Treatment Update: Metastatic Triple-Negative Breast Cancer (TNBC)

Chemotherapy

Because TNBC does not have receptors for estrogen or progesterone and does not contain an overabundance of the HER2 protein, many drugs that work for hormone receptor-positive tumors are not an effective treatment option. However, TNBC often responds well to chemotherapy.

The most common chemotherapies used to treat TNBC 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).

• Antitumor antibiotics, such as mitoxantrone (Novantrone).

• Platinum agents, such as cisplatin (Platinol) 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 TNBC are generally given intravenously.

Antibody-drug conjugate

In April 2021, the U.S. Food and Drug Adminstration (FDA) approved sacituzumab govitecan-hziy (Trodelvy) for the treatment of metastatic TNBC that has been treated with at least two prior therapies. Sacituzumab govitecan-hziy works by linking a chemotherapy with an antibody (an immune system protein) that seeks out cancer cells. It is given intravenously.

Immunotherapy

Our immune system works constantly to keep us healthy. It recognizes and fights against danger, such as infections, viruses and growing cancer cells. In general terms, immunotherapy uses our own immune system as a treatment against cancer.

Immunotherapy is a newer approach for the treatment of metastatic breast cancer. The immunotherapy pembrolizumab (Keytruda), in combination with chemotherapy, is approved by the FDA for the treatment of TNBC. Pembrolizumab targets PD-1, a protein that can prevent the body’s immune system from attacking tumors.

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

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 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 bone down.

By blocking RANK ligand, these drugs increase bone density and strength. Currently, the only drug approved in this class is denosumab (Xgeva, Prolia). Like bisphosphonates, RANK ligand inhibitors are a type of osteoclast inhibitor.

Hot Flashes

Breast cancer treatments can lead to menopausal symptoms, such as hot flashes and night sweats. If you are experiencing these side effects, speak with your health care team about ways to cope with them. There are several medications that potentially help decrease hot flashes. Talk to your doctor to determine if medication is an option for you.

The following tips may also help: * Identify the triggers for your hot flashes. For many, hot flashes can be triggered by stress, a hot shower, caffeine or spicy foods. * Change your lifestyle habits to cope with your specific triggers. That may mean regular exercise, using relaxation techniques and changing your diet. * Dress in layers so that you can remove clothing if needed. * Keep ice water handy to help you cool off. * Avoid synthetic materials, especially at nighttime. Wear pajamas and use sheets made of cotton. * Take a cool shower before going to bed.

Vaginal Dryness

Treatments for breast cancer can lead to vaginal dryness and a lowered sex drive. Use of a personal lubricant (such as Astroglide) and/or a moisturizer (such as Replens) can often help. If vaginal dryness persists, talk to your doctor about whether a prescription medicine is right for you. You may wish to ask for a referral to a health care professional who specializes in these issues.

Chemotherapy

The side effects specific to chemotherapy depend on the type and dose of drugs given and the length of time they are used. They can include the following:

• Hair loss. Depending on the treatment, hair loss may start anywhere from one to three weeks after the first chemotherapy session. If you choose to wear a wig, consider buying one before you lose much hair so you feel more prepared and you can match your own hair color. You can have your wig professionally fitted and styled by a full-service wig salon. Look for a salon in your community that specializes in hair loss resulting from chemotherapy. Hair usually starts to grow back after the end of treatment. It may have a different texture or color, but these changes are usually temporary. Specially-designed scalp-cooling caps worn during chemotherapy infusions can reduce hair loss from some chemotherapies for some patients.

• Nerve damage. Some people being treated with chemotherapy experience nerve damage with symptoms that may include difficulty picking up objects or buttoning clothing, problems maintaining balance, difficulty walking and hearing loss. Peripheral neuropathy is a form of nerve damage that may cause numbness or tingling in the hands and feet. Often, nerve damage due to cancer treatments is temporary. If you are coping with this side effect, take extra care when handling hot, sharp or dangerous objects. You should also use handrails on stairs and in the tub or shower.

• Low white blood cell counts. Chemotherapy may lead to low white blood cell counts, a condition called neutropenia. White blood cells play a key role in fighting infection. Your doctor can prescribe medication designed to help increase white blood cell counts. If you develop a fever (a sign of infection), let your health care team know immediately so that you can get proper treatment.

• Mouth sores (mucositis) are also a side effect of chemotherapy. Your doctor may recommend treatments such as:

• Coating agents. These medications coat the entire lining of your mouth, forming a film to protect the sores and minimize pain.

• Topical painkillers. These are medications that can be applied directly to your mouth sores.
• Over-the-counter treatments. These include rinsing with baking soda or salt water or using “magic mouthwash,” a term given to a solution to treat mouth sores. Magic mouthwash usually contains at least three of these ingredients: an antibiotic, an antihistamine or local anesthetic, an antifungal, a corticosteroid and/or an antacid.

Chemotherapy can also cause changes in the way food and liquids taste, including an unpleasant metallic taste in the mouth. Many people find that switching to plastic utensils helps. It may also help to avoid eating or drinking anything that comes in a can and to use enamel-coated pots and pans for food preparation.

Immunotherapy

Immunotherapy travels through the bloodstream, helping to prompt what is called an “immune response.” Because immunotherapy can attack healthy cells as well as cancer cells, certain side effects may be experienced.

Common side effects of immunotherapy used in the treatment of TNBC include rash, diarrhea, fatigue, shortness of breath, thyroid dysfunction and joint pain.

Q: Are there any recent clinical trial results for the treatment of metastatic TNBC?

A: TNBC continues to be studied in clinical trials. Recent results include:

• KEYNOTE-355. The final analysis of the phase III KEYNOTE-355 trial showed a statistically significant improvement in overall survival when pembrolizumab was added to chemotherapy as a first-line treatment of metastatic TNBC that is strongly positive for the protein PD-L1. These findings provide support for the combination of pembrolizumab and chemotherapy as a standard of care for the treatment of PD-L1–positive TNBC.

• TROPION-PanTumor01. Updated data from the phase I TROPION-PanTumor01 trial showed the investigational drug datopotamab deruxtecan had encouraging durable tumor response and disease control in the treatment of metastatic triple-negative breast cancer that had progressed after standard therapy. Datopotamab deruxtecan is an antibody drug conjugate (ADC), a type of targeted therapy.

• ASCENT. In April 2021, sacituzumab govitecan-hziy (Trodelvy) was approved by the FDA for the treatment of metastatic triple-negative breast cancer that has been treated with at least two prior therapies. Additional data from the phase III ASCENT trial reinforce the benefits of sacituzumab govitecan-hziy when given in these circumstances.

Q: I have been diagnosed with TNBC and am being treated with chemotherapy. What can I do to preserve my fertility?

A: Chemotherapy may induce a temporary or permanent menopause among younger patients. For many of these individuals, preserving their fertility (the ability to have a child) plays a large part in their treatment decisions and should be discussed with their oncologist before starting chemotherapy.

There are steps that can be taken if you are concerned about your ability to have children after treatment:

• Discuss treatment plans with members of your health care team. The discussion should include the coverage provided by your health insurance plan.

• Consider consulting with a specialist in reproductive medicine, who can help weigh the benefits and risks of a specific treatment.

• Ask about newer options for preserving fertility, such as oocyte cryopreservation, also known as egg freezing. In this process, the patient’s eggs are removed, frozen and stored for later use.

Another option includes freezing fertilized eggs. You can discuss which option is best for you with your fertility specialist.

Q: What is a treatment summary and why is it important?

A: Keeping your own records up-to-date in the form of a treatment summary can be helpful, as it allows you and your family members to have instant access to the specifics of your TNBC diagnosis and treatment. A treatment summary should include:

• Your name and date of birth
• Date of diagnosis
• Prescribed therapy/therapies, including dates started and stopped and dosages when appropriate
• Dates and types of baseline and post-diagnosis testing and the results of these tests
• Other medications and supplements you are taking
• Names, affiliations and contact information of all members of your health care team

Ask the members of your health care team what they suggest be included. Take your personal record with you when you visit any doctor, not just your oncologist.