Treatment Update: Metastatic Breast Cancer

Treatment approaches for metastatic breast cancer are individualized, taking into consideration its specific type, the parts of the body where it has spread and the preferences of the patient.

Hormone receptor (HR) positive metastatic breast cancer

Hormone therapy is typically the first treatment approach for HR-positive metastatic breast cancer. In premenopausal patients, therapy generally begins with ovarian suppression. This prevents the production of estrogen, which can fuel cancer growth. Ovarian suppression can involve the surgical removal of the ovaries (oophorectomy), but it is more common to use drugs, such as leuprolide (Lupron) or goserelin (Zoladex) to temporarily stop the ovaries from producing estrogen.

Hormone therapy begins along with ovarian suppression therapy, typically with one of the following drugs:

• Tamoxifen (Soltamox, Nolvadex) is an estrogen-blocking treatment given to both pre- and postmenopausal patients. Designed to stop the growth of the cancer and shrink the tumor, tamoxifen is often the first treatment approach for young women with metastatic breast cancer who have not received any prior hormonal therapy, and is given until ovarian suppression is achieved.

• Aromatase inhibitors (AIs) block the action of the enzyme aromatase. This results in lower levels of estrogen and has the effect of slowing the growth of hormone-sensitive tumors. Three types of AIs are approved by the U.S. Food and Drug Administration (FDA): anastrozole (Arimidex and others), letrozole (Femara and others) and exemestane (Aromasin and others). AIs are a treatment option for postmenopausal women and for premenopausal women who receive ovarian suppression therapy.

• Fulvestrant (Faslodex), an estrogen-blocking drug, attaches to estrogen receptors and changes their shape, preventing the receptors from working properly, which slows the growth of breast cancer cells. Fulvestrant is approved by the FDA for postmenopausal women with metastatic breast cancer whose tumors have not responded well to other hormone treatments, such as tamoxifen and an AI. In certain situations, fulvestrant can also be used in the treatment of HR-positive metastatic breast cancer in premenopausal women.

Tamoxifen and AIs are given in pill form. Fulvestrant is given by injection.

HER2-positive and HER2-negative metastatic breast cancer

Targeted therapies are the typical treatment approach for HER2- positive and HER2-negative metastatic breast cancer. These therapies focus on specific molecules and cell mechanisms thought to be important for cancer cell survival and growth, taking advantage of what researchers have learned in recent years about how cancer cells grow. Targeted therapies are meant to spare healthy tissues and cause fewer and less severe side effects than chemotherapy.

HER2-positive metastatic breast cancer

Treatment approaches for HER2-positive metastatic breast cancer include:

• Trastuzumab (Herceptin). Trastuzumab targets HER2-positive cancer cells, slowing or stopping their growth. Trastuzumab can be used alone, in combination with chemotherapy or with chemotherapy plus other HER2-directed medications.

• Trastuzumab emtansine (Kadcyla). Trastuzumab emtansine, also called T-DM1, is the combination of trastuzumab and a chemotherapy called DM1. Combining these drugs allows for the targeted delivery of chemotherapy to HER2-positive cancer cells.

• Pertuzumab (Perjeta). Like trastuzumab, pertuzumab targets HER2-positive cancer cells. Pertuzumab is often given in combination with trastuzumab and chemotherapy.

• Lapatinib (Tykerb). Lapatinib blocks certain enzymes, inhibiting the growth of cancer cells. Lapatinib is used for the treatment of HER2-positive metastatic breast cancer that has already been treated with chemotherapy and trastuzumab. It is sometimes combined with hormone therapy or chemotherapy.

• Margetuximab-cmkb (Margenza). Margetuximab-cmkb, in combination with chemotherapy, is used for the treatment of HER2-positive metastatic breast cancer that was previously treated with at least two anti-HER2 regimens.

• Tucatinib (Tukysa). Tucatinib is used in combination with trastuzumab and the chemotherapy capecitabin as a therapy for HER2-positive metastatic breast cancer that was previously treated with one or more anti-HER2 regimens.

• Fam-trastuzumab deruxtecan-nxki (Enhertu). In May 2022, the FDA approved fam-trastuzumab deruxtecan-nxki for previously-treated HER2-positive metastatic breast cancer that recurred within 6 months of completing therapy.

All of the above drugs except lapatinib are given intravenously (into a vein). Lapatinib is given in pill form.

HER2-negative metastatic breast cancer

Treatment approaches for HER2-negative metastatic breast cancer include:

• CDK4/6 inhibitors. CDK4/6 inhibitors interrupt enzymes that promote the growth of cancer cells. The CDK4/6 inhibitors used in treating ER-positive, HER2-negative metastatic breast cancer are abemaciclib (Verzenio), palbociclib (Ibrance) and ribociclib (Kisqali). Each of these drugs can be given in combination with hormone therapy, such as letrozole or fulvestrant. Abemaciclib can also be used alone for the treatment of ER-positive, HER2-negative metastatic breast cancer. Abemaciclib, palbociclib and ribociclib are all given in pill form.

• mTOR (mammalian target of rapamycin) inhibitors. mTOR inhibitors are a type of targeted therapy that may increase the effectiveness of hormone therapy. The mTOR inhibitor everolimus (Afinitor) is used in combination with exemestane for the treatment of postmenopausal women with hormone-positive, HER2-negative metastatic breast cancer. Everolimus is given in pill form.

• PARP inhibitors. PARP is a type of enzyme that helps repair DNA. In cancer treatment, PARP inhibitors are used to prevent cancer cells from repairing their damaged DNA. This prevention can cause the cancer cells to die, especially those with defective DNA repair pathways, such as BRCA1/2-associated breast cancers. Talazoparib (Talzenna) is approved for the treatment of BRCA-positive, HER2-negative metastatic breast cancer. Olaparib (Lynparza) is approved for the treatment of BRCA-positive, HER2-negative metastatic breast cancer that was previously treated with chemotherapy.

• PIK3CA inhibitor. Alpelisib (Piqray), in combination with the endocrine therapy fulvestrant, is approved to treat HR-positive, HER2-negative, PIK3CA-mutated metastatic breast cancer following treatment with an endocrine-based therapy.

Triple-negative metastatic breast cancer

Chemotherapy is typically the first approach for treating triple-negative metastatic breast cancer. The most common chemotherapies used include:

• Anthracyclines, such as doxorubicin (Adriamycin), pegylated liposomal doxorubicin (Doxil, Caelyx) and epirubicin (Ellence).

• Antimetabolites, such as capecitabine (Xeloda) and gemcitabine (Gemzar).

• Antimicrotubule agents, such as ixabepilone (Ixempra), eribulin (Halaven), and vinorelbine (Navelbine).

• Platinum agents, such as platinol (Cisplatin) and carboplatin (Paraplatin).

• Taxanes, such as paclitaxel (Taxol), docetaxel (Taxotere) and albumin-bound paclitaxel (Abraxane).

Chemotherapy can be given as a single drug or as a combination of drugs. Multiple courses of treatment are often given, with breaks between each course. If one treatment approach does not work or stops working, a different chemotherapy (or combination of chemotherapies) is often used. The chemotherapies used for the treatment of metastatic breast cancer are generally given intravenously.

In April 2021, the FDA approved sacituzumab govitecan-hziy (Trodelvy) for the treatment of metastatic triple-negative breast cancer that has been treated with at least two prior therapies. Sacituzumab govitecan-hziy, an antibody-drug conjugate, works by combining (linking) a chemotherapy with an antibody that seeks out cancer cells. It is given intravenously.

A note about chemotherapy in the treatment of metastatic breast cancer

In addition to treating triple-negative metastatic breast cancer, chemotherapy can be given for hormone-positive metastatic breast cancer that is no longer responding to hormone therapy and for HER2-positive metastatic breast cancer (in combination with anti-HER2 treatments).

Treatment Side Effects

All cancer treatments can cause side effects. It’s important that you report any side effects that you experience to your health care team so they can help you manage them. Report them right away—don’t wait for your next appointment. Doing so will improve your quality of life and allow you to stick with your treatment plan. It’s important to remember that not all patients experience all side effects, and patients may experience side effects not listed here.

Side Effects of Chemotherapy

The side effects of chemotherapy depend on the type and dose of drugs given and the length of time they are used, and can include:

• Fatigue
• Headaches
• Reduction in blood cell counts, with need for transfusions of red blood cells or platelets
• Fatigue
• Bruising or bleeding
• Abnormal taste of food; loss of appetite
• Nausea
• Rashes
• Hair loss
• Hearing loss
• Diarrhea
• Mouth sores or painful swallowing
• Changes in the skin (dryness, rashes, darkening, or lines on the fingernails)
• Pain, tingling, and numbness, especially in hands and feet (neuropathy)

Side Effects of Targeted Treatments and Hormone Therapy

Targeted treatment drugs and hormone therapy don’t have the same effect on the body as do chemotherapy drugs, but they can still cause side effects.

Side effects of certain targeted therapies can include diarrhea, liver problems (such as hepatitis and elevated liver enzymes), nerve damage, problems with blood clotting and wound healing, and high blood pressure.

The side effects of hormone therapy are dependent on the type of therapy and include hot flashes (seen more with tamoxifen) and joint pain (seen more with aromatase inhibitors).

Side Effects of Radiation Therapy

Changes to the skin are the most common side effects of radiation therapy; those changes can include dryness, swelling, peeling, redness, and blistering. It’s especially important to contact your health care team if there is any open skin or painful areas, as this could indicate an infection.

You may want to add that radiation can also produce systemic symptoms such as fatigue. In the setting of metastatic breast cancer, radiation is used to palliate symptoms and is often given to treat bone pain. Side-effects depend on the radiation site (also known as field). For example, if a patient is getting radiation to the pelvis or low back, she may also have diarrhea because there is bowel in or near the field being treated.

General Side Effects

Some side effects may occur across treatment approaches. This section provides tips and guidance on how to manage these side effects should they occur.

Digestive Tract Symptoms

Nausea and vomiting

• Avoid food with strong odors, as well as overly sweet, greasy, fried, or highly seasoned food.
• Nibble on dry crackers or toast. These bland foods are easy on the stomach.
• Having something in your stomach when you take medication may help ease nausea.
• Many effective medications for nausea and vomiting have been developed in recent years; talk to your doctor about whether any may be right for you.

Diarrhea

• Drink plenty of water. Ask your doctor about using drinks such as Gatorade which provide electrolytes as well as liquid. Electrolytes are body salts that must stay in balance for cells to work properly.
• Over-the-counter medicines such as loperamide (Imodium A-D and others) and prescription drugs are available for diarrhea but should be used only if necessary. If the diarrhea is bad enough that you need medicine, discuss it with your doctor or nurse.
• Choose foods that contain soluble fiber—for example beans, oat cereals, oranges, and flaxseeds. High-pectin foods such as peaches, apples, oranges, grapefruit, bananas, and apricots can also help to avoid diarrhea.
• Low fat food choices are less likely to cause diarrhea than fatty, greasy, or fried foods. The fats you eat should come from healthy sources, such as olive oil, canola oil, avocado, olives, nuts, and seeds.

Loss of appetite

• To help maintain your weight, eat small meals throughout the day. That’s an easy way to take in more protein and calories. Try to include protein in every meal.
• Be as physically active as you can. Sometimes, taking a short walk an hour or so before meals can help you feel hungry.
• Keep high-calorie, high-protein snacks on hand such as hard-boiled eggs, peanut butter, cheese, ice cream, granola bars, liquid nutritional supplements, puddings, nuts, canned tuna, or trail mix.
• If you are struggling to maintain your appetite, talk to your health care team about whether appetite-building medication could be right for you.

Fatigue

Fatigue (extreme tiredness not helped by sleep) is one of the most common side effects of many cancer treatments. If you are taking a medication, your doctor may lower the dose of the drug, as long as it does not make the treatment less effective. If you are experiencing fatigue, talk to your doctor about whether taking a smaller dose is right for you.

There are a number of other tips for reducing fatigue:

• Take several short naps or breaks.
• Take short walks or do some light exercise, if possible.
• Try easier or shorter versions of the activities you enjoy.
• Ask your family or friends to help you with tasks you find difficult or tiring.

Fatigue can be a symptom of other illnesses, such as anemia, diabetes, thyroid problems, heart disease, rheumatoid arthritis, and depression. So be sure to ask your doctor if he or she thinks any of these conditions may be contributing to your fatigue.

Pain

There are a number of options for pain relief, including prescription and over-the-counter medications. It’s important to talk to a member of your health care team before taking any over-the counter medication, to determine if they are safe and will not interfere with your treatments. Many pain medications can lead to constipation, which may make your pain worse. Your doctor can prescribe medications that help to avoid constipation.

Physical therapy, acupuncture, and massage may also be of help in managing your pain. Other techniques, such as mindfulness meditation, deep breathing exercises, and yoga may also be helpful. Consult with a member of your health care team before beginning any of these activities.

Bone Loss

Hormone therapies and chemotherapy can cause bone loss, which increases a woman’s risk for osteoporosis (a condition in which bones become weak and brittle, leading to a higher risk of fracture). Talk with your health care team about how exercise and changes in your diet may help keep your bones healthy.

It’s also important to talk to your doctor about the medications available for bone health:

• Bisphosphonates such as zoledronic acid (Zometa and others) slow the process by which bone wears away and breaks down. These medications belong to a class of drugs called osteoclast inhibitors.
• RANK ligand inhibitors block a factor in bone development known as RANK ligand, which stimulates cells that break down bone. By blocking RANK ligand, these drugs increase bone density and strength. So far, the only drug approved in this class is denosumab (Xgeva, Prolia). Like bisphosphonates, RANK ligand inhibitors are a type of osteoclast inhibitor.

As you manage your cancer, it’s important to remember that you are a consumer of health care. The best way to make decisions about health care is to educate yourself about your diagnosis and get to know the members of your health care team, including doctors, nurse practitioners, physician assistants, nurses, dietitians, social workers and patient navigators.

Here are some tips for improving communication with your health care team:

Start a health care journal. Having a health care journal or notebook will allow you to keep all of your health information in one place. You may want to write down the names and contact information of the members of your health care team, as well as any questions for your doctor. Keep a diary of your daily experiences with symptoms related to your illness or treatment. You can separate your journal or notebook into different sections to help keep it organized.

Prepare a list of questions. Before your next medical appointment, write down your questions and concerns. Because your doctor may have limited time, you should ask your most important questions first, and be as specific and brief as possible.

Bring someone with you to your appointments. Even if you have a journal and a prepared list of questions or concerns, it’s always helpful to have support when you go to your appointments. The person who accompanies you can serve as a second set of ears. He or she may also think of questions to ask your doctor or remember details about your symptoms or treatment that you may have forgotten.

Write down your doctor’s answers. Taking notes will help you remember your doctor’s responses, advice, and instructions. If you cannot write down the answers, ask the person who accompanies you to do that for you. If you have a mobile device, ask if you can use it to take notes or record the conversation. Taking notes will help you review the information later.

Q: Are there any immunotherapies approved for the treatment of metastatic breast cancer?

A: The purpose of cancer-targeting immunotherapy is to modify the immune system to recognize that the cancer is foreign to the body and needs to be attacked. Immunotherapy travels through the bloodstream, helping to prompt what is called an “immune response.”

Immunotherapy is a newer approach for the treatment of metastatic breast cancer. In combination with chemotherapy, pembrolizumab (Keytruda) is approved by the FDA for the treatment of triple-negative metastatic breast cancer. Pembrolizumab targets PD-L1, a protein that can prevent the body’s immune system from attacking tumors.

Q: I have been diagnosed with metastatic breast cancer and will be treated with chemotherapy. I want to preserve my fertility. What are my options?

A: Chemotherapy can induce a temporary or permanent menopause in younger women. Before treatment begins, consider consulting with a specialist in reproductive medicine about options that might be right for you. Ask about newer options for preserving fertility, such as oocyte cryopreservation, also known as egg freezing. In this process, the woman’s eggs are removed, frozen and stored for later use. Another option involves the freezing of fertilized eggs.

Q: Am I at higher risk of osteoporosis while being treated for metastatic breast cancer?

A: Hormone therapies and chemotherapy can cause bone loss, which increases the risk of osteoporosis (a condition in which bones become weak and brittle). Talk with your health care team about how exercise and changes in your diet may help keep your bones healthy, and about the medications available for bone health:

• Bisphosphonates such as zoledronic acid (Zometa and others) slow the process that causes bone to wear away and break down. These medications belong to a class of drugs called osteoclast inhibitors, which can be used to prevent bone loss and to maintain bone strength if breast cancer has spread to the bones.

• The RANK ligand inhibitor denosumab (Xgeva, Prolia) blocks a factor in bone development known as RANK ligand, which stimulates cells that break bone down. By blocking RANK ligand, these drugs increase bone density and strength. Like bisphosphonates, RANK ligand inhibitors are a type of osteoclast inhibitor.

Q: What is a tumor marker?

A: Tumor markers are proteins manufactured by tumors and shed into the blood. They can be measured through a blood test, and some oncologists find the measurements useful in assessing the success of treatment in women with metastatic breast cancer. In those women, the presence or absence of tumor markers may help guide treatment options.

Q: Is radiation a treatment approach for metastatic breast cancer?

A: Radiation is not a primary treatment approach for metastatic breast cancer, but it can be used in conjunction with other treatments to shrink tumors and improve quality of life, as it can:

• Lessen pain from tumors that have spread to the bone or the spine.

• Remove pressure from a pinched nerve to reduce pain, numbness or weakness.

• Decrease bleeding.

• Improve breathing by opening a blocked airway.

If radiation treatments are given, the dose and schedule is based on a number of factors, including the severity of the pain or loss of function, and the type and schedule of other treatments being given for the cancer.