You may wonder what estrogen receptor-positive (ER-positive), human epidermal growth factor 2-negative (HER2-negative) metastatic breast cancer stands for. ER-positive means the hormone estrogen helps your cancer grow.
HER2-negative means that your tumor cells lack the protein normally triggered by certain growth chemicals. And metastatic is a term for the spread of your cancer cells, usually to other body parts like your bones or liver.
After your diagnosis, your doctor will come up with a plan to treat your ER-positive metastatic breast cancer. Hormone therapy with tamoxifen or an aromatase inhibitor is one of the first treatments. Often, this hormone therapy is combined with a targeted drug called a CDK 4/6 inhibitor.
Most metastatic ER-positive breast cancers respond to hormone therapy at first. But up to half eventually develop a gene change called an estrogen receptor 1 (ESR1) mutation.
Cancers with an ESR1 mutation often stop responding to hormone therapy. Resistance means the treatment stops working over time, and the cancer starts to grow again.
Your doctor can test you for an ESR1 mutation if your cancer progresses. A liquid or tissue biopsy is the way to test for these mutations. Using DNA from these blood or breast tissue samples, doctors can identify changes to the ESR1 gene.
ESR1 mutations make ER-positive metastatic breast cancer harder to treat. But new medicines that target these gene changes are helping improve the outlook for people with this type of breast cancer.
How Do ESR1 Mutations Affect Breast Cancer?
Breast cancer cells have a protein called a receptor on their surface. In ER-positive breast cancers, estrogen attaches to the receptor like a key fits into a lock.
Once attached, estrogen “turns on" the receptor, which sends out signals that help the cancer cell grow. But ESR1 gene mutations change the shape of estrogen receptors, too.
This change makes the receptors stay "on" when estrogen isn't attached. Even when you take hormone therapy to lower estrogen levels (block making more of it), the receptors keep signaling cancer cells to grow.
This makes hormone therapy not work as well against your cancer.
Treatments for ESR1 Mutations
A few treatments help to overcome treatment resistance in people with ESR1 gene mutations.
Selective estrogen receptor degraders (SERDs)
SERDs are a newer medicine that blocks estrogen from attaching to hormone receptors on breast cancer cells to stop cancer growth. SERDs also break down the hormone receptors so that they can't send signals to the cancer cell.
What does the research say about SERDs?
In a study called EMERALD, people who took elacestrant (Orserdu) lived longer without their cancer progressing, compared to those who took an aromatase inhibitor or standard hormone treatment. For people with ESR1 mutations, taking elacestrant also:
- Lowered breast cancer progression risk
- Decreased risk of dying from cancer by 45%
Research also suggests that imlunestrant (Inluriyo) may help you live longer without your cancer coming back, compared to standard hormone therapy.
Side effects for SERDs
Your doctor will tell you about all the possible side effects and how to manage them. SERDs might also cause lower than normal levels of:
- Hemoglobin, the protein in red blood cells that carries oxygen to your body
- Neutrophils, white blood cells that fight infection
- Platelets, cells that help blood clot
- Calcium
- Sodium
The medicine might raise levels of these substances:
- Cholesterol
- Triglycerides, a type of fat in the blood
- Creatinine, a waste product made when muscles break down
- Aspartate aminotransferase (AST), which can be a sign of muscle or heart damage
- Alanine aminotransferase (ALT), which can be a sign of liver damage
If you have liver damage, you may need to take a lower dose of SERDs or avoid them altogether. These medicines aren't safe to take during pregnancy or while breastfeeding because they could harm a fetus or a growing baby.
Hormone therapy
Another way to treat ER-positive metastatic breast cancer with an ESR1 mutation is to take a different hormone therapy than the one you already tried. Your cancer may respond better to one hormone therapy than to another.
Aromatase inhibitors and tamoxifen are two hormone therapy options.
Aromatase inhibitors block an enzyme called aromatase, which turns other hormones into estrogen. Blocking the aromatase enzyme lowers the amount of estrogen in your body.
This group of medicines includes:
- Anastrozole (Arimidex)
- Exemestane (Aromasin)
- Letrozole (Femara)
Tamoxifen is another hormone therapy your doctor might try if you haven't already taken it. It belongs to a group of medicines called selective estrogen receptor modulators (SERMs). SERMs stop estrogen from attaching to cancer cells and helping them grow. Tamoxifen may slow or stop breast cancer growth.
These side effects are less common:
- Blood clots
- Weak bones
- Cataracts
Hormone therapy plus alpelisib (Piqray)
Some ER-positive metastatic breast cancers also test positive for the PIK3CA gene mutation. The PIK3CA gene carries instructions for cell growth, division, and survival. Changes to this gene allow cancer cells to divide faster than usual.
Adding alpelisib (Piqray) to a hormone therapy like Faslodex is a way to treat ER-positive, HER2-negative metastatic breast cancer with both ESR1 and PIK3CA gene mutations. Piqray is a targeted therapy. It blocks signals that help breast cancer cells divide.
Piqray comes in tablet form. You take two tablets once a day.
In studies, treatment with Piqray plus Faslodex helped people with ER-positive, HER2-negative breast cancer with a PIK3CA mutation live longer without their cancer progressing.
The medicine may lead to these abnormal test results:
- Low lymphocytes, white blood cells that fight infection and cancer
- Low hemoglobin
- Low calcium
- High blood sugar
- High creatinine
- High gamma-glutamyl transferase (GGT), an enzyme that can signal liver damage
- High ALT
- High lipase, which can mean that there's a problem with the pancreas
Piqray isn't safe to use during pregnancy or while breastfeeding.
Hormone therapy plus everolimus (Afinitor)
Everolimus (Afinitor) is another targeted drug that may be combined with hormone therapy. It treats late-stage cancers by stopping the growth of cancer cells. Afinitor is a pill you take once a day.
Targeted Protein Degrader
A new targeted therapy, vepdegestrant (Veppanu) is the first FDA-approved proteolysis targeting chimera (PROTAC), a targeted protein degrader. It is an oral cancer drug taken once daily with food for people with ER+ HER2- ESR1-mutated advanced or metastatic breast cancer, whose disease has progressed after at least one prior hormone therapy. An FDA-authorized test confirming ESR1 mutation must be given before starting treatment.
How Your Doctor Creates a Treatment Plan
If your cancer starts to grow again after treatment, your oncologist (cancer doctor) may test you for the ESR1 gene mutation. Then the doctor will work with you to develop a new treatment plan.
You have many options. Next steps might include taking a SERD, a different hormone therapy than the one you had before, or a combination of medicines. The choice depends on things like which medicine you tried before, how long you took it, and what gene mutations you have besides ESR1.
You are a member of your treatment team. It's important that you feel comfortable with your doctor's recommendations. Your doctor should listen to your questions and concerns. If something about your treatment plan doesn't feel right, you can always ask for a second opinion.
Questions to Ask
Here are a few questions to help you have a more informed discussion with your treatment team:
- Should I get tested for ESR1, PIK3CA, or other gene mutations?
- What other tests will I need?
- What treatment do you recommend next?
- Why do you recommend that treatment?
- How might it affect my cancer, outlook, and quality of life?
- What side effects might the treatment cause?
- What happens if the next medicine I try doesn't slow my cancer or it stops working?
- How will I know if it isn't working?
- Should I join a clinical trial? Which trials are available for my type of cancer?
Show Sources
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SOURCES:
American Cancer Society: "Hormone Therapy for Breast Cancer," "Treatment of Stage IV (Metastatic) Breast Cancer."
BreastCancer.org: "ASCO Recommends ESR1 Mutation Testing for Certain Metastatic Breast Cancers," "Piqray (Alpelisib): What to Expect, Side Effects, and More," "Selective Estrogen Receptor Degraders (SERDs) for Breast Cancer," "Treatment for Metastatic Breast Cancer."
Cancer: "ESR1 Mutations in Breast Cancer."
Cancers (Basel): "Efficacy of Fulvestrant Monotherapy after CDK 4/6 Inhibitor Exposure: Is This a Viable Choice?"
Cleveland Clinic: "Estrogen Receptor-Positive Breast Cancer (ER+)."
College of American Pathologists: "ESR Mutations in Hormone Receptor Positive Breast Cancer."
FDA: "FDA Approves Imlunestrant for ER-Positive, HER2-Negative ESR1-Mutated Advanced or Metastatic Breast Cancer," "Highlights of Prescribing Information: Afinitor/Afinitor Disperz," "Highlights of Prescribing Information: Fulvestrant Injection," "Highlights of Prescribing Information: Inluriyo," "Highlights of Prescribing Information: Orserdu," "Highlights of Prescribing Information: Piqray," “FDA approves vepdegestrant for ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer.”
Journal of Clinical Oncology: "Elacestrant (Oral Selective Estrogen Receptor Degrader) Versus Standard Endocrine Therapy for Estrogen Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: Results from the Randomized Phase III EMERALD Trial," "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."
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Mayo Clinic: "Everolimus (Oral Route)."
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Memorial Sloan Kettering Cancer Center: "MSK Discovery of ESR1 Gene Mutation Leads to Approval of Breast Cancer Drug Elacestrant."
The New England Journal of Medicine: "Alpelisib for PIK3CA-Mutated, Hormone Receptor-Positive Advanced Breast Cancer."
UpToDate: “Treatment for hormone receptor-positive, HER2-negative advanced breast cancer.”
