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Archive for the ‘Alternatives to Anti-Hormone Therapy For Breast Cancer’ Category

Why Aromatase Inhibitors Fail Women

In Alternative Cancer Therapies, Alternatives to Anti-Hormone Therapy For Breast Cancer, Alternatives to Hormone Therapy for Breast Cancer, Alternatives to Tamoxifen, Breast Cancer, Tamoxifen, Uncategorized on November 13, 2017 at 5:27 am

Aromatase inhibitors fail when tumors outsmart them.  Researchers have long been studying how resistance to aromatase inhibitors (AIs) happens so that they can find a solution. The resistance effectively makes these drugs powerless, causing the cancer to return. One in every four or five women relapse within ten years of AI treatment and develop metastatic cancer. [i]

Estrogen plays an important role in the development of hormone-dependent breast carcinomas, or at least some estrogens do. While ovarian estrogen synthesis ceases at menopause, peripheral and local tissue’s aromatization of androgens to estrogens continues and becomes the main source of estradiol (the more cancer-promoting estrogen). What this means is that while your ovaries are no longer producing estrogen after menopause, and your adrenals are producing only a small amount, breast cancer cells may actually have a way to produce their own food supply.

Theoretically, the aromatase inhibitor could be reducing circulating estrogen to dangerously low levels, while estrogen in the breast, axillary, and belly could still be dangerously high. Hence, AIs fail the patient, who then suffers the ill-effects of the drugs with no benefit.

The Research

Until recently, scientists assumed the tumors developed resistance in some way, but didn’t know how. Scientists have now discovered why AIs may stop working in some patients. Research done at the Imperial College London and the European Institute of Oncology in Milan has found that some breast tumors evolve to make their own estrogen, rendering AIs ineffective. While the ovaries cease to produce estrogen after menopause, the hormone is still made in other tissues via the enzyme aromatase.[ii] The team, led by Dr Luca Magnani, found that in one in four patients taking AIs, the tumors had increased production of aromatase in the cancer cells. They found that the tumors were able to increase the number of aromatase genes via a process known as amplification.

So, while AIs work by cutting off the tumor’s fuel supply (estrogen), the cancer adapts by making its own –an efficient survival mechanism. The research points to a particular gene (CYP19A1).  When more copies of this gene are produced, it triggers the increased production of aromatase, the very enzyme the drugs are trying to block. This allows cancer cells to make their own estrogen and thus reproduce and spread.[iii] It seems to be a bit of a survival mechanism-the AI cuts off the food supply so the tumor outsmarts it by making its own.

We found that 21.5% of AI-treated, relapsed patients had acquired CYP19A1 (encoding aromatase) amplification (CYP19A1amp)…CYP19A1 amplification caused increased aromatase activity and estrogen-independent ERα binding to target genes, resulting in CYP19A1amp cells showing decreased sensitivity to AI treatment. These data suggest that AI treatment itself selects for acquired CYP19A1amp and promotes local autocrine estrogen signaling in AI-resistant metastatic patients.[iv]

When an aromatase inhibitor stops working, most oncologists will try another type of AI.  The problem is that if the cancer cells have started making their own aromatase, the second (or third) drug will be useless. Identifying the over-expression of the CYP19A1 may help doctors determine which women are not good candidates for AI therapy or who might be candidates for alternative therapies. The aforementioned researchers are now working on a test to identify whether a patient’s tumor has started to increase aromatase production, and make its own estrogen.

Dr. Magnani also suggested that when cancer returns, a biopsy should be done to see how the cancer has evolved, which may help guide treatment decisions. Often this can be helpful, but just as often, it fails to offer much information. This is a decision you need to make in consultation with your oncologist or other qualified professional.

Obesity Plays a Role

Excess body weight has been linked to an increased risk of postmenopausal breast cancer, and research also suggests that obesity is associated with poor prognosis in women diagnosed with early-stage breast cancer. Fat tissue contains the enzyme aromatase that converts hormones called androgens to estrogens. Human abdominal, breast, and axillary fat have the ability to convert androgens into estrogens.

So, heavier women end up with higher blood estrogen levels as well as enhanced local production of estrogen than leaner women. Elevated serum estrogen levels as well as enhanced local production of estrogen have been considered primary mediators of how increased body weight promotes breast cancer development in postmenopausal women.

On the Horizon

I have long been pointing out that most of have seriously declining levels of estrogen as we age –which has been found to compromise overall health. For this reason, AIs are quite dangerous as they block essential estrogen.

However, it has recently been reported that plasma estrogen levels do not necessarily reflect tissue estrogen concentrations. Several studies have found that tissue estrogen levels may be ten- to 20-fold higher compared to plasma levels in postmenopausal women. Furthermore, recent studies have demonstrated that a large proportion (close to 100%) of the biologically active estrogen is considered to be produced locally in the breast carcinoma after menopause.[v] Therefore, likely a more effective method would be to inhibit estrogen of breast tissue than that of systemic circulation. More studies need to be done on this.

At this point, studies are being conducted in China to see if a locally-applied aromatase-inhibiting patch using letrozole would be effective and offer a less toxic solution to the standard drug AIs.

As reported in AAPS PharmSCiTech (a Journal of the American Association of Pharmaceutical Scientists), a mouse study revealed that compared with oral administration, transdermal administration could produce high local drug concentrations and low circulating drug concentrations. This could reduce systemic side effects. Therefore, it might be a new option for breast cancer therapy to inhibit aromatase activity via transdermal patches for site-specific delivery of letrozole.

But again, more studies need to be done to determine if a local patch would be effective for cells outside the breast area, and independent studies should also be done (ones not paid for by a pharmaceutical company).

So, should women with estrogen receptor-positive breast cancer take inhibitors of estrogens? The decision of whether or not to use estrogen blockers is a complex one that each woman can only make if fully informed. The potential negative effects on the brain, heart, and overall quality and quantity of life, as well as treatment failure, should be weighed against the immediate risk of recurrence.

However, in making a treatment decision, it is most important to speak with an oncologist who is fully aware of the limitations and potential negative effects of these drugs and who is prepared to discuss alternative options. It is equally important to educate yourself on natural alternatives as typically these options are not discussed by medical doctors.

Important is to realize that in the presence of adequate progesterone, estrogen cannot easily fuel breast cancer tumors.[vi] Perhaps for now, a better solution is to make every effort to reduce aromatase activity and to increase production of progesterone.

Progesterone may also be the answer to why AIs seem to work for some.  I could postulate that the answer again might be progesterone, especially for those patients who are PR + as well as ER+, but that is just one possibility.

For more information regarding consideration of natural alternatives, please read:

Natural Alternatives to Hormone Therapy for Breast Cancer  

Why You May Want to Reconsider Estrogen-Blocking Aromatase Inhibitors and Tamoxifen 

* The CYP19A1 gene provides instructions for making an enzyme called aromatase. This enzyme converts a class of hormones called androgens, which are involved in male sexual development, to different forms of the female sex hormone estrogen. Mutations in this gene can result in either increased or decreased aromatase activity.

This information is for educational purposes only and is not a recommendation to forgo anti-hormone therapy. It is not intended to treat, cure, prevent, or diagnose any disease or condition. This post does not represent medical advice nor should it be considered to be medical advice or a replacement for medical advice.  I encourage you to discuss this information with your integrative oncologist, naturopathic doctor, or conventional oncologist and make your own decisions.  The information provided is from my research and not to be taken as scientific evidence. 

ej portrait 150resElyn

~~If you don’t know your options, you don’t have any~~

Elyn Jacobs is a breast cancer survivor and holistic cancer strategist who helps people make better, healthier, non-toxic choices. She emphasizes the critical nature of addressing the root cause of cancer and not just its presenting symptoms (such as the tumor). Elyn specializes in understanding the role of estrogen in breast cancer and debunks the myths associated. She is a Contributing Editor for The Truth About Cancer and was creator and host of the Survive and Live Well Radio Show on the Cancer Support Network. Elyn is on the Medical Advisory Board for BeatCancer.Org and is on the Advisory Board to the Radical Remission Project. Elyn was the former Executive Director of the Emerald Heart Cancer Foundation. Contact Elyn via her website. Elyn offers consults via Skype, phone or in person.

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[i] https://www.nature.com/articles/ng.3773   https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5326683/

[ii]

http://www3.imperial.ac.uk/newsandeventspggrp/imperialcollege/newssummary/news_23-1-2017-16-57-16

[iii] https://www.ncbi.nlm.nih.gov/pubmedhealth/behindtheheadlines/news/2017-01-24-new-insights-into-why-breast-cancer-drugs-fail-for-some-women/

[iv] https://www.nature.com/articles/ng.3773

[v] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2974128/

[vi]  http://ajcn.nutrition.org/content/45/1/277.short

 

Why You May Want to Reconsider Estrogen-Blocking Aromatase Inhibitors and Tamoxifen

In Alternatives to Anti-Hormone Therapy For Breast Cancer, Alternatives to Tamoxifen, Breast Cancer, Natural Alternatives to Aromatase Inhibitors, Uncategorized on November 7, 2017 at 9:50 am

The current oncological recommendations for anti-hormone therapy (endocrine therapy) for postmenopausal women with early-stage breast cancer vary. Some oncologists recommend aromatase inhibitors for five years, with tamoxifen to follow and some the reverse, and some just one or the other. However, the recommendations rarely take into consideration risk of prior cardiovascular disease history, cardiovascular disease risk, or overall risk of death when choosing between the different therapeutic options. (For premenopausal women, the standard is usually tamoxifen, with little attention to risk factors for blood clots, stroke, and endometrial cancer.)  Importantly, while both therapies can prolong disease-free survival, they don’t necessarily increase overall survival.

In the discussion of adjuvant endocrine therapy, doctors downplay the fact that aromatase inhibitors (AIs) are associated with musculoskeletal symptoms, heart damage, osteoporosis, and increased risk of bone fracture. Estrogen protects against heart disease, and consistent research has suggested that the suppression of estrogen raises the risk of cardiovascular disease, among other life-challenging issues. AI treatment reduces nearly all circulating estrogen. Estrogen is essential to the health of all parts of your body, from your eyes to your heart to your brain to everywhere else.

Many doctors also fail to stress that tamoxifen is associated with an increased risk of uterine cancer, stroke, deep venous thrombosis (blood clots), and severe muscle pain. They also fail to inform their patients that while both therapies can prolong disease-free survival, they rarely increase overall survival—especially in the case of aromatase inhibitors. All this at a tremendous cost to quality of life.

Tamoxifen and aromatase inhibitors have distinct toxicity profiles. However, individual studies have not shown a significant difference in overall toxicity between patients treated with these therapies. The lack of association between disease-free survival and overall survival prompted a 2011 meta-analysis published in the Journal of the National Cancer Institute. The study evaluated the toxicities of the two endocrine therapy options.

The Research:

The meta-analysis confirmed that an aromatase inhibitor (AI) may not the best therapy for all postmenopausal women with hormone-receptor positive, early-stage, breast cancer. The authors conducted the study to clarify why AIs, when compared with tamoxifen, increased disease-free survival but not overall survival. AI toxicities were suspected to counteract decreased recurrence rates.[i] However, as presented in the analysis, tamoxifen wasn’t necessarily safer than AIs, so the authors concluded that switching from tamoxifen to AIs would  balance the efficacy and toxicity of these treatments. What this means to you is that they are recommending that you ‘switch’ from one drug to another after a few years to reduce toxicity–but that also means you suffer the consequences of both drugs.

The authors noted that although several large randomized trials have examined the benefit of the aromatase inhibitors anastrozole, letrozole, and exemestane — as compared with 5 years of tamoxifen — the trials have failed to demonstrate a statistically significant improvement in overall survival.

The Methods:

Relevant trials were identified through a search of the MEDLINE and EMBASE databases, a search of the American Society of Oncology Annual Meetings from 2000 through 2009, and a search of the San Antonio Breast Cancer Symposium Annual Meetings from 2000 through 2009. 377 relevant articles were identified, of which 7 randomized controlled phase-3 trials with 30,023 patients met inclusion criteria.

The analysis considered six adverse events: cardiovascular disease, cerebrovascular disease, venous thrombosis (DVT), bone fracture, endometrial cancer, and other secondary cancers.

The Highlights: (Noting that longer duration of one therapy implies a shorter duration of the other)

  • Longer duration of AI use was associated with higher odds of developing cardiovascular disease.
  • Longer duration of AIs was associated with a 66% reduction in the odds of developing endometrial cancer compared with tamoxifen use.
  • Both AIs and tamoxifen increase the risk of other second cancers, but switching from tamoxifen to aromatase inhibitors may decrease the odds of second cancers.
  • Longer durations of aromatase inhibitor use were associated with decreased odds of venous thrombosis compared with tamoxifen.
  • Longer durations of AIs were associated with increased odds of bone fractures compared with tamoxifen.
  • Longer durations of AI use was associated with a statistically significant increase in the risk of raised cholesterol (hypercholesterolemia. Shorter durations of AIs might reduce the odds of high cholesterol.
  • The relative harm of 2 to 3 years of tamoxifen was not reduced by switching to aromatase inhibitors.
  • Compared with those treated with 5 years of either tamoxifen or aromatase inhibitors, those treated with a switching strategy had a statistically lower risk of death without breast cancer recurrence.
  • A retrospective cohort study of women diagnosed with breast cancer at age 66 or older between 1992 and 2000 found that more patients died of cardiovascular disease than of breast cancer.[ii] The researchers recommended that the age of the patient be taken into consideration when choosing between endocrine therapies (or in this author’s opinion, instead offering holistic alternatives).

While the study was performed to compare the two conventional treatment options, sadly they did not simultaneously compare the effectiveness of natural alternatives. Again, use of aromatase inhibitors vs tamoxifen is associated with increased risk for cardiovascular disease, cholesterol, severe muscle and joint aches, and bone fractures. Use of tamoxifen vs aromatase inhibitors is associated with increased risk for venous thrombosis, stroke, and endometrial cancer. Clearly both of these toxic therapies cause harm, often more harm than good — even if one does switch from one therapy to the other.

Other Reasons for Opting Out in Favor of Natural Alternatives:

  • A study published in the Journal of Clinical Oncology, 2016, reported that women in their 40’s with chemotherapy-induced amenorrhea should avoid aromatase inhibitors. Many women who have ceased menstruating post-chemo later recover ovarian function. What the researchers found was that ovarian estrogen production will decrease the effectiveness of AI therapy and that the therapy could actually stimulate ovarian production of estrogen. Unfortunately, the researchers concluded that the way to prevent this would be to shut down ovarian function as well as to offer tamoxifen.  [iii]
  • A study reported at the San Antonio Breast Cancer Symposium in 2106 reported that endothelial dysfunction, a predictor of cardiac disease, is a significant side effect of AI therapy among postmenopausal women, posing the problem again — that while the therapy may inhibit recurrence, it does not improve overall survival time.[iv] Estradiol appears to be important for regulating healthy endothelial function.
  • Endogenous estrogen (the estrogen your body produces) is neuroprotective. The breadth of literature on the role of estrogen in cognitive function is vast. Many women will attest to the fact that peak cognitive function corresponds with cyclic changes in circulating estrogen during their menstrual cycle.
  • Estrogen has also been found to suppress the inflammatory processes that contribute to neurodegeneration as well as to improve stroke outcome.[v] It is well documented that women are ‘protected’ against stroke until menopause, when estrogen levels decline.
  • Numerous studies have shown that beyond the aforementioned complications, tamoxifen can increase the risk of developing liver cancer and raises overall inflammation of the body, a known precursor to cancer.
  • A study reported at the San Antonino Breast Cancer Symposium 2016 looked at endothelial dysfunction, a predictor of cardiac disease.  Interestingly, they determined that the vast majority of participants who had increased cardiac risk after taking AI therapy would not have been considered at risk pre-treatment. The study indicated that the cancer benefit may not be worth the cardiac risk, both for younger and older patients.
  • Also reported at the 2016 Symposium was that AIs, associated with reductions in endothelial function, could contribute to cardiovascular disease independent of the duration of therapy.

With a growing number of cancer survivors, it is very important that we look to understand the long-term complications of conventional cancer treatment. Most postmenopausal women with early-stage breast cancer are at greater risk of dying from cardiovascular disease than their breast cancer. Further, they are at greater risk of a significant reduction in quality and quantity of life from the other overwhelming effects of conventional treatments in general.  Even worse, most doctors don’t even bother to run hormone level tests–they simply prescribe the harmful drugs. Clearly, the current toxic anti-hormonal therapies cause harm, often more harm than good. The question to be asked is ‘is it worth it?”

But, my doctor says they work:

Research published in 2106 in the Journal of Clinical Oncology analyzed the information collected for the BIG 1-98 study that was designed to see whether AIs or tamoxifen was most effective. The study was rather useless—all it managed to say was that the treatments were so toxic that most women were either non-compliant or discontinued treatment due to the side effects. Sure can’t blame them. Again, while these treatments can prolong disease-free survival, they do not always prolong overall survival. This study made no mention of those who died without recurrence (meaning from treatment-induced effects). [vi] It also made no mention of safer alternatives, and likely instilled more unnecessary fear-based compliance out of those who read the study.

If your reason for reading this article was your desire for natural alternatives to anti-hormone therapy, please readNatural Alternatives to Hormone Therapy for Breast Cancer.

This information is for educational purposes only and is not a recommendation to forgo anti-hormone therapy. It is not intended to treat, cure, prevent, or diagnose any disease or condition. This post does not represent medical advice nor should it be considered to be medical advice or a replacement for medical advice.  I encourage you to discuss this information with your integrative oncologist, naturopathic doctor, or conventional oncologist and make your own decisions.  The information provided is from my research and not to be taken as scientific evidence. 

ej portrait 150resElyn

~~If you don’t know your options, you don’t have any~~

Elyn Jacobs is a breast cancer survivor and holistic cancer strategist who helps people make better, healthier, non-toxic choices. She emphasizes the critical nature of addressing the root cause of cancer and not just its presenting symptoms (such as the tumor). Elyn specializes in understanding the role of estrogen in breast cancer and debunks the myths associated. She is a Contributing Editor for The Truth About Cancer and was creator and host of the Survive and Live Well Radio Show on the Cancer Support Network. Elyn is on the Medical Advisory Board for BeatCancer.Org and is on the Advisory Board to the Radical Remission Project. Elyn was the former Executive Director of the Emerald Heart Cancer Foundation. Contact Elyn via her website. Elyn offers consults via Skype, phone or in person.

Follow Elyn on Facebook

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[i] https://www.medscape.com/viewarticle/756567

[ii] https://www.ncbi.nlm.nih.gov/pubmed/21689398?dopt=Abstract&holding=f1000,f1000m,isrctn ; https://www.ncbi.nlm.nih.gov/pubmed/16944964

[iii] http://ascopubs.org/doi/abs/10.1200/JCO.2015.62.2985?rss=1

[iv] http://www.pnas.org/content/108/47/18879

[v] https://www.ncbi.nlm.nih.gov/pubmed/9445346

http://www.pnas.org/content/108/47/18879.full.pdf

[vi] http://ascopubs.org/doi/abs/10.1200/JCO.2015.63.8619

http://www.mdedge.com/oncologypractice/article/119926/breast-cancer/aromatase-inhibitor-effect-endothelial-function-may