Treatment for hormone receptor–positive (HR-positive)/HER2-negative metastatic breast cancer often starts with hormone therapy (tamoxifen or an aromatase inhibitor) and a CDK 4/6 inhibitor.e60dc2a1-f33c-4a05-9b50-8e3e8e5976298c541cc9-7684-4cb9-bcbc-f016dc060bb0 But it doesn’t always end there. At some point, you may need to switch treatments. The growing number of options to manage HR-positive/HER2-negative metastatic breast cancer can offer reassurance and hope for the future. Learn which treatments are available now and which treatments are on the horizon, and find out how to determine whether a clinical trial is the right next step for you.
Looking Ahead to the Next Step Looking Ahead When to take the next step depends on your response to the first treatment . “The general rule is to stay on each therapy for as long as possible, as long as the disease is under control and quality of life is maintained,” says Akshjot Puri, MD , a breast medical oncologist at Houston Methodist in Texas. Doctors consider making a change when symptoms return, imaging tests like a computed tomography (CT) scan or positive emission tomography (PET) scan show that the cancer is progressing, or there are new areas of cancer, says Dr. Puri. Another reason to switch is if you test positive for a gene mutation like ESR1 or PIK3CA. An ESR1 mutation makes breast cancer resistant to hormone therapy and CDK4/6 inhibitors.e60dc2a1-f33c-4a05-9b50-8e3e8e5976290cdb5107-4376-4ec7-9eae-4afd6755cc9de60dc2a1-f33c-4a05-9b50-8e3e8e59762911fcdd8b-5eb5-4f73-a7a0-c4a452bab895 A PIK3CA mutation causes cancer cells to grow uncontrollably, which makes it more difficult to treat.e60dc2a1-f33c-4a05-9b50-8e3e8e597629054b4209-7311-4a9c-8dcd-47ad8f3f9873 Genomic testing with a liquid or tissue biopsy can find the most effective targeted therapy for your cancer and its gene mutations.e60dc2a1-f33c-4a05-9b50-8e3e8e597629f97b7532-4ad9-47c1-a8e7-e2d7570b3a9a A liquid biopsy uses a simple blood test to look for signs of cancer cells or DNA in your blood, whereas a tissue biopsy involves taking a sample of tissue from the tumor, which will likely involve local anesthetic.e60dc2a1-f33c-4a05-9b50-8e3e8e597629e500a417-444b-4a5b-ab58-67bb714d6be7 Both of these tests give your doctor information that can help decide which therapy might work best for you. Your goals and preferences are also considered in the decision. “There are several oral therapy options, and even the IV drugs have different schedules. Different drugs have different side effect profiles,” Puri says. “Picking an option that is best suited for the patient is prudent.”
Second-Line Options Second-Line Options 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.e60dc2a1-f33c-4a05-9b50-8e3e8e5976297d04665f-635d-4a90-9d59-d0098d022aed 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.e60dc2a1-f33c-4a05-9b50-8e3e8e5976297d04665f-635d-4a90-9d59-d0098d022aed 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.e60dc2a1-f33c-4a05-9b50-8e3e8e597629ab02326e-e7d5-406f-9ebd-85e955b4c90b 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.e60dc2a1-f33c-4a05-9b50-8e3e8e597629873f043c-d8b2-4412-8136-5b1a8b24b28b Two SERDs are approved to treat HR-positive/HER2-negative breast cancers with an ESR1 mutation:e60dc2a1-f33c-4a05-9b50-8e3e8e5976297d04665f-635d-4a90-9d59-d0098d022aed elacestrant (Orserdu) imlunestrant (Inluriyo) These medicines are for people who have already taken at least one type of hormone therapy.e60dc2a1-f33c-4a05-9b50-8e3e8e5976297d04665f-635d-4a90-9d59-d0098d022aed 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.e60dc2a1-f33c-4a05-9b50-8e3e8e597629c3dedda1-5690-4b47-a5cc-8e0a76c77633 Giredestrant is taken orally. PIK3CA Inhibitors About 40 percent of HR-positive/HER2-negative breast cancers have a PIK3CA gene mutation.e60dc2a1-f33c-4a05-9b50-8e3e8e59762920d4094d-8b07-4869-9aad-05ca0388c832 The PIK3CA gene holds the instructions for making a protein that helps cancer cells grow, divide, and survive. PIK3CA inhibitors block this protein.e60dc2a1-f33c-4a05-9b50-8e3e8e59762977cff101-81e3-40e9-9bc5-0541a17e4915 Three PIK3CA inhibitors are approved for HR-positive/HER2-negative metastatic breast cancer: e60dc2a1-f33c-4a05-9b50-8e3e8e59762977cff101-81e3-40e9-9bc5-0541a17e4915 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. e60dc2a1-f33c-4a05-9b50-8e3e8e59762977cff101-81e3-40e9-9bc5-0541a17e4915 PIK3CA inhibitors are not recommended for people with diabetes , because high blood sugar is a possible side effect.e60dc2a1-f33c-4a05-9b50-8e3e8e5976296d9d187f-e528-4c5f-b2af-0874fcbfbf46 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.e60dc2a1-f33c-4a05-9b50-8e3e8e5976296e6f1b09-aaa2-43e2-9ae6-61994f554d8c 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).e60dc2a1-f33c-4a05-9b50-8e3e8e597629af6b8c7e-83f2-4977-b7dd-35aa6eccbc1b 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 .e60dc2a1-f33c-4a05-9b50-8e3e8e5976295798e6ef-8634-4681-a80a-6d053e11db13 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.e60dc2a1-f33c-4a05-9b50-8e3e8e597629f24086aa-2074-4220-a442-ad7c84192579 Chemotherapy drugs that treat HR-positive/HER2-negative metastatic breast cancer include: e60dc2a1-f33c-4a05-9b50-8e3e8e597629f24086aa-2074-4220-a442-ad7c84192579 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)
Immunotherapy Immunotherapy Immunotherapy boosts the immune system response to make it a more effective cancer fighter.e60dc2a1-f33c-4a05-9b50-8e3e8e597629bfb9fa65-4259-42f2-8224-12df79fc0817 Antibody-Drug Conjugates Antibody-drug conjugates contain a monoclonal antibody (a lab-made antibody that recognizes a specific target) linked to a chemotherapy drug.e60dc2a1-f33c-4a05-9b50-8e3e8e597629064bc207-6d35-4653-9c9f-4648cf038323 The monoclonal antibody locks onto a protein on the surface of the cancer cell and delivers the chemotherapy directly to the cell. This treatment is so precise at targeting cancer cells that it’s sometimes called a “biological missile.” Examples of antibody-drug conjugates are:e60dc2a1-f33c-4a05-9b50-8e3e8e597629064bc207-6d35-4653-9c9f-4648cf038323 fam-trastuzumab deruxtecan (Enhertu) sacituzumab govitecan (Trodelvy) datopotamab deruxtecan (Datroway) Fam-trastuzumab deruxtecan treats HR-positive metastatic breast cancers that are HER2-low or HER2-ultralow.e60dc2a1-f33c-4a05-9b50-8e3e8e5976296ec92a6a-37f9-4ffd-a151-79ffa1245a90 HER2-low and HER2-ultralow breast cancer cells contain much less HER2 protein than HER2-positive breast cancer cells. But they still have enough of this protein on their surface for the drug to latch onto.e60dc2a1-f33c-4a05-9b50-8e3e8e597629bc7aaec6-cc49-46c2-a788-2234f92dd80f Sacituzumab govitecan is for people with HR-positive/HER2-negative metastatic breast cancer who have taken hormone therapy, plus at least two other medicines (such as targeted therapy or chemotherapy).e60dc2a1-f33c-4a05-9b50-8e3e8e597629a33c07b5-6b0c-42ab-b99d-b93502ab2a53 Datopotamab deruxtecan is given after hormone therapy and chemotherapy stop working.e60dc2a1-f33c-4a05-9b50-8e3e8e597629f3f52e5f-d53a-42e3-887d-9856a5cb7584 Immune Checkpoint Inhibitors Immune checkpoint inhibitors are a type of immunotherapy being investigated for HR-positive/HER2-negative metastatic breast cancer. These medications basically act like switches, turning on the immune system so that it can fight the cancer.e60dc2a1-f33c-4a05-9b50-8e3e8e597629bfb9fa65-4259-42f2-8224-12df79fc0817 In early studies, immunotherapy wasn’t very effective against HR-positive/HER2-negative metastatic breast cancer. In recent years, researchers have tried combining it with other medicines, such as chemotherapy, hormone therapy, and targeted treatments like AKT inhibitors and CDK 4/6 inhibitors, to see whether it might improve the outcome. Some of these combinations were somewhat successful, but adding another drug also increased side effects.e60dc2a1-f33c-4a05-9b50-8e3e8e5976296e4deae7-d75f-4902-a6db-9a6200e3d628 PD-1/PD-L1 inhibitors are one type of immune checkpoint inhibitor that has shown promise in recent studies for HR-positive/HER2-negative metastatic breast cancer.e60dc2a1-f33c-4a05-9b50-8e3e8e597629378697fc-cf14-4476-a460-a4f677c34187 PD-1 is a protein on the outside of immune cells. When PD-1 binds to another protein, PD-L1, on the surface of cancer cells, it switches off the immune cell’s attack on the cancer cell. PD-1/PD-L1 inhibitors block these proteins to help the immune system kill cancer cells.e60dc2a1-f33c-4a05-9b50-8e3e8e597629bfb9fa65-4259-42f2-8224-12df79fc0817 Pembrolizumab (Keytruda) and nivolumab (Opdivo) are examples of PD-1/PD-L1 inhibitors.e60dc2a1-f33c-4a05-9b50-8e3e8e597629378697fc-cf14-4476-a460-a4f677c34187 Researchers still need to learn which tumors might respond best to which type of immunotherapy, and how to minimize side effect risks before this treatment can be approved for HR-positive/HER2-negative metastatic breast cancer.e60dc2a1-f33c-4a05-9b50-8e3e8e597629378697fc-cf14-4476-a460-a4f677c34187 Many studies of immunotherapy drugs alone, and in combination with other medicines, are happening now. If you’re interested in joining one of these trials, you can search ClinicalTrials.gov , or ask your oncologist to recommend a study.
Clinical Trials Clinical Trials Researchers study emerging treatments for HR-positive/HER2-negative metastatic breast cancer in clinical trials. Joining one of these studies could give you the chance to try a new treatment that isn’t available to the public, says Puri. Another benefit to joining a clinical trial is the opportunity to contribute to medical advancements and help future breast cancer patients. “Science moves forward quickly only because of our patients who are willing to try something new and different,” Cairo says. Understanding Clinical Trial Phases Researchers conduct clinical trials in steps called phases. The study phase affects which drug you get.e60dc2a1-f33c-4a05-9b50-8e3e8e5976298026638e-ee1a-4738-9c4f-906d946bb22d The investigational drugs used in phase 1 trials are in the early stage of development. Researchers don’t have much information yet on their safety or effectiveness. “A phase 1 trial is generally reserved for patients who have tried multiple [treatments] before, and do not have many remaining options,” Puri says. Phase 2 trials show whether the new drug works. Usually all the participants get the study drug, says Puri. Phase 3 trials include a few thousand people and compare the experimental drug with standard treatments. You’ll either get the new drug or an FDA-approved treatment if you join.e60dc2a1-f33c-4a05-9b50-8e3e8e5976298026638e-ee1a-4738-9c4f-906d946bb22d Common Eligibility Criteria In the past, clinical trials were one-size-fits-all. They enrolled very large groups of people with breast cancer. “Now the trials are becoming much more precise,” Cairo says. Each study has specific criteria to determine who is and who isn’t eligible to join. These criteria include:e60dc2a1-f33c-4a05-9b50-8e3e8e5976298026638e-ee1a-4738-9c4f-906d946bb22d Age Gender Cancer type and stage Past treatments Other medical conditions Before you can join a study, the research team will ask you a series of questions to determine whether it is safe and appropriate for you.e60dc2a1-f33c-4a05-9b50-8e3e8e5976298026638e-ee1a-4738-9c4f-906d946bb22d You may need to undergo additional testing to make sure you don’t have any other medical conditions that might interfere with the trial treatment. If one clinical trial isn’t a good fit, you can try to enroll in another one. Questions to Ask Your Doctor Have a discussion with your oncologist and the clinical trial team so you can be a more informed participant. Here are some questions to ask.e60dc2a1-f33c-4a05-9b50-8e3e8e5976295269458a-b71e-415a-b166-a23a35442761 What is the purpose of the study? Why is it a good fit for me? Has this treatment been tested before? What do you know about its safety and effectiveness? What are the possible risks and side effects? How long will the study take? How much time will I have to commit? Who will pay for the treatments I receive during the trial? Are there any other studies that might help me?
The Takeaway The first treatment for HR-positive/HER2-negatie metastatic breast cancer is often hormone therapy plus a CDK 4/6 inhibitor. A second-line treatment may be considered if the cancer starts to grow again or you test positive for a gene mutation like ESR1 or PIK3CA. Second-line treatments include SERDs, PIK3CA inhibitors, everolimus, PARP inhibitors, and antibody-drug conjugates. Joining a clinical trial is a way to try a new breast cancer treatment before it is approved.
Resources We Trust Mayo Clinic: Breast Cancer Types: What Your Type Means Cleveland Clinic: HER2-Negative Breast Cancer American Cancer Society: Treatment of Stage IV (Metastatic Breast Cancer) Breast Cancer Research Foundation: All About Breast Cancer Hormone Receptor Status BreastCancer.org: Treatment for Metastatic Breast Cancer
Looking Ahead to the Next Step Looking Ahead When to take the next step depends on your response to the first treatment . “The general rule is to stay on each therapy for as long as possible, as long as the disease is under control and quality of life is maintained,” says Akshjot Puri, MD , a breast medical oncologist at Houston Methodist in Texas. Doctors consider making a change when symptoms return, imaging tests like a computed tomography (CT) scan or positive emission tomography (PET) scan show that the cancer is progressing, or there are new areas of cancer, says Dr. Puri. Another reason to switch is if you test positive for a gene mutation like ESR1 or PIK3CA. An ESR1 mutation makes breast cancer resistant to hormone therapy and CDK4/6 inhibitors.e60dc2a1-f33c-4a05-9b50-8e3e8e5976290cdb5107-4376-4ec7-9eae-4afd6755cc9de60dc2a1-f33c-4a05-9b50-8e3e8e59762911fcdd8b-5eb5-4f73-a7a0-c4a452bab895 A PIK3CA mutation causes cancer cells to grow uncontrollably, which makes it more difficult to treat.e60dc2a1-f33c-4a05-9b50-8e3e8e597629054b4209-7311-4a9c-8dcd-47ad8f3f9873 Genomic testing with a liquid or tissue biopsy can find the most effective targeted therapy for your cancer and its gene mutations.e60dc2a1-f33c-4a05-9b50-8e3e8e597629f97b7532-4ad9-47c1-a8e7-e2d7570b3a9a A liquid biopsy uses a simple blood test to look for signs of cancer cells or DNA in your blood, whereas a tissue biopsy involves taking a sample of tissue from the tumor, which will likely involve local anesthetic.e60dc2a1-f33c-4a05-9b50-8e3e8e597629e500a417-444b-4a5b-ab58-67bb714d6be7 Both of these tests give your doctor information that can help decide which therapy might work best for you. Your goals and preferences are also considered in the decision. “There are several oral therapy options, and even the IV drugs have different schedules. Different drugs have different side effect profiles,” Puri says. “Picking an option that is best suited for the patient is prudent.”
Second-Line Options Second-Line Options 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.e60dc2a1-f33c-4a05-9b50-8e3e8e5976297d04665f-635d-4a90-9d59-d0098d022aed 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.e60dc2a1-f33c-4a05-9b50-8e3e8e5976297d04665f-635d-4a90-9d59-d0098d022aed 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.e60dc2a1-f33c-4a05-9b50-8e3e8e597629ab02326e-e7d5-406f-9ebd-85e955b4c90b 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.e60dc2a1-f33c-4a05-9b50-8e3e8e597629873f043c-d8b2-4412-8136-5b1a8b24b28b Two SERDs are approved to treat HR-positive/HER2-negative breast cancers with an ESR1 mutation:e60dc2a1-f33c-4a05-9b50-8e3e8e5976297d04665f-635d-4a90-9d59-d0098d022aed elacestrant (Orserdu) imlunestrant (Inluriyo) These medicines are for people who have already taken at least one type of hormone therapy.e60dc2a1-f33c-4a05-9b50-8e3e8e5976297d04665f-635d-4a90-9d59-d0098d022aed 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.e60dc2a1-f33c-4a05-9b50-8e3e8e597629c3dedda1-5690-4b47-a5cc-8e0a76c77633 Giredestrant is taken orally. PIK3CA Inhibitors About 40 percent of HR-positive/HER2-negative breast cancers have a PIK3CA gene mutation.e60dc2a1-f33c-4a05-9b50-8e3e8e59762920d4094d-8b07-4869-9aad-05ca0388c832 The PIK3CA gene holds the instructions for making a protein that helps cancer cells grow, divide, and survive. PIK3CA inhibitors block this protein.e60dc2a1-f33c-4a05-9b50-8e3e8e59762977cff101-81e3-40e9-9bc5-0541a17e4915 Three PIK3CA inhibitors are approved for HR-positive/HER2-negative metastatic breast cancer: e60dc2a1-f33c-4a05-9b50-8e3e8e59762977cff101-81e3-40e9-9bc5-0541a17e4915 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. e60dc2a1-f33c-4a05-9b50-8e3e8e59762977cff101-81e3-40e9-9bc5-0541a17e4915 PIK3CA inhibitors are not recommended for people with diabetes , because high blood sugar is a possible side effect.e60dc2a1-f33c-4a05-9b50-8e3e8e5976296d9d187f-e528-4c5f-b2af-0874fcbfbf46 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.e60dc2a1-f33c-4a05-9b50-8e3e8e5976296e6f1b09-aaa2-43e2-9ae6-61994f554d8c 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).e60dc2a1-f33c-4a05-9b50-8e3e8e597629af6b8c7e-83f2-4977-b7dd-35aa6eccbc1b 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 .e60dc2a1-f33c-4a05-9b50-8e3e8e5976295798e6ef-8634-4681-a80a-6d053e11db13 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.e60dc2a1-f33c-4a05-9b50-8e3e8e597629f24086aa-2074-4220-a442-ad7c84192579 Chemotherapy drugs that treat HR-positive/HER2-negative metastatic breast cancer include: e60dc2a1-f33c-4a05-9b50-8e3e8e597629f24086aa-2074-4220-a442-ad7c84192579 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)
Immunotherapy Immunotherapy Immunotherapy boosts the immune system response to make it a more effective cancer fighter.e60dc2a1-f33c-4a05-9b50-8e3e8e597629bfb9fa65-4259-42f2-8224-12df79fc0817 Antibody-Drug Conjugates Antibody-drug conjugates contain a monoclonal antibody (a lab-made antibody that recognizes a specific target) linked to a chemotherapy drug.e60dc2a1-f33c-4a05-9b50-8e3e8e597629064bc207-6d35-4653-9c9f-4648cf038323 The monoclonal antibody locks onto a protein on the surface of the cancer cell and delivers the chemotherapy directly to the cell. This treatment is so precise at targeting cancer cells that it’s sometimes called a “biological missile.” Examples of antibody-drug conjugates are:e60dc2a1-f33c-4a05-9b50-8e3e8e597629064bc207-6d35-4653-9c9f-4648cf038323 fam-trastuzumab deruxtecan (Enhertu) sacituzumab govitecan (Trodelvy) datopotamab deruxtecan (Datroway) Fam-trastuzumab deruxtecan treats HR-positive metastatic breast cancers that are HER2-low or HER2-ultralow.e60dc2a1-f33c-4a05-9b50-8e3e8e5976296ec92a6a-37f9-4ffd-a151-79ffa1245a90 HER2-low and HER2-ultralow breast cancer cells contain much less HER2 protein than HER2-positive breast cancer cells. But they still have enough of this protein on their surface for the drug to latch onto.e60dc2a1-f33c-4a05-9b50-8e3e8e597629bc7aaec6-cc49-46c2-a788-2234f92dd80f Sacituzumab govitecan is for people with HR-positive/HER2-negative metastatic breast cancer who have taken hormone therapy, plus at least two other medicines (such as targeted therapy or chemotherapy).e60dc2a1-f33c-4a05-9b50-8e3e8e597629a33c07b5-6b0c-42ab-b99d-b93502ab2a53 Datopotamab deruxtecan is given after hormone therapy and chemotherapy stop working.e60dc2a1-f33c-4a05-9b50-8e3e8e597629f3f52e5f-d53a-42e3-887d-9856a5cb7584 Immune Checkpoint Inhibitors Immune checkpoint inhibitors are a type of immunotherapy being investigated for HR-positive/HER2-negative metastatic breast cancer. These medications basically act like switches, turning on the immune system so that it can fight the cancer.e60dc2a1-f33c-4a05-9b50-8e3e8e597629bfb9fa65-4259-42f2-8224-12df79fc0817 In early studies, immunotherapy wasn’t very effective against HR-positive/HER2-negative metastatic breast cancer. In recent years, researchers have tried combining it with other medicines, such as chemotherapy, hormone therapy, and targeted treatments like AKT inhibitors and CDK 4/6 inhibitors, to see whether it might improve the outcome. Some of these combinations were somewhat successful, but adding another drug also increased side effects.e60dc2a1-f33c-4a05-9b50-8e3e8e5976296e4deae7-d75f-4902-a6db-9a6200e3d628 PD-1/PD-L1 inhibitors are one type of immune checkpoint inhibitor that has shown promise in recent studies for HR-positive/HER2-negative metastatic breast cancer.e60dc2a1-f33c-4a05-9b50-8e3e8e597629378697fc-cf14-4476-a460-a4f677c34187 PD-1 is a protein on the outside of immune cells. When PD-1 binds to another protein, PD-L1, on the surface of cancer cells, it switches off the immune cell’s attack on the cancer cell. PD-1/PD-L1 inhibitors block these proteins to help the immune system kill cancer cells.e60dc2a1-f33c-4a05-9b50-8e3e8e597629bfb9fa65-4259-42f2-8224-12df79fc0817 Pembrolizumab (Keytruda) and nivolumab (Opdivo) are examples of PD-1/PD-L1 inhibitors.e60dc2a1-f33c-4a05-9b50-8e3e8e597629378697fc-cf14-4476-a460-a4f677c34187 Researchers still need to learn which tumors might respond best to which type of immunotherapy, and how to minimize side effect risks before this treatment can be approved for HR-positive/HER2-negative metastatic breast cancer.e60dc2a1-f33c-4a05-9b50-8e3e8e597629378697fc-cf14-4476-a460-a4f677c34187 Many studies of immunotherapy drugs alone, and in combination with other medicines, are happening now. If you’re interested in joining one of these trials, you can search ClinicalTrials.gov , or ask your oncologist to recommend a study.
Clinical Trials Clinical Trials Researchers study emerging treatments for HR-positive/HER2-negative metastatic breast cancer in clinical trials. Joining one of these studies could give you the chance to try a new treatment that isn’t available to the public, says Puri. Another benefit to joining a clinical trial is the opportunity to contribute to medical advancements and help future breast cancer patients. “Science moves forward quickly only because of our patients who are willing to try something new and different,” Cairo says. Understanding Clinical Trial Phases Researchers conduct clinical trials in steps called phases. The study phase affects which drug you get.e60dc2a1-f33c-4a05-9b50-8e3e8e5976298026638e-ee1a-4738-9c4f-906d946bb22d The investigational drugs used in phase 1 trials are in the early stage of development. Researchers don’t have much information yet on their safety or effectiveness. “A phase 1 trial is generally reserved for patients who have tried multiple [treatments] before, and do not have many remaining options,” Puri says. Phase 2 trials show whether the new drug works. Usually all the participants get the study drug, says Puri. Phase 3 trials include a few thousand people and compare the experimental drug with standard treatments. You’ll either get the new drug or an FDA-approved treatment if you join.e60dc2a1-f33c-4a05-9b50-8e3e8e5976298026638e-ee1a-4738-9c4f-906d946bb22d Common Eligibility Criteria In the past, clinical trials were one-size-fits-all. They enrolled very large groups of people with breast cancer. “Now the trials are becoming much more precise,” Cairo says. Each study has specific criteria to determine who is and who isn’t eligible to join. These criteria include:e60dc2a1-f33c-4a05-9b50-8e3e8e5976298026638e-ee1a-4738-9c4f-906d946bb22d Age Gender Cancer type and stage Past treatments Other medical conditions Before you can join a study, the research team will ask you a series of questions to determine whether it is safe and appropriate for you.e60dc2a1-f33c-4a05-9b50-8e3e8e5976298026638e-ee1a-4738-9c4f-906d946bb22d You may need to undergo additional testing to make sure you don’t have any other medical conditions that might interfere with the trial treatment. If one clinical trial isn’t a good fit, you can try to enroll in another one. Questions to Ask Your Doctor Have a discussion with your oncologist and the clinical trial team so you can be a more informed participant. Here are some questions to ask.e60dc2a1-f33c-4a05-9b50-8e3e8e5976295269458a-b71e-415a-b166-a23a35442761 What is the purpose of the study? Why is it a good fit for me? Has this treatment been tested before? What do you know about its safety and effectiveness? What are the possible risks and side effects? How long will the study take? How much time will I have to commit? Who will pay for the treatments I receive during the trial? Are there any other studies that might help me?
The Takeaway The first treatment for HR-positive/HER2-negatie metastatic breast cancer is often hormone therapy plus a CDK 4/6 inhibitor. A second-line treatment may be considered if the cancer starts to grow again or you test positive for a gene mutation like ESR1 or PIK3CA. Second-line treatments include SERDs, PIK3CA inhibitors, everolimus, PARP inhibitors, and antibody-drug conjugates. Joining a clinical trial is a way to try a new breast cancer treatment before it is approved.
Resources We Trust Mayo Clinic: Breast Cancer Types: What Your Type Means Cleveland Clinic: HER2-Negative Breast Cancer American Cancer Society: Treatment of Stage IV (Metastatic Breast Cancer) Breast Cancer Research Foundation: All About Breast Cancer Hormone Receptor Status BreastCancer.org: Treatment for Metastatic Breast Cancer