When the Cancer Keeps Coming Back: Why Blocking Estrogen Does Not Always Work

BREAST CANCERENDOCRINE THERAPY
Written By JILL CHMIELEWSKI

Published: July 8, 2026

A woman finishes five years of endocrine therapy. She did everything that her oncology team told her to do. She took the pill every day. She lived with the hot flashes, the aching joints, the foggy brain, the sleepless nights. She was told this treatment would lower her chance of the cancer returning.

And then, years later, it comes back anyway.

I hear this story more often than most women are ever told to expect. And when it happens, the question we ask is almost always the wrong one. We ask, “What did the woman do wrong?” when we should be asking, “Why did the treatment fail, and why?”

What women are told about endocrine therapy

If your breast cancer was estrogen-receptor positive, or ER-positive, you were likely told a simple story. Your cancer feeds on estrogen. So the plan is to starve it. Take a drug that blocks estrogen, or a drug that stops your body from making estrogen, and the cancer should stay away.

The two main types of drugs are tamoxifen and aromatase inhibitors. Tamoxifen binds to the estrogen receptor and blocks or alters the signaling. An aromatase inhibitor lowers the amount of estrogen your body can make. Together, these are called endocrine therapy, or hormone-blocking treatment.

The story sounds clean. Block the estrogen, stop the cancer. But the body is not that simple. And the numbers tell a more honest story.

The numbers most women never see

Here is where the story unravels. If blocking estrogen worked for every woman, we would almost never see the cancer return. But it does return. So the treatment is helping some women, but not all. That gap is the whole question.

Look at the real numbers. Endocrine therapy is usually described to women in relative terms. “This cuts your risk of recurrence in half.” That sounds powerful. But relative risk hides the part that matters most: how much your own risk drops in real terms. This is called absolute risk.

Five years of tamoxifen in some women may lower the chance of dying from breast cancer over the following years [1]. But when you look at 100 women who take it, the picture is humbling.

A handful of women are truly saved. Many would have done fine without it. And some will have the cancer return no matter what. Every one of those 100 women takes the drug. Every one of them lives with the side effects. Only a few gain the benefit that the whole group was promised [1].

Aromatase inhibitors do a little better than tamoxifen for some women. But the gap between the two is small in real terms. It is often just two or three women out of 100 [2]. Taking these drugs for longer adds even less. And it adds more broken bones, more system-wide collateral damage, and poorer quality of life [2].

I am not going to tell you these drugs are useless. For a small number of women, they matter. But the honest math tells us something important. Endocrine therapy helps a minority of the women who take it.

So we have to ask the real question. What is happening in the bodies of the women it does not help?

The cell that wants its estrogen back

To answer that, we have to stop thinking of estrogen as a poison and start thinking of it as a signal.

Estradiol, progesterone, and testosterone are often called ovarian hormones. But they are made in many places beyond the ovaries, including the adrenal glands, the brain, fat tissue, and the skin. These hormones talk to nearly every cell in the body. Estrogen is not an on-off switch for cancer. It is a regulatory signal. It tells cells how to grow, how to repair themselves, and how to keep their DNA in good order.

When you block that signal for years, the cell does not simply die. It adapts. And a cancer cell is very good at adapting.

Researcher Dr. Zsuzsanna Suba has spent years studying this. Her work describes endocrine therapy as something that works for a while and then provokes the very thing it was meant to prevent [3]. When you take estrogen away, the surviving cells push back. They find new ways to get the signal they are missing. Suba’s larger body of work reframes the whole picture: breast cancer is not caused by too much estrogen, but by a slow breakdown of the systems that estrogen normally helps keep in order [4, 5].

Think of it in stages. At first, blocking estrogen slows the cancer down. Then the surviving cells adapt and find estrogen elsewhere. Finally, the cells become so good at finding or making their own signal that the blockade stops working at all. This is why resistance to endocrine therapy is so common. Roughly 3 in 10 women never respond to it from the start. Many more stop responding over time. And in advanced disease, resistance is nearly universal [6].

Three ways cells get the estrogen they need

So how does a cell get estrogen when the drugs are working to take it away? There are several routes. Block one lane, and the traffic moves through another.

1- The antenna changes shape

The estrogen receptor is like an antenna. It waits for the estrogen signal and passes it inside the cell. Under years of drug pressure, the gene for that antenna can mutate. The changed antenna no longer waits for estrogen at all. It switches itself on and stays on, with no estrogen needed [7, 8]. These changes, called ESR1 mutations, show up in a large share of cancers that come back after endocrine therapy [9].

2 - The cell builds its own estrogen factory

Aromatase is the enzyme that makes estrogen. Aromatase inhibitors are supposed to shut it down across the whole body. But some tumors respond by making far more aromatase, right inside the tumor itself [10]. The blood test still shows low estrogen. Meanwhile, the cancer is quietly running its own small factory. Local estrogen production near a tumor has been measured as far higher than what circulating blood levels suggest [11].

3 - The back door nobody tests for

There is a second way to make active estrogen that aromatase inhibitors do not touch at all. The body stores a large, inactive reserve of estrogen in a sulfate form. An enzyme called steroid sulfatase, or STS, unlocks that reserve and turns it back into active estrogen [12, 13]. This is a whole separate supply line. And here is the part that should stop us: none of this shows up on a standard blood panel [13, 14]. A woman can have low estrogen in her blood and rising estrogen inside her tissue at the same time. Inflammation makes this worse because inflammatory signals turn up the very enzymes that make local estrogen [15].

There is one more nuance worth mentioning. Testosterone can be converted into estrogen locally, which is one reason women are told testosterone is dangerous. But testosterone also acts on its own receptor, and that receptor can slow breast cell growth [16]. So testosterone is not simply a raw material for more estrogen. The story is more balanced than women are usually told.

Estrogen is not the only signal

Even if you could block every route to estrogen, you would not have blocked every route to growth. Cancer cells use more than one growth pathway.

One of the biggest is a growth signal driven by insulin and a related messenger called IGF-1. Higher levels of IGF-1 in the blood are linked to a higher risk of ER-positive breast cancer. This shows up across many large studies [17]. Inside the cell, these signals feed a growth network. That network can keep the cancer dividing even when estrogen is low [18]. This is why a woman’s metabolic health, her blood sugar, her insulin, her inflammation, should ALWAYS be part of the cancer story, not a side note.

Some researchers go further. Dr. Thomas Seyfried and others describe cancer as, at its root, a disease of damaged cell energy [19, 20]. In this view, the cell’s power plants, called mitochondria, stop working properly, and the cell switches to a cruder way of making energy that favors constant growth. If that is even partly true (and I believe it is), then blocking one hormone will never be enough on its own. The terrain the cell lives in, its fuel, its energy, and its inflammation matter just as much as any single signal.

Why the cell fight so hard to keep estrogen

Here is the part that turns the whole fear-based story around estrogen upside down. The cell is not fighting to keep estrogen because estrogen is its fuel. It is fighting because estrogen is doing a job it cannot do without.

Estrogen helps run the cell’s power plants.

Estrogen receptors reside within mitochondria, and estrogen helps the cell build new ones and maintain energy production [21]. Estrogen also plays a role in keeping DNA stable. The repair protein BRCA1 works hand in hand with estrogen signaling to clean up normal DNA stress, and when that repair partner is missing, the same estrogen signaling that was harmless before can leave damage behind [22, 23]. Dr. Suba’s work pushes this further, describing estrogen as a signal that can actually drive damaged cells toward orderly death rather than away from it [24].

Read that again. Under the right conditions, estrogen may help the body clear out faulty cells rather than create them. This is a very different picture from “estrogen feeds cancer.”

It also explains a finding that stuns most people. In women whose advanced cancer had stopped responding to estrogen-blocking drugs, giving them estrogen, on purpose, shrank tumors in a meaningful share of cases [25]. The cells had adapted so hard to a low-estrogen world that a flood of estrogen became a shock they could not survive. You cannot explain that with a simple “estrogen bad” model. You can only explain it if estrogen is a signal, and signals can cut both ways.

What women deserve

Women deserve to know that endocrine therapy helps some women and not others, and that this is not their fault. Women deserve to see absolute numbers, not just the reassuring relative ones. Women deserve to know that a normal estrogen blood test does not mean their tissue has no estrogen. And women deserve a real conversation about the benefits and the risks of these drugs, the alternatives, and the risks of blocking hormones for years. That conversation is a shared decision. It is your body and your choice to make with your care team, not a rule handed down to you.

Because there are risks to blocking hormones, and they are rarely discussed. Long-term hormone loss is tied to bone loss, muscle loss, insulin resistance, heart disease, and changes in mood and memory [1, 2]. These are not rare surprises. They are the expected result of taking a whole-body signal away for years. Cardiovascular disease, not breast cancer, is the leading cause of death in women. A full conversation weighs the cancer risk against these other risks, over the same years of a woman’s life.

None of this means your oncologist does not care. It means the system is built for populations, not for the person in front of it. Guidelines favor a single, simple rule because it is easier to teach and follow. But your body is not a population. It is one physiology, with its own fuel, its own repair systems, and its own way of finding the signals it needs.

Survival matters. Of course it does. But so does understanding why a treatment works for some women and not others, and what else is happening in the body while the cancer is being fought. These are not competing goals. They are both part of good medicine.

If your cancer came back after you did everything asked of you, this is not a story about your failure. It is a story about a treatment that blocks one signal while the cell quietly finds three more. The more clearly you understand that, the better the questions you can bring to your own care. And asking better questions, for yourself or for someone you love, matters more than you may know.

Want to learn more?

Disclaimer: This article is for educational and informational purposes only and is not intended to replace personalized medical advice or individualized care. It is meant to help you understand your physiology, explore evidence-based options, and make informed choices about your health and wellness. Healthcare should be a partnership, not a permission slip, and proactive care is just as essential as treatment. Use this information to engage in open, collaborative discussions with your provider or to make empowered decisions that align with your own values, goals, and comfort level. You are the ultimate authority on your body.


References

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2.     Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). (2015). Aromatase inhibitors versus tamoxifen in early breast cancer: patient-level meta-analysis of the randomised trials. The Lancet, 386(10001), 1341-1352. https://doi.org/10.1016/S0140-6736(15)61074-1

3.     Suba, Z. (2015). The pitfall of the transient, inconsistent anticancer capacity of antiestrogens and the mechanism of apparent antiestrogen resistance. Drug Design, Development and Therapy, 9, 4341-4353. https://doi.org/10.2147/DDDT.S89536

4.     Suba, Z. (2014). Diverse pathomechanisms leading to the breakdown of cellular estrogen surveillance and breast cancer development: new therapeutic strategies. Drug Design, Development and Therapy, 8, 1381-1397. https://doi.org/10.2147/DDDT.S70570

5.     Suba, Z. (2023). Rosetta Stone for cancer cure: comparison of the anticancer capacity of endogenous estrogens, synthetic estrogens and antiestrogens. Oncology Reviews, 17, 10708. https://pubmed.ncbi.nlm.nih.gov/37152665/

6.     Mills, J., et al. (2018). Mechanisms of resistance in estrogen receptor positive breast cancer: overcoming resistance to tamoxifen/aromatase inhibitors. Current Opinion in Pharmacology, 41, 59-65. https://doi.org/10.1016/j.coph.2018.04.009

7.     Toy, W., et al. (2013). ESR1 ligand-binding domain mutations in hormone-resistant breast cancer. Nature Genetics, 45(12), 1439-1445. https://doi.org/10.1038/ng.2822

8.     Robinson, D., et al. (2013). Activating ESR1 mutations in hormone-resistant metastatic breast cancer. Nature Genetics, 45(12), 1446-1451. https://doi.org/10.1038/ng.2823

9.     Schiavon, G., et al. (2015). Analysis of ESR1 mutation in circulating tumor DNA demonstrates evolution during therapy for metastatic breast cancer. Science Translational Medicine, 7(313), 313ra182. https://doi.org/10.1126/scitranslmed.aac7551

10.  Magnani, L., et al. (2017). Acquired CYP19A1 amplification is an early specific mechanism of aromatase inhibitor resistance in ER-alpha metastatic breast cancer. Nature Genetics, 49(3), 444-450. https://doi.org/10.1038/ng.3773

11.  O’Neill, J., & Miller, W. (1987). Aromatase activity in breast adipose tissue from women with benign and malignant breast diseases. British Journal of Cancer, 56(5), 601-604. https://doi.org/10.1038/bjc.1987.248

12.  Foster, P. (2021). Steroid sulphatase and its inhibitors: past, present, and future. Molecules, 26(10), 2852. https://doi.org/10.3390/molecules26102852

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14.  McNamara, K., et al. (2018). In breast cancer subtypes steroid sulfatase (STS) is associated with less aggressive tumour characteristics. British Journal of Cancer, 118(9), 1208-1216. https://doi.org/10.1038/s41416-018-0034-9

15.  Purohit, A., et al. (2002). The role of cytokines in regulating estrogen synthesis: implications for the etiology of breast cancer. Breast Cancer Research, 4(2), 65-69. https://doi.org/10.1186/bcr425

16.  Hickey, T., et al. (2012). Minireview: the androgen receptor in breast tissues: growth inhibitor, tumor suppressor, oncogene? Molecular Endocrinology, 26(8), 1252-1267. https://doi.org/10.1210/me.2012-1107

17.  Key, T., et al. (2010). Insulin-like growth factor 1 (IGF1), IGF binding protein 3 (IGFBP3), and breast cancer risk: pooled individual data analysis of 17 prospective studies. The Lancet Oncology, 11(6), 530-542. https://doi.org/10.1016/S1470-2045(10)70095-4

18.  du Rusquec, P., et al. (2020). Targeting the PI3K/Akt/mTOR pathway in estrogen-receptor positive HER2 negative advanced breast cancer. Therapeutic Advances in Medical Oncology, 12, 1758835920940939. https://doi.org/10.1177/1758835920940939

19.  Seyfried, T., & Shelton, L. (2010). Cancer as a metabolic disease. Nutrition & Metabolism, 7, 7. https://doi.org/10.1186/1743-7075-7-7

20.  Seyfried, T. (2015). Cancer as a mitochondrial metabolic disease. Frontiers in Cell and Developmental Biology, 3, 43. https://doi.org/10.3389/fcell.2015.00043

21.  Klinge, C. (2008). Estrogenic control of mitochondrial function and biogenesis. Journal of Cellular Biochemistry, 105(6), 1342-1351. https://doi.org/10.1002/jcb.21936

22.  Savage, K., et al. (2014). BRCA1 deficiency exacerbates estrogen-induced DNA damage and genomic instability. Cancer Research, 74(1), 332-342. https://doi.org/10.1158/0008-5472.CAN-13-2611

23.  Sasanuma, H., et al. (2018). BRCA1 ensures genome integrity by eliminating estrogen-induced pathological topoisomerase II-DNA complexes. Proceedings of the National Academy of Sciences, 115(45), E10642-E10651. https://doi.org/10.1073/pnas.1803177115

24.  Suba, Z. (2024). Estrogen regulated genes compel apoptosis in breast cancer cells in a Janus-faced manner. Current Oncology, 31(9), 4885-4907. https://doi.org/10.3390/curroncol31090362

25.  Ellis, M., et al. (2009). Lower-dose vs high-dose oral estradiol therapy of hormone receptor-positive, aromatase inhibitor-resistant advanced breast cancer: a phase 2 randomized study. JAMA, 302(7), 774-780. https://doi.org/10.1001/jama.2009.1204

 
JILL CHMIELEWSKI
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