Breast cancer – the basics

What is breast cancer?

Breast cancer is a type of cancer originating from breast tissue, most commonly from the milk ducts or the milk-producing glands (lobules). Cancers originating from ducts are known as ductal carcinomas, while those originating from lobules are known as lobular carcinomas. Breast cancer may also (rarely) arise from the tissue surrounding the ducts and lobules (stroma).

Breast cancer is much more common in women, but men can get the disease as well. Breast cancer sometimes runs in families.

Can breast cancer be prevented? — Women who are at high risk of getting breast cancer can sometimes take a medicine to help prevent the disease. If you have a strong family history of breast cancer, ask your doctor what you can do to prevent cancer.

Symptoms

Breast cancer most commonly appears as a lump in the breast or the lymph nodes located in the armpits. Other symptoms that may occur with breast cancer include:

• Dimpling of the skin
• A change in the size or shape of one breast
• A nipple changing position or shape or becoming inverted (pulling in)
• A discoloration of the skin of the breast
• Discharge from nipple/s
• Constant pain in part of the breast or armpit
• Swelling beneath the armpit or around the collar-bone

Inflammatory breast cancer is a particular type of breast cancer whose symptoms resemble breast inflammation and may include itching, pain, swelling, nipple inversion, warmth and redness throughout the breast, as well as an orange-peel texture to the skin.

Breast lumps can be caused by conditions other than cancer, but it is a good idea to have any new lump checked by your healthcare provider.

Screening and diagnostic tests

Breast cancer screening includes tests to detect breast cancer at an early stage, before a woman discovers a lump. The purpose of screening is to detect the disease at an earlier stage when the chances of successful treatment are higher. Early detection and treatment of breast cancer improve survival because the breast tumor can be removed before it has a chance to spread (metastasize).

There are three main ways to screen for breast cancer: mammogram, breast exam with your doctor or nurse, and breast self-exam on a regular basis (see ‘Screening and diagnostic tests’ section under ‘Breast cancer – beyond the basics’).

To evaluate a breast lump, a mammogram and a breast ultrasound are usually recommended. A mammogram is a breast (low-dose) x-ray. If your mammogram is abnormal, you will need further testing, most usually a test called a biopsy. During a biopsy, a doctor withdraws one or more small samples of tissue from the breast, and another doctor examines them under a microscope to see if they are cancerous.

An ultrasound uses sound waves to look at breast tissue and may help distinguish between a solid (sometimes malignant) lump and a fluid filled cyst which is benign.

Another diagnostic test is the breast Magnetic resonance imaging (MRI). Breast MRI may be recommended to aid in the diagnosis of breast cancer only in selected situations, as it is less efficient than a mammogram to detect certain breast conditions.

Watch this video Breast cancer statistics and overview (02:13)

Staging

Cancer staging system is a standardized way for doctors to summarize information about how far a cancer has spread, and to adjust the appropriate treatment. Stage is usually expressed as a number on a scale of 0 through IV, with stage 0 describing non-invasive early cancers that remain within their original location, and stage IV describing invasive cancers that have spread to other parts of the body. The right treatment for you will depend, in part, on the stage of your cancer.

Treatment

Most patients with breast cancer have one or more of the following treatments:

• Surgery – Breast cancer is usually treated with surgery to remove the cancer. Many women with breast cancer can choose between mastectomy and breast conserving therapy (also called “lumpectomy”):
• Breast conserving therapy (lumpectomy) is surgery to remove the cancer and a section of healthy tissue around it. Women who choose this option keep their breast, but they usually must have radiation therapy after surgery.
• Mastectomy is surgery to remove the whole breast. If you choose this option, you might have to decide whether to have surgery to reconstruct your breast and when.
• In a modified radical mastectomy both the entire breast and local lymph nodes are removed.
• Radiation therapy – a machine that emits external beam radiation, directing X-rays at the affected breast.
• Chemotherapy – cancer eradicating drugs. Some women take these medicines before surgery to shrink the cancer and make it easier to remove. Some women take these medicines after surgery to keep cancer from growing, spreading, or coming back.
• Hormone therapy – Some forms of breast cancer grow in response to hormones. Your doctor might give you treatments to block hormones or to prevent your body from making certain kinds of hormones.
• Targeted therapy – Some medicines work only on cancers that have certain characteristics. Your doctor might test you to see if you have a kind of cancer that would respond to this kind of therapy.

Watch this video: Extending breast cancer survival through healthy lifestyle interventions (05:32)

Living with breast cancer

Follow ups — After treatment, you will need to be checked every so often to see if the cancer comes back. You will have tests, usually including more mammograms. You should also watch for symptoms that could mean the cancer has come back. Examples of these symptoms include new lumps in the breast area, pain (in the bones, chest, or stomach), trouble breathing, and headaches. If you start having any new symptom, mention it to your doctor.

If cancer comes back or spreads — Treatment in this case depends on where the cancer is. Most people get hormone therapy or chemotherapy. Some people also have surgery to remove new tumors.

Quality of life — Many people with breast cancer do very well after treatment. The important thing is to take your medicines as directed and to follow all your doctors’ instructions about visits and tests. Also talk to your doctor about any side effects or problems you have during treatment.

Video : Types of Breast Cancer (10:09)

Video : Breast cancer statistics and overview (02:13)

Video : Extending breast cancer survival through healthy lifestyle interventions (05:32)

Screening and diagnostic tests

Screening for breast cancer

Breast cancer screening includes tests to detect breast cancer at an early stage, before a woman discovers a lump. The goal of screening is to detect the disease at an earlier stage when the chances of successful treatment are higher. Early detection and treatment of breast cancer improve survival because the breast tumor can be removed before it has a chance to spread (metastasize).

There are three main ways to screen for breast cancer: mammogram (see ‘Mammogram’ below), breast exam with your doctor or nurse, and breast self-exam on a regular basis.

Breast Self-Exam

A breast self-exam is an examination of the breasts for changes or abnormalities. A self breast-exam should be performed monthly and any changes or abnormalities should be discussed with your doctor.

Clinical Breast Exam

A clinical breast exam is an exam preformed by a qualified nurse or doctor; they will observe both breasts and then check for lumps or other physical changes in the breast and under the armpits.

Diagnostic tests

The initial sign of breast cancer may involve a new lump or change in the breast or armpit. A new nipple inversion, an area of significant irritation or redness, dimpling or thickening of the breast skin, and persistent breast pain or discomfort are reasons to seek prompt medical evaluation.

To evaluate a breast lump, a mammogram and a breast ultrasound are usually recommended. A breast biopsy may also be recommended (see 'Breast biopsy' below).

Mammogram - Having a regularly scheduled mammogram, the standard diagnostic scan, is especially important. A mammogram is an x-ray; the breast is exposed to a small dose of iodizing radiation that produces an image of the breast tissue.

If your mammogram or a clinical exam detects a suspicious site, further investigation is always necessary. Although lumps are usually non-cancerous, the only way to be certain is to obtain additional tests, such as an ultrasound. If a solid mass appears on the ultrasound, your radiologist may recommend a biopsy, a procedure in which cells are removed from a suspicious area to check for the presence of cancer.

Breast ultrasound - An ultrasound is a scan that uses sound waves to look at breast tissue and can tell if a lump is a fluid filled cyst or a solid lump. Ultrasounds are helpful when a lump is easily felt and can be used to further evaluate any abnormalities discovered on a mammogram.

Breast MRI - MRI is not recommended as a routine test to detect breast cancer in most women.

Breast biopsy — A biopsy is a diagnostic procedure in which cells are removed from a suspicious area to check for the presence of breast cancer. There are three types of biopsy: fine needle aspiration, core needle biopsy, and surgical biopsy.

Fine Needle Aspiration is used if the lump is easily accessible, or if the doctor suspects that it may be a fluid-filled cystic lump. A needle is used to draw fluid from the lump, sometimes under ultrasound guidance. If the lump persists, the radiologist or surgeon will perform a fine needle aspiration biopsy (FNABx), a similar procedure using the needle to obtain cells from the lump for examination.

Core needle biopsy is the procedure to remove a small amount of tissue from the breasts with a larger “core” needle. Similar to fine needle aspiration, an ultrasound might be used to help your doctor guide the needle to the exact site. Once removed, the suspicious area tissue will be examined for traces of cancer.

During a surgical (or wide local excision) biopsy, the doctor will remove all or part of the lump from the breast as well as a small amount of normal-looking tissue. This procedure is often performed in a hospital and requires local anesthesia. If the lump cannot be easily felt, an ultrasound might be used to help guide your doctor to the suspicious area. Once removed, the abnormal tissue will be examined for traces of cancer. The surrounding margin, or small amount of normal–looking tissue, will be examined to determine if the cancer has been completely removed.

After the breast biopsy, a tiny metal clip is usually placed into the breast lump or imaging abnormality to mark the spot. If the diagnosis of breast cancer or atypical cells is made, the metal clip is targeted with a thin wire inserted into the abnormal area under x-ray guidance. A surgeon then uses the wire to guide the operation and remove the proper area of the breast. This procedure is called a needle (wire) localization excisional breast biopsy if the surgery is being done for diagnosis, or needle (wire) localization lumpectomy if the surgery is done for cancer.

TYPES OF BREAST CANCER

Although there are several different types of breast cancer, they are treated similarly, with some exceptions.

In situ breast cancer

The earliest breast cancers are called "in situ" cancers, or stage 0.

Ductal carcinoma in situ (DCIS) — If cancers arise in the ducts of the breast (the tubes that carry milk to the nipple when a woman is breastfeeding) and do not grow outside of the ducts, the tumor is called ductal carcinoma in situ (abbreviated DCIS). DCIS cancers do not spread beyond the breast tissue. However DCIS may develop into invasive cancers if not treated.

Even though Stage 0 cancer is still noninvasive, it does require immediate treatment and is typically treated with surgery or radiation, or a combination of the two. Chemotherapy is not part of the treatment regimen for earlier stages of cancer.

Lobular carcinoma in situ (LCIS) — If abnormal cells arise in the lobules of the breast (where breast milk is made), and they do not extend outside of the breast lobule, they are referred to as lobular carcinoma in situ (LCIS).

Invasive breast cancer

The majority of breast cancers are referred to as invasive (or infiltrating) breast cancers because they have grown or "invaded" beyond the ducts or lobules of the breast into the surrounding tissue. Several varieties of invasive breast cancers are possible (eg, ductal, lobular, medullary, tubular, metaplastic). In general, they are all treated similarly.

Watch this video about types of breast cancer: Types of Breast Cancer (10:09)

Staging of breast cancer

Stage 0 (carcinoma in situ)

Two common types of breast carcinoma in situ:

• Ductal carcinoma in situ (DCIS) is a noninvasive condition in which abnormal cells are found in the lining of a breast duct. The abnormal cells have not spread outside the duct to other tissues in the breast. In some cases, DCIS may become invasive cancer and spread to other tissues. At this time, there is no way to know which lesions could become invasive.
• Lobular carcinoma in situ (LCIS) is a condition in which abnormal cells are found in the lobules of the breast. This condition seldom becomes invasive cancer. Information about LCIS is not included in this summary.

Stage I

In stage I, cancer has formed. Stage I is divided into stages IA and IB.

• In stage IA, the tumor is 2 centimeters or smaller. Cancer has not spread outside the breast.
• In stage IB, small clusters of breast cancer cells (larger than 0.2 millimeter but not larger than 2 millimeters) are found in the lymph nodes and either: no tumor is found in the breast; or the tumor is 2 centimeters or smaller.

Stage II

Stage II is divided into stages IIA and IIB.

• In stage IIA: no tumor is found in the breast or the tumor is 2 centimeters or smaller. Cancer (larger than 2 millimeters) is found in 1 to 3 axillary lymph nodes or in the lymph nodes near the breastbone (found during a sentinel lymph node biopsy); or the tumor is larger than 2 centimeters but not larger than 5 centimeters. Cancer has not spread to the lymph nodes.
• In stage IIB, the tumor is: larger than 2 centimeters but not larger than 5 centimeters. Small clusters of breast cancer cells (larger than 0.2 millimeter but not larger than 2 millimeters) are found in the lymph nodes; or larger than 2 centimeters but not larger than 5 centimeters. Cancer has spread to 1 to 3 axillary lymph nodes or to the lymph nodes near the breastbone (found during a sentinel lymph node biopsy); or larger than 5 centimeters. Cancer has not spread to the lymph nodes.

Stage III

Stage III is divided into stages IIIA, IIIB, and IIIC.

• In stage IIIA: no tumor is found in the breast or the tumor may be any size. Cancer is found in 4 to 9 axillary lymph nodes or in the lymph nodes near the breastbone (found during imaging tests or a physical exam); or the tumor is larger than 5 centimeters. Small clusters of breast cancer cells (larger than 0.2 millimeter but not larger than 2 millimeters) are found in the lymph nodes; or the tumor is larger than 5 centimeters. Cancer has spread to 1 to 3 axillary lymph nodes or to the lymph nodes near the breastbone (found during a sentinel lymph node biopsy).
• In stage IIIB, the tumor may be any size and cancer has spread to the chest wall and/or to the skin of the breast and caused swelling or an ulcer. Also, cancer may have spread to: up to 9 axillary lymph nodes; or the lymph nodes near the breastbone.
• In stage IIIC, no tumor is found in the breast or the tumor may be any size. Cancer may have spread to the skin of the breast and caused swelling or an ulcer and/or has spread to the chest wall. Also, cancer has spread to: 10 or more axillary lymph nodes; or lymph nodes above or below the collarbone; or axillary lymph nodes and lymph nodes near the breastbone. For treatment, stage IIIC breast cancer is divided into operable and inoperable stage IIIC.

Stage IV

In stage IV, cancer has spread to other organs of the body, most often the bones, lungs, liver, or brain.

Factors affecting treatment decisions

Assessment of the axillary lymph nodes

One of the first sites of breast cancer spread is to the lymph nodes located in the armpit (axilla). These nodes (referred to as axillary lymph nodes) can become enlarged and can sometimes be felt during a breast examination. However, even if the lymph nodes are enlarged, the only way to determine if they truly contain cancer is to examine a sample of the tissue under the microscope.

The presence or absence of lymph node involvement is one of the most important factors in determining the long-term outcome of the cancer (prognosis), and it often guides decisions about treatment. Having cancer cells in the axillary lymph nodes (positive nodes) suggests an increased risk of the cancer spreading. Therefore most of these women are advised to have adjuvant systemic (whole-body) treatment, which involves hormonal therapy (for women with estrogen receptor positive breast cancer), and may also include chemotherapy.

Even if the axillary lymph nodes are negative, there is a small chance that the tumor has spread elsewhere in the body, and adjuvant therapy is recommended for some of these women.

How are axillary lymph nodes evaluated for cancer spread?

This is done first by physical exam and, sometimes with ultrasound. If the nodes are enlarged or feel suspicious, a needle biopsy can be performed. If the needle biopsy is positive and the nodes contain cancer cells then surgical removal of additional axillary lymph nodes may be performed. This is called axillary lymph node dissection (ALND).

In cases where the axillary lymph nodes are not enlarged, the ultrasound is negative, or if the needle biopsy of the lymph node is negative, a surgical procedure called a sentinel lymph node biopsy is performed. In this procedure, one, or at most a few, of the most important nodes are removed. The major benefit of the sentinel lymph node procedure is that it provides important staging information, while causing fewer problems such as arm swelling (also called lymphedema) than a more extensive axillary lymph node dissection.

Most patients do not have cancer in their sentinel lymph nodes and will not need additional surgery. Some studies have shown that there are patients for whom an axillary lymph node dissection is not necessary even if the sentinel lymph nodes are positive. This issue remains controversial and should be discussed with your doctor.

Presence of hormone receptors, and genetic testing

An essential part of breast cancer diagnosis is to determine the presence of two types of proteins; hormone receptors (estrogen and progesterone receptors) and HER2. These proteins are important factors in deciding what treatment method would be most effective.

Identification of these proteins is performed by the pathologist, the doctor responsible for examining the breast cancer tissue under the microscope and making the diagnosis. The pathologist will also grade the cancer. Grade is assigned to the tumor cells based on how aggressive the individual cancer cells look under the microscope.

Hormone receptor assay — An Assay is a type of thest tha can be be used to identify whether or not the breast cancer cells have receptors for the hormones estrogen (ER) and progesterone (PR). Hormone receptors are proteins that are found in and on breast cells. These receptors pick up hormone signals telling the cells to grow. More than a half of breast cancers require the female hormone estrogen to grow.

If hormone receptors are present within a woman’s breast cancer, she is likely to benefit from treatments that lower estrogen levels or block the actions of estrogen. These treatments are referred to as endocrine or hormone therapies and such tumors are referred to as hormone-responsive or hormone receptor positive (ER+ or PR+). If the cancer is hormone-receptor-negative (no receptors are present), then hormonal therapy is unlikely to work. You and your doctor will then choose other kinds of treatment.

HER2 — HER2 (human epidermal growth factor receptor 2) is a protein that plays a central role in the development of breast cancer. HER2 is present in about 20% of all breast cancers. HER2-positive breast cancers tend to grow faster and may benefit from treatments directed against the HER2 protein. Drugs that target the HER2 protein include trastuzumab (Herceptin) and lapatinib (Tykerb®). The benefit from trastuzumab and lapatinib appears to be limited to women whose breast cancers make very high levels of this protein.

21 gene test (Oncotype DX) — The Oncotype DX test is used to estimate a woman’s risk of recurrence of early-stage, estrogen-receptor-positive breast cancer, as well as how likely she is to benefit from chemotherapy after breast cancer surgery. The Oncotype DX test analyzes the activity of 21 genes and then calculates a recurrence score number between 0 and 100; the higher the score, the greater the risk of recurrence. Women with estrogen receptor positive, node negative breast cancer that have low recurrence scores will not need chemotherapy while women with high scores may benefit from chemotherapy.

TREATMENT OPTIONS FOR BREAST CANCER

The treatment of breast cancer is “custom made”, and must take into account all of the factors mentioned above. Optimal management in most cases is multidisciplinary, and requires collaboration between surgeons (breast cancer surgeons and reconstructive surgeons, who are typically plastic surgeons) and doctors who specialize in radiation and oncology. Each woman should discuss the available treatment options with her doctors to determine what treatment is best for her.

Surgery

Two surgical options are available for treating breast cancer: Mastectomy (removal of the entire breast) and breast conserving surgery (removal of the cancerous tissue, called lumpectomy). A modified radical mastectomy involves removal of both the affected breast and regional lymph nodes.

Breast conserving surgery may also be referred to as wide excision, quadrantectomy, or partial mastectomy. Breast conserving therapy (BCT) consists of breast conserving surgery in conjunction with Radiation therapy of the remainder of the affected breast. The combination of surgery and radiation usually results in cosmetically acceptable preservation of the breast without compromising breast cancer outcomes. Survival outcomes are the same whether BCT or mastectomy is performed.

Breast reconstruction is an important option for women who undergo mastectomy and may be considered at the time of the mastectomy or at a later date. Consultation with a plastic surgeon prior to the mastectomy is essential if immediate reconstruction is desired.

Additional therapies

Additional anti-cancer treatment can be given before (neo-adjuvant) or after surgery (adjuvant). Four types of treatments are commonly used for breast cancer therapy:

• Radiation therapy
• Chemotherapy
• Hormonal therapy
• Molecularly targeted therapies

Radiation therapy

Radiation therapy is a cancer treatment that uses high-energy x-rays or other types of radiation to kill cancer cells or keep them from growing. There are two types of radiation therapy. External radiation therapy uses a machine outside the body to send radiation toward the cancer. Internal radiation therapy uses a radioactive substance sealed in needles, seeds, wires, or catheters that are placed directly into or near the cancer. The way the radiation therapy is given depends on the type and stage of the cancer being treated. External radiation therapy is used to treat breast cancer.

Chemotherapy

Chemotherapy is a cancer treatment that uses drugs to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. When chemotherapy is taken by mouth or injected into a vein or muscle, the drugs enter the bloodstream and can reach cancer cells throughout the body (systemic chemotherapy). When chemotherapy is placed directly into the cerebrospinal fluid, an organ, or a body cavity such as the abdomen, the drugs mainly affect cancer cells in those areas (regional chemotherapy). The way the chemotherapy is given depends on the type and stage of the cancer being treated. Systemic chemotherapy is used in the treatment of breast cancer.

Hormone therapy

Hormone therapy is a cancer treatment that removes hormones or blocks their action and stops cancer cells from growing. Hormones are substances made by glands in the body and circulated in the bloodstream. Some hormones can cause certain cancers to grow. If tests show that the cancer cells have places where hormones can attach (receptors), drugs, surgery, or radiation therapy is used to reduce the production of hormones or block them from working. The hormone estrogen, which makes some breast cancers grow, is made mainly by the ovaries. Treatment to stop the ovaries from making estrogen is called ovarian ablation. Hormone therapy with tamoxifen is often given to patients with early localized breast cancer that can be removed by surgery and those with metastatic breast cancer (cancer that has spread to other parts of the body). Hormone therapy with tamoxifen or estrogens can act on cells all over the body and may increase the chance of developing endometrial cancer. Women taking tamoxifen should have a pelvic exam every year to look for any signs of cancer. Any vaginal bleeding, other than menstrual bleeding, should be reported to a doctor as soon as possible. Hormone therapy with an aromatase inhibitor is given to some postmenopausal women who have hormone receptor–positive breast cancer. Aromatase inhibitors decrease the body's estrogen by blocking an enzyme called aromatase from turning androgen into estrogen. Anastrozole and letrozole are two types of aromatase inhibitors. For the treatment of early localized breast cancer that can be removed by surgery, certain aromatase inhibitors may be used as adjuvant therapy instead of tamoxifen or after 2 to 3 years of tamoxifen use. For the treatment of metastatic breast cancer, aromatase inhibitors are being tested in clinical trials to compare them to hormone therapy with tamoxifen.

Targeted therapy

Targeted therapy is a type of treatment that uses drugs or other substances to identify and attack specific cancer cells without harming normal cells. Monoclonal antibodies, tyrosine kinase inhibitors, and cyclin-dependent kinase inhibitors are types of targeted therapies used in the treatment of breast cancer. Monoclonal antibody therapy is a cancer treatment that uses antibodies made in the laboratory, from a single type of immune system cell. These antibodies can identify substances on cancer cells or normal substances that may help cancer cells grow. The antibodies attach to the substances and kill the cancer cells, block their growth, or keep them from spreading. Monoclonal antibodies are given by infusion. They may be used alone or to carry drugs, toxins, or radioactive material directly to cancer cells. Monoclonal antibodies may be used in combination with chemotherapy as adjuvant therapy. Types of monoclonal antibody therapy include the following:

• Trastuzumab is a monoclonal antibody that blocks the effects of the growth factor protein HER2, which sends growth signals to breast cancer cells. About one-fourth of patients with breast cancer have tumors that may be treated with trastuzumab combined with chemotherapy.
• Pertuzumab is a monoclonal antibody that may be combined with trastuzumab and chemotherapy to treat breast cancer. It may be used to treat certain patients with HER2 positive breast cancer that has metastasized (spread to other parts of the body). It may also be used as neoadjuvant therapy in certain patients with early stage HER2 positive breast cancer.
• Ado-trastuzumab emtansine is a monoclonal antibody linked to an anticancer drug. This is called an antibody-drug conjugate. It is used to treat HER2 positive breast cancer that has spread to other parts of the body or recurred (come back).

Tyrosine kinase inhibitors are targeted therapy drugs that block signals needed for tumors to grow. Tyrosine kinase inhibitors may be used with other anticancer drugs as adjuvant therapy. Tyrosine kinase inhibitors include the following:

• Lapatinib is a tyrosine kinase inhibitor that blocks the effects of the HER2 protein and other proteins inside tumor cells. It may be used with other drugs to treat patients with HER2 positive breast cancer that has progressed after treatment with trastuzumab.

Cyclin-dependent kinase inhibitors are targeted therapy drugs that block proteins called cyclin-dependent kinases, which cause the growth of cancer cells. Cyclin-dependent kinase inhibitors include the following:

• Palbociclib is a cyclin-dependent kinase inhibitor used with the drug letrozole to treat breast cancer that is estrogen receptor positive and HER2 negative and has spread to other parts of the body. It is used in postmenopausal women whose cancer has not been treated with hormone therapy.

PARP inhibitors are a type of targeted therapy that block DNA repair and may cause cancer cells to die. PARP inhibitor therapy is being studied for the treatment of patients with triple negative breast cancer or tumors with BRCA1 or BRCA2 mutations.

Treatment selection by stage

Early stage localized breast cancer — Women with stage I and II breast cancer are treated similarly with minor exceptions. Both are treated with surgery – either Mastectomy or breast conserving surgery (lumpectomy), followed by radiation therapy (together refer to as “breast conserving therapy”).   

Following surgery, adjuvant systemic therapy is recommended for the vast majority of women with stage II breast cancer and for some women with stage I disease. Women with ER-positive breast cancer usually receive adjuvant hormonal therapy, whereas those with receptor-negative breast cancer, or high “Recurrence Score” may be treated with chemotherapy.   

Locally advanced and inflammatory breast cancer — The likelihood of curing locally advanced and inflammatory breast cancer is lower than it would be if the cancer were small and confined to the breast, but is still possible with appropriate treatment. Treatment generally includes a combination of chemotherapy, hormonal therapy (if the tumor is hormone receptor-positive), trastuzumab (if the tumor is HER2-positive), radiation therapy, and surgery. In most cases, systemic therapy (chemotherapy, trastuzumab, and sometimes hormonal therapy) is given before surgery.

Metastatic breast cancer — Metastatic breast cancer is generally treated with “systemic therapy” that treats the whole body, such as chemotherapy, hormonal therapy, trastuzumab, or some combination of these options. Surgery and radiation therapy that are more localized can sometimes be added to control disease in certain areas. While metastatic disease is often aggressive, treatment can prolong life, delay the progression of the cancer, relieve cancer-related symptoms, and improve quality of life.

The choice of treatment for metastatic breast cancer depends upon many individual factors, including features of the woman's breast cancer (especially whether it produces hormone receptors and HER2), the expected response of the cancer to various therapies, treatment-related side effects, the extent and location of metastases, and a woman's personal preferences.

Each woman should discuss the available treatment options with her physician to determine which choice is best for her. 

Treatment for noninvasive, or in situ, breast cancer = stage 0

Ductal carcinoma in situ (DCIS)

Stage 0, DCIS is a noninvasive cancer where abnormal cells have been found in the lining of the breast milk duct.

The best local treatment for DCIS will depend on the size of the tumor, its grade and the overall health of the woman. Most women are treated with a surgical procedures involving removal of the entire cancerous area (lumpectomy) followed by radiation therapy. This surgical treatment of DCIS is an option particularly for older women and for those with small, low grade tumors.  Women with small areas of DCIS who are being treated with lumpectomy do not need their lymph nodes checked for spread of tumor.

The 21 gene test (Oncotype DX, see above) is an assay carried out by healthcare professionals who examine the level of genes expressed in sampe of tumor.  The results of this assay are used to estimate a woman’s recurrence risk of DCIS and/or the risk of a new invasive cancer developing in the same breast, as well as how likely she is to benefit from radiation therapy after DCIS surgery.

Women with extensive DCIS may need a Mastectomy which may be done with or without reconstruction. A sentinel lymph node biopsy, a special technique to identify and remove only the most important lymph nodes in the armpit is usually recommended for women who are having a mastectomy surgery and is carried out at the same time. This is because it is not possible to perform sentinel node biopsy after a mastectomy. Large areas of DCIS have an increased chance of being associated with hidden invasive cancer and if the lymph nodes are involved this will affect treatment decisions.

Chemotherapy is not necessary for women with DCIS. However, they may be recommended hormonal treatment with tamoxifen for prevention of recurrence if the DCIS is hormone receptor-positive, particularly if they did not have a mastectomy. The tamoxifen reduces the chances that the cancer will come back in the treated breast and also decreases the chances of developing a new breast cancer in the other breast.

Lobular carcinoma in situ (LCIS)

In LCIS, cancerous cells arise in the lobules of the breast (where breast milk is made), and do not extend outside of the breast lobule.

LCIS is not considered a true cancer but instead is considered a risk factor for developing cancer in the future in either breast. Women with LCIS should see a high risk specialist and discuss how to reduce the risk of developing breast cancer in the future. Methods to reduce the chance of developing breast cancer are considered for women with a strong family history of breast cancer. These may include medications and in some cases preventive mastectomies. Women with LCIS should have yearly mammograms and report any changes in their breasts to their physicians.

Treatment of early localized breast cancer

PREMENOPAUSAL WOMEN

Following surgery, systemic (body-wide) anticancer treatment is often recommended to eliminate any residual microscopic tumor cells in the body. This type of therapy is called adjuvant therapy, and is an important component of breast cancer treatment which significantly decreases the chance that the cancer will return (or recur). Consequently it also improves a woman's chance of surviving her cancer.

There are three options for systemic adjuvant therapy of early breast cancer: hormonal therapy, chemotherapy, and trastuzumab (Herceptin). The choice between these treatments depends upon whether the breast cancer cells have the estrogen and progesterone receptors and is therefore a hormone-responsive tumor and whether it makes a protein called HER2.

HORMONE- RESPONSIVE BREAST CANCERS

About 50%-70% of breast cancers require the female hormone estrogen to grow, while other breast cancers are able to grow without estrogen. Tumors made up of breast caner cells that do require estrogen to grow are called estrogen-dependent and produce hormone receptors which detect the presence of the hormone. These hormone receptors are simply called estrogen receptors (ER). Breast cancers can also be responsive to a hormone called progesterone, which is produced by the ovaries, the adrenal glands, and the placenta during pregnancy. Receptors which detect the presence of progesterone are called progesterone receptors (PR).  Cancer cells may have estrogen or progesterone receptors alone, or both. These cancers are known as "hormone-responsive".

If your breast cancer is hormone-responsive, you are more likely to benefit from treatments that lower estrogen levels or block the actions of estrogen. These treatments are referred to as endocrine or hormone therapies.

HORMONAL THERAPIES

The goal of adjuvant hormonal therapy is to prevent breast cancer cells from being stimulated to grow by estrogen. The options for hormonal therapy in premenopausal women include the following:

• The drug tamoxifen
• A drug or surgery that blocks estrogen production by the ovaries (see 'Ovarian suppression' below)

Tamoxifen — Tamoxifen (Nolvadex) prevents estrogen from stimulating growth of the breast cancer cells. Treatment with tamoxifen is not usually recommended for periods longer than five years. However the benefits of tamoxifen treatment last for at least ten years after the patients stop taking the drug. Taking tamoxifen for more than five years does not add further benefit, and the risk of side effects such as uterine cancer increases with longer treatment.

Side effects — Tamoxifen may increase the risk of the following, particularly in women over age 55 years:

• Cancer of the uterus (endometrial cancer and sarcoma)
• Blood clots within deep veins (deep vein thrombosis), usually in the legs, which can travel to the lungs (pulmonary embolism)
• Tamoxifen MAY increase the risk of stroke, particularly in women under the age of 55

For most women, the benefits of taking tamoxifen in preventing a recurrence of breast cancer are far greater than the risks associated with its side effects. However, the risk of having a tamoxifen related side effect may be higher for women with risk factors for blood clots or stroke (eg, prior history of blood clots in the leg or lung, history of smoking).

Tamoxifen may cause other side effects, particularly hot flashes and vaginal discharge. Tamoxifen does not cause infertility, however premenopausal women receiving adjuvant tamoxifen are discouraged from becoming pregnant. Premenopausal women who are taking tamoxifen and are sexually active should use effective nonhormonal contraception such as condoms, a diaphragm, contraceptive sponge, or a non-hormonal copper intra-uterine device (IUD) while they are on tamoxifen and for about two months after discontinuing the therapy.

Ovarian suppression — Ovarian suppression refers to any treatment that stops estrogen production by the ovaries. The ovaries can be suppressed in one of several ways:

• Surgical removal of the ovaries (called oophorectomy) or radiation treatment of the ovaries. Both of these methods stop the ovaries from making hormones and therefore cause infertility.
• Drugs called gonadotropin releasing hormone (GnRH) agonists stop the ovaries from making estrogen temporarily. The most commonly used drug in this class is goserelin (Zoladex), which is given as a monthly injection. This treatment is usually given for five years.

All forms of ovarian suppression cause a rapid onset of menopause symptoms such as hot flashes, night sweats, mood swings and vaginal dryness. These symptoms can be severe, but are manageable.

Aromatase inhibitors — These are a class of drugs used for hormonal therapy and include drugs called anastrozole, letrozole and exemestane. Treatment with these drugs is normally preferred in postmenopausal rather than premenopausal women. However women who are premenopausal before they start treatment for breast cancer may become menopausal; an aromatase inhibitor may then be considered. You should discuss the indications, risks, and benefits of this option with your doctor.

HORMONAL THERAPY AND / OR CHEMOTHERAPY?

Hormonal therapy is recommended for women with ER-positive breast cancer. However, it is not clear if additional treatment (chemotherapy) is also needed.

Hormonal therapy alone is commonly used for premenopausal women with low-risk tumors (i.e., those that are node-negative, ER/PR-positive, small (less than 1 cm) and lacking unfavorable microscopic features). Women with higher risk ER-positive breast cancers (ie, those with involved lymph nodes, tumor size larger than 1 cm, or unfavorable microscopic features) may benefit from additional chemotherapy.

• A test called the 21-gene recurrence score assay (also called Oncotype DX™) may be useful to select those women with ER-positive, node-negative early breast cancer who will benefit the most from chemotherapy (see “21 gene test” under “Factors affecting treatment decisions” above).

FOLLOW UP AFTER TREATMENT

After treatment, you will need to be checked every so often to see if the cancer comes back, and repeat mammograms. The frequency of these checkups will however decrease if you remain clear of any symptoms and reccurences of the breast cancer. You should also check your breasts yourself at home regulary and watch for symptoms that could mean the cancer has come back. Examples of these symptoms include new lumps in the breast area, pain (in the bones, chest, or stomach), trouble breathing, and headaches. If you notice any new symptom, mention it to your doctor. If you have a high risk for cancer recurrence (e.g. familial cancer syndrome; personal history of ovarian cancer) you should consider genetic counseling.

SUMMARY

There are many options for the adjuvant therapy of breast cancer. Expert guidelines can help to guide decisions. However, because individual factors strongly influence the choice of therapy, you should discuss the options for adjuvant therapy with your doctor to determine which therapy is best for you.

POSTMENOPAUSAL WOMEN

Following surgery, systemic (body-wide) anticancer treatment is often recommended to eliminate any residual microscopic tumor cells in the body. This type of therapy is called adjuvant therapy, and is an important component of breast cancer treatment which significantly decreases the chance that the cancer will return (or recur). Consequently it also improves a woman's chance of surviving her cancer.

There are three options for systemic adjuvant therapy of early breast cancer: hormonal therapy, chemotherapy, and trastuzumab (Herceptin). The choice between these treatments depends upon whether the breast cancer cells have the estrogen and progesterone receptors and is therefore a hormone-responsive tumor and whether it makes a protein called HER2.

HORMONE- RESPONSIVE BREAST CANCERS

About 50%-70% of breast cancers require the female hormone estrogen to grow, while other breast cancers are able to grow without estrogen. Tumors made up of breast caner cells that do require estrogen to grow are called estrogen-dependent and produce hormone receptors which detect the presence of the hormone. These hormone receptors are simply called estrogen receptors (ER). Breast cancers can also be responsive to a hormone called progesterone, which is produced by the ovaries, the adrenal glands, and the placenta during pregnancy. Receptors which detect the presence of progesterone are called progesterone receptors (PR).  Cancer cells may have estrogen or progesterone receptors alone, or both. These cancers are known as "hormone-responsive".

If your breast cancer is hormone-responsive, you are more likely to benefit from treatments that lower estrogen levels or block the actions of estrogen. These treatments are referred to as endocrine or hormone therapies.

HORMONAL THERAPIES

The goal of adjuvant hormonal therapy is to prevent breast cancer cells from being stimulated to grow by estrogen. In postmenopausal women with early breast cancer, two hormonal treatments are possible: tamoxifen and a class of drugs called aromatase inhibitors (AIs).

Tamoxifen — Tamoxifen (Nolvadex) prevents estrogen from stimulating growth of the breast cancer cells. Treatment with tamoxifen is not usually recommended for periods longer than five years. However the benefits of tamoxifen treatment last for at least ten years after the patients stop taking the drug. Taking tamoxifen for more than five years does not add further benefit, and the risk of side effects such as uterine cancer increases with longer treatment.

Side effects — Tamoxifen may increase the risk of the following, particularly in women over age 55 years:

• Cancer of the uterus (endometrial cancer and sarcoma)
• Blood clots within deep veins (deep vein thrombosis), usually in the legs, which can travel to the lungs (pulmonary embolism)
• Tamoxifen MAY increase the risk of stroke
• Hot flashes
• Vaginal discharge

For most women, the benefits of taking tamoxifen in preventing a recurrence of breast cancer are far greater than the risks associated with its side effects. However, the risk of having a tamoxifen related side effect may be higher for women with risk factors for blood clots or stroke (eg, prior history of blood clots in the leg or lung, history of smoking).

Aromatase inhibitors — Aromatase inhibitors are a type of medicine that block estrogen from being produced in postmenopausal women.

Studies suggest that aromatase inhibitors such as anastrozole (Arimidex), letrozole (Femara), and exemestane (Aromasin) are at least as effective and may be more effective than five years treatment alone with tamoxifen in postmenopausal women with early breast cancer. There also appears to be added benefit from switching over to an aromatase inhibitor after taking tamoxifen for a length of time between two and five years.

Side effects — Side effects of aromatase inhibitors include bone loss and bone fractures, pain in the muscles and joints, blood clots, and cardiovascular events such as a heart attack and heart failure.

HORMONAL THERAPY AND / OR CHEMOTHERAPY?

Chemotherapy provides benefit for some women with ER-positive early breast cancer, especially women with positive lymph nodes. It is less clear which women with ER-positive and lymph node negative breast cancer need chemotherapy.

• A test called the 21-gene recurrence score assay (also called Oncotype DX™) may be useful to select those women with ER-positive, node-negative early breast cancer who will benefit the most from chemotherapy (see “21 gene test” under “Factors affecting treatment decisions” above).

Treatment of locally advanced breast cancer

Occasionally, a breast cancer will not be discovered until it is fairly large or locally advanced. The term locally advanced breast cancer (LABC) is used to describe a breast cancer that has progressed locally but has not yet spread outside the breast and local lymph nodes.

This article will cover the treatment of locally advanced breast cancer, including inflammatory breast cancer.

WHAT IS LOCALLY ADVANCED BREAST CANCER? — Locally advanced breast cancer (LABC) includes:

• Large breast tumors (more than 5 centimeters in diameter)
• Cancers that involve the skin of the breast
• Cancers that involve the underlying muscles of the chest
• Cancers that involve multiple local lymph nodes (those located in the arm pit or the soft tissues above and below the collarbone)
• Inflammatory breast cancer, a rapidly growing type of cancer that makes the breast appear red and swollen (hence the term inflammatory)

Although the likelihood of curing LABC is lower than it would be if the cancer were small and confined to the breast, cure is possible with aggressive treatment. In most cases, this requires a combination of chemotherapy, radiation therapy, and surgery.

SIGNS AND SYMPTOMS

Locally advanced breast cancer (LABC) — Although the cancer may not be visible most LABCs can be felt by both the woman and her doctor.

Inflammatory breast cancer — Inflammatory breast cancer (IBC) is a specific type of LABC that has unique symptoms. IBC often does not produce a lump that can be felt within the breast. Instead, it causes thickening and swelling of the skin of the breast, which may be reddened and warm to the touch, or may resemble the texture of orange peel. The breast is often painful and enlarged, and appears inflamed.

DIAGNOSIS AND STAGING — Once the diagnosis of a breast cancer is suspected, several tests will be done to confirm the diagnosis. Most women with LABC have affected lymph nodes or glands that can be felt in the axilla (armpit). Testing can be done to confirm this finding and to show what other areas are affected by the cancer.

Mammogram — A mammogram of both breasts is needed to see how large the cancer is and to determine if the opposite breast is affected. A breast magnetic resonance imaging (MRI) or ultrasound may also be recommended.

Biopsy of the tumor — In order to confirm the diagnosis and type of breast cancer, a biopsy is required. The biopsy technique depends upon whether a lump is present in the breast. If the physician feels a lump, the biopsy can often be performed in the office. However if the the breast feels normal and the abnormality suspected to be breast cancer is only seen on the mammogram then a technique is needed to guide where to perform the biopsy, a mammogram is often used for this purpose. The radiologist finds the abnormality on the mammogram and marks its location, often with a thin wire that is inserted into the abnormal area. A surgeon then uses the wire to know which area to biopsy. This procedure is called a needle localization biopsy.

The tissue biopsy will be examined with a microscope to see if there are signs of cancer and further tests will be performed to identify if the cancer has hormone receptors (ER or PR) and a protein called HER2. These two factors are important in selecting the best treatment.

Hormone receptors — About 50%-70% of breast cancers require the female hormone estrogen (estradiol) to grow; other breast cancers are able to grow without estrogen. Estrogen-dependent breast cancer cells produce proteins called hormone receptors, these are used by the cancer cells to detect the presence of estrogen, consequently they are called estrogen receptors (ER).  Cancer cells can also have hormone receptors for progesterone, these are called progesterone receptors. One or both of these receptor types may be present on cancer cells and a woman with these receptors is more likely to benefit from treatments that lower estrogen levels or block the actions of estrogen. These treatments are referred to as hormonal or hormone therapy and such tumors are referred to as "hormone-responsive". Women whose tumors do not contain any hormone receptors are not given hormonal therapy.

HER2 expression — HER2 is a protein that is present on about one-third of breast tumors. Having HER2 determines if the cancer will respond to a medicine called trastuzumab (see 'Trastuzumab (Herceptin®)' below).

TREATMENT OF LOCALLY ADVANCED BREAST CANCER — LABC is often treated with a combination of chemotherapy, surgery, and radiation therapy.

Chemotherapy — Chemotherapy refers to medicines used to stop or slow the growth of cancer cells. In most cases, chemotherapy includes a combination of two or more drugs, most often given intravenously (IV). These combinations are referred to as regimens.

Chemotherapy is not given every day but instead is given in cycles. A cycle of chemotherapy refers to the time it takes to give the chemotherapy and then allow the body to recover. A cycle of chemotherapy typically ranges from two to four weeks.

Preoperative chemotherapy — For most women with LABC, chemotherapy is recommended before surgery. Preoperative (also called neoadjuvant) chemotherapy can successfully shrink the breast tumor. In about 30% of cases, chemotherapy removes all traces of the cancer from the breast and lymph nodes. This is termed a complete clinical response.

Shrinking a large breast tumor with chemotherapy might allow you to have less aggressive surgery. For example, it might be possible to remove only the tumor (lumpectomy) rather than the entire breast (Mastectomy). (See 'Surgery and radiation therapy' below.)

Hormonal therapy — Breast cancers that produce hormone receptors are responsive to hormonal therapy. In some cases, hormonal therapy is given instead of chemotherapy as the first treatment for LABC.

• Taking hormonal therapy before surgery (called neoadjuvant therapy) can successfully shrink breast cancers that are hormone-responsive. Hormonal therapy has fewer side effects than chemotherapy (and can be taken by mouth rather than IV). Thus, it might be recommended as a first-line treatment, instead of chemotherapy, for women who are older or who are not healthy enough to tolerate chemotherapy.
• For most women with hormone-responsive LABC, hormonal therapy is recommended after surgery for five or more years. When hormonal therapy is given after surgery, it is referred to as adjuvant therapy. The purpose of this treatment is to get rid of any tumor cells that remain in the body (often termed micrometastases) after surgery.

Adjuvant hormonal therapy is usually started after an entire course of chemotherapy is completed.

Trastuzumab (Herceptin®) — Trastuzumab (Herceptin) is a unique drug that works differently than chemotherapy. It targets a protein called HER2, which is found on the cells of some breast cancers. About 20% of breast cancers express very high levels of HER2, and trastuzumab appears to work only in this group of women (see 'HER2 expression' above).

Surgery and radiation therapy — Following chemotherapy, tests are performed to see how the tumor responded to treatment. You will have an exam and imaging studies (using mammography, breast ultrasound, or MRI) to see how much of the cancer remains. If there are still signs of cancer, surgery may be recommended.

• A surgery to remove part of the breast (called breast-conserving surgery) is an option for many women with LABC, as long as there are no signs of inflammatory breast cancer (see 'Inflammatory breast cancer' above).
• Mastectomy (total removal of the breast) is necessary if skin involvement has not improved following chemotherapy or if the tumor is still fixed to the underlying chest wall.

After surgery, radiation therapy is recommended to women who had breast conserving surgery. This can significantly lower the chance of the cancer recurring in the remaining breast tissue.

Women who have had a mastectomy will likely receive radiation therapy to the chest wall and possibly to the lymph nodes. This is especially true if there was lymph node involvement or inflammatory breast cancer. Having a combination of surgery and radiation therapy decreases the chance that the breast cancer will return in the breast or the chest wall. Radiation therapy is given every day (five days a week) for a period of six to seven weeks.

INFLAMMATORY BREAST CANCER — The treatment of inflammatory breast cancer is similar to that of other types of locally advanced breast cancer (LABC). Treatment usually includes chemotherapy, surgery, and radiation therapy. As with other forms of LABC, two types of chemotherapy agents including and anthracycline and a taxane are usually used.

One difference in the treatment of LABC is that a mastectomy is usually recommended, even if the cancer responded well to neoadjuvant chemotherapy. After mastectomy, radiation therapy to the chest wall and lymph nodes is strongly recommended.

Treatment for stage IV (metastatic) breast cancer

The extent of cancer involvement within the breast is usually determined by the findings on the biopsy, the results of the mammogram and, in some cases, the results of a breast MRI scan.

Although by definition, breast cancer starts within the breast, tiny microscopic cells or pieces of the cancer may break off from the breast tumor at any point and travel to other places through the bloodstream or the lymph channels; this process is called metastasis.

When these stray tumor cells lodge themselves in a lymph node (also called glands) or an organ such as the liver or the bones, they grow, eventually producing a mass or lump that can sometimes be felt (e.g., if it involves the skin or the lymph nodes in the armpit). In other cases, metastases may only be evident because they cause symptoms such as bone pain and can be seen on an x-ray such as a CT scan, a bone scan, or a PET scan.

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 average time for survival of individuals with metastatic breast cancer is 18 to 24 months, although it can vary from a few months to many years. This article will review the treatment options for metastatic breast cancer.

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 a new tumor in the axillary lymph nodes (glands in the armpits).

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 may be an alternative treatment.

APPROACH TO PATIENTS WITH METASTATIC DISEASE — All patients with metastatic breast cancer should 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 radiotherapy 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 hormonal therapy, chemotherapy, and/or biologic agents. A choice between them depends on how many tumors there are, 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 the presence of these receptors is reassessed 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 5% of the time. (See 'HER2-targeted agents' below.).

Treatment options

Anti-estrogen treatment — Anti-estrogen treatment is also known as hormonal 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 is with medications such as gonadotropin-releasing hormone antagonists including those called goserelin or leuprolide are used to preventing the ovaries from making estrogen. Another method of preventing the production of estrogen is surgery to remove the ovaries (oophorectomy)..

Alternatively other medications work by preventing the receptors on the cancer cells from recognizing estrogen, these are called selective Estrogen Receptor Modulators (SERM). Tamoxifen is a SERM that is taken orally and is used as a first-line hormonal therapy for premenopausal women and for men with advanced breast cancer. Most but not all individuals with ER and/or PR-positive breast cancer will respond to tamoxifen.  However most if not all breast cancers eventually stop responding.

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 hormonal 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 (aromatase) that helps make estrogen outside of the ovary. Drugs in this class include anastrozole, letrozole, and exemestane. They are indicated for use in postmenopausal women and can be used in men with metastatic breast cancer. However, AIs should not be given to women with intact ovarian function. Side effects of aromatase inhibitors include bone loss and bone fractures and pain in the muscles and joints.

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, increased levels of 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 are taken orally and include both medroxyprogesterone or megestrol acetate. This type of medication is sometimes used in women who have stopped responding to tamoxifen. The side effects of treatment include increased risk of blood clots, weight gain, fluid retention, and vaginal bleeding. In some studies, a reduction in the quality of life has been seen in women who have these drugs.
• Estrogen — For women who have progressed on multiple treatments with antiestrogens, the use of estradiol may be used. It is given as a pill and is taken daily. Side effects include vaginal bleeding, breast tenderness, nausea, 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 — The use of androgens in metastatic breast cancer is rarely used. Despite evidence that it can help tumors shrink, the side effects of treatment (virilization, edema, and jaundice) make it a less attractive option for both women and their clinicians. These side effects include virilization which is the changing of the body to a more masculine appearance, edema which is swelling due to fluid retention, and jaundice (yellowing of the skin).

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 of chemotherapy refers to the time it takes to give the chemotherapy and then allow the body to recover. A cycle of chemotherapy typically ranges from two to four weeks.

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 two drugs in this category, trastuzumab and lapatinib. These are often used with chemotherapy or hormonal therapy in the treatment of metastatic breast cancer.

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%-5% of women treated with trastuzumab. Trastuzumab-related heart damage may not be permanent, and improvements have been seen once trastuzumab is discontinued.

Lapatinib — Lapatinib is an oral medication that targets HER2 in a different way than trastuzumab. 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.

Bevacizumab — The angiogenesis inhibitor, bevacizumab, is an active agent for the treatment of metastatic breast cancer, particularly when combined with the drug paclitaxel. It is often used as a first-line treatment of metastatic breast cancer. However, the benefit of bevacizumab is not clear and the Food and Drug Administration has recently rescinded its approval of this agent in metastatic breast cancer.

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 — 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, treatment directed at the tumor site may be an option and may include surgical resection, targeted radiation, radiation frequency ablation or chemoembolization where the anticancer drugs are inserted directly into  tumor.

Patients who are considered to be candidates for a site-specific treatment, criteria are used to select those most likely to benefit.. 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 to 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 — Outcomes for patients following surgery are best in those who undergo a complete tumor resection, removing the tumor and healthy tissue surrounding it.

TREATMENT RECOMMENDATIONS — 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 or in women with symptoms related to metastatic breast cancer. Combination chemotherapy is associated with increased responses compared to 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 hormonal 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, the studies are too small to render a conclusion on the benefits of this approach.
• Sequential hormonal 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 hormonal therapy.
• For individuals who have not received prior treatment (ie, those who present with metastatic disease), those with ER-negative breast cancer, and those with tumors that do not respond to hormonal therapy, chemotherapy is indicated as primary treatment. There is no one standard of care.
• Chemotherapy with biologic therapy, such as the angiogenesis inhibitor, bevacizumab.
• 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.
• Available options include anthracyclines (eg, doxorubicin), taxanes (eg, paclitaxel or docetaxel), capecitabine, vinorelbine, gemcitabine, ixabepilone, and eribulin.
• Individuals with HER2-positive breast cancers should receive HER2-directed therapy.
• For individuals with ER-positive cancer that is not life-threatening or symptomatic, hormonal therapy plus HER2-directed treatment (eg, lapatinib or trastuzumab) should be used. For similar patients with ER-negative cancer, single agent trastuzumab is an appropriate choice.
• For individuals with symptomatic, life-threatening disease, or disease that is involving the organs (eg, liver or lungs), combination chemotherapy with trastuzumab should be used. Most clinicians combine HER2-directed treatment with chemotherapy, such as paclitaxel, docetaxel, vinorelbine, carboplatin, and gemcitabine.

Lapatinib can be used in combination with capecitabine, aromatase inhibitors, paclitaxel, or trastuzumab. It is indicated for individuals who have disease progression on trastuzumab.

New research

For some patients, taking part in a clinical trial may be the best treatment choice. Clinical trials are part of the cancer research process. Clinical trials are done to find out if new cancer treatments are safe and effective or better than the standard treatment. Many of today's standard treatments for cancer are based on earlier clinical trials. Patients who take part in a clinical trial may receive the standard treatment or be among the first to receive a new treatment. Patients who take part in clinical trials also help improve the way cancer will be treated in the future. Even when clinical trials do not lead to effective new treatments, they often answer important questions and help move research forward. Patients can enter clinical trials before, during, or after starting their cancer treatment.

For example, clinical trials are currently investigating the use of high-dose chemotherapy with stem cell transplantation. This allows giving high doses of chemotherapy while replacing blood -forming cells destroyed by the cancer treatment. Stem cells (immature blood cells) are removed from the blood or bone marrow of the patient or a donor and are frozen and stored. After the chemotherapy is completed, the stored stem cells are thawed and given back to the patient through an infusion. These reinfused stem cells grow into (and restore) the body’s blood cells.

Sources and Acknowledgements

• National cancer institute at National Institutes of Health