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Morning Rounds With Dr Economou: The Unanswered Question of What Causes Breast Cancer

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Rounds with Steve Economou MD Rush Hospital Chicago 1977
Morning Rounds With Steven G. Economou MD

by Jeffrey Dach MD  ( Link to this article)

In 1977, I was a surgical intern at Rush Presbyterian St Luke's Hospital on the west side of Chicago.  One floor of the hospital was devoted to caring for women with breast cancer, supervised by attending surgeon, Steven Economou MD.  

As a surgical intern, it was mandatory to attend a daily ritual called "morning rounds" to start off every work day.(see left image)  Wearing long white coats and stethoscopes, we followed Dr. Economou around the floor, from patient room to patient room, reviewing charts, performing bedside examinations, and dispensing orders for diagnostic testing and treatment. 

Above Left image: courtesy of wikimedia commons, house staff on hospital rounds   File:Bundesarchiv_Bild_183-1988-0809-316,_Rostock,_Klinik .

A Game Called, "Stump the House Staff"

During "Morning Rounds", Dr. Economou enjoyed playing a game called, "Stump the House Staff".  He would think up difficult questions and pose them to us, as if they were small darts thrown to an imaginary target painted on the forehead of one of us interns.  As if it were yesterday, I can remember one such question he asked me:

"Dr. Dach, Does Estrogen cause breast cancer?"

I was a cocky intern, just out of medical school, so I replied:

"Of course estrogen causes breast cancer.  Estrogen stimulates growth of breast tissue, and any growth stimulation will cause cancer." 

I assumed Dr Economou knew the correct answer and would provide it.  To my surprise, he was silent, and offered no reply.  He changed the subject and we continued on to the next patient room. 

Since that day in 1977, another 35 years of clinical research has elapsed, and medical science has embellished the answer in ways Dr Economou would have appreciated 35 years ago in 1977.  Dr Steven G. Economou passed away at the age of 84 in 2007.(5) 

Steven Economou MD, Surgeon Rush Medical Center Chicago, courtesy of the NIH and  Raphael E Pollock MD , Annals of Surgical Oncology March 2008.

Does Estrogen Cause Breast Cancer ?

There are two parts to this answer:
1) It Depends on the Type of Estrogen Used.
2) It Depends on the Type of Progesterone Given Along With the Estrogen.

Let's First look at the Effect of the Type of Estrogen Alone:

Estradiol Alone - YES, this increases risk of breast by 30% French Cohort study. (5 )
Premarin Alone - NO, this decreases risk of breast cancer (WHI Second Arm)(1)

Let's Look at the Added Progesterone :

Progesterone Alone - No, this decreases risk of breast cancer. (35)
Medroxyprogesterone (Provera) added- Yes, this increases risk of breast cancer (2)
Norethinstrone added- another progestin- Yes, increased risk of breast cancer.(4,5)

The use of Estradiol-Alone IS associated with a 1.3 fold increase in breast cancer risk, as reported by Dr Fournier in the 2008 French Cohort study.(5)   However, the combination of Estradiol and Progesterone (bioidentical) are not associated with increased breast cancer risk.  

This underscores the importance of the Estrogen/Progesterone  combination as the safest program.  For added safety, our Estrogen is a combination two ovarian estrogens, Estradiol (E2) and Estriol (E1) in a ratio of 20/80 called Bi-Est, invented and pioneered by Jonathan Wright MD.  Estriol (E1) has been extensively studied and found preventive of breast cancer .(41-48)

Premarin - No This Does NOT Cause Breast Cancer

Premarin is estrogen from pregnant horses also called CEE, conjugated equine estrogen. The Premarin-Alone study, the 11 year follow up of the Women's Health Initiative was covered here.(1)   Rather than causing breast cancer, Premarin (CEE) prevented it, finding a reduction in breast cancer for Post-Menopausal women using Premarin-Alone compared to placebo .  To be exact, there was a 23% reduction in breast cancer in Premarin Users compared to placebo. (1)

Premarin Plus MedroxyProgesterone (PremPro) -
Yes, this Does
Cause Breast Cancer

The PremPro study was discussed here which was published in the October 2010 issue of JAMA.  This study was the 11 year follow-up for the First Arm of the Women's Health Initiative.  In this study, Prempro (Premarin plus Medroxyprogesterone) was given to  post menopausal women. This PremPro study showed INCREASED breast cancer in the hormone treated group.(2)  The hormone users had a 25 % increase in invasive breast cancer compared to placebo users.  Breast cancer in the Prem-Pro users tended to more aggressive, with 78% more lymph node invasion, and greater mortality as well. (2)

Premarin is OK, Premarin Plus Medroxyprogesterone is NOT OK

So, here we see an obvious conclusion, that Premarin alone does not cause breast cancer and may even be preventive.  Adding a synthetic chemically altered version of progesterone called a progestin (Medroxyprogesterone), DOES CAUSE breast cancer.  Not only does Medroxyprogesterone cause breast cancer, these cancers tend to be more aggressive and are deadlier. (2)

Progestins are Carcinogenic

Medroxyprogesterone is Carcinogenic

An explanation of the carcinogenic effect of progestins is contained in an article by Dr Horowitz in 2009  entitled " Progestins in Hormone Replacement Therapies Reactivate Cancer Stem Cells in Women With Preexisting Breast Cancers: A Hypothesis" (3)

Noresthisterone is Carcinogenic

Another Progestin known to be carcinogenic is Norethisterone which is widely used in Finland, and was the added Progestin in the HABITS study which showed (surprise) increased breast cancer in the hormone users.(4,5)

Hormone Replacement for Breast Cancer Survivors -

Will Hormone Replacement Cause  Breast Cancer Recurrence ?

For the past four decades, mainstream medicine has held the belief that hormone replacement is contra-indicated in the breast cancer survivor because of risk of causing cancer recurrence. Back in my internship days, Dr Economou frequently asked us this question: 
"If We Give Hormone Replacement to Breast Cancer Survivors, Will This  Increase Rate of Breast Cancer Recurrence ?"
Breast Cancer Prevention Program

Firstly before we discuss giving hormones to the breast cancer survivor, let's give you information about our office program for breast cancer prevention which includes:

Vitamin D Supplementation

Vitamin D testing is important, and we optimize vitamin D to the upper end of the normal range for all patients.  In a study reported in 2011 from Germany, lower vitamin D levels were inversely related to breast cancer recurrence and mortality.  Higher Vitamin D levels were protective.(6)

Iodine Supplementation

Another test we use is the Spot Urinary Iodine level.  We use Iodine supplementation with Iodoral. My previous article describes how iodine deficiency is a risk factor for breast cancer, and how Iodine supplementation prevents breast cancer, and can be used as  adjuvant treatment. 

Here is the link:  Iodine Treats Breast Cancer article by Jeffrey Dach MD

2/16 Ratio - Urinary Estrogen Metabolite Testing- Meridian Valley Lab

Meridian Valley is Jonathon Wright's lab which does urinary metabolite testing. He is the inventor of Bi-Est formula commonly used in bioidentical hormone programs.  Urinary metabolite testing is useful because some women will produce harmful estrogen metabolites which can increase the risk for breast cancer.   The lab test is called the 2/16 ratio.  Women with higher ratios have a 42% decrease in breast cancer (9,10).  Nutritional supplements such as Indole-3-carbinol and Di-Indole-Methane are known to adjust the 2/16 ratio into a higher, more favorable balance.(11)  Metametrix Lab also does this testing.

Another question that frequently came up on rounds with Dr Steven G Economou is:

Is Hormone Replacement Contra-Indicated for the Breast Cancer Survivor?

Let's Ask William T. Creasman and Philip J. DiSaia

Both Drs. William T. Creasman and Philip J. DiSaia are highly regarded academic professors of Obstetrics and Gynecology, and authors of medical textbooks of  Gynecologic Oncology  and Women's Health.  They advised in the 1980's that hormone replacement was beneficial for the breast cancer survivor, and did not increase breast cancer recurrence.   Over the many decades of their careers, they have written extensively about hormone replacement for the breast cancer survivor. 

William T. Creasman and Philip J. DiSaia Receiving Award for Excellence in OB Gyne Surgery.

In a 2009 Letter to the Editor published in the journal, Oncology, Dr. Creasman writes the following:
"numerous published articles have noted that recurrence rates in breast cancer survivors who chose to take HRT (Hormone Replacement Therapy) for symptom relief were very low. "

"In view of the present data, we feel it is important for women to know there are choices, and current data would suggest that there is no increased risk of recurrence with HRT." HRT = Hormone Replacement Therapy (7)
In 2005 Current Opinions in Oncology, Dr Creasman writes:
"Several case-control and cohort studies have noted either no increased risk or actually less risk of recurrence in women taking estrogen after therapy after breast cancer. Although the general consensus is that such a recommendation is contraindicated, the data do not support this admonition." (7A,B,C)
Dr Xydakis - Greece

In agreement with Dr Creasman is Dr. Xydakis from Greece in the 2006 Annals of the New York Academy of Science says this (8):
"No observational or retrospective study in breast cancer survivors (whether in pre- or postmenopausal women) has shown an increased risk of tumor recurrence or increased mortality associated with HRT use."(8)
Eva Durna MD - Australia

Also in agreement is Dr. Eva Durna from Australia.(12,13) She reported two observational studies.  One in  2002 in which hormone replacement was given to post-menopausal breast cancer survivors, and one in 2004 in which hormone replacement was given to  pre-menopausal (younger) breast cancer survivors.  In both studies, Dr Eva Durna reports reduced mortality and reduced recurrence rates in the hormone users.(12,13)

Dr Pelin Batur of the Cleveland Clinic

Also in agreement is Dr. Pelin Batur of the Cleveland Clinic in a 2006 review of the medical literature published in Maturitas reviewing hormone replacement for breast cancer survivors.(39)  Dr Pelin Batur identified s even studies which included a control group.  Among 1,416 hormone replacement users, cancer reoccurrence was noted in 10.0%, while cancer recurrence was doubled (20%) for the non-hormone users.  Cancer related mortality for hormone users was only 2.6% which was one third of the 7.8% cancer mortality in the non-hormone users.(39) 

Here is Dr. Batur's conclusion:
"In our review, menopausal HT (hormone therapy) use in breast cancer survivors was not associated with increased cancer reoccurrence, cancer-related mortality or total mortality." (39)
The Randomized Controlled Trial

The way medical research works, first a number of observational studies are done which are reported in the medical literature, always with the caveat that they are only observational.(14,15,16)  As Dr. Creasman reports, these observational studies are all in agreement that hormone replacement does not cause increased cancer recurrence in breast cancer survivors. Eventually the observational studies are either confirmed or refuted by randomized controlled trials (RCT's) which are considered more definitive evidence, the Gold Standard in medical research.

Randomized Controlled Trials of HRT in Breast Cancer Survivors

Two RCT studies were done, both from Sweden.  The first is called HABITS (17,18,19), and the second is called the Stockholm study (20).  Both studies gave hormone replacement to breast cancer survivors in a randomized trial compared to placebo. The HABITS study showed three times greater breast cancer recurrence in the hormone treated women, while the Stockholm study showed no increased recurrence. (17-20). 

How to Explain these Discrepant Findings? 

It Is The Tumor Grade ! 

Dr Chlebowski from Brown Medical School lamented in his 2005 systematic review of the medical literature that the findings of the randomized controlled trials were discrepant with the observational studies. (38)   Dr. Chlebowski noted that the observation studies tended to enroll women with less aggressive breast cancers that were axillary lymph node negative.(38) 

This is common sense.  If we as doctors are going to make the decision to either give or withhold HRT from the breast cancer survivor, it makes sense to withhold HRT from the more aggressive cases with axillary node involvement, and provide HRT for women with the less aggressive cancer cell types, and with no evidence of metastatic spread.

It is the Progestin ! 

While it is clear that the horse estrogen-alone, Premarin-alone does not increase breast cancer risk(1), adding a synthetic progestin (MPA) increases breast cancer risk.
For example, adding medroxyprogesterone resulted in a 1.48 fold increase, and Norethisterone a 2.11 increase in breast cancer. (5) Similarly, increased breast cancer risk was reported by the First Arm of the WHI using MedroxyProgesterone (2).

HABITS- Norethisterone

The ill-fated HABITS study used Norethisterone , a progestin that is known to be carcinogenic, associated with a 2-3 fold increase in breast cancer rates in Finland.(4,5)  On the other hand, the more favorable Stockholm Study (20) had a larger number of women on Estrogen-Alone, as well the combination of estrogen and Medroxy-Progesterone.  Medroxyprogesterone is carcinogenic, but less so than Norethisterone (4,5, 17)

In both these Randomized Controlled Studies (RCT) of Breast Cancer Surivors given HRT, a Bioidentical Progesterone should have been used, as this is non-carcinogenic and actually preventive, as demonstrated in the French Cohort study reported by Plu-Bureau in 1999 in which users of topical progesterone had a significant reduction in breast cancer risk.  (35)

Previous studies in breast cancer survivors given a combination estrogen and progestin, Megace (21,22), also called Megestrol, showed protection from breast cancer recurrence, as this progestin has actually been useful in treatment of advanced breast cancer.(21,22) 

So in conclusion, the exact chemical composition of the added progestin plays a huge role in determining if the hormone replacement program will prevent or cause breast cancer.  This is the point made by Dr Fournier in his 2008 French Cohort Study on the Unequal Risks For Breast Cancer Associated with Different Hormone Replacement Therapies.

A quote from Dr Fournier 2008 report:
"These findings suggest that the choice of the progestagen component in combined HRT is of importance regarding breast cancer risk; it could be preferable to use progesterone..."
Another author, Dr Collins from Canada, independently agrees with Dr. Fournier.  The added progestin determines breast cancer risk.  Here is the quote from a 2005 article:
"valid evidence from randomized controlled trials (RCTs) indicates that breast cancer risk is increased with estrogen-progestin use more than with estrogen alone." 
This is equally true for the breast cancer survivor seeking relief from menopausal symptoms.   Of course, the safest and preferred hormone combination consists of replicating the endogenous ovarian hormones, Estradiol and Progesterone with topical delivery the preferred method.  This, of course, is the concept of Bioidentical Hormones.

BRCA Gene Positive Women and Hormone Replacement

Studies on BRCA gene women are most revealing.(23-27)  The BRCA gene is associated with 80% lifetime risk of breast cancer, and 20%-50% risk for ovarian cancer.  BRCA Gene carrier women will frequently choose to have preventive oophorectomy (surgical removal of the ovaries) which induces surgical menopause.  Therefore, it is not surprising that many of these women suffer with menopausal symptoms, and will seek relief with hormone replacement.  A number of  studies looking at hormone replacement in BRCA carrier women prior to or after oophorectomy show no increase in breast cancer risk from hormone replacement.

A 2008 study by Dr. Eisen followed 472 post-menopausal women with BRCA mutation on hormone replacement for menopausal symptoms.  In the BRCA gene women who took Estrogen-Alone, they found a 50% reduction in breast cancer rates.(23)  Again, results for Estrogen-Alone were superior to the estrogen-progestin combination.  Natural progesterone (bioidentical) is preferrable to the synthetic progestins.

The experience with hormone replacement in BRCA gene carriers again suggests that Estrogen does not cause breast cancer, and is actually preventive.  Rather, we know from current research that breast cancer is caused by oxidative damage to the DNA of breast cells.  The BRCA gene mutation does exactly this, it causes malfunction of the anti-oxidant system. leading to oxidative damage to the DNA of the breast cell.  Breast cancers in BRCA gene women tend to be triple negative ,  ie.  estrogen, and progesterone receptor negative which are non-responsive to ovarian ablation.

Ovarian Ablation as Treatment for Breast Cancer

Breast cancer can occur in the younger pre-menopausal woman.  Most commonly this is an indolent form of cancer called DCIS (ductal carcinoma in situ) which has a very good prognosis.  However, another form of cancer (infiltrating ductal cancer) can be very aggressive in this age group with poor prognosis regardless of treatment.  This variety tends to be estrogen receptor positive , and highly aggressive with a median survival of 26 months . (27-34)  In this type of highly aggressive Estrogen-Receptor-Positive breast cancer in younger pre-menopausal women the mainstream medical treatment is ovarian ablation (either surgical or drug induced) to eliminate endogenous Estrogen.(28) 

In 2,100  pre-menopausal estrogen receptor positive breast cancer patients, ovarian ablation improved 15 year survival from 46% to 52%. (29)  This is a six per cent absolute benefit, which is quite disappointing.(29)  This again underscores the aggressive nature of this variety of breast cancer, and the futility of mainstream treatment.

Obviously, in this scenario, hormone replacement would be contra-indicated.  For women over the age of 50, ovarian ablation was of no benefit regardless of tumor receptor status.(29)   So, patient age, tumor grade and hormone receptor status, and disease free years since diagnosis and treatment  are important considerations when considering whether or not to offer hormone replacement program for the breast cancer survivor. (27-34)

Family History of Breast Cancer

The benefits of hormone replacement extend to women with a family history of breast cancer.  A 1997 study in Iowa followed 41,800 women for 8 years.  Those women using hormone replacement who had a history of breast cancer in a family member still had a 50% reduction in over all mortality compared to non-users.(36)  There was a slight increase in breast cancer in the hormone users in this observational study. However this was not statistically significant. (36)

Opposing Opinions - Confusing Progestins with Progesterone

To be fair, a number mainstream authors oppose Dr. Creasman's opinion such as Dr Labriola in a 2009 rebuttal letter (40)  Again, the opposing views are usually based on the confusion of chemically altered progestins which are known to be carcinogenic, with the ovarian hormone, progesterone.  Progestins are not progesterone.  They have an entirely different chemical structure and different biological activity profile.

As you read through the medical literature you will find a common mistake. Many of the reference articles on this topic use mistaken terminology, referring to a "progestin" hormone as "progesterone" which it is not.(7a)(23)  For example Dr Andrea Eisen's BRCA gene article says that the first arm of the WHI used a combination pill consisting of Estrogen and Progesterone which increased breast cancer risk. (23)  This is entirely incorrect, as the WHI study actually used Premarin and Provera (medroxyprogesterone), a progestin. 

Progestin use is associated with increased breast cancer, while Progesterone is not.  This mistake permeates the women's hormone literature explaining the many discrepancies in findings and opinions.  So when you see the word progesterone in a medical report, you have to ask yourself, does the author really mean "progesterone", or was in fact a "progestin" given to these women?

Randomized Trials With Bioidentical Estradiol and Progesterone Urgently Needed

Unfortunately, as yet, after all these years, there are still no randomized trials (RCT) of postmenopausal hormone replacement with commonly used bioidentical hormone preparations such as topical Bi-Est (80% estriol and 20% estradiol) and topical Progesterone.  We urgently need RCT studies of bioidentical hormone therapies in breast cancer survivors as well.

For Part Two of this series: Don't Monkey With My Hormones

Articles With Related Interest:
Iodine Treats Breast Cancer, Overwhelming Evidence Breast Cancer Prevention and Iodine

Author : Jeffrey Dach MD

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