Breast Cancer

Overview of Breast Cancer and Introduction to Personalized Treatment

Breast cancer is the most common type of cancer among women in the United States, accounting for more than a quarter of all cancers in women. Approximately 2.5 million women in this country are breast cancer survivors, and an estimated 192,370 new cases of breast cancer were diagnosed in women in 2009. Advances in treatment have enabled more women to live longer overall and to live longer without disease progression. Yet not every treatment is effective for every woman. Why?

In an attempt to answer that question, researchers have studied tumors from hundreds of thousands of women with breast cancer and have found that not all breast tumors are alike. In fact, breast tumors vary in some very important ways, and an enhanced understanding of the biology of tumors has led to improved treatments and more personalized therapies.

Treatment for breast cancer was once chosen only according to the stage of disease (the size of the tumor and whether cancer had spread to nearby lymph nodes or other organs) and its histologic classification, that is, the type of tissue in which the cancer originated. Breast cancer is either invasive — spreading beyond the tissue where it arises — or is noninvasive. Most breast cancers arise in the ducts, and invasive ductal carcinoma accounts for 70-80% of all breast cancers. The second most common type of breast cancer, comprising about 5-10% of all cases, is infiltrating lobular carcinoma, which arises from the lobules, the milk-secreting glands. Other, less common histologic types are tubular, medullary, and inflammatory breast cancer. In addition, ductal carcinoma in situ is breast cancer that is growing in the ducts of the breast but does not invade the surrounding tissues, where they can develop the capacity to spread to other organs.

These histologic types remain important, but the identification of tumor markers and the development of technology for genetic profiling (studying several genes in a tumor simultaneously) have led to a different classification of breast cancer — one based on molecular subtypes. These subtypes are based on tumor markers such as estrogen and progesterone receptors (ER and PR) and human epidermal growth factor receptor 2 (HER2), and the presence or absence of these tumor markers has become a major factor in selecting treatment and determining prognosis (outcome). As such, they form the basis for personalized treatment in breast cancer. Molecular subtypes are discussed in more detail in The Importance of Tumor Markers and Other Tools in Diagnosis and Treatment.

This content is designed to help you better understand the personalized treatment of breast cancer, or treatment tailored to the specific characteristics of a particular tumor. Before discussing personalized treatment, it is important to be familiar with several other aspects of breast cancer and its treatment.

As with all cancers, the development of breast cancer starts from just one genetically abnormal (or mutant) cell. This abnormal cell divides and multiplies in a disorderly fashion to become a mass of cells, or a tumor. As the tumor grows, it develops a blood supply to help sustain its growth. Cells may break off a large tumor and travel through the lymph system to nearby lymph nodes (tiny, bean-shaped organs that are part of the immune system); lymph nodes near the breast are located under the arm, in the neck, and just above the collarbone. Tumor cells can also travel to other parts of the body; this spread of cancer is known as distant metastasis. The most common sites of breast cancer metastasis are the bones, lungs, and liver.

Approximately 90-95% of all breast cancers are sporadic, which means that they occur by chance. The remaining 5-10% of breast cancers are caused by inherited abnormalities in genes, known as genetic mutations. The primary breast cancer-related genetic mutations are abnormalities in BRCA1 and BRCA2. Because hereditary breast cancer affects so few women, genetic testing is not for everyone. The content on genetic testing describes when testing is appropriate and how determining whether cancer is hereditary can help women and their doctors make better informed choices about treatment.

As noted, ER, PR, and HER2 are tumor markers that play an important role in the diagnosis and treatment of breast cancer. The benefit and limitations of these and other tumor markers are discussed in more detail in The Importance of Tumor Markers in the Diagnosis & Treatment of Breast Cancer. In addition, advanced technology now enables doctors to better predict recurrence and the course of breast cancer, which allows for more informed decision-making about adjuvant treatment for women with early-stage disease and for monitoring treatment in women with metastatic disease (see below).

Your pathology report, prepared after biopsy of a suspicious lump or after definitive surgery (as treatment for a cancerous tumor), serves as a guide in treatment decision-making. An explanation of the various details included in your pathology is given in Your Pathology Report.

The core of this content page describes various options for the treatment of breast cancer, beginning with an overview of targeted therapy, which allows for personalized treatment, especially with regard to ER+/PR+ and HER2+ breast cancer. This content page also provides an overview of standard treatments, including surgery, radiation therapy, and chemotherapy, and of the potential side effects of treatment. Throughout, you will be directed to Web sites where you can find more details to help you better understand breast cancer and its treatment.

Learn all you can about your cancer and your treatment options. Knowledge is power.

Tools for Personalizing Treatment

Advances in technology have given oncologists additional tools to help them personalize treatment and to make more informed predictions about the course of disease and the response to treatment. The tools are designed to provide specific information within two distinct populations of women with breast cancer: women with early-stage disease (stage I or II) and women with metastatic (advanced) disease.

Two tests can be used to predict recurrence in women with early stage, small (less than 5 centimeters [approximately 2 inches]), ER+ invasive breast cancer that has not spread to the lymph nodes (node-negative). Predicting recurrence is important in this setting, as it relates to the issue of adjuvant therapy, or treatment given after primary treatment (surgery). Decisions regarding adjuvant therapy for women with early-stage breast cancer are among the most challenging in cancer treatment, as studies have shown that adjuvant therapy offers substantial benefit in some cases and little benefit in others.

A third test is useful for determining the response to treatment in women with metastatic breast cancer. The technique provides a new way to monitor response to treatment, offering several advantages compared with traditional monitoring with imaging studies and tumor markers.

These three tests help oncologists make treatment decisions based on the clinical situation of an individual woman.

Predicting Recurrence in Early-Stage Breast Cancer

Treatment with tamoxifen after surgical removal of breast cancer (lumpectomy or mastectomy) is a standard of care for women with early-stage disease, provided that the hormone receptor test is positive, and chemotherapy is sometimes added to the treatment regimen. However, studies have shown that not all women benefit from the addition of chemotherapy; in fact, about 70-80% of women with this type of breast cancer will have long-term disease-free survival without chemotherapy.

The two tests for predicting recurrence in early-stage breast cancer take advantage of a technology known as gene expression profiling, which allows for several genes in a tumor specimen to be studied simultaneously. The analysis provides information on the expression (activity) of genes that activate and suppress the development of cancer cells. Researchers have found that the genetic profile of a tumor is related to its behavior; that is, the activity of specific genes can indicate whether the tumor will recur or metastasize.

One test, Oncotype DX (Genomic Health, Redwood, CA), provides a profile of the activity of 21 genes (16 cancer genes and 5 control genes) in a tissue specimen, and the activity is calculated as a Recurrence Score® of 0 to 100 points. A low score indicates low risk and a high score indicates high risk of recurrence within 10 years after diagnosis.

Oncotype DX assay has been recommended by both ASCO and NCCN for predicting the risk of recurrence for women with newly diagnosed ER+, node-negative breast cancer. The ASCO statement also notes that the test can be used to identify women who may be successfully treated with tamoxifen and may not require adjuvant chemotherapy.

Similar to Oncotype DX is MammaPrint (Agendia, Amsterdam, Netherlands), an assay of 70 genes that research has found to be related to distant recurrence of breast cancer. The results of testing indicate either a high or low risk of the cancer recurring within 10 years after diagnosis. Several studies have demonstrated that MammaPrint is a reliable predictor of disease-free survival, and in 2007, the US Food and Drug Administration (FDA) cleared the test for use in the United States (not a requirement for use). At present, the MammaPrint test requires a specimen of fresh tissue, so arrangements for the test must be made before surgery so that tissue can be obtained at that time.

The benefit of both Oncotype DX and MammaPrint is that treatment can be tailored — or personalized — to the specific risk and needs of each individual woman. In determining the optimum treatment plan, the oncologist will consider the risk identified by either test in addition to traditional factors, such as the size or grade of the tumor. In general, women with a low risk can avoid the side effects of chemotherapy and be treated safely with hormone therapy (tamoxifen) alone. Women with a high risk can be treated with adjuvant chemotherapy to help reduce the risk of recurrence and can be monitored closely to help ensure early intervention if cancer does recur.

Predicting Response to Treatment in Metastatic Breast Cancer

Researchers have found that some cells detach from metastatic tumors and enter the bloodstream. The number of these cells, known as circulating tumor cells (CTCs), is thought to decrease as a tumor shrinks in response to treatment. Thus, knowing the number of CTCs (the CTC count) can help oncologists better assess the effectiveness of therapy. The test for measuring the number of CTCs, CellSearch (Veridex, a Johnson & Johnson company, Raritan, NJ), has been cleared by the FDA for use in the United States for women who have metastatic breast cancer. (The test is also used for colorectal and prostate cancer.)

The primary benefit of using CTC counts to monitor response to treatment is that monitoring can begin as early as the end of the first cycle (3 to 4 weeks) of treatment, 2-3 months earlier than response can be detected on imaging studies or by tumor marker levels. Measuring CTC counts allows doctors to identify the most effective treatment regimen for each individual patient as early as possible. Earlier assessment improves decision-making and increases the chance for a better outcome. Earlier changes in treatment may help improve progression-free survival (the length of time before disease progresses) and overall survival.

The technology used to measure CTCs is cutting-edge, and the test is precise, with an ability to detect as few as one CTC in a vial of blood. Research has shown that progression of metastatic breast cancer is substantially more likely when the CTC count is 5 or more (as opposed to less than 5) per blood sample.

In addition to the substantial benefit of more timely assessment of response, monitoring with CTC counts offers other advantages. First, CTC monitoring is done on a small sample of blood drawn from a vein (usually in the arm), making it more convenient than imaging studies. Second, the cost of CTC testing is much lower than imaging studies. Until the results of more studies are available, however, CTC counts should be used in conjunction with imaging studies.

No recommendations for the use of CTC counts to guide treatment planning have been made, as many researchers believe that further studies are necessary to confirm the value of the test. However, more oncologists are integrating the use of CTC counts into their routine monitoring for women with metastatic breast cancer. Although CTC counts are not formally recommended, their cost is covered by Medicare, and many private insurers have modified their coverage since the FDA approval of the test.

Additional Resources

Treatment: A Personalized Approach

The personalized approach to treatment involves making decisions on the basis of many factors, including tumor-related factors: the type of cancer, the stage of disease, the results of tumor marker testing, and the genetic make-up of the tumor and patient-related factors: age, overall health and menopausal status. Among the treatment options to be considered are surgery, radiation therapy, chemotherapy, hormone treatment and targeted therapy (Table 1).

In some cases, the best treatment approach is clearly evident, but decision-making, especially in cases of early-stage breast cancer, can be more complex and require even more of your input about selecting treatment options. Many women are faced with several decisions: What kind of surgery should I have? Do I need chemotherapy? Will radiation therapy help me? Is there a targeted therapy for my type of breast cancer? What kind of hormone therapy should I take? All treatment decisions should be made only after discussing your options with your doctor and/or other members of your health care team. At each decision point, you should ask questions to make sure you understand your treatment options and their risks and benefits (see Table 2). You are also encouraged to ask your doctor about clinical trials that are available for your particular type of breast cancer.

Clinical Trials

All women with breast cancer are encouraged to seek clinical trials that may be appropriate for them. The purpose of clinical trials is to improve the standard of care. As such, participants in a clinical trial are guaranteed to receive the best available care (the standard of care) and may be included among those who receive novel treatment that is thought to be better than the standard of care. Clinical trials are carefully planned and structured so that all patients—no matter where they are treated — eceive the same high-quality care.

There are hundreds of clinical trials in breast cancer. You can search for clinical trials on www.clinicaltrials.gov, a Web site hosted by the National Cancer Institute. Your doctor can also help you review clinical trial options for your particular cancer.

Surgery and Radiation Therapy

Surgery for breast cancer was the first treatment to be tailored to the type of breast cancer. Mastectomy was once done for all types of breast cancer until research showed that a less invasive procedure could be done for smaller tumors. Now, many women can choose between lumpectomy and mastectomy because the survival rates for the two options are essentially the same, while the quality of life issues are quite different.

Lumpectomy

Lumpectomy is also known as breast-conserving or breast-sparing treatment because only the tumor (lump) is removed, along with a small margin of healthy breast tissue surrounding the lump, leaving the breast intact. Some lymph nodes from under the arm (axillary lymph nodes) may also be removed. Lumpectomy is usually done for ductal carcinoma in situ (DCIS) or for stage I or II invasive breast cancer (a tumor that is less than 5 centimeters).

A lumpectomy is not usually recommended for women who have larger tumors. However, if a woman has a strong desire to save the breast, chemotherapy is recommended before surgery to shrink the tumor and/or destroy cancer cells that have spread beyond the tumor. Treatment given before the primary treatment (in this case, surgery) is known as neoadjuvant therapy. Radiation therapy is almost always done after lumpectomy to make sure that any remaining cancer cells are destroyed. Studies have shown that women with a small tumor who have a lumpectomy followed by radiation therapy live as long as women who have mastectomy.

Mastectomy

A mastectomy is necessary for larger tumors, especially those that have spread to nearby lymph nodes. Treatment guidelines developed by the National Comprehensive Cancer Network (NCCN) recommend that women with stage IIIA, IIIB, or IIIC breast cancer receive neoadjuvant chemotherapy before mastectomy. Some women with a small tumor may wish to have a mastectomy because it offers greater peace of mind about recurrence. A mastectomy instead of lumpectomy for a small tumor may also be desired in order to avoid the need for radiation therapy.

Because of advances in surgical techniques and knowledge about breast cancer, most mastectomies performed today are much less extensive and disfiguring than those done several decades ago. Mastectomy once meant removal of the entire breast with cancer, the chest wall muscles underneath the breast, and all the axillary nodes. This type of mastectomy is now called a radical mastectomy, and it is done only for extensive tumors or tumors that have invaded the chest wall. More often, a modified radical mastectomy or a simple (total) mastectomy is done, which preserves the chest wall muscles and some axillary nodes.

Radiation therapy can be safely avoided by many women who have mastectomy. The need for radiation therapy is determined primarily by the number of involved lymph nodes (especially if there are four or more lymph nodes with cancer in them) as well as the size of the tumor and whether cancer cells were found in the margin of healthy tissue around the tumor. Radiation therapy is usually given in small doses once a day over the course of several weeks. If breast cancer has metastasized, radiation therapy may be given to another part of the body.

Removal of lymph nodes (axillary dissection)

Removal of lymph nodes (known as axillary dissection) is done so that a pathologist can examine the nodes for signs of cancer cells. This procedure is generally done only when evidence of spread to the lymph nodes as been demonstrated by evaluation of a specimen obtained by needle biopsy or sentinel node biopsy (to be discussed). In general, at least 10 lymph nodes are removed, but the number can range from five to 30 depending on several factors, such as how many nodes the surgeon thinks are involved with cancer, how many nodes a woman has in the area, whether the features of the tumor indicate a favorable prognosis (outcome), and whether the choice of treatment will be affected by the number of nodes involved.

Sentinel lymph node biopsy has now become the preferred method to determine whether cancer has spread to the lymph nodes in women who do not have any evidence of this based on the clinical examination or findings of imaging studies. The rationale of sentinel lymph node dissection is that cancer is most likely to travel first to the node closest to the tumor, known as the sentinel node. If no cancer cells are detected on examination of the sentinel node or the nodes near it, a partial axillary dissection — along with its side effects — can be avoided, as cancer is unlikely to be present in nodes that are farther away. If cancer is detected in the sentinel lymph node, the surgeon will remove other nodes in the area to determine the extent of disease. Studies have shown that the 5-year survival rate for women with small breast cancers (less than 2 centimeters) after sentinel lymph node dissection is the same as after standard axillary dissection.

Reconstructive surgery

Breast reconstructive surgery is done by an experienced plastic surgeon. This surgery is usually done after mastectomy; it is done after lumpectomy only when the surgery will cause the breast to appear significantly different from the other breast. Breast reconstruction can either be done immediately — at the same time as mastectomy — or later (within months after mastectomy).

Immediate reconstruction can be done for early-stage breast cancer, but it is usually best to wait for reconstruction when breast cancer is more advanced. In such cases, the longer healing time needed for reconstructive surgery would delay the start of chemotherapy. If you are to have a mastectomy and think you will want reconstructive surgery, it is best to discuss your choice with your cancer surgeon and a plastic surgeon before the mastectomy so they can properly plan your treatment, even if the reconstructive surgery will not be done until later.

Reconstructive surgery cannot be done for all types of breast cancer. Women who do not want or cannot have reconstructive surgery can be fitted with a breast prosthesis. This prosthesis is a breast form (made of artificial materials) that you put in your bra to make your breast look natural and balanced.

Chemotherapy

Chemotherapy given after primary treatment (such as surgery) is known as adjuvant therapy. Adjuvant therapy is given to destroy cancer cells that may remain after surgery or that may be too small to be detected with laboratory testing or imaging studies. Adjuvant chemotherapy decreases the risk of recurrence, which can help extend survival.

The issue of whether to receive adjuvant therapy is often challenging, especially for women with early-stage disease. New technology has led to two tools that can help determine whether adjuvant chemotherapy will be of benefit. In addition, several decision aids are available; for example, Adjuvant! Online is a Web-based decision-making aid that can help you and your doctor determine whether adjuvant therapy is the best option. All of these tools allow women and their oncologists to choose treatment that is tailored to the unique characteristics of an individual tumor.

The NCCN has noted that some chemotherapy regimens are preferred because of their effectiveness in terms of response and survival, but other combinations may also be effective in many cases. Choosing a chemotherapy regimen involves considering not only whether there is benefit but also how much benefit in relation to the side effects. In addition, certain drugs or types of drugs may be more effective for tumors with specific characteristics. Researchers continue to study various combinations of chemotherapy drugs, as well as the genetic make-up of tumors, to determine which regimens offer the best chance of a long period of disease-free and overall survival for women with specific types of tumors.

Learning the names of chemotherapy drugs can be challenging because some are better known by their generic name, while others are better known by their trade name (Table 3). Also, abbreviations for chemotherapy combinations can look like alphabet soup. But the abbreviations for combinations are widely used and soon become familiar to women with breast cancer (Table 4).

For women receiving chemotherapy for late-stage cancer, the disease response to treatment will be evaluated to ensure that the chemotherapy regimen is effective. If it is not, your doctor will select another regimen for second-line therapy. The chemotherapy regimen can also be changed if breast cancer recurs during adjuvant treatment for early-stage cancer.

The personalized approach to breast cancer treatment involves such options as hormone therapy or targeted therapy, which are used according to hormone receptor status or the HER2 status.

Personalized Treatment based on Hormone Receptor Status

Treatment beyond surgery (with or without radiation therapy) and chemotherapy is personalized even further according to the hormone receptor status of the tumor (see The Importance of Tumor Markers in the Diagnosis and Treatment of Breast Cancer). Hormone therapy is effective only for tumors that are ER+ and/or PR+; they are not effective for women with ER- and PR- breast cancer.

It is important to understand that hormone therapy for breast cancer is different from hormone replacement therapy that is used to reduce the symptoms of menopause. The hormone therapy drugs used for breast cancer treatment are used to reduce the effects of estrogen, which drives the growth of ER+/PR+ tumors. These drugs, known as antiestrogen agents, lower the amount of estrogen in the body or block its action so that cancer cells will no longer get signals to grow and will eventually die.

The types of hormone therapy drugs are classified as selective estrogen-receptor modulators (SERMs), estrogen receptor downregulators, and aromatase inhibitors (AIs). Hormone therapy drugs differ with respect to how they work, who they can be used for, and what side effects they can cause (see Table 5). SERMs and AIs are taken as a once-daily pill; an estrogen receptor downregulator is given as a once-monthly injection.

SERMs

Tamoxifen has been used for several decades as part of adjuvant breast cancer treatment. Studies have shown that the use of tamoxifen for 5 years after surgery for early-stage breast cancer reduces the chances of cancer recurrence by more than 40%. The drug can also be used as part of treatment for metastatic breast cancer. Tamoxifen can be used regardless of a woman’s menopausal status; in other words, both premenopausal and postmenopausal women can take the drug. Another SERM, toremifene (Fareston) is used only for postmenopausal women who have an advanced ER+ and/or PR+ breast cancer.

Tamoxifen and toremifene are associated with side effects, primarily symptoms similar to the effects of menopause: hot flashes, irritability, fluctuations in emotions, etc. Serious side effects, although rare, can occur; the drugs may increase the risk of uterine cancer or deep vein thrombosis (blood clots in the leg). For most women, however, the benefit of tamoxifen or toremifene outweighs the risks.

Estrogen Receptor Downregulators

Fulvestrant is an estrogen receptor downregulator, which means that it eliminates estrogen receptors on the tumor cells, rather than just blocking them. The drug is approved only for postmenopausal women who have advanced breast cancer that no longer responds to tamoxifen or toremifene.

AIs

AIs represent a newer class of hormone therapy drugs. They block the production of estrogens in your body. Because of the way they work, AIs are recommended only for women who were postmenopausal at the time of the breast cancer diagnosis. The results of some clinical trials have indicated that AIs are better than tamoxifen in several ways. First, AIs have been shown to offer a significant survival benefit compared with tamoxifen. Also, AIs have been shown to substantially reduce the risk of recurrence, whether used as the initial hormone treatment, as sequential treatment (used after a period of treatment with tamoxifen) or as extended treatment (used after the traditional 5 years of treatment with tamoxifen). Lastly, AIs are usually associated with fewer serious side effects than tamoxifen. The most common side effects of AIs are joint stiffness and pain, and the risk for osteoporosis and heart problems may be increased. There are still many unresolved issues surrounding the choice of tamoxifen or an AI for postmenopausal women:

  • The three available AIs have not been directly compared with each other, so it is not clear if one is more effective than the others.
  • Because AIs have not been in use for as long as tamoxifen, much less is known about their long-term side effects.
  • The optimum length of treatment with an AI has not been clearly defined.
  • It is not known whether greater benefit is gained with the initial, sequential, or extended use of an AI.
  • The cost of hormone treatment may also be a factor; tamoxifen is less expensive than an AI.

Two studies have demonstrated a survival benefit with the use of tamoxifen followed by an AI, which led the NCCN to recommend the use of tamoxifen alone only for women who do not wish to take an AI or women for whom an AI is contraindicated. Several clinical trials are being done in an effort to answer continuing questions about the choice of tamoxifen or an AI and the optimum course of hormone therapy.

Other Hormone Therapies

Another form of hormone therapy currently being evaluated in clinical trials is the use of drugs to block the mechanism that causes the ovaries to make estrogen. These drugs, called luteinizing hormone-releasing hormone (LHRH) analogs, are an alternative to surgical removal of the ovaries in women who are premenopausal. Goserelin (Zoladex) and leuprolide (Lupron) are two LHRH analogs that are being studied as adjuvant therapy in conjunction with tamoxifen or an AI in premenopausal women.

Personalized Treatment based on HER2 Status

Treatment can also be personalized according to the HER2 status of the breast cancer (Table 6). If your tumor had a high level of HER2, an anti-HER2 agent will be effective. In addition, research has indicated that some conventional chemotherapy agents may be more effective for HER2+ tumors.

Trastuzumab (Herceptin) was approved as targeted therapy for HER2+ breast cancer in 1998. Since then, studies have consistently shown that trastuzumab has helped women with HER2+ breast cancer to live significantly longer overall and without cancer recurrence. Trastuzumab is usually given in combination with specific chemotherapy drugs.

Adjuvant treatment with trastuzumab is recommended for HER2+ breast cancers that are larger than 1 cm, regardless of whether cancer has spread to the lymph nodes. Trastuzumab is given once weekly (or once every 3 weeks) as an intravenous infusion over 30-90 minutes and treatment continues for 1 year. The agent is also recommended as first-line treatment of HER2+ metastatic breast cancer and is given in the same manner. The use of trastuzumab and chemotherapy for metastatic breast cancer has led to higher response rates and longer progression-free survival (length of time without progression of disease) than trastuzumab alone.

Lapatinib (Tykerb) is another anti-HER2 agent. In combination with capecitabine, lapatinib has delayed the progression of breast cancer for nearly twice as long as capecitabine alone in women with metastatic HER2+ breast cancer. Lapatinib has been approved by the FDA for use with capecitabine to treat HER2+ metastatic breast cancer that has stopped responding to anthracyclines, taxanes (paclitaxel or docetaxel), and trastuzumab.

Personalized Treatment based on Hormone Receptor and HER2 Status

Treatment for breast cancer may also be personalized according to the status of both the hormone receptors and HER2. Breast cancer cells that overexpress ER/PR as well as HER2 have been less responsive to some hormone therapies, and targeting both ER/PR and HER2 has emerged as a potential way to address this problem. In general, treatment consists of a combination of agents known to be effective for each tumor marker status. For example, research has shown that when women with ER+/PR+, HER2+ tumors were treated with the combination of letrozole (an AI) and lapatinib (an anti-HER2 agent), the time before disease progressed was more than double the time for women treated with letrozole alone. On the basis of these findings, in February 2010, the FDA approved the use of this combination.

Research is also beginning to indicate that some treatments may be more effective for tumors that test negatively for ER/PR and HER2, which are known as triple-negative breast cancers. These tumors, which represent about 10-15% of all breast cancers, have the disadvantage of not being eligible for either hormone therapy or anti-HER2 agents. They also tend to be associated with a higher risk of recurrence, and the effectiveness of chemotherapy is often limited. As a result, investigators are searching for combinations of drugs that may be more effective. Studies have shown that the combination of ixabepilone (Ixempra) and capecitabine is of greater benefit for women with metastatic triple-negative breast cancer than women with other types of breast cancer.

The limitations in the effectiveness of chemotherapy and the lack of adequate treatment for triple-negative breast cancer that does not respond to chemotherapy call for new agents targeted to this particular type of tumor. Because of this, many studies of targeted therapy agents are focused on triple-negative disease. The results of early reports suggest that the use of PARP inhibitors, either alone or in combination with chemotherapy, is highly effective for the management of metastatic triple-negative breast cancers, especially those associated with BRCA1 mutation. Large confirmatory trials are in progress.

Other agents are being evaluated for HER2- metastatic breast cancer. These agents target the vascular endothelial growth factor (VEGF) system, which plays an important role in the formation of blood vessels that supply the tumor with blood and other nutrients needed to grow. This process of blood vessel formation is called angiogenesis, and the agents that target this process are known as antiangiogenesis drugs. These drugs include bevacizumab (Avastin), sunitinib (Sutent) and sorafenib (Nexavar), and they have shown modest activity when used as a single agent and have increased response rates and duration of disease control when used in combination with chemotherapy. Bevacizumab is the only antiangiogenesis agent approved for use in breast cancer; its approved indication is in combination with paclitaxel for HER2- metastatic breast cancer.

Summary

The range in treatment options for breast cancer can seem overwhelming. Learning as much as you can about your particular type of breast cancer and the tumor characteristics can help you work with your doctors to make informed decisions about treatment.

Table 1. Types of Breast Cancer Treatment

Treatment Description Purpose
Surgery, Lumpectomy or Mastectomy Removal of cancerous breast tissue, as well as lymph nodes that may contain cancer cells Primary treatment for ductal carcinoma in situ and most invasive breast cancers
Breast reconstruction Plastic surgery to rebuild the breast Optional treatment to have the breast look as similar as possible to its appearance before surgery
Other Removal of ovaries (ovarian ablation) or the contralateral breast Prophylactic treatment (to reduce the risk of ovarian cancer or cancer in the contralateral breast)
Radiation therapy Use of high-energy x-rays to destroy cancer cells
Primary treatment when given after lumpectomy
 
Adjuvant or neoadjuvant therapy after mastectomy
Chemotherapy Use of cytotoxic drugs (drugs that kill cells) to destroy cancer cells that may be present in the axillary lymph nodes and/or throughout the body
Adjuvant or neoadjuvant therapy
 
First-line treatment for metastatic breast cancer
Hormone therapy Use of drugs to decrease the production of estrogen in the body Adjuvant therapy for breast cancers with high levels of estrogen receptors (ER) or progesterone receptors (PR), otherwise known as ER+ or PR+ tumors
Targeted thearpy Use of agents that are designed to block signals that contribute to the growth or survival of cancer cells Adjuvant therapy for breast cancers in which specific tumor markers have been identified

Table 2. Questions to Ask Your Doctor about Treatment

What are the goals of treatment?
What are the risks if I choose lumpectomy rather than mastectomy?
How will my breast look after mastectomy?
Am I a candidate for breast reconstruction?
Can sentinel lymph node dissection be done?
Am I at high risk for cancer recurrence?
What are the benefits and risks of adjuvant chemotherapy for my particular tumor?
If the cancer does not respond to chemotherapy, are there other options?
What are the side effects of chemotherapy and can they be prevented or managed?
Do I need hormone therapy?
Which is better for me - tamoxifen or an aromatase inhibitor?
How long do I need to take hormone therapy?
What are the side effets of hormone therapy?
Will targeted therapy help me?

Table 3. Names of Chemotherapy Drugs

Generic Name Brand Name
Albumin-bound paclitaxel Abraxane
Capecitabine Xeloda
Carboplatin Paraplatin
Cisplatin Platinol
Cyclophosphamide Cytoxan
Docetaxel Taxotere
Doxorubicin Adriamycin
Epirubicin Ellence
Etoposide Vepesid, VP-16
Fluorouracil 5-FU, Adrucil
Gemcitabine Gemzar
Ixabepilone Ixempra
Methotrexate Amethopterin, Mexate, Folex
Paclitaxel Taxol
Pegylated liposomal doxorubicin Doxil
Vinblastine Velbe
Vinorelbine Navelbine

Table 4. Chemotherapy Regimens

  Abbreviation
Docetaxel, doxorubicin, and cyclophosphamide TAC
Doxorubicin and cyclophosphamide followed by paclitaxel AC → T
Docetaxel and cyclophosphamide TC
Doxorubicin and cyclophosphamide AC
Fluorouracil, doxorubicin, and cyclophosphamide FAC or CAF
Fluorouracil, epirubicin, and cyclophosphamide FEC or CEF
Cyclophosphamide, methotrexate, and fluorouracil CMF
Epirubicin and cyclophosphamide EC
Doxorubicin followed by paclitaxel followed by cyclophosphamide A → T → C
Fluorouracil, epirubicin, and cyclophosphamide followed by docetaxel FEC → T

Table 5. Types of Hormone Therapy for Breast Cancer

  Menopause Status Action Notes
SERMs
 Tamoxifen (Nolvadex)
 
 
 Toremifene (Fareston)
 
Premenopausal and
  postmenopausal
 
Postmenopausal women
   with advanced ER+/PR+   
   cancers or cancers with
   unknown ER/PR status
Temporarily block estrogen receptors on breast cancer cells, preventing estrogen from binding to them
Has been traditional adjuvant hormone therapy for almost 30 years
Estrogen receptor downregulator
 Fulvestrant (Faslodex)
Postmenopausal
Eliminates estrogen receptors on the tumor
Approved only for advanced breast cancers that have stopped responding to tamoxifen or toremifene
Aromatase inhibitors (AIs)
   Anastrozole (Arimidex)
   Exemestane (Aromasin)
   Letrozole (Femara)
Postmenopausal
Prevent the body from making estrogen by blocking the enzyme aromatase
Associated with fewer serious side effects than tamoxifen

SERMs = selective estrogen-receptor modulators.

Table 6. Treatment Options Based on HER2 Status

Treatment Base Type of Breast Cancer Approved/Recommended Treatment Notes
Trastuzumab (Herceptin)
HER2+ node-positive or node-negative breast cancer
In combination with chemotherapy regimen of doxorubicin plus cyclophosphamide, followed by either paclitaxel or docetaxel
 
In combination with chemotherapy regimen of docetaxel and carboplatin
 
As a single agent following chemotherapy that includes an anthracycline (doxorubicin, epirubicin, pegylated liposomal doxorubicin)
Approved for use in 1998
 
HER2+ metastatic breast cancer
In combination with paclitaxel for first-line treatment
 
As a single agent after failure of one or more chemotherapy regimens
 
Lapatinib (Tykerb)
HER2+ metastatic breast cancer
In combination with capecitabine after failure of anthracyclines, taxanes (paclitaxel or docetaxel) and trastuzumab
Approved for use in 2007
 
ER+/PR+, HER2+ breast cancer
In combination with letrozole
Approved for use in 2010
Ixabepilone (Ixempra)
Triple-negative (ER-/PR-, HER2-) metastatic breast cancer
In combination with capecitabine
Used in clinical trials only
PARP inhibitors
Triple-negative metastatic breast cancer
In combination with chemotherapy
Used in clinical trials only
Antiangiogenesis agents (bevacizumab [Avastin])
HER2-negative metastatic breast cancer
In combination with paclitaxel
Approved for use in 2008

Additional Resources

 

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