Adjuvant Endocrine Therapy for Breast Cancer Survivors, Dr Jekyll and Mr. Hyde
by Jeffrey Dach MD
Marjorie is a 54 year old stay at home mom who had a lumpectomy and radiation therapy for breast cancer about four years ago. She had been taking an estrogen blocking drug called letrozole, an aromataste inhibitor (AI) which inhibits production of estrogen, leading to undetectable serum estrogen levels. The letrozole estrogen blocking drug is causing severe menopausal symptoms, vaginal dryness, recurrent urinary tract infections, hot flashes, night sweats and insomnia. Marjorie is so miserable, she is thinking of stopping the estrogen blocking drug and starting hormone replacement, a plan vigorously opposed by her oncologist. In this newsletter, we review the mainstream oncology treatment of breast cancer with the two most common estrogen blocking drugs, tamoxifen and the aromatase inhibitors (AIs). Even mainstream medicine recognizes the Dr. Jekyl and Mr. Hyde qualities of this class of medications, in some cases they help and in others they harm. The 5-year survival rate for breast cancer was approximately 90 % in the U.S. from 2012 to 2018…However, this survival rate is only 28% if there is metastatic spread, suggesting a need for better treatments in patients with metastatic disease. Note: tamoxifen is an estrogen receptor blocker, while AIs prevent conversion of testosterone to estrogen.(1)
Header Image: La Grenouillére (or Bain à la Grenouillère) (1869). Oil on canvas, Metropolitan Museum of Art, New York City by Claude Monet (1840–1926), public domain, courtesy of wikimedia commons
The History of Breast Cancer and Its Treatment
In 1896, Dr. George Beatson was first to observe oophorectomy (surgical removal of ovaries) induced a favorable tumor response in a premenopausal patient with metastatic breast cancer. The oophorectomy procedure removed the source of estrogen production, creating an estrogen depletion state, thus oophorectomy and estrogen depletion became mainstream treatment of breast cancer. By 1944, the oophorectomy cases were compiled and reviewed by Dr. Alexander Haddow from the U.K. finding a tumor response rate of about 30 percent. Despite this low efficacy rate, a 30 percent response rate became the “magic number”, and the future outcome for all endocrine therapies to follow. Sadly, tumor responses after oophorectomy were only transient. This state of affairs left much to be desired, leading to the search for a better treatment. (2)
High Dose Synthetic Estrogen as Treatment for Breast Cancer 1944-1972
In 1944, medicine reversed course, switching from estrogen depletion to the opposite treatment, giving high dose estrogen to women with metastatic breast cancer. Dr. Alexander Haddow reported treatment of metastatic breast cancer with high dose synthetic estrogen (DES) provided a 30 percent tumor response rate. DES treatment was quickly adopted, replacing oophorectomy, since it gave the same 30 percent response rate without submitting the patient to a surgical procedure. DES seemed to work best in women more than 5 years post-menopause, women who had been deprived of estrogen for the long term. Note: first synthesized in 1938, DES is diethylstilbestrol, an endocrine disrupting chemical, later banned in 1971 in the U.S. when it was discovered to cause clear cell vaginal and cervical cancer in daughters of mothers who used DES during pregnancy. Sons were also affected with reproductive problems. (3-6)
Invention of Tamoxifen and Aromatase Inhibitors in the early 1970s.
Since 1896, more than 128 years ago, estrogen hormones have been mistakenly regarded as causing breast cancer, thus leading to the idea that estrogen blocking drugs should be the ideal prevention and treatment for breast cancer. Thus, in the early 1970’s estrogen blocking drugs (anti-estrogens) were invented and adopted for prevention and treatment of breast cancer. Invented as a “morning after” contraceptive pill in 1962, tamoxifen languished as a failed drug. In 1972, Dr. V. Craig Jordan, the “father of tamoxifen”, proposed the drug for prevention and treatment of breast cancer. Tamoxifen is an estrogen receptor blocker, thus preventing proliferative effects of estrogen signalling. Later, aromatase inhibitors (AIs) such as anastrozole, letrozole, exemestane were invented. AI’s prevent conversion of testosterone to estrogen, the main pathway for estrogen production. Thus creating a chemical form of oophorectomy. Dr. V. Craig Jordan also made the paradoxical discovery that once exhaustive anti-tamoxifen resistance develops in the breast cancer patient, estrogen treatment can be used with success. The cancers cells are now sensitized to low dose estrogen which induces apoptosis, programmed cell death. (7-8)
Opposite Hormonal Treatments Have Same Efficacy
in the 1981, clinical trials were done to answer the question, which drug is better, the estrogen receptor blocking drug tamoxifen, or the high dose synthetic estrogen drug DES? These are two drugs with quite opposite mechanisms of action, yet they both achieve the same result of a 30 percent tumor response rate. Despite equivalent efficacy, tamoxifen quickly replaced DES and became standard of care because it was easier to tolerate with less patient drop-out. The estrogen treatment of breast cancer was sent to the medical museum and forgotten. Note: this magic number of 30 percent response rate for tamoxifen applies to all breast cancer cases grouped together, both ER positive and negative. When only estrogen receptor (ER) positive cases are considered, this number increases to 40-50 percent, as ER negative cases are rarely responsive to tamoxifen. (9-10)
What is the Mechanism of Opposite Hormonal Manipulations ?
The next obvious question is how can opposite endocrine treatments give the same results? And if anti-estrogen is the correct treatment for breast cancer, how do we explain the development of anti-estrogen resistance with transformation of the cancer into a more aggressive cell type? What is the biological mechanism here? In 2015, Dr. Zsuzsanna Suba provides the answer. Medical science has misunderstood the connection between estrogen signaling and development of breast cancer. Mainstream medicine ignores the role of estrogen in DNA stabilization and maintenance of genome stability. Estrogen works closely in association with the BRCA gene, a tumor suppressor gene involved in DNA repair, cell cycle control, apoptosis, and genome stability. (11-14)
Crosstalk Between Estrogen and DNA Repair
In 2022, Dr. Lia Yedidia-Aryeh studied the tight crosstalk between estrogen and DNA repair gene activation, finding impaired DNA repair when ER positive cells are depleted of estrogen, writing:
We and others have shown that estrogen is required for intact DSB [double stranded break] [DNA] repair, since we found that DSB repair is impaired in ER-positive cells depleted for estrogen ….Studies indicate that there is a tight crosstalk between estrogen and [DNA] repair. Estrogen regulates the expression of [DNA repair] factors and the activity of [DNA repair]. (15)
Cell survival depends on maintaining DNA repair mechanisms and genome integrity. This in turn, is dependent upon maintaining estrogenic signalling. Thus, all cells including tumor cells will desperately try to maintain estrogen signalling whenever threatened with estrogen deprivation. If genome integrity can not be maintained in the damaged cell, then estrogen signalling triggers apoptosis to eliminate the defective cell which is beyond repair. This paradoxical estrogen induced apoptosis after exhaustive tamoxifen treatment, or a period of long term estrogen deprivation, was recognized early on by Dr. V. Craig Jordan. (16-18)
Explaining the Mechanism of How Opposing Endocrine Treatments Yield Similar Results
In 2015, Dr. Zsuzsanna Suba explains how opposing endocrine treatments yield similar results. Both low and high estrogen levels upregulate estrogen receptor signalling to maintain genome stability. ER-alpha signalling is the major player for maintaining genome stability, working closely with the BRCA genes. ER-alpha signalling also triggers cancer cell apoptosis, i.e. programmed cell death. In 2015, Dr. Zsuzsanna Suba writes:
Comprehensive analysis of experimental and clinical–epidemiologic results suggests that ER-alpha signaling is the chief safeguard of genome stability in strong interplay with DNA controlling and repairing systems, such as BRCA genes and their protein products…estrogen signaling recognizes and destroys malignant tumor cells by means of apoptotic mechanisms…Both low and high estrogen levels promote enhanced expression and transcriptional activity of ERs aiming to maintain the crucial cellular estrogen surveillance. (19)
The Pitfalls of Anti-Estrogen Treatment
In 2015, Dr. Suba reviews the pitfalls of antiestrogen treatment and the mechanism of antiestrogen resistance. The treatment of breast cancer cells by either estrogen or antiestrogen drug results in estrogen receptor overexpression making the tumor cells more sensitive to estrogen induced apoptosis at a later time when exogenous estrogen is re-introduced. In the 30 percent of breast cancer tumors which respond to tamoxifen administration, up-regulation of estrogen receptors is sufficient to supply the cancer cells with estrogen, causing tumor regression from the apoptotic effects of estrogen. However if estrogen signalling is completely blocked, then the tumor cell’s capacity to compensate becomes exhausted. This is called tamoxifen resistance, leading to unrestrained tumor proliferation and metastatic spread. Even at this stage, all is not lost. The re-introduction of high dose estrogen restores signalling and tumor regression. In 2015, Dr. Zsuzsanna Suba writes:
ER overexpression in tumor cells treated with either estrogens or antiestrogens may be explained by the fundamental regulatory capacity of estrogens. These apparently contradictory treatments can similarly upregulate abundant ER expressions and transcriptional activities. Estrogen-induced upregulation of estrogen signaling is a physiologic process, while in case of antiestrogen administration, it may be regarded as a counteraction for the defense of endangered cellular estrogen surveillance…Increased estrogen signaling displays a unique dichotomy effect: it safeguards the survival and proliferative activity of healthy cells, while induces apoptotic death of malignant tumor cells…In patients with breast cancer, estrogen administration is capable of exerting self-generating, increased ER expression and estrogen synthesis as well so as to achieve the strong upregulation of estrogen signaling and apoptotic tumor cell damage. Paradoxically, antiestrogen treatment may also provoke compensatory ER overexpression in tumor cells and extreme estrogen synthesis in the patient so as to restore the apoptotic capacity of estrogen signaling. When these counteractions are sufficient, tamoxifen administration seems to be deceivingly effective, resulting in transient tumor regression…By contrast, primary insufficiency or exhaustion of the defensive counteractions in patients treated with antiestrogens may lead to the complete blocking of estrogen signaling, since the patient has limited capacities for extreme ER expression and estrogen synthesis. In such cases, the result is unrestrained proliferative activity of the tumor cells, and the rapid tumor spread is mistakenly evaluated as de novo or acquired antiestrogen resistance. Nevertheless, high-dose estrogen treatment is capable of restoring the suppressed estrogen signaling even after heavy exposure to antiestrogen treatment. Exogenous and newly synthesized estrogens are in competition with tamoxifen for binding sites on newly expressed, abundant ERs, and the higher the concentration of estrogens, the higher is the probability of successful defeat of tamoxifen. The triumph of estrogens leads to apoptotic tumor cell death and clinical regression of the disease…In conclusion, during long-term antiestrogen treatment, the upregulation of both estrogen and ER synthesis exhibits gradual exhaustion and the development of complete antiestrogen blockade of estrogen signaling results in rapid tumor spread. Fortunately, high-dose estrogen treatment is capable of restoring the estrogen signaling even after exhaustive antiestrogen therapy with the achievement of rapid tumor regression. (20-25) (10) (67) (126)
The Three Phases of Antiestrogen Administration
In 2015, Dr. Zsuzsanna Suba describes the three phases of antiestrogen administration and the mechanism of antiestrogen resistance. In the first phase, preservation of estrogen signaling indicates successful antiestrogen therapy with tumor regression. In the second phase, the tumor appears stable with no progression. In the third and final phase, the tumor cell’s ability to compensate by upregulating ERs and aromatase enzyme is exhausted leading to rapid proliferation, metastatic disease and death, writing:
There are three phases of antiestrogen administration in genetically proficient breast cancer cases, treated by either ER blocker [tamoxifen] or aromatase inhibitor, which can be characterized by [first] good tumor regression, [second] stagnation of tumor growth, and [third] aggressive tumor spread…During this first period, estrogen signaling may exhibit compensatory upregulation in tamoxifen-treated premenopausal patients experiencing regular cycles and ovulatory activity with the potential to become pregnant…Moreover, in breast cancer biopsy specimens, active estrogen signaling characterized by intense phosphorylation at Ser(167) of ERs predicted longer disease-free survival and overall survival for the patients…[Note: When AKT phosphorylates Ser167 on the estrogen receptor (ER), this activate ER-alpha’s transcriptional activity without the need for an estrogen molecule binding to it. Obviously this massively upregulates estrogen signalling during periods of estrogen deprivation without depending upon serum estrogen molecules.] In sequential biopsies of large primary breast tumors, measurement of aromatase content before and during effective treatment with aromatase inhibitor showed a surprisingly marked, counteractive increase in [aromatase] enzyme activity…These results support [the concept] that the provoked compensatory upregulation of estrogen signaling may be in correlation with successful tumor regression instead of an antiestrogenic effect...Tamoxifen treatment induces artificial estrogen resistance in women. These patients mimic the chaotic findings, which are characteristic of cases suffering from the genetic failures of ER expression and/or transcriptional activity coupled with counteractive defense mechanisms, such as extreme [increase in] estrogen synthesis…In tamoxifen-treated cases, very high compensatory estrogen levels and even an increased ER expression may be associated with the symptoms of ER blockade-induced estrogen resistance, such as multiple ovarian cysts or endometrial hyperplasia…On the other hand, exhaustive aromatase inhibitor treatment in breast cancer cases mimics the symptoms of aromatase deficiency syndrome deriving from the genetic defect of aromatase synthesis…In the case of this artificial aromatase deficiency, patients may exhibit even an increased counteractive expression in aromatase enzyme synthesis besides the overexpression of ERs. In the second phase of aromatase inhibitor treatment, apparent resistance to aromatase inhibitors is mistakenly regarded as an increased cross talk between intensified ER and GFR [growth factor receptor] signaling pathways…In the third phase of antiestrogen treatment, both extreme ER expression and aromatase synthesis are exhausted, and the completion of estrogen signal blockage results in rapid growth and metastatic spread of breast cancer leading to the death of the patient. At the same time, diverse toxic effects of estrogen deficiency and accidentally developing cancers at different sites, particularly in the endometrium, may be diagnosed. This phase of complete antiestrogen blockade of estrogen signaling is mistakenly referred to as acquired antiestrogen resistance…In the remaining half of patients [ER positive patients with no response to tamoxifen, i.e. de novo resistance], the key for ineffective antiestrogen medication against ER-positive breast cancers may be the manifestation of earlier hidden point mutations affecting either estrogen signaling or the associated gene stabilizer systems…These cases do not have sufficient extra capacities for defensive ER overexpression and increased estrogen synthesis against the artificial inhibition of estrogen signaling. In such patients, the failure of tumor prevention or regression by antiestrogen treatment is erroneously regarded as de novo resistance against antiestrogen treatment. (26-33)
Explaining What Went Wrong with the HABITS Study
In the previous chapter on Hormone Replacement for Breast Cancer Survivors, Part Two, we discussed the 26 studies compiled by Dr. Avrum Bluming. Of these 26, the only one showing increased breast cancer recurrence was the 2004 HABITS study by Dr. Lars Holmberg of Sweden. The HRT used in this study was estradiol (E2) combined with norethisterone, a highly carcinogenic progestin derived from a testosterone backbone. In addition, all the patients with recurrent cancer in the HRT group were also taking tamoxifen, the antiestrogen drug which blocks estrogen receptors. HRT users had 3-fold increase in cancer recurrence compared to non-users. Dr. Holmberg suggested the carcinogenic progestin, norethisterone was the main culprit. Now that we have learned about the three phases of antiestrogen resistance of Dr. Suba (above), we can now speculate as to what went wrong with the HABITS study. Note HRT= hormone replacement therapy. (48-49) (105)
Switching to Androgenic Signalling
Firstly, in the HABITS study patients with breast cancer recurrence were all taking tamoxifen which blocked the estrogen receptors, so giving exogenous estradiol (E2) was a futile gesture having no effect on estrogen signalling. As mentioned above, the first phase of antiestrogen resistance is a desperate attempt by the breast cells to upregulate estrogen receptors and estrogen signalling. In the HABITS trial, I speculate this was done by switching from estrogenic to androgenic signalling. According to Dr. Charles Dai (2023), AR (androgen receptor) can bind to the same DNA regions as ER (estrogen receptor). In 2021, Dr. Theresa E. Hickey did an in-vitro breast cancer study finding AR (androgen receptor protein) was detected at 42% of estrogen-stimulated ER-binding sites on chromatin. Thus, androgens are upregulated to replace deficient estrogen signalling during anti-estrogen treatment. In addition, androgen signalling, much like estrogen, can induce apoptosis within breast cancer cells. (52-56)
Androgens Provide Complete Relief of Menopausal Symptoms
In 2011, Dr. Rebecca Glaser studied relief of menopausal symptoms using testosterone pellets showing excellent crosstalk between estrogen and androgen signalling, strong enough to completely relieve menopausal symptoms of estrogen deficiency. This is more completely discussed in the chapter on Testosterone for Prevention and Treatment of Breast Cancer. (50)
Blocking Both Estrogen and Androgen Signalling
What happens when the HABITS patient on tamoxifen is given the synthetic progestin, norethisterone, an androgen receptor blocking drug? This blocks the alternate androgen pathway used to maintain estrogen signalling. According to Dr. Suba’s three phases of antiestrogen administration, I speculate that these two drugs, the tamoxifen and the progestin completely exhausted the cancer cells’ ability to compensate, thus leading to tamoxifen resistance and cancer progression. Obviously, this is a very bad thing.
The Solution to the HABITS Study
What is the solution? Firstly, do not give androgen blocking drugs such as synthetic progestins to patients on tamoxifen or aromatase inhibitors (AI’s). Instead of the synthetic progestins, use natural progesterone or reduce exposure to the progestin. The parallel study to the HABITS trial was the 2005 Stockholm study by Dr. who recognized this problem with norethisterone, and switched to a less androgenic blocking progestin, medroxyprogesterone (MPA). Dr. Eva von Schoultz further reduced the patient exposure to MPA with a schedule of 10 days a month every other month, thus obtaining a more favorable result. The Stockholm Study HRT users enjoyed a 50 percent reduction in both breast cancer mortality and overall mortality compared to non-users. There were 4 deaths in the HRT group and 9 deaths in the non-user group. The recurrence rate for HRT users was not increased as it was in the HABITS trial, 11 in the menopausal hormone therapy group and 13 in the control no-treatment group. (34)
In support of the above speculation are the studies by Dr. Kiyoshi Takagi (2010 and 2022) that reveal intra-tumoral androgen (DHT) levels increase after treatment with aromatase inhibitors as a desperate measure to compensate for loss of estrogen signaling. In my opinion, AI induced dramatic upregulation of intratumoral AR signalling is a major anticancer benefit of AI drugs. The definitive studies on AI induced increased intratumoral androgen levels were done by Dr. Luciana Macedo (2006) and Dr. Niramol Chanplakorn (2011). Both authors suggest the beneficial anti-cancer effects of aromatase inhibitors are not due to estrogen depletion, it is due to the upregulation of intratumoral androgens. In 2006, Dr. Luciana Macedo writes:
In conclusion, the results suggest that aromatase inhibitors may exert their antiproliferative effect not only by reducing the intracellular production of estrogens but also by unmasking the inhibitory effect of androgens acting via the AR [androgen receptor]. (35)
And Dr. Niramol Chanplakorn writes:
These results suggest that increased 5-alpha-Red2 [5-alpha reductase converts testosterone to its more potent form DHT] and AR [androgen receptor] following AI [aromatase inhibitor] treatment may partly contribute to reduce the tumor cell proliferation through increasing intratumoral androgen concentrations and its receptor. (36)
In 2019, Dr. Lanyang Gao studied the androgenic actions of aromatase inhibitors in vitro and in vivo breast cancer cell studies finding aromatase inhibitor drugs are themselves chemically modified within cancer cells into androgens, and this androgenic activity is the main benefit, writing:
Direct treatment of ER (+) breast cancer with Formestane [aromatase inhibitor drug] diminishes the tumor [breast cancer xenograft] within weeks. This is unlikely due to lack of estrogens alone. We proposed that it is the negative influence of androgens on the growth of ER(+) breast cancer…We found that breast cancer cells can metabolize Formestane and Exemestane to androgenic compounds which inhibit proliferation…Our experiments have elucidated the antiproliferative effect of androgens on breast cancer cells. We could demonstrate that the steroidal aromatase inactivators formestane and exemestane are chemically modified within the cancer cells and that the modified sterols act predominantly as antiproliferative androgens. (141) (142) (143)
How to Do a Failed Clinical Trial: Block the Androgen Receptors
Working in quite the opposite direction, a misguided, failed trial in 2020 by Dr.
Dr. Rebecca Glaser to the Rescue: Give Testosterone !
What if we reverse course here and give testosterone? Instead of blocking testosterone with a progestin or another drug such as published a case series of 72 breast cancer survivors on letrozole, an aromatase inhibitor, also treated with a testosterone pellet, showing no breast cancer recurrence over 8 years of follow-up. This case series of Dr. Glaser is very supportive of the above speculation, that helping the breast cancer cells upregulate androgen signalling is beneficial. (43)
In 2024, Dr. Amy H. Tien reviewed the role of androgen receptors in breast cancer, and discussed a previous 2021 study by Dr.Theresa E. Hickey, writing,
a study by Hickey and colleagues [2021] demonstrated that AR [androgen receptor] behaves as a tumor suppressor in ER-alpha-positive breast cancer…They showed that AR transactivation with androgen inhibited ER-driven cell proliferation in an ex vivo patient-derived explant model. Using breast cancer cell lines, they also showed that AR was detected at 42% of estrogen-stimulated ER-binding sites on chromatin when both AR and ER were activated. This suggests that AR could directly affect ER transcriptional activity by redistributing ER. Interestingly, the binding or recruitment of coactivators p300 and SRC-3, which are required for ER signaling, were both reduced and replaced by AR upon AR activation. (44-46)
Aromatase Inhibitors Up-Regulate Androgen Induced Genes
In 2024, Dr. Amy H. Tien found aromatase inhibitor (AI) administration up-regulates 305 of 610 of androgen-induced genes, and suggests that the main anticancer benefit is androgen upregulation. However, not all breast cancers respond in this way. Dr. Tien also observed in a small number, one percent or so of cancer variants, androgens make things worse, and stimulate cancer growth. One such variant is the luminal AR (LAR) subgroup of TNBC triple negative breast cancer. Here, anti-androgen drugs would be more suitable, since for this rare variant, androgens act as proliferative oncogenic driver, rather than as tumor suppressor. Androgens are not suitable for ER negative, HER2-amplified breast cancer, and for AR-positive TNBC. Dr. Amy H. Tien writes:
The analysis of 19 published studies revealed AR expression in about 75% of ER-alpha- positive breast cancer and approximately 32% of ER-alpha-negative breast cancer. In ER alpha-positive breast cancer, higher levels of nuclear AR protein are usually correlated with improved outcomes and better survival regardless of treatments. The prognostic value of AR in ER-alpha-positive breast cancer has been demonstrated in many studies…DHT concentrations are elevated (three-fold higher) in tissues of DCIS and breast carcinoma compared to non-neoplastic tissues. The expression levels of 5α-reductase are elevated, and its activity is 4–8 times higher in breast carcinoma tissues than in non-neoplastic tissues…Aromatase is the enzyme that converts testosterone to estrogens. The gene expression analyses of breast cancer tissue from patients neoadjuvant treated with the aromatase inhibitor exemestane revealed that approximately one-half of the 610 androgen-induced genes examined were increased in response to blocking aromatase activity…AR expression also increases with neoadjuvant treatment with aromatase inhibitors...In ER-positive breast cancer, AR behaves as a tumor suppressor, with its function being opposite to ER…Patients with TNBC [triple negative breast cancer] usually have larger and more aggressive tumors, leading to poor clinical outcomes. Although TNBC patients respond to chemotherapy, they commonly develop distant recurrence and metastases. TNBC tumors account for 10–20% of all breast cancers…luminal AR (LAR). The LAR subgroup represents a range of 11–22% of TNBC depending on the population studied and analysis methods and is classified based on the luminal gene expression pattern. The LAR subgroup is particularly sensitive to antiandrogens. In this sub- group, AR behaves as an oncogenic driver for tumor cell proliferation…AR has distinct roles in different subtypes of breast cancers…In HER2-amplified breast cancer, AR behaves as the oncogenic driver instead of ER…AR also acts as an oncogenic driver in AR-positive TNBC…(47-60)
Efficacy and Adverse Effects of Antiestrogen Treatment
Tumor Efficacy of Tamoxifen: Tamoxifen as a first line therapy for ER-positive breast cancer induces tumor regression rate of 40%–50%. Nearly all responders eventually acquired tumor resistance, leading to rapid progression of aggressive disease. (61-63)
ER Negative Breast Cancer and Acquired TAM Resistance in ER positives:
Tamoxifen is ineffective for ER-alpha negative breast cancer. Loss of ER alpha expression is associated with TAM resistance and poor prognosis. In 2014, Dr. Floris H Groenendijk writes:
Response to tamoxifen is rare in ER-alpha‐negative breast cancer...A portion of ER-alpha‐positive tumors becomes independent of estrogen signaling after which they lose ER-alpha expression and, hence, are tamoxifen resistant. Gutierrez et al. studied the ER-alpha expression in paired clinical breast cancer samples from before the start of tamoxifen treatment and after tumor progression (Gutierrez et al., 2005). They found loss of ER-alpha expression in 17% of ERα‐positive tumors at the time of tumor progression. This was in line with earlier reports showing that ER-alpha loss occurs in 15–30% of the tumors at the time of recurrence (Encarnacion et al., 1993; Johnston et al., 1995; Kuukasjarvi et al., 1996). Loss of ER-alpha was associated with tamoxifen resistance (Johnston et al., 1995) and can be used as a predictor of poor response to subsequent endocrine therapy (Kuukasjarvi et al., 1996). (64)
Adverse Side Effects of Tamoxifen: Tamoxifen has estrogenic effects which increase blood clots, stroke, pulmonary emboli, coronary artery disease, and endometrial cancer. (65)
Dual Qualities of Tamoxifen as Dr. Jekyl and Mr. Hyde
in 2004, Dr. Daniel Hayes recognized the Dr. Jekyll and Mr. Hyde dual nature of tamoxifen. Women on tamoxifen for 10-15 years will have a 15 percent reduction in mortality. Yet, among ER positive breast cancer cases, only about half the women benefit. In women with the ER positive and overexpressed HER-2 breast cancer variants, the tamoxifen is harmful, worsening the prognosis by increasing recurrence and mortality, writing:
worldwide overviews of prospective clinical trials demonstrate that adjuvant tamoxifen reduces the annual odds of death for women with invasive breast cancer by approximately 15% over 10–15 years…However, tamoxifen is not ideal. Even among women with ER-positive breast cancer, only 40–50% of patients benefit, suggesting that a substantial fraction of ER-positive cancers are resistant to this drug…patients with HER-2–overexpressing tumors who were assigned to adjuvant tamoxifen had higher rates of recurrence and mortality than those who did not receive the agent. (66)
Efficacy of Aromatase inhibitors: Tumor response rates are low, less than 30 percent, similar to results of other endocrine therapies such as tamoxifen, DES, and androgens). (67)
Efficacy of Tamoxifen and Aromatase Inhibitors for Primary Prevention of Breast Cancer
In 1976, Dr. Marc Lippman administered estrogen to breast cancer cell cultures finding that estrogen stimulates proliferation and growth of cancer cells in-vitro, while antiestrogens inhibit proliferation and growth. These studies supported the belief that estrogen causes breast cancer, and that antiestrogens should be the ideal treatment for prevention and treatment of breast cancer. Let us next look at the efficacy of antiestrogens for primary prevention of breast cancer. (106-110)
In 2019, Dr. Simone Mocellin reviewed the numerous clinical trials evaluating antiestrogens for primary prevention of breast cancer in healthy women. Dr. Simone Mocellin found 17 RCT studies as of August 2018 showing TAM reduced breast cancer risk by 32 percent over a follow up period of 6-16 years. The placebo group risk for breast cancer was 7.2 percent, and TAM group was 4.9 percent. This means the placebo group had a 92.8 percent chance of remaining cancer free. And, the TAM group had a 95.1 percent chance to remain cancer free. Note: RCT = randomized control trial.
For the aromatase inhibitor studies, the follow up period was 3-5 years. The relative risk reduction in the AI group was 53 percent. The cancer risk in the placebo group was 3.1 percent, and in the AI group was 1.4 percent. This means the placebo group had a 96.9 percent chance to remain cancer free. And, the AI group had a 98.6 percent chance to remain cancer free. The obvious question: is this small improvement in cancer free survival from 96.9 percent 98.6 percent worth the adverse side effects of AIs, estrogen deficiency symptoms mimicking severe menopause? The other factor, as discussed below, is the lack of data showing any reduction in all cause mortality in primary prevention studies using aromatase inhibitors (antiestrogen drugs). Lack of mortality benefit with AI’s should not be surprising in view of the 2024 study by Dr. Hilla Haapakoski from Finland showing increased mortality associated with early menopause. Dr. Hilla Haapakoski studied 22,859 women with premature ovarian failure before age 40 compared to controls, finding more than 3-fold increased mortality in women with premature ovarian failure. Aromatase inhibitors induce a state of estrogen depletion, very similar to that of premature ovarian failure, and thus would be expected to increase mortality in users. Dr. Hilla Haapakoski writes:
The mean follow-up time for all groups was 17.5 years. At the end of the follow-up, 9.8% of women with spontaneous POI [premature ovarian insufficiency] and 2.9% of controls were deceased. (70-71)
IBIS II 2020 Anastrozole for Primary Prevention of Breast Cancer
What is the reduction in overall mortality in studies of primary prevention of breast cancer using antiestrogen drugs? NONE FOUND. In 2020, Dr. Jack Cuzick reported in Lancet the long term results of the IBIS II clinical trial using the AI, anastrozole for primary prevention of breast cancer in healthy women with increased risk for breast cancer due to family or personal history. 1,920 women were randomly assigned to anastrozole one mg. per day oral tablet, and another 1920 women were assigned to placebo for 5 years of treatment. The study continued for 131 months (11 years) finding a 49% reduction in breast cancer for anastrozole (85 vs 165 breast cancer cases, hazard ratio [HR] =0.51). There was no reduction in overall mortality (69 vs 70) AI vs. placebo, and no significant reduction in breast cancer mortality (two anastrozole vs three placebo). Of note, the AI treated group had a 28 percent reduction in skin cancers (basal and squamous cell) suggesting efficacy of antiestrogen drugs in skin cancer, likewise a hormonal sensitive cancer. (72-74)
Comparing Anastrozole to Premarin for Primary Prevention
In 2014, Dr. D.A. Cameron comments on the IBIS-II study by Dr Jack Cuzick in which the use of the antiestrogen drug anastrozole over 5 years reduced the incidence of breast cancer by 53 percent in 1,920 women compared to placebo. However, there was no benefit in terms of overall mortality nor breast cancer mortality. Compare this to the second arm 2004 WHI study (Women’s Health Initiative) using Premarin alone (CEE) in women with prior hysterectomy. The 18 year follow up showed a 22 percent reduction in breast cancer incidence and a 40 percent reduction in breast cancer mortality as reported in 2020 by Dr. Rowan T. Chlebowski. Which would you rather take, an aromatase inhibitor which induces estrogen deficiency with severe menopausal symptoms, yet has no mortality benefit either for all cause nor breast cancer specific mortality? Or would you rather take estrogen hormone replacement which reduces mortality from breast cancer by 40 percent and avoid the uncomfortable menopausal symptoms? This one is a no-brainer. The estrogen hormone replacement is the obvious choice. (75-76)
Time to Re-Examine Breast Cancer Risk Reduction and Clinical Stategy
In 2021, Dr. Rowan Chlebowski professor of medicine and chief of Medical Oncology and Hematology at UCLA Medical Center reviewed the medical literature on primary prevention of breast cancer with antiestrogens and concluded it is time for a change. Current antiestrogen stategies to prevent breast cancer do not reduce mortality from breast cancer. On the other hand, dietary intervention with a low fat diet reduces mortality from breast cancer by 22 percent. Citing the 2004 WHI study, second arm, Dr. Rowan Chlebowski states giving post menopausal women Premarin-alone (CEE) reduced breast cancer (ER positive, PR negative) by 46 percent and reduced breast cancer mortality by 40 percent. These results are far better than any antiestrogen trial. Thus, Dr. Rowan Chlebowski agrees with Dr. Zsuzsanna Suba’s position that antiestrogens for primary prevention of breast cancer is a medical mistake, writing:
Agency breast cancer prevention guidelines for other than hereditary cancers have not materially changed in 20 years; endocrine-targeted agents (then, tamoxifen; now, adding raloxifene and aromatase inhibitors) reduce good prognosis estrogen receptor (ER)–positive, progesterone receptor (PR)–positive cancers without reducing deaths from breast cancer. Across three tamoxifen placebo-controlled prevention trials (N = 23,360) begun almost 30 years ago, although there were 226 fewer breast cancer cases, there were nine more deaths from breast cancer in the tamoxifen groups. Following clinical advances, currently more than half of breast cancer cases are solved problems with extremely low risk of death. As endocrine-targeted agents commonly prevent these cancers, widespread implementation of current prevention strategies may not reduce deaths from breast cancer… Against this background, in the Women’s Health Initiative Dietary Modification randomized trial (N = 48,835), ER-positive, PR-negative cancers were statistically significantly reduced in the intervention group (hazard ratio, 0.77; 95% CI, 0.64 to 0.94) and deaths from breast cancer were reduced 21% (P = .02). In the Women’s Health Initiative randomized, placebo-controlled trial evaluating conjugated equine estrogen (N = 10,739), ER-positive, PR-negative cancers were statistically significantly reduced in the intervention group (hazard ratio, 0.44; 95% CI, 0.27 to 0.74) and deaths from breast cancer were reduced 40% (P = .04). These findings suggest that reexamination of breast cancer risk reduction strategies and clinical practice is needed. (140)
Barriers to Antiestrogen Use for Primary Prevention
10 million high risk women 35-79 years of age in the U.S. are eligible for tamoxifen for primary prevention of breast cancer, yet only one percent of eligible women are using tamoxifen for this purpose. In 2015, Dr. Andrea DeCensi lamented this low uptake for tamoxifen, citing concerns about adverse side effects and lack of demonstrated mortality reduction. Dr. Andrea DeCensi writes:
Unsurprisingly, in a recent survey conducted among over 200 breast cancer specialists…the top three important or very important reasons for low [tamoxifen] uptake were the following:
(1) the drugs may have serious side effects;
(2) there is no evidence for a reduction in mortality [for primary prevention]
(3) the drugs are off label in Europe.
The issue of lack of effect on mortality...is a main point of contention…Preventive therapy trials of SERMs [tamoxifen] have not yet shown a reduction in breast cancer-specific or all-cause mortality, and this has been one of the main arguments against their use. (77-79)
More on Aromatase Inhibitors, Loss of Estrogen Receptors Lead to AI Resistance
In 2014, Dr. William R. Miller reviewed the mechanism of resistance to aromatase inhibitor drugs, writing:
In postmenopausal women, drugs such as letrozole, anastrozole and exemestane can inhibit aromatization of androgen in vivo by more than 99%, often decrease circulating estrogens to undetectable levels and, in hormone-dependent breast cancers, reduce tumour proliferation and growth. Third-generation aromatase inhibitors (AIs) are now front-line treatments for breast cancer. However, response rates range between 35 and 70% in neoadjuvant studies, and benefits may be lower in advanced disease. Acquired resistance after initial successful treatment also occurs. Note: estrogen is made in the body by the aromatase enzyme, which converts testosterone to estradiol. Thus, aromatase inhibitor drugs prevent the production of estrogen, leading to low serum levels of estradiol and menopausal symptoms. (80)
Aromatase Inhibitor Resistance – Mutation from ER Positive to ER Negative
In 2024, Dr. Pieter J. Westenend found that resistance to aromatase inhibitor therapy in about 30 percent of ER positive patients initially responding, is due to loss of the estrogen receptors. In other words, the breast cancer mutates from ER positive to ER negative status which is a poor prognostic indicator. Loss of the estrogen receptor has a negative effect on overall survival, writing:
In metastatic estrogen-receptor (ER)-positive HER2-negative breast cancer, resistance to endocrine therapy can be caused by ER loss and the mutation of ESR1, the gene coding for ERs…We found that, in a population of 136 patients, one of these mechanisms was responsible for endocrine resistance in 30% of the patients…Furthermore, we demonstrated that ER loss has a negative effect on overall survival…(81)
Antiestrogen Drugs May Not Be Ideal
According to Dr. Zsuzsanna Suba, almost all breast cancers responding to TAM will eventually acquire TAM resistance resulting in rapid progression of advanced metastatic disease. Regarding AIs, the vast majority of patients with advanced (metastatic) breast cancer will either be resistant or acquire resistance to aromatase inhibitor (estrogen blocking drug) treatment. Because of the above findings, Dr. Zsuzsanna Suba suggests estrogen blocking drugs are not the ideal treatment for breast cancer, writing:
Antiestrogen therapy of advanced breast cancer yielded many difficulties and failures from the onset. …Considering the whole population of breast cancer patients, antiestrogen treatment could not surpass the “magic” 30% of tumor response rate, similarly to the weaknesses of other endocrine therapies; such as oophorectomy [surgical removal of ovaries to prevent estrogen production] or high doses of synthetic estrogens [DES was mainstay treatment for breast cancer in the 1940s]. The majority of even the targeted ER-positive tumors were not responsive to the endocrine treatment showing primary resistance…In addition, patients showing earlier good tumor responses to antiestrogens later experienced secondary resistance leading to metastatic disease and fatal outcome… These experiences strongly suggest that our therapeutic efforts against breast cancer [with estrogen blocking drugs] are not appropriate. Further insights into the mechanisms of tumor growth and tumor recurrence are necessary for the improvement of breast cancer care…(82-83)
Maintaining Genome Integrity
Why is blocking estrogen problematic? Aside from the obvious adverse side effects of estrogen deficiency on all organ systems of the body, and the induction of severe menopausal symptoms, the estrogen signal is a fundamental regulator for all of our cells, and estrogen blockade is toxic to our genome, provoking desperate countermeasures to maintain the estrogen signal. These counter-measures are provoked because all our cells, including breast cancer cells, need to maintain genome integrity, and estrogen [E2] signaling controls the gene network involved in maintaining genome integrity. In 2021, Dr. Sara Pescatori discussed the dual role of estadiol in balancing DNA damage with genome integrity, making this knowledge difficult to reconcile with the idea of estrogen working as a carcinogen, writing:
The sex hormone 17β-estradiol (E2) exerts diverse pleiotropic physiological effects including the control of the reproductive system in females and the development of primary and secondary sexual characteristics in humans. E2 regulates a plethora of physiological functions in non-reproductive tissues including heart, bone, and brain systems. Accordingly, E2 can exert beneficial effects being protective against osteoporosis, cardiovascular and neurodegenerative diseases...the most frequent BCs [breast cancers] (i.e., 75%) express the ER-alpha at the diagnosis. The ER-alpha is an important prognostic factor because its expression drives the treatment (i.e., the endocrine therapy [with AI’s]), which aims to block different aspects of the E2:ER-alpha proliferative signaling…Nonetheless, it is difficult to reconcile how E2, which controls crucial physiological processes both in females and males and contributes to body homeostasis, could work as a carcinogen inducing the development of BC [breast cancer]. (84)
A few compelling pieces of evidence make the case against estrogen as a carcinogen.
1) Estrogen prevents breast cancer and reduces breast cancer mortality. The 2004 WHI study (using estrogen-alone, Premarin, CEE) showed estrogen treatment reduced incidence of breast cancer by 22 percent, and the 18 year follow up showed 40 percent reduction in mortality from breast cancer. (85)
2) Estrogen deficiency, not estrogen excess is associated with oral cancer. (86)
3) Estrogen deficiency after menopause increases the risk for breast cancer. However, this risk for breast cancer is lower for premenopausal women when estrogen levels are higher. Roughly 80 percent of breast cancer cases occur in the postmenopausal age group. On the other hand, only 20 percent of breast cancer cases occur in the premenopausal age group. (87)
4) High estrogen levels of pregnancy confer protection from breast cancer. Conversely, nulliparity [no pregnancy] increases the risk for breast and other female cancers. (88-91)
5) Pregnancy Protects Mice from Induction of Breast Cancer with Chemical Carcinogens
Animal experiments using mice shows that pregnancy before or soon after exposure to a chemical carcinogen (DMBA) is strongly protective against developing breast cancer. Short term exogenous hormone exposure mimicking pregnancy is highly protective in mouse models of carcinogen induced breast cancer, reducing tumor formation by 60-70 percent. Even synthetic estrogens confer protection. (92-97)
Interrupting Adjuvant Hormone Therapy for Pregnancy
If high estrogen levels cause recurrence in breast cancer survivors, one would expect increased recurrence after pregnancy when estrogen levels are extreme.This was studied and found to be false. In 2023, Dr. Ann Partridge of the Dana Farber Cancer Institute published her POSITIVE trial in which temporary interruption of adjuvant hormonal therapy for ER positive breast cancer in order to carry a pregnancy does not increase breast cancer recurrence compared to controls. Among 516 women with a median age was 37 years, over three years, the incidence of recurrent breast cancer was 8.9% in the treatment-interruption-pregnancy group and 9.2% in the control group.(98)
In 2017, Dr. Javaid Iqbal found that a pregnancy 6 months or more after breast cancer is associated with dramatic improvement in outcome. Dr. Javaid Iqbal did a retrospective cohort study using a health database in Toronto, Canada including 7553 women aged 20 to 45 years with the diagnosis of invasive breast cancer. Dr. Javaid Iqbal was specifically interested in women who became pregnant 6 months or more after the diagnosis of breast cancer, finding this group had a 75 percent reduction in mortally compared to the non pregnancy cohort, writing:
compared with nonpregnant women, the risk of death significantly dropped for women who delivered [a full term pregnancy] 6 months or more after diagnosis of breast cancer (multivariable HR, 0.25 ). The 5-year actuarial survival rate was 96.7% [3.3% mortality] for women who had pregnancy 6 months or more after diagnosis of breast cancer, vs 87.5% (95% CI, 86.5%-88.4%) [12.5% mortality] for women with no pregnancy) (age-adjusted HR, 0.22). (119-122) (88) (92-97)
6) Tamoxifen or AI resistant Breast Cancers Regress with Estrogen Therapy
Long term tamoxifen or AI treatment eventually transforms earlier responsive ER positive breast cancers into artificially created ER negative, anti-estrogen-treatment-resistant cancers. These aggressive cancers may now be treated with estrogen with dramatic reduction in cancer related mortality. In 2024, Dr Zsuzsanna Suba writes:
In tumors exhaustively treated with tamoxifen, the achieved ER blockade may be regarded as an artificially created ER-negative status, as estrogen signaling suffers irreparable damage. Among patients with tamoxifen-resistant advanced breast cancer, [subsequent] estrogen treatment dramatically decreases breast cancer related mortality…In tumors, with tamoxifen-blocked ERs, estrogen treatment induces abundant new ER expression and drives genome stabilization. In patients with aromatase inhibitor-resistant tumors, estrogen treatment induces regression of metastatic cancers and extends survival. (99-101)
How to Prevent Breast Cancer?
In 2015, Dr. Zsuzsanna Suba reviewed the pitfalls of anti-estrogen treatment as a prevention and treatment of breast cancer. Both estrogen and anti-estrogen treatments result in extreme up-regulation of estrogen signalling, the key mechanism for prevention and treatment of breast cancer. Dr. Suba writes:
whatever type of available endocrine therapies may be used, including estrogen, antiestrogen treatment, or oophorectomy, an extreme upregulation of ER signaling seems to be the crucial mechanism of successful prevention and treatment for breast cancer. (102) (118)
The Dawn of a New Era – Estrogen for Breast Cancer Treatment
Animal transfection experiments were done in 1992 by Dr. Marcel Garcia and in 1994 by Dr. Anait Levenson using mice given breast cancer xenografts. The breast cancer cells were first transfected with the estrogen receptor genes, transforming the xenografted cancer cells into ER positive cancer cells. In 1992, Dr. Marcel Garcia found that estrogen negative breast cancer cells transfected with the ER so they became ER positive, produced lung metastatic disease when xenografted into mice. These lung metastatic lesions were unresponsive to tamoxifen, but were inhibited three-fold by estrogen. Re-administration of tamoxifen reversed the benefits of estrogen. Dr. Marcel Garcia writes:
We transfected the human estrogen receptor into the estrogen receptor-negative metastatic breast cancer cell line MDA-MB-231 in an attempt to restore their sensitivity to antiestrogens. Two stable sublines of MDA-MB-231 cells (HC1 and HE5) expressing functional estrogen receptors were studied for their ability to grow and invade in vitro and to metastasize in athymic nude mice. The number and size of lung metastases developed by these two sublines in ovariectomized nude mice was not markedly altered by tamoxifen but was inhibited 3-fold by estradiol. Estradiol also significantly inhibited in vitro cell proliferation of these sublines and their invasiveness in Matrigel, a reconstituted basement membrane, whereas the antiestrogens 4-hydroxytamoxifen and ICI 164,384 reversed these effects. These results show that estradiol inhibits the metastatic ability of estrogen receptor-negative breast cancer cells following transfection with the estrogen receptor, whereas estrogen receptor-positive breast cancers are stimulated by estrogen, indicating that factors other than the estrogen receptor are involved in progression toward hormone independence. (103-104)
Adverse Effects of Aromatase Inhibitors
Since aromatase inhibitors induce an artificial menopause, it is not surprising the adverse side effects of aromatase inhibitors mimick severe menopausal symptoms of hot flashes, night sweats, insomnia, “brain fog”, vaginal dryness, arthralgia, decreased bone mineral density, and an increased bone fracture rate. (68-69)
Harms and Perils of Prolonged Hypoestrogenism – 50% Discontinuation Rate
In 2021, Dr. Robert P Kauffman from Amarillo, Texas discusses the perils of prolonged hypoestrogenism as treatment for breast cancer, and questions if the antiestrogen treatment is worse than breast cancer recurrence. As mentioned in chapter 11, surgical induced estrogen deprivation with hysterectomy is associated with increased all cause mortality. For more on this, see chapter 11. Likewise, drug induced long-term estrogen deprivation [LTED] using tamoxifen, aromatase inhibitors and ovarian suppression drugs, is associated with an increase in all-cause mortality. Profound estrogen deficiency, especially in the premenopausal group is not well tolerated leading to a treatment discontinuation rate of about fifty percent before the end of the 5 years of treatment. These bothersome symptoms mimic severe menopausal symptoms, vasomotor instability, sleep disturbance, depression/anxiety, cognitive decline, cardiovascular disease and stroke, diabetes, bone loss, joint and connective tissue discomfort, genitourinary syndrome of menopause, and sexual dysfunction. The breast cancer survivor who seeks help for these adverse symptoms may find themselves a walking drug store. The primary care or the oncologist will prescribe a list of drugs: SSRI antidepressants and benzodiazepines for depression and anxiety, sleeping pills for insomnia, bisphosphonates and denosumab for osteoporosis, celecoxib, ibuprofen and NSAIDs for joint pain, repeated antibiotics for recurrent urinary tract infections, and cognitive therapy for sexual dysfunction, statin drugs for cardiovascular disease, and diabetic drugs for elevated blood sugar. The breast cancer patient is left on her own to ponder the question: Is antiestrogen drug treatment worse than the disease? Dr. Robert P Kauffman writes:
Long-term estrogen deprivation is associated with an increase in all-cause mortality…Profound hypoestrogenism in the premenopausal age group may not be well tolerated due to a host of bothersome side effects (primarily vasomotor symptoms, musculoskeletal complaints, genitourinary syndrome of menopause, and mood disorders). Prolonged hypoestrogenism in younger women is associated with premature development of cardiovascular disease, bone loss, cognitive decline, and all-cause mortality…Sustained lower serum [estrogen[ levels are associated with cardiovascular disease, osteoporosis, neurodegeneration, and inflammatory processes…The side-effects and potential harm of prolonged estrogen suppression are many: vasomotor instability, sleep disturbance, depression/anxiety, cognitive decline, cardiovascular disease and stroke, diabetes, bone loss, joint and connective tissue discomfort, genitourinary syndrome of menopause, and sexual dysfunction—to name the most common…The effect of low circulating estrogen levels on human physiology has been well studied in non-cancer populations. Prolonged disruption or cessation of ovarian function before the age of natural menopause or for prevention of heritable ovarian cancer is associated with multisystem disease (diabetes, cardiovascular disease, stroke, depression, osteoporosis, and others). (111-117)
Our Office Protocol for the Breast Cancer Survivor
Approximately 50 percent of breast cancer survivors make the decision on their own to discontinue the antiestrogen drugs within 5 years of use. These patients are very motivated to seek relief from their severe menopausal symptoms with bioidentical hormone replacement. Our office HRT formula is Bi-est (20 percent estradiol E2 and 80 percent estriol E3) and progesterone as a topical cream or vaginal capsule. The HRT formula always includes testosterone which metabolizes to 3-beta-diol which binds to and activates ER-beta, the tumor suppressor receptor. We also test for iodine levels and supplement when found low. All patients receive DIM, di-indole methane. Over the past 20 years, not a single breast cancer survivor treated in my office has had a recurrence.
Conclusion:
Estrogen (DES) was mainstream treatment for metastatic breast cancer for 30 years from 1942 to 1972, after which antiestrogen drugs became the new standard of care. After 50 years of using anti-estrogen drugs, new research has brought us full circle, providing a greater understanding of the role of estrogen in prevention and treatment of breast cancer.
In 2023, Dr. Suba provides us with an over view of antiestrogen therapies with tamoxifen and aromatase inhibitors. These therapies are disappointing because the majority of breast cancers show primary resistance, and those that do respond, nearly all later develop secondary resistance leading to progressive metastatic disease and fatal outcome. Dr. Suba’s three stages of antiestrogen resistance tell us the good responders are able to compensate by up-regulating estrogen signalling, while those patients with complete inhibition of ER signalling have exhausted their capacity to compensate, leading to stimulation of breast cancer growth, metastatic disease and fatal outcome. In my opinion, androgen signalling may represent a compensatory alternate pathway in the antiestrogen treated patient, and when androgen signalling is blocked, this leads to poor outcome as seen in the HABITS study. (2)
For mainstream oncology, antiestrogens remain the cornerstone of breast cancer treatment. I myself have seen patients with dramatic regression of metastatic cancer using the aromatase inhibitor drug, exemestane, and can attest to its success. Is the success of exemestane due to blocking the estrogen growth factor, or this success due to breast cancer cell apoptosis induced by sudden shock and up-regulation of estrogen signalling as suggested by Dr. Zsuzsanna Suba? Or is their success due to upregulation of androgenic signalling within the cancer cell by conversion of the AI drug into androgenic metabolites? This is still an unresolved question for mainstream medicine. I predict that future studies will vindicate Dr. Suba and show she has been right all along. Turning to antiestrogens as adjunctive therapy for the breast cancer survivor, mainstream medicine recognizes the dual features of Dr. Jekyll and Mr. Hyde. As we all know, Dr. Jekyll is the kind healing doctor, while Mr. Hyde is the serial killer. Dr. Robert P. Kauffman asks if such adjunctive use of antiestrogen drugs is worse than the risk for recurrence. The many severe adverse side effects of antiestrogens leads to a 50 percent discontinuation rate. Obviously, the adjunctive treatment of breast cancer with antiestrogen drugs has much to be desired. Hopefully pioneers such as Dr. Suba will lead the way to better treatments. We already have considerable medical literature making the case for estrogen for breast cancer prevention. Yet, the wheels of change turn slowly in mainstream medicine, so I wouldn’t hold my breath for this to change anytime soon. (118) (123-140)
Credit and thanks goes to Dr. Zsuzsanna Suba, professor emeritus at Semmelweis University in Budapest for her insights over decades of work on this topic. Dr. Suba’s three phases of antiestrogen resistance has given us a framework for understanding what went wrong with the HABITS study by Lars Holmberg of Sweden. The main anticancer benefit of aromatase inhibors may not be the depletion of estrogen, but the upregulation of intratumoral androgens.
Professor Doctor Zsuzsanna Suba MD, PhD, is professor emeritus at Semmelweis University in Budapest, where she earned both MD and PhD degrees. During this time, she also obtained postdoctoral board certification in pathology, laying the foundation for her expertise in cancer research…As a professor emeritus, Suba continues to shape the future of cancer research, advocating for new strategies that prioritize DNA stabilization in cancer cases.
Articles With Related Interest:
Hormone Replacement for Breast Cancer Survivors Part Two
Hormone Replacement for Breast Cancer Survivvors Part One
Estrogen Metabolism, Iodine, 2MEO Part Three
Testosterone for Breast Cancer Prevention and Treatment
All Bioidentical Hormone Articles
Jeffrey Dach MD
7450 Griffin Road, Suite 190
Davie, Fl 33314
954-792-4663
my blog: www.jeffreydachmd.com
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76) Chlebowski, Rowan T., et al. “Association of menopausal hormone therapy with breast cancer incidence and mortality during long-term follow-up of the women’s health initiative randomized clinical trials.” Jama 324.4 (2020): 369-380.
77) DeCensi, Andrea, et al. “Barriers to preventive therapy for breast and other major cancers and strategies to improve uptake.” Ecancermedicalscience 9 (2015).
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79) Cameron DA. Breast cancer chemoprevention: little progress in practice? Lancet. 2014;383(9922):1018–1020.
80) Miller, William R., and Alexey A. Larionov. “Understanding the mechanisms of aromatase inhibitor resistance.” Breast Cancer Research 14 (2012): 1-11.
81) Westenend, Pieter J., et al. “Estrogen-Receptor Loss and ESR1 Mutation in Estrogen-Receptor-Positive Metastatic Breast Cancer and the Effect on Overall Survival.” Cancers 16.17 (2024).
82) Suba, Zsuzsanna. “Rosetta stone for cancer cure: comparison of the anticancer capacity of endogenous estrogens, synthetic estrogens and antiestrogens.” Oncology Reviews 17 (2023): 10708.
83) Jordan, V. Craig. “Tamoxifen: toxicities and drug resistance during the treatment and prevention of breast cancer.” Annual review of pharmacology and toxicology 35 (1995): 195-211.
84) Pescatori, Sara, et al. “A tale of ice and fire: the dual role for 17β-estradiol in balancing DNA damage and genome integrity.” Cancers 13.7 (2021): 1583.
85) Chlebowski RT, Anderson GL, Aragaki AK, et al. Association of menopausal hormone therapy with breast cancer incidence and mortality during long-term follow-up of the Women’s Health Initiative randomized clinical trials. JAMA. 2020;324(4):369–380.
86) Suba, Zsuzsanna. “Gender-related hormonal risk factors for oral cancer.” Pathology & Oncology Research 13 (2007): 195-202.
87) McGuire, Andrew, et al. “Effects of age on the detection and management of breast cancer.” Cancers 7.2 (2015): 908-929.
88) Britt, K.; Ashworth, A.; Smalley, M. Pregnancy and the risk of breast cancer. Endocr. -Relat. Cancer2007, 14, 907–933.
89) Papaioannou, S.; Tzafettas, J. Anovulation with or without PCO, hyperandrogenaemia and hyperinsulinaemia as promoters of endometrial and breast cancer. Best Pract. Res. Clin. Obstet. Gynaecol.2010, 24, 19–27.
90) Gleicher, N. Why are reproductive cancers more common in nulliparous women? Reprod. Biomed. Online2013, 26, 416–419.
91) Suba, Zsuzsanna. “Estrogen Regulated Genes Compel Apoptosis in Breast Cancer Cells, Whilst Stimulate Antitumor Activity in Peritumoral Immune Cells in a Janus-Faced Manner.” Current Oncology 31.9 (2024): 4885-4907.
92) Sinha, D.K.; Pazik, J.E.; Dao, T.L. Prevention of mammary carcinogenesis in rats by pregnancy: Effect of full-term and inter-rupted pregnancy. Br. J. Cancer 1988, 57, 390–394.
93) Medina, D.; Smith, G.H. Chemical Carcinogen-Induced Tumorigenesis in Parous, Involuted Mouse Mammary Glands. JNCI J. Natl. Cancer Inst. 1999, 91, 967–969.
94) Yang, J.; Yoshizawa, K.; Nandi, S.; Tsubura, A. Protective effects of pregnancy and lactation against N-methyl-N-nitrosourea-induced mammary carcinomas in female Lewis rats. Carcinog 1999, 20, 623–628.
95) Guzman, R.C.; Yang, J.; Rajkumar, L.; Thordarson, G.; Chen, X.; Nandi, S. Hormonal prevention of breast cancer: Mimicking the protective effect of pregnancy. Proc. Natl. Acad. Sci. USA 1999, 96, 2520–2525.
96) Rajkumar, L.; Guzman, R.C.; Yang, J.; Thordarson, G.; Talamantes, F.; Nandi, S. Short-term exposure to pregnancy levels of estrogen prevents mammary carcinogenesis. Proc. Natl. Acad. Sci. USA 2001, 98, 11755–11759.
97) Rajkumar, L.; Guzman, R.C.; Yang, J.; Thordarson, G.; Talamantes, F.; Nandi, S. Prevention of mammary carcinogenesis by short-term estrogen and progestin treatments. Breast Cancer Res. 2003, 6, R31–R37.
98) Partridge, Ann H., et al. “Interrupting endocrine therapy to attempt pregnancy after breast cancer.” New England journal of medicine 388.18 (2023): 1645-1656.
99) Jordan, V. Craig. “Linking estrogen-induced apoptosis with decreases in mortality following long-term adjuvant tamoxifen therapy.” Journal of the National Cancer Institute 106.11 (2014): dju296.
100) Jordan, V. Craig. “The new biology of estrogen-induced apoptosis applied to treat and prevent breast cancer.” Endocrine-related cancer 22.1 (2015): R1.
101) Suba, Zsuzsanna. “Estrogen Regulated Genes Compel Apoptosis in Breast Cancer Cells, Whilst Stimulate Antitumor Activity in Peritumoral Immune Cells in a Janus-Faced Manner.” Current Oncology 31.9 (2024): 4885-4907.
102) Suba, Zsuzsanna. “The pitfall of the transient, inconsistent anticancer capacity of antiestrogens and the mechanism of apparent antiestrogen resistance.” Drug Design, Development and Therapy 9 (2015): 4341.
103) Garcia, Marcel, et al. “Activation of estrogen receptor transfected into a receptor-negative breast cancer cell line decreases the metastatic and invasive potential of the cells.” Proceedings of the National Academy of Sciences 89.23 (1992): 11538-11542.
104) Levenson, Anait S., and V. Craig Jordan. “Transfection of human estrogen receptor (ER) cDNA into ER-negative mammalian cell lines.” The Journal of steroid biochemistry and molecular biology 51.5-6 (1994): 229-239.
105) Bluming, Avrum Zvi. “Hormone replacement therapy after breast cancer: it is time.” The Cancer Journal 28.3 (2022): 183-190.
106) Lippman, M., G. Bolan, and K. Huff. “The effects of estrogens and antiestrogens on hormone-responsive human breast cancer in long-term tissue culture.” Cancer research 36.12 (1976): 4595-4601.
107) Chalbos, Dany, et al. “Estrogens stimulate cell proliferation and induce secretory proteins in a human breast cancer cell line (T47D).” The Journal of Clinical Endocrinology & Metabolism 55.2 (1982): 276-283.
108) Soto, A. M., and C. Sonnenschein. “The role of estrogens on the proliferation of human breast tumor cells (MCF-7).” Journal of steroid biochemistry 23.1 (1985): 87-94.
109) Osborne, C. Kent, Kim Hobbs, and Gary M. Clark. “Effect of estrogens and antiestrogens on growth of human breast cancer cells in athymic nude mice.” Cancer research 45.2 (1985): 584-590.
110) Huseby, R. A., T. M. Maloney, and C. M. McGrath. “Evidence for a direct growth-stimulating effect of estradiol on human MCF-7 cells in vivo.” Cancer research 44.6 (1984): 2654-2659.
111) Kauffman, Robert P., Christina Young, and V. Daniel Castracane. “Perils of prolonged ovarian suppression and hypoestrogenism in the treatment of breast cancer: Is the risk of treatment worse than the risk of recurrence?.” Molecular and Cellular Endocrinology 525 (2021): 111181.
112) Molinelli, Chiara, et al. “Ovarian suppression: early menopause and late effects.” Current Treatment Options in Oncology 25.4 (2024): 523-542.
Hot flashes are a group of vasomotor symptoms characterized by a sensation
of warmth, flashing and perspiration in response to a hypothalamic ther-
moregulatory recalibration precipitated by a decline in estrogen levels…Hormonal agents [estrogen], although used to treat vasomotor symptoms in the general population, are contraindicated in patients with a history of breast cancer because they are associated with an increased risk of recurrence.
Psychiatric disorders, depression and anxiety are common in cancer survivors
and are associated with an increased risk of all-cause mortality [79]. A large
French cohort study including data from over 4800 women with breast cancer
demonstrated that nearly one third of patients experienced significant depres-
sive symptoms during and after treatment [80]. Although the frequency of
depression varies between different series, several studies suggest that OFS is
associated with an increased incidence. In the SOFT trial, the incidence of any-
grade depression increased from 46.6% to 51.9% with the addition of OFS to
endocrine therapy [45]…Pharmacological management of anxiety commonly includes the
use of benzodiazepines, SSRIs, antipsychotics and neuroleptics, sometimes in
combination [86]. Sleeping disorders are a related symptom whose incidence
can reach up to 57% in patients under OFS [45].
Cognitive impairment is a known adverse effect of several oncological thera-
pies, and may be associated with dysfunctions in multiple domains, includ-
ing memory impairment and difficulty in concentrating. Both cytotoxic
chemotherapies and endocrine therapies have been associated with cognitive
changes [87, 88]. It is hypothesized that the cognitive effect of endocrine ther-
apies is associated with a local reduction in estrogen levels since the expres-
sion of estrogen receptors and aromatase throughout the hypothalamus,
amygdala, dorsolateral prefrontal cortex, hippocampus, areas are involved
in memory, executive function and learning [89, 90].
Osteoporosis…Early menopause induced by OFS may anticipate and accelerate the devel-
opment of events associated with estrogen levels drop, including bone loss[68]. In the SOFT study, the addition of OFS to endocrine monotherapy was
associated with an increased risk of osteoporosis (defined as T score < − 2.5)
from 3.5 to 5.8% [45]….Bisphos-
phonates and denosumab are standard therapies for the treatment of osteo-
porosis and its prevention. In premenopausal patients receiving OFS plus AI
or tamoxifen with or without OFS, intravenous zoledronic acid (4 mg once
every 3–6 months) should be considered the preferred choice considering
the lack of evidence in this indication for denosumab [99–101].
Sexual dysfunction is a common side effect of OFS. About 50% of breast
cancer survivors report sexual dysfunction during or after the treatment. Par-
ticularly, 45% report sexual pain [103]. Sexual dysfunction includes different
manifestations such as vaginal dryness, dyspareunia, decreased libido, low
self-esteem, barriers on intimacy and difficulties in communicating with the
partner…Cognitive behavioural therapy is highly rec-
ommended in breast cancer survivors reporting sexual dysfunction.
113) Scharl, A., and A. Salterberg. “Significance of ovarian function suppression in endocrine therapy for breast cancer in pre-menopausal women.” Geburtshilfe und Frauenheilkunde 76.05 (2016): 516-524.
Endocrine treatments administered over a period of many years show waning compliance, which tends to be only around 50 % after five years…To prevent recurrence in the long run, it is much more effective to prescribe a somewhat less effective therapy that
will actually be carried out than to prescribe one that is theoretically more effective, but is not adhered to consistently…studies report that in year 5, only around half the patients are still undergoing the endocrine therapy [30, 32]. In addition to inadequate awareness about the
value of the therapy and waning motivation, side effects are often responsible for the patient discontinuing the therapy. While muscle and joint pain, as well as menopausal symptoms, are typical side effects of endocrine therapy, they are also typical symptoms of ageing. The need to explain the reason for the symptoms
Unfortunately, physicians apparently do not address adequately the symptoms occurring during hormonal therapy when they counsel their patients. Comparative studies show that patients experience side effects much more frequently and intensively than physicians realize [34].
The side effects included typical menopausal symptoms such as hot flushes, sweating, loss of libido, vaginal dryness, poor sleep quality, depression, musculoskeletal pain, hypertension, impaired glucose tolerance and osteoporosis.
Combined therapy with OFS [Ovarian Function Suppression] and TAM and especially with OFS and exemestane should therefore be initiated only if long-term high-quality care for the patient and a high level of reliability on the part of the patient are absolutely guaranteed. Otherwise, the therapy may lead to a worse prognosis rather than a better one.
114) Hershman DL, Shao T, Kushi LH et al. Early discontinuation and non-ad-
herence to adjuvant hormonal therapy are associated with increased
mortality in women with breast cancer. Breast Cancer Res Treat 2011;
126: 529–537
115) Hadji P, Ziller V, Kyvernitakis J et al. Persistence in patients with breast
cancer treated with tamoxifen or aromatase inhibitors: a retrospective
database analysis. Breast Cancer Res Treat 2013; 138: 185–191
116) Sarrel, Philip M., et al. “The mortality toll of estrogen avoidance: an analysis of excess deaths among hysterectomized women aged 50 to 59 years.” American journal of public health 103.9 (2013): 1583-1588.
117) Michelsen, Trond M., et al. “All‐cause and cardiovascular mortality after hysterectomy and oophorectomy in a large cohort (HUNT2).” Acta Obstetricia et Gynecologica Scandinavica 102.4 (2023): 465-472.
118) Mueck, A. O., and H. Seeger. “Estrogen as a new option for prevention and treatment of breast cancer–does this need a “time gap”?.” Climacteric: the journal of the International Menopause Society 18.4 (2015): 444-447.
119) Iqbal, Javaid, et al. “Association of the timing of pregnancy with survival in women with breast cancer.” JAMA oncology 3.5 (2017): 659-665.
The 5-year actuarial survival rate was 96.7% (95% CI, 94.1%-99.3%) [3.3% mortality] for women who had pregnancy 6 months or more after diagnosis of breast cancer, vs 87.5% (95% CI, 86.5%-88.4%) [12.5% mortality]for women with no pregnancy) (age-adjusted HR, 0.22; 95% CI, 0.10-0.49; P < .001).
120) Knabben, Laura, and Michel D. Mueller. “Breast cancer and pregnancy.” Hormone molecular biology and clinical investigation 32.1 (2017). A big meta-analysis of 14 studies by Azim et al. [31] found no negative impact of pregnancy following breast cancer on OS. Women who became pregnant after breast cancer even had improved survival compared to patients with breast cancer who did not.
121) Azim Jr, Hatem A., et al. “Safety of pregnancy following breast cancer diagnosis: a meta-analysis of 14 studies.” European journal of cancer 47.1 (2011): 74-83.
Fourteen studies were included in this meta-analysis (1244 cases and 18,145 controls). Women who got pregnant following breast cancer diagnosis had a 41% reduced risk of death compared to women who did not get pregnant [PRR: 0.59 (90% confidence interval (CI): 0.50-0.70)]. This difference was seen irrespective of the type of the study and particularly in women with history of node-negative disease.
122) Lambertini, Matteo, et al. “Pregnancy after breast cancer: a systematic review and meta-analysis.” Journal of Clinical Oncology 39.29 (2021): 3293-3305.
Of 6,462 identified records, 39 were included involving 8,093,401 women from the general population and 112,840 patients with BC of whom 7,505 had a pregnancy after diagnosis….Compared to patients with BC without subsequent pregnancy, those with a pregnancy had better disease-free survival (HR, 0.66; 95% CI, 0.49 to 0.89) and overall survival (HR, 0.56; 95% CI, 0.45 to 0.68).
123) Onwude, J. L. “Does Unopposed Peri-menopausal or Post-menopausal Estrogen Protect against Breast Cancer.” A Systematic Review. J Surg Surgical Res 7.2 (2021): 075-082.
124) Ingle, James N. “Estrogen as therapy for breast cancer.” Breast Cancer Research 4 (2002): 1-4.
125) Suba, Zsuzsanna. “Causal therapy of breast cancer irrelevant of age, tumor stage and ER-status: stimulation of estrogen signaling coupled with breast conserving surgery.” Recent Patents on Anti-cancer Drug Discovery 11.3 (2016): 254-266.
Estradiol-induced upregulation of estrogen signaling coupled with sparing of the estrogen-rich mammary fatpad are the most effective strategies against breast cancer.
Low estrogen level mean a high risk for breast cancer development [41, 42], while a counteractive overexpression of ERs may strengthen estrogen signaling and reduce the risk of malignancies [36].
Estrogen induced upregulation of ER-expression in pregnant women may explain why anticancer estrogen effects are prolonged and powerful in multiparous women.
In breast cancer cases, accidentally occurring hyperestrogenism is mistakenly thought of as an etiologic factor of tumor development, while breast cancer risk is in direct correlation with defective estrogen signaling irrespective of serum estrogen levels.
estradiol induced upregulation of ER expression may have a strengthening impact on apoptotic activity even in poorly differentiated, apparently ER-negative tumor cells.
Tamoxifen blockade of ERs induces artificial estrogen resistance provoking extreme estrogen synthesis. The estradiol concentrations in the breast of premenopausal women taking tamoxifen was 8.2 times higher that observed in the breast of healthy cycling women, while 17.3 times higher that observed in postmenopausal women taking tamoxifen [56]. These findings explain that the transient anticancer effect in tamoxifen-treated premenopausal patients may be attributed to counteractive increase in estradiol concentration.
In breast cancer cases, of all tumor markers, ER-negativity is the strongest predictor of poor prognosis and fatal outcome of the disease [57, 58]. In women, the stronger the defect of estrogen signaling, the higher is the risk of poorly differentiated, ER-negative breast cancer development, irrespective of serum estrogen concentrations [53].
In obese postmenopausal women, the maintenance of high estrogen concentrations in healthy breasts is mistakenly regarded as possibility for a high rate of cancer development in spite of the low circulating estrogen levels [63, 67].
Both accumulation of aromatase synthesizing fibrous adipocytes and increased estrogen level close to invasive cancer cells are mistakenly regarded as essential inducers of breast cancer proliferation and invasion [64, 70, 71].
In conclusion, increased aromatase activity of mammary adipocytes and local estrogen synthesis are recruited at the interface of tumor and fatty tissue for the inhibition of tumor proliferation.
126) Iwase, H., et al. “Ethinylestradiol is beneficial for postmenopausal patients with heavily pre-treated metastatic breast cancer after prior aromatase inhibitor treatment: a prospective study.” British Journal of Cancer 109.6 (2013): 1537.
127) Bennink, Herjan JT Coelingh, et al. “The use of high-dose estrogens for the treatment of breast cancer.” Maturitas 95 (2017): 11-23.
128) Traphagen, Nicole A., et al. “High estrogen receptor alpha activation confers resistance to estrogen deprivation and is required for therapeutic response to estrogen in breast cancer.” Oncogene 40.19 (2021): 3408-3421.
129) Schwartz, Gary N., et al. “Alternating 17β-Estradiol and aromatase inhibitor therapies is efficacious in postmenopausal women with advanced endocrine-resistant ER+ breast cancer.” Clinical Cancer Research 29.15 (2023): 2767-2773.
130) Hosford, Sarah R., et al. “Estrogen therapy induces an unfolded protein response to drive cell death in ER+ breast cancer.” Molecular oncology 13.8 (2019): 1778-1794.
131) Fan, Ping, and V. Craig Jordan. “Estrogen receptor and the unfolded protein response: double-edged swords in therapy for estrogen receptor-positive breast cancer.” Targeted oncology 17.2 (2022): 111-124.
132) Zhou, Zhenqi, et al. “Proteomic Analysis Reveals Major Proteins and Pathways That Mediate the Effect of 17-β-Estradiol in Cell Division and Apoptosis in Breast Cancer MCF7 Cells.” Journal of Proteome Research 23.11 (2024): 4835-4848.
133) Treatment of MCF7 cells with E2 and the PI3K inhibitor Ly294002 significantly enhanced apoptosis compared to those treated with E2 alone, suggesting that combining estrogen with a PI3K inhibitor could be a promising strategy for treating ERα-positive breast cancer
134) Maximov, Philipp Y., et al. “Estrogen receptor complex to trigger or delay estrogen-induced apoptosis in long-term estrogen deprived breast cancer.” Frontiers in Endocrinology 13 (2022): 869562.
Induction of estrogen-induced apoptosis in LTED breast cancer may become a feasible and safe alternative therapy for many patients with lower side effects for many patients in the future.
135) Chimento, Adele, et al. “Estrogen receptors-mediated apoptosis in hormone-dependent cancers.” International journal of molecular sciences 23.3 (2022): 1242.
136) Suba, Zsuzsanna. “Turn in Breast Cancer Care: Upregulation of Estrogen Signal May Be Much More Effective than Its Inhibition.” 2022. 1-17.
137) Suba, Zsuzsanna Key to estrogen anticancer capacity , unpublished
Breast cancer stimulation by estrogen is a medical misbelief…Antiestrogen treatment of tumors is a medical mistake…
138) Suba, Zsuzsanna. “DNA Damage Responses in Tumors Are Not Proliferative Stimuli, but Rather They Are DNA Repair Actions Requiring Supportive Medical Care.” Cancers 16.8 (2024): 1573.
The spontaneous healing of early breast tumors is a well-known finding justifying the capacity of initial cancers for self-directed remission. A systematic review and meta-analysis study evaluated a high prevalence of incidental breast cancer and precursor lesions in autopsy studies on clinically tumor-free cases. The estimated mean prevalence of incidental cancer and precursor lesions were surprisingly high: 19.5% and 0.85% [126].
139) Thomas, Elizabeth T., et al. “Prevalence of incidental breast cancer and precursor lesions in autopsy studies: a systematic review and meta-analysis.” BMC cancer 17 (2017): 1-10.
140) Chlebowski, Rowan T., Aaron K. Aragaki, and Kathy Pan. “Breast cancer prevention: time for change.” JCO Oncology Practice 17.12 (2021): 709-716.
Agency breast cancer prevention guidelines for other than hereditary cancers have not materially changed in 20 years; endocrine-targeted agents (then, tamoxifen; now, adding raloxifene and aromatase inhibitors) reduce good prognosis estrogen receptor (ER)–positive, progesterone receptor (PR)–positive cancers without reducing deaths from breast cancer. Across three tamoxifen placebo-controlled prevention trials (N = 23,360) begun almost 30 years ago, although there were 226 fewer breast cancer cases, there were nine more deaths from breast cancer in the tamoxifen groups. Following clinical advances, currently more than half of breast cancer cases are solved problems with extremely low risk of death. As endocrine-targeted agents commonly prevent these cancers, widespread implementation of current prevention strategies may not reduce deaths from breast cancer. Compared with other breast cancers, ER-positive, PR-negative cancers and triple-negative cancers have inferior survival (90.6% v 83.8% v 78.1%, respectively; P < .001). Against this background, in the Women’s Health Initiative Dietary Modification randomized trial (N = 48,835), ER-positive, PR-negative cancers were statistically significantly reduced in the intervention group (hazard ratio, 0.77; 95% CI, 0.64 to 0.94) and deaths from breast cancer were reduced 21% (P = .02). In the Women’s Health Initiative randomized, placebo-controlled trial evaluating conjugated equine estrogen (N = 10,739), ER-positive, PR-negative cancers were statistically significantly reduced in the intervention group (hazard ratio, 0.44; 95% CI, 0.27 to 0.74) and deaths from breast cancer were reduced 40% (P = .04). These findings suggest that reexamination of breast cancer risk reduction strategies and clinical practice is needed.
141) Gao, Lanyang, et al. “The beneficial androgenic action of steroidal aromatase inactivators in estrogen-dependent breast cancer after failure of nonsteroidal drugs.” Cell death & disease 10.7 (2019): 494.
Our experiments have elucidated the antiproliferative effect of androgens on breast cancer cells. We could demonstrate that the steroidal aromatase inactivators formestane and exemestane are chemically modified within the cancer cells and that the modified sterols act predominantly as antiproliferative androgens.
142) Ariazi, Eric A., et al. “Exemestane’s 17-hydroxylated metabolite exerts biological effects as an androgen.” Molecular cancer therapeutics 6.11 (2007): 2817-2827.
143) Santacana-Font, Gemma, et al. “Exemestane and its primary metabolite 17-hydroexemestane inhibit synergically the tumor growth of ER/AR positive breast cancer tumors.” Cancer Research 84.6_Supplement (2024): 7576-7576.
Exemestane, an aromatase inactivator of the third generation, plays a crucial role in breast cancer therapy by targeting the P450 aromatase enzyme and, thus, decreasing estrogen synthesis. Exemestane (Aromasin™) is currently the only steroidal aromatase inactivator widely used in clinical routine treatment of ER+ breast cancer in all phases of the disease in a global perspective. However, the complex mechanisms underlying its therapeutic effects, besides being an aromatase inhibitor, remain incompletely understood. In this study, we employed a combination of human samples and in vitro data to unveil a compelling insight: Exemestane (EXE) and its primary metabolite, 17β-hydroxyexemestane (HEXE), exhibit potent inhibitory effects on tumor growth when present together in patient serum. Our biochemical analysis establishes a critical threshold—20% HEXE metabolite of the total EXE in patient serum—to trigger a tumor growth inhibition exceeding 90%, as evidenced by Ki67 staining. Mechanistically, our data reveals that both HEXE and EXE bind to the Androgen Receptor (AR), triggering a synergistic activation that induces a transcriptional program leading to cell death while diminishing the intracellular signaling activated by the oncogene Ras. Notably, patients with tumors characterized by a minimum of 20% AR+ epithelial cancer cells stand to benefit the most from exemestane and HEXE. Intriguingly, the binding of AR to chromatin in tumors gives rise to a molecular signature capable of distinguishing responsive from non-responsive patients to both EXE and HEXE. Collectively, our findings elucidate a dual therapeutic role for Exemestane in selected patients: it not only restrains estrogen-driven proliferation by estrogen suppression but also stimulates cell death by establishing a specific interactome with the AR at the genomic level. These insights suggest that both EXE and HEXE are necessary to achieve the best therapeutic effects in ER+/AR+ breast cancer tumors. Moreover, our findings suggest that AR-expression and targeting should be investigated further to potentially add novel strategies to our existing algorithms in ER+/AR+ MBC.
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Suba, Zsuzsanna
1) Suba, Zsuzsanna. “Rosetta stone for cancer cure: comparison of the anticancer capacity of endogenous estrogens, synthetic estrogens and antiestrogens.” Oncology Reviews 17 (2023): 10708.
This work presents the history of the recognition of principal regulatory capacities of estrogen hormones having been mistakenly regarded as breast cancer promoting agents for more than 120 years.
Antiestrogen therapy of advanced breast cancer yielded many difficulties and failures from the onset. Tamoxifen as a first line therapy induced moderate tumor regression rate (<40%–50%) even among the targeted ER-positive breast cancer cases, while the remaining patients could not exhibit tumor responses or experienced tumor growth. Therapeutic failures were designated as de novo (primary) antiestrogen resistance (13). During long term tamoxifen administration, near all earlier responsive breast cancers exhibited an “acquired (secondary) antiestrogen resistance” resulting in rapid progression of the disease(14).
14 Osborne, C. Kent. “Tamoxifen in the treatment of breast cancer.” New England Journal of Medicine 339.22 (1998): 1609-1618.
In addition, tamoxifen treatment induced various toxic side effects, which could occasionally be life threatening, such as stroke, coronary heart disease, pulmonary emboli and malignancies at various sites particularly in the endometrium (15).
Aromatase inhibitors (AIs) also were developed for the therapeutic reduction of estrogen synthesis in breast cancer cases (16). Among AI treated patients, the experienced tumor response rate also was low (<30%) similarly to the results of other endocrine therapies. AI treatment against breast cancer seemed to be somewhat safer than tamoxifen use; it provoked somewhat lower rates of thromboembolic complications and endometrial toxicity. De novo or acquired resistance to AI treatment also developed in the vast majority of patients with advanced breast cancer.
Following the failures in high dose estrogen treatment the development of antiestrogen therapy could also not realize the enthusiastic expectations for breast cancer defeat. In breast cancer cases diagnosed and treated at the earliest stage, unforeseeable tumor recurrence and fatal outcome may occur even after decades (17). Tumor responses to antiestrogen treatment were transient and inconsistent coupled with high toxicity in breast cancer cases (18).
18. Suba, Zsuzsanna. “The pitfall of the transient, inconsistent anticancer capacity of antiestrogens and the mechanism of apparent antiestrogen resistance.” Drug design, development and therapy (2015): 4341-4353.
Continue….
These experiences strongly suggest that our therapeutic efforts against breast cancer are not appropriate. Further insights into the mechanisms of tumor growth and tumor recurrence are necessary for the improvement of breast cancer care.
2002 WHI
In 2002, the results of a great, prospective, placebo controlled Women’s Health Initiative (WHI) study strengthened that combined CEE plus medroxyprogesterone-acetate (MPA) treatment (PremPro, Pfizer) increased the risk of breast and colon cancer, thromboembolism, cardiovascular diseases and hip fracture (9). Following these serious experiences, there was a consequential precipitous decrease in MHT use among postmenopausal women and a thorough re-evaluation of MHT practice became necessary (5). Later, in a prospective MHT study, highly toxic effects of MPA were published as compared with other synthetic progestins (77). This finding illuminated that in the WHI study published in 2002, the MPA component of PremPro may be blamed for the catastrophic results of MHT instead of the horse urine deriving Premarin (46).
Antiestrogens are Chemotherapeutic Agents Targeting the Liganded Activation of ERs, Which is the Principal Means of Genomic Regulation
Considering the whole population of breast cancer patients, antiestrogen treatment could not surpass the “magic” 30% of tumor response rate, similarly to the weaknesses of other endocrine therapies; such as oophorectomy or high doses of synthetic estrogens (87). The majority of even the targeted ER-positive tumors were not responsive to the endocrine treatment showing primary resistance (13).
13. Hayes, Daniel F. “Tamoxifen: Dr. Jekyll and Mr. Hyde?.” Journal of the National Cancer Institute 96.12 (2004): 895-897.
worldwide overviews of prospective clinical trials demonstrate that adjuvant tamoxifen reduces the annual odds of death for women with invasive breast cancer by approximately 15% over 10–15 years.
However, tamoxifen is not ideal. Even among women with ER-positive breast cancer, only 40–50% of patients benefit, suggesting that a substantial fraction of ER-positive cancers are resistant to this drug.
Why does tamoxifen not seem to work in nearly one-half of women whose tumors appear, at least by ER measurement, to be estrogen dependent?
Preclinical and clinical data over the last 20 years have demonstrated that tamoxifen is not, as originally designated, an “anti-estrogen” (6). Rather, tamoxifen has been designated a “selective estrogen receptor modulator” (SERM).
This class of drugs has variable agonistic and/or antagonistic activities, depending on the type of ER (alpha versus beta) and on the coactivator and corepressor milieu in which they bind to the ER (7). Thus, it is possible that, by acting as an agonist within certain hormone-dependent breast cancers, tamoxifen, like Dr. Jekyll, might become a “Mr. Hyde.”
This hypothesis is supported by in vitro studies that demonstrate that estrogen dependent breast cancer cell lines, which are initially growth inhibited by tamoxifen and other SERMs, can become growth dependent on these same agents after long-term exposure to low concentrations (8,9).
If these results hold true clinically, then it may be that a major form of resistance to tamoxifen in certain ER-positive cancers occurs because this agent acts as an estrogen, as it does in bone and liver tissue, rather than an antiestrogen (10).
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patients with HER-2–overexpressing tumors who were assigned to adjuvant tamoxifen had higher rates of recurrence and mortality than those who did not receive the agent(14,15).
First, in the HER-2–transfected cells, tamoxifen acted like an estrogen agonist by every measure studied. Second, the EGFR inhibitor gefitinib—presumably by inhibiting HER-2–to–ER crosstalk—restored the ER antagonistic properties of tamoxifen. These results are consistent with those of other investigators who have reported enhancement of tamoxifen activity in ER-positive, HER-2–positive cultured cells by treatment with trastuzumab, a monoclonal antibody that binds the extracellular domain of HER-2 (17).
Aromatase inhibitors are bereft of toxicities associated with estrogenic activity of tamoxifen and other SERMs, such as increased thrombosis and uterine cancer risk. However, they are clearly associated with problems related to estrogen depletion, including high rates of osteoporosis and bone fracture, which are of major concern in the group of patients most likely to receive them: postmenopausal women (25).
Given the choice between a SERM or an aromatase inhibitor in the adjuvant setting, the preclinical studies by Shou et al. (11) suggest that one might elect to recommend the latter in patients with ER-positive, HER-2–positive breast cancers to avoid the potential estrogen agonist activity that might be associated with tamoxifen. This concept is far from confirmed. However, it is supported by results from the retrospective clinical study discussed above (14,15), as well as by recently reported preliminary correlative science studies of HER-2 in large randomized clinical trials comparing tamoxifen with anastrozole and tamoxifen with letrozole in both classic and neo-adjuvant settings (26,27).
Like Dr. Jekyll, tamoxifen has clearly contributed immensely to the well-being of patients. Like Mr. Hyde, cloaked in the disguise of an agonist rather than an antagonist for its receptor, it may also have harmed some
Continue Here…….
In addition, patients showing earlier good tumor responses to antiestrogens later experienced secondary resistance leading to metastatic disease and fatal outcome.
Tamoxifen induces HIGH estradiol levels in Pre-menopausal women
Yamazaki, Rena, et al. “Tamoxifen-induced ovarian hyperstimulation during premenopausal hormonal therapy for breast cancer in Japanese women.” Springerplus 4 (2015): 1-5.
Eleven patients who received surgical therapy for endocrine-dependent breast cancer and showed high values of serum estradiol during post-operative tamoxifen therapy were recruited in this study and evaluated by examining the serum concentration of follicular stimulating hormone (FSH) and follicular development.
Results: The mean age, serum concentrations of estradiol and FSH, and follicular diameter were 41.3 years old, 1015.8 pg/mL, 11.8 mIU/mL, and 3.47 cm, respectively. In 6 cases, multiple follicular development was observed, while the other cases showed single follicular development with a mean serum estradiol level of 848.6 pg/mL and follicular diameter of 4.46 cm.
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Suba, Zsuzsanna. “Estrogen Regulated Genes Compel Apoptosis in Breast Cancer Cells, Whilst Stimulate Antitumor Activity in Peritumoral Immune Cells in a Janus-Faced Manner.” Current Oncology 31.9 (2024): 4885-4907.
In the early 1970s, antiestrogen compounds were developed for ER positive breast cancer therapy. Blockers of liganded ER activation and aromatase enzyme inhibitors were introduced so as to spare tumors from excessive estrogen signaling [20]. However, liganded estrogen signaling is the fundamental regulator of mammalian cells, and its blockade is genotoxic, provoking desperate counteractions in both patients and their tumors [21].
!!!!!!!!!!!!!!!!!!!!!!!! Important !!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!
Turning enthusiasm into frustration
The initial enthusiasm rapidly turned into frustration as about 50% of even the targeted breast tumors with ER expression proved to be non-responders to endocrine therapy. It was nominated as primary resistance [22]. Moreover, following long-term therapy, all patients showing previously good tumor responses turned to secondary endocrine resistance, resulting in metastatic tumor spread and lethal outcome. Studies on ER-positive tumors responsive to endocrine therapy mistakenly suggested that the overexpression of ERs is an effort for survival [23], while in non-responsive tumors, the increased expression of growth factor receptors is the survival technique [24].
!!!!!!!!!!!!!!!!!!!!! Important !!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!
Breast cancers responsive to endocrine therapy successfully counteract the endocrine disruption via over-expression of ERs and restoring estrogen signaling [28].
28. Suba, Zsuzsanna. “Compensatory Estrogen Signal Is Capable of DNA Repair in Antiestrogen‐Responsive Cancer Cells via Activating Mutations.” Journal of Oncology 2020.1 (2020): 5418365.
Conversely, when the liganded activation of ERs is completely blocked in tumors, growth factor receptor overexpression desperately targets ER activation via an unliganded pathway. Non-responsive breast cancers are not fighting for their survival against antiestrogen therapy, but rather, they are incapable of counteracting the endocrine blockade.
Recently, the vision of E2 as a pro-carcinogenic hormone seems to be somewhat questionable [54].
54. Pescatori, Sara, et al. “A tale of ice and fire: the dual role for 17β-estradiol in balancing DNA damage and genome integrity.” Cancers 13.7 (2021): 1583.
Indeed, E2 is a regulator of the DNA damage response, which this hormone exploits to calibrate its genotoxicity with its physiological effects. Accordingly, the genes required to maintain genome integrity belong to the E2-controlled cellular signaling network and are essential for the appearance of the E2-induced cellular effects.
The sex hormone 17β-estradiol (E2) exerts diverse pleiotropic physiological effects including the control of the reproductive system in females and the development of primary and secondary sexual characteristics in humans. E2 regulates a plethora of physiological functions in non-reproductive tissues including heart, bone, and brain systems. Accordingly, E2 can exert beneficial effects being protective against osteoporosis, cardiovascular and neurodegenerative diseases [1].
the most frequent BCs (i.e., 75%) express the ERα at the diagnosis. The ERα is an important prognostic factor because its expression drives the treatment (i.e., the endocrine therapy), which aims to block different aspects of the E2:ERα proliferative signaling [3].
Nonetheless, it is difficult to reconcile how E2, which controls crucial physiological processes both in females and males and contributes to body homeostasis, could work as a carcinogen inducing the development of BC.
Continue Here…..
Suba, Zsuzsanna. “Estrogen Regulated Genes Compel Apoptosis in Breast Cancer Cells, Whilst Stimulate Antitumor Activity in Peritumoral Immune Cells in a Janus-Faced Manner.” Current Oncology 31.9 (2024): 4885-4907.
In 2004, a large Women’s Health Initiative (WHI) study reported on a strikingly decreased risk of breast cancer in CEE (Premarin)-treated women compared to the placebo control cases [55]. The authors did not believe in their unusual findings and suggested strengthening investigations. CEE treatment alone without synthetic progestin was capable of genome stabilization, improving the health advantage of postmenopausal women [56].
Despite our developing knowledge concerning the complex roles of estrogen signaling in the genomic regulation and health maintenance of mammalians, breast cancer has been considered an estrogen-induced disease until now [61] 61. Al-Shami, Khayry, et al. “Estrogens and the risk of breast cancer: A narrative review of literature.” Heliyon 9.9 (2023).
Estrogen Deficiency as Risk for Oral Cancer
In 2007, estrogen deficiency was revealed as a risk for oral cancer based on the findings of a Hungarian clinical–epidemiological study [62]. Age- and gender-related analysis of oral cancer cases revealed that men are increasingly affected by this aggressive tumor during their whole life, attributed to their smoking and drinking habits. By contrast, women in their premenopausal period are nearly completely protected from this disease. Above 50, a steeply increasing oral cancer incidence may be observed among non-smoking, non-drinking older women, parallel with their estrogen loss.
Estrogen Deficiency of Menopause Increases Risk of Breast Cancer
In postmenopausal women, estrogen loss maybe an obvious risk factor for breast cancer as compared with premenopausal patients. In premenopausal patients, inherited or acquired gene mutations may result in weak estrogen signaling, genetic instability, and increased breast cancer risk. Among breast cancer cases, about 80% are above 50, being predominantly postmenopausal, while only 20% of them are younger, premenopausal women [64].
64. McGuire, Andrew, et al. “Effects of age on the detection and management of breast cancer.” Cancers 7.2 (2015): 908-929.
High Estrogen Levels of Pregnancy Protective
A strikingly decreased breast cancer risk may be observed in correlation with parity and, particularly, multiparity as compared with nulliparous women [68]. Conversely, anovulatory disorders and nulliparity increase the risk for breast tumors and further female cancers [69,70]. These epidemiological studies support the pathogenic role of defective estrogen signaling in breast cancer development.
In conclusion, either estrogen deficiency or defective liganded ER activation may lead to genomic instability, increasing the risk for breast cancer.
Genes Activated by Estrogen Upregulate DNA Stabilization and Silence Cell Proliferation in Breast Cancer Cells
Estrogen Prevention and Therapy for Breast Cancer – Pregnancy is protective
Pregnancy in Mice protects from Carcinogen induced breast cancer
Experiments on carcinogen-induced mammary tumor models have justified that pregnancy either before or soon after exposure to a chemical carcinogen is proven to be highly protective against breast cancer development in rodents [142,143,144]. Short-term treatment with high, pregnancy-mimicking levels of estradiol with or without progesterone was also highly protective against mammary carcinogenesis in rodents [145,146]. Synthetic estrogen (ethinylestradiol) plus synthetic progesterone (megesterol acetate) treatment for 3 weeks resulted in significantly lower mammary cancer incidence in rats as compared with untreated controls after 6 months of the exposure to a chemical carcinogen [147].
!!!!!!!!!!!!!!!!!!!!! Important !!!!!!!!!!!!!!!!!!!
The mechanism of breast cancer preventive hormone activity…mouse models
!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!
The mechanism of breast cancer-preventive hormonal activity was examined in genetically challenged mouse models [148].
148. Rajkumar, Lakshmanaswamy, et al. “Hormone-induced protection of mammary tumorigenesis in genetically engineered mouse models.” Breast Cancer Research 9 (2007): 1-11.
High-dose estrogen/progesterone treatment reduced the incidence of mammary tumors by more than 60% in mice with oncogenic overexpression of the HER2/neu. Considering that growth factor overexpression is not oncogenic action, but rather an unliganded activation of weak, E2-refractory ERs, estrogen treatment helps in ER activation and genome stabilization [24].
24.Massarweh, Suleiman, et al. “Tamoxifen resistance in breast tumors is driven by growth factor receptor signaling with repression of classic estrogen receptor genomic function.” Cancer research 68.3 (2008): 826-833.
Moreover, in mice with homozygous deletions of the Tp53 gene, exogenous estrogen/progesterone treatment reduced mammary tumor development by at least 70% [148]. 148. Rajkumar, Lakshmanaswamy, et al. “Hormone-induced protection of mammary tumorigenesis in genetically engineered mouse models.” Breast Cancer Research 9 (2007): 1-11.
These results justify that hormone-mediated protection of breast tissue may also have alternate pathways independent of p53 protein activation [149].|
Jerry, D. Joseph. “Roles for estrogen and progesterone in breast cancer prevention.” Breast Cancer Research 9 (2007): 102.
In spite of significant differences between rodent models and human breast tissue, the fact remains that parity is protective in both. A growing body of evidence suggests that parity reduces risk, even among women bearing heritable mutations in BRCA1 and BRCA2 [14]. Thus, it appears that a full-term pregnancy engages multiple pathways that effectively antagonize tumors resulting from a spectrum of underlying oncogenic lesions. The signals initiated by pregnancy appear to converge upon a set of pathways that are shared by both rodent mammary and human breast tissues
!!!!!!!!! Tamoxifen !!!!!!!!!!
In tumors exhaustively treated with tamoxifen, the achieved ER blockade may be regarded as an artificially created ER-negative status, as estrogen signaling suffers irreparable damage. Among patients with tamoxifen-resistant advanced breast cancer, estrogen treatment dramatically decreases breast cancer related mortality[155].
155.Jordan, V. Craig. “Linking estrogen-induced apoptosis with decreases in mortality following long-term adjuvant tamoxifen therapy.” Journal of the National Cancer Institute 106.11 (2014): dju296.
In tumors, with tamoxifen-blocked ERs, estrogen treatment induces abundant new ER expression and drives genome stabilization. In patients with aromatase inhibitor-resistant tumors, estrogen treatment induces regression of metastatic cancers and extends survival [156].
156. Jordan, V. Craig. “The new biology of estrogen-induced apoptosis applied to treat and prevent breast cancer.” Endocrine-related cancer 22.1 (2015): R1.
In tumors exhaustively treated with aromatase inhibitor, therapeutic estrogen is bound by the overexpressed ERs driving the genome stabilization circuit. These findings help to reevaluate the view of estrogen-induced breast cancer and the role of antiestrogens in breast cancer therapy [157].
157. Abderrahman, Balkees, and V. Craig Jordan. “Estrogen for the treatment and prevention of breast cancer: a tale of 2 Karnofsky lectures.” The Cancer Journal 28.3 (2022): 163-168.
Antiestrogens – PITFALLS
Suba, Zsuzsanna. “The pitfall of the transient, inconsistent anticancer capacity of antiestrogens and the mechanism of apparent antiestrogen resistance.” Drug Design, Development and Therapy 9 (2015): 4341.
!!!!!!!!!!!! an extreme upregulation of ER signaling seems to be the crucial mechanism of successful prevention and treatment for breast cancer.
Analysis of the fairly controversial results justifies that whatever type of available endocrine therapies may be used, including estrogen, antiestrogen treatment, or oophorectomy, an extreme upregulation of ER signaling seems to be the crucial mechanism of successful prevention and treatment for breast cancer.
High-dose estrogen treatment is capable of restoring ER signaling and anticancer capacity even after heavy exposure to antiestrogen therapy.
In 1896, a favorable tumor response in a premenopausal patient with metastatic breast cancer was reported after oophorectomy.2 This result suggested that ovarian estrogen synthesis may be the fuel of breast cancer development, since oophorectomy seemed to be an appropriate therapeutic measure, presumably by means of withdrawal of the ovarian hormones. Some years later, all known ovariectomized breast cancer cases had been assembled in the UK, and a 30% tumor response rate was established.3
3.Haddow, Alexander, et al. “Influence of synthetic oestrogens on advanced malignant disease.” British medical journal 2.4368 (1944): 393.
Despite the fairly low effectiveness of this first clinical trial for breast cancer treatment, a 30% response rate is to be regarded as a standard result of endocrine therapy ever since. Tumor responses achieved via oophorectomy proved, however, to be transient, and no responses in the majority of breast cancer cases were established. The limited anticancer capacity of estrogen withdrawal led to a search for a different approach to mammary carcinogenesis.
It was reported in 1944 that high doses of a synthetic estrogen, diethylstilbestrol (DES) were able to produce a 30% tumor response rate among women with metastatic breast cancer, presenting a surprising turn in breast cancer care.4
4.Haddow, Alexander, et al. “Influence of synthetic oestrogens on advanced malignant disease.” British medical journal 2.4368 (1944): 393.
Thus, the effectiveness of high-dose DES therapy, as new paradox medication against breast cancer for >5 years after menopause, was inconsistent as in the case of the removal of circulating estrogens by oophorectomy. Nevertheless, in this new method, patients were not exposed to the risk of surgery for obtaining a doubtful, transient tumor response.
During the fight against breast cancer, there was a second turn of events leading to the development of tamoxifen in the early 1970s. It was the first compound nominated as an antiestrogen or more exactly, a selective estrogen receptor modulator (SERM) capable of binding to estrogen receptors (ERs).6 The aim of tamoxifen medication was to inhibit the presumed cancer promoter signaling pathways of ERs. Aromatase inhibitors were also introduced for the treatment of breast cancer, since the maintenance of low estrogen concentrations supposedly inhibits the proliferative activity of tumor cells.7
!!!!!!!!!!!!!!!!! Important opposite hormonal manipulations !!!!!!!!!!!!!!
The usage of quite opposite hormonal manipulations;namely synthetic estrogens and antiestrogens could achieve equally low rates of inconsistent tumor regression even among the targeted ER-positive breast cancer cases.The uncertain and weak results of both opposing efforts suggest that the biologic mechanisms affecting the correlation between estrogen signaling and tumor development are fairly misinterpreted.11
Since estrogen signaling has a crucial role in DNA stabilization and surveillance of cell proliferation,the therapeutic impact of antiestrogens against breast cancers seems to be an unexpected contradiction.11
Moreover, the acquired antiestrogen resistance of tumors characterized in turn by tumor growth stimulation instead of tumor inhibition is regarded as an unexpected switch, and the cellular mechanisms behind these changes are unknown in spite of thorough investigations.
Comprehensive analysis of experimental and clinical–epidemiologic results suggests that ER-alpha signaling is the chief safeguard of genome stability in strong interplay with DNA controlling and repairing systems, such as BRCA genes and their protein products.11
estrogen signaling recognizes and destroys malignant tumor cells by means of apoptotic mechanisms.11
Both low and high estrogen levels promote enhanced expression and transcriptional activity of ERs aiming to maintain the crucial cellular estrogen surveillance.11
!!!!!!!!!!!!! Animal Experiments !!!!!!!!!!!!!!!!
In animal experiments, ovariectomy-associated estrogen withdrawal significantly increased the levels of ER-alpha expression in the uterus, kidney, and cerebral cortex of female rats, while a 12-week treatment of ovariectomized rats with 17-beta estradiol was capable of restoring the previous ER-alpha mRNA level.20
!!!!!!!!!!!! Not High Estrogen— It is Low Estrogen are high risk for Breast Cancer !!!!!!!!!!!
in women, low estrogen levels are high risks of breast cancer.21,22
21 Suba, Zsuzsanna. “Interplay between insulin resistance and estrogen deficiency as co-activators in carcinogenesis.” Pathology & Oncology Research 18 (2012): 123-133.
22 Suba, Zsuzsanna. “Circulatory estrogen level protects against breast cancer in obese women.” Recent patents on anti-cancer drug discovery 8.2 (2013): 154-167.
!!!!!!!!!!!!!! higher expression of ER alpha is a response to estrogen deficiency !!!!!!!!!!!
In benign proliferative breast lesions, the higher expression of ER alpha showed close correlation with the later development of breast cancer as compared to tumors with lower ER density.23
23 Santen, R. J., et al. “Long-term estradiol deprivation in breast cancer cells up-regulates growth factor signaling and enhances estrogen sensitivity.” Endocrine-Related Cancer 12.Supplement_1 (2005): S61-S73.
Reactive increase in the ER expression of hyperplastic mammary cells may be a defensive counteraction against the dangers of low estrogen supply, but the insufficiency of this counteraction may result in cancer development.11
11. Suba, Zsuzsanna. “DNA stabilization by the upregulation of estrogen signaling in BRCA gene mutation carriers.” Drug design, development and therapy (2015): 2663-2675.
In a breast cancer cell line, long-term estradiol deprivation induced estrogen hypersensitivity by overexpression of ERs. Hypersensitivity may be characterized by the ability of tumor cells to respond to levels of estrogens at concentrations 2–3 logs lower than required to stimulate wild-type cells.24
24. Santen, R. J., et al. “Long-term estradiol deprivation in breast cancer cells up-regulates growth factor signaling and enhances estrogen sensitivity.” Endocrine-Related Cancer 12.Supplement_1 (2005): S61-S73.
In tumor cells, estrogen hypersensitivity upregulates estrogen signaling and its apoptotic activity even in an estrogen-deficient milieu.11
11. Suba, Zsuzsanna. “DNA stabilization by the upregulation of estrogen signaling in BRCA gene mutation carriers.” Drug design, development and therapy (2015): 2663-2675.
!!!! Tamoxifen stimulates Tumor Growth MCF7 cells in vitro !!!!!!!!!!!!!!!!!
SERM treatment of ER-alpha-positive tumors is a chemical block of available ERs inhibiting the transduction of estrogen signaling. Raloxifene or tamoxifen treatment strongly stimulated the tumor growth of antiestrogen-resistant MCF-7/Ral.
When a 9-week raloxifene or tamoxifen treatment of tumors was followed by a 5-week estradiol treatment, estradiol statistically significantly reduced the size of tumors earlier stimulated by raloxifene or tamoxifen pretreatment.25
25 Liu, Hong, et al. “Apoptotic action of 17β-estradiol in raloxifene-resistant MCF-7 cells in vitro and in vivo.” Journal of the National Cancer Institute 95.21 (2003): 1586-1597.
These observations justify that the completion of the antiestrogen blockade of estrogen signaling leads to antiestrogen-induced tumor growth, which may be counteracted by estradiol treatment via induction of ER overexpression (estrogen hypersensitivity) in tumor cells. This process seems to be an unexpected kamikaze action of tumor cells, since the restored upregulation of estrogen signaling results in their apoptotic death.
Pregnancy- Over Expression of ERs
Extreme physiologic increase in estrogen concentrations in pregnancy also promotes overexpression of ERs, resulting in a self-generating upregulation of both estrogen signaling and DNA-stabilizer systems. These interactions ensure the safe estrogen-mediated transcriptional activity on target genes in rapidly proliferating maternal and fetal structures.11
In pregnancy, abundant estradiol supply was shown to promote uterine blood flow, rapid myometrial growth, and breast growth at term, mediated by the increased expression of myometrial and mammary ERs.26
Estrogen-mediated upregulation of ER expression in pregnancy may explain why defensive estrogen effects are prolonged and powerful in multiparous women.11
!!!!!!!!! Estrogen Treatment upregulates ER expression and Transcription in TUMOR cells
Estrogen treatment increases the ER expression and transcriptional activity even in tumor cells. Two ER-positive breast cancer cell lines (ZR 75-1 and HCC 1500) were treated by four types of estrogens: estrone, estradiol, estriol, and estetrol, and all four elicited significantly increased ER expressions as compared to untreated controls.27
27 Liu, Shunyu, et al. “Oestetrol stimulates proliferation and oestrogen receptor expression in breast cancer cell lines: comparison of four oestrogens.” The European Journal of Contraception & Reproductive Health Care 20.1 (2015): 29-35.
These observations justify the estradiol-induced upregulation of ER signaling, however, in tumor cells; the increased transcriptional activity of ERs induces apoptotic death instead of proliferation.11
Estrogen synthesis is upregulated by both decreased and increased ER expressions
!!!!!!!!!!!!!!!!!! Genetic Mutation in Estrogen Receptors !!!!!!!!!!!!!!!!!!!!!!!!!
Compensatory hyperestrogenism occurs as a feedback mechanism against defective ER signaling caused by mutations of ER regulator genes (ESRs). Severe mutation of ESRs was reported in a 28-year-old man exhibiting extremely high estrogen levels, grave signs of insulin resistance, obesity, and premature cardiovascular disease.30
Smith, Eric P., et al. “Estrogen resistance caused by a mutation in the estrogen-receptor gene in a man.” New England Journal of Medicine 331.16 (1994): 1056-1061.
Inherited estrogen resistance was also reported in the case of an 18-year-old girl presenting sky-high estrogen levels in her blood, and at the same time, the classic symptoms of estrogen deficiency, such as delayed puberty, were also observed.31
Quaynor, Samuel D., et al. “Delayed puberty and estrogen resistance in a woman with estrogen receptor α variant.” New England Journal of Medicine 369.2 (2013): 164-171.
Laboratory examinations revealed that 240 times the normal estrogen level was required to get a response out of her ERs.
Pregnancy
During healthy pregnancy, abundant ER expression in proliferating maternal and fetal structures upregulates the synthesis of both the BRCA protein and aromatase enzyme. Extreme increase in estrogen and BRCA protein production ensures the safeguarding of cell proliferation and all cellular mechanisms.11
Parity is regarded as a protective factor against breast cancer development, while nulliparity is a high risk of breast malignancies.32
Britt, Kara, Alan Ashworth, and Matthew Smalley. “Pregnancy and the risk of breast cancer.” Endocrine-related cancer 14.4 (2007): 907-933.
In the resting breast of parous women, significantly lower ER-alpha expression was detectable as compared to nulliparous subjects.33
Asztalos, Szilard, et al. “Gene expression patterns in the human breast after pregnancy.” Cancer prevention research 3.3 (2010): 301-311.
In parous women, appropriate estrogen levels and safety estrogen signaling are linked with relatively lower ER-alpha expression in mammary cells. By contrast, in hormonally challenged nulliparous women, the increased ER-alpha synthesis of mammary cells calls for a higher estrogen concentration because of the dangerous deficiency of the estrogen supply.
!!!!!!!!!!!!!!!! Anti-Estrogens !!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!
Controversial results of antiestrogen use in breast cancer prevention and treatment
!!!!!!!!!!!!! Errroneous Concept !!!!!!!!!!
The development of ER-blocker tamoxifen in the early 1970s was based on the erroneous concept that excessive estrogen signaling leads to unrestrained tumor proliferation in strongly hormone-responsive sites, such as the breasts.
It was established that the rate of tumor responses to tamoxifen was similarly low compared to DES, but the advantage of tamoxifen over synthetic estrogen seemed to be equivocal due to the apparently lower incidence rate of toxic side effects.8,36
Natural estrogens were not easily available for therapeutic use, and the toxic side effects obtained with synthetic DES therapy led to the abandonment of treatment with all estrogenic compounds.37
!!!!!!!!!!!! Ambiguous Results with TAM
Use of selective blockers of ER signaling in the therapy of breast cancer yielded fairly ambiguous results. Primarily successful tumor regression was exhibited in only 40%–50% of targeted women with ER-positive breast cancers, while the majority of cases could not react positively, which was designated as de novo antiestrogen resistance.38
38. Hayes, Daniel F. “Tamoxifen: dr. Jekyll and mr. Hyde?.” Journal of the National Cancer Institute 96.12 (2004): 895-897.
!!!!!!!!!!!! Problems with Tamoxifen !!!!!!!!!!!!!!!!!!!!
Considering the whole population of breast cancer patients, these results correspond exactly to the “magic” biologic response rate of 30%, achieved by either synthetic estrogen therapy or oophorectomy. Moreover, a large proportion of earlier responsive breast cancers may acquire secondary resistance during tamoxifen therapy, leading to rapid progression of the disease.39
Osborne, C. Kent. “Tamoxifen in the treatment of breast cancer.” New England Journal of Medicine 339.22 (1998): 1609-1618.
Tamoxifen may elicit common side effects, which can be occasionally life threatening, such as stroke, pulmonary emboli, and malignancies at certain sites, particularly in the endometrium, attributed to the anomalous estrogen agonist activities of this compound.40
Braithwaite, R. Scott, et al. “Meta-analysis of vascular and neoplastic events associated with tamoxifen.” Journal of general internal medicine 18 (2003): 937-947.
Tamoxifen was characterized as being like Dr Jekyll, when tumor regression was achieved, attributed to its antiestrogenic activity, while possibly becoming Mr Hyde when the presumed estrogenic activity resulted in toxic side effects and endometrial cancer coupled with progression of breast tumor.38
Hayes, Daniel F. “Tamoxifen: dr. Jekyll and mr. Hyde?.” Journal of the National Cancer Institute 96.12 (2004): 895-897.
!!!!!!!!!!!!!!!! anticancer capacity of estrogen signaling !!!!!!!!!!!!!
By contrast, being aware of the anticancer capacity of estrogen signaling, the presumed estrogenic behavior of tamoxifen emerged as an inducer of tumor regression, while the predominance of its antiestrogenic impact results in rapid tumor progression.41
41.Suba Z. Failures and controversies of the antiestrogen treatment of breast cancer. In: Suba Z, editor. Estrogen Prevention for Breast Cancer. New York: Nova Science Publishers Inc; 2013. pp. 105–125. Chap 6.
!!!!!!!!!!!!!!!!!! Aromatase Inhibitors !!!!!!!!!!!!!!!!!!!!!!!!!
Another group of antiestrogens is known as aromatase inhibitors. They block the activity of P450 aromatase enzyme, which converts steroid precursors and androgens to estrogen, causing estrogen deprivation in both healthy tissues and tumors.35
Lin, Nancy U., and Eric P. Winer. “Advances in adjuvant endocrine therapy for postmenopausal women.” Journal of Clinical Oncology 26.5 (2008): 798-805.
Use of aromatase inhibitors in breast cancer cases seemed to be safer than tamoxifen, because it induces lower rates of endometrial toxicity and thromboembolic complications. In postmenopausal women, the side effects of aromatase inhibitors are numerous, including hot flashes, vaginal dryness, arthralgia, decreased bone mineral density, and an increased bone fracture rate.42
Howell, Anthony, et al. “Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years’ adjuvant treatment for breast cancer.” Lancet 365.9453 (2005): 60-62.
While using an aromatase inhibitor, pure estrogen withdrawal was the presumed therapeutic mechanism against breast cancer, excluding the possibility of aberrant estrogenic actions.43
Nevertheless, de novo or acquired resistance to aromatase inhibitor treatment was also observed in postmenopausal patients with advanced breast cancer.44
44. Jiang J, Sarwar N, Peston D, et al. Phosphorylation of estrogen receptor-alpha at Ser167 is indicative of longer disease-free and overall survival in breast cancer patients. Clin Cancer Res. 2007;13(19):5769–5776.
Compensatory upregulation of estrogen signaling in estrogen-deficient milieu was erroneously regarded as a strong promoter of tumor cell survival and proliferation justifying antiestrogen resistance.45,46
45. Dowsett M, Martin LA, Smith I, Johnston S. Mechanisms of resistance
to aromatase inhibitors. J Steroid Biochem Mol Biol. 2005;95(1–5):
167–172.
46. Tolhurst RS, Thomas RS, Kyle FJ, et al. Transient over-expression of
estrogen receptor-α in breast cancer cells promotes cell survival and
estrogen-independent growth. Breast Cancer Res Treat. 2011;128(2):
357–368
Lately, antiestrogens are being strongly recommended for breast cancer prevention as well, in spite of the controversial results of their use in tumor therapy.10
Colditz, Graham A., and Kari Bohlke. “Priorities for the primary prevention of breast cancer.” CA: a cancer journal for clinicians 64.3 (2014): 186-194.
!!!!!!!!!!!! brca CARRIERS ANTI-ESTROGENS INEFFECTIVE !!!!!
In BRCA1 mutation carriers, however, with high risk of familiar breast cancer, antiestrogen administration proved frequently to be ineffective or quite deteriorative.47,48
47. Gorski JJ, Kennedy RD, Hosey AM, Harkin DP. The complex relation-
ship between BRCA1 and ERalpha in hereditary breast cancer. Clin
Cancer Res. 2009;15(5):1514–1518.
48. Miller WR. Aromatase inhibitors: mechanism of action and role in the
treatment of breast cancer. Semin Oncol. 2003;30:3–11.
Based on these data, it was presumed that BRCA1 mutation-linked mammary cancers are distinct diseases arising in a hormonally independent manner.
!!!!!!!!!!!!!!!!!! grade of phosphorylation activity at Ser167 site of ERs
Interestingly, the grade of phosphorylation activity at Ser167 site of ERs in breast tumors of tamoxifen-treated patients proved to be an excellent predictor of a good prognosis of the disease.44
44. Jiang J, Sarwar N, Peston D, et al. Phosphorylation of estrogen receptor-alpha at Ser167 is indicative of longer disease-free and overall survival in breast cancer patients. Clin Cancer Res. 2007;13(19):5769–5776.
Yamashita, Hiroko, et al. “Phosphorylation of estrogen receptor α serine 167 is predictive of response to endocrine therapy and increases postrelapse survival in metastatic breast cancer.” Breast cancer research 7 (2005): 1-12.
Yamashita, Hiroko, et al. “Low phosphorylation of estrogen receptor α (ERα) serine 118 and high phosphorylation of ERα serine 167 improve survival in ER-positive breast cancer.” Endocrine-related cancer 15.3 (2008): 755-763. patients with either high phosphorylation of ER-α Ser167, or high expression of ER-α, PR, PRA, or PRB had a significantly longer survival after relapse.
Ishida, Naoko, et al. “PIK3CA mutation, reduced AKT serine 473 phosphorylation, and increased ERα serine 167 phosphorylation are positive prognostic indicators in postmenopausal estrogen receptor-positive early breast cancer.” Oncotarget 9.25 (2018): 17711.
Motomura, Kazuyoshi, et al. “Expression of estrogen receptor beta and phosphorylation of estrogen receptor alpha serine 167 correlate with progression-free survival in patients with metastatic breast cancer treated with aromatase inhibitors.” Oncology 79.1-2 (2010): 55-61.
Huderson, B. P., et al. “Stable inhibition of specific estrogen receptor α (ERα) phosphorylation confers increased growth, migration/invasion, and disruption of estradiol signaling in MCF-7 breast cancer cells.” Endocrinology 153.9 (2012): 4144-4159.
!!!!!!!!! Good Estrogen Signalling indicates Longer Disease Free Survival !!!!!!!!!
Since Ser167 phosphorylation is the most important element of the physiologic transcriptional activity of ERs, this work unconsciously justified that compensatory maintenance of good estrogen signaling is indicative of longer disease-free survival as well as overall survival even among antiestrogen-treated breast cancer patients.
AI: Serine 167 phosphorylation on the Estrogen Receptor (ER) is considered the most important for its transcriptional activity because it significantly enhances the receptor’s ability to bind to DNA (estrogen response elements) and recruit coactivator proteins, thereby promoting the transcription of target genes, which is the primary function of the ER; essentially, this phosphorylation event acts as a key switch to fully activate the receptor and drive gene expression.
Key points about Ser167 phosphorylation:
Enhanced DNA binding:
Phosphorylation at Ser167 improves the ER’s affinity for DNA, allowing it to more effectively bind to estrogen response elements (EREs) in the genome.
Coactivator recruitment:
This phosphorylation site facilitates the interaction with coactivator proteins, which are essential for further enhancing transcription by modifying chromatin structure and recruiting RNA polymerase.
……….end AI
!!!!!!!!!!!!!!!!!! ER Pos Breast Cancer Xenografts !!!!!!!!!!!!!!!!
In ER-positive breast cancer xenografts, both epidermal growth factor receptor (EGFR) and HER2 expressions were increased with tamoxifen treatment and markedly increased when tumors became antiestrogen resistant.56
56 Massarweh, Suleiman, et al. “Tamoxifen resistance in breast tumors is driven by growth factor receptor signaling with repression of classic estrogen receptor genomic function.” Cancer research 68.3 (2008): 826-833.
It was established that upregulation of both EGFR and HER2 expressions mediated tamoxifen resistance in ER-positive breast cancers, while genomic ER functions were continuously suppressed by tamoxifen treatment.
In clinical practice, patients with ER-positive, HER-2 overexpressing tumors exhibited higher rates of recurrence and fatal spread after tamoxifen therapy as compared to those who did not receive the agent.57,58
The elevated insulin-like growth factor-I receptor signaling also rendered MCF-7 cells highly resistant to antiestrogens, although tumor cell lines were under continuous suppression of ER transcriptional activity by antiestrogens.59
Considering that both ER-alpha expression and transcriptional activity is downregulated by excessive GF administration,60 antiestrogen blockade of ERs is plausibly strengthened by increased GFR signaling.
Successful estrogen treatment of postmenopausal breast cancer patients after heavy exposure to antiestrogen therapy
!!! Super Important !!!
the dawn of a new epoch in estrogen-related cancer research
!!!!!!!!!!! Transfection EXPERIMENTS !!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!
At the end of the past century, transfection experiments were performed by the insertion of exogenous ERs into ER-negative tumor cells.63
63. Levenson, Anait S., and V. Craig Jordan. “Transfection of human estrogen receptor (ER) cDNA into ER-negative mammalian cell lines.” The Journal of steroid biochemistry and molecular biology 51.5-6 (1994): 229-239.
Garcia, Marcel, et al. “Activation of estrogen receptor transfected into a receptor-negative breast cancer cell line decreases the metastatic and invasive potential of the cells.” Proceedings of the National Academy of Sciences 89.23 (1992): 11538-11542.
Breast cancers containing estrogen receptors are responsive to antiestrogen treatment and have a better prognosis than estrogen receptor-negative tumors. The loss of estrogen and progesterone receptors appears to be associated with a progression to less-differentiated tumors. We transfected the human estrogen receptor into the estrogen receptor-negative metastatic breast cancer cell line MDA-MB-231 in an attempt to restore their sensitivity to antiestrogens. Two stable sublines of MDA-MB-231 cells (HC1 and HE5) expressing functional estrogen receptors were studied for their ability to grow and invade in vitro and to metastasize in athymic nude mice. The number and size of lung metastases developed by these two sublines in ovariectomized nude mice was not markedly altered by tamoxifen but was inhibited 3-fold by estradiol.Estradiol also significantly inhibited in vitro cell proliferation of these sublines and their invasiveness in Matrigel, a reconstituted basement membrane, whereas the antiestrogens 4-hydroxytamoxifen and ICI 164,384 reversed these effects. These results show that estradiol inhibits the metastatic ability of estrogen receptor-negative breast cancer cells following transfection with the estrogen receptor, whereas estrogen receptor-positive breast cancers are stimulated by estrogen, indicating that factors other than the estrogen receptor are involved in progression toward hormone independence.
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!!!!!!!!!!!!!!! growth inhibition !!!!!!!!!!!!!!!!!!!!!!
The reexpression of ERs activated a number of estrogen-regulated genes, and treatment with estrogen surprisingly led to growth inhibition instead of the increased proliferative activity of tumor cells. This experimental finding was the dawn of a new epoch in estrogen-related cancer research.
Working groups in the US and Europe started to examine the antitumor effect of high-dose estrogen in postmenopausal patients with advanced breast cancer, who were becoming resistant to estrogen deprivation.37,64
37.Ingle, James N. “Estrogen as therapy for breast cancer.” Breast Cancer Research 4.4 (2002).
64.Lønning, P. E. “Stepwise estrogen suppression manipulating the estrostat.” The Journal of steroid biochemistry and molecular biology 79.1-5 (2001): 127-132.
From the early 2000s, further researchers tried to clarify the mechanisms of antiestrogen resistance of tumors and the secret of the anticancer capacity of estrogens in patients with antiestrogen resistant, advanced breast cancer.65–69
65.Jordan VC, Lewis-Wambi JS, Patel RR, Kim H, Ariazi EA. New hypotheses and opportunities in endocrine therapy: amplification of oestrogen-induced apoptosis. Breast. 2009;18(suppl 3):S10–S17.
66.Lønning PE. Additive endocrine therapy for advanced breast cancer back to the future. Acta Oncol. 2009;48:1092–1101.
67.Ellis MJ, Gao F, Dehdashti F, et al. Lower-dose versus high dose oral estradiol therapy of hormone receptor-positive, aromatase inhibitor-resistant advanced breast cancer: a phase-2 randomized study. JAMA. 2009;302(774–780):2009.
68.Lobanova YS, Scherbakov AM, Shatskaya VA, Evteev VA, Krasil’nikov MA. NF-kappaB suppression provokes the sensitization of hormone-resistant breast cancer cells to estrogen apoptosis. Mol Cell Biochem. 2009;324(1–2):65–71.
69.Mahtani RL, Stein A, Vogel CL. High-dose estrogen as salvage hormonal therapy for highly refractory metastatic breast cancer: a retrospective chart review. Clin Ther. 2009;31(pt 2):2371–2378.
In clinical practice, physiologic estrogen-induced apoptosis is successfully applied for breast cancer prevention and treatment following estrogen deprivation.70
70.Jordan VC. The new biology of estrogen-induced apoptosis applied to treat and prevent breast cancer. Endocr Relat Cancer. 2015;22(1):R1–R31.
ER overexpression in tumor cells treated with either estrogens 27,28 or antiestrogens 46,50 may be explained by the fundamental regulatory capacity of estrogens. These apparently contradictory treatments can similarly upregulate abundant ER expressions and transcriptional activities. Estrogen-induced upregulation of estrogen signaling is a physiologic process, while in case of antiestrogen administration, it may be regarded as a counteraction for the defense of endangered cellular estrogen surveillance.
27. 27.Liu S, Ruan X, Schultz S, et al. Oestetrol stimulates proliferation and oestrogen receptor expression in breast cancer cell lines: comparison of four oestrogens. Eur J Contracept Reprod Health Care. 2015;20(1):29–35.
28.Stoica GE, Franke TF, Moroni M, et al. Effect of estradiol on estrogen receptor-alpha gene expression and activity can be modulated by the ErbB2/PI 3-K/Akt pathway. Oncogene. 2003;22(39):7998–8011.
46. Tolhurst RS, Thomas RS, Kyle FJ, et al. Transient over-expression of estrogen receptor-α in breast cancer cells promotes cell survival and estrogen-independent growth. Breast Cancer Res Treat. 2011;128(2):357–368.
50.Kuske B, Naughton C, Moore K, et al. Endocrine therapy resistance can be associated with high estrogen receptor alpha (ERalpha) expression and reduced ERalpha phosphorylation in breast cancer models. Endocr Relat Cancer. 2006;13(4):1121–1133.
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Increased estrogen signaling displays a unique dichotomy effect: it safeguards the survival and proliferative activity of healthy cells, while induces apoptotic death of malignant tumor cells.11
In patients with breast cancer, estrogen administration is capable of exerting self-generating, increased ER expression and estrogen synthesis as well so as to achieve the strong upregulation of estrogen signaling and apoptotic tumor cell damage. Paradoxically, antiestrogen treatment may also provoke compensatory ER overexpression in tumor cells and extreme estrogen synthesis of the patients so as to restore the apoptotic capacity of estrogen signaling (Figure 1). When these counteractions are sufficient, tamoxifen administration seems to be deceivingly effective, resulting in transient tumor regression.
By contrast, primary insufficiency or exhaustion of the defensive counteractions in patients treated with antiestrogens may lead to the complete blocking of estrogen signaling, since the patient has limited capacities for extreme ER expression and estrogen synthesis. In such cases, the result is unrestrained proliferative activity of the tumor cells, and the rapid tumor spread is mistakenly evaluated as de novo or acquired antiestrogen resistance. Nevertheless, high-dose estrogen treatment is capable of restoring the suppressed estrogen signaling even after heavy exposure to antiestrogen treatment. Exogenous and newly synthesized estrogens are in competition with tamoxifen for binding sites on newly expressed, abundant ERs, and the higher the concentration of estrogens, the higher is the probability of successful defeat of tamoxifen. The triumph of estrogens leads to apoptotic tumor cell death and clinical regression of the disease
In conclusion, during long-term antiestrogen treatment, the upregulation of bothestrogen and ER synthesisexhibits gradual exhaustion and the development of complete antiestrogen blockade of estrogen signaling results in rapid tumor spread. Fortunately, high-dose estrogen treatment is capable of restoring the estrogen signaling even after exhaustive antiestrogen therapy with the achievement of rapid tumor regression.
!!!!!!!!!!! Three Phases of Anti-Estrogen Administration !!!!!!!!!!!!!!!!!
There are three phases of antiestrogen administration in genetically proficient breast cancer cases, treated by either ER blocker or aromatase inhibitor, which can be characterized by good tumor regression, stagnation of tumor growth, and aggressive tumor spread
There are reports on embarrassing data that suggest direct correlations between preserved estrogen signaling and the good anticancer capacity of antiestrogens. During this first period, estrogen signaling may exhibit compensatory upregulation in tamoxifen-treated premenopausal patients experiencing regular cycles and ovulatory activity with the potential to become pregnant.72
Jordan, V. Craig, et al. “Alteration of endocrine parameters in premenopausal women with breast cancer during long-term adjuvant therapy with tamoxifen as the single agent.” JNCI: Journal of the National Cancer Institute 83.20 (1991): 1488-1491.
Moreover, in breast cancer biopsy specimens, active estrogen signaling characterized by intense phosphorylation at Ser(167) of ERs predicted longer disease-free survival and overall survival for the patients.44
Jiang, Jie, et al. “Phosphorylation of estrogen receptor-α at Ser167 is indicative of longer disease-free and overall survival in breast cancer patients.” Clinical Cancer Research 13.19 (2007): 5769-5776.
!!!!!! Treatment with AIs causes Compensatory Increase in AI enzyme !!!!!!!!!!!!!!!!!!
In sequential biopsies of large primary breast tumors, measurement of aromatase content before and during effective treatment with aromatase inhibitor showed a surprisingly marked, counteractive increase in enzyme activity.73
Miller, W. R., and J. O’neill. “The importance of local synthesis of estrogen within the breast.” Steroids 50.4-6 (1987): 537-548.
These results support that the provoked compensatory upregulation of estrogen signaling may be in correlation with successful tumor regression instead of an antiestrogenic effect.
Tamoxifen treatment induces artificial estrogen resistance in women. These patients mimic the chaotic findings, which are characteristic of cases suffering from the genetic failures of ER expression and/or transcriptional activity coupled with counteractive defense mechanisms, such as extreme estrogen synthesis.31
In tamoxifen-treated cases, very high compensatory estrogen levels and even an increased ER expression may be associated with the symptoms of ER blockade-induced estrogen resistance, such as multiple ovarian cysts74 or endometrial hyperplasia.75 The authors mistakenly attributed these complications to the reactive hyperestrogenism, and luteinizing hormone-releasing treatment was erroneously recommended for the suppression of residual ovarian function so as to achieve proper hypoestrogenic status.75
Madeddu, Clelia, et al. “Ovarian hyperstimulation in premenopausal women during adjuvant tamoxifen treatment for endocrine‑dependent breast cancer: A report of two cases.” Oncology letters 8.3 (2014): 1279-1282.
On the other hand, exhaustive aromatase inhibitor treatment in breast cancer cases mimics the symptoms of aromatase deficiency syndrome deriving from the genetic defect of aromatase synthesis.76
76. Morishima, A. K. I. R. A., et al. “Aromatase deficiency in male and female siblings caused by a novel mutation and the physiological role of estrogens.” The Journal of clinical endocrinology & metabolism 80.12 (1995): 3689-3698.
In the case of this artificial aromatase deficiency, patients may exhibit even an increased counteractive expression in aromatase enzyme synthesis besides the overexpression of ERs. In the second phase of aromatase inhibitor treatment, apparent resistance to aromatase inhibitors is mistakenly regarded as an increased cross talk between intensified ER and GFR signaling pathways.45
In the third phase of antiestrogen treatment, both extreme ER expression and aromatase synthesis are exhausted, and the completion of estrogen signal blockage results in rapid growth and metastatic spread of breast cancer leading to the death of the patient. At the same time, diverse toxic effects of estrogen deficiency and accidentally developing cancers at different sites, particularly in the endometrium, may be diagnosed. This phase of complete antiestrogen blockade of estrogen signaling is mistakenly referred to as acquired antiestrogen resistance.
In the remaining half of patients, the key for ineffective antiestrogen medication against ER-positive breast cancers may be the manifestation of earlier hidden point mutations affecting either estrogen signaling or the associated gene stabilizer systems.11
These cases do not have sufficient extra capacities for defensive ER overexpression and increased estrogen synthesis against the artificial inhibition of estrogen signaling. In such patients, the failure of tumor prevention or regression by antiestrogen treatment is erroneously regarded as de novo resistance against antiestrogen treatment.
Dangers of antiestrogen treatment in women with BRCA gene mutations
In women with BRCA gene mutations, antiestrogens exhibited a very low degree of protection against familiar breast cancer risk by treatment with either ER blockade or aromatase inhibition.47,48 These unfavorable effects were erroneously explained by the presumed hormonally independent development of BRCA-mutation linked cancers.47
In BRCA gene mutation carriers, the genetically defined serious defects of ER expression and transcriptional activity as well as the baseline increased estrogen synthesis may explain the antiestrogen refractory status. The increased compensatory estrogen concentration in BRCA-mutation carriers may frequently be enough for the restoration of genetically defective ER signaling; however, the additional provocation of antiestrogen treatment may exhaust the defensive increase in aromatase synthesis.11
Oophorectomy as erroneous breast cancer prevention strategy in BRCA gene mutation carriers
Considering the health disadvantage of estrogen withdrawal even in BRCA-proficient cases, neither surgical nor chemical ovarian suppression may be the appropriate choice for cancer prevention and therapy in BRCA-mutation carriers. By contrast, exogenous estrogen treatment has protective effect against breast cancer even in women with BRCA gene mutation, while the anticancer effect requires higher hormone doses depending on the resistance grade of ERs.11,19,79
Conclusion
In conclusion, it can be established that whatever type of available endocrine therapies may be used, including anti-estrogen, estrogen treatment, or oophorectomy, a provoked upregulation of ER signaling seems to be the key mechanism of successful prevention and treatment for ER-positive breast cancer. Satisfactory upregulation of ER expression and aromatase enzyme activity may highly increase estrogen signaling and results in apoptotic death of tumor cells.
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!!!!!!!!! Good Charts !!!!!!
https://pmc.ncbi.nlm.nih.gov/articles/PMC5734609/
Pan, Hongchao, et al. “20-Year Risks of Breast-Cancer Recurrence after Stopping Endocrine Therapy at 5 Years.” The New England journal of medicine 377.19 (2017): 1836.
In this meta-analysis of the results of 88 trials involving 62,923 women with ER-positive breast cancer who were disease-free after 5 years of scheduled endocrine therapy,
After 5 years of adjuvant endocrine therapy, breast-cancer recurrences continued to occur steadily throughout the study period from 5 to 20 years. The risk of distant recurrence was strongly correlated with the original TN status, with risks ranging from 10 to 41%, depending on TN status and tumor grade.
In conclusion, even after 5 years of adjuvant endocrine therapy, women with ER-positive, early-stage breast cancer still had a persistent risk of recurrence and death from breast cancer for at least 20 years after the original diagnosis. This finding has implications for long-term follow-up strategies and highlights the need for new approaches to reduce late recurrence.
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https://pmc.ncbi.nlm.nih.gov/articles/PMC8885431/
Early Breast Cancer Trialists’ Collaborative Group. “Aromatase inhibitors versus tamoxifen in premenopausal women with oestrogen receptor-positive early-stage breast cancer treated with ovarian suppression: a patient-level meta-analysis of 7030 women from four randomised trials.” The Lancet. Oncology 23.3 (2022): 382-392.
For women with early-stage oestrogen receptor (ER)-positive breast cancer, adjuvant tamoxifen reduces 15-year breast cancer mortality by a third. Aromatase inhibitors are more effective than tamoxifen in postmenopausal women but are ineffective in premenopausal women when used without ovarian suppression.
We did a meta-analysis of individual patient data from randomised trials comparing aromatase inhibitors (anastrozole, exemestane, or letrozole) versus tamoxifen for 3 or 5 years in premenopausal women with ER-positive breast cancer receiving ovarian suppression (goserelin or triptorelin) or ablation.
We obtained data from all four identified trials (ABCSG XII, SOFT, TEXT, and HOBOE trials), which included 7030 women with ER-positive tumours enrolled between June 17, 1999, and Aug 4, 2015. Median follow-up was 8·0 years (IQR 6·1–9·3). The rate of breast cancer recurrence was lower for women allocated to an aromatase inhibitor than for women assigned to tamoxifen (RR 0·79, 95% CI 0·69–0·90, p=0·0005). The main benefit was seen in years 0–4 (RR 0·68, 99% CI 0·55–0·85; p<0·0001), the period when treatments differed, with a 3·2% (95% CI 1·8–4·5) absolute reduction in 5-year recurrence risk (6·9% vs 10·1%). There was no further benefit, or loss of benefit, in years 5–9 (RR 0·98, 99% CI 0·73–1·33, p=0·89) or beyond year 10. Distant recurrence was reduced with aromatase inhibitor (RR 0·83, 95% CI 0·71–0·97; p=0·018).
!!!!!!!!!!!!!!!!!!! Mortality !!!!!!!!!!!!!!!!!!!!!!!!!!
No significant differences were observed between treatments for breast cancer mortality (RR 1·01, 95% CI 0·82–1·24; p=0·94), death without recurrence (1·30, 0·75–2·25; p=0·34), or all-cause mortality (1·04, 0·86–1·27; p=0·68). There were more bone fractures with aromatase inhibitor than with tamoxifen (227 [6·4%] of 3528 women allocated to an aromatase inhibitor vs 180 [5·1%] of 3502 women allocated to tamoxifen; RR 1·27 [95% CI 1·04–1·54]; p=0·017). Non-breast cancer deaths (30 [0·9%] vs 24 [0·7%]; 1·30 [0·75–2·25]; p=0·36) and endometrial cancer (seven [0·2%] vs 15 [0·3%]; 0·52 [0·22–1·23]; p=0·14) were rare.
Interpretation
Using an aromatase inhibitor rather than tamoxifen in premenopausal women receiving ovarian suppression reduces the risk of breast cancer recurrence. Longer follow-up is needed to assess any impact on breast cancer mortality.
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serum estrogen levels during tamoxifen therapy
https://pubmed.ncbi.nlm.nih.gov/9168075/
Lum, Sharon S., et al. “Changes in serum estrogen levels in women during tamoxifen therapy.” The American journal of surgery 173.5 (1997): 399-402.
Background: Tamoxifen is considered an antiestrogen against breast cancer, yet it has known estrogenic side effects. We hypothesized that long-term administration of tamoxifen may significantly increase circulating estrogen levels in women with breast cancer.
Methods: Serum dehydroepiandrosterone (DHEA), estrone (E1), and estradiol (E2) levels were prospectively measured in 47 breast cancer patients before and during tamoxifen therapy for 2 years. Differences in baseline and peak hormone levels during treatment were compared, and significance was determined by paired Student’s t test.
Results: Mean DHEA levels increased by 133% from 61 mg/L to 142 mg/L (P <0.001) and mean E2 levels increased by 239% from 28 pg/mL to 95 pg/mL (P <0.05). Mean E1 levels increased by 264% from 42 pg/mL to 153 pg/mL (P = 0.06).
Conclusions: Long-term tamoxifen therapy can be associated with increased serum levels of DHEA, E1, and E2. Elevated serum estrogens may explain tamoxifen’s estrogenic effects and may represent a mechanism for the development of drug resistance.
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While improvements in detection and treatment measures are continuously introduced in developed countries, we are perhaps missing something big in how we try to prevent and treat breast cancer in the global context.1
Seymour, Colin B., and Carmel Mothersill. “Breast cancer causes and treatment: where are we going wrong?.” Breast Cancer: Targets and Therapy (2013): 111-119.
Suba, Zsuzsanna. “DNA stabilization by the upregulation of estrogen signaling in BRCA gene mutation carriers.” Drug design, development and therapy (2015): 2663-2675.
Suba, Zsuzsanna. “Diverse pathomechanisms leading to the breakdown of cellular estrogen surveillance and breast cancer development: new therapeutic strategies.” Drug Design, Development and Therapy (2014): 1381-1390.
Helguero, Luisa A., et al. “Estrogen receptors alfa (ERα) and beta (ERβ) differentially regulate proliferation and apoptosis of the normal murine mammary epithelial cell line HC11.” Oncogene 24.44 (2005): 6605-6616.
Suba, Zsuzsanna. “Triple-negative breast cancer risk in women is defined by the defect of estrogen signaling: preventive and therapeutic implications.” OncoTargets and therapy (2014): 147-164.
Suba, Zsuzsanna. “Compensatory Estrogen Signal Is Capable of DNA Repair in Antiestrogen-Responsive Cancer Cells via Activating Mutations.” Journal of Oncology 2020 (2020).
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Reply to HABITS study where Norethisterone Acts as testosterone blocker in tamoxifen users.
Chen, Rong, et al. “Antiproliferative effects of anastrozole on MCF‑7 human breast cancer cells in vitro are significantly enhanced by combined treatment with testosterone undecanoate.” Molecular Medicine Reports 12.1 (2015): 769-775.
Previous studies have evaluated the association between AR expression in breast cancer and the effectiveness of hormone therapies, including tamoxifen and AI treatments, using ER-positive breast cancer cell lines. The results indicated that AR overexpression may induce tamoxifen resistance (30–32); and therefore, if AR expression influences the activity of tamoxifen (33), then tamoxifen should only be used in the treatment of AR-negative subtypes of breast cancer (13).
Further studies have also demonstrated that the cytotoxic effects of anastrozole on breast cancer cells could be enhanced by treating with androgens simultaneously (34–36).
However, based on the results of the present study, various concentrations of testosterone undecanoate were utilized to reduce the expression of AR protein, as previously reported (37), and therefore significantly enhance the cytotoxic effects of anastrozole. Further studies are required to evaluate these hypotheses and confirm the present findings.
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Hickey, Theresa E., et al. “Minireview: The Androgen Receptor in Breast Tissues: Growth Inhibitor, Tumor Suppressor, Oncogene?.” Molecular Endocrinology 26.8 (2012): 1252-1267.
De Amicis et al. (107) demonstrated that tamoxifen stimulates colony formation and xenograft growth of an AR-overexpressing derivative of MCF-7 cells (MCF7-AR11) in an AR-dependent manner under conditions of estrogen deprivation. Collectively, these in vitro studies, together with the clinical studies discussed in the previous section, indicate that the role of AR in breast epithelial cells may shift from an antiproliferative to a proliferative stimulus depending on the relative status of AR and ERα and the availability of their cognate ligands.
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Application to HABITS study ???
AR acts as an estrogen ?????
file:///C:/Users/Jeffrey%20Dach/Downloads/ijms-25-01817-1.pdf
Tien, Amy H., and Marianne D. Sadar. “Treatments Targeting the Androgen Receptor and Its Splice Variants in Breast Cancer.” International Journal of Molecular Sciences 25.3 (2024): 1817.
a study by Hickey and colleagues demonstrated that AR behaves as a tumor suppressor in ERα-positive breast cancer [ 71 ].
71. Hickey, T.E.; Selth, L.A.; Chia, K.M.; Laven-Law, G.; Milioli, H.H.; Roden, D.; Jindal, S.; Hui, M.; Finlay-Schultz, J.; Ebrahimie,E.; et al. The androgen receptor is a tumor suppressor in estrogen receptor-positive breast cancer. Nat. Med. 2021, 27, 310–320.
They showed that AR transactivation with androgen inhibited ER-driven cell proliferation in an ex vivo patient-derived explant model. Using breast cancer cell lines, they also showed that AR was detected at 42% of estrogen-stimulated ER-binding sites on chromatin when both AR and ER were activated.
This suggests that AR could directly affect ER transcriptional activity by redistributing
ER. Interestingly, the binding or recruitment of coactivators p300 and SRC-3, which are
required for ER signaling, were both reduced and replaced by AR upon AR activation.
This led to the repression of ER-regulated cell cycle genes and the inhibition of tumor cell proliferation. Thus, AR activation suppressed ER signaling in ERα-positive breast cancer cells. In this case, the activation of AR, rather than its inhibition, would be the more suitable treatment option for patients with ERα-positive breast cancer when AR behaves as a tumor suppressor. These data support the application of androgenic compounds such as the nonsteroidal selective AR modulator (SARM) enobosarm, which decreases the growth of some ERα-positive breast cancers [ 72 ], and they form the rationale for the clinical testing of SARMs for the treatment of some breast cancers.
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END Z SUBA and START NEXT SEQUENCE of References
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!!!!!!!!!!!!!!!!!!!!! Breast Cancer and Aromatase !!!!!!!!!!!!!!!!! ZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZ
Breast cancer cells have upregulated aromatase to make their own estrogen, serving as growth factor. Usefulness of letrazole. for ER+ Breast cancer.
Kijima, Ikuko, Toru Itoh, and Shiuan Chen. “Growth inhibition of estrogen receptor-positive and aromatase-positive human breast cancer cells in monolayer and spheroid cultures by letrozole, anastrozole, and tamoxifen.” The Journal of steroid biochemistry and molecular biology 97.4 (2005): 360-368.
Mukhopadhyay, Keya De, et al. “Aromatase expression increases the survival and malignancy of estrogen receptor positive breast cancer cells.” PloS one 10.4 (2015): e0121136.
In postmenopausal women, local estrogen produced by adipose stromal cells in the breast is believed to support estrogen receptor alpha (ERα) positive breast cancer cell survival and growth. This raises the question of how the ERα positive metastatic breast cancer cells survive after they enter blood and lymph circulation, where estrogen level is very low in postmenopausal women. In this study, we show that the aromatase expression increased when ERα positive breast cancer cells were cultured in suspension.Furthermore, treatment with the aromatase substrate, testosterone, inhibited suspension culture-induced apoptosis whereas an aromatase inhibitor attenuated the effect of testosterone suggesting that suspended circulating ERα positive breast cancer cells may up-regulate intracrine estrogen activity for survival. Consistent with this notion, a moderate level of ectopic aromatase expression rendered a non-tumorigenic ERα positive breast cancer cell line not only tumorigenic but also metastatic in female nude mice without exogenous estrogen supplementation. The increased malignant phenotype was confirmed to be due to aromatase expression as the growth of orthotopic tumors regressed with systemic administration of an aromatase inhibitor. Thus, our study provides experimental evidence that aromatase plays an important role in the survival of metastatic ERα breast cancer cells by suppressing anoikis.
!!!!!!!!!!!!!!! Role of Androgens on Breast Cancer Cells !!!!!!!!!!!!!!!!!!!!!!!!!
Androgens strongly reducing Bcl-2 expression in MCF-7 cells,
Macedo, Luciana F., et al. “Role of androgens on MCF-7 breast cancer cell growth and on the inhibitory effect of letrozole.” Cancer research 66.15 (2006): 7775-7782.
Previous work has shown that androgens inhibit breast cancer cells and tumor growth. On the other hand, androgens can be converted to mitogenic estrogens by aromatase in breast cancer cells. Here, we report that androgens, such as the aromatizable androstenedione and the non-aromatizable 5A-dihydrotestosterone, inhibit MCF-7 cell proliferation.
We also show that suppression of the estrogen-induced antiapoptotic protein Bcl-2 may be involved in the antiproliferative effects of androgens and letrozole. ..Bcl-2 protein has been extensively characterized as an inhibitor of apoptosis.
The results showed that MCF-7 breast cancer cells are responsive to androgens and estrogens. Estrogens stimulate MCF-7 and Ac1 (MCF-7 aromatase transfected) cell proliferation over a physiologic range of concentrations, and their effects are mediated by the ER.
In contrast, androgens show the opposite effect and inhibit cell growth. MCF-7 cell proliferation was inhibited by androstenedione and 5a-dihydrotestosterone at concentrations found in women and breast cancer patients (1-10 and 0.3-0.7 nmol/L, respectively;ref. 2).
We show that androstenedione and dihydrotestosterone at physiologic concentration act by strongly reducing Bcl-2 expression in MCF-7 cells, and that the androgenic inhibitory effect is mediated by the AR.
Estradiol showed an opposite effect and increased the Bcl-2 levels of expression. The finding that Bcl-2 expression was reduced by letrozole is consistent with the inhibition of the conversion of androstenedione to estradiol.
In summary, our results suggest that there are two hormonal forces regulating proliferation in AR and ER positive breast cancer cells. The androgenic signaling, through the AR, induces cell growth inhibition, whereas the estrogen-mitogenic signaling is mediated by the ER. The dominance of an inhibitory or stimulatory response seems to depend on the estrogen milieu. A change in the balance between androgenic and estrogenic influences could modify the overall growth rate of breast cancer cells. The balance can be shifted to stimulate proliferation when sufficient amounts of estrogens are produced due to expression of cellular aromatase and also due to blockade or down-regulation of the AR. On the other hand, the balance can be shifted to inhibit proliferation when ER is down-regulated or blocked and when the production of estrogens is reduced by aromatase inhibitors, such as letrozole. During aromatase inhibition, precursor androgens, such as androstenedione, can act directly or be converted to dihydrotestosterone and exert their antiproliferative effect by interacting with the AR. Thus, it seems that estrogens and androgens act in concert to regulate cell growth. The antiproliferative actions of androgens exposed by inhibiting estrogen production seem to play an important role in the efficacy of aromatase inhibitors in controlling breast cancer.
Our studies show that not only the inhibition of estrogenic production but also the activation of the intracellular androgenic signaling are involved in the actions of aromatase inhibitors.
Lapointe, Jacques, et al. “Androgens down-regulate bcl-2 protooncogene expression in ZR-75-1 human breast cancer cells.” Endocrinology 140.1 (1999): 416-421.
POULIN, RICHARD, et al. “Down-regulation of estrogen receptors by androgens in the ZR-75-1 human breast cancer cell line.” Endocrinology 125.1 (1989): 392-399.
Ortmann, J., et al. “Testosterone and 5α-dihydrotestosterone inhibit in vitro growth of human breast cancer cell lines.” Gynecological Endocrinology 16.2 (2002): 113-120.
Takagi, Kiyoshi, et al. “Increased intratumoral androgens in human breast carcinoma following aromatase inhibitor exemestane treatment.” Endocrine-related cancer 17.2 (2010): 415-430.
These findings suggest that intratumoral androgen actions are increased during exemestane treatment.
Zhou, Dujin, et al. “Aromatase gene is amplified in MCF-7 human breast cancer cells.” The Journal of Steroid Biochemistry and Molecular Biology 46.2 (1993): 147-153.
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Both tamoxifen and aromatase inhibitors
!!!!!!!!!!!!!!!! AI generated: !!!!!!!!!!!!!!!!!!!!!!!!!!!!
According to research, when used as adjunctive treatment after breast cancer, aromatase inhibitors (AIs) can lead to a roughly 15% reduction in all-cause mortality compared to tamoxifen, particularly in postmenopausal women, with the greatest benefit seen in reducing breast cancer-specific mortality by lowering the risk of recurrence by around one-third.
Limited overall mortality benefit: While AIs can decrease all-cause mortality, the absolute reduction is usually around 15%, meaning the overall survival benefit is primarily due to lowering breast cancer-specific mortality.
AI’s can decrease Mortality by 40 percent compared to no AI, particularly in postmenopausal women with hormone-receptor positive breast cancer
According to research, aromatase inhibitors can lead to a roughly 15% reduction in 10-year breast cancer mortality rates compared to tamoxifen, which translates to approximately a 40% proportional decrease in [breast cancer] mortality when compared to no endocrine treatment at all;
According to research, aromatase inhibitors can result in a roughly 40% proportional decrease in breast cancer mortality when compared to not receiving any endocrine treatment at all, particularly in postmenopausal women with hormone-receptor positive breast cancer; this means that when using an aromatase inhibitor, the risk of death from breast cancer is significantly lower (around 40%) compared to not using any hormonal therapy.
5 years of an aromatase inhibitor reduces 10-year breast cancer mortality rates by about 15% compared with 5 years of tamoxifen, hence by about 40% (proportionately) compared with no endocrine treatment. Funding: Cancer Research UK, Medical Research Council.
studies have shown no significant difference in overall (all-cause) mortality when comparing aromatase inhibitors to tamoxifen in postmenopausal women with breast cancer.
What are the risks and side effects of aromatase inhibitors?
The most common side effects of AIs are symptoms of menopause, such as hot flashes, night sweats, and vaginal dryness. These drugs can also cause muscle and joint pain. This side effect can be serious enough to cause some women to stop taking the drugs.
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Iwase, Takuji, et al. “Postoperative adjuvant anastrozole for 10 or 5 years in patients with hormone receptor–positive breast cancer: AERAS, a randomized multicenter open-label phase III trial.” Journal of Clinical Oncology 41.18 (2023): 3329-3338.
We enrolled 1,697 patients from 117 facilities between November 2007 and November 2012. Follow-up information was available for 1,593 patients (n = 787 in the continue group, n = 806 in the stop group), who were defined as the full analysis set, including 144 patients previously treated with tamoxifen and 259 patients who underwent breast-conserving surgery without irradiation.
The 5-year DFS rates were 91% (95% CI, 89 to 93) in the continue group and 86% (95% CI, 83 to 88) in the stop group (hazard ratio, 0.61; 95% CI, 0.46 to 0.82; P < .0010).
Notably, extended anastrozoletreatment reduced the incidence of local recurrence (continue group, n = 10; stop group, n = 27) and second primary cancers (continue group, n = 27; stop group, n = 52).
There was no significant difference in overall or distant DFS. Menopausal or bone-related all-grade adverse events were more frequent among patients in the continue group than those in the stop group, but the incidence of grade ≥3 adverse events was <1% in both groups.
Taking Arimidex for 10 years [extended] after breast cancer surgery reduced recurrence risk, but didn’t improve overall survival.
Extended anastrozole treatment significantly improved disease-free survival (DFS), defined as time from random assignment to breast cancer recurrence, second primary cancers, and death from any cause. However, extending anastrozole had no significant effect on overall survival or distant DFS.
Although mild menopausal and bone-related adverse events were more frequent in patients who continued anastrozole, there were no serious adverse events and bone density was managed with oral bisphosphonates.
The American Society of Clinical Oncology (ASCO) updated its guidelines on adjuvant hormonal therapy in 2018, recommending post-menopausal women diagnosed with early-stage, node-positive, hormone receptor-positive breast cancer take hormonal therapy, including an aromatase inhibitor, for 10 years after surgery.
=====================================
https://pmc.ncbi.nlm.nih.gov/articles/PMC9901948/
Jayasekera, Jinani, et al. “Reassessing the Benefits and Harms of Risk-Reducing Medication Considering the Persistent Risk of Breast Cancer Mortality in Estrogen Receptor–Positive Breast Cancer.” Journal of Clinical Oncology 41.4 (2023): 859-870.
Several randomized controlled trials have shown that risk-reducing medications such as tamoxifen and aromatase inhibitors (AIs) could decrease the incidence of ER+ breast cancer by 30%-50% in women who are at high risk of developing breast cancer.3-23 However, in clinical practice, the uptake of risk-reducing medication has remained extremely low.3
Risk-reducing tamoxifen with annual screening (± MRI) decreased the risk of invasive breast cancer by 40% and breast cancer death by 57%, compared with no tamoxifen or screening. This is equivalent to an absolute reduction of 95 invasive breast cancers, and 42 breast cancer deaths per 1,000 high-risk women. However, these drugs are associated with side effects. For example, tamoxifen could increase the number of endometrial cancers up to 11 per 1,000 high-risk women.
but some studies have posited that insufficient data on the long-term benefits and harms of risk-reducing drugs, lack of biomarkers to measure response to medication, and fear of rare but serious side effects (eg, endometrial cancer and pulmonary embolism) are deterrents
https://pmc.ncbi.nlm.nih.gov/articles/PMC8902439/
Pedersen, Rikke Nørgaard, et al. “The incidence of breast cancer recurrence 10-32 years after primary diagnosis.” JNCI: Journal of the National Cancer Institute 114.3 (2022): 391-399.
Among 36 924 women with breast cancer, 20 315 became 10-year disease-free survivors. Of these, 2595 developed late BCR (incidence rate = 15.53 per 1000 person-years, 95% confidence interval = 14.94 to 16.14; cumulative incidence = 16.6%, 95% confidence interval = 15.8% to 17.5%) from year 10 to 32 after primary diagnosis. Tumor size larger than 20 mm, lymph node–positive disease, and estrogen receptor–positive tumors were associated with increased cumulative incidences and hazards for late BCR.
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DUPLICATE
2023 Benefits and Harms
Jayasekera, Jinani, et al. “Reassessing the Benefits and Harms of Risk-Reducing Medication Considering the Persistent Risk of Breast Cancer Mortality in Estrogen Receptor–Positive Breast Cancer.” Journal of Clinical Oncology 41.4 (2023): 859-870.
We evaluated the effects of 5 years of risk-reducing medication (tamoxifen/aromatase inhibitors) with annual screening mammography ± magnetic resonance imaging (MRI) compared with no screening, MRI, or risk-reducing medication. The modeled outcomes included invasive breast cancer, breast cancer death, side effects, false positives, and overdiagnosis. We conducted subgroup analyses for individual risk factors such as age, family history, and prior biopsy.
Risk-reducing tamoxifen with annual screening (± MRI) decreased the risk of invasive breast cancer by 40% and breast cancer death by 57%, compared with no tamoxifen or screening.
This is equivalent to an absolute reduction of 95 invasive breast cancers, and 42 breast cancer deaths per 1,000 high-risk women. However, these drugs are associated with side effects. For example, tamoxifen could increase the number of endometrial cancers up to 11 per 1,000 high-risk women. Benefits and harms varied by individual characteristics.
Estrogen receptor–positive (ER+) breast cancer is generally considered to have a favorable prognosis.
However, recent studies have shown that the annual rates of recurrence and breast cancer death could remain up to 3% for almost three decades after an ER+ breast cancer diagnosis.1,2
Several randomized controlled trials have shown that risk-reducing medications such as tamoxifen and aromatase inhibitors (AIs) could decrease the incidence of ER+ breast cancer by 30%-50% in women who are at high risk of developing breast cancer.3-23 However, in clinical practice, the uptake of risk-reducing medication has remained extremely low.3
3.Nelson, Heidi D., et al. “Medication use for the risk reduction of primary breast cancer in women: updated evidence report and systematic review for the US Preventive Services Task Force.” Jama 322.9 (2019): 868-886.
However, use of medications for breast cancer risk reduction is low in clinical practice7-9 because of women’s concerns about adverse effects and beliefs that benefits are not worth the harms,3
women and their clinicians to conclude that the harms of risk-reducing medications outweigh their potential benefits.24-26
Overall, 5 years of risk-reducing tamoxifen and screening (± MRI) helped avoid 40% of invasive (ER+/ER−) breast cancers, and 57%-58% of breast cancer deaths in high-risk women compared with no screening or risk-reducing tamoxifen (Table 2). This is equivalent to an absolute reduction of 95-96 invasive breast cancer cases, and 42-43 breast cancer deaths per 1,000 high-risk women.
AIs Versus Tamoxifen in 50- and 65-Year-Old Women
AIs resulted in higher benefits and lower harms compared with tamoxifen in 50- and 65-year-old women (Table 4; Data Supplement for ER+). The absolute reduction attributable to AIs alone in 50- and 65-year-olds were 133-134 and 84 invasive breast cancers, and 54-55 and 14 breast cancer deaths per 1,000 women, respectively.
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2016
Primary Prevention
Hum, S., et al. “Physician and Patient Barriers to Breast Cancer Preventive Therapy.” Current Breast Cancer Reports 8.3 (2016): 158-164.
Although an estimated 15 % of high-risk American women aged 35–79 years are eligible for breast cancer preventive therapy [4], <5 % who are offered this option accept it [5]
5. Ropka, Mary E., Jess Keim, and John T. Philbrick. “Patient decisions about breast cancer chemoprevention: a systematic review and meta-analysis.” Journal of Clinical Oncology 28.18 (2010): 3090-3095.
Two AIs, exemestane and anastrozole, have been evaluated for the primary prevention of breast cancer in post-menopausal women. In a randomized, placebo-controlled trial, exemestane significantly reduced invasive breast cancers (RR = 0.65; 95 % CI 0.18–0.70) without the toxicities (thromboembolic, cancer events) associated with SERM therapy [3]. Arthralgias and menopausal symptoms, including hot flashes, were the main adverse events in women taking exemestane, but women’s quality of life was minimally affected, although age-related bone loss worsened despite adequate intake of calcium and Vitamin D [12, 13].
Similar to the MAP.3 trial, the IBIS-II trial compared the AI anastrozole to placebo, demonstrating a significant decrease in risk of invasive breast cancer and a reduction in ER-positive tumors by 50 and 58 %, respectively [14].
========================== BEST ==============
IBIS II 2020 Anastrozole for Primary Prevention of Breast Cancer
Cuzick, Jack, et al. “Use of anastrozole for breast cancer prevention (IBIS-II): long-term results of a randomised controlled trial.” The lancet 395.10218 (2020): 117-122.
women enrolled were at increased risk of breast cancer, whether because of family history or previous diagnosis of non-invasive lesions (eg, ductal carcinoma in situ, lobular carcinoma in situ, and atypical ductal hyperplasia).1
IBIS-II is an international, randomised, double-blind, placebo-controlled trial. Postmenopausal women at increased risk of developing breast cancer were recruited and were randomly assigned (1:1) to either anastrozole (1 mg per day, oral) or matching placebo daily for 5 years. After treatment completion, women were followed on a yearly basis to collect data on breast cancer incidence, death, other cancers, and major adverse events (cardiovascular events and fractures). The primary outcome was all breast cancer.
Findings
3864 women were recruited between Feb 2, 2003, and Jan 31, 2012. 1920 women were randomly assigned to 5 years anastrozole and 1944 to placebo.
After a median follow-up of 131 months (IQR 105–156), a 49% reduction in breast cancer was observed for anastrozole (85 vs 165 cases, hazard ratio [HR] 0·51, 95% CI 0·39–0·66, p<0·0001). The reduction was larger in the first 5 years (35 vs 89, 0·39, 0·27–0·58, p<0·0001), but still significant after 5 years (50 vs 76 new cases, 0·64, 0·45–0·91, p=0·014), and not significantly different from the first 5 years (p=0·087). Invasive oestrogen receptor-positive breast cancer was reduced by 54% (HR 0·46, 95% CI 0·33–0·65, p<0·0001), with a continued significant effect in the period after treatment. A 59% reduction in ductal carcinoma in situ was observed (0·41, 0·22–0·79, p=0·0081), especially in participants known to be oestrogen receptor-positive (0·22, 0·78–0·65, p<0·0001).
!!!!!!!!!!!!!!!! No effect on overall or breast cancer mortality !!!!!!!!!!!!!!!!!!!!!!!!!
No significant difference in deaths was observed overall (69 vs 70, HR 0·96, 95% CI 0·69–1·34, p=0·82) or for breast cancer (two anastrozole vs three placebo).
A significant decrease in non-breast cancers was observed for anastrozole (147 vs 200, odds ratio 0·72, 95% CI 0·57–0·91, p=0·0042), owing primarily to non-melanoma skin cancer. No excess of fractures or cardiovascular disease was observed.
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2015 Primary Prevention
DeCensi, Andrea, et al. “Barriers to preventive therapy for breast and other major cancers and strategies to improve uptake.” Ecancermedicalscience 9 (2015).
Tamoxifen uptake for eligible high-risk women remains very low primarily due to concerns about side effects and lack of demonstrated mortality reduction [6, 8].
The uptake of breast cancer preventive therapy has been below 1% in spite of a potential population of approximately 10 million high-risk women aged 35–79 years in the United States according to FDA criteria [14]
overall pictures suggests a shift away from tamoxifen and towards raloxifene for this purpose [16].
Unsurprisingly, in a recent survey conducted among over 200 breast cancer specialists during different breast cancer meetings in Italy and Switzerland or sent electronically among the alumni of the European School of Oncology, the top three important or very important reasons for low uptake were the following:
(1) drugs may have serious side effects;
(2) no evidence for a reduction in mortality; (for primary prevetion)
(3) drugs are off label in Europe (manuscript in preparation).
The issue of lack of effect on mortality discussed in detail below is a main point of contention.
!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!
Countering prejudices – the issue of lack of reduction in mortality
Preventive therapy trials of SERMs [1] have not yet shown a reduction in breast cancer-specific or all-cause mortality, and this has been one of the main arguments [28, 29] against their use.
28.Narod SA. Tamoxifen chemoprevention-end of the road? JAMA Oncol. 2015.
29. Cameron DA. Breast cancer chemoprevention: little progress in practice? Lancet. 2014;383(9922):1018–1020. doi: 10.1016/S0140-6736(13)62555-6.
In The Lancet, Jack Cuzick and colleagues report the first results from IBIS-II (International Breast cancer Intervention Study II),1 in which 3864 postmenopausal women at high risk of breast cancer were randomly assigned to receive the potent, non-steroidal aromatase inhibitor anastrozole or placebo every day for 5 years. After a median follow-up of 5 years, 40 (2%) of 1920 women in the anastrozole group and 85 (4%) of 1944 in the placebo group had developed breast cancer (hazard ratio 0·47, 95% CI 0·32–0·68). This finding is in keeping with those of other similar studies.2–4 So far, unsurprisingly, the investigators have not recorded evidence for a difference in breast cancer or all-cause mortality: 18 deaths had been reported in the anastrozole group and 17 in the placebo group.1
women enrolled were atincreased risk of breast cancer, whether because of family history or previous diagnosis of non-invasive lesions (eg, ductal carcinoma in situ, lobular carcinoma in situ, and atypical ductal hyperplasia).1The predicted cumulative incidence of all breast cancers after 7 years in the control group (5·6%) reflects an increased risk in the participants, and is in line with other similar studies of breast cancer prevention.2,3
In 2002, Kinsinger and Harris11 noted on the publication of the IBIS-I tamoxifen chemoprevention trial: “For chemoprevention to find a prominent role in reducing the burden of breast cancer, research must develop along at least three paths.
First, longer-term research must find that the reduction in incidence translates into a reduction in breast cancer mortality.
Second, newer drugs that have a better safety profile need to be developed. Finally, better ways are needed to target the drugs to those women who will benefit most.” Unfortunately, although Cuzick and colleagues report important data,1 IBIS-II has not addressed any of these challenges.
===========================
Aromatase Inhibitors
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2023
Discontinuing adjuvant hormone therapy
https://pmc.ncbi.nlm.nih.gov/articles/PMC10409554/
Camejo, Natalia, et al. “Assessing adherence to adjuvant hormone therapy in breast cancer patients in routine clinical practice.” World Journal of Oncology 14.4 (2023): 300.
A lack of adherence to adjuvant endocrine therapy is common, 31.0-73.0% of women discontinue endocrine treatment before 5 years
Totally, 118 patients were included; 65.2% were treated with aromatase inhibitors (AIs), 36.0% presenting polypharmacy. The adherence rate at the end of 2 years was 81.0 %; and it was associated with age (P = 0.03, OR = 0.96 for non-adherence), with adherent and non-adherent patients having a mean age of 65.0 and 60.3 years, respectively;
Adherence to HT was assessed in real life, with 19.0% of the patients not adhering to the treatment
A systematic review published in 2012 showed that 31.0-73.0% of patients discontinue HT[9], and other systematic review published in 2022 reported that adherence at 5 years of HT treatment ranged from 33.3% to 88.6%, resulting in an increased risk of relapse[10].
9. Murphy, Caitlin C., et al. “Adherence to adjuvant hormonal therapy among breast cancer survivors in clinical practice: a systematic review.” Breast cancer research and treatment 134 (2012): 459-478.
10.Yussof, Izzati, et al. “Factors influencing five-year adherence to adjuvant endocrine therapy in breast cancer patients: a systematic review.” The Breast 62 (2022): 22-35.
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2021 HARMS of Endocrine Therapy
Kauffman, Robert P., Christina Young, and V. Daniel Castracane. “Perils of prolonged ovarian suppression and hypoestrogenism in the treatment of breast cancer: Is the risk of treatment worse than the risk of recurrence?.” Molecular and Cellular Endocrinology 525 (2021): 111181.
Long-term estrogen deprivation is associated with an increase in all-cause mortality.
• Quality-of-life deterioration during estrogen suppression should be addressed to improve treatment compliance and satisfaction.
• Aggressive adjuvant therapy should be balanced with a discussion of quality-of-life and potential development of chronic diseases.
Bilateral oöphorectomy has been recognized as a potential treatment strategy in premenopausal women since 1896, providing a historical precedent for medically induced hypoestrogenism as adjuvant therapy (Adank et al., 2006; Beatson, 1896).
Paradoxically, in postmenopausal populations, high dose systemic estrogens (such as diethylstilbesterol) have long been appreciated to promote tumor regression. The first paper demonstrating this association was published in 1944 by Haddow et al. (Haddow, 1944), and these findings have been replicated by other investigators (Kennedy and Brown, 1965; Kennedy et al., 1964; Taylor et al., 1948; Huseby, 1954).
This “estrogen paradox” has not been altogether forgotten. In 2015, the “time gap” hypothesis was proposed. According to this theory, after an extended but unspecified time interval (gap), estrogen-deprived breast cancer cells become vulnerable to estrogen mediated apoptosis (Jordan, 2015). In this setting, cancer cell estrogen receptors switch off mRNA transcription after binding with estradiol or estrogen metabolites which subsequently promotes cancer cell apoptosis instead of growth.
there is clinical evidence to support this theory based on the relative safety of
(1) pregnancy following completion of breast cancer treatment, and
(2)administering low-dose estrogen to symptomatic women after completion of adjuvant endocrine therapy (AET)
Mueck, A. O., and H. Seeger. “Estrogen as a new option for prevention and treatment of breast cancer–does this need a “time gap”?.” Climacteric: the journal of the International Menopause Society 18.4 (2015): 444-447.
PREGNANCY AFTER Breast Cancer Associated with 78% reduced mortality
Iqbal, Javaid, et al. “Association of the timing of pregnancy with survival in women with breast cancer.” JAMA oncology 3.5 (2017): 659-665.
The 5-year actuarial survival rate was 96.7% (95% CI, 94.1%-99.3%) [3.3% mortality] for women who had pregnancy 6 months or more after diagnosis of breast cancer, vs 87.5% (95% CI, 86.5%-88.4%) [12.5% mortality]for women with no pregnancy) (age-adjusted HR, 0.22; 95% CI, 0.10-0.49; P < .001).
Knabben, Laura, and Michel D. Mueller. “Breast cancer and pregnancy.” Hormone molecular biology and clinical investigation 32.1 (2017). A big meta-analysis of 14 studies by Azim et al. [31] found no negative impact of pregnancy following breast cancer on OS. Women who became pregnant after breast cancer even had improved survival compared to patients with breast cancer who did not.
Azim Jr, Hatem A., et al. “Safety of pregnancy following breast cancer diagnosis: a meta-analysis of 14 studies.” European journal of cancer 47.1 (2011): 74-83.
Fourteen studies were included in this meta-analysis (1244 cases and 18,145 controls). Women who got pregnant following breast cancer diagnosis had a 41% reduced risk of death compared to women who did not get pregnant [PRR: 0.59 (90% confidence interval (CI): 0.50-0.70)]. This difference was seen irrespective of the type of the study and particularly in women with history of node-negative disease.
Lambertini, Matteo, et al. “Pregnancy after breast cancer: a systematic review and meta-analysis.” Journal of Clinical Oncology 39.29 (2021): 3293-3305.
Of 6,462 identified records, 39 were included involving 8,093,401 women from the general population and 112,840 patients with BC of whom 7,505 had a pregnancy after diagnosis….Compared to patients with BC without subsequent pregnancy, those with a pregnancy had better disease-free survival (HR, 0.66; 95% CI, 0.49 to 0.89) and overall survival (HR, 0.56; 95% CI, 0.45 to 0.68).
Lambertini, Matteo, et al. “Pregnancy after breast cancer in patients with germline BRCA mutations.” Journal of Clinical Oncology 38.26 (2020): 3012-3023.
Partridge, Ann H., et al. “Interrupting endocrine therapy to attempt pregnancy after breast cancer.” New England journal of medicine 388.18 (2023): 1645-1656.
Kim, Yunyeong, et al. “Subsequent pregnancy and long-term safety from breast cancer patients.” (2020): e13575-e13575.
!!!!!!!!!!!!!!!!!!!!!!!!!
Continued……..
Kauffman, Robert P., Christina Young, and V. Daniel Castracane. “Perils of prolonged ovarian suppression and hypoestrogenism in the treatment of breast cancer: Is the risk of treatment worse than the risk of recurrence?.” Molecular and Cellular Endocrinology 525 (2021): 111181.
Hazards of Estrogen Depletion !!!!!
Sustained lower serum levels [estrogen levels] are associated with cardiovascular disease, osteoporosis, neurodegeneration, and inflammatory processes
Jia et al., 2015;
Patel et al., 2018;
Gillies and McArthur, 2010;
Nilsson et al., 2001).
Cardiovascular Disease:
Khosrow-Khavar, Farzin, et al. “Aromatase inhibitors and the risk of cardiovascular outcomes in women with breast cancer: a population-based cohort study.” Circulation 141.7 (2020): 549-559.
In this population-based cohort study of 17 922 women with breast cancer, the use of aromatase inhibitors was associated with increased risks of heart failure and cardiovascular mortality and trends toward increased risks of myocardial infarction and ischemic stroke compared with the use of tamoxifen.
!!!!!!!!!!!!!!!!!!!!!! Kauffman, Robert Continued !!!!!!!!!!!!!!!!!!!!!
At 8 years, a larger difference in disease-free survival and freedom from distal recurrences persisted but with no change in overall survival for the exemestane + GnRHaarm (HR 0.85, 95% CI 0.62–1.15)
Francis, Prudence A., et al. “Tailoring adjuvant endocrine therapy for premenopausal breast cancer.” New England Journal of Medicine 379.2 (2018): 122-137.
The side-effects and potential harm of prolonged estrogen suppression are many: vasomotor instability, sleep disturbance, depression/anxiety, cognitive decline, cardiovascular disease and stroke, diabetes, bone loss, joint and connective tissue discomfort, genitourinary syndrome of menopause, and sexual dysfunction—to name the most common.
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Generali, Daniele, et al. “Aromatase inhibitors: the journey from the state of the art to clinical open questions.” Frontiers in Oncology 13 (2023): 1249160.
Historically, patients with ER-positive breast cancer treated with TAM for 5 years had a decreased risk of deathby approximately half during pharmacological treatment. This risk increases to about one-third at 15 years (16). AIs impede the conversion of androgens to estrogens; therefore, they cannot be adopted in premenopausal women unless they are exposed to ovarian function suppression (OFS) (17). In contrast, in postmenopausal women, AIs reduce the serum estrogen levels, thereby inhibiting ER-positive breast cancer cell stimulation (Figure 1).
This paper’s key findings consist mainly of the proportional risk reduction of approximately 30% in recurrence observed in the AIs vs. TAM comparison period and the proportional risk reduction of about 15% in mortality rate reported in the first 10 years.
AIs administered for 5 years in the absence of any endocrine therapy lower relapse rates by about two-thirds while patients are actively on treatment and by about one-third in the following 5 years and reduce the mortality rate by approximately 40% throughout the first decade and perhaps beyond. Moreover, all the trials commencing endocrine treatment with an AI showed, collectively, a highly significant drop of 30% in recurrence during years 0 to 1, conf irming the superiority of AIs over TAM (28)
In summary, the results of this meta-analysis suggest that when AIs are initiated instead of TAM in premenopausal women, in addition to OFS, the absolute recurrence risk can be decreased by 3% at 5 and 10 years. In postmenopausal women, approximately 70% of all breast cancers are hormone receptor-responsive and candidates for endocrine therapy (35).
AIs are a cornerstone for both pre- and postmenopausal women with hormone receptor-positive breast cancers. During adjuvant endocrine therapy, no significant decrease in health-related quality of life has been reported in several large-scale trials (86–88).
The data suggest that up to 30% of patients do not adhere to AI therapy because of its adverse effects.
Adherence to endocrine therapy is fundamental, as it can improve patient outcomes and survival curves (89, 90). Patients who disrupt their AI treatment early are exposed to an increased risk of all-cause mortality, cancer death, and recurrence because they do not fully receive the intended therapy-related benefits (91). Most women who fail to adhere to their endocrine treatment discontinue therapy during the first 6 months because the most severe toxicities related to AIs tend to occur within this period (92–94) (Table 3).
one of the most significant adverse effects that play a fundamental role in the quality of life of this group of patients is bone loss. ..Endocrine therapy works by directly or indirectly removing the effect of estradiol on the breast tissue. The same effect is exerted on the bone tissue, leading to bone loss (95, 96).
All women presenting a BMD score of 2.0 SD or more than two risk factors (prior fragility fractures, parental history of hip fracture, diabetes, BMI 20 kg/m2, rheumatoid arthritis, recurrent falls, use of glucocorticoids for more than 3 months, current smoking, and alcohol consumption) should be offered anti-resorptive therapy. Regarding follow-up, when no antiresorptive therapy has started, DEXA should be repeated yearly after AI initiation and every 2 years in patients on antiresorptive medication.
Cardiotoxicity is a major concern in the prescription of AIs. Several adjuvant randomized controlled trials comparing AIs with TAM have shown that the risk of developing a cardiovascular disease increases with AIs (99–101).
Currently, AIs are the cornerstone in the management of breast cancer in every patient setting (pre- and postmenopausal, eBC, and mBC). Their use is widespread, as the literature has fully demonstrated their efficacy in improving survival and their low toxicity profile. Adverse effects on bone health, the cardiovascular system, and metabolism can be easily handled with dedicated network paths in which patients feel completely managed by experts and are globally followed up on every aspect of their disease. Greater efforts should be made to improve adherence to endocrine therapy, especially in a selected subset of patients undergoing extended adjuvant therapy because of the high risk of relapse after 5 years. Modern technology can help physicians; however, reaching the optimal point remains a long way off. The more patients follow endocrine therapy, the more we can achieve longer and better responses.
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Toxicity 2011
Amir, Eitan, et al. “Toxicity of adjuvant endocrine therapy in postmenopausal breast cancer patients: a systematic review and meta-analysis.” Journal of the National Cancer Institute 103.17 (2011): 1299-1309.
Aromatase inhibitors are associated with consistent improvements in disease-free survival but not in overall survival.
We conducted a literature-based meta-analysis of randomized trials to examine whether the relative toxicity of aromatase inhibitors compared with tamoxifen may explain this finding.
Methods We conducted a systematic review to identify randomized controlled trials that compared aromatase inhibitors and tamoxifen as primary adjuvant endocrine therapy in postmenopausal women by searching MEDLINE, EMBASE, and databases of the American Society of Clinical Oncology and San Antonio Breast Cancer Symposium. Odds ratios (ORs), 95% confidence intervals (CIs), absolute risks, and the number needed to harm associated with one adverse event were computed for prespecified serious adverse events including cardiovascular disease, cerebrovascular disease, bone fractures, thromboembolic events, endometrial carcinoma and other second cancers not including new breast cancer. All statistical tests were two-sided.
Results Seven trials enrolling 30 023 patients met the inclusion criteria.
Longer duration of aromatase inhibitor use was associated with increased odds of developing cardiovascular disease (OR = 1.26, 95% CI = 1.10 to 1.43, P < .001; number needed to harm = 132) and bone fractures (OR = 1.47, 95% CI = 1.34 to 1.61, P < .001; number needed to harm = 46), but a decreased odds of venous thrombosis (OR = 0.55, 95% CI = 0.46 to 0.64, P < .001; number needed to harm = 79) and endometrial carcinoma (OR = 0.34, 95% CI = 0.22 to 0.53, P < .001; number needed to harm = 258).
Five years of aromatase inhibitors was associated with a non-statistically significant increased odds of death without recurrence compared with 5 years of tamoxifen alone or tamoxifen for 2–3 years followed by an aromatase inhibitor for 2–3 years (OR = 1.11, 95% CI = 0.98 to 1.26, P = .09).
Conclusions The cumulative toxicity of aromatase inhibitors when used as up-front treatment may explain the lack of overall survival benefit despite improvements in disease-free survival.
Switching from tamoxifen to aromatase inhibitors reduces this toxicity and is likely the best balance between efficacy and toxicity.
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2014 MICE Rajkumar Lakshmanaswamy
Natural Hormone Treatment yield better tumor reduction than current treatments
Arumugam, Arunkumar, Elaine A. Lissner, and Rajkumar Lakshmanaswamy. “The role of hormones and aromatase inhibitors on breast tumor growth and general health in a postmenopausal mouse model.” Reproductive Biology and Endocrinology 12 (2014): 1-13.
Ovariectomized nude mice were transplanted with MCF-7 breast cancer cells constitutively
expressing aromatase. The mice were treated with different combinations and doses of
steroids, [estrogen (25 pg, 40 pg, 100 pg), progesterone (6 ng) and testosterone (50 ng)] along with dehydroepiandrostenedione (100ug). Serum levels of HDL, LDL/VLDL, free and total cholesterol, total and bone specific alkaline phosphatase and triglycerides were analyzed after 5, 10 and 15 months.
Results Free cholesterol and LDL/VLDL levels in serum were reduced in groups mimicking estrous cycle and menstrual cycle hormones treatment. HDL cholesterol was increased in all the hormone treated groups except the estrous cycle-mimicking group. Bone specific alkaline phosphatase was decreased in menstrual cycle levels of estrogen and progesterone treatment.
Conclusions
All together our results show that use of natural hormones in appropriate combinations have
beneficial effects on cardiac and bone toxicity, along with better tumor reduction than current treatments.
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2007
Barron, Thomas I., et al. “Early discontinuation of tamoxifen: a lesson for oncologists.” Cancer: Interdisciplinary International Journal of the American Cancer Society 109.5 (2007): 832-839.
About 75% of breast cancers are hormone receptor positive, and, therefore, the women are candidates for treatment with tamoxifen or other hormonal agents.
“Five years of adjuvant tamoxifen is the recommended treatment and results in a reduction in the relative breast cancer recurrence risk of 46% and the relative risk of death of 26%,”
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Tamoxifen Articles
2023
Nordenskjöld, Anna, et al. “Breast cancer survival and incidence of second primary cancers after 30 years in a randomized study of two versus five years of adjuvant tamoxifen therapy.” The Breast 71 (2023): 63-68.
After 5 years of follow-up, when tamoxifen treatment was finished in both groups, until 15 years of follow-up, overall mortality (HR 0.80, 95% CI 0.72–0.90, p < 0.001), breast cancer mortality for all patients (HR 0.80, 95% CI 0.68–0.94, p = 0.006) and breast cancer mortality for patients with estrogen receptor positive disease (HR 0.67, 95% CI 0.55–0.83, p < 0.001) were significantly reduced in the five-year group as compared to the two-year group. After 15 years, the difference remained but did not further increase.
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2024
Fohlin, Helena, et al. “Breast cancer hormone receptor levels and benefit from adjuvant tamoxifen in a randomized trial with long-term follow-up.” Acta Oncologica 63 (2024).
Background: Hormone receptor positivity predicts benefit from endocrine therapy but the knowledge about the long-term survival of patients with different tumor receptor levels is limited. In this study, we describe the 25 years outcome of tamoxifen (TAM) treated patients.
Patients and methods: Between 1983 and 1992, a total of 4,610 postmenopausal patients with early-stage breast cancer were randomized to receive totally 2 or 5 years of TAM therapy. After 2 years, 4,124 were alive and free of breast cancer recurrence. Among these, 2,481 had demonstrated estrogen receptor positive (ER+) disease. From 1988, the Abbot enzyme immunoassay became available and provided quantitative receptor levels for 1,210 patients, for which our analyses were done.
Results: After 5 years of follow-up, when all TAM treatment was finished, until 15 years of follow-up, breast cancer mortality for patients with ER+ disease was significantly reduced in the 5-year group as compared with the 2-year group (hazard ratios [HR] 0.67, 95% confidence intervals [CI] 0.55–0.83, p < 0.001). After 15 years, the difference between the groups remained but did not increase further.
A substantial benefit from prolonged TAM therapy was only observed for the subgroup of patients with ER levels below the median (HR = 0.62, 95% CI 0.46–0.84, p = 0.002).
Similarly, patients with progesterone receptor negative (PR-) disease did benefit from prolonged TAM treatment. For patients with progesterone receptor positive (PR+) disease, there was no statistically significant benefit from more than 2 years of TAM.
Interpretation: As compared with 2 years of adjuvant TAM, 5 years significantly prolonged breast cancer-specific survival.
The benefit from prolonged TAM therapy was statistically significant for patients with
ER levels below median or PR-negative disease. There was no evident benefit from prolonged TAM for patients with high ER levels or with PR+ tumors.
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2023 Howell, Anthony
Howell, Anthony, and Sacha J. Howell. “Tamoxifen evolution.” British Journal of Cancer 128.3 (2023): 421-425.
The first endocrine therapy was surgical oophorectomy in young women with advanced disease [8].
Stilboestrol became the mainstay of oestrogen therapy until the development of tamoxifen 30 years later.
The first single-arm Phase 2 trial of tamoxifen was initiated in 1969. Forty-six patients were recruited and 22% were assessed as responding to treatment. The response rates to tamoxifen were compared with the hospital records of 64 patients treated will stilbestrol, of which 16 (25%) responded, and 60 with high-dose androgens of which 11 (18%) responded. The response rates of the compounds were, therefore, comparable but major differences in toxicity profiles were reported [2].
Tamoxifen was subsequently compared in randomised trials with other agents/surgical procedures used at the time, including stilbestrol, megestrol acetate, medroxyprogesterone acetate, fluoxymesterone, nandronolone, first and second-generation aromatase inhibitors, surgical oophorectomy and adrenalectomy. A comprehensive review of all these trials reported no significant difference in survival (24 comparisons HR = 1.02) but a higher incidence of side effects with the other therapies, including fatigue, lethargy, congestive cardiac failure, alopecia and weight gain compared with tamoxifen [3].
The first trial initiated in 1976 tested 1 year of tamoxifen treatment, the second 2 years and the third 5 years [26,27,28]. These, and multiple later adjuvant trials, were reviewed by the Early Breast Cancer Trials Collaborative Group [29]. Reductions in recurrence after about 10 years of follow-up were 21%, 29% and 47% for 1, 2 and 5 years of treatment, respectively. The corresponding mortality reductions were 12%, 17% and 26%, respectively, with a significantly significant test for trends in both recurrence and mortality.
The ATLAS trial randomised 12,894 patients to either stop tamoxifen treatment at 5 years or to continue to complete a total of 10 years of therapy and showed a significant reduction in recurrence and mortality with the longer versus shorter treatment (recurrence at years 21.4% vs 25% and mortality 12.2% vs 15.0% for 5 and 10 years, respectively). Extended tamoxifen was associated with small increases in pulmonary embolism (HR 1.87; P = 0.01, and endometrial cancer (HR 1.30; P = 0.0002) and a reduction in ischaemic heart disease (HR 0.75; P = 0.02).
This led to the introduction of the first adjuvant trial which randomised postmenopausal women to tamoxifen or anastrozole for 5 years. Recruitment began in 2002 and demonstrated that anastrozole was significantly superior to tamoxifen for relapse-free [27] and overall survival [36].
!!!!!!!!!!!!! premenopausal women with concomitant ovarian suppression. 1111
Tamoxifen was also compared with AIs in four trials in premenopausal womenwith concomitant ovarian suppression. There was a greater reduction in relapse by AIs (RR 0.79 P 0.0005) but, at present no significant impact on mortality [37].
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Tamoxifen and prevention of breast cancer
In women randomised to tamoxifen versus placebos, there was a 38% reduction in breast cancer incidence irrespective of age of the women treated. A follow-up of the UK/ANZ trial indicated a continued risk reduction up to at least 15 years after the 5-year treatment period [42]. Studies of AIs (exemestane and anastrozole) versus placebo report 50–60% reduction in breast cancer risk in postmenopausal women, which appears superior to tamoxifen. However, no head-to-head comparisons of AIs and tamoxifen have been made for cancer prevention.
However, with time, improved aromatase inhibitors and the development of SERDs such as fulvestrant have led to a reduction in the indications for tamoxifen and it is now mainly used as adjuvant therapy for lower-risk premenopausal breast cancer and for prevention. A recent review of the treatment of advanced ER + ve breast cancer does not include tamoxifen at all in the suggested treatment algorithm for the disease [57].
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2017
Şendur, Mehmet AN, et al. “Do all aromatase inhibitors have similar efficacy and safety?.” Future Oncology 13.19 (2017): 1673-1676.
Patients with invasive breast cancers that estrogen receptor and/or progesterone receptor are positive should be treated with adjuvant endocrine therapy regardless of stage of the disease, patient age, prior chemotherapy and menopausal status [Citation1].
In the adjuvant hormonal treatment of postmenopausal breast cancer patients, most of the trials have showed the superiority of aromatase inhibitors over tamoxifen.
In a meta-analyses of breast cancer outcomes in adjuvant trials of aromatase inhibitors versus tamoxifen, aromatase inhibitors significantly lower recurrence rates compared with tamoxifen treatment either as initial monotherapy or after 2–3 years of tamoxifen [Citation2].
In a metanalyses of 31,920 postmenopausal patients, 5 years of an aromatase inhibitor reduces recurrence rates by about 30% and 10-year breast cancer mortality rates by about 15% compared with 5 years of tamoxifen
Dowsett, M., et al. “Early Breast Cancer Trialists’ Collaborative G. Aromatase inhibitors versus tamoxifen in early breast cancer: patient-level meta-analysis of the randomised trials.” Lancet 386.10001 (2015): 1341-1352.
Due to the better progression-free survival rate and lower recurrences with aromatase inhibitors compared with tamoxifen in early breast cancer, aromatase inhibitors have been accepted as first-line treatment in the adjuvant treatment of hormone receptor-positive postmenopausal breast cancer
[Citation4].
2015
https://www.icr.ac.uk/news-archive/oestrogen-suppressing-drugs-substantially-reduce-breast-cancer-deaths
Early Breast Cancer Trialists’ Collaborative Group. “Aromatase inhibitors versus tamoxifen in early breast cancer: patient-level meta-analysis of the randomised trials.” The Lancet 386.10001 (2015): 1341-1352.
Oestrogen-suppressing drugs substantially reduce breast cancer deaths
The study, published in The Lancet today, is relevant to postmenopausal women with ER-positive breast cancer, which accounts for over 80% of cases which occur after the menopause. Each trial had used both aromatase inhibitors and tamoxifen at various times during the course of treatment.
In the study, researchers from the Aromatase Inhibitors Overview Group – chaired by Professor Mitch Dowsett at The Institute of Cancer Research, London and The Royal Marsden NHS Foundation Trust – collaborated with colleagues at the Clinical Trials Service Unit at The University of Oxford, to combine the results from 31,920 women in nine clinical trials.
The current study showed that taking aromatase inhibitors for five years reduced the risk of postmenopausal women with ER positive breast cancer dying of their disease by 40% within 10 years of starting treatment, compared with no hormonal treatment. This compares with the 30% reduction achieved by taking tamoxifen for five years.
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Premenopausal Patients With Breast Cancer
2021
Bradley R, Braybrooke J, Gray R, et al; Early Breast Cancer Trialists’ Collaborative Group. Aromatase inhibitors versus tamoxifen in premenopausal women with ER+ early stage breast cancer treated with ovarian suppression: a patient level meta-analysis of 7,030 women in four randomized trials. Presented at: 2021 San Antonio Breast Cancer Symposium; December 7-10, 2021; San Antonio, TX. Abstract GS2-04.
https://www.curetoday.com/view/aromatase-inhibitors-reduce-recurrence-risk-but-not-death-rates-in-premenopausal-patients-with-breast-cancer
Aromatase Inhibitors Reduce Recurrence Risk, But Not Death Rates, in Premenopausal Patients With Breast Cancer
Author(s):Lindsay Fischer
“Using (aromatase inhibitors) rather than tamoxifen in premenopausal women receiving ovarian suppression reduces the risk of breast cancer recurrence by around 21%,” Rosie Bradley, a medical statistician at Oxford Population Health, University of Oxford, said during a presentation of the findings. “The reduction in distant recurrence (is) 17%, but (has) no effect on breast cancer mortality or overall survival;
three-year study period (in ABCSG 12) or a five-year period in other trials (SOFT, TEXT, and HOBOE).
Early Breast Cancer Trialists’ Collaborative Group pooled individual data available from 7,030 premenopausal women with ER-positive breast cancer who had participated in one of the following randomized controlled trials:
- ABCSG 12 (NCT00295646)
- TEXT (NCT00066703)
- SOFT (NCT00066690)
- HOBOE (NCT00412022).
Overall, the recurrence risk was 14.7% in women treated with an aromatase inhibitor, compared with 17.5% in those given tamoxifen. At a five-year follow-up, the rate of recurrence was 10.1% vs 6.9%, for the aromatase inhibitor and tamoxifen groups, respectively. Despite the distant recurrence reduction, breast cancer mortality was similar between the two groups.
women with disease that spread to four or more lymph nodes did not appear to derive benefit from aromatase inhibitor treatment.
In addition, more women receiving an aromatase inhibitor experienced bone fractures compared with women receiving tamoxifen (5% vs 3.8%, respectively), and few non-breast cancer deaths occurred (0.5% vs 0.2%, respectively).
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2015 IBIS-1 7,154 healthy pre- and postmenopausal women
New research from UC Davis and three other universities suggests that most women who take tamoxifen to prevent breast cancerdo not extend their life expectancy.
https://medauth2.mdedge.com/content/20-years-after-initiating-preventive-tamoxifen-less-breast-cancer-no-survival-benefit
IBIS-1 randomized 7,154 healthy pre- and postmenopausal women to 5 years of either 20 mg daily tamoxifen or placebo. These women were aged 35-70 years at baseline and presented with an increased breast cancer risk attributable to a family history.
20 years after initiating preventive tamoxifen, less breast cancer but no survival benefit(refering to Cusick , JAck 2015)
However, their 20-year all-cause mortality was no different from those taking placebo (182 vs. 166 deaths), nor was their mortality from breast cancer (31 vs. 26, respectively), Jack Cuzick, Ph.D., said at the San Antonio Breast Cancer Symposium.
Dr. Jack Cuzick says:
“While we saw clear, lasting benefits of tamoxifen in reducing breast cancer incidence, uncertainty with respect to mortality remains,” said Dr. Cuzick, the John Snow professor of epidemiology at Wolfson Institute of Preventive Medicine at Queen Mary University, London.
Recurrent breast cancer was the single largest cause of death, but the between-group difference was not significant (26 vs. 31). Cardiovascular deaths were similar between the groups, and all that did occur, did so during the treatment period.
Cuzick, Jack, et al. “Tamoxifen for prevention of breast cancer: extended long-term follow-up of the IBIS-I breast cancer prevention trial.” The lancet oncology 16.1 (2015): 67-75.
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2014 DCIS Tamoxifen after local excision for DCIS
Staley, H., I. McCallum, and J. Bruce. “Postoperative Tamoxifen for ductal carcinoma in situ: Cochrane systematic review and meta-analysis.” Breast (Edinburgh, Scotland) 23.5 (2014): 546-551.
This review concludes that while Tamoxifen after local excision for DCIS, with or without adjuvant radiotherapy, reduced the risk of recurrent DCIS, it did not reduce the risk of all-cause mortality.
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2009
HUGHES-DAVIES, L., C. CALDAS, and GC WISHART. “Tamoxifen: the drug that came in from the cold.” British journal of cancer 101.6 (2009): 875-878.
Improved mortality from breast cancer during the past two decades has been partly attributed to increased use of adjuvant hormonal treatment. The Oxford Overviews showed that tamoxifen, an oestrogen receptor ligand, can halve the risk of recurrence and reduce the risk of death by about a quarter in oestrogen receptor positive patients (EBCTCG, 2005).
There is increasing concern that some of the most influential AI trials have been unable to demonstrate an overall survival (OS) advantage of AI’s compared with tamoxifen particularly when used up front.
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Both tamoxifen and aromatase inhibitors
Adverse Effects extended adjuvant therapy
free pdf
Goldvaser, Hadar, et al. “Toxicity of extended adjuvant therapy with aromatase inhibitors in early breast cancer: a systematic review and meta-analysis.” JNCI: Journal of the National Cancer Institute 110.1 (2018): 31-39.
Death Without Recurrence
Death without breast cancer recurrence was reported in five studies (11–13,22,23). There was no statistically significant association between death without breast cancer recurrence and longer use of AIs (OR¼1.11, 95% CI¼ 0.90 to 1.36, P ¼ .34) (see Figure 2E). There was no evidence of statistically significant heterogeneity (Cochran Q P ¼ .44, I2 ¼ 0%).
In absolute terms, 3.3% of the patients treated with prolonged AIs and 2.9% of those treated with placebo or no treatment died without breast cancer
recurrence. The weighted pooled absolute difference was 0.3%,
with a NNH of 371.
There was no association between the relative odds of death without breast cancer recurrence and median age at random assignment, median duration of follow-up, or
the proportion of patients who had received prior tamoxifen or prior AIs (see Table 4).
In an exploratory analysis, despite improvement in disease free survival (pooled OR=0.78, 95% CI= 0.68 to 0.88, P< .001) (see Supplementary Figure 2, available online), no effect onoverall survival was observed(OR=1.01, 95% CI= 0.89 to 1.14, P<.92) (see Supplementary Figure 2, available online).
The 25% improvement in DFS failed to have any impact on overall survival.
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2023 Extended Adjuvant therapy
Pandey, Praful, and Ajay Gogia. “Time to question extended adjuvant endocrine therapy for all.” Cancer Research, Statistics, and Treatment 6.4 (2023): 636-637.
We believe that the corpus of available evidence does not justify recommending extended adjuvant therapy to everyone. Prospective studies evaluating better patient selection (possibly via biomarkers) or extended tamoxifen therapy after 5 years of aromatase inhibitors may change this. Till then, the recurrence risk in patients after 5 years of adjuvant endocrine therapy remains an unmet clinical need.
Luijendijk, Maryse J., et al. “Effects of tamoxifen on cognitive function in patients with primary breast cancer.” British Journal of Cancer (2024): 1-8.
Fardell, Joanna E., et al. “Cognitive function among women with breast cancer receiving endocrine therapy: what are the impacts?.” JNCI Cancer Spectrum 7.2 (2023): pkad026.
Abdallah, Ichrak Ben, et al. “Cognitive complaints during breast cancer endocrine therapy: aromatase inhibitors versus tamoxifen.” BMJ Supportive & Palliative Care 14.e2 (2024): e1954-e1959.
Ilhan, Rukiye Guler, et al. “The effect of using adjuvant aromatase inhibitors on cognitive functions in postmenopausal women with hormone receptor-positive breast cancer.” Journal of Cancer Research and Therapeutics 19.Suppl 1 (2023): S368-S372.
Sharma, Saryu, and Heather Harris Wright. “Tamoxifen Effects on Cognition and Language in Women with Breast Cancer.” Seminars in Speech and Language. Vol. 44. No. 03. Thieme Medical Publishers, Inc., 2023.
Taguchi, Tetsuya, et al. “Osteoporotic fracture risk in women with breast cancer treated with aromatase inhibitors: a health insurance claims database study in Japan.” Expert Opinion on Pharmacotherapy 25.3 (2024): 325-334.
Martin, Hilary, and Andrew Redfern. “Bone mineral density fall during aromatase inhibitor treatment may predict lower breast cancer recurrence.” Cancer Medicine 13.1 (2024): e6846.
Rezaeianzadeh, Ramin. Risk of dry eye disease with aromatase inhibitors among women with breast cancer: a retrospective cohort study. Diss. University of British Columbia, 2024.
Karaboyun, Kubilay, et al. “Tamoxifen or aromatase inhibitors: which one is the culprit of urinary incontinence in premenopausal breast cancer patients receiving adjuvant hormone therapy?.” Supportive Care in Cancer 31.6 (2023): 330.
Alfaris, Ibrahim, et al. “The cardiovascular risks associated with aromatase inhibitors, tamoxifen, and GnRH agonists in women with breast cancer.” Current atherosclerosis reports 25.4 (2023): 145-154.
Lund, Marie, et al. “Ischaemic cardiotoxicity of aromatase inhibitors in postmenopausal patients with early breast cancer in Denmark: a cohort study of real-world data.” The Lancet Oncology 25.11 (2024): 1496-1506.
Ho, Isaac, et al. “Aromatase inhibitor therapy increases the risk of new-onset atrial fibrillation in patients with breast cancer.” JACC: Asia 4.2 (2024): 150-160.
Hiasa, Yu, et al. “Impact of Aromatase Inhibitors Treatment Duration on Coronary Artery Calcification in Postoperative Patients With Breast Cancer.” Canadian Journal of Cardiology (2024).
Gue, Ying, et al. “The cardiovascular and metabolic effects of ovarian suppression in combination with tamoxifen or an aromatase inhibitor as adjuvant therapy for early estrogen receptor-positive breast cancer: a systematic review.” Archives of Medical Science.
Polter, Elizabeth J., et al. “Cardiovascular Disease With Hormone Therapy and Ovarian Suppression in Premenopausal Breast Cancer Survivors.” JACC: CardioOncology (2024).
Feng, Zhao Xun, et al. “Risk of ocular adverse events with aromatase inhibitors.” Canadian Journal of Ophthalmology 59.5 (2024): e431-e434.
Bhakhri, Raman, et al. “Tamoxifen Retinopathy: Retinal cavitation without crystalline deposits.” Canadian Journal of Optometry 85.2 (2023): 45-51.
Simoncini, Tommaso, et al. “Menopausal symptom burden and quality of life in women with breast cancer on endocrine adjuvant therapy: findings from the REALISE study.” Maturitas 173 (2023): 80.
Ghanavati, Matin, et al. “Tamoxifen use and risk of endometrial cancer in breast cancer patients: A systematic review and dose–response meta‐analysis.” Cancer Reports 6.4 (2023): e1806.
Wilson, Kalin L., et al. “Aromatase inhibitor-induced arthralgia ameliorated by Mediterranean diet and active lifestyle guided by continuous glucose monitoring: a case report and review of the literature.” Frontiers in Oncology 14 (2024): 1189287.
Christensen Holz, Sara. “Aromatase inhibitor musculoskeletal syndrome and bone loss: a review of the current literature.” Current Oncology Reports 25.7 (2023): 825-831.
Kim, Sara, Nan Chen, and Pankti Reid. “Current and future advances in practice: aromatase inhibitor–induced arthralgia.” Rheumatology Advances in Practice 8.2 (2024): rkae024.
Molinelli, Chiara, et al. “Ovarian suppression: early menopause and late effects.” Current Treatment Options in Oncology 25.4 (2024): 523-542.
Despite its efficacy, ovarian function suppression may lead to several side effects that can have a major negative impact on patients’ quality of life if not properly managed (e.g. hot flashes, depression, cognitive impairment, osteoporosis, sexual dysfunction, weight gain).
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Tamoxifen, sold under the brand name Nolvadex
Serious side effects include a small increased risk of uterine cancer, stroke, vision problems, and pulmonary embolism.[14] Common side effects include irregular periods, weight loss, and hot flashes.[14]
With time, risk of endometrial cancer may be doubled to quadrupled, which is a reason tamoxifen is typically only used for five years.[50]
The American Cancer Society lists tamoxifen as a known carcinogen, stating that it increases the risk of some types of uterine cancer while lowering the risk of breast cancer recurrence.[51]
there is an increased risk of thromboembolism especially during and immediately after major surgery or periods of immobility.[53] Use of tamoxifen has been shown to slightly increase risk of deep vein thrombosis, pulmonary embolism, and stroke.[54]
Liver toxicity
Tamoxifen has been associated with a number of cases of hepatotoxicity.[55] Several different varieties of hepatotoxicity have been reported.[55] Tamoxifen can also precipitate non-alcoholic fatty liver disease in obese and overweight women (not in normal weight women) at an average rate of 40% after a year use with 20 mg/day.[56]
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4.4-fold(95% CI: 1.03 to 19.0) increased risk of ER− contralateral breast cancer.
Long-term tamoxifen use increases the risk of an aggressive, difficult to treat type of second breast cancer …Study finds a more than four-fold increased risk of ER negative second cancers SEATTLE — Aug. 25, 2009
Li, Christopher I., et al. “Adjuvant Hormonal Therapy for Breast Cancer and Risk of Hormone Receptor–Specific Subtypes of Contralateral Breast Cancer.” Cancer research 69.17 (2009): 6865-6870.
We conducted a population-based nested case-control study including 367 women diagnosed with both first primary estrogen receptor (ER) positive invasive breast cancer and second primary contralateral breast cancer and 728 matched control women diagnosed only with a first breast cancer.
Compared to women not treated with hormonal therapy, users of adjuvant tamoxifen for ≥5 yearshad a reduced risk of ER+ contralateral breast cancer [odds ratio = 0.4, 95% confidence interval (CI) = 0.3 to 0.7], but a 4.4-fold(95% CI: 1.03 to 19.0) increased risk of ER− contralateral breast cancer. Tamoxifen use for <5 years was not associated with ER− contralateral breast cancer risk.
Vogel, Victor G., et al. “National surgical adjuvant breast and bowel project update: prevention trials and endocrine therapy of ductal carcinoma in situ.” Clinical cancer research 9.1 (2003): 495s-501s.
Women in the tamoxifen group had fewer breast cancer events at 5 years than did those on placebo (8.2% versus 13.4%, P = 0.0009)
Pan, Hsiang-Ju, Hong-Tai Chang, and Chien-Hung Lee. “Association between tamoxifen treatment and the development of different stages of nonalcoholic fatty liver diseaseamong breast cancer patients.” Journal of the Formosan Medical Association 115.6 (2016): 411-417.
Yoo, Jeong-Ju, et al. “Risk of fatty liver after long-term use of tamoxifen in patients with breast cancer.” PloS one 15.7 (2020): e0236506.
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Written by: Jon Barron September 12, 2009 Tamoxifen Ups The Risk of Breast Cancer
long-term use of tamoxifen ups the risk of getting aggressive cancer in the other breast by 440 percent.
The study followed 1100 women aged 40-79 who received treatment for estrogen-receptive breast cancer between 1990 and 2005. Those who took tamoxifen were 60 percent less likely to develop estrogen-dependent breast cancer in the other breast compared to those not taking the drug. But those women who took the drug for more than five years, as already mentioned, had a hugely increased risk of developing estrogen-negative tumors. The study did not include women who took the drug long-term to prevent breast cancer in the first place. If it had included that group, the risk most likely would reflect far higher numbers.
The tumors appeared in only 14 of the 358 women treated for longer than five years. But, two troublesome key points make those arguments look lame. First, tamoxifen causes life-threatening problems other than breast cancers.
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Also, studies have found that while tamoxifen may prevent estrogen-dependent breast tumors, it does very little, if anything, to prolong life expectancy, at least when used as a cancer preventative.
First, the other health problems associated with tamoxifen include blood clots, strokes, uterine cancer (about double the risk), ovarian cancer, liver cancer, gastrointestinal cancers, and cataracts among them, as well as the usual chemotherapy discomforts — nausea, vomiting, headaches and so on
A huge study of 13,000 women by the National Cancer Institute back in the 1990’s found that while tamoxifen did indeed cut “the incidence” of breast cancer by 30-50 percent in the high-risk group of women who took it as a preventative, seven years into the follow-up, women in the no-tamoxifen control group had fewer deaths from breast cancer than those in the tamoxifen group — marginally fewer, but fewer none-the-less.-
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Primary Prevention Study:
Women (N=13388) at increased risk for breast cancer because they
1) were 60 years of age or older,
2) were 35-59 years of age with a 5-year predicted risk for breast cancer of at least 1.66%, or
3) had a history of lobular carcinoma in situ
were randomly assigned to receive placebo (n=6707) or 20 mg/day tamoxifen (n=6681) for 5 years. Gail’s algorithm, based on a multivariate logistic regression model using combinations of risk factors, was used to estimate the probability (risk) of occurrence of breast cancer over time.
Results: Tamoxifen reduced the risk of invasive breast cancer by 49% (two-sided P<.00001), with cumulative incidence through 69 months of follow-up of 43.4 versus 22.0 per 1000 women in the placebo and tamoxifen groups, respectively. The decreased risk occurred in women aged 49 years or younger (44%), 50-59 years (51%), and 60 years or older (55%); risk was also reduced in women with a history of lobular carcinoma in situ (56%) or atypical hyperplasia (86%) and in those with any category of predicted 5-year risk. Tamoxifen reduced the risk of noninvasive breast cancer by 50% (two-sided P<.002). Tamoxifen reduced the occurrence of estrogen receptor-positive tumors by 69%, but no difference in the occurrence of estrogen receptor-negative tumors was seen.
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The National Cancer Institute’s Breast Cancer Prevention Trial reported that there was a 49 percent decrease in the incidence of breast cancer in women who took tamoxifen for four to five years.” That’s stunning. If your doctor told you that using tamoxifen cut your chances of getting breast cancer by 49%, would there be any question in your mind on whether or not to use it? But if you look past the statistics, the truth is that according to the study, your odds of getting breast cancer without using tamoxifen were only 1.3%. With tamoxifen it dropped to .68%. And yes, that could be represented as a 49% difference between the two numbers. But the reality is we’re talking about a difference of just 86 women out of 13,388, or just a little over one-half of one-percent (0.64%) in real terms.
If you already have breast cancer, it’s your call whether or not to take on the risks tamoxifen brings. On the other hand, if you’re going the mainstream medical route, you may want to consider the fact that aromatase inhibitors beat tamoxifen in terms of survival rates,plus they have far fewer side effects. The only proviso here is that these drugs work only for post-menopausal women, and they cost more than tamoxifen.
Dr. Li just released the results of another study a few days ago that found that a simple change in diet can drop your risk of breast cancer by 40%. That makes it virtually as effective as tamoxifen, but with only beneficial side effects.
Message Board
I’m on tamoxifen for 2 years 2 months now. I feel tired all the time. My joints ache all the time. My memory sucks and just feel bad all the time. I don’t know if I should stop it or take it 2 1/2 years more. Please give me some suggestions. Thanks
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111 women Pilot Breast Cancer Prevention Trial at the Royal Marsden Hospital
Kedar, R. P., et al. “Effects of tamoxifen on uterus and ovaries of postmenopausal women in a randomised breast cancer prevention trial.” The Lancet 343.8909 (1994): 1318-1321.
Randomised, double-blind controlled trials have been started to determine whether tamoxifen can prevent or delay development of breast cancer in healthy women with a family history of the disease. We recruited a randomised cohort of 111 postmenopausal women (aged 46-71 years) from the Pilot Breast Cancer Prevention Trial at the Royal Marsden Hospital to study the effect of tamoxifen on the uterus and ovaries. The main outcome measures were obtained by transvaginal ultrasonography with colour doppler imaging and microscopic examination of endometrial biopsies removed at the time of the scan. There was no significant difference between tamoxifen (20 mg/day) and placebo groups in the age of the women, or the time of the scan (and sampling) after randomisation. Women taking tamoxifen had a significantly larger uterus and a lower impedance to blood flow in the uterine arteries. 39% of women taking tamoxifen had histological evidence of an abnormal endometrium compared with 10% in the control group. 10 patients in the tamoxifen group (16%) had atypical hyperplasia and another 5 (8%) had a polyp. Women with a histological abnormality had a significantly thicker endometrium and a decreased impedance to blood flow in the uterine arteries. There was no correlation between the presence of uterine abnormalities and the age of the women, or the concentrations of tamoxifen or desmethyl tamoxifen in the peripheral blood. These findings confirm that tamoxifen can cause potentially malignant changes in the endometrium of postmenopausal women. Transvaginal ultrasonography can be used to identify those women who should have endometrial samples removed for microscopic analysis.
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Carthew, Philip, et al. “Tamoxifen induces endometrial and vaginal cancer in rats in the absence of endometrial hyperplasia.” Carcinogenesis 21.4 (2000): 793-797.
Martin, E. A., et al. “32P-postlabelled DNA adducts in liver obtained from women treated with tamoxifen.” Carcinogenesis 16.7 (1995): 1651-1654.
Boocock, David J., et al. “α-Hydroxytamoxifen, a genotoxic metabolite of tamoxifen in the rat: identification and quantification in vivo and in vitro.” Carcinogenesis 20.1 (1999): 153-160.
White, Ian NH. “The tamoxifen dilemma.” Carcinogenesis 20.7 (1999): 1153-1160.
Phillips, David H., et al. “α-Hydroxytamoxifen, a metabolite of tamoxifen with exceptionally high DNA-binding activity in rat hepatocytes.” Cancer Research 54.21 (1994): 5518-5522.
Gary, Williams M., et al. “The triphenylethylene drug tamoxifen is a strong liver carcinogen in the rat.” Carcinogenesis 14.2 (1993): 315-317.
Hirsimäki, Pirkko, et al. “Tamoxifen induces hepatocellular carcinoma in rat liver: a 1-year study with two antiestrogens.” Archives of toxicology 67 (1993): 49-54.
Dragan, Yvonne P., et al. “Studies of tamoxifen as a promoter of hepatocarcinogenesis in female Fischer F344 rats.” Breast cancer research and treatment 31 (1994): 11-25.
Greaves, Peter, et al. “Two-year carcinogenicity study of tamoxifen in Alderley Park Wistar-derived rats.” Cancer Research 53.17 (1993): 3919-3924.
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Ritter, Andreas, et al. “Cancer-educated mammary adipose tissue-derived stromal/stem cells in obesity and breast cancer: spatial regulation and function.” Journal of Experimental & Clinical Cancer Research 42.1 (2023): 35.
Breast adipose tissue-derived mesenchymal stromal/stem cells (bASCs) are crucial components of the tumor microenvironment. A key step initially involved in this process might be the de-differentiation of bASCs into tumor supporting phenotypes.
isolated bASCs from adipose tissues adjacent to the tumor (aT bASCs) from lean- (ln-aT bASCs, BMI ≤ 25) and breast cancer patients with obesity (ob-aT bASCs, BMI ≥ 35), and analyzed their phenotypes with functional assays and RNA sequencing, compared to their counterparts isolated from adipose tissues distant from the tumor (dT bASCs).
We show that ln-aT bASCs are susceptible to be transformed into an inflammatory cancer-associated phenotype, whereas ob-aT bASCs are prone to be cancer-educated into a myofibroblastic phenotype. Both ln-aT- and ob-aT bASCs compromise their physiological differentiation capacity, and upregulate metastasis-promoting factors. While ln-aT bASCs stimulate proliferation, motility and chemoresistance by inducing epithelial-mesenchymal transition of low malignant breast cancer cells, ob-aT bASCs trigger more efficiently a cancer stem cell phenotype in highly malignant breast cancer cells.
We show that ln-aT bASCs are susceptible to be transformed into an inflammatory cancer-associated phenotype, whereas ob-aT bASCs are prone to be cancer-educated into a myofibroblastic phenotype. Both ln-aT- and ob-aT bASCs compromise their physiological differentiation capacity, and upregulate metastasis-promoting factors. While ln-aT bASCs stimulate proliferation, motility and chemoresistance by inducing epithelial-mesenchymal transition of low malignant breast cancer cells, ob-aT bASCs trigger more efficiently a cancer stem cell phenotype in highly malignant breast cancer cells.
Tiwari, Payal, et al. “Metabolically activated adipose tissue macrophages link obesity to triple-negative breast cancer.” Journal of Experimental Medicine 216.6 (2019): 1345-1358.
Obesity is associated with increased incidence and severity of triple-negative breast cancer (TNBC); however, mechanisms underlying this relationship are incompletely understood. Here, we show that obesity reprograms mammary adipose tissue macrophages to a pro-inflammatory metabolically activated phenotype (MMe) that alters the niche to support tumor formation. Unlike pro-inflammatory M1 macrophages that antagonize tumorigenesis, MMe macrophages are pro-tumorigenic and represent the dominant macrophage phenotype in mammary adipose tissue of obese humans and mice. MMe macrophages release IL-6 in an NADPH oxidase 2 (NOX2)–dependent manner, which signals through glycoprotein 130 (GP130) on TNBC cells to promote stem-like properties including tumor formation.
Yang, Zihui, et al. “Dissecting the emerging role of cancer-associated adipocyte-derived cytokines in remodeling breast cancer progression.” Heliyon 10.15 (2024).
Adipocytes, serving as energy storage and endocrine cells, are the major stromal cells in the breast. Cancer-associated adipocytes (CAAs) are adjacent and dedifferentiated adipocytes located at the invasive front of human breast tumors. Adipocytes can transform into CAA phenotype with morphological and biological changes under the remodeling of breast cancer cells. CAAs play an essential role in breast cancer progression, including remodeling the tumor microenvironment (TME), regulating immunity, and interacting with breast cancer cells. CAAs possess peculiar secretomes and are accordingly capable to promote proliferation, invasiveness, angiogenesis, metastasis, immune escape, and drug resistance of breast cancer cells. There is a complex and coordinated crosstalk among CAAs, immune cells, and breast cancer cells. CAAs can release a variety of cytokines, including IL-6, IL-8, IL-1β, CCL5, CCL2, VEGF, G-CSF, IGF-1, and IGFBP, thereby promoting immune cell recruitment and macrophage polarization, and ultimately stimulating malignant behaviors in breast cancer cells.
Pascuzzi, Nicholas, et al. “Recent Breakthroughs in Breast Cancer Endocrinology and Tumor Microenvironmental Interactions.” (2024).
As reported by the National Cancer Institute in 2024, approximately 310,720 new breast cancer cases and 42,250 related deaths occurred in the United States [3].
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references added from Laptop below this
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CROSSTALK AR and ER
!!!!!!!!!!!!!!!!!! SUPER BEST !!!!!!!!!!!!!!!!!!!!!!!!!!!
This Explains why blocking AR’s with Norethisterone triple Breast cancer risk in tamoxifen treate pts in the HABITS trial
(duplicate)
Tien, Amy H., and Marianne D. Sadar. “Treatments Targeting the Androgen Receptor and Its Splice Variants in Breast Cancer.” International Journal of Molecular Sciences 25.3 (2024): 1817.
The first case of breast cancer was recorded approximately 3500 years ago in 1600 BC, when the ancient Egyptians noted lumps spreading across the breast [1]. Today, female breast cancer is the most commonly diagnosed cancer worldwide, with approximately 2.26 million cases [ 2]. Fortunately, the survival rate for breast cancer has improved primarily due to early detection and more effective treatment options. The 5-year relative survival rate for female breast cancer was approximately 89% in the United States from 2012 to 2018.
However, the relative survival rate drops to only 28% if the disease disseminates to form distant metastases [ 3]. This poor survival rate emphasizes the need for better treatment options for metastatic disease.
In the search for the development of alternative targeted therapies for breast cancer, it was discovered that the closely related androgen receptor (AR) can be detected in the majority of all types of breast cancers [5]
to date, there is no approved AR targeting therapy for breast cancer, which is largely considered to be due to inadequate patient selection criteria for clinical trials. In addition, currently, the clinical significance of AR expression and its biological functions, as well as the reliance on cross-talk between the AR, ERα, and other molecules, remains controversial [8,9].
4.2. AR Role in ERα-Positive Breast Cancer
The analysis of 19 published studies revealed AR expression in about 75% of ERα- positive breast cancer and approximately 32% of ERα-negative breast cancer [50 ]. In ERα-positive breast cancer,higher levels of nuclear AR protein are usually correlated with improved outcomes and better survival regardless of treatments.The prognostic value of AR in ERα-positive breast cancer has been demonstrated in many studies.
4.3. Elevated Levels of Androgen in Breast Cancer
Androgens, testosterone, and DHT are physiological ligands for the AR. Testosterone is reduced to DHT by 5α-reductase enzymes. In breast tissue, it is the 5α-reductase type 1 isoform that is primarily responsible for the conversion of testosterone to DHT [ 61 ]. DHT has a much stronger affinity for AR compared to testosterone. DHT concentrations are elevated (three-fold higher) in tissues of DCIS and breast carcinoma compared to non-neoplastic tissues[62 ]. The expression levels of 5α-reductase are elevated, and its activity is 4–8 times higher in breast carcinoma tissues than in non-neoplastic tissues [ 63 , 64]. The expression levels of specific isoforms of 5α-reductase have been correlated to lymph node metastases and shorter OS of breast cancer patients, with levels of 5α-reductase 1 negatively correlated to histological grade and tumor size [63,65].
!!!!!!!!!!!!!!!!!!!!! DHT elevated in Response to AIs !!!!!!!!!!!!!!!!!
The levels of DHT or testosterone are also elevated (2.3-for cancer tissues and breast cancer models in response to aromatase inhibitors [66, 67 ].
66. Spinola, P.G.; Marchetti, B.; Merand, Y.; Belanger, A.; Labrie, F. Effects of the aromatase inhibitor 4-hydroxyandrostenedione and the antiandrogen flutamideon growth and steroid levels in DMBA-induced rat mammary tumors. Breast Cancer Res. Treat. 1988, 12, 287–296. [CrossRef] [PubMed]
67. Takagi, K.; Miki, Y.; Nagasaki, S.; Hirakawa, H.; Onodera, Y.; Akahira, J.; Ishida, T.; Watanabe, M.; Kimijima, I.; Hayashi, S.; et al.
Increased intratumoral androgens in human breast carcinoma following aromatase inhibitor exemestane treatment. Endocr. Relat.
Cancer 2010, 17, 415–430.
Intratumoral DHT concentration was significantly higher in breast carcinoma tissues following exemestane treatment (nZ9) than those without the therapy (nZ7), and 17b-hydroxysteroid dehydrogenase type 2 (17bHSD2) status was significantly altered to be positive after the treatment. Following
in vitro studies showed that 17bHSD2 expression was dose dependently induced by both DHT and exemestane in T-47D breast carcinoma cells, but these inductions were not additive. DHT-mediated induction of 17bHSD2 expression was markedly suppressed by estradiol (E 2) in T-47D cells.
E2-mediated cell proliferation was significantly inhibited by DHT in T-47D cells, associated with an increment of 17bHSD2 expression level. These findings suggest that intratumoral androgen actions are increased during exemestane treatment.
17bHSD2 is a potent DHT-induced gene in human breast carcinoma, and may not only be involved in anti-proliferative effects of DHT on breast carcinoma cells but also serve as a potential marker for response to aromatase inhibitor in the breast carcinoma patients
receptors increase when hormone is deficient….
68. Fujii, R.; Hanamura, T.; Suzuki, T.; Gohno, T.; Shibahara, Y.; Niwa, T.; Yamaguchi, Y.; Ohnuki, K.; Kakugawa, Y.; Hirakawa, H.;
et al. Increased androgen receptor activity and cell proliferation in aromatase inhibitor-resistant breast carcinoma. J. Steroid
Biochem. Mol. Biol. 2014, 144 Pt B, 513–522. [CrossRef]
Continue………..
Aromatase is the enzyme that converts testosterone to estrogens. The gene expression analyses of breast cancer tissue from patients neoadjuvant treated with the aromatase inhibitor exemestane revealed that approximately one-half of the 610 androgen-induced genes examined were increased in response to blocking aromatase activity[67 ]. Consistent with these data, the expression levels of the androgen-induced gene, KLK3, or prostate-specific antigen were increased in aromatase-resistant breast cancer tissues [ 68 ].
AR expression also increases with neoadjuvant treatment with aromatase inhibitors[69 ]. Together, these studies point to an altered hormone milieu in response to treatments and emphasize the need to examine the levels of the enzymes involved in the androgen pathway in addition to the levels of AR proteins
On the other hand, a study by Hickey and colleagues demonstrated that AR behaves as a tumor suppressor in ERα-positive breast cancer [ 71 ]. They showed that AR transactivation with androgen inhibited ER-driven cell proliferation in an ex vivo patient-derived explant model. Using breast cancer cell lines, they also showed that AR was detected at 42% of estrogen-stimulated ER-binding sites on chromatin when both AR and ER were activated.
This suggests that AR could directly affect ER transcriptional activity by redistributing ER. Interestingly, the binding or recruitment of coactivators p300 and SRC-3, which are required for ER signaling, were both reduced and replaced by AR upon AR activation. This led to the repression of ER-regulated cell cycle genes and the inhibition of tumor cell proliferation. Thus, AR activation suppressed ER signaling in ERα-positive breast cancer cells.
In this case, the activation of AR, rather than its inhibition, would be the more suitable treatment option for patients with ERα-positive breast cancer when AR behaves as a tumor suppressor. These data support the application of androgenic compounds such as the nonsteroidal selective AR modulator (SARM) enobosarm, which decreases the growth of some ERα-positive breast cancers [ 72 ], and they form the rationale for the clinical testing of SARMs for the treatment of some breast cancers.
Patients with TNBC usually have larger and more aggressive tumors, leading to poor clinical outcomes [ 42 ,44 ]. Although TNBC patients respond to chemotherapy, they commonly develop distant recurrence and metastases [78]. TNBC tumors account for 10–20% of all breast cancers
luminal AR (LAR). The LAR subgroup represents a range of 11–22% of TNBC depending on the popula-tion studied and analysis methods and is classified based on the luminal gene expression pattern [78 ,80]. The LAR subgroup is particularly sensitive to antiandrogens. In this sub- group, AR behaves as an oncogenic driver for tumor cell proliferation, and tumors have a high expression of FOXA1, XBP1, and KRT18 [78].
Clinical trials in TNBC have tested, or are currently testing, combinations of AR antagonists with PI3K inhibitors (NCT02457910 [86] and NCT03207529)
AR has distinct roles in different subtypes of breast cancers. In ER-positive breast cancer, AR behaves as a tumor suppressor, with its function being opposite to ER.
In HER2-amplified breast cancer, AR behaves as the oncogenic driver instead of ER. AR also acts as an oncogenic driver in AR-positive TNBC.
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Paakinaho, Ville, and Jorma J. Palvimo. “Genome-wide crosstalk between steroid receptors in breast and prostate cancers.” Endocrine-Related Cancer 28.9 (2021): R231-R250.
The TNBC is usually treated with chemotherapy; however, as highlighted in the next sections, in addition to ER and PR, other SRs could be considered as potential and alternative targets of therapy.
Interestingly, in ER+ BCa cells, the genome-wide binding of GR to chromatin is similar to that of ER, while AR binds in a similar manner as PR (Kittler et al. 2013). Furthermore, in male and female BCa patients, AR, PR, and GR have been shown to occupy ER-binding chromatin sites (Severson et al. 2018).
Historically, PR expression in BCa has been used as a proxy for the function of ER in the disease. PGR encoding PR is a well-known E2-regulated gene, and its expression is thought to reflect the transcriptional activity of ER (Creighton et al. 2009, Siersbæk et al. 2018). Thus, both receptors are expressed at a similar frequency of ~50–80% in all BCa cases although the PR is not expressed in all ER+BCa patients, the actual percentage is around 75% (McGuire et al. 1978, Swinstead et al. 2018).
Recently, PR has been suggested to play a more prominent role in BCa rather than being a mere diagnostic marker (Carroll et al. 2017). In 2015, the Carroll laboratory reported that the activation of PR by progesterone could reprogram the chromatin occupancy of ER in a BCa cell line (Mohammed et al. 2015). This reprogramming resulted in thousands of new ER-binding sites not observed in BCa cells stimulated by E2 alone. Proteomic and motif analyses suggested that this had occurred through tethering of ER to chromatin-bound PR (Fig. 1A).
!!!!!!!!!!!!!!!!!!!! important !!!!!!!!!!!!!!!!!!!!!!
Interestingly, the activation of PR decreased ER-driven proliferation and blocked tumor growth. This suggests that instead of being a mere marker of functional ER in BCa, the PR is a major determinant of ER-driven gene programs in BCa.
In addition to influencing the progression of BCa in cell and animal models, the status of PR correlates with patient survival (Table 1).
The loss of PR expression in ER+ BCa decreases patient survival, whereas patients who have ER+ and PR+ BCa show increased survival compared to PR+ and ER- patients. Due to the evident importance of PR activity in BCa survival, clinical trials are being conducted to assess the influence of a PR agonist in the treatment of ER+ BCa (NCT03306472, NCT03024580).
The AR is expressed in ~80% of BCa cases (McNamara et al. 2014), with a high expression of AR in ER+ BCa patients correlating with a better survival(Table 2). However, this is not the case in ER− BCa patients (Peters et al. 2009). AR interestingly regulates the same transcriptional programs in molecular apocrine BCa (AR+TNBC) cells as ER in luminal BCa cells (Robinson et al. 2011, McNamara et al. 2014). Thus, AR has been recognized as a potentially valuable drug target in TNBC, as its inhibition could offer an alternative form of therapy(McNamara et al. 2014, Gerratana et al. 2018). Moreover, the AR’s value as a drug target is strengthened by the concept that the molecular apocrine BCa and castration-resistant PCa (CRPC) cells share a core AR cistrome and target gene signature linked to cancer cell growth (Malinen et al. 2015). However, a recent study indicated that AR+ TNBC displayed heterogeneity in AR levels, which influenced AR-targeted therapy in combination with cell cycle inhibitors (Christenson et al. 2021).
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These results suggest that in the presence of the ER, the AR could suppress BCa cell growth, whereas the AR could promote it in the absence of ER.
Although a high expression level of AR has been associated with increased survival of ER+ BCa patients, the Richer group found that inhibition of AR by enzalutamide (ENZ) (a second generation antiandrogen) decreased BCa cell proliferation and tumor size (D’Amato et al. 2016). Interestingly, these investigators showed that ER and AR could bind to the same genomic sites and that ENZ-inhibited chromatin binding not only of the AR but also the ER (Fig. 2A). These results suggest that the AR supports the chromatin-binding of ER, influencing BCa cell proliferation and tumor growth.
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In clinical trials, a combination of bicalutamide (first generation antiandrogen) with AI did not, however, confer any clinical benefit (NCT02910050) in ER+ and AR+ BCa patients, but a clinical trial combining fulvestrant (ER degrader) and ENZ is underway (NCT02953860).
A later study suggested that a selective AR modulator (SARM)/agonist, rather than ENZ, would be capable of inhibiting ER+ BCa tumor growth (Ponnusamy et al. 2019).
In confirmation, a more recent investigation indicated a redistribution of ER occupancy and the inhibition of ER-induced BCa proliferation upon AR activation with an agonist (Hickey et al. 2021).
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estrogen alone use significantly reduces breast cancer incidence
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Chlebowski, Rowan T., et al. “Randomized trials of estrogen-alone and breast cancer incidence: a meta-analysis.” Breast Cancer Research and Treatment (2024): 1-8.
In the Women’s Health initiative (WHI) randomized clinical trial, conjugated equine estrogen (CEE)-alone significantly reduced breast cancer incidence (P = 0.005). As cohort studies had opposite findings, other randomized clinical trials were identified to conduct a meta-analysis of estrogen-alone influence on breast cancer incidence.
Methods
We conducted literature searches on randomized trials and: estrogen, hormone therapy, and breast cancer, and searches from a prior meta-analysis and reviews. In the meta-analysis, for trials with published relative risks (RR) and 95% confidence intervals (CI), each log-RR was multiplied by weight = 1/V, where V = variance of the log-RR, and V was derived from the corresponding 95% CI. For smaller trials with only breast cancer numbers, the corresponding log-RR = (O – E)/weight, where O is the observed case number in the oestrogen-alone group and E the corresponding expected case number, E = nP.
Results
Findings from 10 randomized trials included 14,282 participants and 591 incident breast cancers. In 9 smaller trials, with 1.2% (24 of 2029) vs 2.2% (33 of 1514) randomized to estrogen-alone vs placebo (open label, one trial) (RR 0.65 95% CI 0.38–1.11, P = 0.12).
For 5 trials evaluating estradiol formulations, RR = 0.63 95% CI 0.34–1.16, P = 0.15. Combining the 10 trials, 3.6% (262 of 7339) vs 4.7% (329 of 6943) randomized to estrogen-alone vs placebo (overall RR 0.77 95% CI 0.65–0.91, P = 0.002).
Conclusion
The totality of randomized clinical trial evidence supports a conclusion that estrogen-alone use significantly reduces breast cancer incidence.
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Endogenous estrogen is an excellent therapy against breast cancer as facilitates self directed death of tumor cells and strengthens the immune defense against cancer. Using natural estrogen even is high doses and stimulation of estrogen receptor expression is the adequate therapy of breast cancer.
professor Zsuzsanna Suba
National Institute of Oncology Budapest
From: Estrogen Regulated Genes Compel Apoptosis in Breast Cancer Cells, Whilst Stimulate ntitumor Activity in Peritumoral Immune Cells in a Janus-Faced Manner
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Mortality Reduction of Anti-Estrogen Treatment in early stage breast cancer
Qian, Jingjing, and Bang Truong. “Initiation of Oral Endocrine Therapy and Survival Benefit Among Women with Early-Stage Breast Cancer.” Journal of Women’s Health 33.11 (2024): 1509-1517.
This observational study assessed ET initiation and 1-year adherence and its survival benefit among female Medicare beneficiaries with early-stage breast cancer.
This retrospective cohort study analyzed the linked 2011–2019 Surveillance, Epidemiology, and End Results-Medicare data. Female beneficiaries newly diagnosed with hormone receptor positive, stage I-III breast cancer were included. Beneficiaries who initiated tamoxifen, anastrozole, letrozole, or exemestane within 3 months after cancer diagnosiswere defined as initiators (n = 24,289), and those who never initiated these treatments were noninitiators (n = 8,899). Adherence was measured using proportion of days covered (PDC) in the continuous 12 months follow-up period.
Results: Among eligible female beneficiaries (n = 55,893), 43% initiated ET within 3 months of cancer diagnosis. Among initiators, 77% had PDC ≥ 80% during the first year. Patient’s demographics (e.g., older age, race/ethnicity) and baseline health services utilization (e.g., mammography) were associated with ET initiation and adherence. ET initiation and adherence was associated with [38 percent] reduced risk of all-cause (adjusted HR = 0.62, 0.59–0.66; HR = 0.55, 0.53–0.59; respectively) and [43 percent] breast cancer related (adjusted HR = 0.57, 0.50–0.64; HR = 0.41, 0.36–0.47; respectively) mortality compared with noninitiators.
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Anti-Estrogen Treatment Ineffective in BRCA Gene Carriers
In BRCA1 mutation carriers, at high ligefetime trisk for breast cancer, antiestrogen drugs are ineffective and potentially harmful. Gorski JJ, Kennedy RD, Hosey AM, Harkin DP. The complex relationship between BRCA1 and ERalpha in hereditary breast cancer. Clin Cancer Res. 2009;15(5):1514–1518.
Miller WR. Aromatase inhibitors: mechanism of action and role in the treatment of breast cancer. Semin Oncol. 2003;30:3–11.
Narod, Steven A., et al. “Tamoxifen and risk of contralateral breast cancer in BRCA1 and BRCA2 mutation carriers: a case-control study.” The Lancet 356.9245 (2000): 1876-1881.
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Tien, Amy H., and Marianne D. Sadar. “Treatments Targeting the Androgen Receptor and Its Splice Variants in Breast Cancer.” International Journal of Molecular Sciences 25.3 (2024): 1817.
In ER-positive breast cancer, AR behaves as a tumor suppressor, with its function being opposite to ER. In HER2-amplified breast cancer, AR behaves as the oncogenic driver instead of ER. AR also acts as an oncogenic driver in AR-positive TNBC.
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objective response rate at 6 months Zero. The median PFS was 2.7 months.
Lu, Qianyi, et al. “Bicalutamide plus aromatase inhibitor in patients with estrogen receptor‐positive/androgen receptor‐positive advanced breast cancer.” The Oncologist 25.1 (2020): 21-e15.
Bicalutamide, one of the commonly used AR inhibitors in prostate cancer, in combination with AI, did not show synergistic activity in patients with estrogen receptor-positive and AI-resistant disease in this phase II, single-arm study. The clinical benefit rate and objective response rate at 6 months were 16.7% and 0%, respectively, and the study was terminated after the first stage.
A total of 19 patients enrolled in the first stage, and 18 patients met all criteria for analysis. The trial terminated according to protocol after the first stage. After a median follow-up of 14 months, the CBR at 6 months was 16.7% (3/18); no patients with partial or complete response were observed. The median PFS was 2.7 months. Bicalutamide in combination with AI was well tolerated.
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