If you have estrogen receptor-positive (ER-positive) metastatic breast cancer, your doctor will most likely recommend hormone (endocrine) therapy.
That's because the estrogen hormone can attach to breast cancer receptors to help it grow. But hormone treatments can lower estrogen levels in your body, and in some cases block estrogen receptors to slow cancer growth.
Endocrine therapies work very well to treat breast cancer. But if you are on certain forms, like aromatase inhibitors or tamoxifen, your breast cancer can get a gene change called an ESR1 mutation.
An ESR1 mutation can mean that your cancer treatment may stop working, or, in some cases, your cancer may recur. The good news is that new medications work very well to treat this type of breast cancer.
Here's a closer look at ESR1 mutations. Learn about how these mutations impact metastatic breast cancer, and get the latest updates for treatment and outlook, too.
How Do ESR1 Mutations Affect Metastatic Breast Cancer?
The ESR1 gene normally makes a type of protein called the estrogen receptor. These proteins help your breast tissue cells grow. They also play a role in sexual development and pregnancy.
But in breast cancer, the ESR1 gene may get changed, causing the signal to become overactive and drive your breast cells to grow rapidly.
"The receptors receive signals from estrogen that encourage estrogen receptor-positive breast cancer to grow," explains Jason Mouabbi, MD, an assistant professor of breast medical oncology at MD Anderson Cancer Center in Houston.
How do ESR1 mutations develop?
ESR1 mutations develop as a result of prior treatment for hormone receptor-positive breast cancer.
"The main form of treatment for a long time has been either tamoxifen or aromatase inhibitors such as anastrozole or letrozole, which block estrogen from binding to estrogen receptors," says Mariya Rozenblit, MD, a medical oncologist at the Yale School of Medicine in New Haven, Connecticut.
These medications have been shown to work very well to treat hormone receptor-positive breast cancer. But after you have been treated for a while, cancer cells can find ways to outsmart hormone therapy.
Breast cancer cells can get ESR1 gene mutations that change the estrogen receptor shape. The shape change means your breast cancer cells grow without estrogen. As a result, cancer cells can continue to grow, and spread.
Are ESR1 mutations common in breast cancer?
It's very rare for your first diagnosis to have breast cancer with an ESR1 mutation.
That's because breast cancer with an ESR1 mutation only makes up about 1% of all primary tumors, says Komal Jhaveri, MD, a breast cancer medical oncologist at the Memorial Sloan Kettering Cancer Center in New York City.
But ESR1-mutated breast cancers are present in up to half of all metastatic hormone receptor-positive breast cancers that don't respond well to hormone therapy.
"We see them more and more frequently when it comes to second- and third-line treatments for metastatic breast cancers," Jhaveri says.
ESR1 Mutation Testing
If you have hormone receptor-positive breast cancer, your doctor may check for the ESR1 mutation. They may test for breast cancer with an ESR1 mutation, if your:
- Early-stage cancer comes back as metastatic breast cancer.
- Metastatic breast cancer gets worse when you are on treatment.
"You'll want to get this done even if you had testing done on your tumor at the time of your diagnosis," says Rozenblit.
How do you test for the ESR1 mutation?
There are two ways your doctor can test for the ESR1 gene mutation:
Liquid biopsy. This is a blood test that analyzes fragments of DNA to look for mutations such as ESR1.
Tissue biopsy. This takes a sample of metastatic breast cancer tissue to look for an ESR1 mutation.
The American Society of Clinical Oncology recommends liquid biopsy over tissue biopsy if possible because it's more sensitive. Some doctors like to do both.
Even if you don't test positive for the ESR1 gene mutation, you may need to repeat testing in the future if your cancer continues to progress, or if it no longer responds to treatment.
ESR1 Mutation Treatment in Metastatic Breast Cancer
Even if you do test positive for the ESR1 mutation, there are very effective treatments available.
"We now have therapies that target the ESR1 mutation head on," says Mouabbi.
These are known as selective estrogen receptor degraders (SERDs). SERDs are also a type of hormone therapy, but they bind to the estrogen receptor in the cancer cell and break it down.
"They don't block estrogen production, but instead go straight to the receptor and destroy it," says Mouabbi.
Selective estrogen receptor degraders (SERDs)
Can SERDs improve my outlook?
The two SERDs that treat ESR1-mutated metastatic breast cancer can greatly improve your outlook (prognosis).
"Before we began to specifically target the ESR1 mutation, the prognosis used to be very poor," says Mouabbi. "But we've made remarkable progress just by using the SERDs as single agents."
Right now, researchers are studying the use of SERDs with another type of medication often used to treat hormone receptor-positive breast cancer called CDK4/6 inhibitors. These medications target specific proteins known as CDK4/6, which help breast cancer cells grow and divide.
Watching for ESR1 Gene Mutations
Right now, there's no way to prevent an ESR1 mutation from occurring in your breast cancer.
"The SERDs haven't been FDA approved for first-line treatment among women diagnosed with early-stage hormone-positive breast cancer, but the hope is they will at some point," says Mouabbi.
If you've had treatment for hormone receptor-positive breast cancer, your cancer care team will watch you closely to make sure that your cancer doesn't recur. But if it does, ask for a liquid or tissue biopsy right away, Mouabbi says.
"The sooner we learn that you have an ESR1 gene mutation, the faster we can put you on treatment to help target it," he says.
Promising studies under investigation, but not available
It's still being studied, but liquid biopsy is used to monitor when hormone receptor-positive breast cancer develops the ESR1 mutation. The study monitors people during treatment with an aromatase inhibitor and CDK4/6 inhibitor.
If a mutation is found, even if the cancer doesn't progress, doctors can switch to an investigational SERD called camizestrant while the patient is on the same CDK4/6 inhibitor.
A study in the American Society of Clinical Oncology journal, published in June 2025, found that liquid biopsy monitoring may greatly increase the amount of time before the metastatic disease gets worse. And combination therapy helped lower the risk of breast cancer progression or death by 56%.
"This approach is very promising, but it's not ready for prime time yet," says Rozenblit. "We want to see if patients actually live longer, if we actively screen for the ESR1 mutation, and switch them over."
People in the study using both medicines remained stable for about 16 months, compared to 9.2 months for people who stayed on an aromatase inhibitor along with a CDK4/6 inhibitor.
"But if people can actually live longer, this approach will really be a game changer, not just ESR1-mutated breast cancer, but for metastatic breast cancer in general," says Rozenblit.
Show Sources
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SOURCES:
Jason Mouabbi, MD, assistant professor, breast medical oncology, MD Anderson Cancer Center, Houston.
Mariya Rozenblit, MD, medical oncologist, Yale School of Medicine, New Haven, Connecticut.
Komal Jhaveri, MD, breast cancer medical oncologist, Memorial Sloan Kettering Cancer Center, New York City.
College of American Pathologists: "ESR1 Mutations in Hormone Receptor."
American Cancer Society: "Hormone Therapy for Breast Cancer | Breast Cancer Treatment."
National Cancer Institute: "Definition of ESR1 gene – NCI Dictionary of Cancer Term."
Journal of Clinical Oncology: "Testing for ESR1 Mutations to Guide Therapy for Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer: ASCO Guideline Rapid Recommendation Update," "Camizestrant + CDK4/6 inhibitor (CDK4/6i) for the treatment of emergent ESR1 mutations during first-line (1L) endocrine-based therapy (ET) and ahead of disease progression in patients (pts) with HR+/HER2- advanced breast cancer (ABC): Phase 3, double-blind ctDNA-guided SERENA-6 trial."
FDA: "FDA approves elacestrant for ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer," "FDA approves imlunestrant for ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer."
Future Oncology: "Design of SERENA-6, a phase III switching trial of camizestrant in ESR1-mutant breast cancer during first-line treatment."
AstraZeneca: "Camizestrant demonstrated highly statistically significant and clinically meaningful improvement in progression-free survival in 1st-line advanced HR-positive breast cancer with an emergent ESR1 tumour mutation in SERENA-6 Phase III trial."
The New England Journal of Medicine: "First-Line Camizestrant for Emerging ESR1-Mutated Advanced Breast Cancer."
