invalid. The question is – does cell type truly predict prognosis? If cancer development depends on gene mutation, cell type, per se, may have little or nothing to do with it. Further, there may well be other factors such as diet (use of protective phytoestrogen-rich food, or use of transfatty acids, or lack of certain essential fatty acids or amino acids, etc) or stress.

The dominance of ductal carcinoma in situ may mask the estrogen-induced cancer potential of the other morphologic types in Group 1. According to Lancet, carcinoma is an oxymoron since it is well known that the majority of carcinoma in situ patients never progress to true carcinoma. The suffix "oma" means tumor, or lump. Carcinoma in situ means the pathologist spotted some individual suspicious cells scattered here and there in a bed of normal cells, and it does not mean he found a tumor. Since it is not a tumor, it is not palpable, and can be found only by micro-calcifications appearing on a mammogram. Unfortunately, the natural history of carcinoma in situ can not be accurately predicted. However, it is not correct to count it as a true cancer.

The study did not report HRT dosage or measure serum or saliva hormone levels. People differ in binding protein concentrations, as reported by Cummings, et al. From the study one can not infer anything concerning the concentration of bioavailable hormone. This could easily have been accomplished by using saliva hormone assay. It is possible, for example, that many postmenopausal women produce sufficient endogenous hormone and actually do not need any supplement. Would these women be the ones that decide to discontinue their estrogen supplements?

Given the findings of Formby and Wiley showing progesterone's activation of gene p53 product that inhibits breast cell proliferation and restores normal apoptosis rates, it is disappointing that the authors did not include HRT with progesterone rather than merely HRT with progestins. The balance of estradiol to progesterone is perhaps the most important and most easily modified breast cancer protection factor known. If a study such as the one from the Iowa Women's Health Study is ever mounted again, one should hope that it would include saliva hormone assay and a subgroup of women using progesterone alone or as part of their HRT. Wouldn't it be nice to find an easily modified factor that truly prevents breast cancer? Unless something is looked for, it is unlikely that it will be found.