There are a few options when hormone therapy and CDK4/6 inhibitors stop working. Which treatment comes next depends on how sensitive the cancer is to hormone therapy, and whether it has any gene mutations.
Selective Estrogen Receptor Degraders (SERDs)
In HR-positive breast cancer, estrogen attaches to receptors on the surface of cancer cells and helps them grow. SERDs block those receptors, which slows or stops cancer cell growth.
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Fulvestrant (Faslodex) is a SERD that can be taken alone or in combination with other therapies, and can be used either as a primary or second-line treatment. It’s received as two injections, biweekly for the first month, and once a month after the first round of injections.
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If you have an ESR1 mutation, you’ll likely hear about two specific SERD drugs. Up to 40 percent of people with HR-positive/HER2-negative metastatic breast cancer develop this mutation after receiving hormone therapy.
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The ESR1 gene makes estrogen receptors, and mutations in this gene allow breast cancer cells to grow without estrogen binding to the receptor. Blocking this receptor with a SERD weakens or destroys the receptor to stop or slow cell growth.
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Two SERDs are approved to treat HR-positive/HER2-negative breast cancers with an ESR1 mutation:
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- elacestrant (Orserdu)
- imlunestrant (Inluriyo)
These medicines are for people who have already taken at least one type of hormone therapy.
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They come as once-daily pills.Giredestrant is a new SERD that isn’t yet approved by the U.S. Food and Drug Administration (FDA), but it has shown promising results in studies for HR-positive/HER2-negative metastatic breast cancer, says Puri. Compared with people who took tamoxifen or aromatase inhibitors, people who took giredestrant were less likely to have cancer return.
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Giredestrant is taken orally.
PIK3CA Inhibitors
About 40 percent of HR-positive/HER2-negative breast cancers have a PIK3CA gene mutation.
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The PIK3CA gene holds the instructions for making a protein that helps cancer cells grow, divide, and survive. PIK3CA inhibitors block this protein.
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Three PIK3CA inhibitors are approved for HR-positive/HER2-negative metastatic breast cancer:
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- alpelisib (Vijoice)
- capivasertib (Truqap)
- inavolisib (Itovebi)
These medicines come as once-daily pills.
Capivasertib also treats breast cancers with an AKT1 or PTEN gene mutation or both.
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PIK3CA inhibitors are not recommended for people with diabetes, because high blood sugar is a possible side effect.
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mTor Inhibitors
“If you don’t have an ESR1 or PIK3CA mutation, you are going to use a drug that we’ve been using for ages, called everolimus,” says Michelina Cairo, MD, a breast oncologist with Texas Oncology, Memorial City in Houston, and Gulf Coast Breast Research Coordinator.
Everolimus (Afinitor) belongs to a class of drugs called mTOR inhibitors.
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The mTOR protein helps control cell division. Blocking this protein prevents breast cancer cells from multiplying.You might get this medicine after an aromatase inhibitor like letrozole (Femara) or anastrozole (Arimidex).
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Everolimus is usually given with an injectable SERD like fulvestrant.
PARP Inhibitors
Olaparib (Lynparza) and talazoparib (Talzenna) are PARP inhibitors used to treat HR-positive/HER2-negative metastatic breast cancers with a BRCA1 or BRCA2 gene mutation.
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BRCA mutations prevent cancer cells from repairing their damaged DNA. Breast cancer cells with this mutation instead use the PARP protein to fix DNA damage. PARP inhibitors prevent the cancer cells from repairing themselves, which causes them to die. They are taken by mouth as a pill.
Chemotherapy
This medicine kills fast-growing cells, including cancer cells, all over the body. Chemotherapy can be an option when hormone therapy and targeted drugs like CDK4/6 inhibitors stop working. While early-stage breast cancer is often treated with combinations of chemotherapy drugs, for metastatic breast cancer usually one drug is given at a time.
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Chemotherapy drugs that treat HR-positive/HER2-negative metastatic breast cancer include:
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- capecitabine (Xeloda)
- gemcitabine (Gemzar)
- ixabepilone (Ixempra)
- vinorelbine (Navelbine)
- anthracyclines such as doxorubicin (Adriamycin) and epirubicin (Ellence)
- platinum drugs (cisplatin, carboplatin)
- taxanes like paclitaxel (Taxol) and docetaxel (Taxotere)
