Hormone Therapy Resistance in Breast Cancer: What it Means and What Comes Next

If your hormone therapy has stopped working, or you have heard the term hormone therapy resistance and want to understand what it means for you, this guide is for you. In plain language, it explains how hormone (endocrine) therapy works, why it can stop holding breast cancer back over time, how a simple blood test can now help show what is driving the change, and the treatments that can be matched to your particular cancer. We follow UK guidance from NICE and the NHS, and we note where things differ in the United States and Europe, as treatments often become available there first. 

Key takeaways

  • Hormone therapy resistance is common and well understood. It means the cancer has found a way to keep growing despite treatment. It is not caused by anything you did. 
  • Resistance often comes from changes the cancer picks up over time, including changes in the ESR1 gene (which affects the oestrogen receptor) and in the PIK3CA, AKT1 and PTEN genes (which affect a growth signal inside the cell). 
  • A blood test (a liquid biopsy) can now detect some of these changes, sometimes before a scan shows anything, and help match your next treatment to your cancer. 
  • Several treatments are available on the NHS after hormone therapy stops working, including CDK4/6 inhibitors, fulvestrant, the oral tablet elacestrant for an ESR1 mutation, and capivasertib for a PIK3CA, AKT1 or PTEN change. 
  • More oral treatments are approved in the United States (such as imlunestrant and vepdegestrant) or are being studied in trials, so it is worth asking your team what fits your situation. 
  • Keeping a record of your symptoms and treatments in the OWise app can help you notice changes early and make the most of every appointment. 

In this article

  • How hormone-sensitive breast cancer grows 
  • What is hormone therapy resistance? 
  • What causes hormone therapy resistance? 
  • The main hormone therapies, and how resistance affects them 
  • Treatments that target resistance 
  • Newer treatments and research to watch 
  • Questions to ask your care team 

How hormone-sensitive breast cancer grows 

Most breast cancers are hormone receptor positive (HR+), often written as ER positive (ER+). This means the cancer cells carry oestrogen receptors and use the hormone oestrogen as a signal to grow. When oestrogen attaches to its receptor, the receptor switches on genes inside the cell that tell it to divide. Hormone therapy (also called endocrine therapy) works by interrupting this signal, either by lowering the amount of oestrogen in the body or by blocking the receptor itself. It is one of the most effective treatments for ER positive breast cancer1. For many people it controls the cancer for a long time, but in some cases the cancer eventually finds a way around it. To learn more about your diagnosis, see The pathology report explained.

What is hormone therapy resistance?

Hormone therapy resistance means the cancer keeps growing despite hormone therapy, because it has found a way to grow that no longer depends on the treatment working as it should. It is common: up to about 30% of women taking tamoxifen for primary (early) breast cancer can become resistant over time, and resistance develops in most people with hormone receptor positive secondary (metastatic) breast cancer at some point1. 

hormone therapy resistance Importantly, resistance is not a sign that you did anything wrong, and it does not mean treatment has stopped helping you altogether. It usually means it is time to look at what is driving the cancer now, and to switch to a treatment that targets that. 

What causes hormone therapy resistance?

There is no single cause. Resistance can arise in several ways at once, but the best understood involves the oestrogen receptor pathway. Two changes matter most for treatment choices today. 

Changes in the ESR1 gene

ESR1 is the gene that makes the oestrogen receptor2. A change (mutation) in ESR1 can leave the receptor switched on even without oestrogen, so lowering oestrogen with an aromatase inhibitor no longer works as well. ESR1 mutations are uncommon in breast cancer that has not yet been treated, but they become more common after hormone therapy, especially after aromatase inhibitors. In hormone receptor positive breast cancer that has spread, ESR1 mutations are found in roughly a third of people, and often there is more than one ESR1 mutation working together. To put numbers on it, ESR1 mutations are found in fewer than 5% of breast cancers before treatment, rising to around 30 to 40% of ER positive advanced breast cancers after treatment with an aromatase inhibitor3,4. 

mutations causing hormone therapy resistance

Changes in the PIK3CA, AKT1 and PTEN genes 

These genes control a growth signalling pathway inside the cell (the PI3K, AKT and mTOR pathway). Changes in them can drive the cancer to grow even when the oestrogen signal is blocked. Together, PIK3CA, AKT1 or PTEN changes are found in about half of people with ER positive, HER2 negative advanced breast cancer6, and there are now treatments aimed specifically at them. Of these, PIK3CA changes are the most common, affecting around 30% of ER positive, HER2 negative breast cancers5, while AKT1 and PTEN changes are each less common, at roughly 5 to 10%.

OWise Joint PainIs my treatment still working? You will not always feel a change, but tracking how you feel over time can help. With the OWise app you can record over 30 symptoms and side effects, see them on a simple graph, and share the trends with your care team, so any change is noticed and discussed early.

The main hormone therapies, and how resistance affects them 

There are three main types of hormone therapy. Knowing which you have had helps explain what might work next. You can read more in Tamoxifen and aromatase inhibitors.

Aromatase inhibitors 

Aromatase inhibitors, such as letrozole (Femara®), anastrozole (Arimidex®) and exemestane (Aromasin®), lower the amount of oestrogen the body makes after the menopause. An ESR1 mutation is one reason they can stop working, because the receptor no longer needs oestrogen to be switched on. 

Tamoxifen

Tamoxifen blocks the oestrogen receptor directly and is often used before the menopause. It can be affected by changes in the receptor and by other resistance mechanisms inside the cell. 

Fulvestrant, and what a SERD is 

Fulvestrant (Faslodex®) is a selective oestrogen receptor degrader, usually shortened to SERD. A SERD does two things: it blocks the oestrogen receptor and it breaks the receptor down, so there is less of it for the cancer to use. Fulvestrant was the first SERD. It is given as an injection, usually once a month. 

On the NHS, NICE recommends fulvestrant combined with a CDK4/6 inhibitor (described below) for people who have already had hormone therapy7, and it is also used on its own. It remains a mainstay of treatment, and it is especially relevant when the cancer does not have an ESR1 mutation (called ESR1 wild type), because the newer oral SERD tablets described later are designed specifically for cancers that do carry an ESR1 mutation. The same approach is standard in the United States and Europe. 

Treatments that target resistance

When hormone therapy is no longer holding the cancer back, what comes next increasingly depends on testing the cancer for the gene changes described above. This can be done on a sample of the tumour or, increasingly, on a blood sample (a liquid biopsy). On the NHS, ESR1 testing is being introduced to help choose treatment. We explain testing in more detail in our Genomic Testing blog, which covers how liquid biopsies work and how they are used. 

CDK 4/6 inhibitors

CDK4/6 inhibitors block proteins (CDK4 and CDK6) that the cancer needs to divide. The three available are palbociclib (Ibrance®), ribociclib (Kisqali®) and abemaciclib (Verzenios®). They are taken as tablets and combined with hormone therapy, either an aromatase inhibitor as a first treatment, or fulvestrant after earlier hormone therapy8,9. They are a standard NHS option and have become one of the most important treatments for this type of breast cancer. 

CDKR/6 inhibitors impact on hormone therapy resistance

Abemaciclib is taken twice a day continuously, while palbociclib and ribociclib are taken in cycles (21 days on, 7 days off). Their side effects differ, so the choice is made with your team. We are planning a separate, more detailed blog on CDK4/6 inhibitors. 

If your cancer has an ESR1 mutation: oral SERD tablets 

If a blood test shows an ESR1 mutation, an oral SERD tablet may be an option. Elacestrant (called Korserdu® in the UK and Orserdu® in the US and Europe) is recommended on the NHS by NICE for ER positive, HER2 negative advanced breast cancer with an ESR1 mutation, after at least one line of hormone therapy that included a CDK4/6 inhibitor10,11. It is also approved in Europe and the United States. Other oral SERDs are approved in the US but are not yet available in the UK or Europe. The table below shows where each one stands. 

Oral SERD approval status in the UK, Europe and US 2026.

If your cancer has a PIK3CA, AKT1 or PTEN change: PI3K and AKT pathway treatments 

If testing shows a change in PIK3CA, AKT1 or PTEN, a treatment aimed at this pathway may be added to fulvestrant. Capivasertib (Truqap®) with fulvestrant is recommended on the NHS by NICE for tumours with one of these changes after hormone therapy12. Alpelisib (Piqray®) with fulvestrant is available on the NHS through the Cancer Drugs Fund for a PIK3CA mutation13. In the United States, a further option, inavolisib (Itovebi®) with palbociclib and fulvestrant, is approved as a first treatment for PIK3CA mutated disease14. In the UK it is licensed but NICE has not yet recommended it for NHS use, so its availability here is still being decided. 

Everolimus

Everolimus (Afinitor®) blocks a protein called mTOR, part of the same growth pathway. It is generally used later, after CDK4/6 inhibitors and after any treatment matched to a gene change. It is given with hormone therapy: the licensed combination is with the aromatase inhibitor exemestane15, and there is also evidence for combining it with fulvestrant16. It can cause side effects such as raised blood sugar, mouth soreness and tiredness, so it is usually considered once other options have been used. 

Newer treatments and research to watch

This is a fast moving area. Some treatments are already approved in the United States and may reach the UK and Europe in time, and others are being tested in trials. It is always worth asking your team whether a clinical trial might suit you. 

  • More oral SERDs: Imlunestrant (Inluriyo®) is approved in the US for ESR1 mutated disease, and the combination of imlunestrant with abemaciclib is listed as an option in US guidelines, including for some people without an ESR1 mutation17. Vepdegestrant (Veppanu®) is a newer type of oral degrader (a PROTAC) that was approved in the US in 2026 for ESR1 mutated disease18. Neither is available yet in the UK or Europe. 
  • Catching resistance earlier: The SERENA-6 trial tested using a blood test during treatment to detect an ESR1 mutation appearing, and switching to the oral SERD camizestrant (Etcamah®) before a scan shows the cancer is growing. This lengthened the time before progression19, but it is investigational, and a US advisory committee questioned whether switching on the blood test alone, before any sign of growth, is better than the usual approach, so a decision is awaited. 
  • All oral combinations: In the evERA trial, the oral SERD giredestrant combined with everolimus lengthened the time before the cancer grew in people previously treated with a CDK4/6 inhibitor20. It is investigational and under review by regulators. 

Questions to ask your care team 

Use the OWise app to create your own question lists and add the questions below to make sure you cover everything you need:

  • Has my cancer been tested for gene changes such as ESR1, or PIK3CA, AKT1 or PTEN, and what did the results show? 
  • Would a blood test (liquid biopsy) be useful for me, now or later? 
  • Which treatment options match my cancer’s specific profile, and are they available to me here? 
  • What are the benefits and possible side effects of each option for someone in my situation? 
  • Are there any clinical trials I could consider? 
  • What matters most to me about my treatment, and does this plan fit with that? 

Related OWise blogs

You may also find these helpful: 

Hormone therapy resistance does not mean you are out of options. The right next treatment increasingly depends on knowing what is driving your cancer. Keep your symptoms, test results, treatments and questions together in the OWise app, and bring the full picture to your next appointment, so you and your team can decide together. 

Get the app

Editorial Information 

Written by: OWise editorial team  |  Clinically reviewed by: A. Bruinvels, MSc PhD  |  Last reviewed: June 2026 

References 

  1. Musgrove EA, Sutherland RL. (2009) Biological determinants of endocrine resistance in breast cancer. Nature Reviews Cancer 9:631-643.
  2. Alluri PG, Speers C, Chinnaiyan AM. (2014) Estrogen receptor mutations and their role in breast cancer progression. Breast Cancer Research 16(6).
  3. Fribbens C, O’Leary B, Kilburn L, et al. (2016) Plasma ESR1 mutations and the treatment of estrogen receptor-positive advanced breast cancer. Journal of Clinical Oncology 34(25):2961-2968.
  4. Najim O, et al. (2019) The association between type of endocrine therapy and development of ESR1 mutations in patients with hormone-sensitive advanced breast cancer. Biochimica et Biophysica Acta – Reviews on Cancer.
  5. Anderson EJ, Mollon LE, Dean JL, et al. (2020) A systematic review of the prevalence and diagnostic workup of PIK3CA mutations in HR-positive, HER2-negative metastatic breast cancer. Targeted Oncology 15(3):343-352.
  6. Cancer Genome Atlas Network. (2012) Comprehensive molecular portraits of human breast tumours. Nature 490:61-70.
  7. National Institute for Health and Care Excellence (2022) Palbociclib with fulvestrant for hormone receptor-positive HER2-negative advanced breast cancer after endocrine therapy. NICE technology appraisal guidance TA836. Ribociclib with fulvestrant (TA593) and abemaciclib with fulvestrant (TA725) are also recommended.
  8. Cristofanilli M, Turner NC, Bondarenko I, et al. (2016) Fulvestrant plus palbociclib versus fulvestrant plus placebo (PALOMA-3). Lancet Oncology 17(4):425-439.
  9. Sledge GW, Toi M, Neven P, et al. (2020) The effect of abemaciclib plus fulvestrant on overall survival in hormone receptor-positive, HER2-negative advanced breast cancer (MONARCH 2). JAMA Oncology 6(1):116-124.
  10. National Institute for Health and Care Excellence (2025) Elacestrant for treating ER-positive HER2-negative advanced breast cancer with an ESR1 mutation after endocrine treatment. NICE technology appraisal guidance TA1036.
  11. Bidard FC, Kaklamani VG, Neven P, et al. (2022) Elacestrant versus standard endocrine therapy for ER-positive, HER2-negative advanced breast cancer (EMERALD). Journal of Clinical Oncology 40(28):3246-3256.
  12. National Institute for Health and Care Excellence (2025) Capivasertib with fulvestrant for treating hormone receptor-positive HER2-negative advanced breast cancer after endocrine treatment. NICE technology appraisal guidance TA1063.
  13. National Institute for Health and Care Excellence (2022) Alpelisib with fulvestrant for hormone receptor-positive, HER2-negative, PIK3CA-mutated advanced breast cancer. NICE technology appraisal guidance TA816.
  14. Jhaveri KL, Im S-A, Saura C, et al. (2024) Inavolisib with palbociclib and fulvestrant in PIK3CA-mutated, hormone receptor-positive, HER2-negative advanced breast cancer (INAVO120). New England Journal of Medicine.
  15. Baselga J, Campone M, Piccart M, et al. (2012) Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer (BOLERO-2). New England Journal of Medicine 366:520-529.
  16. Kornblum N, Manola J, Klein P, et al. (2018) Fulvestrant plus everolimus or placebo in aromatase inhibitor-resistant metastatic breast cancer (PrE0102). Journal of Clinical Oncology 36(16):1556-1563.
  17. Jhaveri KL, Im S-A, Saura C, et al. (2024) Imlunestrant with or without abemaciclib in advanced breast cancer (EMBER-3). New England Journal of Medicine.
  18. Hamilton EP, De Laurentiis M, Jhaveri K, et al. (2025) Vepdegestrant versus fulvestrant in ER-positive, HER2-negative advanced breast cancer (VERITAC-2). New England Journal of Medicine. FDA approval May 2026.
  19. Turner NC, Mayer EL, Park YH, et al. (2025) Camizestrant plus a CDK4/6 inhibitor for emergent ESR1 mutation during first-line endocrine therapy (SERENA-6). New England Journal of Medicine 393:569-580.
  20. Mayer EL, Tolaney SM, Martin M, et al. (2025) Giredestrant plus everolimus versus standard endocrine therapy plus everolimus after a CDK4/6 inhibitor (evERA Breast Cancer). Annals of Oncology 36 (suppl 2).