Patient information: Treatment of metastatic breast cancer (Beyond the Basics)
- Daniel F Hayes, MD
Daniel F Hayes, MD
- Section Editor — Breast Cancer
- Professor of Medicine
- University of Michigan School of Medicine
The term "metastatic breast cancer" means that cancer has spread to organs outside the breast or surrounding lymph nodes, such as the liver, lung, and brain. Metastatic breast cancer is not a curable condition. However, treatment can prolong life, delay the progression of the cancer, relieve cancer-related symptoms, and improve quality of life. The median survival of individuals with metastatic breast cancer is 18 to 24 months, although the range in survival spans between a few months to many years and depends very much on the type if breast cancer the patient has. This article will review the treatment options for metastatic breast cancer. More detailed information about metastatic breast cancer is available by subscription.
GOALS OF TREATMENT
In addition to the goal of prolonging survival, treatment may help relieve cancer-associated symptoms, leading to an improvement or stability in quality of life.
APPROACH TO PATIENTS WITH A CHEST WALL OR BREAST RECURRENCE
Women treated for breast cancer are at risk of a local recurrence. For women who underwent breast conserving treatment (BCT), this may present as a new breast lesion. For women who underwent a mastectomy, it may present as a mass on the skin or chest wall. Regardless of primary surgery, all patients may also present with new disease in the axilla.
The approach to treatment will depend on the tumor size and location, as well as whether or not prior radiation was administered. Talk to your surgeon to determine the most appropriate treatment. If surgery is not an option, radiation therapy (RT) may be an alternative treatment.
APPROACH TO PATIENTS WITH METASTATIC DISEASE
All patients with metastatic breast cancer usually receive systemic therapy. However, in certain circumstances, treatment may also involve surgery or radiation.
Symptomatic metastases — Treatment to a specific lesion may be required if symptoms are present or there is a threat of complications (ie, spinal cord compression or fracture, brain metastases at risk for herniation, or a pending fracture due to a lesion in the hip). This may require either a surgical approach or radiation therapy (RT) to stabilize the affected area. The approach must be tailored to the specific situation and the patient’s clinical status.
Systemic therapy — Systemic therapy includes the use of endocrine therapy, chemotherapy, and/or biologic agents. A choice between them depends on the tumor burden, patient symptoms, and several predictive factors including:
●Status of hormone receptors – Individuals with hormone-receptor (estrogen [ER] and/or progesterone [PR] receptor) positive cancers tend to do better than those whose tumors are ER- and/or PR-negative. Hormone-receptor positive patients are candidates for anti-estrogen therapy, but hormone-receptor negative patients are not. It is important that reassessment of both ER and PR be done during relapse because metastatic breast cancer does not necessarily have the same characteristics as the ones found in the primary breast cancer. (See 'Anti-estrogen treatment' below.)
●HER2 expression – With the availability of treatment targeted against the human epidermal growth factor 2 (HER2) receptor, a protein that is sometimes made by certain types of aggressive breast cancers, HER2 overexpression in breast cancer cells predicts who should receive HER2-targeted treatment. It is important to reassess the HER2 status of recurrent disease, as discrepancy between the primary and recurrent cancer occurs at least five percent of the time. (See 'HER2-targeted agents' below.).
Anti-estrogen treatment — Anti-estrogen treatment is also known as endocrine therapy. This includes:
●Selective estrogen receptor modulators (SERMs) – Tamoxifen or toremifene
●Aromatase inhibitors (AIs) – Anastrazole, letrozole, exemestane
●Selective estrogen receptor downregulators (SERDs) – Fulvestrant
●Progestogens – Megestrol acetate or medroxyprogesterone
●Other sex steroid hormones – Progestins, estrogens, androgens
●For premenopausal women, treatment aimed at preventing the ovaries from making estrogen, such as surgery to remove the ovaries (oophorectomy) or medications (ie, gonadotropin-releasing hormone antagonists, such as goserelin or leuprolide)
Selective estrogen receptor modulators (SERM) — These agents block estrogen from stimulating breast cells. The one used in the treatment of breast cancer is tamoxifen.
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.
Most individuals with ER and/or PR-positive breast cancer will respond to tamoxifen therapy. However, some do not respond at all to tamoxifen. Others originally respond to tamoxifen but later become resistant. Unfortunately, most if not all breast cancers eventually stop responding to tamoxifen.
A subset of individuals with metastatic breast cancer experience a "flare" of their breast cancer within two days to three weeks after starting tamoxifen. This may cause an increase in bone pain, a high blood calcium level, and in individuals with breast cancer involving the skin, an increase in the size and/or number of these skin nodules, or skin redness. Tumor flares usually subside within four to six weeks. In the meantime, the symptoms can be treated with measures 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. Side effects of tamoxifen include hot flashes, an increased risk of blood clots, uterine bleeding, and endometrial cancer.
Aromatase inhibitors — Aromatase inhibitors (AIs) are drugs that reduce estrogen levels in the body by blocking the protein that helps make estrogen outside of the ovary (aromatase). Drugs in this class include anastrozole, letrozole, and exemestane. They are indicated for use only in postmenopausal women as single agents. Side effects of AIs include hot flashes, bone loss and bone fractures, and pain in the muscles and joints.
Some data show that an AI with other kinds of drugs may be better than the AI alone. These include the combination of letrozole and palbociclib and the combination of exemestane and everolimus. While effective, however, they are associated with more side effects than seen with just the AI by itself.
AIs should not be given to premenopausal women with intact ovarian function (unless they are also on treatment to stop their ovaries from working).
Pure antiestrogens — Pure antiestrogens block the influence of estrogen on breast cancer cells. The agent from this class used in metastatic breast cancer is fulvestrant. It is given as a monthly intramuscular (IM) injection and is approved for use in postmenopausal women whose cancers have progressed on tamoxifen and/or an AI. Whether it is as useful for premenopausal women or for men with metastatic breast cancer is not known, but there is no reason to believe it would not have the same efficacy and toxicity in older women.
Side effects of fulvestrant include hot flashes, increases in your liver enzymes, injection site pain, and joint pain.
Sex steroid hormones — Progestins, estrogens, and androgens may play a role in the third- or fourth-line treatment of metastatic breast cancer.
●Progestins – These include both medroxyprogesterone or megestrol acetate and are taken as a pill. It is sometimes used in women who have stopped responding to tamoxifen. The side effects of treatment include blood clot formation, weight gain, fluid retention, and vaginal bleeding. In some studies, a reduction in the quality of life has been seen in women taken these drugs.
●Estrogen – For women who have progressed on multiple treatments with antiestrogens, estradiol may be used. It is given as a pill and is taken daily. Side effects include vaginal bleeding, breast tenderness, nausea and vomiting, and venous thrombosis. Women on estrogen may also experience a tumor flare. For women who experience bleeding on estrogens, progestin treatment can provide control of symptoms.
●Androgens – Male hormones, called androgens, are rarely used in metastatic breast cancer. Despite evidence that they can help tumors shrink, they are not as effective as more modern therapies, such as tamoxifen, the AIs, or fulvestrant, and the side effects of treatment (virilization, edema, and jaundice) make them a less attractive option for both women and their clinicians.
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.
Chemotherapy drugs may be given alone, one after another, or in combination. There are a variety of drugs that can be used to treat breast cancer as both single agents or in combination. You should discuss which treatment is right for you with your doctor.
It is not clear how many doses of chemotherapy are best for individuals with metastatic breast cancer. Several studies have compared the benefit of continuous chemotherapy (giving chemotherapy until it becomes ineffective) versus intermittent chemotherapy (giving approximately six cycles of chemotherapy followed by no chemotherapy until the cancer progresses). In general, overall survival is the same in women treated with continuous or intermittent chemotherapy, although tumor growth may be slowed somewhat in women treated with continuous therapy. Intermittent chemotherapy may allow for a better quality of life. This is a reasonable option if your cancer-related symptoms stay under control during treatment.
Biologic therapy — Biologic therapy aims to target a specific protein or pathway in an effort to stop cancer cells from growing or dividing. For individuals with metastatic breast cancer, these agents include HER2-targeted agents and bone modifying agents.
HER2-targeted agents — Individuals whose breast cancers produce high levels of HER2 benefit from treatments that target this protein. There are several drugs in this category, including antibodies that are directed towards HER2 (trastuzumab and pertuzumab), and an antibody-drug conjugate, in which a very potent chemotherapy agent (emtansine) has been bound, or "conjugated" to the antibody, trastuzumab (called ado-trastuzumab emtansine), so that the latter takes the chemotherapy right to the HER2-producing cell. Finally, lapatinib is also available as a non-antibody anti-HER2 treatment.
Anti-HER2 therapies can be used alone, or with chemotherapy or endocrine therapy, or even with each other in the treatment of metastatic breast cancer. Your oncologist will decide which of these strategies is preferable based on your circumstances.
Trastuzumab — Trastuzumab is generally given IV once per week or once every three weeks. The most common side effect of trastuzumab is fever and/or chills. Heart failure develops in about 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 another antibody against HER2. It has not been tested by itself, or by itself with other types of therapies like endocrine or chemotherapies. 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 — Emtansine is a very potent and very toxic chemotherapy. However, it has been joined, or "conjugated" to trastuzumab, so that the trastuzumab carries it directly, and only, to cells that make HER2. The conjugate is then taken inside the cell, where the link is broken and the emtansine is released to kill the cell. Ado-trastuzumab emtansine has been found to be active even when trastuzumab itself does not work. In addition, it is just as active as some trastuzumab plus chemotherapy combinations. However, some of the emtansine does leak out into the blood system, and therefore, there are more side effects than are seen with trastuzumab by itself – most notably, low platelets counts (platelets are made in your bone marrow and stop bleeding) and damage to the nerves of the fingers and toes ("peripheral neuropathy").
Lapatinib — Lapatinib is an oral medication that targets HER2 in a different way than trastuzumab, pertuzumab, or ado-trastuzumab emtansine. Lapatinib may be used alone, in combination with chemotherapy, or even in combination with trastuzumab. The most common side effects of lapatinib alone are diarrhea, a skin rash that resembles acne, and nausea.
Bone modifying agents — While not used to treat breast cancer metastases, bone modifying agents are an important component of the treatment of bone metastases. These agents prevent the complications of breast cancer involving bones, such as fractures, spinal cord compression, and hypercalcemia of malignancy. Two classes of agents used are the bisphosphonates (pamidronate, zoledronic acid, clodronate and ibandronate) and the RANK (receptor activator of nuclear factor kappa B) ligand inhibitor, denosumab.
Role of surgery or radiation therapy — The main role of surgery or RT for treatment of metastatic breast cancer is to alleviate particularly severe, urgent, or life-threatening complications of cancer in specific sites, such as in the brain, spinal cord, or bones. These therapies are most often recommended if systemic therapy (endocrine therapy, chemotherapy, anti-HER2 therapy) is not likely to work, or not likely to work sufficiently rapidly to alleviate the emergent issue.
Some patients will develop metastatic disease that is confined to one organ, such as involvement in one area of the liver or one lobe of the lung. In these cases, some doctors have advocated treatment directed at the tumor site. This may consist of surgical resection, targeted radiation, radiation frequency ablation, chemoembolization, or other methods. None of these have been shown to improve survival in metastatic breast cancer and these are rarely indicated, although they may be appropriate in highly selected situations.
For those who are considered to be candidates for a local treatment approach, criteria are used to select patients most likely to benefit from site-specific treatment. Some criteria used to help identify patients most likely to benefit include:
●Good functional status – Patients who are minimally symptomatic from their cancer and independent with their activities of daily living tend to do better following surgery for metastatic disease.
●Limited number of sites of disease – Patients with limited disease appear to benefit from surgery compared with those with multiple sites of disease or with multi-organ involvement.
●Long disease-free interval – Patients 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 patients who undergo a complete resection of their disease with negative margins at pathologic review.
With these selection criteria, a patient may have some period of time with no immediate need for systemic therapy and therefore can have a break from any treatment-related toxicities, at least for a while.
Treating metastatic breast cancer takes in to account the type of cancer that you have and whether your cancer expresses hormone receptors and/or HER2. It also takes in to account the extent of cancer you are living with.
Most clinicians recommend initial treatment with chemotherapy for rapidly progressive disease in lungs or liver or in women with severe symptoms related to metastatic breast cancer. Combination chemotherapy is associated with increased responses compared with single-agent chemotherapy. However, treatment using single agents in a sequential fashion is associated with less toxicity than the use of a combination regimen. For all individuals with metastatic breast cancer the following recommendations apply:
●Individuals with hormone-receptor positive metastatic breast cancer who are not terribly symptomatic, do not have life-threatening disease, or evidence of visceral involvement do not require chemotherapy and can be treated with endocrine therapy.
●Some clinicians prefer to combine ovarian suppression (OS) or ablation (OA) with tamoxifen for peri- or premenopausal women with metastatic breast cancer. Although some clinicians also use an aromatase inhibitor in combination with OS or OA, this approach does not appear to improve overall survival and may be associated with more side effects than if the therapies are used in sequence.
●Sequential endocrine therapy is recommended to treat hormone positive breast cancer. Most clinicians will recommend chemotherapy only for individuals who progress despite two or three trials of endocrine therapy.
●For individuals who have with ER-negative breast cancer and those with ER-positive breast cancer that does not respond to endocrine therapy, chemotherapy is indicated. There is no one standard of care.
•Available options include alkylating agents (eg, cyclophosphamide), methotrexate, anthracyclines (eg, doxorubicin or lipo-doxorubicin), taxanes (eg, paclitaxel or docetaxel), capecitabine, vinorelbine, gemcitabine, ixabepilone, and eribulin. Other available options include the platinum salts (cis or carboplatin) and etoposide.
•Combination options include capecitabine and docetaxel, gemcitabine and paclitaxel. For chemotherapy naïve patients, doxorubicin (alone or as part of a combination regimen) is also used. However, combination therapy has not been proven to be more effective in prolonging survival than using the drugs alone, in sequence, and it is usually reserved for patients with particularly rapidly growing metastases in vital organs, such as the liver or lung.
•Chemotherapy with biologic therapy, such as the angiogenesis inhibitor, bevacizumab, although this is rarely recommended anymore.
•Individuals with HER2-positive breast cancers should receive HER2-directed therapy (eg, trastuzumab, pertuzumab, ado-trastuzumab emtansine, or lapatinib). The precise combinations of these drugs with each other, or with endocrine or chemotherapies, should be discussed with your oncologist.
WHERE TO GET MORE INFORMATION
Your healthcare 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 healthcare 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.
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.
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 approach to metastatic hormone receptor-positive breast cancer: Endocrine therapy
Systemic treatment for metastatic breast cancer: General principles
Systemic treatment of metastatic breast cancer in women: Chemotherapy
Metastatic breast cancer: Local treatment
Treatment of metastatic breast cancer in older women
Breast cancer in men
Overview of the use of osteoclast inhibitors in early breast cancer
The following organizations also provide reliable health information.
●American Society of Clinical Oncology
●National Comprehensive Cancer Network
●National Cancer Institute 1-800-4-CANCER (226237)
●American Cancer Society 1-800-ACS-2345
●National Library of Medicine
All topics are updated as new information becomes available. Our peer review process typically takes one to six weeks depending on the issue.