ESR1 mutation testing

A woman having blood drawn

For metastatic breast cancer that is estrogen-receptor positive and HER2-negative, endocrine therapy is a main part of the treatment plan. This is true whether metastatic breast cancer is the first breast cancer diagnosis (de novo metastatic breast cancer) or if it develops as a recurrence of an early-stage breast cancer.

Over time, though, metastatic breast cancers treated with endocrine therapy can develop a mutation in a gene called ESR1. If this mutation develops, in most cases, it’s after some time on aromatase inhibitor treatment for metastatic breast cancer. Rarely, these mutations may develop after tamoxifen treatment for metastatic breast cancer.

When breast cancer has an ESR1 mutation, it may not respond as well to some types of endocrine therapy as it once did, or it may stop responding entirely. This is called treatment resistance.

If you have been diagnosed with estrogen receptor-positive, HER2-negative metastatic breast cancer that is a recurrence of an earlier breast cancer or that has progressed during endocrine therapy, ESR1 mutation testing can help you and your healthcare team make decisions about the most effective treatment options for you.


What is an ESR1 mutation?

The ESR1 gene carries instructions for building receptors for estrogen on the surface of cells. In estrogen receptor-positive breast cancer, these receptors respond to the presence of the hormone estrogen. Estrogen attaches to the receptors on the cancer cells and transmits signals that tell the cancer cells to grow and multiply.

Endocrine therapy can be an effective treatment for estrogen receptor-positive breast cancers:

  • Selective estrogen response modifiers (SERMs), such as tamoxifen, can block estrogen from attaching to estrogen receptors.
  • Aromatase inhibitors lower the overall amount of estrogen in the body, which also controls cancer growth.
  • Fulvestrant (Faslodex), an estrogen receptor degrader (SERD) approved to treat estrogen receptor-positive metastatic breast cancer, not only attaches to estrogen receptors but also breaks them down, reducing the number of receptors.

People with estrogen receptor-positive metastatic breast cancer require ongoing treatment, and they often take aromatase inhibitors as part of their therapy. Researchers have discovered that up to half of these metastatic breast cancers treated with aromatase inhibitors will develop mutations, or unusual changes, in certain areas of the ESR1 gene. An ESR1 mutation can happen during first-line treatment that uses an aromatase inhibitor, but it becomes more common as people go through repeated rounds of treatment. When an ESR1 mutation is present, the cancer may not respond as well, or at all, to any type of endocrine therapy.


Video: ESR1 testing: What you need to know

Eleonora Teplinksy, MD, Head of Breast and Gynecological Medical Oncology at Valley-Mount Sinai Comprehensive Cancer Care, explains more about more about ESR1 testing, who should get tested and when, and how it impacts treatments for metastatic breast cancer.


How ESR1 mutations cause treatment resistance

In estrogen receptor-positive, HER2-negative metastatic breast cancer that does not have an ESR1 mutation, endocrine therapy blocks or lowers estrogen signals that reach estrogen receptors and tell the cancer cells to grow.

When breast cancer develops ESR1 gene mutations, the mutations change the shape of the estrogen receptors. With this shape change, the receptors become activated, like an “on” switch that stays on, and tells the cancer cells to grow. In many cases, endocrine therapy is not as effective as it once was, because even if these medicines block or lower estrogen, in ESR1-mutated breast cancer, the estrogen receptors continue telling the cancer cells to grow.

But even with an ESR1 mutation, endocrine therapies can still be partially effective for some people. If doctors confirm that an endocrine therapy is still working to slow the cancer’s growth, they may recommend continuing to take these medicines.

A newer treatment, elacestrant, is a more effective endocrine therapy for treating estrogen receptor-positive, HER2-negative, ESR1-mutated metastatic breast cancer. You can read more about elacestrant in the treatment options section below. You can also visit our elacestrant page for more information.


Types of ESR1 tests

There are blood and tissue tests available to detect ESR1 mutations.

Blood tests known as liquid biopsy or circulating tumor DNA (ctDNA) tests (also sometimes called cell-free DNA tests) analyze circulating fragments of DNA in a blood sample to find mutations. Guardant360 CDx is one of many approved ctDNA tests that can effectively confirm an ESR1 mutation.

After the blood sample is sent to the lab, the blood cells are separated from the liquid portion of blood, called plasma. The DNA is taken from the plasma and mixed with chemicals that can identify mutations in the ESR1 gene.

Your healthcare team may order tests for other cancer-related mutations at the same time, which can further help guide treatment choices. The American Society of Clinical Oncology (ASCO) recommends testing for PIK3CA mutations, for example, to learn whether a person might be eligible for treatment that targets PIK3CA-mutated breast cancer.

Some doctors might use a tissue biopsy, or sample of the metastatic breast cancer tissue, to test for an ESR1 mutation using a technology called next-generation sequencing.

ASCO recommends liquid biopsy as a more sensitive test, though. Some doctors might order both blood and tissue tests. You can ask your healthcare team what they recommend.

A Black doctor prepares a test slide

When ESR1 testing should be done

ASCO recommends that people diagnosed with estrogen receptor-positive, HER2-negative breast cancer treated with endocrine therapy, with or without a targeted therapy called a CDK 4/6 inhibitor, have an ESR1 mutation test when:

  • An early-stage cancer recurs as metastatic breast cancer
  • Metastatic breast cancer progresses while on treatment

If the test result is negative, your healthcare team is likely to recommend repeat testing in the future if the cancer keeps growing. An ESR1 mutation can develop over time, as more treatments are given. Your healthcare team would determine when to test and how often.

If you’ve been diagnosed with estrogen receptor-positive, HER2-negative metastatic breast cancer, talk with your doctor about testing for an ESR1 mutation.


Treatment options for ESR1 mutation-positive breast cancer

If the cancer tests negative for an ESR1 mutation and you’ve already taken endocrine therapy and a CDK 4/6 inhibitor, ASCO recommends considering several different treatment options, including:

If cancer tests positive for an ESR1 mutation and you have already taken endocrine therapy and a CDK 4/6 inhibitor, options include:

If the cancer tests positive for an ESR1 mutation and you are taking endocrine therapy that is effective at slowing the cancer’s growth, doctors will generally recommend staying on that therapy until it’s confirmed that cancer has progressed.

If you are a man diagnosed with estrogen receptor-positive, HER2-negative metastatic breast cancer, all the above treatments are options for you.

Your healthcare team may also recommend other treatments, such as chemotherapy.

You and your healthcare team can work together to make treatment decisions based on your treatment history, your menopausal status, and the details of your diagnosis.

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Reviewed and updated: November 27, 2023

Reviewed by: Virginia Kaklamani, MD, DSc


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