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. 

Elyn

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

Elyn Jacobs is a breast cancer survivor and certified 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