Patient education: Treatment of metastatic breast cancer (Beyond the Basics)

INTRODUCTION — The word "metastatic" describes cancer that has spread beyond its original location in the body. Metastatic breast cancer is cancer that started in the breast and spread to the lymph nodes or other organs such as the liver, lung, or brain. Most of the time, metastatic breast cancer cannot be cured. However, treatment can help you live longer, slow your cancer's progression, relieve your symptoms, and improve your quality of life.

CANCER CARE DURING THE COVID-19 PANDEMIC — COVID-19 stands for "coronavirus disease 2019." It is an infection caused by a virus called SARS-CoV-2. The virus first appeared in late 2019 and has since spread throughout the world. Getting vaccinated lowers the risk of severe illness; experts recommend COVID-19 vaccination for anyone with cancer or a history of cancer.

In some cases, if you live in an area with a lot of cases of COVID-19, your doctor might suggest rescheduling or delaying medical appointments. But this decision must be balanced against the importance of getting care to screen for, monitor, and treat cancer. Your doctor can talk to you about whether to make any changes to your appointment schedule. They can also advise you on what to do if you test positive or were exposed to the virus.

LOCAL RECURRENCE — Anyone who has been treated for breast cancer is at risk of a "local" recurrence. This is not the same as metastatic cancer; it means cancer that comes back in the breast area rather than a more distant part of the body. The exact site of a local recurrence may depend on how the original cancer was treated:

●For women who had breast-conserving treatment (BCT), meaning surgery to remove the cancer but not the entire breast, a local recurrence may present as a new tumor in the breast.

●For women who had a mastectomy (removal of one or both breasts), a local recurrence may present as a mass on the skin or chest wall.

Women who had either type of surgery may also experience recurrence in the axilla (armpit area). A local recurrence should be distinguished from an entirely new breast cancer in the opposite breast, which is treated as such and is not considered a "recurrence" or a "metastasis" (when the original cancer spreads).

The approach to treating a local recurrence will depend on the size and location of your tumor, as well as whether or not you have had radiation therapy (RT). Your doctors and surgeons can talk with you to determine the most appropriate treatment plan. If surgery is not an option, radiation may be an alternative treatment.

METASTATIC DISEASE — As discussed above, the term "metastatic" means cancer that has spread to other parts of the body, eg, organs or lymph nodes.

Goals of treatment — Unfortunately, few if any people with metastatic breast cancer will be cured, meaning that the cancer completely disappears and never comes back. However, there are treatment options that can help you live longer, relieve cancer-related symptoms, and improve your overall quality of life. Many doctors describe this goal as "keeping you feeling as good as you can for as long as you can."

Since the main goal of therapy is to get you feeling as good as possible, your oncologist (cancer doctor) will attempt to do so by recommending therapies that are most likely to work and have the fewest side effects. Available therapies can either be those that work in one area (called "local" therapies), such as surgery and/or radiation, and those that work everywhere in your body (called "systemic" therapies).

Systemic treatment — Systemic therapy includes the use of antiestrogen, or more commonly called "endocrine" therapy, chemotherapy, and/or a drug that is a type of "targeted therapy," meaning it blocks a certain protein in cancer cells that is important for their survival and growth. The choice between the treatment options depends on the tumor's characteristics (including whether certain genetic mutations are present), your symptoms, and several other factors including:

●Status of hormone receptors – Some breast cancers have "receptors" to certain hormones (estrogen or progesterone), meaning those hormones can increase their growth. These are referred to as estrogen receptor (ER)- or progesterone receptor (PR)-positive cancers. People whose cancer falls into this category tend to have better outcomes than those whose tumors are ER and/or PR negative. Additionally, people with hormone receptor-positive cancer are candidates for a type of treatment called endocrine therapy, but those with hormone receptor-negative cancer are not (since these medications do not work in this situation). (See 'Approach to treatment of hormone receptor-positive disease' below.)

●HER2 expression – Human epidermal growth factor receptor 2 (HER2) is a protein that is present in approximately one-fifth of all breast cancers. People with HER2-positive cancer are very likely to benefit from certain treatments that target this protein. (See 'Approach to treatment of HER2-positive disease' below.)

Hormone receptor and HER2 status should be reassessed if you have a relapse (recurrence) of breast cancer. This is because metastatic cancer can have different characteristics from the primary (original) breast cancer, and if this is the case, you may have different treatment options than previously.

The best approach to treating metastatic breast cancer depends on your situation, your preferences, and the specific characteristics of your cancer.

Approach to treatment of hormone receptor-positive disease — People with hormone receptor-positive, HER2-negative metastatic breast cancer who don't have severe symptoms, and do not have life-threatening disease or evidence of visceral involvement (tumors affecting certain vital organs), do not require initial chemotherapy and can be treated first with endocrine therapy.

The approach to patients with hormone receptor-positive, HER2-positive disease is discussed below. (See 'Approach to treatment of HER2-positive disease' below.)

Endocrine therapy — The goal of endocrine therapy is to prevent cancer cells from being stimulated by estrogen. Endocrine therapy is also known as "antiestrogen treatment." This includes:

●Selective estrogen receptor modulators (SERMs)

●Aromatase inhibitors (AIs)

●Selective estrogen receptor down-regulators (SERDs)

●Progestogens

●Other sex steroid hormones

Endocrine therapy is often used in women with hormone receptor-positive cancer who have already been through menopause (and whose ovaries are no longer producing estrogen).

Women who have not yet been through menopause (when monthly periods stop and the ovaries stop producing estrogen) are also treated with endocrine therapy, but in this case, some medications must be combined with another treatment to stop the ovaries from making estrogen. This might involve surgery to remove the ovaries ("oophorectomy") or medications called luteinizing hormone-releasing hormone (LHRH) agonists and antagonists (eg, goserelin and leuprolide). However, some may choose to take a drug called tamoxifen alone. (See 'Tamoxifen' below.)

Sequential endocrine therapies are typically used. Most clinicians will recommend chemotherapy only for people who progress despite two or three trials of endocrine therapy.

A targeted therapy may be recommended along with endocrine therapy. (See 'Treatments frequently added to endocrine therapy' below.)

Aromatase inhibitors — Aromatase inhibitors (AIs) are drugs that reduce estrogen levels in the body. They do this by blocking the protein that helps make estrogen outside of the ovary (aromatase). Medications in this class include anastrozole, letrozole, and exemestane. These agents are only effective in postmenopausal women; in fact, if a woman's ovaries are functional (ie, she has not yet gone through menopause), use of an AI can cause a paradoxical increase in estrogen levels (which is the opposite of the desired goal in breast cancer). If your doctor is not sure whether your ovaries are still producing estrogen, he or she may do blood tests or suggest medicine to suppress their function (or surgery to remove the ovaries altogether).

Side effects of AIs include hot flashes, weakening of the bones and bone fractures, and pain in the muscles and joints.

There is evidence that combining an AI with other kinds of drugs may be more effective than the AI alone. (See 'Treatments frequently added to endocrine therapy' below.)

Fulvestrant — Fulvestrant is another medication that blocks the influence of estrogen on breast cancer cells. It can be used when metastatic disease has progressed despite prior endocrine therapy, or as a first line of therapy in postmenopausal women, or in premenopausal women if their ovaries have been removed or suppressed with medication. Because it is not absorbed when given orally, and because it disappears from the bloodstream very quickly after an intravenous (IV) injection, fulvestrant must be given as an injection into the muscle. This usually involves getting two simultaneous injections (one in each buttock) once a month. In some cases, fulvestrant may be given along with an AI. (See 'Aromatase inhibitors' above.)

Side effects of fulvestrant include hot flashes, increases in liver enzymes, injection site pain, and joint pain.

Tamoxifen — Tamoxifen is a type of drug called a selective estrogen receptor modulator (SERM). These agents block estrogen from stimulating breast cells.

Tamoxifen is a pill that you take by mouth. It is commonly used as a first-line endocrine therapy for premenopausal women and for men with advanced breast cancer.

Well over one-half of people with hormone receptor-positive breast cancer who take tamoxifen will have their disease stop growing or decrease in size. However, some do not respond at all to tamoxifen. Regardless, even if tamoxifen treatment is effective at first, almost all cancers will eventually stop responding.

A subset of people with metastatic breast cancer experience a disease "flare" within two days to three weeks after starting tamoxifen. This may cause an increase in bone pain, a high blood calcium level, and (in people with breast cancer involving the skin) skin redness or an increase in the size and/or number of skin nodules. These flares usually subside within four to six weeks. In the meantime, the symptoms can be treated with medications that reduce pain and lower blood levels of calcium. In severe cases, your doctor may tell you to temporarily stop taking tamoxifen until the flare subsides. Many doctors consider a flare reaction to be a sign that endocrine therapy is working. Possible side effects of tamoxifen include hot flashes, an increased risk of blood clots, uterine bleeding, and endometrial cancer.

Sex steroid hormones — Progestins, estrogens, and androgens are all sex steroid hormones. They may play a role in the third- or fourth-line treatment of metastatic breast cancer (ie, they may be appropriate in situations in which other therapies have not been successful).

Treatments frequently added to endocrine therapy — These are medications that target and interfere with the function of specific enzymes in the body.

●Cyclin-dependent kinase (CDK) 4/6 inhibitors – These drugs include palbociclib, ribociclib, and abemaciclib; one of these medications may be given along with an AI or fulvestrant. (See 'Aromatase inhibitors' above and 'Fulvestrant' above.)

●Alpelisib – This drug may be added to fulvestrant for people whose tumors have a mutation in a gene called phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA). (See 'Fulvestrant' above.)

●Everolimus – This is a type of medication called a mechanistic target of rapamycin (mTOR) inhibitor; it is sometimes used in combination with an AI or tamoxifen. (See 'Aromatase inhibitors' above and 'Tamoxifen' above.)

While effective, these combined regimens are typically associated with more side effects than seen with one agent alone.

Chemotherapy — Chemotherapy is a different kind of treatment to attack cancer, and is typically used for people with hormone receptor-positive cancers after their cancer has progressed on multiple lines of endocrine therapy, or for those with cancer that is growing quickly or affecting organs like the liver or lungs. Chemotherapy is discussed in more detail below. (See 'Chemotherapy' below.)

Approach to treatment of HER2-positive disease — People whose breast cancers produce high levels of the protein human epidermal growth factor receptor 2 (HER2) can benefit from treatments that target this protein. These kinds of cancers are called HER2-positive breast cancers and are typically treated with a HER2-directed agent plus chemotherapy, particularly if they are also hormone receptor negative. (See 'Chemotherapy' below.)

For people with HER2-positive disease that is also hormone receptor positive, HER2-directed therapy is typically given first with chemotherapy for several cycles and then with endocrine therapy. However, for some women whose disease is not causing significant symptoms or burden, a HER2 agent can be used with endocrine therapy as initial therapy. Endocrine therapies are discussed above. (See 'Endocrine therapy' above.)

There are several drugs that target HER2; these are discussed in more detail below. Your doctor will talk to you about whether HER2-targeted therapies (or combination of therapies) are options for you and help you decide on a treatment plan.

Trastuzumab — Trastuzumab is a "monoclonal antibody"; it can work by itself or in combination with endocrine therapy or chemotherapy. It is generally given IV once per week or once every three weeks. The most common side effect is fever and/or chills. Heart failure develops in approximately 3 to 5 percent of women treated with trastuzumab. Trastuzumab-related heart damage may not be permanent, and improvements have been seen once trastuzumab is discontinued.

Pertuzumab — Pertuzumab is a similar drug to trastuzumab. It has not been tested by itself, or by itself with other types of therapies like endocrine therapy or chemotherapy. However, when combined with chemotherapy and trastuzumab, pertuzumab is more effective than just chemotherapy and trastuzumab, and so it is often added to chemotherapy and trastuzumab.

Ado-trastuzumab emtansine — This drug contains a highly potent chemotherapy agent (emtansine) linked to trastuzumab. This way, the trastuzumab carries the emtansine directly, and only, to cells that make HER2. Inside the cells, the emtansine is released to kill the cell. Ado-trastuzumab emtansine is only given by itself, not in combination with other medications; it has been found to be effective even when trastuzumab itself does not work. In addition, it is just as effective as some combinations of trastuzumab plus chemotherapy. However, some of the emtansine does leak out into the blood system, which can lead to more side effects than are seen with trastuzumab alone, most notably, low platelet counts (platelets are made in your bone marrow and stop bleeding) and damage to the nerves of the fingers and toes ("peripheral neuropathy").

Other drugs that target HER2 — If disease progresses after initial treatment, other options may include:

●Fam-trastuzumab deruxtecan – This contains two drugs, a HER2 antibody and a topoisomerase I inhibitor. It can cause lung damage in some people.

●An oral tyrosine kinase (TKI) inhibitor – Drugs in this category include tucatinib, lapatinib, and neratinib. They are often used along with trastuzumab and/or a chemotherapy agent. Side effects may include skin rash, diarrhea, and nausea.

Approach to treatment of "triple negative" disease — People with HER2-negative, hormone receptor-negative (also called "triple-negative") metastatic breast cancer are typically treated with chemotherapy. Strategies involving a combination of chemotherapy and immunotherapy, which harnesses the body's own immune system to fight cancer, are also starting to be used for treating triple-negative disease. Different immunotherapy drugs are being studied for this purpose. Chemotherapy is discussed in the section below. (See 'Chemotherapy' below.)

Chemotherapy — Chemotherapy is a treatment given to slow or stop the growth of cancer cells. Chemotherapy is not given every day but instead is given in cycles. A cycle is the time it takes to give the treatment and then allow the body to recover from the side effects of the medicines. A typical cycle of chemotherapy is 21 or 28 days. Different drugs are given on different schedules; for example, a cycle could involve multiple daily or weekly doses, in many cases followed by a recovery period.

Chemotherapy is usually suggested in the following situations, depending on the receptor status of your cancer (see 'Systemic treatment' above):

●After your cancer has become refractory (resistant) to endocrine therapies, if you have ER-positive breast cancer

●Early on, if you have ER-negative breast cancer

●Frequently early on, with a HER2-directed agent, if you have HER2-positive breast cancer

Chemotherapy drugs may be given alone, one after another, or in combination. In metastatic breast cancer, a single chemotherapy agent is usually given. If it is effective, then that agent is continued; if not, your doctor might suggest trying a different chemotherapy agent.

However, in certain cases, especially if the cancer appears to be growing rapidly and is causing damage to certain organs (such as your lungs or liver), combinations of different chemotherapy drugs are used at the same time. Many times, these will be continued together for a while until the cancer is sufficiently shrunk so as not to be life threatening, and then one of the drugs is discontinued while the other is maintained.

There are a variety of chemotherapy drugs that can be used to treat breast cancer as single agents or in combination. Some are given by IV, and some as pills (orally). Some are more likely to cause bothersome side effects, such as hair loss, while others are less so. Nausea and vomiting used to be quite common with chemotherapy, but when a single agent is used, and in combination with modern antinausea drugs, this side effect has become less common. All chemotherapy suppresses bone marrow function; as new blood cells are made in the bone marrow, this means you will have fewer blood cells, which can lead to symptoms of anemia (such as fatigue) and temporarily make you more susceptible to infection. Different classes of chemotherapy agents may be associated with different side effects. You will be monitored closely while undergoing chemotherapy, so any side effects can be quickly identified and managed. Your doctor can talk to you about the best approach for your situation.

It is not clear how many cycles of chemotherapy are best for treating metastatic breast cancer. In general, overall survival is the same in women treated with continuous chemotherapy (repeating cycles until it becomes ineffective) or intermittent chemotherapy (giving several cycles and then stopping until the cancer progresses), although tumor growth may be slowed somewhat in women treated with continuous therapy. Intermittent chemotherapy may allow for a better quality of life, since it involves taking breaks from treatment. This may be a reasonable option if your cancer-related symptoms stay under control during treatment.

Women with a BRCA mutation — Mutations in two genes, known as breast cancer susceptibility genes 1 and 2 (BRCA1 and BRCA2), are associated with an increased risk of hereditary breast (as well as ovarian) cancer. (See "Patient education: Genetic testing for hereditary breast, ovarian, prostate, and pancreatic cancer (Beyond the Basics)".)

BRCA carriers with metastatic triple-negative breast cancer who have a BRCA mutation and have already received chemotherapy may benefit from a medication called a poly(ADP-ribose) polymerase (PARP) inhibitor. A PARP inhibitor may also be suggested for BRCA carriers with hormone receptor-positive, HER2-negative disease whose cancer has progressed after treatment with chemotherapy and endocrine therapy. (See 'Endocrine therapy' above.)

Other types of treatments

Bone-modifying agents — Bone-modifying agents are not used to treat breast cancer directly; however, they can help prevent complications involving bones, such as fractures, spinal cord compression, and hypercalcemia of malignancy (in which there is too much calcium in the blood). Two classes of agents used are the bisphosphonates (pamidronate, zoledronic acid, clodronate, and ibandronate) and a medication called denosumab.

Of these, the most commonly used is zoledronic acid, which is given by IV over approximately 15 minutes. Pamidronate may be equally effective, but takes longer to administer (90 minutes) and thus is less convenient for most people. The main side effects of these drugs are occasional muscle and bone aches for a few days after the injection.

Studies have demonstrated that zoledronic acid can be given every three months, although in some situations (eg, people with extensive or symptomatic bone metastases), the schedule may start with monthly injections for six months before switching to every three months. In the past, these drugs were discovered to cause a problem called osteonecrosis of the jaw, in which bone cells in the jaw die due to lack of blood. However, subsequent studies have demonstrated that this complication is very rare when injections are spread out to every three months (versus continued monthly injections) and the person has healthy teeth.

Denosumab is a drug given as a monthly subcutaneous (under the skin) injection. It is as effective as the bisphosphonates, but is more convenient and may be less likely to cause the post-treatment aches and pains. However, it is much more expensive, and so many insurances require treatment with zoledronic acid first if possible.

Role of surgery or radiation therapy — Treatment to a specific lesion (mass) may be required if it is causing symptoms or there is a threat of complications (eg, a tumor compressing the spinal cord and causing a lot of swelling in the brain, or affecting the hip and raising the risk of fracture). This may require either surgery or radiation therapy (RT), or both, in the affected area. The exact approach depends on your situation and preferences.

The main goal in these situations is to alleviate particularly severe, urgent, or life-threatening complications of metastases in specific sites, such as in the brain, spinal cord, or bones. These therapies are most often recommended if systemic therapy (eg, endocrine therapy, chemotherapy, or targeted therapy) is not likely to work, or not likely to work quickly enough.

Some people will develop metastatic disease that is confined to one organ, such as one area of the liver or one lobe of the lung. In these cases, some doctors favor treatment directed at the tumor site. This may consist of surgical resection (to remove the affected part of the organ), targeted radiation, radiation frequency ablation, chemoembolization, or other methods. None of these have been shown to improve survival in metastatic breast cancer and these approaches are rarely used, although they may be appropriate in highly selected situations.

Your doctor can talk to you about whether you might benefit from a local treatment approach. The decision will depend on several factors. Some criteria used to help identify people most likely to benefit include:

●Good functional status – People who have minimal cancer-related symptoms and are independent with their activities of daily living tend to do better following surgery for metastatic disease.

●Limited number of sites of disease – People with limited disease appear to benefit more from surgery compared with those with multiple sites of disease or with multiorgan involvement.

●Long disease-free interval – People who experienced a recurrence after a long period of remission do better than those with rapidly progressive cancer.

●Likelihood of a complete tumor resection – The outcomes following surgery are best in people who undergo a complete resection of their disease with no evidence of cancer cells remaining after surgery.

WHERE TO GET MORE INFORMATION — Your health care provider is the best source of information for questions and concerns related to your medical problem.

This article will be updated as needed on our web site (www.uptodate.com/patients). Related topics for patients, as well as selected articles written for health care professionals, are also available. Some of the most relevant are listed below.

Patient level information — UpToDate offers two types of patient education materials.

The Basics — The Basics patient education pieces answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials.

Patient education: Breast cancer (The Basics)

Beyond the Basics — Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are best for patients who want in-depth information and are comfortable with some medical jargon.

Patient education: Breast cancer guide to diagnosis and treatment (Beyond the Basics)

Professional level information — Professional level articles are designed to keep doctors and other health professionals up-to-date on the latest medical findings. These articles are thorough, long, and complex, and they contain multiple references to the research on which they are based. Professional level articles are best for people who are comfortable with a lot of medical terminology and who want to read the same materials their doctors are reading.

Treatment for hormone receptor-positive, HER2-negative advanced breast cancer
Overview of the approach to metastatic breast cancer
Endocrine therapy resistant, hormone receptor-positive, HER2-negative advanced breast cancer
The role of local therapies in metastatic breast cancer
Treatment of metastatic breast cancer in older women
Breast cancer in men
Use of osteoclast inhibitors in early breast cancer

The following organizations also provide reliable health information.

●American Society of Clinical Oncology

(www.cancer.net/portal/site/patient)

●National Cancer Institute 1-800-4-CANCER (226237)

(www.nci.nih.gov)

●American Cancer Society 1-800-ACS-2345

(www.cancer.org)

●National Library of Medicine

(www.nlm.nih.gov/medlineplus/healthtopics.html)