Bioidentical Hormones for Breast Cancer Survivors 

by Jeffrey Dach MD

Morning Rounds With Dr Steven Economou at Rush Hospital Breast Cancer Surgeon

Thirtyfive years ago, breast surgeon Steven Economou MD asked me, “Does estrogen cause breast cancer, and does hormone replacement increase cancer recurrence in breast cancer survivors?” Back then, I did not know the answer, and neither did he. Thirtyfive years later, we now have the answer.

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

Morning Rounds With Dr Economou

Left Image of hospital rounds courtesy of John Hopkins Nursing Magazine.

In Chicago in 1977, a Rush Hospital breast surgeon by the name of Steven Economou was making rounds with his entourage of interns and residents. I was one of the interns in his group. Wearing long white coats and brandishing stethosopes, we followed Dr. Economou from room to room.  Dr. Economou’s specialty was breast cancer surgery, and one of the surgical floors of Rush Hospital was filled with women either waiting for surgery or else recovering from their breast cancer operation.

Morning rounds with Steven Economou MD was a daily ritual, and as we bobbed in and out of hospital rooms, examining patients and reviewing charts, Dr Economou enjoyed stumping the house staff with difficult medical questions, as if they were small darts deftly thrown to an imaginary target on our foreheads.  As if it was yesterday, I can remember one such question he asked me:

Dr. Dach, does estrogen cause breast cancer?

I had just finished medical school, and I really did not know. I did not even know if the answer was known. So, as was my usual custom in those days, I made up a plausible answer based on accepted knowledge. 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 answer to his question 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 case.    Fast forward 47 years years, and medical science is still looking for the answer, continuing to debate the question. Dr Steven G. Economou passed away at the age of 84 in 2007.(5)

Does Estrogen Cause Breast Cancer ? It All Depends. The Answer is NO – Estrogen Does NOT Cause Breast Cancer

In 2011, Dr. Andrea Z. LaCroix published the data on the 11 year follow up of the Women’s Health Initiative (WHI), estrogen-only, second-arm. Paradoxically, rather than causing breast cancer, estrogen prevented it. This estrogen-only arm of the WHI study found  a 23 percent reduction in breast cancer in post-menopausal women using estrogen-alone after hysterectomy. (1)

In 2018, Dr. Howard Hodis reviewed the 18 year follow up of this same  WHI estrogen-alone, second arm showing a 45 percent reduction in breast cancer mortality in the estrogen-alone group. (73-74)

For more on this, see Hormone Replacement Therapy HRT Does NOT Cause Breast Cancer and Errors in Modern Medicine: The Fear of Estrogen

Yes, Estrogen Does Cause Breast Cancer

In 2010, Dr. Rowan T. Chlebowski published in JAMA the data on the 11 year follow up on the first arm of the Women’s Health Initiative (WHI) treating postmenopausal women with Prempro (Premarin plus medroxyprogesterone, MPA). The hormone treated group had a 25 percent increase in invasive breast cancer compared to the placebo group.  The breast cancer in this Prem-Pro group tended to more aggressive, with 78% more lymph node invasion. Mortality from breast cancer was doubled in the Prempro group compared to placebo. (2)

For more see: Hormone Therapy Increases Breast Cancer Says JAMA Study

Estrogen is OK, Medroxyprogesterone is NOT OK

So, here we see an obvious conclusion, that estrogen-alone does not increase breast cancer risk and may even be protective, while adding a progestin, medroxyprogesterone (MPA) a synthetic chemically altered form of progesterone to the estrogen increases breast cancer risk.  Not only does MPA induce breast cancer in animals, these cancers tend to be more aggressive and are deadlier. (46-48)

Progestins are Carcinogenic

Medroxyprogesterone is Carcinogenic

in 2000, Dr. Ronald K. Ross at the Norris Comprehensive Cancer Center in Los Angeles studied menopausal HRT with estrogen versus estrogen plus progestin (MPA). Dr. Ross writes:

This study provides strong evidence that the addition of a progestin [MPA] to HRT enhances markedly the risk of breast cancer relative to estrogen use alone. (75)

In 2007, Dr. Stephen N. Birell made the discovery that synthetic progestins such as MPA act as endocrine disruptors to androgen signalling which negates the protective effects of androgen signaling in breast tissue, thus explaining the carcinogenicity of MPA, writing:

There is now considerable evidence that using a combination of synthetic progestins and estrogens in hormone replacement therapy (HRT) increases the risk of breast cancer compared with estrogen alone. Furthermore, the World Health Organization has recently cited combination contraceptives, which contain synthetic progestins, as potentially carcinogenic to humans, particularly for increased breast cancer risk. Given the above observations and the current trend toward progestin-only contraception, it is important that we have a comprehensive understanding of how progestins act in the millions of women worldwide who regularly take these medications. While synthetic progestins, such as medroxyprogesterone acetate (MPA), which are currently used in both HRT and oral contraceptives were designed to act exclusively through the progesterone receptor, it is clear from both clinical and experimental settings that their effects may be mediated, in part, by binding to the androgen receptor (AR). Disruption of androgen action by synthetic progestins may have serious deleterious side effects in the breast, where the balance between estrogen signaling and androgen signaling plays a critical role in breast homeostasis. Here, we review the role of androgen signaling in the normal breast and in breast cancer and present new data demonstrating that androgen receptor function can be perturbed by low doses of MPA, similar to doses achieved in serum of women taking HRT…We propose that the observed excess of breast malignancies associated with combined HRT may be explained, in part, by synthetic progestins such as MPA acting as endocrine disruptors to negate the protective effects of androgen signaling in the breast. Understanding the role of androgen signaling in the breast and how this is modulated by synthetic progestins is necessary to determine how combined HRT alters breast cancer risk, and to inform the development of optimal preventive and treatment strategies for this disease…Nevertheless, given that more than 25% of postmenopausal women who require HRT use a combination of estrogen and synthetic progestins, it is important to understand the actions of progestins in the breast at a molecular level. Whereas synthetic progestins are generally considered to act via progesterone receptor (PR)-mediated pathways in female reproductive tissues, we have demonstrated that treatment failure with the progestin medroxyprogesterone acetate (MPA) in advanced breast cancer is associated with reduced levels of androgen receptors (AR) or impaired AR function…MPA binds to the AR [androgen receptor] with an affinity comparable to the native androgenic ligand, 5-dihydrotestosterone (DHT)…In addition, the observation that MPA interacts with the glucocorticoid receptor (GR) to increase levels of the metastasis suppressor gene, nm-23, in human breast cancer provides further evidence for extensive crosstalk by progestins with non-PR signaling pathways in breast cancer cells…Notably, in France the majority of women taking combined HRT receive oral micronized progesterone rather than a synthetic progestin. In two French studies- the E3N-EPIC cohort of 54,548 women and a smaller study of 3175 women, no significant increase in breast cancer risk due to HRT use with micronized progesterone was observed compared with untreated women (32, 33). (76)

In the above quote, Dr. Stephen N. Birell mentions two French studies by De Lignieres (2002) and Fournier (2005) in which micronized progesterone was subsituted for the synthetic progestin, MPA, with improved results, with no increased breast cancer in the HRT group. (77-78)

In 2009, Dr. Kathryn B.Horowitz hypothesized synthetic progestins such as MPA reactivate dormant cancer cells in the breast tissue, writing:

We propose that women who develop breast cancer while on estrogens plus progestins harbor undiagnosed nascent disease [dormant breast cancer cells] before the start of therapy. The progestin component, in a nonproliferative step, reactivates receptor negative cancer stem cells within such germinal, perhaps even dormant tumors….(3)

Medroxy-Progesterone (MPA) Model of Breast Cancer in Animals

MPA is a well known animal model of breast cancer. When MPA is injected into mice, about 80 percent will develop breast cancer over 52 weeks. In 2009, Dr. Claudia Lanari discussed the MPA mouse breast cancer model, writing:

the administration of medroxyprogesterone acetate (MPA) to BALB/c female mice induces mammary ductal carcinomas with a mean latency of 52 weeks and an incidence of about 80%. These tumors are hormone-dependent (HD), metastatic, express both ER and PR, and are maintained by syngeneic transplants. (46-48)

Norethisterone is Carcinogenic

Another progestin known to be carcinogenic is norethisterone, widely used in Finland, was the added progestin in a randomized controlled trial, called the HABITS study which showed (surprise) roughly doubled the incidence breast cancer in the norethisterone treated group compared to placebo.(4-5)

Hormone Replacement for Breast Cancer Survivors – Will Hormones Cause  Recurrence ?

For the past four decades, mainstream medicine has held the belief that hormone replacement is contra-indicated in breast cancer survivors because of risk of cancer recurrence. Surely if estrogen causes cancer, then we should see recurrence in women who have already had breast cancer, breast cancer survivors. Surely, HRT is a bad idea because we all believe HRT will cause these women to suffer recurrence of their breast cancer. We are faced with the question, does HRT (hormone replacement therapy) increase the risk of breast cancer recurrence in breast cancer survivors?

Breast Cancer Prevention Program

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

Vitamin D

1) We routine test vitamin D3 levels and optimize vitamin D to above 50 ng/mL. In 2020, Dr. William Grant reviewed the recent medical literature finding optimal Vitamin D levels decrease risk for breast, colorectal, prostate, and all other cancers, writing:

medical practice should embrace and public health advice should encourage use of vitamin D to reduce cancer risk and increase survival rates after diagnosis. (80)

In 2024, Dr Antia Torres from Spain analyzed the recent medical literature on vitamin D and breast cancer prevention, finding an inverse relationship between serum vitamin D level and risk for breast cancer, breast cancer recurrence, and breast cancer mortality. A serum vitamin D level above 40 ng/ml is protective, writing:

From the results analyzed in this study, the deficiency of vitamin D is closely associated with the development of BC [breast cancer]. In general, higher serum levels of vitamin D may exert a protective effect against the development of the disease. In the present study, it has been observed and discussed that serum levels of vitamin D ≥ 40.6 ng/mL ± 14.19 ng/mL could be considered protective against the risk of developing BC. (81-82)

2) Selenium Supplementation: We test for selenium levels routinely and supplement when found low, using 135 as a cut-off based on the 2008 study by Dr Joachim Bleys. (134).

Selenium is a critical mineral involved in the intracellular anti-oxidant system (i.e. glutathione peroxidase) and the DNA repair mechanism. Selenium deficiency is associated with increased risk for all cancers, including breast cancer. In 2021, Dr. Kamil Demircan studied selenium status biomarkers in relation to mortality from breast cancer finding patients with low selenium status indicated by all three biomarkers had the highest mortality risk, writing:

Patients with low selenium status according to all three biomarkers (triple deficient) had the highest mortality risk with an overall survival probability of ∼50% after 8 years…Prediction of mortality based on all three biomarkers outperformed established tumour characteristics like histologic grade, number of involved lymph nodes or tumour size. An assessment of Se [selenium] status at breast cancer diagnosis identifies patients at exceptionally high risk for a poor prognosis. (131-134)

Selenium is especially important for those patients harboring genetic mutations in the selenoprotein anti-oxidant and DNA repair mechanisms, as highlighted by the below discussion selenum for BRCA gene carriers. For more see the three chapters on selenium. Part One-Selenium Metamorphosis, Part Two-The Case for Selenium, Part Three-Selenium Deficiency

3) Iodine Supplementation: For all patients, we routinely include spot urinary Iodine level testing, and iodine supplementation when found low. Iodine deficiency is a risk factor for breast cancer, and iodine supplementation is not only preventive, but also useful as adjuvant treatment of breast cancer.(83) For more see the two chapters Iodine, Iodine for Prevention of Breast Cancer and Iodine Treats Breast Cancer

4) Use Progesterone, not Progestin: Our office uses human bioidentical progesterone, in both topical and oral forms, avoiding the carcinogenic synthetic progestins such as medroxyprogesterone, norethisterone and norethindrone. (101-103)

In 2022, Dr. Haim A Abenhaim reviewed hormone formulation and breast cancer risk, concluding:

Although menopausal HT [hormone therapy] use appears to be associated with an overall increased risk of breast cancer, this risk appears predominantly mediated through formulations containing synthetic progestins. When prescribing menopausal HT, micronized progesterone may be the safer progestogen to be used. (102)

5) Estrogen Formulation: Our office uses Bi-Est which is 80% Estriol (E3) and 20% Estradiol (E2). Estriol is breast cancer protective. Both Estriol (E3) and metabolites of Testosterone predominantly target ER Beta (Estrogen Receptor Beta) which is a tumor suppressor. Topical delivery of estrogen is used rather than oral route realizing topical estrogen is safer because this does not cause blood clotting found with oral delivery of estrogen. (104) For more see: The Safety of Transdermal Estrogen Part One and Transdermal vs Oral Estrogen Part Two

6) Progesterone: My office uses oral micronized progesterone, FDA approved (Schering/Solvay December 1998) for prevention of endometrial hyperplasia and endometrial cancer. Usual dosage is micronized progesterone 100 mg oral capsule taken at bedtime. Although mainstream OB/Gyne practice is to withhold progesterone in post hysterectomy patients, our office practice is to give progesterone to these patients as well, realizing progesterone has other health benefits not related to endometrial protection. For example, progesterone has an antiproliferative effect and is breast cancer preventive. Although estradiol-alone increases proliferation of breast cells in human and monkey studies, the addition of progesterone to the estradiol opposes and neutralizes this proliferative effect of estrogen. Progesterone has neurological and neuropsyciatric benefits. Progesterone stimulates neurogenesis and has neuroprotective effects in traumatic brain injury and stroke. Progesterone relieves depression, anxiety, vasomotor symptoms, and somatic symptoms of post menopausal women. Progesterone improves bone density and has beneficial cardiovascular effects. (97-101)

Progesterone for Peri-Menopausal Transition

Progesterone is also commonly used for treatment of the menopausal transition characterized by irregular menstrual cycles, high or fluctuating estrogen levels, and low or non-existent progesterone levels. During this menopausal transition, hormone fluctuations cause mood disturbance, which is relieved by oral micronized progesterone. (109-115)

7) Testosterone: My office HRT program includes testosterone routinely for all postmenopausal women. A 2019 study by Dr. Rebecca Glaser shows testosterone is breast cancer preventive, decreasing breast cancer risk by 39-40 per cent. For more on this see the chapter on: Testosterone for Prevention and Treatment of Breast Cancer) (84)

8) DIM (Di-Indole-Methane): All pre and post menopausal women are routinely supplemented with DIM (Di-Indole-Methane), diverting estrogen metabolism toward favorable metabolic pathways, and serving as an excellent breast cancer preventive. (93-96)

Sulforaphane, Resveratrol and NAC Preventing Reactive Estrogen Quinones

9) 4-Hydroxy Quinones: The latest breast cancer research reveals certain estrogen metabolites called 4-hydroxy-quinones are DNA adducts which attach directly to DNA causing oxidative damage and depurination. This leads to DNA mutations and increased risk for cancer. In 2021, Dr. Ercole Cavalieri studied these reactive metabolites of estrogen, the catechol estrogen 3,4, quinones, finding the nutritional supplements resveratrol, NAC (N-acetyl cysteine) and sulforaphane prevent oxidative damage to DNA caused by catechol-estrogen-quinones. Dr. Cavalieri writes:

Cancer can be initiated by increased formation of reactive estrogen metabolites called catechol estrogen-3,4-quinones. If estrogen metabolism becomes unbalanced and significant amounts of these quinones arise, depurinating estrogen-DNA adducts are primarily formed, leading to cancer-causing mutations. (85)

Note: Depurination is the removal or loss of a purine base such as adenine or guanine from the DNA double helix, causing a mutation which may lead to cancer if not repaired. (116)

In 2019, Dr. Suyu Miao studied 4-hydroxy estrogen metabolites in breast cancer patients and controls, finding oxidative estrogen metabolites may be the most important risk factor for breast cancer, and the levels of 4-hydroxy estrogen metabolites in urine samples serve as bio-markers for breast cancer risk, writing:

Among many alterations of sex hormone metabolisms, 4-hydroxy estrogen (4-OH-E) metabolite was found to be significantly increased in the urine samples of patients with breast cancer compared with the normal healthy controls. This was the most important risk factor for breast cancer. (86-91)

A number of comercially available laboratoriues offer urine testing for estrogen metabolites, including the 4-hydroxy estrogens. At the time of writing, these include Genova lab, ZRT lab, Doctor’s Data Lab, and Dutch Test. Note: I have no financial interest in any laboratory. Interventions to reduce 4 hydroxy quinones are part of our breast cancer prevention program. These supplements include DIM, resveratrol, NAC, and sulforaphane.

10) Polymorphisms in Estrogen Metabolism Increase Breast Cancer Risk – Genotype Analysis

Normally, carcinogenic estrogen metabolites of the 4-OH-quinone variety are metabolized and rendered harmless by methylation pathways. If there is a genetic mutation in these metabolic pathways such as the MTHFR mutation, or COMT (catechol-O-methyl transferase), this creates a bottleneck in the pathway causingh accumulation of 4-OH-estrogen quinone metabolites, thus increasing cancer risk. Genetic testing for polymorphisms is useful here. We routinely give all patients on HRT a good quality multivitamin containing methyl-folate to cover the possibility of underlying MTHR mutation. Inexpensive cheek swab kits are available online for home testing for methylation pathways, and MTHFR and COMT mutations. (92)

11) Low Fat Diet: In 2017, Dr. R.T. Chlebowski reviewed the data from the Low-Fat Diet arm of the WHI study, revealing a 35 percent reduction in mortality after breast cancer, thus suggesting a considerable benefit from the low fat diet, writing:

Results In the dietary group, fat intake and body weight decreased (all P < .001). During the 8.5-year dietary intervention [low-fat-diet], with 1,764 incident breast cancers… deaths after breast cancer (n = 134) were significantly reduced (40 deaths [0.025% per year] vs. 94 deaths [0.038% per year]; HR, 0.65; 95% CI, 0.45 to 0.94; P = .02) by the dietary intervention. (118-120)

Are Hormones Contra-Indicated in the Breast Cancer Survivor? The Answer from Drs. 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, Clinical Gynecologic Oncology and Women’s Health Review. (135-136)

Left Image: Book Cover Courtesy of Drs. Drs. William T. Creasman and Philip J. DiSaia, Clinical Gynecologic Oncology available on Amazon.

In the 1980’s, Drs. Creasman and DiSaia first advised hormone replacement beneficial for the breast cancer survivor, with no increase breast cancer recurrence. Over the many decades of their careers, they have written extensively about hormone replacement for the breast cancer survivor.

In 2009, Drs. William T. Creasman and Philip J. DiSaia wrote a letter to the editor of Oncology, stating current data suggests no increased breast cancer recurrence with hormone replacement in breast cancer survivors, writing:

numerous published articles have noted that recurrence rates in breast cancer survivors who chose to take HRT (Hormone Replacement) 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. (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. (105-106)

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 seven 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 quote:

In our review, menopausal HT (hormone therapy) use in breast cancer survivors was not associated with increased cancer re-occurrence, 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 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.

Two RCT studies were done, both from Sweden.  The first is called HABITS, and the second is called the Stockholm study.  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. The HABITS study used a carcinogenic progestin, Norethisterone, discussed below. (17-20).

How to Explain these Discrepant Findings?

The Tumor Type !

Dr. Rowan T. 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. Dr. Chlebowski noted that the observation studies tended to enroll women with less aggressive breast cancers that were axillary lymph node negative. (38)

It is the Progestin !

It is clear after all these years of published studies that the horse estrogen, Premarin, when used alone, does not increase breast cancer risk. And, while the combined ovarian hormones estradiol and progesterone are not associated with increased breast cancer risk, use of estradiol-alone was associated with a 1.3 fold increase in risk, as reported by in 2008 by Dr. Agnès Fournier in the French Cohort study. (1)(5)

As noted by Dr Fournier, adding a synthetic progestin is the major factor increasing breast cancer risk.  For example, adding medroxyprogesterone resulted in a 1.48 fold increase, and adding Norethisterone, a 2.11 increase in breast cancer. Similarly, increased breast cancer risk was reported by the first arm of the WHI (2004) using medroxyprogesterone. (2)(5)

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. On the other hand, the more favorable Stockholm Study had a larger number of women taking estrogen-alone, as well the combination of estrogen and medroxyprogesterone, a syntheetic progestin known to be carcinogenic, but less so than Norethisterone. (4-5)(17)(20)

In both of the above RCT studies, a bioidentical progesterone should have been used, as this is non-carcinogenic and actually breast cancer preventive, as demonstrated in the French Cohort study reported in 1999 by Dr. G. Plu-Bureau. In this study, topical progesterone use conferred a significant reduction in breast cancer. (35)

The added progestin plays a huge role in determining if the hormone replacement program will prevent or cause breast cancer.  The use of natural bioidential progesterone is preferable to synthetic progestins which are carcinogenic. This same point made by Dr. Agnès Fournier in the 2008 French Cohort study, writing:

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.(5)

In 2005, Dr. Collins from Canada, independently agrees with Dr. Fournier. The added progestin determines breast cancer risk.  Dr. Collins writes:

valid evidence from randomized controlled trials (RCTs) indicates that breast cancer risk is increased with estrogen-progestin use more than with estrogen-alone.  (37)  Note: estrogen-alone here means Premarin (CEE), the estrogen used in the WHI study.

Dr. Avrum Bluming, Author of “Estrogen Matters”

In 2022, Dr Avrum Bluming reviewed all 25 studies (1980 to 2013) of hormone replacement in breast cancer survivors, and 20 reviews of these studies (1994-2021), finding only one of the 25 studies showed increased breast cancer recurrence in hormone users, the HABITS which used synthetic progestins known to be carcinogenic (as mentioned above). None of the 25 studies showed increased breast cancer mortality in the hormone treated group. Thus, Dr. Avrum Bluming is in agreement with  Drs. William T. Creasman and Philip J. DiSaia. The data shows breast cancer survivors have no increased risk of breast cancer recurrence when using hormone replacement. Dr. Blumin writes:

Twenty-five studies of HRT after a breast cancer diagnosis, published between 1980 and 2013, are discussed, as are the 20 reviews of those studies published between 1994 and 2021…Only 1 of the 25 studies, the HABITS trial, demonstrated an increased risk of recurrence, which was limited to local or contralateral, and not distant, recurrence. None of the studies, including HABITS, reported increased breast cancer mortality associated with HRT. (49)

BRCA Gene Positive Women and Hormone Replacement

Studies on BRCA gene women are most revealing. The BRCA gene is associated with 80% lifetime risk of breast cancer. Lifetime risk for ovarian cancer are 54% for BRCA1 and 23% for BRCA2 mutation carriers.  BRCA Gene carriers will frequently choose to have preventive oophorectomy, surgical removal of the ovaries, a form of surgically induced menopause, causing troublesome menopausal symptoms relieved 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. (23-27) (107-108)

For example, in 2008,  Dr. Andrea Eisen studied 472 post-menopausal women with BRCA mutation on hormone replacement for menopausal symptoms. In these BRCA gene women who took estrogen-alone after hysterectomy, Dr. Eisen found a 50% reduction in breast cancer. Similar to the WHI study, Dr. Eisen conducted two studies, one for estrogen-alone and a second study for the estrogen-progestin combination, finding estrogen alone gave superior results. Again, it is prudent to avoid carcinogenic synthetic progestins. (23)

The experience with hormone replacement in BRCA gene carriers shows that estrogen is not causative and is actually preventive of breast cancer.  As mentioned above in the discussion of carcinogenic effect of 4-hydroxy estrogen quinones, the current theory of breast cancer is oxidative damage to the DNA of breast cells by estrogen metabolites. This mechanism is similar in the BRCA gene mutation carriers in which a malfunction in the anti-oxidant system leads to oxidative damage to the DNA of the breast cell. According to Dr. Haixia Chen (2018), breast cancers in BRCA gene carriers tend to be triple negative, ie. estrogen, progesterone and HERS (human epidermal growth factor) receptor negative, the most aggressive cell type, usually associated with poor prognosis. (130)

Selenium Supplementation for BRCA Gene Carriers

Three studies from Poland by Kowalska (2005), Huzarski (2006) and  Dziaman (2009) show selenium supplementation beneficial for the BRCA gene carrier patient. The BRCA gene is involved in DNA repair of oxidative damage using a selenoprotein repair system. Thus, BRCA gene carriers have more DNA oxidative damage, leading to increased risk for cancer. In 2005, Dr. Elzbieta Kowalska studied lymphocytes in 55 women BRCA1 carriers, finding excess rates of chromosomal breakage from DNA oxidative damage. BRCA gene carriers had twice the DNA damage compared to their normal siblings. The fifty five women with the BRCA1 gene mutation were then supplemented with selenium for 8 weeks (275 µg/d). The selenium supplementation reduced DNA damage to normal levels, same as their normal siblings. A second larger study in 2006, by Drs. Huzarski and Kowalska verified that selenium supplementation indeed reduces breast cancer incidence in BRCA1 gene carriers. After two years of selenium supplementation in 100 BRCA gene carriers, the expected BRCA1-associated cancers were reduced in half compared to matched control BRCA carriers not supplemented. This is a very impressive finding! Dr Kowalska writes:

The product of the BRCA1 gene is involved in the repair of double-stranded DNA breaks and it is believed that increased susceptibility to DNA breakage contributes to the cancer phenotype…the frequency of chromosome breaks was measured in cultured blood lymphocytes..BRCA1 serves multiple functions, including DNA damage response (3), nucleotide excision repair (6), and protection against oxidative stress (7)…The frequency of chromosome breaks was greatly reduced following 1 to 3 months of oral selenium supplementation (mean, 0.63 breaks per cell versus 0.40; P < 10−10). The mean level of chromosome breaks in carriers following supplementation was similar to that of the noncarrier controls (0.40 versus 0.39). Oral selenium is a good candidate for chemoprevention in women who carry a mutation in the BRCA1 gene. (126)

We performed two pilot studies involving 200 healthy BRCA1 mutation carriers (100 matched pairs – cases and controls). After two years of oral selenium administration the frequency of BRCA1-associated tumours was two times lower in women who supplemented their diet with selenium, as compared to women without supplementation. (127)

In 2009, Dr. Dziaman from Poland examined at DNA damage in BRCA gene carriers. Dr. Dziaman measured serum and urinary products of DNA oxidation (8-oxodG and 8-oxoGua) with and without selenium supplementation, finding that damaged DNA products were higher in women with BRCA mutations, and were reduced by selenium supplementation. Their results suggest that BRCA1 deficiency contributes to oxidative damage and breaks in cellular DNA, which may be responsible for cancer development. In addition, selenium supplementation is beneficial because it protects from oxidative DNA damage and restores the DNA repair mechanisms. In addition, selenium supplementation reduces cancer risk in BRCA carriers. Dr. Dziaman writes:

BRCA1 plays a role in repair of oxidative DNA damage…we determined 8-oxodG level in cellular DNA and urinary excretion of 8-oxodG and 8-oxoGua in the mutation carriers. We found that 8-oxodG level in leukocytes DNA is significantly higher in BRCA1 mutation carriers…In the distinct subpopulation of BRCA1 mutation carriers without symptoms of cancer who underwent adnexectomy and were supplemented with selenium, the level of 8-oxodG in DNA decreased significantly in comparison with the subgroup without supplementation. Simultaneously in the same group, an increase of urinary 8-oxoGua, the product of base excision repair (hOGG1 glycosylase), was observed. Therefore, it is likely that the selenium supplementation of the patients is responsible for the increase of BER enzymes activities, which in turn may result in reduction of oxidative DNA damage. Importantly, in a double-blinded placebo control prospective study, it was shown that in the same patient groups, reduction in cancer incidents was observed. Altogether, these results suggest that BRCA1 deficiency contributes to 8-oxodG accumulation in cellular DNA, which in turn may be a factor responsible for cancer development in women with mutations, and that the risk to developed breast cancer in BRCA1 mutation carriers may be reduced in selenium-supplemented patients who underwent adnexectomy. (128)
Note: BER is base excision repair, a mechanism for DNA repair. (129)
For more on Selenium supplementation see this three part series: For Part One, for Part Two ,  for Part Three

Contra-Indications to HRT in the Breast Cancer Patient

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 called infiltrating ductal can be very aggressive in this age group with poor prognosis regardless of treatment. This cancer cell type 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 and prevent cancer cells from making their own estrogen. The drugs used usually luteinizing hormone-releasing hormone agonists, tamoxifen and  aromatase inhibitors letrazole, anastrazole, exemestane.

In 2021, Dr. Yen-Shen Lu reviewed the suppression of ovarian function suppression with luteinizing hormone-releasing hormone agonists (LHRHa) as treatment of hormone receptor-positive early breast cancer in the premenopausal female, writing:

As treatment options have rapidly expanded, management of adjuvant treatment of premenopausal women with early and advanced breast cancer has become more complicated. The most recent evidence suggests that addition of LHRHa to adjuvant endocrine therapy, with both tamoxifen and AIs, can provide significant benefits in some premenopausal patients who are at high risk of recurrence and have poor prognostic characteristics. Longer-acting depot and implant LHRHa formulations may help to overcome some of the barriers to adding OFS to endocrine therapy in the adjuvant setting in premenopausal women. (30)

in 2004, Dr. Tatiana Prowell did a metanalysis including 2,100  pre-menopausal estrogen receptor positive breast cancer patients in which ovarian ablation improved 15 year survival from 46% to 52%. This is a disappointing six per cent absolute benefit. Dr. Prowell  writes:

This overview of 12 randomized controlled trials enrolling a total of 2,102 patients reported that women under the age of 50 with early invasive breast cancer who underwent oophorectomy or ovarian irradiation, experienced approximately a 25% relative reduction in the risks of recurrence and mortality at 15 years of follow-up compared with those receiving no adjuvant therapy…In summary, virtually all premenopausal women with early-stage HR+ breast cancer should receive adjuvant endocrine therapy. Combined endocrine therapy appears to be at least as effective as adjuvant CMF chemotherapy in this population…Among 2102 women aged under 50 when randomised, most of whom would have been premenopausal at diagnosis, 1130 deaths and an additional 153 recurrences were reported. 15-year survival was highly significantly improved among those allocated ovarian ablation (52.4 vs 46.1%, 6.3 fewer deaths per 100 women, as was recurrence-free survival (45.0 vs 39.0%, 2p = 0.0007).(28-29)

Again, this poor prognosis underscores the aggressive nature of this breast cancer cell-type and the futility of mainstream treatment. Obviously, in this scenario, hormone replacement would be contra-indicated. For post-menopausal women over the age of 50, ovarian ablation is of no benefit regardless of tumor receptor status, since these women are post-menopasual with very little ovarian function. The patient age, tumor cell-type and grade, hormone receptor status, and disease free number of years since 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 (HRT) extend to women with a family history of breast cancer.  A 1997 study by Dr. Thomas A. Sellers from Iowa followed 41,800 women for 8 years. Those women using hormone replacement who had a family history of breast cancer had a 50% reduction in overall mortality compared to HRT non-users. Dr. Sellars writes:

These data suggest that HRT [hormone replacement therapy] use in women with a family history of breast cancer is not associated with a significantly increased incidence of breast cancer but is associated with a significantly reduced total mortality rate. (36)

Opposing Opinions – Confusing Progestins with Progesterone

To be fair, a number mainstream authors oppose Dr. DiSaia and Creasman’s opinion, such as Dr Labriola in a 2009 rebuttal letter. There are many others.  Again, this opposing view is 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. (40)

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. For example, in 2008, Dr Andrea Eisen’s BRCA gene article says the first arm of the WHI used a combination pill consisting of estrogen and progesterone which increased breast cancer risk, and in 2005, Dr. William Creaseman is guilty of this same mistake. Here is another example of this mistake by Dr. Nanette Santoro in 2021 writing:

In the Women’s Health Initiative (WHI), women with VMS [Vasomotor Symptoms] experienced an 85% reduction in symptoms after treatment with estrogen plus progesterone. (117)

The WHI study did not use natural bioidentical progesterone. This study used Premarin (the estrogen, CEE) and Provera (medroxyprogesterone), a progestin. Progestins are associated with increased breast cancer risk, 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 statement, progesterone causes breast cancer in a medical report, you will know the author is making this same mistake. In fact, the study used a progestin, thus explaining the results of increased breast cancer. This mistake is obvious because progesterone does not cause breast cancer. (23)(105)(117)

Randomized Trials With Bioidentical Estradiol, Progesterone and Testosterone Urgently Needed

Unfortunately, as yet, after all these years, there are still no randomized trials of postmenopausal hormone replacement with commonly used bioidentical hormone preparations. My dream would be to do such a menopausal hormone replacement RCT study using our standard office compounded hormone formula: Bi-Est (80% estriol and 20% estradiol), topical (50 mg/d)  and oral progesterone 100 mg/qhs, and topical testosterone 3 mg/d. In addition, I would combine this with the dietary modification and nutritional supplements for breast cancer prevention mentioned above. There is an urgent need for RCT studies treating breast cancer survivors with this same bioidentical hromoe formula.

Conclusion: Returning to 1977, making rounds on the breast cancer surgery floor at Rush Presbyterian Hospital with Dr. Steven Economou, and his pop question, does estrogen cause breast cancer? The answer is more nuanced than a simple, YES. After a period of estrogen deprivation, estrogen undergoes transformation from a growth signal to a death signal and causes apoptosis of breast cancer cells. This is the estrogen-paradox. Thus explaining the use of estrogen in the form of diethylstilbestrol as mainstay treatment for metastatic breast cancer, first used by Sir Alexander Haddow in 1944 until the introduction of tamoxifen in the 1970’s. Dr. Economou probably knew this because he lived through the era when estrogen was routinely used to treat metastatic breast cancer with a 30 percent response rate to treatment. Yet, he remained silent, rushing in and out of patient rooms with little time to discuss the nuances of estrogen use. (121-125)

Articles With Related Interest:

All Bioidentical Hormone Articles

Hormone Studies in Primates

Iodine Prevents Breast Cancer Part One

Iodine Prevents and Treats Breast Cancer Part Two

Jeffrey Dach MD
7450 Griffin Road, Suite 190
Davie, Fl 33314
954-792-4663

www.drdach.com
www.naturalmedicine101.com
www.bioidenticalhormones101.com
www.truemedmd.com

Links and References …

(0) http://articles.chicagotribune.com/2007-04-28/news/0704271171_1_surgery-department-rush-university-medical-center-presbyterian-hospital
Steven G. Economou: 1922 – 2007 Surgeon, writer, doodler
April 28, 2007|By Trevor Jensen, Tribune staff reporter

Steven G. Economou was adept with both scalpel and pen, chairing the surgery department at what is now Rush University Medical Center and writing dozens of medical articles and doodling abstract figures that illustrated his self-published books.  Dr. Economou, 84, died Saturday, April 7, at Rush North Shore Medical Center in Skokie of complications from illnesses including Parkinson’s disease, said his wife, Kathryn, who goes by the name “Kitty.”

1) LaCroix, Andrea Z., et al. “Health outcomes after stopping conjugated equine estrogens among postmenopausal women with prior hysterectomy: a randomized controlled trial.” Jama 305.13 (2011): 1305-1314.

Over the entire follow-up, lower breast cancer incidence in the CEE group persisted and was 0.27% compared with 0.35% in the placebo group (HR, 0.77; 95% CI, 0.62-0.95).

2) Chlebowski, Rowan T., et al. “Estrogen plus progestin and breast cancer incidence and mortality in postmenopausal women.” Jama 304.15 (2010): 1684-1692.
Participants were randomized to receive conjugated equine estrogens, 0.625 mg/d, and medroxyprogesterone acetate, 2.5 mg/d, in a single tablet (Prempro; Wyeth Ayerst, Collegeville, Pennsylvania) or an identical-appearing placebo pill.

Following the initial report of results from the WHI trial,1 a substantial decrease in breast cancer incidence occurred in the United States, which was attributed24-25 to the marked decrease in postmenopausal hormone therapy use that occurred after publication of the trial results.26 The adverse influence of estrogen plus progestin on breast cancer mortality suggests that a future reduction in breast cancer mortality in the United States may be anticipated as well.

In intention-to-treat analysis, estrogen plus progestin compared with placebo increased the incidence of invasive breast cancer (385 cases [0.42% per year] vs 293 cases [0.34% per year], respectively; HR, 1.25; 95% confidence interval [CI], 1.07-1.46; P = .004).

A significantly larger fraction of breast cancers presented with positive lymph nodes in the combined hormone therapy group compared with the placebo group (81 [23.7%] vs 43 [16.2%], respectively; HR, 1.78; 95% CI, 1.23-2.58; P = .03).

In conclusion, use of estrogen plus progestin increases the incidence of breast cancer, and the cancers are more commonly node-positive. Mortality data analyses suggest that breast cancer mortality may also be increased.

3) Horwitz, Kathryn B., and Carol A. Sartorius. “Progestins in hormone replacement therapies reactivate cancer stem cells in women with preexisting breast cancers: a hypothesis.” The Journal of Clinical Endocrinology & Metabolism 93.9 (2008): 3295-3298.

An increased risk of invasive, estrogen receptor-positive (ER+) breast cancer in the combined estrogen plus progestin arm of the Women’s Health Initiative menopausal hormone replacement therapy (HRT) trial was in large part responsible for stopping the study prematurely in 2002. Subsequent studies offered several possibilities to explain how addition of progestins to estrogens increases the risk of breast cancer. The authors of this report offer a hypothesis for the increased risk based on their research and that of other investigators.

A rare small tumorigenic subpopulation of estrogen receptor-negative, progesterone receptor-negative cancer stem cells is present in experimental ER+, progesterone receptor-positive human breast cancers.

Progestins but not estrogens act on the ER+, progesterone receptor-positive differentiated cells (especially in small nascent tumor colonies) to reactivate and revert to the more primitive estrogen receptor-negative, progesterone receptor-negative stem cells without requiring proliferation. The authors propose that a reservoir of occult, undetected, preinvasive breast cancer or dormant breast cancer stem cells is present before the start of estrogen plus progestin therapy in some women.

Autopsy data of women over 40 years of age who did not have known breast cancer during life showed that the median prevalence of invasive breast cancer at death was 1.3% (range: 0%-1.8%), and the median prevalence of ductal carcinoma in situ was 8.9% (range: 0%-14%). Estrogens are not involved in the activation process, but once receptors are reacquired, they can act through their mitogenic properties to expand the tumor cell population.

The authors believe that improved screening methods are needed to detect occult, possibly dormant, breast cancers before initiation of hormone replacement therapy. If the hypothesis is correct, women with such preexisting malignancies should be excluded from regimens containing systemic progestins.

2010 – Finland – Norethisterone known to double breast cancer rate

4) Lyytinen, Heli, et al. “Do the dose or route of administration of norethisterone acetate as a part of hormone therapy play a role in risk of breast cancer: National‐wide case‐control study from Finland.” International journal of cancer 127.1 (2010): 185-189.

In Finland, the most common progestagen as a part of EPT is norethisterone acetate (NETA), which can be given both orally and transdermally.3 The use of a “low” dose NETA-regimen was associated with an increased risk for breast cancer already in 3 years of use (1.94; 1.39–2.70)

2008 – Norethisterone Doubles Breast Cancer- French Cohort Study

5) Fournier, Agnès, Franco Berrino, and Françoise Clavel-Chapelon. “Unequal risks for breast cancer associated with different hormone replacement therapies: results from the E3N cohort study.” Breast cancer research and treatment 107 (2008): 103-111.

Vitamin D prevents >55 improves overall and disease-free survival after BRCA. Germany

6) Vrieling, Alina, et al. “Serum 25-hydroxyvitamin D and postmenopausal breast cancer survival: a prospective patient cohort study.” Breast cancer research 13 (2011): 1-9.

the aim of our study was to assess the effect of post-diagnostic serum 25-hydroxyvitamin D [25(OH)D] concentrations on overall survival and distant disease-free survival.

METHODS: We conducted a prospective cohort study in Germany including 1,295 incident postmenopausal breast cancer patients aged 50-74 years. Patients were diagnosed between 2002 and 2005 and median follow-up was 5.8 years.

RESULTS: Lower concentrations of 25(OH)D were linearly associated with higher risk of death (hazard ratio (HR) = 1.08 per 10 nmol/L decrement; 95% confidence interval (CI), 1.00 to 1.17) and significantly higher risk of distant recurrence (HR = 1.14 per 10 nmol/L decrement; 95%CI, 1.05 to 1.24). Compared with the highest tertile (≥ 55 nmol/L), patients within the lowest tertile (< 35 nmol/L) of 25(OH)D had a HR for overall survival of 1.55 (95%CI, 1.00 to 2.39) and a HR for distant disease-free survival of 2.09 (95%CI, 1.29 to 3.41).

CONCLUSIONS:In conclusion, lower serum 25(OH)D concentrations may be associated with poorer overall survival and distant disease-free survival in postmenopausal breast cancer patients.

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7) Creasman, William T., and Philip J. DiSaia. “Hormone replacement and breast cancer risk: reconsidering the data.” Breast Cancer 23.12 (2009).

We remain amazed at the literature that incriminates estrogen/progestin and estrogen alone, quoting the 2002 WHI article for estrogen/progestin even though there have been over 100 articles from the WHI since then, in which a significant amount of the 2002 data have been temporized or shown not to support the conclusions of the 2002 publication. Many articles have been written severely criticizing the methodology of the WHI study, including eligibility, surveillance, presentation of nonadjudicated data, and certainly the age of the participants, to name a few. We are not writing to reiterate those faults, but to suggest that recent WHI data do not note an increase in breast cancer risk.

The 2002 article stated that the hazard ratio (HR) for estrogen plus progestin was 1.26 (95% confidence interval [CI] = 1.0–1.59), which is not statistically significant but was the reason for stopping the study. In a 2003 article, the HR was 1.24 (95% CI = 1.01–1.54), now barely significant as the number of breast cancers had increased since the 2002 publication.[2]

In the 2006 publication on estrogen plus progestin, the adjusted HR was 1.20 (95% CI = 0.94–1.53).[3] Although the WHI investigators may have been under significant pressure to publish data from the study, we suggest that it may have been reported prematurely, and the bulk of the patients were elderly women upon enrollment. More women who were 50 to 59 years of age, or less than 10 years from menopause should have been enrolled. In truth, how many 70-year-old women are placed on HRT for the first time?

In the 50- to 59-year-old age group, not only was there no increased risk, but the HR was actually less than 1.[4] In their rather detailed article on younger women with cardiovascular disease, the investigators commented that women less than 10 years since menopause had an HR of 1.19 (95% CI = 0.84–1.70) for breast cancer.[4] This is certainly not statistically significant.

In 2004, the data on estrogen alone was presented for the first time (a prospective randomized study of about 10,000 women compared to over 16,000 women in the estrogen/progestin study). The HR for breast cancer was 0.77 (95% CI = 0.59–1.01).[5] In the 50- to 59-year-olds, the HR was 0.72 (95% CI = 0.43–1.21). In 2006, a 7.1-year follow-up of estrogen and breast cancer risk was published. If a woman had no prior replacement therapy history, her HR was 0.76 (95% CI = 0.58–0.99), her risk for ductal cancer was 0.71 (95% CI = 0.52–0.99), and if she was adherent in regard to taking her medication, the HR was 0.67 (95% CI = 0.47–0.97).[6] Therefore, we question the assumption that estrogen/progestin and estrogen alone increase the risk of breast cancer using the studies that the commentary referenced.

That being the case, why is traditional HRT contraindicated in women who have had breast cancer? From a historical perspective, for many years estrogen was used as primary treatment for postmenopausal women with recurrent or metastatic breast cancer. In the 1970s and early 1980s, several prospective randomized studies compared estrogen with tamoxifen(Drug information on tamoxifen) in such women. The results were similar.[7]

Since alternatives, as noted in the commentary, are not very effective, numerous published articles have noted that recurrence rates in breast cancer survivors who chose to take HRT for symptom relief were very low. Yes, these were retrospective studies with built-in bias. One bias may come from the woman herself, as she chooses to take the hormones.

Several case control and cohort studies have compared HRT with such controls, and in over 1,200 cases and 3,800 controls, there was twice as many recurrences in the controls as in those on hormones.[6]

Two prospective randomized studies have compared hormones with controls. Both of these studies originated in Sweden.

In the HABITS study, 442 women were randomized to receive hormones or no hormones for 2 years. The initial report in 2004 noted an HR of 3.3 (95% CI = 1.5–7.4), and the study was stopped.[9] A 4-year follow-up noted an adjusted HR of 2.2 (95% CI = 1.0–5.0).[10]

The other study (the Stockholm trial) randomized 359 breast cancer women to 5 years of hormones or no hormones. Data reported in 2008 noted an HR of 0.8 (95% CI = 0.35–1.9).[11] The investigators found no difference in breast cancer deaths between the hormone and no-hormone groups in either study.

Why is HRT contraindicated in a 50-year-old newly menopausal breast cancer survivor who was successfully treated for her cancer at 40 years of age? Hasn’t she been getting endogenous estrogen for the last 10 years? This question and others make these authors question the tenet that postmenopausal estrogen therapy is always contraindicated in a woman who has had breast cancer.

8) Xydakis, Antonios M., Evangelos Gr Sakkas, and George Mastorakos. “Hormone replacement therapy in breast cancer survivors.” Annals of the New York Academy of Sciences 1092.1 (2006): 349-360.

It is well known that women with breast cancer who undergo therapies beyond the surgical intervention (adjuvant chemotherapy, hormone therapy, or both) often suffer from the lack of estrogen, manifesting as climacteric symptoms in either treated premenopausal or postmenopausal women. Although HRT (hormone replacement therapy) is traditionally viewed as a contraindication in women with a history of breast cancer, more women are willing to receive HRT for symptom relief.

“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.”

Nevertheless, because these studies are retrospective and different in terms of lymph node status, estrogen receptor (ER) status, and type of HRT used, firm conclusions on potential HRT use cannot be safely drawn. The few prospective studies appear controversial possibly due to differences in the studies’ design. A potential scheme for possible HRT use in selected breast cancer survivors with severe climacteric symptoms is suggested. The duration of HRT use is debatable because there is insufficient evidence at present.

However, the available data suggest that 3-year and possibly 5-year HRT use may be safe.

In summary, while HRT cannot currently be recommended as first-line therapy, it may still be of benefit in the management of selected early stage breast cancer survivors with refractory climacteric symptoms after a well-informed decision and an individualized risk benefit discussion.

2/16 alpha-hydroxyestrone ratio

9) Ho, G. H., et al. “Urinary 2/16 alpha-hydroxyestrone ratio: correlation with serum insulin-like growth factor binding protein-3 and a potential biomarker of breast cancer risk.” Annals of the Academy of Medicine, Singapore 27.2 (1998): 294-299.

Metabolism of estradiol occurs via two mutually exclusive hydroxylative pathways, yielding metabolites of divergent biological properties.

2-hydroxyestrone (2OHE1) is anti-estrogenic while 16 alpha-hydroxyestrone (16 alpha OHE1) is a potent estrogen.

The ratio of 2OHE1 to 16 alpha OHE1 (2/16 alpha-OHE1 ratio) represents the net in vivo estrogenic activity. In this study, we sought to determine if the urinary 2/16 alpha-OHE1 ratio could be a predictor of breast cancer risk and the factors which influence this ratio. Variables analysed included age at diagnosis, menopausal status, parity, use of oral contraceptives, body mass index, serum levels of insulin-like growth factor-I (IGF-I), IGF binding proteins (BPs) and the presence of breast cancer. Serum and urine were collected from 65 breast cancer patients and 36 controls after an overnight fast. Urinary estrogen metabolites were measured by enzyme immunoassays while serum levels of IGF-I, BP-1 and BP-3 were determined by immunoradiometric assays. 2OHE1 levels and 2/16 alpha-OHE1 ratios were significantly lower (P < 0.05) while 16 alpha OHE1 levels were higher (P < 0.01) in cancer patients. Multiple linear regression analysis showed that levels of urinary metabolites were influenced by parity and breast carcinoma. 2/16 alpha-OHE1 ratio correlated positively with serum BP-3 level (P = 0.03). By multiple logistic regression, 2/16 alpha-OHE1 ratio was the most significant factor predictive of breast cancer. The odds ratio for women with higher 2/16 alpha-OHE1 ratios was 0.10 (0.03-0.38, 95% confidence interval). In conclusion, the profile of urinary estradiol metabolites was distinctly altered in breast cancer patients. In addition, BP-3 may be a potential mechanism by which estradiol metabolites influence breast cancer progression. As 16 alpha OHE1 has been shown to initiate neoplastic transformation of mammary epithelial cells, the 2/16 alpha-OHE1 ratio may serve as a biomarker of increased risk of breast cancer.

10) Muti, Paola, et al. “Estrogen metabolism and risk of breast cancer: a prospective study of the 2:16α-hydroxyestrone ratio in premenopausal and postmenopausal women.” Epidemiology 11.6 (2000): 635-640.

Experimental and clinical evidence suggests that 16alpha-hydroxylated estrogen metabolites, biologically strong estrogens, are associated with breast cancer risk, while 2-hydroxylated metabolites, with lower estrogenic activity, are weakly related to this disease. This study analyzes the association of breast cancer risk with estrogen metabolism, expressed as the ratio of 2-hydroxyestrone to 16alpha-hydroxyestrone, in a prospective nested case-control study. Between 1987 and 1992, 10,786 women (ages 35-69 years) were recruited to a prospective study on breast cancer in Italy, the “Hormones and Diet in the Etiology of Breast Cancer” (ORDET) study. Women with a history of cancer and women on hormone therapy were excluded at baseline. At recruitment, overnight urine was collected from all participants and stored at -80 degrees C. After an average of 5.5 years of follow-up, 144 breast cancer cases and four matched controls for each case were identified among the participants of the cohort.

Among premenopausal women, a higher ratio of 2-hydroxyestrone to 16alpha-hydroxyestrone at baseline was associated with a reduced risk of breast cancer: women in the highest quintile of the ratio had an adjusted odds ratio (OR) for breast cancer of 0.58 [95% confidence interval (CI) = 0.25-1.34]. The corresponding adjusted OR in postmenopausal women was 1.29 (95% CI = 0.53-3.10). Results of this prospective study support the hypothesis that the estrogen metabolism pathway favoring 2-hydroxylation over 16alpha-hydroxylation is associated with a reduced risk of invasive breast cancer risk in premenopausal women.

11) Lord, Richard S., Bradley Bongiovanni, and J. Alexander Bralley. “Estrogen metabolism and the diet-cancer connection: rationale for assessing the ratio of urinary hydroxylated estrogen metabolites.” Alternative Medicine Review 7.2 (2002): 112-129.

Estrogens are known for their proliferative effects on estrogen-sensitive tissues resulting in tumorigenesis. Results of experiments in multiple laboratories over the last 20 years have shown that a large part of the cancer-inducing effect of estrogen involves the formation of agonistic metabolites of estrogen, especially 16-alpha-hydroxyestrone. Other metabolites, such as 2-hydroxyestrone and 2-hydroxyestradiol, offer protection against the estrogen-agonist effects of 16-alpha-hydroxyestrone. An ELISA method for measuring 2- and 16-alpha-hydroxylated estrogen (OHE) metabolites in urine is available and the ratio of urinary 2-OHE/16-alpha-OHE (2/16-alpha ratio) is a useful biomarker for estrogen-related cancer risk. The CYP1A1 enzyme that catalyzes 2-hydroxyestrone (2-OHE1) formation is inducible by dietary modification and supplementation with the active components of cruciferous vegetables, indole-3-carbinol (I-3-C), or diindolylmethane (DIM). Other dietary components, especially omega-3 polyunsaturated fatty acids and lignans in foods like flax seed, also exert favorable effects on estrogen metabolism. Thus, there appear to be effective dietary means for reducing cancer risk by improving estrogen metabolism.

2004- Durna-Australia- Premenopausal BR CA -observational study

12) Durna, E. M., et al. “Breast cancer in premenopausal women: recurrence and survival rates and relationship to hormone replacement therapy.” Climacteric 7.3 (2004): 284-291.

METHODS: The study group comprised 524 women who were diagnosed with breast cancer when they were premenopausal. Of these, 277 women reached menopause before recurrence of the disease, being lost to follow-up, or reaching the end of the study. In this group, 119 women took HRT to control menopausal symptoms. The majority took combined continuous estrogen-progestin treatment. Times from diagnosis to cancer recurrence or new breast cancer, to death from all causes, and to death from primary tumor were compared between HRT users and non-users.

RESULTS: Women who used HRT after their menopause had an adjusted relative risk of recurrence or new breast cancer of 0.75 (95% confidence interval (CI), 0.29-1.95) compared to that of non-users. The relative risk of death from all causes was 0.36 (95% CI, 0.11-1.16) and that of death from primary tumor was 0.24 (95% CI, 0.05-1.14).

CONCLUSION: HRT use in women who were premenopausal at the diagnosis of primary invasive breast cancer is not associated with worse outcomes in terms of breast cancer recurrence or mortality.

2002 -Observational Study Australia Dr – Durna

13) Durna, E. M., et al. “Breast cancer in premenopausal women: recurrence and survival rates and relationship to hormone replacement therapy.” Climacteric 7.3 (2004): 284-291.

To determine whether hormone replacement therapy (HRT) after treatment for breast cancer is associated with increased risk of recurrence and mortality.

DESIGN: Retrospective observational study.
PARTICIPANTS AND SETTING: Postmenopausal women diagnosed with breast cancer and treated by five Sydney doctors between 1964 and 1999.
OUTCOME MEASURES: Times from diagnosis to cancer recurrence or new breast cancer, to death from all causes and to death from primary tumour were compared between women who used HRT for menopausal symptoms after diagnosis and those who did not. Relative risks (RRs) were determined from Cox regression analyses, adjusted for patient and tumour characteristics.
RESULTS: 1122 women were followed up for 0-36 years (median, 6.08 years); 154 were lost to follow-up. 286 women used HRT for menopausal symptoms for up to 26 years (median, 1.75 years). Compared with non-users, HRT users had reduced risk of cancer recurrence (adjusted relative risk [RR], 0.62; 95% CI, 0.43-0.87), all-cause mortality (RR, 0.34; 95% CI, 0.19-0.59) and death from primary tumour (RR, 0.40; 95% CI, 0.22-0.72).

Continuous combined HRT was associated with a reduced risk of death from primary tumour (RR, 0.32; 95% CI, 0.12-0.88) and all-cause mortality (RR, 0.27; 95% CI, 0.10-0.73).

CONCLUSION: HRT use for menopausal symptoms by women treated for primary invasive breast cancer is not associated with an increased risk of breast cancer recurrence or shortened life expectancy.

WILLIAM CREASMAN, MD

14) Creasman, William. “Weighing HRT use after breast cancer.” OBG MANAGEMENT 14.6 (2002): 16-36.

HRT has long been contraindicated in women who have—or have had—breast cancer. Here, the author examines the effects estrogen has on the breast and reviews several studies that suggest HRT actually may be of benefit to these women.

WILLIAM CREASMAN, MD – Dr. Creasman is the J. Marion Sims Professor of OBG at the Medical University of South Carolina in Charleston.

15) deleted

16) Meurer, Linda N., and Sarah Lena. “Cancer recurrence and mortality in women using hormone replacement therapy after breast cancer: Meta-analysis.” Journal of family practice 51.12 (2002): 1056-1064.

We compared the risk of cancer recurrence and all-cause mortality among users and nonusers of estrogen replacement therapy (ERT) after the diagnosis of breast cancer.

STUDY DESIGN:  This was a systematic review of original research. Eligible studies were reviewed by 2 investigators who independently extracted data from each study according to a predetermined form and assessed each study for validity on standard characteristics. Meta-analyses were performed with Review Manager 4.1 to provide a summary of relative risks of cancer recurrence and mortality.

POPULATION:Studies included 717 subjects who used hormone replacement therapy (HRT) at some time after their diagnosis of breast cancer, as well as 2545 subjects who did not use HRT.

OUTCOMES MEASURED: Outcomes included breast cancer recurrence and all-cause mortality.

RESULTS: Nine independent cohort studies and one 6-month pilot randomized controlled trial were identified. Studies were of variable quality. Breast cancer survivors using ERT experienced no increase in the risk of recurrence compared with controls (relative risk, 0.72; 95% confidence interval, 0.47-1.10) and had significantly fewer deaths (3.0%) than did the non-users (11.4%) over the combined study periods (relative risk, 0.18; 95% confidence interval, 0.10-0.31). All tests for heterogeneity were nonsignificant.

CONCLUSIONS: Although limited by observational design, existing research does not support the universal withholding of ERT from well-informed women with a previous diagnosis of low-stage breast cancer. Long-term randomized controlled trials are needed.

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HABITS  2011 Brennan – Australia

17) Brennan, Meagan E., and Nehmat Houssami. “Overview of long term care of breast cancer survivors.” (2011).

6.2. Hormone replacement therapy

The HABITS study,a randomized trial addressing the efficacy and safely of hormone replacement therapy after breast cancer treatment, was stopped after median follow-up of 2 years.

showed a significantly higher risk of breast cancer events in women randomised to treatment with HRT (clinician choice of therapy) compared to those not taking HRT (relative hazard (RH) risk 3.5; 26 vs 7 events). There was a higher risk of new events in women with
hormone receptor positive cancer (RH 4.8), those not taking tamoxifen (RH3.7) and those taking HRT before breast cancer diagnosis (RH 6.9) [71].

In this trial,there was no significant difference in risk between combined preparations,oestrogen-only preparations and other  preparations (such as tibolone) [71]. The Stockholm trial also randomised survivors to treatment with HRT or no HRT ;in this study there was no increased risk of recurrence in women in the HRT arm.  One possible explanation for this is the higher proportion of women taking oestrogen-only preparations rather than continuous combined hormone preparations,indicating that the
oestrogen-only preparations may be less hazardous in this group of women [72].

Based on these studies,systemic HRT is not recommended in breast cancer survivors.

2008 HABITS – Extended Follow Up

RCT – increased breast cancer rate in HRT users -Estradiol hemihydrate and norethisterone: Increased recurrence in BR CA survivors

18) Holmberg, Lars, et al. “Increased risk of recurrence after hormone replacement therapy in breast cancer survivors.” Journal of the National Cancer Institute 100.7 (2008): 475-482.

METHODS: HABITS was a randomized, non-placebo-controlled noninferiority trial that aimed to be at a power of 80% to detect a 36% increase in the hazard ratio (HR) for a new breast cancer event following HT.  Most patients who received HT were prescribed continuous combined or sequential estradiol hemihydrate and norethisterone.

Of the 447 women randomly assigned, 442 could be followed for a median of 4 years. Thirty-nine of the 221 women in the HT arm and 17 of the 221 women in the control arm experienced a new breast cancer event (HR = 2.4, 95% CI = 1.3 to 4.2). Cumulative incidences at 5 years were 22.2% in the HT arm and 8.0% in the control arm. By the end of follow-up, six women in the HT arm had died of breast cancer and six were alive with distant metastases. In the control arm, five women had died of breast cancer and four had metastatic breast cancer (P = .51, log-rank test).

CONCLUSION: After extended follow-up, there was a clinically and statistically significant increased risk of a new breast cancer event in survivors who took HT.

2004 – HABITS – Sweden – used norethisterone (known to be carcinogenic).

19) Holmberg, L., and H. Anderson. “HABITS (hormonal replacement therapy after breast cancer—is it safe?): a randomized comparison trial stopped.” Obstetrical & gynecological survey 59.6 (2004): 442-443.

In the 1990s, two randomised clinical trials started in Scandinavia addressing whether hormone replacement therapy (HRT) is safe for women with previous breast cancer. We report the findings of the safety analysis in HABITS (hormonal replacement therapy after breast cancer–is it safe?), an open randomised clinical trial with allocation to either HRT or best treatment without hormones. The main endpoint was any new breast cancer event. All analyses were done according to intention-to-treat. Until September, 2003, 434 women were randomised; 345 had at least one follow-up report. After a median follow-up of 2.1 years, 26 women in the HRT group and seven in the non-HRT group had a new breast-cancer event. All women with an event in the HRT group and two of those in the non-HRT group were exposed to HRT and most women had their event when on treatment. We decided that these findings indicated an unacceptable risk for women exposed to HRT in the HABITS trial, and the trial was terminated on Dec 17, 2003.

Minimize use of progestin !!!!  2005  StockHolm Randomized Trial

20) von Schoultz, Eva, and Lars E. Rutqvist. “Menopausal hormone therapy after breast cancer: the Stockholm randomized trial.” Journal of the National Cancer Institute 97.7 (2005): 533-535.

In 1997 two independent randomized clinical trials, Hormonal Replacement Therapy After Breast Cancer–Is It Safe? (HABITS; 434 patients) and the Stockholm trial (378 patients), were initiated in Sweden to compare menopausal hormone therapy with no menopausal hormone therapy after diagnosis of early-stage breast cancer. Much of the design of both studies was similar; however, a goal of the Stockholm protocol, not shared with the HABITS trial, was to minimize the use of progestogen combined with estrogen. The HABITS trial was prematurely stopped in December 2003, because, at a median follow-up of 2.1 years, the risk for recurrence of breast cancer among patients receiving menopausal hormone therapy was statistically significantly higher (relative hazard [RH] = 3.3, 95% confidence interval [CI] = 1.5 to 7.4) than among those receiving no treatment. In the Stockholm trial, however, at a median follow-up of 4.1 years, the risk of breast cancer recurrence was not associated with menopausal hormone therapy (RH = 0.82, 95% CI = 0.35 to 1.9). Statistically significant heterogeneity in the rate of recurrence was observed (P = .02; two-sided likelihood-ratio test) between the two studies, indicating that chance may not be the only explanation. Doses of estrogen and progestogen and treatment regimens for menopausal hormone therapy may be associated with the recurrence of breast cancer.

MEGESTROL 2002 Natrajan -Megestrol – Megace

21) Natrajan, Puthugramam K., and R. Don Gambrell Jr. “Estrogen replacement therapy in patients with early breast cancer.” American journal of obstetrics and gynecology 187.2 (2002): 289-295.

Most physicians believe that estrogen replacement therapy is contraindicated once a patient is diagnosed with breast cancer. Recently, several studies have shown that estrogen replacement therapy may be safely used in patients with early breast cancer that has been treated successfully. These women can have severe menopausal symptoms and are at risk for osteoporosis. We reviewed the current status of women in our practice with breast cancer who received estrogen replacement therapy, who did not receive hormone replacement therapy, and who did not receive estrogenic hormone replacement therapy.

STUDY DESIGN:The study group consisted of 123 women (mean age, 65.4 +/- 8.85 years) who were diagnosed with breast cancer in our practice, including 69 patients who received estrogen replacement therapy for < or = 32 years after diagnosis. The comparative groups were 22 women who used nonestrogenic hormones for < or = 18 years and 32 women who used no hormones for < or = 12 years. The group who did not receive estrogenic hormone replacement therapy received androgens with or without progestogens (such as megestrol acetate). Of the 63 living hormone users, 56 women are still being treated in our clinic, as are 15 of the 22 subjects who receive nonestrogenic hormone replacement therapy. Follow-up was done through the tumor registry at University Hospital; those patients whose tumor records were not current were contacted by telephone.

RESULTS:There were 18 deaths in the 123 patients: 6 patients who received estrogen replacement therapy (8.69%), 2 patients who received nonestrogenic hormone replacement therapy (9.09%), and 10 patients who received no hormone replacement therapy (31.25%).

Of the 18 deaths, 9 deaths were from breast cancer (mortality rate, 7.3%); 3 deaths were from lung cancer; 1 death was from endometrial cancer; 1 death was from myocardial infarction; 1 death was from renal failure; and 3 deaths were from cerebrovascular accidents. The 9 deaths from breast cancer included one patient who received nonestrogenic hormone replacement therapy (mortality rate, 4.5%), 6 patients who received no hormone replacement therapy (mortality rate, 11.3%), and 2 patients who received estrogen replacement therapy (mortality rate, 4.28%). The 9 non-breast cancer deaths included 4 patients who received estrogen replacement therapy (endometrial cancer [1 death], lung cancer [1 death], cerebrovascular accident [1 death], and renal failure [1 death]), 1 patient who did not receive estrogenic hormone replacement therapy group (myocardial infarction), and 4 patients who used no hormones (lung cancer, 2 deaths; stroke, 2 deaths). Carcinoma developed in one patient in the estrogen replacement therapy group in the contralateral breast after 4 years of hormone replacement therapy; she is living and well 2.5 years later with no evidence of disease. Metastatic breast cancer developed in one patient after 8 years of hormone replacement therapy; she is living with disease.

CONCLUSION: Estrogen replacement therapy apparently does not increase either the risk of recurrence or of death in patients with early breast cancer. These patients may be offered estrogen replacement therapy after a full explanation of the benefits, risks, and controversies.

1999 Estradiol plus Megace (Megestrol Acetate -used as Br CA Rx)

22) Natrajan, Puthgraman K., Kostas Soumakis, and R. Don Gambrell Jr. “Estrogen replacement therapy in women with previous breast cancer.” American journal of obstetrics and gynecology 181.2 (1999): 288-295.

OBJECTIVE: We sought to review the status of patients with breast cancer who were treated with  estrogen replacement therapy and compare the results with those of nonestrogenic hormone users and  women not treated with hormone replacement.

STUDY DESIGN: The study group consisted of 76  patients with breast cancer, including 50 using estrogen replacement for up to 32 years, 8 using  nonestrogenic hormone replacement for up to 6 years and followed for up to 11 years, and 18 using no hormones for up to 10 years. In addition to estrogen use, 40 of the 50 hormone users were treated with  androgens, usually in the form of implantation of testosterone pellets. Forty-five subjects were also given progestogens, usually megestrol acetate 20 to 40 mg for 10 to 25 days each month. The 8 nonestrogen   hormone users were treated with various combinations of testosterone pellets, tamoxifen, and   progestogens. Forty-two of the 50 estrogen users are still being treated in our clinic, as are 2 of the 8 subjects using nonestrogen hormone. Follow-up was done through the tumor registry at University  Hospital, and those whose tumor records were not current were telephoned.

RESULTS: Of the 50 estrogen users, 3 have died (a mortality rate of 6%), and the rest have been followed for 6 months to 32  years, with a mean duration of follow-up of 83.3 +/- 8.81 months. One of the 8 nonestrogen hormone  users has died (a mortality rate of 12.5%), and the rest have been followed for 2 to 11 years, with a mean   duration of follow-up of 72.0 +/- 5. 93 months. Six of the 18 women not using hormone replacement have   died (a mortality rate of 33.3%), and the rest have been followed for 6 months to 10 years, with a mean   duration of follow-up of 50.5 +/- 6.01 months.

CONCLUSION: Estrogen replacement therapy apparently  does not increase either recurrences or mortality rates. Adding progestogens (Megace) may even decrease   recurrences. Women with early breast cancer should be offered hormone replacement therapy after a  full explanation of the benefits, risks, and controversies.

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HRT in BRCA GENE women after OOphorectomy or Menopause-
less BR CA with HRT – Eisen 2008

23) Eisen, Andrea, et al. “Hormone therapy and the risk of breast cancer in BRCA1 mutation carriers.” Journal of the National Cancer Institute 100.19 (2008): 1361-1367.

The potential association of HT and breast cancer risk is of particular interest to women who carry a mutation in BRCA1 because they face a high lifetime risk of breast cancer and because many of these women take HT after undergoing prophylactic surgical oophorectomy at a young age.

We conducted a matched case-control study of 472 postmenopausal women with a BRCA1 mutation to examine whether or not the use of HT is associated with subsequent risk of breast cancer. Breast cancer case patients and control subjects were matched with respect to age, age at menopause, and type of menopause (surgical or natural).

RESULTS:In this group of BRCA1 mutation carriers, the adjusted OR for breast cancer associated with ever use of HT compared with never use was 0.58 (95% CI = 0.35 to 0.96; P = .03). In analyses by type of HT, an inverse association with breast cancer risk was observed with use of estrogen only (OR = 0.51, 95% CI = 0.27 to 0.98; P = .04); the association with use of estrogen plus progesterone was not statistically significant (OR = 0.66, 95% CI = 0.34 to 1.27; P = .21).
CONCLUSION:Among postmenopausal women with a BRCA1 mutation, HT use was not associated with increased risk of breast cancer; indeed, in this population, it was associated with a decreased risk.

2008 BRCA GENE Carriers

24) Chlebowski, Rowan T., and Ross L. Prentice. “Menopausal hormone therapy in BRCA1 mutation carriers: uncertainty and caution.” Journal of the National Cancer Institute 100.19 (2008): 1341-1343.

2005

25) Rebbeck, Timothy R., et al. “Effect of short-term hormone replacement therapy on breast cancer risk reduction after bilateral prophylactic oophorectomy in BRCA1 and BRCA2 mutation carriers: the PROSE Study Group.” Journal of clinical oncology 23.31 (2005): 7804-7810.

Purpose Bilateral prophylactic oophorectomy (BPO) is widely used for cancer risk reduction in women with BRCA1/2 mutations. Many premenopausal women choose to take hormone replacement therapy (HRT) after undergoing BPO to abrogate immediate symptoms of surgically-induced menopause. Thus, we evaluated whether the breast cancer risk reduction conferred by BPO in BRCA1/2 mutation carriers is altered by use of post-BPO HRT. Methods We identified a prospective cohort of 462 women with disease-associated germline BRCA1/2 mutations at 13 medical centers to evaluate breast cancer risk after BPO with and without HRT. We determined the incidence of breast cancer in 155 women who had undergone BPO and in 307 women who had not undergone BPO on whom we had complete information on HRT use. Postoperative follow-up was 3.6 years.

Results Consistent with previous reports, BPO was significantly associated with breast cancer risk reduction overall (hazard ratio [HR] = 0.40; 95%CI, 0.18 to 0.92). Using mutation carriers without BPO or HRT as the referent group, HRT of any type after BPO did not significantly alter the reduction in breast cancer risk associated with BPO (HR = 0.37; 95% CI, 0.14 to 0.96). Conclusion Short-term HRT use does not negate the protective effect of BPO on subsequent breast cancer risk in BRCA1/2 mutation carriers.

2004

26) Armstrong, Katrina, et al. “Hormone replacement therapy and life expectancy after prophylactic oophorectomy in women with BRCA1/2 mutations: a decision analysis.” Journal of Clinical Oncology 22.6 (2004): 1045-1054.

The decision about prophylactic oophorectomy is difficult for many premenopausal women with BRCA1/2 mutations because of concerns and controversy about the use of hormone replacement therapy (HRT) after oophorectomy.

PATIENTS AND METHODS:A Markov decision analytic model used the most current epidemiologic data to assess the expected outcomes of prophylactic oophorectomy with or without HRT (to age 50 years or for life) in cohorts of women with BRCA1/2 mutations. Sensitivity analyses were conducted to assess the impact of alternative assumptions about effects of HRT, effects of prophylactic oophorectomy, and risks of cancer associated with BRCA1/2 mutations.

RESULTS:In our model, prophylactic oophorectomy lengthened life expectancy in women with BRCA1/2 mutations, irrespective of whether HRT was used after oophorectomy. This gain ranged from 3.34 to 4.65 years, depending on age at oophorectomy.

Use of HRT after oophorectomy was associated with relatively small changes in life expectancy (+0.17 to -0.34 years) when HRT was stopped at age 50, but larger decrements in life expectancy if HRT was continued for life (-0.79 to -1.09 years). HRT was associated with a gain in life expectancy of between 0.39 and 0.79 years for mutation carriers undergoing both prophylactic mastectomy and oophorectomy.

CONCLUSION:On the basis of the results of this decision analysis, we recommend that women with BRCA1/2 mutations undergo prophylactic oophorectomy after completion of childbearing, decide about short-term HRT after oophorectomy based largely on quality-of-life issues rather than life expectancy, and, if using HRT, consider discontinuing treatment at the time of expected natural menopause, approximately age 50 years.

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ovarian ablation  2011

27) Griggs, Jennifer J., et al. “American Society of Clinical Oncology endorsement of the cancer care Ontario practice guideline on adjuvant ovarian ablation in the treatment of premenopausal women with early-stage invasive breast cancer.” Journal of clinical oncology 29.29 (2011): 3939-3942.

chemical suppression using luteinizing hormone-releasing hormone agonists is the chosen method of OA, ovarian ablation

2004 -12 randomized trials of ovarian ablation in premenopausal women with BRCA

28) theoncologist.alphamedpress.org/content/9/5/507.long

Prowell, Tatiana M., and Nancy E. Davidson. “What is the role of ovarian ablation in the management of primary and metastatic breast cancer today?.” The oncologist 9.5 (2004): 507-517.

a more recent meta-analysis by the Early Breast Cancer Trialists’ Collaborative Group of 12 properly designed randomized trials found significantly greater disease-free and overall survival rates for women under the age of 50, regardless of nodal status, receiving ovarian ablation as a single adjuvant therapy.

Ovarian ablation was the original systemic therapy for breast cancer and has been in use for more than a hundred years, producing responses in approximately 30% of unselected women with metastatic breast cancer [1, 2], and in as many as 80% of women with steroid hormone receptor-positive (HR+) breast cancer [3, 4].

More recently, luteinizing hormone releasing hormone (LHRH) analogues, which act on the hypothalamic-pituitary-ovarian axis to suppress circulating estrogens to postmenopausal levels, have largely supplanted surgical and radiation-based approaches because of less morbidity and a lower likelihood of permanent amenorrhea, with the potential for restoration of fertility. Trials of adjuvant ovarian suppression have generally used either 2 [23] or 3 [26] years of treatment with an LHRH analogue, which produces comparable, and possibly even superior, outcomes to those obtained with CMF polychemotherapy in premenopausal HR+ patients. Ovarian ablation has long been established as an effective therapy for premenopausal women with metastatic breast cancer, with response rates ranging from 14%–70% in various studies [27].

Both the presence and degree of HR expression are strongly predictive of response to hormonal manipulation, with responses seen in approximately 60% of women having both ER+ and progesterone-receptor positive (PgR+) tumors, versus 30% in patients with either ER+ or PgR+ status alone [28]. Fewer than 10% of women with receptor negative (ER−/PgR−) disease respond to endocrine therapies [29].

Following the introduction of goserelin, a number of phase II trials of the monthly injections were conducted in premenopausal and perimenopausal women with advanced breast cancer. A meta-analysis of these trials containing more than 200 evaluable patients reported a median survival of 26.5 months, an overall response rate of 36% (44% in ER+ patients), and a median duration of response of 44 weeks [33, 34], which were comparable to the outcomes historically obtained with oophorectomy in similar patient populations. the combination of an LHRH analogue and tamoxifen may be superior to endocrine monotherapy in premenopausal HR+ women with advanced breast cancer and can be considered for first-line therapy. Approximately 25% of breast cancer patients are premenopausal at the time of diagnosis [41]; of these, 60% have HR+ tumors [42]. These women are regarded as potentially appropriate for hormonal manipulation.

!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!

the EBCTCG meta-analysis [10]. This overview of 12 randomized controlled trials enrolling a total of 2,102 patients reported that women under the age of 50 with early invasive breast cancer who underwent oophorectomy or ovarian irradiation, experienced approximately a 25% relative reduction in the risks of recurrence and mortality at 15 years of follow-up compared with those receiving no adjuvant therapy.

In summary, virtually all premenopausal women with early-stage HR+ breast cancer should receive adjuvant endocrine therapy. Combined endocrine therapy appears to be at least as effective as adjuvant CMF chemotherapy in this population.

1996

29) www.ncbi.nlm.nih.gov/pubmed/8898035?dopt=Abstract

Early Breast Cancer Trialists’ Collaborative Group. “Ovarian ablation in early breast cancer: overview of the randomised trials.” The Lancet 348.9036 (1996): 1189-1196.

Among women with early breast cancer, the effects of ovarian ablation on recurrence and death have been assessed by several randomised trials that now have long follow-up. In this report, the Early Breast Cancer Trialists’ Collaborative Group present their third 5-yearly systematic overview (meta-analysis), now with 15 years’ follow-up.

METHODS:In 1995, information was sought on each patient in any randomised trial of ovarian ablation or suppression versus control that began before 1990. Data were obtained for 12 of the 13 studies that assessed ovarian ablation by irradiation or surgery, all of which began before 1980, but not for the four studies that assessed ovarian suppression by drugs, all of which began after 1985. Menopausal status was not consistently defined across trials; therefore, the main analyses are limited to women aged under 50 (rather than “premenopausal”) when randomised. Oestrogen receptors were measured only in the trials of ablation plus cytotoxic chemotherapy versus the same chemotherapy alone.

FINDINGS:Among 2102 women aged under 50 when randomised, most of whom would have been premenopausal at diagnosis, 1130 deaths and an additional 153 recurrences were reported. 15-year survival was highly significantly improved among those allocated ovarian ablation (52.4 vs 46.1%, 6.3 [SD 2.3] fewer deaths per 100 women, logrank 2p = 0.001), as was recurrence-free survival (45.0 vs 39.0%, 2p = 0.0007).

The numbers of events were too small for any subgroup analyses to be reliable. The benefit was, however, significant both for those with (“node positive”) and for those without (“node negative”) axillary spread when diagnosed. In the trials of ablation plus cytotoxic chemotherapy versus the same chemotherapy alone, the benefit appeared smaller (even for women with oestrogen receptors detected on the primary tumour) than in the trials of ablation in the absence of chemotherapy (where the observed survival improvements were about six per 100 node-negative women and 12 per 100 node-positive women).

Among 1354 women aged 50 or over when randomised, most of whom would have been perimenopausal or postmenopausal, there was only a nonsignificant improvement in survival and recurrence-free survival.

INTERPRETATION:In women aged under 50 with early breast cancer, ablation of functioning ovaries significantly improves long-term survival, at least in the absence of chemotherapy. Further randomised evidence is needed on the additional effects of ovarian ablation in the presence of other adjuvant treatments, and to assess the relevance of hormone-receptor measurements.

30) Lu, Yen-Shen, Andrea Wong, and Hee-Jeong Kim. “Ovarian function suppression with luteinizing hormone-releasing hormone agonists for the treatment of hormone receptor-positive early breast cancer in premenopausal women.” Frontiers in Oncology 11 (2021): 700722.

31) www.ncbi.nlm.nih.gov/pubmed/21457974

Haldar, Krishnayan, et al. “Laparoscopic salpingo-oophorectomy for ovarian ablation in women with hormone-sensitive breast cancer.” International Journal of Gynecology & Obstetrics 113.3 (2011): 222-224.

To evaluate institutional experiences regarding laparoscopic salpingo-oophorectomy in breast cancer patients and to compare the technique with gonadotropin-releasing hormone (GnRH) analogs among premenopausal women with hormone-sensitive breast cancer.
METHODS:Between 2004 and 2009, 103 women with breast cancer underwent laparoscopic salpingo-oophorectomy at Addenbrooke’s Hospital, Cambridge, UK.
RESULTS:In the study period, 3 (2.9%) women experienced a recurrence of breast cancer but none had primary peritoneal/ovarian cancer within a median follow-up interval of 34 months (range, 0-70 months). No operative complications were noted among these women and all of them went home on the day of their operation.
CONCLUSION:Laparoscopic salpingo-oophorectomy seems to be a safe, permanent, and cost-effective method of ovarian ablation compared with the use of GnRH analogs. Salpingo-oophorectomy also considerably reduces the risk of subsequent ovarian/fallopian tube malignancy in this high-risk population.

2007

32) www.ncbi.nlm.nih.gov/pubmed/17713096
Kucera, E., Z. Holub, and G. Svobodova. “Laparoscopic oophorectomy either with or without hysterectomy for early breast cancer.” European journal of gynaecological oncology 28.4 (2007): 294-296.

METHODS:Ninety women in early breast cancer stage who underwent laparoscopic bilateral salpingo-oophorectomy (BSO) either with or without hysterectomy were identified in a retrospective study conducted between January 2000 and December 2006. Tamoxifen antiestrogen therapy was used prior to hysterectomy.

RESULTS:Forty-eight consecutive patients underwent laparoscopic hysterectomy with bilateral salpingo-oophorectomy and 42 with ovarian ablation only. The mean operative time for the laparoscopic hysterectomy and bilateral salpingo-oophorectomy or BSO alone was 82 min and 47.8 min, respectively. Blood loss was minimal in both groups (range: 20-250 ml). The rate of postoperative complications was very low (4.4%). One of all ovaries removed by laparoscopy showed ovarian breast carcinoma metastasis. Histopathologic examination revealed concomitant findings of leiomyoma, adenomyosis or endometrial abnormalities in 64.5% of hysterectomy specimens.

CONCLUSION:Our experience with ovarian ablation either with or without hysterectomy confirmed that the use of a minimally invasive technique is feasible. We assume that ovarian ablation and hysterectomy is an appropriate treatment for premenopausal women at risk (BRCA positive) or for patients with concomitant benign uterine pathology, treated with tamoxifen in first-line therapy. Removing the uterus allows women to take only estrogens rather than combination HRT. Further investigation into the indications of disease where laparoscopic ablative surgery is appropriate in the management of early breast cancer is needed.

2003

33) www.ncbi.nlm.nih.gov/pubmed/14998564
Sainsbury, Richard. “Ovarian ablation as a treatment for breast cancer.” Surgical Oncology 12.4 (2003): 241-250.

Ovarian ablation is an effective treatment for premenopausal women with hormone receptor positive breast cancer. It can be achieved permanently by surgery or radiotherapy and reversibly by LhRH agonists. This paper discusses the evidence that it is an effective adjuvant therapy and defines the place of oophorectomy in the management of such patients. The achievement of an amenhorreic state is important and chemotherapy may well exert some of its effects by causing ovarian suppression. The use of LhRH agonists in managing such patients is discussed.

2006

34) www.ncbi.nlm.nih.gov/pubmed/16940812

El-Saghir, Nagi S., et al. “Combined ovarian ablation and aromatase inhibition as first-line therapy for hormone receptor-positive metastatic breast cancer in premenopausal women: report of three cases.” Anti-cancer drugs 17.8 (2006): 999-1002.

Aromatase inhibitors have become well established for the treatment of postmenopausal women with hormone receptor-positive metastatic breast cancer and for adjuvant hormonal therapy for primary breast cancer. Benefit of aromatase inhibition has not yet been extended to premenopausal women. Ovarian ablation by oophorectomy, ovarian radiation or hormonal suppression is the initial recommended treatment for hormone receptor-positive metastatic breast cancer in premenopausal women. The addition of tamoxifen improves the benefit of ovarian ablation/ovarian suppression. Addition of aromatase inhibitors to luteinizing hormone-releasing hormone analogs has been reported to significantly decrease circulating estrogens and produce tumor responses in only a very small number of patients over the last 15 years. We treated three premenopausal patients with hormone receptor-positive metastatic breast cancer with combined oophorectomy or ovarian irradiation and anastrozole. One patient remained free of progression for 4 years, while the other two remained free of progression for more than 5 and 3 years, respectively. We also note that monthly zoledronic acid for 4 years produced sclerosis of vertebral body metastasis. We conclude that combined ovarian ablation and aromatase inhibition is a feasible treatment modality that deserves more attention and further investigation for hormone receptor-positive metastatic breast cancer in premenopausal women.

Topical Progesterone Does NOT Cause Breast Cancer

35)http://ukpmc.ac.uk/abstract/MED/10403900

Plu-Bureau, G., et al. “Percutaneous progesterone use and risk of breast cancer: results from a French cohort study of premenopausal women with benign breast disease.” Cancer detection and prevention 23.4 (1999): 290-296.

Percutaneous progesterone topically applied on the breast has been proposed and widely used in the relief of mastalgia and benign breast disease by numerous gynecologists and general practitioners. However, its chronic use has never been evaluated in relation to breast cancer risk. The association between percutaneous progesterone use and the risk of breast cancer was evaluated in a cohort study of 1150 premenopausal French women with benign breast disease diagnosed in two breast clinics between 1976 and 1979. The follow-up accumulated 12,462 person-years. Percutaneous progesterone had been prescribed to 58% of the women.

There was no association between breast cancer risk and the use of percutaneous progesterone (RR = 0.8; 95% confidence interval 0.4-1.6). Although the combined treatment of oral progestogens with percutaneous progesterone significantly decreased the risk of breast cancer (RR = 0.5; 95% confidence interval 0.2-0.9) as compared with nonusers, there was no significant difference in the risk of breast cancer in percutaneous progesterone users versus nonusers among oral progestogen users. Taken together, these results suggest at least an absence of deleterious effects caused by percutaneous progesterone use in women with benign breast disease.

1997 – Women with family history of breast cancer – Reduced Mortality for HRT users

36) www.ncbi.nlm.nih.gov/pubmed/9412302
Sellers, Thomas A., et al. “The role of hormone replacement therapy in the risk for breast cancer and total mortality in women with a family history of breast cancer.” Annals of internal medicine 127.11 (1997): 973-980.

The risks and benefits of hormone replacement therapy (HRT) are of considerable interest and importance, especially in terms of whether they differ among subsets of women.

OBJECTIVE: To determine whether HRT is associated with increased risks for breast cancer and total mortality in women with a family history of breast cancer.
DESIGN: Prospective cohort study.

SETTING: Population-based sample of midwestern post-menopausal women enrolled in an observational study of risk factors for cancer.

PARTICIPANTS: Random sample of 41,837 female Iowa residents 55 to 69 years of age.

MEASUREMENTS: Incidence rates of and relative risks for breast cancer (n = 1085) and total mortality (n = 2035) through 8 years of follow-up were calculated by using data from the State Health Registry of Iowa and the National Death Index.

RESULTS: A family history of breast cancer was reported by 12.2% of the cohort at risk. Among women with a family history of breast cancer, those who currently used HRT and had done so for at least 5 years developed breast cancer at an age-adjusted annual rate of 61 cases per 10,000 person-years (95% CI, 28 to 94 cases); this rate was not statistically significantly higher than the rate in women who had never used HRT (46 cases per 10,000 person-years [CI, 36 to 55 cases]).

Among women with a family history, those who used HRT had a significantly lower risk for total mortality than did women who had never used HRT (relative risk, 0.67 [CI, 0.51 to 0.89]), including total cancer-related mortality (relative risk, 0.75 [CI, 0.50 to 1.12]).

The age-adjusted annual mortality rate for women using HRT for at least 5 years was 46 deaths per 10,000 person-years (CI, 19 to 74 deaths); this is roughly half the rate seen in women who had never used HRT (80 deaths per 10,000 person-years [CI, 69 to 92 deaths]).

CONCLUSIONS: These data suggest that HRT use in women with a family history of breast cancer is not associated with a significantly increased incidence of breast cancer but is associated with a significantly reduced total mortality rate.

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2005 review-Collins – Canada –
Progestins Increase Breast Cancer in Post Menopausal Women – Estrogen Alone Does NOT

37) humupd.oxfordjournals.org/content/11/6/545.long
www.ncbi.nlm.nih.gov/pubmed/16150813

Collins, John A., Jennifer M. Blake, and Pier Giorgio Crosignani. “Breast cancer risk with postmenopausal hormonal treatment.” Human reproduction update 11.6 (2005): 545-560.

Eligible citations addressed invasive breast cancer risk among postmenopausal women and involved use of the estrogen products with or without progestin that are used as treatment for menopausal symptoms.

The average risk of invasive breast cancer with estrogen use was 0.79 [95% confidence interval (95% CI) = 0.61-1.02] in four randomized trials involving 12 643 women.

The average breast cancer risk with estrogen-progestin use was 1.24 (95% CI = 1.03-1.50) in four randomized trials involving 19 756 women.

The average risks reported in recent epidemiological studies were higher: 1.18 (95% CI = 1.01-1.38) with current use of estrogen alone and 1.70 (95% CI = 1.36-2.17) with current use of estrogen-progestin. The association of breast cancer with current use was stronger than the association with ever use, which includes past use. For past use, the increased breast cancer risk diminished soon after discontinuing hormones and normalized within 5 years. Reasonably adequate data do not show that breast cancer risk varies significantly with different types of estrogen or progestin preparations, lower dosages or different routes of administration, although there is a small difference between sequential and continuous progestin regimens.

Epidemiological studies indicate that estrogen-progestin use increases risk of lobular more than ductal breast cancer, but the number of studies and cases of lobular cancer remains limited.

Among important prognostic factors, the stage and grade in breast cancers associated with hormone use [corrected] do not differ significantly from those in non-users, but breast cancers in estrogen-progestin users are significantly more likely to be estrogen receptor (ER) positive.

In conclusion, valid evidence from randomized controlled trials (RCTs) indicates that breast cancer risk is increased with estrogen-progestin use more than with estrogen alone.

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2005 Review of Literature – Discrepant Findings

2005 Meta-Analysis-Col-Brown Medical school

38) Col, Nananda F., Jung A. Kim, and Rowan T. Chlebowski. “Menopausal hormone therapy after breast cancer: a meta-analysis and critical appraisal of the evidence.” Breast Cancer Research 7 (2005): 1-6.

Menopausal hormone therapy (HT) is typically withheld from breast cancer survivors because of concerns about risk for recurrence. Our objectives were to estimate the effects of HT on recurrence in breast cancer survivors and to examine the reliability of these estimates.
Methods

In a systematic review of the literature we identified all reports of HT use in breast cancer survivors that included comparison groups. Study design features that might affect selection of participants, detection of recurrence, and manuscript publication were assessed. The relative risks for breast cancer recurrence associated with HT were combined with random effects models.
Results Two randomized and eight observational studies included 1,316 breast cancer survivors who used HT and 2,839 nonusers. In the observational studies, HT users were younger and more commonly node negative; only two reported balanced restaging for HT and control groups. Randomized trials suggest that HT increased the risk for recurrence (relative risk 3.41, 95% confidence interval 1.59–7.33), whereas observational studies suggest that HT decreased this risk (relative risk 0.64, 95% confidence interval 0.50–0.82).

Conclusion: Results from observational studies of HT conducted in breast cancer survivors are discrepant with results from randomized trials. Observational studies of HT use in breast cancer survivors have design limitations that cannot be controlled for using standard statistical methods. Therefore, the randomized clinical trial data provide the only reliable estimates of the effect of HT use on recurrence risks in breast cancer survivors.
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2006 BATUR – Cleveland Clinic – Review of ALL studies-
HRT users had decreased recurrence and decreased mortality

39) www.ncbi.nlm.nih.gov/pubmed/16368466

Batur, Pelin, et al. “Menopausal hormone therapy (HT) in patients with breast cancer.” Maturitas 53.2 (2006): 123-132.

To assess the effect of menopausal hormone therapy (HT) on reoccurrence, cancer-related mortality, and overall mortality after a diagnosis of breast cancer.

METHODS:We performed a quantitative review of all studies reporting experience with menopausal HT for symptomatic use after a diagnosis of breast cancer. Rates of reoccurrence, cancer-related mortality, and overall mortality were calculated in this entire group. A subgroup analysis was performed in studies using a control population to assess the odds ratio of cancer reoccurrence and mortality in hormone users versus non-users.

RESULTS: Fifteen studies encompassing 1416 breast cancer survivors using HT were identified. Seven studies included a control group comprised of 1998 patients.

Among the 1416 HT users, reoccurrence was noted in 10.0% (95% CI: 8.4-11.6%). Cancer-related mortality occurred at a rate of 2.6% (95% CI: 1.8-3.7%), while overall mortality was 4.5% (95% CI: 3.4-5.8%).

Compared to non-users, patients using HT had a decreased chance of reoccurrence and cancer-related mortality with combined odds ratio of 0.5 (95% CI: 0.2-0.7) and 0.3 (95% CI: 0.0-0.6), respectively.

CONCLUSIONS:In our review, menopausal HT use in breast cancer survivors was not associated with increased cancer reoccurrence, cancer-related mortality or total mortality. Despite conflicting opinions on this issue, it is important for primary care physicians to feel comfortable medically managing the increasing number of breast cancer survivors. In the subset of women with severe menopausal symptoms, HT options should be reviewed if non-hormonal methods are ineffective. Future trials should focus on better ways to identify breast cancer survivors who may safely benefit from HT versus those who have a substantial risk of reoccurrence with HT use.
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2009 Reply to Creaseman by Labriola,

40)  2009 – Letter to the Editor Hormone Replacement and Breast Cancer Risk:The Authors Reply

Our commentary in the July 2009 issue of ONCOLOGY concluded that the current level of evidence for safety and efficacy of “natural” hormone replacement therapy (NHRT) is not conclusive. In terms of safety, the majority of data suggests that NHRTs demonstrate risks similar to those of conventional hormone replacement therapy (HRT). Efficacy trials of NHRTs have produced mixed and sometimes contradictory results. We further suggested that the administration of hormone therapy rely on evidence-based clinical judgment; NHRT advice to women should be based on the same risk/benefit assessment that would be used when considering conventional HRT.

Drs. Creasman and DiSaia use this as a segue in their Letter to the Editor to defend the use of HRT for women, taking the position that there is really a lot of fuss about nothing with HRT, and if NHRT is the same, no problem. They argue that for breast cancer survivors, “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.”

(MORE: ‘Natural’ Hormone Replacement and Breast Cancer Risk: Evidence for Safety and Efficacy)

Debatable Defense: Their first defense of HRT is a 2002 citation by Chlebowski et al,[1] but the writers fail to mention the fact that these authors concluded, “Relatively short-term combined estrogen plus progestin use increases incident breast cancers, which are diagnosed at a more advanced stage compared with placebo use, and also substantially increases the percentage of women with abnormal mammograms. These results suggest estrogen plus progestin may stimulate breast cancer growth and hinder breast cancer diagnosis.”

They go on to cite other studies including a small (n = 43) 1985 trial by Matelski et al.[2] The writers conclude from this citation that “In the 1970s and early 1980s, several prospective randomized studies compared estrogen with tamoxifen (Drug information on tamoxifen) in such women. The results were similar.” Their conclusion is not shared by the evidence. Even the authors of their citation disagree, concluding that “Initial hormonal therapy with tamoxifen in postmenopausal patients with advanced breast cancer and ERP status positive or unknown is superior to primary estrogen treatment.”

The writers also comment on the HABITS trial,[3] which was stopped as a result of increased breast cancer risk in the HRT arm and the Stockholm trial.[4] They conclude “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.” Once again, their conclusions are not consistent with the evidence or other well considered analyses.

Further Evidence   Prentice et al[5] examined the effects of daily 0.625-mg conjugated equine estrogens (Drug information on estrogens) plus 2.5-mg medroxyprogesterone (Drug information on medroxyprogesterone) acetate in relation to both prior hormone therapy and time from menopause to first use of postmenopausal hormone therapy (“gap time”) in the Women’s Health Initiative (WHI) trial and in a corresponding subset of the WHI observational study on postmenopausal women with a uterus enrolled at 40 US clinical centers during 1993–1998. The authors found that hazard ratios agreed between the two cohorts at a specified gap time and time from hormone therapy.

They determined that the “Combined trial and observational study data support an adverse effect on breast cancer risk.” They further concluded, “The WHI clinical trial and observational study each support an adverse effect of daily 0.625-mg conjugated equine estrogen plus 2.5-mg medroxyprogesterone acetate on breast cancer. Women who initiate treatment soon after menopause and continue for many years appear to be at particularly high risk.” As if this weren’t enough, a recent review by Chlebowski et al[6] showed a significant increase in deaths (not incidence) from lung cancer for women receiving estrogen plus progestin compared to placebo controls enrolled in the WHI.

Conclusion  The writers’ argument in favor of the safety of HRT is not supported by the evidence, including their own references. Our conclusions in the July 2009 ONCOLOGY Commentary remain unchanged—namely that HRT (including NHRT) should be based on a balanced risk/benefit assessment and that high-risk patients including survivors of hormone-driven breast cancer are not appropriate candidates for HRT. As new clinical trials increase our body of knowledge, we will hopefully have more tools and flexibility when making clinical judgments, but at this time we must not lose sight of the principle of “do no harm.”

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In many instances, women are told that HRT is absolutely contraindicated, yet we are unaware of any clinical data to substantiate that statement. 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.

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2011 Howell

41)) www.ncbi.nlm.nih.gov/pubmed/21253794
Howell, Anthony, and Gareth D. Evans. “Hormone replacement therapy and breast cancer.” Clinical Cancer Prevention (2011): 115-124.

There is evidence that hormone replacement therapy (HRT) may both stimulate and inhibit breast cancers, giving rise to a spectrum of activities, which are frequently hard to understand. Here we summarise the evidence for these paradoxical effects and, given the current data, attempt to give an indication where it may or may not be appropriate to prescribe HRT.It is clear that administration of oestrogen-progestin (E-P) and oestrogen alone (E) HRT is sufficient to stimulate the growth of overt breast tumours in women since withdrawal of HRT results in reduction of proliferation of primary tumours and withdrawal responses in metastatic tumours. E-P, E including tibolone are associated with increased local and distant relapse when given after surgery for breast cancer. For women given HRT who do not have breast cancer the only large randomised trial (WHI) of E-P or E versus placebo has produced some expected and also paradoxical results. E-P increases breast cancer risk as previously shown in observational studies. Risk is increased, particularly in women known to be compliant. Conversely, E either has no effect or reduces breast cancer risk consistent with some but not all observational studies.

Two observational studies report a decrease or at least no increase in risk when E-P or E are given after oophorectomy in young women with BRCA1/2 mutations. Early oophorectomy increases death rates from cardiovascular and other conditions and there is evidence that this may be reversed by the use of E post-oophorectomy. HRT may thus reduce the risk of breast cancer and other diseases (e.g., cardiovascular) in young women and increase or decrease them in older women.

42) Christante, Dara, et al. “Improved breast cancer survival among hormone replacement therapy users is durable after 5 years of additional follow-up.” The American Journal of Surgery 196.4 (2008): 505-511

2011 Liotta- Cleveland Clinic

43) www.ncbi.nlm.nih.gov/pubmed/21278517

Liotta, Margaret, and Pedro F. Escobar. “Hormone replacement after breast cancer: is it safe?.” Clinical obstetrics and gynecology 54.1 (2011): 173-179.

The use of hormone therapy for climacteric symptoms in patients with breast cancer has become a significant and important point of discussion due in part to the improved survival from this disease in recent years. “There is a theoretic risk that exogenous hormones will stimulate the growth of microscopic disease and lead to decreased survival and increased recurrence.” In addition, 2 large studies have shown that there is an association between hormone therapy and breast cancer risk in women without an earlier history of breast cancer. Other studies suggest that estrogen alone may have a superior safety profile than estrogen and progesterone in combination.

Hormone therapy could be justified for improvement of quality of life when other options have failed and the patient is informed of the risks.”

2011 Brennan – Australia

44) Brennan, Meagan E., and Nehmat Houssami. “Overview of long term care of breast cancer survivors.” Maturitas 69.2 (2011): 106-112.

6.2. Hormone replacement therapy

The HABITS study,a randomised trial addressing the efficacy
and safely of hormonereplacement therapy after breastcancer
treatment, wasstopped aftermedian follow-upof 2 years a sit
showed asignificantly higher risk of breast cancer events i nwomen
randomised tot reatment with HRT(clinicianchoiceoftherapy)
compared tothosenot taking HRT(relativehazard(RH) risk 3.5;26
vs 7events).Therewasahigherriskofneweventsinwomenwith
hormone receptorpositivecancer(RH4.8),thosenottakingtamox-
ifen (RH3.7)andthosetakingHRTbeforebreastcancerdiagnosis
(RH 6.9) [71]. Inthistrial,therewasnosignificantdifferencein
risk betweencombinedpreparations,oestrogen-onlypreparations
and otherpreparations(suchastibolone) [71]. TheStockholmtrial
also randomisedsurvivorstotreatmentwithHRTornoHRT;in
this studytherewas no increasedriskofrecurrence in women in
the HRTarm.Onepossibleexplanationforthisisthe higher pro-
portion ofwomentakingoestrogen-onlypreparationsratherthan
continuous combinedhormonepreparations,indicatingthatthe
oestrogen-only preparationsmaybelesshazardousinthisgroup
of women [72].

The LIBERATE randomised trial (over3000women
randomised) showedanincreasedriskofrecurrenceinwomentak-
ing tibolonevsplaceboforvasomotorsymptoms [73].
Based on these studies,systemic HRT is not recommended in breastcancer survivors. The use of vaginal oestrogens is discussedbelow.

2011 King UK -Premature Menopause-

HRT contraindicated for premenopausal ER positive BRCA

45) King, Judy, et al. “Hormone replacement therapy and women with premature menopause–a cancer survivorship issue.” European journal of cancer 47.11 (2011): 1623-1632.

Data for this Review were identified by searches of MEDLINE, PubMed, and references from relevant articles using the search terms ‘HRT’, ‘women/female cancer/tumour’, ‘menopause’ and ‘survivorship’. Abstracts and reports from meetings were excluded. Only papers published in English between 1980 and 2010 were included.

The recommendations for practice are that HRT may be offered for the alleviation of vasomotor symptoms in cancer survivors who undergo premature menopause up to the age of natural menopause (51 years in the UK).
“HRT (including vaginal oestrogen preparations) is contraindicated in survivors of oestrogen receptor positive breast cancer and low grade endometrial leiomyosarcoma,where non-HRT alternatives should be considered to alleviate symptoms.”

MPA Mouse Model

46) Lanari, C., et al. “The MPA mouse breast cancer model: evidence for a role of progesterone receptors in breast cancer.” Endocrine-related cancer 16.2 (2009): 333.

Full text links
Review
Endocr Relat Cancer

. 2009 Jun;16(2):333-50.
doi: 10.1677/ERC-08-0244. Epub 2009 Feb 3.
The MPA mouse breast cancer model: evidence for a role of progesterone receptors in breast cancer
Claudia Lanari 1 , Caroline A Lamb, Victoria T Fabris, Luisa A Helguero, Rocío Soldati, María Cecilia Bottino, Sebastián Giulianelli, Juan Pablo Cerliani, Victoria Wargon, Alfredo Molinolo
Affiliations

PMID: 19190078 DOI: 10.1677/ERC-08-0244

Abstract

More than 60% of all breast neoplasias are ductal carcinomas expressing estrogen (ER) and progesterone receptors (PR). By contrast, most of the spontaneous, chemically or mouse mammary tumor virus induced tumors, as well as tumors arising in genetically modified mice do not express hormone receptors. We developed a model of breast cancer in which the administration of medroxyprogesterone acetate to BALB/c female mice induces mammary ductal carcinomas with a mean latency of 52 weeks and an incidence of about 80%. These tumors are hormone-dependent (HD), metastatic, express both ER and PR, and are maintained by syngeneic transplants. The model has been further refined to include mammary carcinomas that evolve through different stages of hormone dependence, as well as several hormone-responsive cell lines. In this review, we describe the main features of this tumor model, highlighting the role of PR as a trigger of key signaling pathways mediating tumor growth. In addition, we discuss the relevance of this model in comparison with other presently used breast cancer models pointing out its advantages and limitations and how, this model may be suitable to unravel key questions in breast cancer.

47) Kordon, Edith, et al. “Hormone dependence of a mouse mammary tumor line induced in vivo by medroxyprogesterone acetate.” Breast cancer research and treatment 17 (1990): 33-43.

The administration of MPA to virgin female BALB/c mice led to the development of mammary adenocarcinomas, which in further in vivo transplants gave rise to both MPA-dependent and MPA-independent lines. In this paper we chose one of the MPA-dependent lines with high contents of estrogen (ER) and progesterone (PR) receptors, and were able to demonstrate that a) the growth of these tumors could be manipulated by the administration or the withdrawal of the hormonal supply; b) PR were down-regulated in MPA-treated mice; c) progesterone had the same stimulatory effect as MPA on tumor growth; d) tumors did not grow in estrogen-treated mice; e) tumor growth was much lower in males than in females; f) the presence of the ovaries had a positive influence on tumor growth, even in the presence of MPA; g) the withdrawal of progestin pellets in ovariectomized mice usually led to complete remissions followed by regrowth of the tumors after several weeks; and h) the regrowing tumors maintained their steroid receptor pattern and (in 3 out of 4 cases) their hormone-dependent behavior in further passages.

48) Molinolo, A. A., et al. “Mouse mammary tumors induced by medroxyprogesterone acetate: immunohistochemistry and hormonal receptors.” Journal of the National Cancer Institute 79.6 (1987): 1341-1350.

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Hormone replacement therapy after breast cancer

49) Bluming, Avrum Zvi. “Hormone replacement therapy after breast cancer: it is time.” The Cancer Journal 28.3 (2022): 183-190.

Abstract: This article reviews the decades of evidence supporting the reproducible benefits of HRT for menopausal symptom control, improved cardiac health, prevention of hip fracture, reduction in the risk and pace of cognitive decline, and enhanced longevity. It quantifies the increased risk of thromboembolism associated with oral, though not transdermal, HRT. It evaluates the repeated claims that HRT is associated with an increased risk of breast cancer development, and, when administered to breast cancer survivors, an increased risk of breast cancer recurrence. Twenty-five studies of HRT after a breast cancer diagnosis, published between 1980 and 2013, are discussed, as are the 20 reviews of those studies published between 1994 and 2021. Only 1 of the 25 studies, the HABITS trial, demonstrated an increased risk of recurrence, which was limited to local or contralateral, and not distant, recurrence. None of the studies, including HABITS, reported increased breast cancer mortality associated with HRT. Even in the HABITS trial, the absolute increase in the number of women who had a recurrence (localized only) associated with HRT administration was 22. It is on the basis of these 22 patients that HRT, with its demonstrated benefits for so many aspects of women’s health, is being denied to millions of breast cancer survivors around the world.

50) McVicker, Lauren, et al. “Vaginal estrogen therapy use and survival in females with breast cancer.” JAMA oncology 10.1 (2024): 103-108.

Importance: Genitourinary syndrome of menopause can be treated with vaginal estrogen therapy. However, there are concerns about the safety of vaginal estrogen therapy in patients with breast cancer.

Objective: To determine whether the risk of breast cancer-specific mortality was higher in females with breast cancer who used vaginal estrogen therapy vs females with breast cancer who did not use hormone replacement therapy (HRT).

Design, setting, and participants: This cohort study analyzed 2 large cohorts, one each in Scotland and Wales, of females aged 40 to 79 years with newly diagnosed breast cancer. These population-based cohorts were identified from national cancer registry records from 2010 to 2017 in Scotland and from 2000 to 2016 in Wales and were followed up for breast cancer-specific mortality until 2020. Females were excluded if they had a previous cancer diagnosis (except nonmelanoma skin cancer). Data analysis was performed between August 2022 and August 2023.

Exposure: Use of vaginal estrogen therapy, including vaginal tablets and creams, was ascertained from pharmacy dispensing records of the Prescribing Information System for the Scotland cohort and from general practice prescription records for the Wales cohort.

Main outcomes and measures: The primary outcome was time to breast cancer-specific mortality, which was obtained from national mortality records. Time-dependent Cox proportional hazards regression models were used to calculate hazard ratios (HRs) and 95% CIs for breast cancer-specific mortality, comparing vaginal estrogen therapy users with HRT nonusers and adjusting for confounders, including cancer stage and grade.

Results: The 2 cohorts comprised 49 237 females with breast cancer (between 40 and 79 years of age) and 5795 breast cancer-specific deaths. Five percent of patients with breast cancer used vaginal estrogen therapy after breast cancer diagnosis. In vaginal estrogen therapy users compared with HRT nonusers, there was no evidence of a higher risk of breast cancer-specific mortality in the pooled fully adjusted model (HR, 0.77; 95% CI, 0.63-0.94).

Conclusions and relevance: Results of this study showed no evidence of increased early breast cancer-specific mortality in patients who used vaginal estrogen therapy compared with patients who did not use HRT. This finding may provide some reassurance to prescribing clinicians and support the guidelines suggesting that vaginal estrogen therapy can be considered in patients with breast cancer and genitourinary symptoms.

In postmenopausal women treated for early-stage estrogen receptor–positive BC, neither VET nor MHT was associated with increased risk of recurrence or mortality. A subgroup analysis revealed an increased risk of recurrence, but not mortality, in patients receiving VET with adjuvant aromatase inhibitors.

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52) Ugras, Stacy K., and Rakhshanda Layeequr Rahman. “Hormone replacement therapy after breast cancer: Yes, No or maybe?.” Molecular and cellular endocrinology 525 (2021): 111180.

Over nine million breast cancer survivors worldwide suffer compromised quality of life attributable to estrogen depletion related symptoms of menopause and side effects of cancer therapy. Hormone Replacement Therapy (HRT) is very effective in managing these symptoms in general population and in breast cancer survivors. However, the concern of breast cancer recurrence as a result of HRT use keeps many oncologists from using this approach in symptom management. Evidence from randomized trials, observational studies and met-analyses on the impact of HRT use on breast cancer recurrence and survival remains controversial. Climacteric symptoms in breast cancer survivors should be delineated for type and severity for methodical management. Lifestyle modifications are effective for mild symptoms, while non-hormonal pharmaceutical approaches can be used as second-line therapy for control of hot flashes, vulvo-vaginal atrophy, arthralgia, mood swings, sleep disturbance, and depression. Evidence does not conclusively render HRT, as a contraindicated approach for these patients; informed consent and shared-decision-making is a reasonable approach for HRT use in symptomatic breast cancer survivors.

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Use of HRT detrimental to BC survivors, particularly in those with hormone receptor-positive disease. estrogen/progestogen combination

53) Poggio, Francesca, et al. “Safety of systemic hormone replacement therapy in breast cancer survivors: a systematic review and meta-analysis.” Breast Cancer Research and Treatment (2022): 1-7.

Purpose: Symptoms of treatment-induced menopause negatively affect quality of life and adherence to endocrine therapy of breast cancer (BC) survivors. Nevertheless, the use of systemic hormone replacement therapy (HRT) to mitigate these symptoms may be associated with an increased risk of disease recurrence in these patients. This systematic review and meta-analysis aimed to assess the safety of systemic HRT on risk of disease recurrence in BC survivors.

Methods: A systematic search of PubMed up to April 20, 2021 was conducted to identify randomized controlled trials (RCTs) that investigated the risk of disease recurrence with the use of HRT in BC survivors. A random-effect model was applied to calculate the risk of recurrence, reported as pooled hazard ratio (HR) with 95% confidence intervals (CI). A subgroup analysis was performed to estimate the risk of recurrence according to hormone receptor status.

Results: Four RCTs were included in the meta-analysis (n = 4050 patients). Overall, 2022 patients were randomized to receive HRT (estrogen/progestogen combination or tibolone) and 2023 to the control group with placebo or no HRT.

HRT significantly increased the risk of BC recurrence compared to placebo (HR 1.46, 95% CI 1.12-1.91, p = 0.006). At the subgroup analysis, the risk of BC recurrence with the use of HRT was significantly increased in patients with hormone receptor-positive disease (HR 1.8, 95% CI 1.15-2.82, p = 0.010) but not in those with hormone receptor-negative tumors (HR 1.19, 95% CI 0.80-1.77, p = 0.390).

Conclusion: Use of HRT was associated with a detrimental prognostic effect in BC survivors, particularly in those with hormone receptor-positive disease. Alternative interventions to mitigate menopause-related symptoms should be proposed.

54) Fahlén, Mia, et al. “Hormone replacement therapy after breast cancer: 10 year follow up of the Stockholm randomised trial.” European journal of cancer 49.1 (2013): 52-59.

After 10.8 years of follow-up, there was no difference in new breast cancer events: 60 in the HRT group versus 48 among controls (hazard ratio (HR) = 1.3; 95% confidence interval (CI) = 0.9–1.9). Among women on HRT, 11 had local recurrence and 12 distant metastases versus 15 and 12 for the controls. There were 14 contra-lateral breast cancers in the HRT group and four in the control group (HR = 3.6; 95% CI = 1.2–10.9; p = 0.013). No differences in mortality or new primary malignancies were found.

The number of new events did not differ significantly between groups, in contrast to previous reports. The increased recurrence in HABITS has been attributed to higher progestogen exposure. As both trials were prematurely closed, data do not allow firm conclusions. Both studies found no increased mortality from breast cancer or other causes from HRT. Current guidelines typically consider HRT contraindicated in breast cancer survivors. Findings suggest that, in some women symptom relief may outweigh the potential risks of HRT.

63) Deli, Tamás, Mónika Orosz, and Attila Jakab. “Hormone replacement therapy in cancer survivors–review of the literature.” Pathology & Oncology Research 26.1 (2020): 63-78.

Thus, an ever increasing number of cancer survivors search endocrinologic help in the form of hormone replacement therapy (HRT). The misinterpretation of the WHI (Women’s Health Initiative) Study has lead to an irrational fear of female hormone replacement, both by the general population and medical professionals. It has seemed the logical and safe conclusion to many physicians to avoid HRT, supposing that this attitude definitely causes no harm, whereas the decision of prescribing estrogen alone or with progestins might bear oncologic and thromboembolic risks and may even lead to litigation in case of a potentially related complication. However, it was known even before the WHI results that premature menopause and hypogonadism decreases the life expectancy of women by years through its skeletal and cardiovascular effects, and this negative effect correlates with the length of the hypoestrogenaemic period. Therefore, the denial of HRT also needs to be supported by evidence and should be weighed againts the risks of HRT. Yet, the oncologic risk of HRT is extremely difficult to assess. In this work we review the latest evidence from in vitro experiments to clinical studies, regarding HRT in survivors of gynecologic and non-gynecologic cancers. Based on our literature research, we group tumours regarding the oncologic risk of properly chosen female hormone replacement therapy in cancer survivors as follows: ’HRT is advantageous’ (e.g. endometrial cancer type I, cervical adenocarcinoma, haematologic malignancies, local cutaneous malignant melanoma, colorectal cancer, hepatocellular cancer); ’HRT is neutral’ (e.g. BRCA 1/2 mutation carriers without cancer, endometrial cancer type II, uterinal carcinosarcoma and adenosarcoma, certain types of ovarian cancer, cervical, vaginal and vulvar squamous cell carcinoma, prolactinoma, kidney cancer, pancreatic cancer, thyroid cancer); ’HRT is relatively contraindicated’ for various reasons (e.g. leiomyosarcoma, certain types of ovarian tumours, brain tumours, advanced metastatic malignant melanoma, lung cancer, gastric cancer, bladder cancer); ’HRT is diasadvantageous and thus contraindicated’ (e.g. breast cancer, endometrial stroma sarcoma, meningioma, glioma, hormone receptor positive gastric and bladder cancer).

55) Wang, Tengteng, et al. “Menopausal hormone therapy use and long-term all-cause and cause-specific mortality in the Long Island Breast Cancer Study Project.” International journal of cancer 147.12 (2020): 3404-3415.

Previous studies have observed a reduced mortality risk associated with menopausal hormone therapy (MHT) use among breast cancer survivors. We sought to clarify whether such association could be explained by tumor heterogeneity, specific causes of death, confounding from comorbidities or health behaviors, and a comparison group of women without breast cancer. We interviewed 1508 women newly diagnosed with first primary breast cancer in 1996 to 1997 (~3 months after diagnosis), and 1556 age-matched women without breast cancer, about MHT use history. The National Death Index was used to ascertain vital status after a median of 17.6 years of follow-up (N = 597 deaths for breast cancer subjects). Multivariable-adjusted Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (95%CIs) for all-cause mortality, and cause-specific HR (cHR) for breast cancer and cardiovascular disease (CVD). The Fine-Gray model was used to account for competing causes of death. Among women with breast cancer, ever vs never MHT use was inversely associated with all-cause (HR = 0.77, 95%CI = 0.62-0.95), breast cancer-specific (cHR = 0.69, 95%CI = 0.48-0.98), and CVD-specific mortality (cHR = 0.57, 95%CI = 0.38-0.85). Difference of the association was observed in breast cancer-specific mortality according to hormone receptor status (negative tumors: cHR = 0.44, 95%CI = 0.19-1.01; positive tumors: cHR = 0.96, 95%CI = 0.60-1.53). Among the comparison group, we observed similar, but more modest inverse associations for all-cause and CVD-specific mortality. MHT use was inversely associated with mortality after breast cancer, even after accounting for competing causes of death and multiple confounders, and was evident among women without breast cancer. Potential heterogeneity by hormone receptor status requires more study.

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2008 HABITS – Extended Follow Up RCT – Estradiol hemihydrate and norethisterone:  Increased recurrence in BR CA survivors

56) Holmberg, Lars, et al. “Increased risk of recurrence after hormone replacement therapy in breast cancer survivors.” Journal of the National Cancer Institute 100.7 (2008): 475-482.

BACKGROUND:Hormone replacement therapy (HT) is known to increase the risk of breast cancer in healthy women, but its effect on breast cancer risk in breast cancer survivors is less clear. The randomized HABITS study, which compared HT for menopausal symptoms with best management without hormones among women with previously treated breast cancer, was stopped early due to suspicions of an increased risk of new breast cancer events following HT. We present results after extended follow-up.

METHODS: HABITS was a randomized, non-placebo-controlled noninferiority trial that aimed to be at a power of 80% to detect a 36% increase in the hazard ratio (HR) for a new breast cancer event following HT. Cox models were used to estimate relative risks of a breast cancer event, the maximum likelihood method was used to calculate 95% confidence intervals (CIs), and chi(2) tests were used to assess statistical significance, with all P values based on two-sided tests. The absolute risk of a new breast cancer event was estimated with the cumulative incidence function. Most patients who received HT were prescribed continuous combined or sequential estradiol hemihydrate and norethisterone.

RESULTS:Of the 447 women randomly assigned, 442 could be followed for a median of 4 years. Thirty-nine of the 221 women in the HT arm and 17 of the 221 women in the control arm experienced a new breast cancer event (HR = 2.4, 95% CI = 1.3 to 4.2). Cumulative incidences at 5 years were 22.2% in the HT arm and 8.0% in the control arm. By the end of follow-up, six women in the HT arm had died of breast cancer and six were alive with distant metastases. In the control arm, five women had died of breast cancer and four had metastatic breast cancer (P = .51, log-rank test).

CONCLUSION: After extended follow-up, there was a clinically and statistically significant increased risk of a new breast cancer event in survivors who took HT.

2007 Review-absence of safety data- Antoine-  Belgium

57) Antoine, Caroline, et al. “Safety of hormone therapy after breast cancer: a qualitative systematic review.” Human reproduction 22.2 (2007): 616-622.

This qualitative review systematically analyses the safety of hormone therapy (HT) in breast cancer (BC) patients.

METHODS:  We systematically searched studies reporting the use of HT in BC patients. We selected 20 studies in which we evaluated the methodology, characteristics of the studied populations and outcomes in terms of mortality and recurrence rates (RRs).

RESULTS:Many studies evaluating HT were uncontrolled and retrospective. Ten prospective and two randomized studies were found. These were characterized by heterogeneity in populations, tumour characteristics, prognostic factors and treatments. Two studies reported a reduced RR, and two reported lowered BC mortality rates in HT users. One randomized study reported an increased rate of new BC events in HT users.

CONCLUSIONS: There are currently no reassuring data indicating the absence of a harmful effect of HT. Further studies should analyse whether some regimens are safer than others. There is a need for randomized trials assessing the safety of these regimens. In the meantime, patients should be informed about the absence of safety data.

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2007 Observational Study Germany – 1072 patients
Better prognosis for those who used  HRT before cancer diagnosis

58) Schuetz, Florian, et al. “Reduced incidence of distant metastases and lower mortality in 1072 patients with breast cancer with a history of hormone replacement therapy.” American Journal of Obstetrics and Gynecology 196.4 (2007): 342-e1.

OBJECTIVE: Substitution of estrogens (hormone replacement therapy [HRT]) is the most common   therapy and prophylaxis of postmenopausal complaints. However, in most studies, long-term HRT    has been associated with an increased risk for breast cancer, but the influence on a prognosis of  breast cancer has been examined rarely.

STUDY DESIGN: For further investigation, we analyzed  1072 patients aged 45-70 years at the time of first diagnosis of breast cancer with and without  preoperative HRT with regard to the incidence of distant metastases and overall survival. Of these,  279 women were premenopausal (mean, 47.8 +/- 3.2 years); 793 women were postmenopausal  (mean, 54.5 +/- 3.5 years);

320 women had received HRT over a minimum of 1 year (mean, 5.5 +/- 4.0   years; group HRT+); and 473 women had not received HRT (group HRT-). The median follow-up time  was 73.2 months.

RESULTS: Although body mass index, tumor size, and grading of group HRT  were significantly higher than in group HRT+, nodal status, S-phase fraction, hormone-receptor   status, and local recurrence showed no significant differences.

In regard to the incidence of distant  metastases, women without HRT have significantly (P < .001) more metastases to bone (68 vs 20 women), lung (47:13 women), and liver (47:13 women). Overall survival was significantly lower in the HRT- group.

CONCLUSION: We were able to show that the use of HRT before the diagnosis of breast cancer results in more favorable primary tumors, with a lower incidence of recurrences   and a better overall survival rate. This might be due to normalized bone metabolism by the use of HRT, which may lower the conditions of tumor cell seeding.

2006-BRCA survivors request HRT for QOL

59) Trinh, Xuan-Bich, Frederik Peeters, and Wiebren AA Tjalma. “The thoughts of breast cancer survivors regarding the need for starting hormone replacement therapy.” European Journal of Obstetrics & Gynecology and Reproductive Biology 124.2 (2006): 250-253.

There is not only a need for scientific data regarding the risk of recurrence of breast cancer by starting hormone replacement therapy (HRT) but also regarding the patients’ needs for HRT.

OBJECTIVES:To examine the severity of climacteric complaints in breast cancer patients and to examine if they are willing to take HRT.

METHODS: In November 2003, a questionnaire was sent to 469 breast cancer survivors. The survey examined on a scale base the severity of climacteric complaints and the patient’s opinion on starting HRT.

RESULTS:More than 76% of the patients complained that they experience or had experienced hot flushes or night sweating. More than half (53%) of this group found the inconvenience severe to extreme, affecting the patient’s quality of life. A majority (80.5%) patients who had already taken HRT, found that it improved their quality of life substantially. When the results of observational studies were explained regarding HRT in breast cancer survivors, a majority said they would take or would consider taking HRT (57.9%).

CONCLUSION: While physicians are more reserved in prescribing HRT in breast cancer survivors, a combination of severe symptomatic climacteric complaints and the willingness of the patient to be treated should at least result in a “consideration” of prescribing HRT.

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60) Colditz, Graham A. “Menopausal hormone therapy after breast cancer.” Breast Cancer Research 7 (2005): 1-3.
There is now resounding evidence that use of exogenous hormones by postmenopausal women increases risk for breast cancer [1-3]. Likewise, obesity among postmenopausal women with breast cancer is a major determinant of relapse and mortality [4,5], being directly related to poor outcomes. On the other hand, tamoxifen provides lasting reduction in risk for recurrence and mortality [6], an effect that is independent of adjuvant chemotherapy.

Biologic evidence supports estrogenic exposures being related to incidence and poor outcome among women with breast cancer. Weight after diagnosis is a strong predictor of outcome [4], and weight gain after diagnosis is associated with increased recurrence and mortality [5]. There are direct positive relations between adiposity and circulating estrogens [10], and between adult weight gain and postmenopausal breast cancer risk [11], and circulating endogenous hormones represent the primary explanation for this positive relation between adiposity and postmenopausal breast cancer incidence [12]. Together, these data support an increase in incidence of breast cancer with use of postmenopausal hormone therapy. Should the effect of exogenous postmenopausal hormonal therapy differ after diagnosis, when adiposity and weight gain have adverse effects on recurrence and mortality?

To cloud further the current evidence, a third randomized trial [13], von Schoultz E, Rutqvist LE. Menopausal hormone therapy after breast cancer: the Stockholm randomized trial. J Natl Cancer Inst. 2005;97:533–535 which has been published since the synthesis by Col and colleagues, found no increase in risk with use of postmenopausal hormone therapy (RR = 0.8, 95% CI = 0.4–1.9), based on 4.1 years of follow up in 434 women (Table ​(Table1).1). The authors raise the intriguing possibility that the choice of hormone regimen may modify the risk for recurrence and account for some of the heterogeneity observed. This trial is of comparable size and design to the HABITS (Hormone Replacement Therapy after Breast Cancer – Is It Safe?) trial, also conducted in Sweden [14]. Clearly, more detailed analysis of this small body of evidence might improve our understanding of the difference between unopposed estrogen and combination estrogen plus progestin therapy among women who have been treated for histologically confirmed breast cancer. Alternatively, we can consider other evidence on use of progestins after diagnosis and breast cancer outcomes.

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2004 Israel Guidelines Changed Bases on HABIT study which used norethisterone – HRT for Breast Cancer Survivors  NO Longer Recommended.

61) Siegelmann-Danieli, Nava, et al. “Hormone replacement therapy in breast cancer survivors: the Israeli Society for Clinical Oncology and Radiotherapy policy letter.” Harefuah 141.11 (2002): 994-6.

The Israeli Society for Clinical Oncology and Radiotherapy appointed experts in breast cancer therapy to assess the Society’s policy regarding hormone replacement therapy (HRT) in breast cancer survivors with menopausal symptoms. The first policy letter was published in November 2002, and referred to available literature at that time which included retrospective data alone.

The professional literature suggested no increased risk in breast cancer recurrence or cancer specific mortality, and no effect on overall survival with the use of HRT for a limited period (up to 3 years).

This data served as the rationale for international prospective studies. Former committee recommendations and precautions are detailed in the original publication. In February 2004, the interim analysis of a prospective trial, the HABIT (Hormonal replacement therapy after breast cancer–is it safe?) was published. In that trial, breast cancer survivors with menopausal symptoms were randomized to HRT (estrogens with or without progestins) or no therapy for 2 years. A total of 434 women were recruited from centers in Scandinavia who participated with the International Breast Cancer and the European Organization for Research and Treatment groups.

Analysis was restricted to 345 women with at least one follow up report; median follow-up period was 2.1 years. The relative risk for breast cancer event was 3.5 (95% C.I. 1.5-8.1) in HRT users as compared with the non-HRT group and the HABIT trial was terminated. Study limitations are discussed.

Thereby, at this time HRT can no longer be considered safe in breast cancer survivors. 

62) Lea, Robert, et al. “Use of hormonal replacement therapy after treatment of breast cancer.” Journal of Obstetrics and Gynaecology Canada: JOGC= Journal D’obstetrique et Gynecologie du Canada: JOGC 26.1 (2004): 49-60.

USE OF HORMONAL REPLACEMENT THERAPY AFTER TREATMENT OF BREAST CANCER This guideline has been reviewed by the Breast Disease Committee and approved by the Executive and Council of the Society of Obstetricians and Gynaecologists of Canada.

CONCLUSIONS
The opinion that estrogens and estrogen treatment are deleterious for breast cancer needs to be refocused. Knowing the current data, a proper risk-benefit assessment of HRT use in women with risk factors for breast cancer or in women diagnosed with a breast cancer needs to be presented. We need to wait for the prospective,
randomized clinical trials that are presently ongoing to have a
definitive conclusion.

RECOMMENDATIONS

1. HRT after treatment of breast cancer has not been demonstrated to have an adverse impact on recurrence and mortality. (II-2

2. HRT is an option in postmenopausal women with previously treated breast cancer. (II-2

3. Prospective, randomized clinical trial results are needed.
(III-A)

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2003 – Observational Study 230 patients France-same relapse rate as case controls

63) Gorins, A., et al. “Hormone replacement therapy in breast cancer patients: a study of 230 patients, with a case-control study.” Gynecologie, Obstetrique & Fertilite 31.7-8 (2003): 614-619.

OBJECTIVES: After recalling the classical contra-indication of hormone replacement therapy (HRT)     concerning patients with a personal history of breast cancer (BC), and arguments that may be opposed,     the authors report the present results of a prospective study undertaken in the Center of Breast Diseases     in Saint-Louis hospital in Paris since February 1992.

PATIENTS AND METHODS: By April 2001, 230 patients had been included. A free interval of 2 years at least since the treatment of the primary BC has been observed. The reasons for prescribing HRT were vasomotor troubles (flushes, nightly sweats) or a  dyspareunia, which were severe and not controlled by non-hormonal treatments. There was also an  indication of a major osteoporotic or cardiovascular danger. In fact, many of these patients had a  premature, artificial, chemo-induced menopause. The HRT most often used was an estro-progestin association (estradiol + a progestin compound) given either continuously or with a 5-d interruption each  month. The mean duration of treatment was 2.5 years.

RESULTS: Results, concerning the improvement   of menopause troubles, were remarkable in the great majority of troubles. HRT had to be stopped in 39 cases, reading as follows: 17 cases for relapses (seven local, six in the contro-lateral breast and four metastases (7%)). Also, 22 patients (9%) interrupted their HRT for serious side-effects. A case-control  study did not show any significant difference between with and without HRT patients concerning the overall survival without relapse.

DISCUSSION AND CONCLUSIONS: Quality of life of patients was often     substantially improved, and a deleterious effect on the cancer disease was not found. Our results are in  agreement with the literature from other countries. However, one must be cautious. In such  circumstances, HRT must be prescribed with the informed consent of the patients and delivered in  appropriate hospital and university centers. It is wished that large randomised prospective studies   may be undertaken.

2002 Pritchard- Canada- HRT recommendation in Breast Cancer Survivors

64) Pritchard, Kathleen I., et al. “Clinical practice guidelines for the care and treatment of breast cancer: 14. The role of hormone replacement therapy in women with a previous diagnosis of breast cancer.” Cmaj 166.8 (2002): 1017-1022.

Systematic review of English-language literature published from January 1990 to July 2001 retrieved from MEDLINE and CANCERLIT.

Recommendations Routine use of HRT (either estrogen alone or estrogen plus progesterone) is not recommended for women who have had breast cancer.

Randomized controlled trials are required to guide recommendations for this group of women. Women who have had breast cancer are at risk of recurrence and contralateral breast cancer. The potential effect of HRT on these outcomes in women with breast cancer has not been determined in methodologically sound studies.

However, in animal and in vitro studies, the development and growth of breast cancer is known to be estrogen dependent. Given the demonstrated increased risk of breast cancer associated with HRT in women without a diagnosis of breast cancer, it is possible that the risk of recurrence and contralateral breast cancer associated with HRT in women with breast cancer could be of a similar magnitude. ·

Postmenopausal women with a previous diagnosis of breast cancer who request HRT should be encouraged to consider alternatives to HRT.

If menopausal symptoms are particularly troublesome and do not respond to alternative approaches, a well-informed woman may choose to use HRT to control these symptoms after discussing the risks with her physician. In these circumstances, both the dose and the duration of treatment should be minimized.

65) Pritchard, Kathleen I. “Hormone replacement in women with a history of breast cancer.” The Oncologist 6.4 (2001): 353-362.

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66) Christante, Dara, et al. “Improved breast cancer survival among hormone replacement therapy users is durable after 5 years of additional follow-up.” The American Journal of Surgery 196.4 (2008): 505-511.

”””””””””
2001 J Nat Cancer Inst O’Meara

67) O’Meara, Ellen S., et al. “Hormone replacement therapy after a diagnosis of breast cancer in relation to recurrence and mortality.” Journal of the National Cancer Institute 93.10 (2001): 754-761.

Hormone replacement therapy (HRT) is typically avoided for women with a history of breast cancer because of concerns that estrogen will stimulate recurrence. In this study, we sought to evaluate the impact of HRT on recurrence and mortality after a diagnosis of breast cancer.
METHODS: Data were assembled from 2755 women aged 35-74 years who were diagnosed with incident invasive breast cancer while they were enrolled in a large health maintenance organization from 1977 through 1994. Pharmacy data identified 174 users of HRT after diagnosis. Each HRT user was matched to four randomly selected nonusers of HRT with similar age, disease stage, and year of diagnosis. Women in the analysis were recurrence free at HRT initiation or the equivalent time since diagnosis. Rates of recurrence and death through 1996 were calculated. Adjusted relative risks were estimated by use of the Cox regression model. All statistical tests were two-sided.
RESULTS:

The rate of breast cancer recurrence was 17 per 1000 person-years in women who used HRT after diagnosis and 30 per 1000 person-years in nonusers (adjusted relative risk for users compared with nonusers = 0.50; 95% confidence interval [CI] = 0.30 to 0.85).

Breast cancer mortality rates were five per 1000 person-years in HRT users and 15 per 1000 person-years in nonusers (adjusted relative risk = 0.34; 95% CI = 0.13 to 0.91).

Total mortality rates were 16 per 1000 person-years in HRT users and 30 per 1000 person-years in nonusers (adjusted relative risk = 0.48; 95% CI = 0.29 to 0.78).

The relatively low rates of recurrence and death were observed in women who used any type of HRT (oral only = 41% of HRT users; vaginal only = 43%; both oral and vaginal = 16%). No trend toward lower relative risks was observed with increased dose.

CONCLUSION:  We observed lower risks of recurrence and mortality in women who used HRT after breast cancer diagnosis than in women who did not. Although residual confounding may exist, the results suggest that HRT after breast cancer has no adverse impact on recurrence and mortality.

Unopposed estrogens only – 50% less recurrence compared to never users.

 

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1999 – Informed consent-   HRT may increase recurrence rate of BR CA

68) Chlebowski, Rowan T., and Anne McTiernan. “Elements of informed consent for hormone replacement therapy in patients with diagnosed breast cancer.” Journal of Clinical Oncology 17.1 (1999): 130-130.

“HRT use is associated with not only the risk of developing a new breast cancer (the end point used in most observational studies describing breast cancer ‘‘risk’’), but also the additional and more proximate risk of stimulating growth and clinical expression of pre-existing breast cancer metastatic foci.”

An approach to providing informed consent to breast cancer survivors considering hormone replacement therapy (HRT) is offered.

METHODS: Current information on HRT, breast cancer, and chronic disease prevention is reviewed in the context of risks faced by women with resected breast cancer.

RESULTS: Breast cancer patients, unwilling to trade symptom reduction for even a small increase in recurrence risk, are at substantially increased risk of death from breast cancer relative to other causes. Observational studies suggest that long-term HRT increases breast cancer development. The influence of HRT on the growth of established breast cancer has not been determined; however, estrogen reduction (oophorectomy) significantly reduces recurrence in premenopausal women, and current evidence cannot exclude a risk that HRT increases recurrence to the same degree. The following issues are of particular relevance to breast cancer survivors: HRT reduces mammographic sensitivity, increases thromboembolic events, and increases endometrial cancer risk. Although benefit for HRT is commonly inferred from observational studies, randomized trials of HRT on all-cause mortality have not been completed. For coronary heart disease prevention, an array of strategies independent of HRT are available, with some (tamoxifen, selective estrogen receptor modifiers [SERMs], diet, and exercise) likely to favorably influence breast cancer risk; for osteoporosis prevention, an array of strategies also are available, with some (bisphosphonates, tamoxifen, SERMs, and exercise) likely to favorably influence breast cancer risk.
CONCLUSION:

Current data preclude the generation of evidence-based guidelines for HRT use in breast cancer survivors, and clinical trials in this setting should be supported. However, given available therapeutic alternatives for menopausal symptom management and chronic disease prevention, breast cancer survivors should be offered HRT only with caution and with their full participation in the decision-making process.

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1999  – 21 Breast Cancer Survivors Treated with HRT  -Slovenia

Estradiol and Progestagens

69) Uršič-Vrščaj, Marjetka, and Sonja Bebar. “A case-control study of hormone replacement therapy after primary surgical breast cancer treatment.” European Journal of Surgical Oncology (EJSO) 25.2 (1999): 146-151.

In order to make a detailed analysis, we selected a group of 21 patients with the diagnosis of invasive breast cancer who had HRT after primary surgical treatment.

Each patient from the selected group was compared with two patients from the control group with the diagnosis of invasive breast cancer who did not have HRT after primary surgical treatment. The control cases were matched to selected HRT patients with regard to age at time of the diagnosis, year of diagnosis, diameter of the tumour, metastatic spread in the axillary lymph nodes, and disease-free    interval until applying HRT. The same criteria were applied in all analyses. The data were analysed by odds ratio (OR) calculation with a confidence interval of 95%, taking into account residual malignancy and death due to breast cancer in both groups (including carcinoma in the contralateral breast).

RESULTS: HRT was applied in 21 patients treated for breast cancer.

In 33% of them, radical mastectomy revealed metastases in the axillary lymph nodes. Hormone receptors could not be found in 57% of patients. In the majority of patients the tumour measured 17.6mm in diameter.

HRT was started on average 62 months (range 1-180 months) after diagnosis, and lasted an average of 28 months (range3 72 months). All 21 patients used oestradiol as HRT, i.e. a non-conjugated oestrogen.

Combined hormonal therapy (oestrogens + progestagens) was given to 95% of patients with median age of 47 years   (range 41-59 years) at the beginning of HRT.

Relapse was observed in four patients (19%) of the HRT group; of these, one had a carcinoma of the contralateral breast.

In the control group, relapse was   observed in five patients (11%); one of these five patients had a carcinoma of the contralateral breast.

In   the HRT group, there were no deaths among the patients with confirmed relapse, while one patient died  in the control group.

The estimated risk (OR= 1.74, 95%S CI 0.34-8.88) of relapse of breast cancer was  calculated by comparing data from HRT users, who had received HRT for 28 months (range 3-72   months) on average, with data from the control group. The estimated risk of breast cancer relapse in HRT  users who had been receiving HRT for less than 24 months was 0.65 (OR = 0.65, 95% CI 0.02-7.85).

CONCLUSION: Despite the inherent limitations of retrospective data and the need for prospective randomized trials to assess the possible influence of HRT on progression after breast cancer treatment,  the present observations suggest that HRT treatment for less than 24 months does not appear to have a  pronounced adverse effect on cancer outcome. Nevertheless, until appropriate clinical trials determine  that HRT is safe, caution is needed.

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1998 Observational study- No increase in breast cancer recurrence after HRT  oral or transdermal estrogen and a progestin

70) Dew, J., et al. “A cohort study of hormone replacement therapy given to women previously treated for breast cancer.” Climacteric 1.2 (1998): 137-142.

Women who have been previously treated for breast cancer are usually advised to avoid hormone therapy for fear of increasing their risk of tumor recurrence. However, for some women, menopausal symptoms are so severe that their quality of life is poor. Because ethic committees are reticent to permit a double-blind randomized trial, we performed a cohort study of hormone therapy after breast cancer.
METHODS:

The study group comprised 1472 women with breast cancer. A total of 167 subjects had used an oral or transdermal estrogen after their treatment for breast cancer. Amongst these estrogen users, 152 (91%) had also used a progestin. In total, 106 other women had used a progestin alone as a treatment for menopausal flushes and not as a treatment for breast cancer. Cox regression analysis was performed using estrogen as a time-dependent covariate with disease-free interval as the outcome.

RESULTS: The uncorrected hazard ratio for the estrogen-progestin users was 0.67 (95% confidence interval (CI) 0.38-1.16) and for the progestin alone users was 0.85 (95% CI 0.44-1.65).

CONCLUSIONS: This study was unable to demonstrate a significant increase in risk of breast cancer recurrence for women who used HRT and suggests that the time is now appropriate for a randomized prospective trial of hormone therapy after breast cancer.

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1996
71) DiSaia, Philip J. “Hormone replacement therapy in the gynecologic and breast cancer patient.” Cancer Control 3.2 (1996): 101-106.

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1993

72) Wile, Alan G., Richard W. Opfell, and David A. Margileth. “Hormone replacement therapy in previously treated breast cancer patients.” The American journal of surgery 165.3 (1993): 372-375.

We report our experience with 25 women previously treated for breast cancer who subsequently received     hormone replacement therapy (HRT) for the relief of menopausal symptoms and the prevention of     postmenopausal cardiovascular disease and osteoporosis.

Two patients had in situ disease, 13 had stage I disease, 7 had stage II disease, 1 had stage III disease, and 2 had invasive cancer of  undetermined stage. Seventeen patients (group I) began HRT less than 24 months after primary breast  cancer therapy, and 8 patients (group II) began HRT more than 24 months after breast cancer therapy.  The HRT-free interval for group I patients averaged 7.9 months and for group II patients averaged 64.5  months. The average period of observation while receiving HRT for the entire group was 35.2 months  (range: 24 to 82 months).

Three of 25 patients have had a recurrence, all in group I. One patient  developed local recurrence after breast conservation treatment, and her condition was salvaged by further     wide excision. Two patients developed recurrence after mastectomy, and one patient ultimately died of  systemic disease. The overall survival rate for the entire group was 96%. Overall survival of high-risk  group I patients, with a mean follow-up of 30.4 months, was 94%.

We recognize that this report of HRT in  a small group of patients does not have the power to demonstrate an adverse effect of HRT on breast cancer. However, the lack of an obvious adverse effect of HRT in this group of breast cancer patients     and the known beneficial effect of HRT on postmenopausal cardiovascular disease and osteoporosis     warrant formal prospective trials of HRT in such patients.

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73) Hodis, Howard N., and P. M. Sarrel. “Menopausal hormone therapy and breast cancer: what is the evidence from randomized trials?.” Climacteric 21.6 (2018): 521-528.

74) Manson, JoAnn E., et al. “Menopausal hormone therapy and long-term all-cause and cause-specific mortality: the Women’s Health Initiative randomized trials.” JAMA 318.10 (2017): 927-938.

75) Ross, Ronald K., et al. “Effect of hormone replacement therapy on breast cancer risk: estrogen versus estrogen plus progestin.” Journal of the National Cancer Institute 92.4 (2000): 328-332.

76) Birrell, Stephen N., et al. “Disruption of androgen receptor signaling by synthetic progestins may increase risk of developing breast cancer.” The FASEB Journal 21.10 (2007): 2285-2293.

77) De Lignieres, B., de Vathaire, F., Fournier, S., Urbinelli, R., Allaert, F., Le, M. G., and Kuttenn, F. (2002) Combined hormone replacement therapy and risk of breast cancer in a French cohort study of 3175 women. Climacteric. 5, 332–340

78) Fournier, A., Berrino, F., Riboli, E., Avenel, V., and Clavel-Chapelon, F. (2005) Breast cancer risk in relation to different types of hormone replacement therapy in the E3N-EPIC cohort. Int. J. Cancer. 114, 448–454

79) Yao, Song, et al. “Association of serum level of vitamin D at diagnosis with breast cancer survival: a case-cohort analysis in the pathways study.” JAMA oncology 3.3 (2017): 351-357.

80) Grant, William B. “Review of recent advances in understanding the role of vitamin D in reducing cancer risk: breast, colorectal, prostate, and overall cancer.” Anticancer Research 40.1 (2020): 491-499.
On the basis of those findings, medical practice should embrace and
public health advice should encourage use of vitamin D to
reduce cancer risk and increase survival rates after diagnosis.

Last updated on June 24th, 2024 by Jeffrey Dach MD