INTRODUCTION — Breast cancer is the most common female cancer in the United States, the second most common cause of cancer death in women (after lung cancer), and the main cause of death in women ages 45 to 55. Every year, approximately 180,000 American women will be diagnosed with breast cancer, and more than 40,000 will die from it. Early detection and treatment of breast cancer clearly improves survival, by removing the breast tumor before it has a chance to spread (metastasize).
Two surgical options are available for treating localized breast cancer: mastectomy (removal of the breast) and breast preserving therapy. After either surgery, systemic (bodywide) therapy is often recommended to decrease the likelihood that the cancer will return. The options for systemic therapy include chemotherapy, hormone therapy, or antibody therapy. (See "Patient information: Adjuvant chemotherapy and trastuzumab (Herceptin) for early stage breast cancer").
The treatment of localized breast cancer must be individualized and is based upon several factors. Optimal management requires collaboration between surgeons and physicians who specialize in radiation and medical oncology. Each woman should carefully discuss the available treatment options with her doctors to determine which is the best choice for her.
BREAST CANCER STAGING — Treatment and prognosis (outcome) depend upon the stage of the cancer, which is based upon the size of the tumor, involvement of the skin, chest wall or local lymph nodes, and whether the cancer has spread to other organs (called metastasis). In situ carcinomas (eg, ductal carcinoma in situ, lobular carcinoma in situ) are the earliest recognizable breast cancers and rarely spread beyond the breast tissue; more advanced breast cancers, which are referred to as invasive carcinomas, metastasize more often.
The size of the breast tumor, involvement of adjacent lymph nodes, and the presence or absence of spread to other organs are described by the "stage grouping" of a breast cancer, which ranges from stage I to IV. Table 1 summarizes these stages (show table 1). Localized invasive breast cancer generally refers to stage I to IIIA breast cancer. (See "TNM staging classification for breast cancer").
The initial evaluation to determine the stage of a breast cancer usually involves a physical examination, mammogram, chest X-ray, and sometimes CT scans (specialized x-rays) and/or a bone scan. An important component of the staging work-up is an evaluation of the opposite breast. Breast MRI may be recommended to screen the opposite breast for cancer in women who have a breast cancer on one side and who have no abnormalities noted within the opposite breast by either physical examination or mammogram [1,2].
The final stage of the cancer depends upon what is found during microscopic examination of the breast and lymph node tissue after surgery; this is called the pathologic stage, and it is the most accurate indicator of tumor extent and prognosis.
FACTORS AFFECTING TREATMENT — Several factors must be considered when choosing the best treatment for localized breast cancer.
Microscopic findings — There are many different varieties of breast cancer as viewed by the pathologist under the microscope. However, from the standpoint of treatment, the most important distinction is between invasive and noninvasive (in situ) breast cancer. Localized invasive breast cancers are generally approached similarly, whether they are ductal, lobular, or any of the so-called "special types" (tubular, mucinous, colloid, medullary). The surgical treatment of in situ cancers is similar to that of invasive cancers, but postoperative adjuvant systemic therapy is generally not recommended.
Size of the breast tumor — The prognosis of a breast cancer depends upon its size; larger tumors recur more often, and usually require more aggressive treatment. In some cases, chemotherapy may be given before surgery to shrink a large tumor or one that has grown into the chest wall. Inflammatory breast cancer refers to any breast cancer that is associated with an "inflamed" appearance of the breast (show picture 1 and show picture 2); this implies spread of the tumor into the lymph system of the overlying skin. These cancers are treated similarly to large tumors, with chemotherapy preceding surgery or radiation. (See "Patient information: Locally advanced and inflammatory breast cancer").
Spread of cancer cells to the lymph nodes — Fluid from the breast tissue normally drains into lymph nodes located in the armpit (the axilla). These nodes (or glands) are often the first site of spread for breast cancer. If a breast cancer has spread to lymph nodes, it is called node-positive; a cancer that has not spread to the lymph nodes is called node-negative. This is an important distinction because if a breast cancer has spread to the lymph nodes, it is twice as likely to have spread elsewhere, and therefore, to recur over the succeeding years postoperatively.
Most women with node-positive breast cancer should receive adjuvant chemotherapy or hormone therapy after surgery, even if the tumor was completely removed. (See "Patient information: Adjuvant chemotherapy and trastuzumab (Herceptin) for early stage breast cancer").
Tumor markers and prognostic factors — Studies suggest that certain markers or characteristics of the tumor may help determine the prognosis or outcome of breast cancer. Some of these tests are hormone receptors, S phase analysis (a measure of cell proliferation or growth), Her2 status. Levels of plasminogen activators (called uPA and PAI-1) are also measured in certain countries, but not routinely in the United States. All of these tests are performed on the tumor material by the pathologist.
Some of these factors may be associated with a worse outcome and might be used by your doctor to predict the need for further treatment after surgery. Others, such as ER, PgR, and Her2 are associated with a greater likelihood that the cancer may respond to specific types of adjuvant therapy (ie, hormone therapy or antibody therapy) (see below) [3].
Hormone receptors — Some breast cancers have proteins called hormone receptors on their surface; these can be estrogen receptors (ER), progesterone receptors (PgR), or both. If hormone receptors are present in the tumor, women are more likely to benefit from treatments that lower hormone levels or block the actions of these hormones. These treatments are referred to as endocrine or hormone therapies. The test for hormone receptors is usually performed by the pathologist who examines the tumor. (See "Patient information: Adjuvant systemic therapy for hormone-responsive early stage breast cancer in premenopausal women").
Her2 — HER2 is a protein that is present on some breast tumors. Although HER2 is not a very helpful prognostic factor (that is, it does not consistently provide information about whether a tumor is more or less likely to recur), it may help to identify women who are most likely to benefit from specific types of chemotherapy. Furthermore, the presence of HER2 indicates if a woman is likely to benefit from a drug called trastuzumab (Herceptin). (See "Patient information: Adjuvant chemotherapy and trastuzumab (Herceptin) for early stage breast cancer").
Presence of other medical conditions — The presence of other medical conditions may limit the available treatment options for breast cancer.
Personal preferences — Personal preference plays a key role in the treatment of breast cancer. Whenever possible, treatment is individualized to each woman's needs and expectations. Therefore, it is important to meet with a trained medical oncologist to discuss the long term outcomes, benefits of therapy, and risks associated with treatment.
SURGICAL TREATMENT — Surgical removal of the tumor is usually the first step in treating localized breast cancer unless the breast tumor is large or locally invasive. If the cancer is large or locally invasive, another treatment may be recommended before surgery. (See "Patient information: Locally advanced and inflammatory breast cancer", section on "Treatment of locally advanced breast cancer").
There are two options for breast surgery: one involves removing the entire breast (mastectomy) while the other involves removing the tumor and surrounding tissue (lumpectomy). Women who choose lumpectomy usually require additional treatment with radiation to lower the risk of recurrence.
In centers that specialize in breast cancer treatment, approximately 75 percent of women with early stage breast cancer are usually considered appropriate candidates for breast preserving therapy, while the remainder have mastectomy.
MASTECTOMY
Modified radical mastectomy — During a modified radical mastectomy (MRM, show figure 1), the tumor is removed along with all of the breast tissue on the side of the tumor, some of the underlying chest wall tissue, and some of the lymph nodes in the armpit (the axillary lymph nodes). Although the skin of the breast, including the nipple, is removed, the skin covering the chest wall is left intact. The skin is stitched together after removal of the breast. Typically, a draining tube is placed under the skin of the incision for a short time to remove fluid that collects after surgery.
In the United States, modified radical mastectomy is the most common surgery for women with invasive breast cancer.
Total or simple mastectomy — In contrast to MRM, a total or simple mastectomy refers to the removal of the entire breast, not including the arm pit (axillary) lymph nodes. Because the axillary lymph nodes are important for staging and further treatment, total mastectomy has not been considered a standard procedure for women with invasive breast cancer. However, a technique called sentinel node biopsy has allowed total mastectomy to become more popular (see "Sentinel lymph node biopsy" below). Total mastectomy is the treatment of choice for women who are at high risk for a new breast cancer, who therefore decide to have a preventive mastectomy.
Breast reconstruction — Many women choose to have breast reconstruction performed during the same procedure or at a later time. There are several options for reconstruction; frequently, women are evaluated by a plastic or reconstructive surgeon during their initial evaluation to discuss these options prior to the breast surgery.
Complications of mastectomy — Mastectomy is generally a safe surgery, although complications can occur: Collection of fluid (seroma) — Almost all women undergoing mastectomy develop a temporary collection of fluid in the wound, called a seroma. This routine side effect is likely to be more troublesome for women if many lymph nodes must be removed, in obese women, and in women who did not undergo a breast biopsy before the mastectomy. Wound infection — Wound infection occurs in less than 15 percent of women undergoing mastectomy. Infection that occurs soon after mastectomy often appears as an abscess, a collection of pus within the chest wall; infections that occur weeks or months after mastectomy may appear as a cellulitis, an inflammation and infection of the chest wall skin. Arm swelling — Arm swelling (edema) is mostly related to the removal of the axillary lymph nodes, but is also more common in women who undergo mastectomy rather than BCT. Arm edema is more likely to occur in women who undergo removal of the axillary nodes followed by radiation of the armpit area. (See "Patient information: Lymphedema after breast cancer surgery").
Radiation therapy after mastectomy — Radiation therapy of the chest wall after mastectomy may increase the chance of surviving the breast cancer in women who have large tumors (5 cm in size or larger), or who have four or more positive lymph nodes [4]. However, the benefit for women with fewer involved lymph nodes is controversial. The risk of long-term complications of radiation, such as rib fracture or injury to the nerves in the armpit (called the brachial plexus), is less than 5 percent. However, these risks are higher if chemotherapy is given at the same time as radiation or if higher doses of radiation are used.
BREAST CONSERVING THERAPY (BCT) — BCT refers to removal of the part of the breast that contains the tumor, followed by radiation therapy to the remaining breast tissue on the same side.
There are two main types of breast conserving surgery: Lumpectomy — Removal of the tumor and a small amount surrounding breast tissue, show figure 1 Quadrantectomy — Removal of the tumor and about one-fourth of the breast tissue on that side, show figure 1
Lumpectomy is more often used in the United States and Canada, whereas quadrantectomy is more often used in Europe.
Lumpectomy — During lumpectomy, the edges of the removed tissue (called the resection margins) are stained with a special ink and examined under the microscope to check for remaining cancer cells. The surgeon continues to remove additional tissue until no remaining cancer cells are detected by the pathologist (the pathologist examines the tissue while the patient has surgery). During the lumpectomy procedure, lymph nodes in the armpit are usually removed to check for the spread of cancer cells to this area.
Complications of lumpectomy — Lumpectomy is generally a safe surgery, although some complications are possible: Breast cellulitis — Breast cellulitis is an inflammation and infection of the breast tissue. Cellulitis after lumpectomy appears to be related to the presence of bruises after surgery, the collection of fluid in the lymphatic system, and the removal of a large amount of breast tissue. Breast abscess — A breast abscess is a collection of pus within the breast tissue, tends to occur, on average, about five months after BCT. This complication is more common in women following the removal of large amounts of breast tissue.
Radiation therapy
What is radiation therapy? — Radiation therapy (RT) refers to the exposure of a tumor to high-energy x-rays in order to slow or stop its growth. Exposure to x-rays damages cells. Unlike normal cells, cancer cells cannot repair the damage caused by exposure to x-rays, particularly when it is administered over several days. This prevents the cancer cells from growing further and causes them to eventually die.
RT for breast cancer is given as external beam radiation therapy, meaning that the radiation beam is generated by a machine that is outside the patient. The radiation is delivered to the patient, who is usually lying on a table underneath the machine.
Exposure to the beam typically takes only a few seconds (similar to having an x-ray). In general, treatment is repeated five days per week for approximately five to six weeks. Treatment cannot be given over a shorter period because the higher daily doses would cause too many side effects.
Radiation therapy is recommended for the remaining breast tissue on the same side of the tumor after breast conserving surgery. The goal of this radiation therapy is to kill any remaining cancer cells that were not removed during surgery. An extra dose of radiation (called a radiation boost) is often given to the area where the tumor was located.
Benefit of radiation therapy — Studies confirm that radiation plays a critical role in preventing a local recurrence of breast cancer after BCT and in improving survival. In many studies of women undergoing lumpectomy for localized breast cancer, cancer recurred within 20 years in 7 to 14 percent of women who received radiation therapy compared with 26 to 39 percent of women who did not receive this therapy [4-6]. Thus, a local recurrence is approximately three times more likely in women who do not undergo RT. Furthermore, women who receive radiation therapy are also more likely to survive their cancer [4,6].
There is currently no reliable method to identify women who will not have a recurrence if they skip radiation. Therefore, radiation is generally recommended for all women after breast conserving surgery. One possible exception is women over the age of 70 who have small (<2 cm) ER-positive breast cancers; these women are usually initially treated with hormone therapy (eg, tamoxifen) and radiation treatment is not given.
New radiation therapy delivery systems — New ways to give radiotherapy are currently under study. These include short course therapy (giving the treatment over five to ten days instead of four to six weeks), brachytherapy (placing the radiation source directly in the tissues of the breast for a few days), and even intraoperative therapy. Currently, these methods of administering radiation therapy are considered investigational.
Cosmetic results of BCT — With modern surgical techniques, breast conserving therapy has excellent cosmetic results (ie, the treated and untreated breast are almost identical) or good cosmetic results (ie, only slight differences between the treated and untreated breast).
The effects of BCT on the appearance of the breast usually take about three years to stabilize. Factors such as weight gain and the normal age-related sagging of breast tissue may further affect the symmetry of the two breasts.
Several other factors influence the cosmetic results of BCT: Surgical factors — The amount of breast tissue removed during surgery plays a key role in the cosmetic result of BCT. Lumpectomy generally produces a better cosmetic result than quadrantectomy.
Other surgical factors that may affect the cosmetic appearance of the breast after BCT include the size and location of the incision, the postoperative care of the space left by lumpectomy, and the extent of surgery required to remove lymph nodes. Individual factors — Several individual factors also affect the cosmetic result of BCT. These factors include the size of the breast, the size of the tumor, the depth of the tumor within the breast, and the quadrant in which the tumor was located. Use of adjuvant chemotherapy — The use of adjuvant chemotherapy and its timing may affect the cosmetic result of BCT. In one study in women who underwent BCT, the cosmetic results were poorer in women who received radiation therapy and chemotherapy at the same time (concurrent treatment) compared to women receiving chemotherapy followed by radiation therapy (sequential treatment) [7]. This is one of the reasons why chemotherapy is generally given before radiation therapy. (See "Patient information: Adjuvant chemotherapy and trastuzumab (Herceptin) for early stage breast cancer").
Complications following BCT — Following BCT, the following complications may occur: Arm problems — Among women who undergo BCT and axillary lymph node removal, one in five develop arm edema; this is less than the number of women who develop lymphedema after mastectomy [8]. The likelihood of arm swelling is twice as high if the armpit area is radiated after a lymph node dissection. The likelihood of arm edema is also related to the extent of the axillary dissection that is done by the surgeon to evaluate the lymph nodes. (See "Patient information: Lymphedema after breast cancer surgery").
One-half of women may have some temporary loss of shoulder movement, and less than 5 percent of women have damage to the nerves in the armpit (called the brachial plexus) that control arm movement and sensation in the arm. Rib fracture — In less than 5 percent of women who undergo BCT, radiation causes changes in the bones of the chest wall that increase the risk for rib fractures.
MASTECTOMY VERSUS BREAST PRESERVING THERAPY — Numerous studies show that women with localized breast cancer are equally likely to survive their cancer whether they are treated with breast conserving therapy (BCT) or a mastectomy [4,9]. However, it is estimated that fewer than 60 percent of women with early-stage breast cancer are treated with BCT. Some evidence suggests that clinicians encourage women to select mastectomy over BCT, and that women themselves prefer mastectomy to BCT [10]. Furthermore, the selection of BCT is influenced by geographic and socioeconomic factors as well.
Despite the equivalent survival, several factors are taken into consideration when determining whether BCT or mastectomy is a better option for a woman with localized breast cancer.
Medical history and physical examination — A medical history and physical exam are useful to determine a woman's overall health and the presence of other medical conditions. The presence of certain conditions may make BCT or mastectomy a better treatment option. A woman's age alone does not determine if BCT or mastectomy is a better choice.
Results of mammography — A preoperative mammogram is essential for determining the size and extent of the tumor and other tumor features that may affect the choice between BCT or mastectomy.
Microscopic examination of the tumor — Microscopic examination of the tissue removed during a biopsy or during surgery may identify features that affect the recommendation for BCT versus mastectomy. One of these features is the presence of residual cancer cells at the margins. If many residual cancer cells are present after a large amount of tissue has been removed, mastectomy may be preferable.
Individual needs and expectations — Each woman should discuss her expectations and concerns about preserving her breast with her doctor. It is particularly important to consider how the choice of BCT or mastectomy is likely to affect a woman's confidence in the effectiveness of cancer treatment as well as her self-esteem, sexuality, and overall quality of life. The discussion regarding the benefits and risks should include several essential points: The long-term survival after breast cancer The possibility and consequences of a local recurrence The psychological adjustment to treatment (including the fear that cancer will return) The likely cosmetic results Sexuality after treatment
For most women, the likelihood of surviving localized breast cancer is the same with mastectomy or BCT [4,9]; in contrast, the choice of mastectomy versus BCT may have a considerable effect on a woman's quality of life. The overall experience of having breast cancer is equally distressing for women who choose BCT and for those who choose mastectomy. However, compared to women who choose mastectomy, women who choose BCT tend to have a more positive body image and experience fewer changes in their feelings of sexual desirability.
Certain clinical factors clearly favor mastectomy over BCT for medical reasons in individual women. These include: The presence of two or more separate tumors in different areas of the breast Diffuse spread of the tumor in the breast tissue Previous radiation of the breast or chest, which makes future radiation inadvisable Pregnancy in the first or second trimester, which makes radiation inadvisable The presence of many residual cancer cells during breast conserving surgery despite the removal of a large amount of tissue
Certain clinical factors somewhat favor mastectomy over BCT for medical reasons in individual women, although exceptions exist: The presence of certain connective tissue (autoimmune) diseases that are associated with marked side effects from radiation therapy; women with scleroderma and active systemic lupus erythematosus (SLE) are usually advised to select mastectomy over BCT, though women with rheumatoid arthritis can safely undergo radiation therapy and can therefore choose between BCT and mastectomy The presence of several adjacent tumors and the presence of calcium deposits in the same area as the breast tumor A larger tumor size; mastectomy is usually recommended for tumors larger than about two inches and for women who have tumors that are large relative to their breast size The size and shape of the breast; It may be difficult to consistently target radiation in women with very large or pendulous breasts, and these women may be advised to select mastectomy over BCT
Several factors do not play a role in the choice between BCT and mastectomy: The spread of cancer cells to lymph nodes in the armpit The specific location of the tumor within the breast; however, certain tumor locations may reduce the cosmetic results of BCT A family history of breast cancer A high likelihood that cancer will metastasize (recur elsewhere in the body); however, an increased risk of metastases indicates the need for adjuvant therapies
MANAGEMENT OF AXILLARY LYMPH NODES — Although some enlarged lymph nodes can be felt on physical examination, surgery is the only accurate way to determine if the cancer has spread to the lymph nodes in the axilla, or armpit. A complete removal of the axillary lymph nodes, an axillary lymph node dissection (ALND), has traditionally been a routine component of the management of early stage breast cancer for women undergoing both mastectomy and BCT. However, considerable controversy exists regarding whether aggressive treatment of draining nodal areas is indicated. Clearly, the information gained from ALND is prognostic. Furthermore, undertreatment of positive axillary lymph nodes increases the risk of a local recurrence. However, it is unclear if more aggressive treatment of the axillary nodes improves survival. Regardless, more aggressive lymph node treatment (surgery and/or radiation) increases the risk of complications.
The extent of an ALND is determined by the number and location of the nodes removed. The most common complication of ALND is lymphedema, the severity of which depends upon the extent of the ALND. (See "Patient information: Lymphedema after breast cancer surgery"). The desire to accurately identify women who have involved lymph nodes while minimizing the chance of arm swelling has led to the development of the sentinel node biopsy technique.
Sentinel lymph node biopsy — Sentinel node biopsy is an alternative to complete removal of the axillary lymph nodes that has significantly fewer arm complications.
The concept is based on the premise that tumor cells from a breast tumor first involve one or a few lymph nodes before involving lymph nodes in other areas or spreading to distant organs. To identify this sentinel node, the surgeon injects blue dye, a radioactive material, or a combination of both into the area surrounding the tumor, where it enters lymphatic channels and then flows to lymph nodes.
If a SLN is identified, it is removed and examined under the microscope. If this node is does not contain any cancer cells, there is a very small chance that other axillary nodes will be positive and a full ALND is not necessary [11]. In contrast, if the SLN is positive, there is a good chance that other nodes will contain tumor cells, and a full ALND is usually performed.
The main problem with SLN biopsy is that a SLN may be "falsely" negative, meaning that the axillary lymph nodes actually contain tumor cells when the SLN predicts that they do not. The likelihood of a false-negative SLN is related to a surgeon's experience with this procedure. In experienced hands, the risk of a false positive is about 5 percent [12].
Guidelines from the American Society of Clinical Oncology support the use of SLN biopsy as an alternative to full ALND in many patients with early stage breast cancer as long as there is no suspicion from the physical examination that the axillary nodes may be involved with tumor spread [11].
RECURRENCE AFTER BCT — A local recurrence refers to a return of cancer in the breast tissue or the surrounding chest wall. After mastectomy, local recurrences are in the chest wall because there is no remaining breast tissue; following BCT, a recurrence is usually within the remaining breast tissue.
In women with stage I or II breast cancer, local recurrence develops in 7 to 20 percent of women treated with BCT, and in 4 to 14 percent of women treated with mastectomy. However, the time course of recurrence is different. A local recurrence is often delayed for many years in women treated with BCT, whereas a local recurrence usually occurs within three years in women treated with mastectomy.
It is important to note that BCT does not completely prevent new breast cancers from arising in the remaining breast tissue. In women treated with BCT, the risk of a new, unrelated tumor on the same side is about 1 percent per year (eg, 13 percent risk over 15 years following the procedure).
Surveillance — Women who have undergone BCT must continue to perform breast self-exams and undergo screening of both breasts with mammography. A summary of the American Society of Clinical Oncology's recommendations for surveillance after breast cancer treatment is provided in table 2 (show table 2).
Risk factors — The likelihood that breast cancer will recur locally after BCT is influenced by individual factors, tumor factors, and treatment factors.
Individual factors — A woman's age appears to influence the risk of a local recurrence after BCT. Women who are age 40 years or younger at the time of BCT are more likely than older women to have a local recurrence after BCT. Other studies suggest that younger women may also be more likely to have a local recurrence after mastectomy. Thus, young age should not be used as a factor in choosing one treatment over another, but instead should be used as an indicator of a higher risk of a local recurrence.
Tumor factors — The likelihood of a local recurrence after BCT is also influenced by two tumor-related factors: Residual cancer cells at the edge of the wound — The presence of residual cancer cells at the edge of the wound (called the resection margin) increases the likelihood of a local recurrence after BCT. In one study, the rate of local recurrence after BCT was 7 percent in women in whom no residual cells are found, compared to 18 percent in women in whom residual cancer cells were found [13]. Although the surgeon will try to remove all of these cells during surgery, residual cells are sometimes detected after surgery on more detailed microscopic examination. Presence of cancer cells within ducts — The presence of cancer cells within many ducts of the removed breast tissue, termed an extensive intraductal component, is useful for assessing the likelihood of a local recurrence. A local recurrence is more likely when cancer cells are present in many ducts within the tumor or within the normal breast tissue, if tumor cells remain at the margin of resection. Certain findings on mammograms taken before surgery often alert the surgeon to the presence of cancer cells in ducts. In such cases, particular care must be taken by the surgeon to make certain that no remaining tumor cells are present at the surgical margins.
Treatment factors — Three treatment factors influence the likelihood of a local recurrence after BCT: Extent of surgery — Local recurrence of breast cancer after BCT is less likely when a greater amount of breast tissue is removed during surgery. Radiation boost — A radiation boost refers to the delivery of an extra dose of radiation to the area of the breast where the tumor was located. Some, but not all studies suggest that a radiation boost slightly reduces the likelihood of a local recurrence of breast cancer, although this boost may slightly reduce the cosmetic results of BCT. Chemotherapy or hormone therapy — Chemotherapy and/or hormonal therapy are often recommended following surgery for localized breast cancer. The addition of these therapies to BCT further reduces the likelihood of a local recurrence, although not all women will need both of these therapies.
As an example, in one study of women with node-negative, ER-negative breast cancer, women were treated with chemotherapy or no chemotherapy after BCT [14]. Cancer recurred locally within eight years in 2.6 percent of the women treated with chemotherapy and in 13.4 percent of the women who were not treated with chemotherapy.
In a second study in women with node-negative, ER-positive breast cancer, women were treated with tamoxifen or a placebo after BCT [15]. Cancer recurred locally within ten years in 4.3 percent of the women treated with tamoxifen, and in 14.7 percent of the women who were treated a placebo.
Treatment — Many women who have a local recurrence can undergo a "salvage" mastectomy, and still have a chance to be cured from their cancer if there is no further spread.
WHERE TO GET MORE INFORMATION — Your healthcare provider is the best source of information for questions and concerns related to your medical problem. Because no two patients are exactly alike and recommendations can vary from one person to another, it is important to seek guidance from a provider who is familiar with your individual situation.
This discussion will be updated as needed every four months on our web site (www.patients.uptodate.com). Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.
A number of web sites have information about medical problems and treatments, although it can be difficult to know which sites are reputable. Information provided by the National Institutes of Health, national medical societies and some other well-established organizations are often reliable sources of information, although the frequency with which they are updated is variable. National Cancer Institute
1-800-4-CANCER
(www.nci.nih.gov)
People Living With Cancer: The official patient information
website of the American Society of Clinical Oncology
(www.plwc.org/portal/site/PLWC)
National Comprehensive Cancer Network
(www.nccn.org/patients/patient_gls.asp)
American Cancer Society
1-800-ACS-2345
(www.cancer.org)
National Library of Medicine
(www.nlm.nih.gov/medlineplus/healthtopics.html)
Susan G. Komen Breast Cancer Foundation
(www.komen.org)
Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Saslow, D, Boetes, C, Burke, W, et al. American Cancer Society guidelines for breast cancer screening with MRI as an adjunct to mammography. CA Cancer J Clin 2007; 57:75.
2. Lehman, CD, Gatsonis, C, Kuhl, CK, et al. MRI evaluation of the contralateral breast in women with recently diagnosed breast cancer. N Engl J Med 2007; 356:1295.
3. Yamauchi, H, Stearns, V, Hayes, DF. When is a tumor marker ready for prime time? A case study of c-erbB-2 as a predictive factor in breast cancer. J Clin Oncol 2001; 19:2334.
4. Clarke, M, Collins, R, Darby, S, et al. Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomised trials. Lancet 2005; 366:2087.
5. Fisher, B, Anderson, S, Bryant, J, et al. Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. N Engl J Med 2002; 347:1233.
6. Vinh-Hung, V, Verschraegen, C. Breast-conserving surgery with or without radiotherapy: pooled-analysis for risks of ipsilateral breast tumor recurrence and mortality. J Natl Cancer Inst 2004; 96:115.
7. Abner, AL, Recht, A, Vicini, FA, et al. Cosmetic results after surgery, chemotherapy, and radiation therapy for early breast cancer. Int J Radiat Oncol Biol Phys 1991; 21:331.
8. Erickson, VS, Pearson, ML, Ganz, PA, et al. Arm edema in breast cancer patients. J Natl Cancer Inst 2001; 93:96.
9. NIH Consensus Development Conference statement on the treatment of early-stage breast cancer. Oncology (Huntingt) 1991; 5:120.
10. Morrow, M, White, J, Moughan, J, et al. Factors predicting the use of breast-conserving therapy in stage I and II breast carcinoma. J Clin Oncol 2001; 19:2254.
11. Lyman, GH, Giuliano, AE, Somerfield, MR, et al. American Society of Clinical Oncology Guideline Recommendations for Sentinel Lymph Node Biopsy in Early-Stage Breast Cancer. J Clin Oncol 2005; 23:7703.
12. Guidelines from the American Society of Breast Surgeons available online at www.breastsurgeons.org/officialstmts/sentinel.shtml (accessed September 13, 2005).
13. Park, CC, Mitsumori, M, Nixon, A, et al. Outcome at 8 years after breast-conserving surgery and radiation therapy for invasive breast cancer: influence of margin status and systemic therapy on local recurrence. J Clin Oncol 2000; 18:1668.
14. Fisher, B, Dignam, J, Mamounas, EP, et al. Sequential methotrexate and fluorouracil for the treatment of node-negative breast cancer patients with estrogen receptor-negative tumors: eight-year results from National Surgical Adjuvant Breast and Bowel Project (NSABP) B-13 and first report of findings from NSABP B-19 comparing methotrexate and fluorouracil with conventional cyclophosphamide, methotrexate, and fluorouracil. J Clin Oncol 1996; 14:1982.
15. Fisher, B, Dignam, J, Bryant, J, et al. Five versus more than five years of tamoxifen therapy for breast cancer patients with negative lymph nodes and estrogen receptor-positive tumors. J Natl Cancer Inst 1996; 88:1529.
Friday, October 12, 2007
Genetic testing for breast and ovarian cancer
INTRODUCTION — Many women feel anxious about their chance of developing breast or ovarian cancer, particularly if they have one or several close relatives with either condition. Women who have a family history of breast or ovarian cancer often wish to know if they have inherited a tendency to develop these tumors, and if so, what their lifetime risk is of developing breast or ovarian cancer.
Other women with a personal history of breast cancer, particularly if it was diagnosed at a young age, may worry that if they have inherited a tendency to develop breast and/or ovarian cancer, it may be passed on to their children.
Inherited mutations in two genes (known as BRCA1 and BRCA2) have been shown to increase the risk of both breast cancer and ovarian cancer. Genetic testing is available that may identify individuals who have inherited an altered form of one of these genes that increases the risk of breast and/or ovarian cancer. Patients who test positive can consider intensified screening or interventions to decrease the risk of cancer (medications or surgical removal of the breasts, ovaries, or both).
However, genetic testing for BRCA mutations is imperfect. Most women with a family history of breast cancer have not inherited one of these two abnormal genes, and not all women who have inherited one of these genes will develop cancer. Furthermore, the results of BRCA testing may be confusing, and do not always lead to a clear action plan. Genetic testing for BRCA mutations can create emotional turmoil and family discord, and may have an impact on future medical care and insurability. Thus, it is important for the patient, her healthcare provider, and family members to carefully consider whether to undergo such testing.
This topic review will focus on which women should consider genetic testing for the presence of BRCA mutations, issues to consider before undergoing testing, and the available options for women who are found to carry one of these mutations.
Genetic testing is not an emergency procedure. Taking time to understand the complexities, and discussing questions with health-care professionals and family members can help to clarify expectations from testing and anticipate future issues.
GENETIC TESTING GOALS — Genetic testing for breast and/or ovarian cancer analyzes the composition of the BRCA genes to look for alterations (mutations) associated with breast and/or ovarian cancer.
How do genes relate to cancer? — A person's visible characteristics (such as hair and eye color) as well as other invisible properties (including predisposition to cancer and other diseases), are determined by his or her genetic "blueprint", which is inherited from both parents as 23 pairs of chromosomes. Each chromosome is made up of a long strand of DNA. Discrete segments or sections of the DNA (called genes) contain the information that is needed to construct specific proteins that carry out the specific function of the individual cells that make up the body. There are approximately 30,000 human genes distributed among the 23 pairs of human chromosomes.
Most of the time, genes function properly and the body develops and performs normally. However, when a gene is altered (often by a mutation or change in the chemical structure of the gene), it may not provide the right signals to the body's cells to carry out their normal functions. If the affected gene is normally involved in the regulation of cell growth, a mutated gene may result in signals that allow uncontrolled cell growth. This process of uncontrolled cell growth causes tumors such as breast cancer to grow unchecked within the body.
An inherited mutation (ie, one that is passed from parent to child, and is present in all cells at the time the child is born) is called a germline mutation. In contrast, a noninherited mutation (ie, one that comes about during a person's lifetime) is called an acquired mutation. Acquired mutations can be caused by exposure to environmental agents such as radiation, chemicals (including those found in tobacco smoke), or viruses; they may also happen spontaneously. Most human cancers are thought to be caused by acquired mutations.
Most breast cancers (at least 90 percent) are not related to inherited (germline) mutations. However, for those 5 to 10 percent that are due to germline mutations, BRCA1 and BRCA2 mutations are thought to account for the majority. These genes are called tumor suppressor genes, meaning that they normally function to keep the growth of the body's cells under control. When one of these genes becomes mutated, cell growth becomes unregulated, paving the way for the development of a cancer. Most scientists believe that a cancer develops only if additional genetic mutations are acquired.
Other genes — Besides BRCA1 and BRCA2, a few other genes have been identified that are associated with breast and/or ovarian cancer, but in general, these involve rare syndromes that are related to other medical conditions and cancer types. There are also likely other, not-yet-identified, genes that are involved in inherited breast and/or ovarian cancer. This topic review will focus only on the BRCA genes.
WHO SHOULD CONSIDER GENETIC TESTING? — Genetic testing should not be done in all women with a family history of breast and/or ovarian cancer since BRCA1 and BRCA2 mutations are rare. Determining which women should consider genetic testing involves examination of an individual's personal and family history of breast cancer and/or ovarian cancer.
BRCA mutations occur in approximately 0.1 percent of individuals (1 in 1000 people). However, some ethnic groups have a higher chance of inheriting one of these mutations. For example, about 2 percent of women of Ashkenazi Jewish (Eastern European) descent carry a BRCA1 or BRCA2 mutation, and between 12 and 30 percent of breast cancers in this group are thought to be caused by mutations in the BRCA1 or BRCA2 genes. These statistics do not consider a family history of breast and/or ovarian cancer.
Because germline mutations are rare, and testing for them can produce indeterminate results, testing is usually offered to women who are at a high risk of having a BRCA mutation. Tools are available (such as a computer program called BRCAPRO [1]) to estimate the likelihood of a woman having a BRCA mutation based on her individual and personal history. Typically, a woman's health care provider or a genetics counselor will ask a set of questions about a woman's personal and family history and plug the answers into this risk assessment tool. The program then calculates an estimate of the chances of finding a BRCA mutation based upon a number of risk assessment tools. Guidelines from national organizations suggest that if the estimated chance of inheriting one of these mutations is greater than 10 percent (one in ten), genetic testing may be appropriate.
However, current recommendations are moving away from numerical cut-off values for determining when genetic testing should be offered. Instead, many organizations advocate using more details of an individual's and family's history as a screening tool to identify women who should be considered for BRCA testing.
Family history patterns — Doctors and patients should be aware of family history patterns that are associated with a higher risk of a BRCA mutation. These include: Multiple relatives affected with breast and/or ovarian cancer, particularly if they were diagnosed at an early age (less than 50 years old) A relative with more than one cancer, such as breast cancer involving both breasts or breast and ovarian cancer Evidence that multiple generations of a family are affected.
Women who develop breast cancer before the age of 50 are more likely to have a mutation than those who develop breast cancer at an older age. If a young woman develops breast cancer and also has a family history of breast and/or ovarian cancer, her chance of carrying a mutation increases dramatically. Family history on the father's side is as important as maternal history.
When there is a strong family history of breast and/or ovarian cancer, BRCA testing should be done on the relative who has the cancer whenever possible. If a mutation is not found, it is usually not helpful to test unaffected relatives. If a relative with breast cancer tests positive for a BRCA mutation, genetic testing should be considered for all of her at-risk adult relatives (male and female).
TESTING PROCEDURE
Pre-test counseling — Genetic testing involves taking a sample of blood and sending it to a lab for testing. However, a woman must consider a number of factors before deciding to undergo genetic testing. These include medical, emotional, practical, and financial factors that can profoundly affect a woman and her family. Women who are considering genetic testing should discuss these issues with a certified genetic counselor, if possible, to understand what is involved in the process of genetic testing. A list of certified genetics counselors and their phone numbers is available through the National Cancer Institute [2].
An example of a consent form is presented in table 1 (show table 1A-1D), and briefly discussed below.
Emotional effects for patient — Although anxiety may cause some high-risk individuals to refuse genetic testing, the available data suggest that there are no major adverse psychological effects of learning the results of BRCA testing. In fact, data from families with hereditary cancer and from individuals who underwent genetic testing in clinic settings suggest less distress in members of high-risk families who test negative for a familial mutation.
While it is normal for individuals who test positive (mutation carriers) to experience some level of distress, anxiety, or sadness, most studies suggest that these individuals do not suffer serious psychological effects or significantly increased distress levels. For many individuals, learning about positive test results can also produce feelings of relief, as risk information is clarified and a plan for managing that risk can be put into place. Women who have less significant family histories and who do not expect to receive positive results may be more vulnerable to psychological problems or high levels of distress after BRCA testing. In families that have a known BRCA mutation, it is not unusual for women who test negative to experience "survivor's guilt" for being spared a burden that other relatives have to endure.
Effects on family members — A discussion of the implications of the test results for family members is an important component of counseling. This includes identifying at-risk family members and encouraging patients to share results with their relatives.
The decision to share test results with relatives and the ramifications of that decision can cause significant emotional strain and family discord. The role of information "gatekeeper" may be overwhelming for some women, particularly as they try to attend to their own needs for emotional support. Nevertheless, studies have found that most individuals, including carriers and non-carriers, opt to share their results with at-risk relatives. For many individuals who seek testing, gaining information for family members is one of the most important benefits of testing.
Costs and insurance coverage — Because the BRCA genes are large and include hundreds of different mutations, testing is expensive. Commercial charges by Myriad Genetics Laboratories® (which are subject to change) are as follows: Full BRCA1/2 testing, which includes testing for five large rearrangements in BRCA1 and for very high risk families, rearrangement testing in BRCA1 and BRCA2 — $3120 Once a mutation is identified in an affected individual, analysis for the specific mutation in relatives costs $385 Analysis of the three specific mutations most commonly seen in Ashkenazi Jewish individuals is $460
A list of testing laboratories is available through the Gene Tests website, at www.genetests.org (click on "Laboratory Directory"). However, full sequencing is provided in the United States by only one commercial laboratory, Myriad Genetic Laboratories®. Genetic testing for BRCA1 and BRCA2 is very expensive, but in the United States, most health insurance companies will cover 80 percent or more of the costs. In many instances, a letter of medical necessity is required from a physician or genetic counselor to demonstrate the potential impact of a positive test result on future care (eg, whether a positive result will be used to intensify screening efforts or recommend surgery). Many people are concerned about the possibility of health insurance discrimination if they have a positive result from a genetic test. This phenomenon has been difficult to document. Two types of insurance may be affected for patients who test positive: the person's health insurance and their life insurance.
The 1996 Health Insurance Portability and Accountability Act (HIPAA) contains provisions to protect individuals with group insurance from having their individual health insurance premiums raised or canceled because of a preexisting condition, including a genetic test result. Some state laws also provide protection. However, there are loopholes that do not cover people with individual (private) insurance and those applying for life insurance. Several websites are available that provide additional information on this subject [3,4]. The effect of a positive genetic test on the ability to obtain life insurance is less clear. Presently there are no federal laws addressing this issue.
Options for treatment if a mutation is identified — Before a genetic test is done, it is important that the woman understand her options for treatment (see "Options after testing positive" below).
Post-test counseling — It is a good idea to schedule an in-person meeting with a genetics counselor or physician to receive the genetic testing results. During this meeting, test results will be explained. This is an excellent time to bring up any questions related to the testing technique or reliability of results.
During the post-test counseling session, patients should review the possible implications of test results on family members. Patients are encouraged to share their results with family members.
INTERPRETING THE RESULTS — Interpretation of test results is not always clear cut. A negative test does not mean that a woman will never develop cancer; nor does a positive test mean that she will definitely develop cancer.
The easiest tests to interpret are those done after a mutation has already been identified in one or more close relatives who have breast and/or ovarian cancer. A positive result occurs when an individual tests positive for the same mutation as their relatives. A negative result occurs when an individual tests negative for a mutation that has already been identified in their family.
If an affected high-risk individual is the first to be tested in a specific family, results may be less clear. There are a number of possible results: A mutation could be present in BRCA1 or BRCA2 but was not detected by available methods A mutation in another risk-conferring gene that is rare and/or not yet identified could be present The individual being tested could have developed a sporadic (noninherited) rather than hereditary cancer. Another possibility is that a BRCA1 or BRCA2 alteration may be identified that is considered to be a "variant of uncertain significance." This means that it could possibly be a newly identified deleterious mutation or it could simply be a normal change in the gene. Such changes appear to be more common in certain ethnic groups, such as African-Americans. Further research will clarify the significance of many of these changes.
OPTIONS AFTER TESTING POSITIVE — Usually, women who test positive for a BRCA mutation are referred to specialists who can review their options. Several alternatives are available for women who are at increased risk for breast and ovarian cancer: increased surveillance (screening) for breast and ovarian cancer, preventive surgery, and/or the use of medications to reduce the risk of cancer (called chemoprevention). Cancer risk might best be decreased through a combination of some or all of these methods (show table 2). Women considering genetic testing should discuss the table with their healthcare provider.
Intensified breast cancer screening — Women who have inherited BRCA1 or BRCA2 mutations are recommended to increase the level and frequency of screening strategies as follows: Monthly breast self-examination (BSE) beginning at age 18; women should be specifically instructed on how to perform BSE) Clinical breast examination two to four times annually beginning at age 25 Annual mammography beginning at age 25; in some women, mammography may be recommended every 6 months Annual breast MRI to take place approximately 6 months after the annual mammogram. Magnetic resonance imaging (MRI) uses a strong magnet rather than x-rays or radiation to create a detailed image of a part of the body. Breast MRI appears to be more sensitive than screening mammogram for detecting early breast cancers in high-risk women, and several experts groups (including the National Comprehensive Cancer Network and the American Cancer Society) now recommend annual breast MRI for these women.
However, there are insufficient data to recommend breast MRI instead of screening mammography in any group of women. One reason is that MRI does not appear to be as sensitive for diagnosing conditions such as ductal carcinoma in situ (DCIS), a noninvasive form of breast cancer.
Despite these recommendations by several expert groups, studies do not definitively prove that intensive screening improves cancer outcomes in women who inherit BRCA mutations. A major problem is that many of the screening tests are not sensitive enough to pick up early cancers at a time when they are most likely to be cured.
Ovarian cancer screening
High risk women — Women who have inherited a BRCA mutation have an increased risk of developing ovarian cancer and may benefit from tests to detect it at an early stage. However, unlike screening for breast cancer, screening tests for ovarian cancer are not very accurate in detecting disease. These tests have suboptimal sensitivity (ability to detect early ovarian cancer) and specificity (ability to differentiate ovarian cancer from other conditions that cause abnormal test results).
Nevertheless, periodic surveillance is often recommended for women with a BRCA mutation who do not undergo prophylactic (preventive) surgery to remove the ovaries (see below). Screening for these women involves a combination of pelvic examination, vaginal ultrasound, and measurement of blood levels of CA 125 (a tumor marker used to determine the effectiveness of treatment in women with ovarian cancer that may also be useful in detecting ovarian cancer in women with no history of this cancer). The optimal frequency for screening has not been determined, although most centers recommend considering ovarian cancer screening every 6 to 12 months beginning between ages 25 and 35.
Family history of ovarian cancer — Women with a family history of ovarian cancer but who do not have a BRCA mutation should discuss their individual risk factors (age, number of children, and history of oral contraceptive pill use) with a healthcare provider. A woman is said to have a family history if she has one first degree relative (eg, mother, sister) or two second-degree relatives (eg, grandmother, aunt) with ovarian cancer.
Screening for ovarian cancer in this group has not proven to prevent death related to ovarian cancer. In addition, there are potential risks of screening, including the need for surgery if screening is positive. However, selected postmenopausal women with a family history of ovarian cancer may benefit from screening. An optimal screening strategy for this group has not yet been defined; one screening approach includes an annual CA 125 blood test; transvaginal ultrasound is recommended if the CA 125 level is above 30 U/mL.
Trials are currently underway to better identify the risks and benefits of screening low and high-risk women, and also to determine the most accurate combination of screening tests.
Prophylactic (preventive) surgery — As an alternative to undergoing frequent screening, some high-risk women consider prophylactic surgery to reduce their risk of developing a cancer. Prospective studies of women who undergo surgical removal of both breasts (termed a prophylactic bilateral mastectomy) show at least 90 percent reduction in the risk of breast cancer for high-risk women, including those with BRCA mutations [6,7].
Surgical removal of the ovaries and fallopian tubes (termed a prophylactic bilateral salpingo-oophorectomy, or BSO) has been shown to be protective against ovarian cancer (approximately 85 to 95 percent reduction) and breast cancer (approximately 40 to 50 percent reduction for premenopausal women) in carriers of BRCA mutations [8,9]. The benefits of BSO are greatest in women undergoing the procedure before menopause, particularly before age 40, after childbearing has been completed. Due to the lack of effective tests for ovarian cancer screening (see "Ovarian cancer screening" above), it is recommended that BRCA1 and BRCA2 carriers undergo prophylactic BSO by age 35, or once childbearing is completed.
Despite these benefits, only a small minority of women who are mutation carriers pursue prophylactic surgery, particularly mastectomy. However, studies of women who have undergone prophylactic mastectomy have found that the large majority reported satisfaction [15]. Prophylactic BSO is generally more accepted, perhaps because of the limited effectiveness of screening for ovarian cancer and because it reduces risk of both ovarian and breast cancer.
Prophylactic surgery may have psychological benefits by reducing a woman's concern that she'll develop cancer, but there are also risks that her quality of life may be negatively affected by surgery. It is important to discuss the medical, psychological, and emotional impact of prophylactic surgery before considering such surgery.
Medications to reduce the risk of cancer — The drugs tamoxifen and raloxifene may prevent the development of breast cancer (see "Patient information: Tamoxifen and raloxifene for the prevention of breast cancer"). Oral contraceptives have also been studied for use in preventing breast cancer.
Tamoxifen — Studies evaluating the benefit of tamoxifen in BRCA mutation carriers are limited. Early reports suggest that at least in women who have breast cancer and a BRCA mutation, tamoxifen can reduce the risk of getting a second breast cancer in the opposite breast by about 40 to 50 percent [10]. However, whether this improves survival, and whether tamoxifen is beneficial for mutation carriers who do not have breast cancer are unknown.
There are risks of taking tamoxifen. It increases the risk of the following, particularly in patients over the age of 50 (see "Patient information: Tamoxifen and raloxifene for the prevention of breast cancer"): Cancer of the lining of the uterus (endometrial cancer and sarcoma) Stroke Blood clots within deep veins, usually in the legs (deep vein thrombosis) Blood clots in the lungs (pulmonary embolism)
Raloxifene, in contrast to tamoxifen, is not associated with many of the most serious side effects seen with tamoxifen. However, it has not been studied yet in women with BRCA mutations, and its benefits in this group are unknown.
Oral contraceptives — Use of oral contraceptives (birth control pills) is associated with a decreased risk of ovarian cancer in the general population. The situation in women with inherited BRCA mutation is less clear. At least one study suggests that oral contraceptives decrease ovarian cancer risk in BRCA mutation carriers [11], but other studies have not confirmed this finding. In addition, there is concern that oral contraceptives may increase the risk of breast cancer, particularly in BRCA1 mutation carriers. More information about oral contraceptives is available in a separate topic review. (See "Patient information: Hormonal methods of birth control").
WHERE TO GET MORE INFORMATION — Your healthcare provider is the best source of information for questions and concerns related to your medical problem. Because no two patients are exactly alike and recommendations can vary from one person to another, it is important to seek guidance from a provider who is familiar with your individual situation.
This discussion will be updated as needed every four months on our web site (www.patients.uptodate.com). Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.
A number of web sites have information about medical problems and treatments, although it can be difficult to know which sites are reputable. Information provided by the National Institutes of Health, national medical societies and some other well-established organizations are often reliable sources of information, although the frequency with which they are updated is variable. National Cancer Institute
(www.nci.nih.gov/)
People Living With Cancer: The official patient information
website of the American Society of Clinical Oncology
(www.plwc.org/portal/site/PLWC)
The National Comprehensive Cancer Network (NCCN)
Includes physician guidelines for hereditary breast and/or ovarian cancer
(www.nccn.org)
The American Cancer Society
Includes a guide to the causes of breast cancer with a discussion of BRCA genes
(www.cancer.org)
The Susan G. Komen Breast Cancer Foundation
(www.komen.org)
National Ovarian Cancer Coalition
(www.ovarian.org/)
Facing Our Risk of Cancer Empowered (FORCE)
(www.facingourrisk.com)
[1-4,6-14]
Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. BRCAPRO is a component of the CancerGene program, available online at www3.utsouthwestern.edu/cancergene/ (Accessed April 24, 2007).
2. www.cancer.gov/search/genetics_services/ (accessed April 24, 2007).
3. www.genome.gov/PolicyEthics/ (acceessed April 24, 2007).
4. www.facingourrisk.org (accessed April 24, 2007).
5. Saslow, D, Boetes, C, Burke, W, et al. American Cancer Society guidelines for breast cancer screening with MRI as an adjunct to mammography. CA Cancer J Clin 2007; 57:75.
6. Rebbeck, TR, Friebel, T, Lynch, HT, et al. Bilateral Prophylactic Mastectomy Reduces Breast Cancer Risk in BRCA1 and BRCA2 Mutation Carriers: The PROSE Study Group. J Clin Oncol 2004; 22:1055.
7. Hartmann, LC, Schaid, DJ, Woods, JE, et al. Efficacy of bilateral prophylactic mastectomy in women with a family history of breast cancer [see comments]. N Engl J Med 1999; 340:77.
8. Rebbeck, TR, Lynch, HT, Neuhausen, SL, et al. Prophylactic oophorectomy in carriers of BRCA1 or BRCA2 mutations. N Engl J Med 2002; 346:1616.
9. Kauff, ND, Satagopan, JM, Robson, ME, et al. Risk-reducing salpingo-oophorectomy in women with a BRCA1 or BRCA2 mutation. N Engl J Med 2002; 346:1609.
10. Metcalfe, K, Lynch, HT, Ghadirian, P, et al. Contralateral breast cancer in BRCA1 and BRCA2 mutation carriers. J Clin Oncol 2004; 22:2328.
11. Narod, SA, Risch, H, Moslehi, R, et al. Oral contraceptives and the risk of hereditary ovarian cancer. N Engl J Med 1998; 339:424.
12. Genetic risk assessment and BRCA mutation testing for breast and ovarian cancer susceptibility: recommendation statement. Ann Intern Med 2005; 143:355.
13. Hampel, H, Sweet, K, Westman, JA, et al. Referral for cancer genetics consultation: a review and compilation of risk assessment criteria. J Med Genet 2004; 41:81.
14. Segal, J, Esplen, MJ, Toner, B, et al. An investigation of the disclosure process and support needs of BRCA1 and BRCA2 carriers. Am J Med Genet 2004; 125A:267.
15. Geiger, AM, Nekhlyudov, L, Herrinton, LJ, et al. Quality of life after bilateral prophylactic mastectomy. Ann Surg Oncol 2007; 14:686.
Other women with a personal history of breast cancer, particularly if it was diagnosed at a young age, may worry that if they have inherited a tendency to develop breast and/or ovarian cancer, it may be passed on to their children.
Inherited mutations in two genes (known as BRCA1 and BRCA2) have been shown to increase the risk of both breast cancer and ovarian cancer. Genetic testing is available that may identify individuals who have inherited an altered form of one of these genes that increases the risk of breast and/or ovarian cancer. Patients who test positive can consider intensified screening or interventions to decrease the risk of cancer (medications or surgical removal of the breasts, ovaries, or both).
However, genetic testing for BRCA mutations is imperfect. Most women with a family history of breast cancer have not inherited one of these two abnormal genes, and not all women who have inherited one of these genes will develop cancer. Furthermore, the results of BRCA testing may be confusing, and do not always lead to a clear action plan. Genetic testing for BRCA mutations can create emotional turmoil and family discord, and may have an impact on future medical care and insurability. Thus, it is important for the patient, her healthcare provider, and family members to carefully consider whether to undergo such testing.
This topic review will focus on which women should consider genetic testing for the presence of BRCA mutations, issues to consider before undergoing testing, and the available options for women who are found to carry one of these mutations.
Genetic testing is not an emergency procedure. Taking time to understand the complexities, and discussing questions with health-care professionals and family members can help to clarify expectations from testing and anticipate future issues.
GENETIC TESTING GOALS — Genetic testing for breast and/or ovarian cancer analyzes the composition of the BRCA genes to look for alterations (mutations) associated with breast and/or ovarian cancer.
How do genes relate to cancer? — A person's visible characteristics (such as hair and eye color) as well as other invisible properties (including predisposition to cancer and other diseases), are determined by his or her genetic "blueprint", which is inherited from both parents as 23 pairs of chromosomes. Each chromosome is made up of a long strand of DNA. Discrete segments or sections of the DNA (called genes) contain the information that is needed to construct specific proteins that carry out the specific function of the individual cells that make up the body. There are approximately 30,000 human genes distributed among the 23 pairs of human chromosomes.
Most of the time, genes function properly and the body develops and performs normally. However, when a gene is altered (often by a mutation or change in the chemical structure of the gene), it may not provide the right signals to the body's cells to carry out their normal functions. If the affected gene is normally involved in the regulation of cell growth, a mutated gene may result in signals that allow uncontrolled cell growth. This process of uncontrolled cell growth causes tumors such as breast cancer to grow unchecked within the body.
An inherited mutation (ie, one that is passed from parent to child, and is present in all cells at the time the child is born) is called a germline mutation. In contrast, a noninherited mutation (ie, one that comes about during a person's lifetime) is called an acquired mutation. Acquired mutations can be caused by exposure to environmental agents such as radiation, chemicals (including those found in tobacco smoke), or viruses; they may also happen spontaneously. Most human cancers are thought to be caused by acquired mutations.
Most breast cancers (at least 90 percent) are not related to inherited (germline) mutations. However, for those 5 to 10 percent that are due to germline mutations, BRCA1 and BRCA2 mutations are thought to account for the majority. These genes are called tumor suppressor genes, meaning that they normally function to keep the growth of the body's cells under control. When one of these genes becomes mutated, cell growth becomes unregulated, paving the way for the development of a cancer. Most scientists believe that a cancer develops only if additional genetic mutations are acquired.
Other genes — Besides BRCA1 and BRCA2, a few other genes have been identified that are associated with breast and/or ovarian cancer, but in general, these involve rare syndromes that are related to other medical conditions and cancer types. There are also likely other, not-yet-identified, genes that are involved in inherited breast and/or ovarian cancer. This topic review will focus only on the BRCA genes.
WHO SHOULD CONSIDER GENETIC TESTING? — Genetic testing should not be done in all women with a family history of breast and/or ovarian cancer since BRCA1 and BRCA2 mutations are rare. Determining which women should consider genetic testing involves examination of an individual's personal and family history of breast cancer and/or ovarian cancer.
BRCA mutations occur in approximately 0.1 percent of individuals (1 in 1000 people). However, some ethnic groups have a higher chance of inheriting one of these mutations. For example, about 2 percent of women of Ashkenazi Jewish (Eastern European) descent carry a BRCA1 or BRCA2 mutation, and between 12 and 30 percent of breast cancers in this group are thought to be caused by mutations in the BRCA1 or BRCA2 genes. These statistics do not consider a family history of breast and/or ovarian cancer.
Because germline mutations are rare, and testing for them can produce indeterminate results, testing is usually offered to women who are at a high risk of having a BRCA mutation. Tools are available (such as a computer program called BRCAPRO [1]) to estimate the likelihood of a woman having a BRCA mutation based on her individual and personal history. Typically, a woman's health care provider or a genetics counselor will ask a set of questions about a woman's personal and family history and plug the answers into this risk assessment tool. The program then calculates an estimate of the chances of finding a BRCA mutation based upon a number of risk assessment tools. Guidelines from national organizations suggest that if the estimated chance of inheriting one of these mutations is greater than 10 percent (one in ten), genetic testing may be appropriate.
However, current recommendations are moving away from numerical cut-off values for determining when genetic testing should be offered. Instead, many organizations advocate using more details of an individual's and family's history as a screening tool to identify women who should be considered for BRCA testing.
Family history patterns — Doctors and patients should be aware of family history patterns that are associated with a higher risk of a BRCA mutation. These include: Multiple relatives affected with breast and/or ovarian cancer, particularly if they were diagnosed at an early age (less than 50 years old) A relative with more than one cancer, such as breast cancer involving both breasts or breast and ovarian cancer Evidence that multiple generations of a family are affected.
Women who develop breast cancer before the age of 50 are more likely to have a mutation than those who develop breast cancer at an older age. If a young woman develops breast cancer and also has a family history of breast and/or ovarian cancer, her chance of carrying a mutation increases dramatically. Family history on the father's side is as important as maternal history.
When there is a strong family history of breast and/or ovarian cancer, BRCA testing should be done on the relative who has the cancer whenever possible. If a mutation is not found, it is usually not helpful to test unaffected relatives. If a relative with breast cancer tests positive for a BRCA mutation, genetic testing should be considered for all of her at-risk adult relatives (male and female).
TESTING PROCEDURE
Pre-test counseling — Genetic testing involves taking a sample of blood and sending it to a lab for testing. However, a woman must consider a number of factors before deciding to undergo genetic testing. These include medical, emotional, practical, and financial factors that can profoundly affect a woman and her family. Women who are considering genetic testing should discuss these issues with a certified genetic counselor, if possible, to understand what is involved in the process of genetic testing. A list of certified genetics counselors and their phone numbers is available through the National Cancer Institute [2].
An example of a consent form is presented in table 1 (show table 1A-1D), and briefly discussed below.
Emotional effects for patient — Although anxiety may cause some high-risk individuals to refuse genetic testing, the available data suggest that there are no major adverse psychological effects of learning the results of BRCA testing. In fact, data from families with hereditary cancer and from individuals who underwent genetic testing in clinic settings suggest less distress in members of high-risk families who test negative for a familial mutation.
While it is normal for individuals who test positive (mutation carriers) to experience some level of distress, anxiety, or sadness, most studies suggest that these individuals do not suffer serious psychological effects or significantly increased distress levels. For many individuals, learning about positive test results can also produce feelings of relief, as risk information is clarified and a plan for managing that risk can be put into place. Women who have less significant family histories and who do not expect to receive positive results may be more vulnerable to psychological problems or high levels of distress after BRCA testing. In families that have a known BRCA mutation, it is not unusual for women who test negative to experience "survivor's guilt" for being spared a burden that other relatives have to endure.
Effects on family members — A discussion of the implications of the test results for family members is an important component of counseling. This includes identifying at-risk family members and encouraging patients to share results with their relatives.
The decision to share test results with relatives and the ramifications of that decision can cause significant emotional strain and family discord. The role of information "gatekeeper" may be overwhelming for some women, particularly as they try to attend to their own needs for emotional support. Nevertheless, studies have found that most individuals, including carriers and non-carriers, opt to share their results with at-risk relatives. For many individuals who seek testing, gaining information for family members is one of the most important benefits of testing.
Costs and insurance coverage — Because the BRCA genes are large and include hundreds of different mutations, testing is expensive. Commercial charges by Myriad Genetics Laboratories® (which are subject to change) are as follows: Full BRCA1/2 testing, which includes testing for five large rearrangements in BRCA1 and for very high risk families, rearrangement testing in BRCA1 and BRCA2 — $3120 Once a mutation is identified in an affected individual, analysis for the specific mutation in relatives costs $385 Analysis of the three specific mutations most commonly seen in Ashkenazi Jewish individuals is $460
A list of testing laboratories is available through the Gene Tests website, at www.genetests.org (click on "Laboratory Directory"). However, full sequencing is provided in the United States by only one commercial laboratory, Myriad Genetic Laboratories®. Genetic testing for BRCA1 and BRCA2 is very expensive, but in the United States, most health insurance companies will cover 80 percent or more of the costs. In many instances, a letter of medical necessity is required from a physician or genetic counselor to demonstrate the potential impact of a positive test result on future care (eg, whether a positive result will be used to intensify screening efforts or recommend surgery). Many people are concerned about the possibility of health insurance discrimination if they have a positive result from a genetic test. This phenomenon has been difficult to document. Two types of insurance may be affected for patients who test positive: the person's health insurance and their life insurance.
The 1996 Health Insurance Portability and Accountability Act (HIPAA) contains provisions to protect individuals with group insurance from having their individual health insurance premiums raised or canceled because of a preexisting condition, including a genetic test result. Some state laws also provide protection. However, there are loopholes that do not cover people with individual (private) insurance and those applying for life insurance. Several websites are available that provide additional information on this subject [3,4]. The effect of a positive genetic test on the ability to obtain life insurance is less clear. Presently there are no federal laws addressing this issue.
Options for treatment if a mutation is identified — Before a genetic test is done, it is important that the woman understand her options for treatment (see "Options after testing positive" below).
Post-test counseling — It is a good idea to schedule an in-person meeting with a genetics counselor or physician to receive the genetic testing results. During this meeting, test results will be explained. This is an excellent time to bring up any questions related to the testing technique or reliability of results.
During the post-test counseling session, patients should review the possible implications of test results on family members. Patients are encouraged to share their results with family members.
INTERPRETING THE RESULTS — Interpretation of test results is not always clear cut. A negative test does not mean that a woman will never develop cancer; nor does a positive test mean that she will definitely develop cancer.
The easiest tests to interpret are those done after a mutation has already been identified in one or more close relatives who have breast and/or ovarian cancer. A positive result occurs when an individual tests positive for the same mutation as their relatives. A negative result occurs when an individual tests negative for a mutation that has already been identified in their family.
If an affected high-risk individual is the first to be tested in a specific family, results may be less clear. There are a number of possible results: A mutation could be present in BRCA1 or BRCA2 but was not detected by available methods A mutation in another risk-conferring gene that is rare and/or not yet identified could be present The individual being tested could have developed a sporadic (noninherited) rather than hereditary cancer. Another possibility is that a BRCA1 or BRCA2 alteration may be identified that is considered to be a "variant of uncertain significance." This means that it could possibly be a newly identified deleterious mutation or it could simply be a normal change in the gene. Such changes appear to be more common in certain ethnic groups, such as African-Americans. Further research will clarify the significance of many of these changes.
OPTIONS AFTER TESTING POSITIVE — Usually, women who test positive for a BRCA mutation are referred to specialists who can review their options. Several alternatives are available for women who are at increased risk for breast and ovarian cancer: increased surveillance (screening) for breast and ovarian cancer, preventive surgery, and/or the use of medications to reduce the risk of cancer (called chemoprevention). Cancer risk might best be decreased through a combination of some or all of these methods (show table 2). Women considering genetic testing should discuss the table with their healthcare provider.
Intensified breast cancer screening — Women who have inherited BRCA1 or BRCA2 mutations are recommended to increase the level and frequency of screening strategies as follows: Monthly breast self-examination (BSE) beginning at age 18; women should be specifically instructed on how to perform BSE) Clinical breast examination two to four times annually beginning at age 25 Annual mammography beginning at age 25; in some women, mammography may be recommended every 6 months Annual breast MRI to take place approximately 6 months after the annual mammogram. Magnetic resonance imaging (MRI) uses a strong magnet rather than x-rays or radiation to create a detailed image of a part of the body. Breast MRI appears to be more sensitive than screening mammogram for detecting early breast cancers in high-risk women, and several experts groups (including the National Comprehensive Cancer Network and the American Cancer Society) now recommend annual breast MRI for these women.
However, there are insufficient data to recommend breast MRI instead of screening mammography in any group of women. One reason is that MRI does not appear to be as sensitive for diagnosing conditions such as ductal carcinoma in situ (DCIS), a noninvasive form of breast cancer.
Despite these recommendations by several expert groups, studies do not definitively prove that intensive screening improves cancer outcomes in women who inherit BRCA mutations. A major problem is that many of the screening tests are not sensitive enough to pick up early cancers at a time when they are most likely to be cured.
Ovarian cancer screening
High risk women — Women who have inherited a BRCA mutation have an increased risk of developing ovarian cancer and may benefit from tests to detect it at an early stage. However, unlike screening for breast cancer, screening tests for ovarian cancer are not very accurate in detecting disease. These tests have suboptimal sensitivity (ability to detect early ovarian cancer) and specificity (ability to differentiate ovarian cancer from other conditions that cause abnormal test results).
Nevertheless, periodic surveillance is often recommended for women with a BRCA mutation who do not undergo prophylactic (preventive) surgery to remove the ovaries (see below). Screening for these women involves a combination of pelvic examination, vaginal ultrasound, and measurement of blood levels of CA 125 (a tumor marker used to determine the effectiveness of treatment in women with ovarian cancer that may also be useful in detecting ovarian cancer in women with no history of this cancer). The optimal frequency for screening has not been determined, although most centers recommend considering ovarian cancer screening every 6 to 12 months beginning between ages 25 and 35.
Family history of ovarian cancer — Women with a family history of ovarian cancer but who do not have a BRCA mutation should discuss their individual risk factors (age, number of children, and history of oral contraceptive pill use) with a healthcare provider. A woman is said to have a family history if she has one first degree relative (eg, mother, sister) or two second-degree relatives (eg, grandmother, aunt) with ovarian cancer.
Screening for ovarian cancer in this group has not proven to prevent death related to ovarian cancer. In addition, there are potential risks of screening, including the need for surgery if screening is positive. However, selected postmenopausal women with a family history of ovarian cancer may benefit from screening. An optimal screening strategy for this group has not yet been defined; one screening approach includes an annual CA 125 blood test; transvaginal ultrasound is recommended if the CA 125 level is above 30 U/mL.
Trials are currently underway to better identify the risks and benefits of screening low and high-risk women, and also to determine the most accurate combination of screening tests.
Prophylactic (preventive) surgery — As an alternative to undergoing frequent screening, some high-risk women consider prophylactic surgery to reduce their risk of developing a cancer. Prospective studies of women who undergo surgical removal of both breasts (termed a prophylactic bilateral mastectomy) show at least 90 percent reduction in the risk of breast cancer for high-risk women, including those with BRCA mutations [6,7].
Surgical removal of the ovaries and fallopian tubes (termed a prophylactic bilateral salpingo-oophorectomy, or BSO) has been shown to be protective against ovarian cancer (approximately 85 to 95 percent reduction) and breast cancer (approximately 40 to 50 percent reduction for premenopausal women) in carriers of BRCA mutations [8,9]. The benefits of BSO are greatest in women undergoing the procedure before menopause, particularly before age 40, after childbearing has been completed. Due to the lack of effective tests for ovarian cancer screening (see "Ovarian cancer screening" above), it is recommended that BRCA1 and BRCA2 carriers undergo prophylactic BSO by age 35, or once childbearing is completed.
Despite these benefits, only a small minority of women who are mutation carriers pursue prophylactic surgery, particularly mastectomy. However, studies of women who have undergone prophylactic mastectomy have found that the large majority reported satisfaction [15]. Prophylactic BSO is generally more accepted, perhaps because of the limited effectiveness of screening for ovarian cancer and because it reduces risk of both ovarian and breast cancer.
Prophylactic surgery may have psychological benefits by reducing a woman's concern that she'll develop cancer, but there are also risks that her quality of life may be negatively affected by surgery. It is important to discuss the medical, psychological, and emotional impact of prophylactic surgery before considering such surgery.
Medications to reduce the risk of cancer — The drugs tamoxifen and raloxifene may prevent the development of breast cancer (see "Patient information: Tamoxifen and raloxifene for the prevention of breast cancer"). Oral contraceptives have also been studied for use in preventing breast cancer.
Tamoxifen — Studies evaluating the benefit of tamoxifen in BRCA mutation carriers are limited. Early reports suggest that at least in women who have breast cancer and a BRCA mutation, tamoxifen can reduce the risk of getting a second breast cancer in the opposite breast by about 40 to 50 percent [10]. However, whether this improves survival, and whether tamoxifen is beneficial for mutation carriers who do not have breast cancer are unknown.
There are risks of taking tamoxifen. It increases the risk of the following, particularly in patients over the age of 50 (see "Patient information: Tamoxifen and raloxifene for the prevention of breast cancer"): Cancer of the lining of the uterus (endometrial cancer and sarcoma) Stroke Blood clots within deep veins, usually in the legs (deep vein thrombosis) Blood clots in the lungs (pulmonary embolism)
Raloxifene, in contrast to tamoxifen, is not associated with many of the most serious side effects seen with tamoxifen. However, it has not been studied yet in women with BRCA mutations, and its benefits in this group are unknown.
Oral contraceptives — Use of oral contraceptives (birth control pills) is associated with a decreased risk of ovarian cancer in the general population. The situation in women with inherited BRCA mutation is less clear. At least one study suggests that oral contraceptives decrease ovarian cancer risk in BRCA mutation carriers [11], but other studies have not confirmed this finding. In addition, there is concern that oral contraceptives may increase the risk of breast cancer, particularly in BRCA1 mutation carriers. More information about oral contraceptives is available in a separate topic review. (See "Patient information: Hormonal methods of birth control").
WHERE TO GET MORE INFORMATION — Your healthcare provider is the best source of information for questions and concerns related to your medical problem. Because no two patients are exactly alike and recommendations can vary from one person to another, it is important to seek guidance from a provider who is familiar with your individual situation.
This discussion will be updated as needed every four months on our web site (www.patients.uptodate.com). Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.
A number of web sites have information about medical problems and treatments, although it can be difficult to know which sites are reputable. Information provided by the National Institutes of Health, national medical societies and some other well-established organizations are often reliable sources of information, although the frequency with which they are updated is variable. National Cancer Institute
(www.nci.nih.gov/)
People Living With Cancer: The official patient information
website of the American Society of Clinical Oncology
(www.plwc.org/portal/site/PLWC)
The National Comprehensive Cancer Network (NCCN)
Includes physician guidelines for hereditary breast and/or ovarian cancer
(www.nccn.org)
The American Cancer Society
Includes a guide to the causes of breast cancer with a discussion of BRCA genes
(www.cancer.org)
The Susan G. Komen Breast Cancer Foundation
(www.komen.org)
National Ovarian Cancer Coalition
(www.ovarian.org/)
Facing Our Risk of Cancer Empowered (FORCE)
(www.facingourrisk.com)
[1-4,6-14]
Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. BRCAPRO is a component of the CancerGene program, available online at www3.utsouthwestern.edu/cancergene/ (Accessed April 24, 2007).
2. www.cancer.gov/search/genetics_services/ (accessed April 24, 2007).
3. www.genome.gov/PolicyEthics/ (acceessed April 24, 2007).
4. www.facingourrisk.org (accessed April 24, 2007).
5. Saslow, D, Boetes, C, Burke, W, et al. American Cancer Society guidelines for breast cancer screening with MRI as an adjunct to mammography. CA Cancer J Clin 2007; 57:75.
6. Rebbeck, TR, Friebel, T, Lynch, HT, et al. Bilateral Prophylactic Mastectomy Reduces Breast Cancer Risk in BRCA1 and BRCA2 Mutation Carriers: The PROSE Study Group. J Clin Oncol 2004; 22:1055.
7. Hartmann, LC, Schaid, DJ, Woods, JE, et al. Efficacy of bilateral prophylactic mastectomy in women with a family history of breast cancer [see comments]. N Engl J Med 1999; 340:77.
8. Rebbeck, TR, Lynch, HT, Neuhausen, SL, et al. Prophylactic oophorectomy in carriers of BRCA1 or BRCA2 mutations. N Engl J Med 2002; 346:1616.
9. Kauff, ND, Satagopan, JM, Robson, ME, et al. Risk-reducing salpingo-oophorectomy in women with a BRCA1 or BRCA2 mutation. N Engl J Med 2002; 346:1609.
10. Metcalfe, K, Lynch, HT, Ghadirian, P, et al. Contralateral breast cancer in BRCA1 and BRCA2 mutation carriers. J Clin Oncol 2004; 22:2328.
11. Narod, SA, Risch, H, Moslehi, R, et al. Oral contraceptives and the risk of hereditary ovarian cancer. N Engl J Med 1998; 339:424.
12. Genetic risk assessment and BRCA mutation testing for breast and ovarian cancer susceptibility: recommendation statement. Ann Intern Med 2005; 143:355.
13. Hampel, H, Sweet, K, Westman, JA, et al. Referral for cancer genetics consultation: a review and compilation of risk assessment criteria. J Med Genet 2004; 41:81.
14. Segal, J, Esplen, MJ, Toner, B, et al. An investigation of the disclosure process and support needs of BRCA1 and BRCA2 carriers. Am J Med Genet 2004; 125A:267.
15. Geiger, AM, Nekhlyudov, L, Herrinton, LJ, et al. Quality of life after bilateral prophylactic mastectomy. Ann Surg Oncol 2007; 14:686.
General principles of treatment for metastatic breast cancer
INTRODUCTION — Breast cancer is the most common female cancer in the United States, the second most common cause of cancer death in women (after lung cancer), and the main cause of death in women ages 45 to 55. Every year, approximately 205,000 American women are diagnosed with breast cancer and more than 40,000 die from this disease. Early detection and treatment can improve survival by removing the breast tumor before it has a chance to spread (metastasize).
Despite early diagnosis and treatment, breast cancer can reappear at a later time (termed a recurrence or a relapse). Recurrence can occur even if the cancer was confined to the breast at the time of detection. A recurrence can be either local (confined to the breast area or nearby tissues) or at a distant site (beyond the breast and nearby tissues). Areas of distant tumor involvement are called metastases. The vast majority of women with metastatic breast cancer have a recurrent or relapsed tumor. However, 1 to 5 percent of women newly diagnosed with breast cancer already have metastatic disease at the time their cancers are discovered.
Metastatic breast cancer can be treated with surgery, radiation therapy, chemotherapy, hormone therapy, targeted therapies, or some combination of these options. These treatments rarely lead to long-term survival without disease recurrence (termed relapse-free survival), although they 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 specific features of the woman's breast cancer, the extent and location of metastases, the expected response of the cancer to the various types of therapy, treatment-related side effects, and a woman's personal preferences. Each woman should carefully discuss the many available treatment options to determine which is the best choice for her.
GENERAL TREATMENT PRINCIPLES — Some general principles of treating metastatic breast cancer can help a woman to understand the options that are available and the goals of therapy.
Confirming the diagnosis — It is important to confirm that a suspicious finding or symptom is indeed metastatic breast cancer, because other conditions may produce signs and symptoms that mimic those of breast cancer.
Metastatic breast cancer is usually confirmed by a biopsy (collection of a small sample of tissue or a body fluid for laboratory evaluation). If the biopsy reveals breast cancer, the laboratory evaluation can also help identify alterations in the cancer that may have occurred over time. These changes can impact treatment. Furthermore, the sample may also be tested for the presence of a protein called HER2, which can indicate a higher chance of responding to a specific "targeted" treatment called Herceptin (see "Herceptin (Trastuzumab)" below).
Goals of treatment — For many cancers, cure is the expected goal of treatment, particularly if the cancer is diagnosed at an early stage. However, cure is an unlikely outcome for women with metastatic breast cancer; as a result, other goals are of greater importance. These include relief of symptoms, improved QOL, longer survival, and a longer progression-free or relapse-free survival.
Cure — Breast cancer is considered cured when there is no remaining evidence of the cancer (called a remission) for a defined period of time, and a woman is able to live out a normal life span. However, it is difficult to define the period of time that must pass before a woman is considered cured of breast cancer because this disease can recur many years after initial diagnosis and treatment. For women with early breast cancer, a recurrence is most likely within the first five years after treatment, but can still occur up to 30 years later.
Cure is possible, but it is very uncommon in women with metastatic breast cancer. A few women in whom treatment leads to a complete remission may be long-term survivors. However, further tumor progression is prevented for prolonged periods (five to ten years) in only 2 to 5 percent of cases [1].
Prolonged survival — Despite the disappointing cure rate, treatment prolongs survival in women with metastatic breast cancer. The average survival duration for women treated for metastatic breast cancer has improved over the last 20 years [2,3], and is approximately 24 months, although the range extends from a few months to many years. Survival tends to be slightly longer (by months rather than years) for women whose cancers respond to treatment, compared to those who do not respond (nonresponders).
Improved QOL — Treatment can improve QOL in women with metastatic breast cancer by minimizing symptoms that are caused by the cancer. Studies suggest that chemotherapy effectively improves QOL despite its associated side effects.
Response rates — The response rate for a given treatment is a measure of that treatment's effectiveness. It refers to the proportion of women receiving a specific form of treatment who have a measurable decrease in the amount of breast cancer, either by physical examination or x-ray studies (eg, computed tomography (CT) scan or chest x-ray). Generally, the response to treatment is considered to be an objective, measurable indication of benefit from therapy. It is a commonly used endpoint in many clinical trials to assess the activity of new treatments.
Oncologists classify responses to therapy into four categories: Complete response — no further evidence of the tumor can be detected Partial response — more than 50 percent decrease in the amount of measurable breast cancer Minor response — less than 50 percent decrease in the amount of breast cancer Stable disease — no measurable decrease in the amount of tumor, but no increase in tumor size during treatment.
Sometimes, treatments that do not objectively decrease the amount of breast cancer can stabilize tumor growth; in other words, the tumor persists, but does not progress. Women with stable disease in response to a specific treatment tend to survive longer than women whose breast cancer grows despite treatment (called progressive disease), particularly if tumor size is stable for at least six months.
Clinical benefit — Although response rates in published studies usually include only the patients who have a complete or partial response to a specific therapy, patients with minor responses and stable disease also benefit from therapy, albeit to a lesser degree (see above). More recently, several clinical trials have designated a new term, "clinical benefit" to encompass complete and partial responders as well as those with minor responses and stable disease.
Both the response rate and the clinical benefit rate give an estimate of the likelihood of a woman benefiting from a specific therapy. As an example, if a treatment has a response rate of 60 percent, 60 of every 100 treated women can expect to have a measurable decrease (50 percent or greater decrease) in the amount of breast cancer, as long as treatment is administered on time and in the appropriate doses. Whenever possible, the treatment of metastatic breast cancer is aimed at achieving the highest possible response or clinical benefit rate with the least possible toxicity. When this is achieved, quality of life should be improved.
Disease progression — Even if there is a good response to initial therapy, metastatic breast cancer eventually becomes resistant to treatment and continues to grow despite therapy. This is called progressive disease, and indicates the need to switch to a different therapy. Since there are many different treatments available, it is not uncommon for women with metastatic breast cancer to receive many different therapies.
CHOOSING THE BEST TREATMENT OPTION — Multiple factors are considered when choosing among treatment options, including prognostic factors, response rates, the priorities of treatment, and the balance between the relative benefits and risks (side effects) of each therapy. An important factor is whether a woman's breast cancer makes hormone receptors (indicating that the tumor may be responsive to hormone treatments) or the protein HER2, which indicates that the targeted therapy Herceptin may be beneficial.
Several of the factors that are taken into account when selecting among the many treatment options are discussed in detail below.
Prognostic factors — As noted above, the range of survival for women with metastatic breast cancer ranges from several months to several years. Certain factors can help to determine the likely course of metastatic breast cancer over time (the prognosis). Relapse-free interval — The relapse-free interval refers to the time from initial diagnosis to the first disease recurrence. The prognosis of metastatic breast cancer is usually better when several five years have elapsed between the initial treatment and recurrence. Number of metastatic sites — Tests can help identify the number of locations affected by metastases. Women with metastases involving fewer sites usually have a better prognosis than those with many sites. Vital (visceral) organ involvement — The prognosis of metastatic breast cancer is usually better when metastases are located in the chest wall, lymph nodes, or bones rather than in organs such as the liver or lung. Hormone receptor status — Laboratory tests can determine if the breast cancer cells have hormone receptors such as estrogen receptors (ERs) or progesterone receptors (PRs). Besides indicating which tumors are likely to respond to hormone treatments, the presence of hormone receptors on breast cancer cells is also associated with a better prognosis. HER2 — Some breast cancers express high levels of a protein called HER2. Although controversial, overexpression of HER2 may be associated with a worse prognosis. More importantly, overexpression of this protein is a powerful predictor of a response to the targeted agent Herceptin (trastuzumab), which allows the physician to select those women who stand to benefit from this drug. (See "Herceptin (Trastuzumab)" below).
Predictive factors — Other factors, called predictive factors, can help predict the likelihood that breast cancer will respond to a specific type of therapy.
Hormone therapy — As noted above, the presence of hormone receptors indicates that a breast cancer may respond to hormone treatment. Hormone therapy is often recommended as the initial treatment for women with ER or PR-positive metastatic breast cancer, because it typically has fewer associated side effects than does chemotherapy. (See "Patient information: Endocrine therapy for metastatic breast cancer").
If there is a reasonable doubt that hormone therapy will be effective, then chemotherapy is often recommended as the initial systemic treatment. Several factors decrease the chances of responding to hormone therapy: A short interval between initial treatment and recurrence The presence of metastases in visceral organs like the lung or liver; women who have isolated metastases in bones or soft tissues such as lymph nodes or skin are more likely to respond to hormone therapy. A lower number of ER receptors. Between 50 and 60 percent of breast cancers with high or moderate numbers of ERs respond to hormone therapy, compared with only 10 percent of breast cancers with few ERs The absence of PR receptors
Chemotherapy — Unlike hormone therapy, there are no well-defined factors that predict whether a breast cancer will respond to chemotherapy. Chemotherapy rather than hormone therapy is chosen when a tumor lacks both ERs and PRs. Among women with metastatic breast cancer who have not previously received chemotherapy for metastatic breast cancer, between 50 and 75 percent of women will respond to the initial course of chemotherapy. (See "Patient information: Chemotherapy and Herceptin (trastuzumab) for metastatic breast cancer").
Chemotherapy may also be recommended as the initial therapy (even in women with hormone receptor-positive tumors) when the breast cancer is progressing rapidly, when metastases are present in vital organs, when a woman has many cancer-related symptoms, or when a rapid response to therapy is needed (eg, if the cancer is close to or pushing against the spinal cord). In vitro drug assays — There are laboratory tests of the sensitivity or resistance of tumor cells to chemotherapy drugs, called in vitro drug assays. In these tests, breast cancer cells, which are obtained by biopsy, are combined with a chemotherapy drug (in a laboratory, not in the patient) to determine if the drug could be of benefit.
While these tests are accurate in predicting "extreme drug resistance" (ie, if the cancer is very resistant to a certain chemotherapy drug in the laboratory, it is not likely to be effective in the patient), they do not accurately predict response (ie, if the tumor cells in the laboratory are killed by the drug, this does not always indicate whether the tumor in the patient will respond to that drug). Thus, use of these assays is controversial. Chemotherapy plus hormone therapy — Although simultaneous treatment with chemotherapy and hormone therapy improves the likelihood that hormone receptor-positive metastatic breast cancer will respond to therapy, no studies have shown that such combination therapy improves survival [4]. Furthermore, combined therapy is more likely to cause additional side effects than either treatment alone; these side effects can reduce a woman's QOL.
For these reasons, women with hormone-receptor-positive breast cancer are usually treated sequentially, with hormone therapy first, followed by chemotherapy when the patient becomes refractory to hormone treatment. Occasionally, if a patient has extensive visceral organ involvement, it is appropriate to induce a remission with chemotherapy first, and then follow this therapy with less toxic hormone therapy.
Herceptin (Trastuzumab) — As noted above, whether a breast cancer produces high levels of HER2 is a powerful predictor of benefit from treatment with Herceptin (trastuzumab). At present, Herceptin use is restricted to individuals whose tumors are strongly HER2-positive. (See "Patient information: Chemotherapy and Herceptin (trastuzumab) for metastatic breast cancer").
Herceptin alone is a reasonable choice for women with minimal symptoms and no rapidly progressing disease involving the internal organs (eg, liver, lungs). However, symptomatic women or those with internal organ involvement are often offered Herceptin in combination with a chemotherapy drug such as paclitaxel; there is evidence that both drugs work better together than either one taken alone.
Local versus systemic therapy — The treatments described above are all systemic (or bodywide) therapy; the drug is distributed throughout the body, and the benefit may be seen in metastases, no matter where they are located. In most cases, the treatments are administered into the vein, although most hormone therapies and some chemotherapy drugs (eg, Xeloda [capecitabine]) are given by mouth.
In contrast to systemic therapy, local therapy refers to surgery and/or radiation therapy that is directed specifically at areas affected by breast cancer. Such therapy benefits only the site at which the treatment is directed, and areas of disease elsewhere in the body are not affected.
Women with a breast cancer recurrence that is limited to the breast or chest wall are the most appropriate candidates for local therapy. However, surgery or radiation may also be considered for selected women with metastatic disease. In general, areas of metastatic breast cancer respond better to local rather than systemic therapies, but several factors must be taken into account when considering the need for local therapy. These include how widespread the cancer is, the location of the metastases, and the urgency of treating disease at that specific site.
As an example, if a bone metastasis is threatening a bone that is important for weight bearing, (eg, the thigh bone), surgery may be the best option to prevent a fracture. In these situations, local therapy (surgery followed by radiation) is generally accompanied by, or followed by systemic therapy.
BISPHOSPHONATE THERAPY — In addition to systemic therapy with either chemotherapy or hormone therapy, women who have breast cancer metastases to bone also benefit from therapy with bone-strengthening drugs called bisphosphonates. When combined with systemic therapy, monthly injections of a bisphosphonate (eg, pamidronate or zoledronic acid) can reduce the likelihood of complications from the bone metastases, such as bone fractures. For women with metastatic breast cancer and pain due to bone metastasis, intravenous bisphosphonate may also be of benefit to relieve pain when used in conjunction with systemic chemotherapy or hormone therapy.
MONITORING DURING THERAPY — Regular monitoring is essential for women who are receiving therapy for metastatic breast cancer. This monitoring determines the effectiveness of therapy and aids in monitoring for side effects.
Medical history and physical examination — A periodic medical history and physical examination are useful for monitoring symptoms, treatment-related side effects, and the response to treatment of any obvious signs of breast cancer, such as nodules beneath the skin. However, in 50 percent of women with metastatic breast cancer, a medical history and physical examination do not provide helpful information about the response of the cancer to treatment.
Imaging tests — Imaging tests, including x-rays, CT scans, magnetic resonance imaging scans (MRIs), bone scans, and sometimes PET scans are useful for viewing changes in the location and size of breast cancer metastases. Selected tests are often performed periodically during treatment to assess the response to therapy.
Bone scans are imaging tests that help determine if bone metastases are present, and if they are responding to treatment or progressing. However, the amount of tumor involvement on a bone scan is difficult to measure or quantitate. Thus, bone scans are not as useful as x-rays, CT scans, or MRI studies to characterize the treatment response.
Tumor markers — In women who do not have detectable outward signs of metastatic breast cancer, blood levels of tumor markers (such as CA15-3 and/or carcinoembryonic antigen [CEA]) may be used to measure the cancer's response to treatment. Blood levels of these tumor markers correlate with the course (ie, the clinical behavior) of breast cancer in 60 to 70 percent of women with metastatic breast cancer. However, treatment decisions are rarely, if ever made on the basis of a tumor marker alone, and their use is currently reserved for women with no areas of disease that can be followed to assess the response to treatment.
Circulating tumor cells — Another blood test that may be used to monitor the response to a specific treatment in women with metastatic breast cancer is an assay (the CellSearch assay) that determines the number of breast cancer cells circulating in the blood (termed circulating tumor cells). Although some studies suggest that the persistence of a larger number of tumor cells in the blood after a new treatment is started predicts that the treatment may not be effective [5], it is unknown whether changing the treatment in response to a large number of circulating tumor cells results in a better outcome. Trials are underway to answer this question. Until then, many oncologists restrict the use of the CellSearch assay to patients who lack measurable disease (eg, those with bone-only metastases), in whom the time of disease progression is particularly difficult to determine.
WHERE TO GET MORE INFORMATION — Your healthcare provider is the best source of information for questions and concerns related to your medical problem. Because no two patients are exactly alike and recommendations can vary from one person to another, it is important to seek guidance from a provider who is familiar with your individual situation.
This discussion will be updated as needed every four months on our web site (www.patients.uptodate.com). Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.
A number of web sites have information about medical problems and treatments, although it can be difficult to know which sites are reputable. Information provided by the National Institutes of Health, national medical societies and some other well-established organizations are often reliable sources of information, although the frequency with which they are updated is variable. People Living With Cancer: The official patient information
website of the American Society of Clinical Oncology
(http://www.plwc.org/portal/site/PLWC)
National Comprehensive Cancer Network
(www.nccn.org/patients/patient_gls.asp)
National Cancer Institute
1-800-4-CANCER
(www.nci.nih.gov)
American Cancer Society
1-800-ACS-2345
(www.cancer.org)
National Library of Medicine
(www.nlm.nih.gov/medlineplus)
Susan G. Komen Breast Cancer Foundation
(www.komen.org)
Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Greenberg, PA, Hortobagyi, GN, Smith, TL, et al. Long-term follow-up of patients with complete remission following combination chemotherapy for metastatic breast cancer. J Clin Oncol 1996; 14:2197.
2. Gennari, A, Conte, P, Rosso, R, et al. Survival of metastatic breast carcinoma patients over a 20-year period. Cancer 2005; 104:1742.
3. Giordano, SH, Buzdar, AU, Smith, TL, et al. Is breast cancer survival improving?. Cancer 2004; 100:44.
4. Fossati, R, Confalonieri, C, Torri, V, et al. Cytotoxic and hormonal treatment for metastatic breast cancer: a systematic review of published randomized trials involving 31,510 women. J Clin Oncol 1998; 16:3439.
5. Cristofanilli, M, Budd, GT, Ellis, MJ, et al. Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J Med 2004; 351:781.
Despite early diagnosis and treatment, breast cancer can reappear at a later time (termed a recurrence or a relapse). Recurrence can occur even if the cancer was confined to the breast at the time of detection. A recurrence can be either local (confined to the breast area or nearby tissues) or at a distant site (beyond the breast and nearby tissues). Areas of distant tumor involvement are called metastases. The vast majority of women with metastatic breast cancer have a recurrent or relapsed tumor. However, 1 to 5 percent of women newly diagnosed with breast cancer already have metastatic disease at the time their cancers are discovered.
Metastatic breast cancer can be treated with surgery, radiation therapy, chemotherapy, hormone therapy, targeted therapies, or some combination of these options. These treatments rarely lead to long-term survival without disease recurrence (termed relapse-free survival), although they 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 specific features of the woman's breast cancer, the extent and location of metastases, the expected response of the cancer to the various types of therapy, treatment-related side effects, and a woman's personal preferences. Each woman should carefully discuss the many available treatment options to determine which is the best choice for her.
GENERAL TREATMENT PRINCIPLES — Some general principles of treating metastatic breast cancer can help a woman to understand the options that are available and the goals of therapy.
Confirming the diagnosis — It is important to confirm that a suspicious finding or symptom is indeed metastatic breast cancer, because other conditions may produce signs and symptoms that mimic those of breast cancer.
Metastatic breast cancer is usually confirmed by a biopsy (collection of a small sample of tissue or a body fluid for laboratory evaluation). If the biopsy reveals breast cancer, the laboratory evaluation can also help identify alterations in the cancer that may have occurred over time. These changes can impact treatment. Furthermore, the sample may also be tested for the presence of a protein called HER2, which can indicate a higher chance of responding to a specific "targeted" treatment called Herceptin (see "Herceptin (Trastuzumab)" below).
Goals of treatment — For many cancers, cure is the expected goal of treatment, particularly if the cancer is diagnosed at an early stage. However, cure is an unlikely outcome for women with metastatic breast cancer; as a result, other goals are of greater importance. These include relief of symptoms, improved QOL, longer survival, and a longer progression-free or relapse-free survival.
Cure — Breast cancer is considered cured when there is no remaining evidence of the cancer (called a remission) for a defined period of time, and a woman is able to live out a normal life span. However, it is difficult to define the period of time that must pass before a woman is considered cured of breast cancer because this disease can recur many years after initial diagnosis and treatment. For women with early breast cancer, a recurrence is most likely within the first five years after treatment, but can still occur up to 30 years later.
Cure is possible, but it is very uncommon in women with metastatic breast cancer. A few women in whom treatment leads to a complete remission may be long-term survivors. However, further tumor progression is prevented for prolonged periods (five to ten years) in only 2 to 5 percent of cases [1].
Prolonged survival — Despite the disappointing cure rate, treatment prolongs survival in women with metastatic breast cancer. The average survival duration for women treated for metastatic breast cancer has improved over the last 20 years [2,3], and is approximately 24 months, although the range extends from a few months to many years. Survival tends to be slightly longer (by months rather than years) for women whose cancers respond to treatment, compared to those who do not respond (nonresponders).
Improved QOL — Treatment can improve QOL in women with metastatic breast cancer by minimizing symptoms that are caused by the cancer. Studies suggest that chemotherapy effectively improves QOL despite its associated side effects.
Response rates — The response rate for a given treatment is a measure of that treatment's effectiveness. It refers to the proportion of women receiving a specific form of treatment who have a measurable decrease in the amount of breast cancer, either by physical examination or x-ray studies (eg, computed tomography (CT) scan or chest x-ray). Generally, the response to treatment is considered to be an objective, measurable indication of benefit from therapy. It is a commonly used endpoint in many clinical trials to assess the activity of new treatments.
Oncologists classify responses to therapy into four categories: Complete response — no further evidence of the tumor can be detected Partial response — more than 50 percent decrease in the amount of measurable breast cancer Minor response — less than 50 percent decrease in the amount of breast cancer Stable disease — no measurable decrease in the amount of tumor, but no increase in tumor size during treatment.
Sometimes, treatments that do not objectively decrease the amount of breast cancer can stabilize tumor growth; in other words, the tumor persists, but does not progress. Women with stable disease in response to a specific treatment tend to survive longer than women whose breast cancer grows despite treatment (called progressive disease), particularly if tumor size is stable for at least six months.
Clinical benefit — Although response rates in published studies usually include only the patients who have a complete or partial response to a specific therapy, patients with minor responses and stable disease also benefit from therapy, albeit to a lesser degree (see above). More recently, several clinical trials have designated a new term, "clinical benefit" to encompass complete and partial responders as well as those with minor responses and stable disease.
Both the response rate and the clinical benefit rate give an estimate of the likelihood of a woman benefiting from a specific therapy. As an example, if a treatment has a response rate of 60 percent, 60 of every 100 treated women can expect to have a measurable decrease (50 percent or greater decrease) in the amount of breast cancer, as long as treatment is administered on time and in the appropriate doses. Whenever possible, the treatment of metastatic breast cancer is aimed at achieving the highest possible response or clinical benefit rate with the least possible toxicity. When this is achieved, quality of life should be improved.
Disease progression — Even if there is a good response to initial therapy, metastatic breast cancer eventually becomes resistant to treatment and continues to grow despite therapy. This is called progressive disease, and indicates the need to switch to a different therapy. Since there are many different treatments available, it is not uncommon for women with metastatic breast cancer to receive many different therapies.
CHOOSING THE BEST TREATMENT OPTION — Multiple factors are considered when choosing among treatment options, including prognostic factors, response rates, the priorities of treatment, and the balance between the relative benefits and risks (side effects) of each therapy. An important factor is whether a woman's breast cancer makes hormone receptors (indicating that the tumor may be responsive to hormone treatments) or the protein HER2, which indicates that the targeted therapy Herceptin may be beneficial.
Several of the factors that are taken into account when selecting among the many treatment options are discussed in detail below.
Prognostic factors — As noted above, the range of survival for women with metastatic breast cancer ranges from several months to several years. Certain factors can help to determine the likely course of metastatic breast cancer over time (the prognosis). Relapse-free interval — The relapse-free interval refers to the time from initial diagnosis to the first disease recurrence. The prognosis of metastatic breast cancer is usually better when several five years have elapsed between the initial treatment and recurrence. Number of metastatic sites — Tests can help identify the number of locations affected by metastases. Women with metastases involving fewer sites usually have a better prognosis than those with many sites. Vital (visceral) organ involvement — The prognosis of metastatic breast cancer is usually better when metastases are located in the chest wall, lymph nodes, or bones rather than in organs such as the liver or lung. Hormone receptor status — Laboratory tests can determine if the breast cancer cells have hormone receptors such as estrogen receptors (ERs) or progesterone receptors (PRs). Besides indicating which tumors are likely to respond to hormone treatments, the presence of hormone receptors on breast cancer cells is also associated with a better prognosis. HER2 — Some breast cancers express high levels of a protein called HER2. Although controversial, overexpression of HER2 may be associated with a worse prognosis. More importantly, overexpression of this protein is a powerful predictor of a response to the targeted agent Herceptin (trastuzumab), which allows the physician to select those women who stand to benefit from this drug. (See "Herceptin (Trastuzumab)" below).
Predictive factors — Other factors, called predictive factors, can help predict the likelihood that breast cancer will respond to a specific type of therapy.
Hormone therapy — As noted above, the presence of hormone receptors indicates that a breast cancer may respond to hormone treatment. Hormone therapy is often recommended as the initial treatment for women with ER or PR-positive metastatic breast cancer, because it typically has fewer associated side effects than does chemotherapy. (See "Patient information: Endocrine therapy for metastatic breast cancer").
If there is a reasonable doubt that hormone therapy will be effective, then chemotherapy is often recommended as the initial systemic treatment. Several factors decrease the chances of responding to hormone therapy: A short interval between initial treatment and recurrence The presence of metastases in visceral organs like the lung or liver; women who have isolated metastases in bones or soft tissues such as lymph nodes or skin are more likely to respond to hormone therapy. A lower number of ER receptors. Between 50 and 60 percent of breast cancers with high or moderate numbers of ERs respond to hormone therapy, compared with only 10 percent of breast cancers with few ERs The absence of PR receptors
Chemotherapy — Unlike hormone therapy, there are no well-defined factors that predict whether a breast cancer will respond to chemotherapy. Chemotherapy rather than hormone therapy is chosen when a tumor lacks both ERs and PRs. Among women with metastatic breast cancer who have not previously received chemotherapy for metastatic breast cancer, between 50 and 75 percent of women will respond to the initial course of chemotherapy. (See "Patient information: Chemotherapy and Herceptin (trastuzumab) for metastatic breast cancer").
Chemotherapy may also be recommended as the initial therapy (even in women with hormone receptor-positive tumors) when the breast cancer is progressing rapidly, when metastases are present in vital organs, when a woman has many cancer-related symptoms, or when a rapid response to therapy is needed (eg, if the cancer is close to or pushing against the spinal cord). In vitro drug assays — There are laboratory tests of the sensitivity or resistance of tumor cells to chemotherapy drugs, called in vitro drug assays. In these tests, breast cancer cells, which are obtained by biopsy, are combined with a chemotherapy drug (in a laboratory, not in the patient) to determine if the drug could be of benefit.
While these tests are accurate in predicting "extreme drug resistance" (ie, if the cancer is very resistant to a certain chemotherapy drug in the laboratory, it is not likely to be effective in the patient), they do not accurately predict response (ie, if the tumor cells in the laboratory are killed by the drug, this does not always indicate whether the tumor in the patient will respond to that drug). Thus, use of these assays is controversial. Chemotherapy plus hormone therapy — Although simultaneous treatment with chemotherapy and hormone therapy improves the likelihood that hormone receptor-positive metastatic breast cancer will respond to therapy, no studies have shown that such combination therapy improves survival [4]. Furthermore, combined therapy is more likely to cause additional side effects than either treatment alone; these side effects can reduce a woman's QOL.
For these reasons, women with hormone-receptor-positive breast cancer are usually treated sequentially, with hormone therapy first, followed by chemotherapy when the patient becomes refractory to hormone treatment. Occasionally, if a patient has extensive visceral organ involvement, it is appropriate to induce a remission with chemotherapy first, and then follow this therapy with less toxic hormone therapy.
Herceptin (Trastuzumab) — As noted above, whether a breast cancer produces high levels of HER2 is a powerful predictor of benefit from treatment with Herceptin (trastuzumab). At present, Herceptin use is restricted to individuals whose tumors are strongly HER2-positive. (See "Patient information: Chemotherapy and Herceptin (trastuzumab) for metastatic breast cancer").
Herceptin alone is a reasonable choice for women with minimal symptoms and no rapidly progressing disease involving the internal organs (eg, liver, lungs). However, symptomatic women or those with internal organ involvement are often offered Herceptin in combination with a chemotherapy drug such as paclitaxel; there is evidence that both drugs work better together than either one taken alone.
Local versus systemic therapy — The treatments described above are all systemic (or bodywide) therapy; the drug is distributed throughout the body, and the benefit may be seen in metastases, no matter where they are located. In most cases, the treatments are administered into the vein, although most hormone therapies and some chemotherapy drugs (eg, Xeloda [capecitabine]) are given by mouth.
In contrast to systemic therapy, local therapy refers to surgery and/or radiation therapy that is directed specifically at areas affected by breast cancer. Such therapy benefits only the site at which the treatment is directed, and areas of disease elsewhere in the body are not affected.
Women with a breast cancer recurrence that is limited to the breast or chest wall are the most appropriate candidates for local therapy. However, surgery or radiation may also be considered for selected women with metastatic disease. In general, areas of metastatic breast cancer respond better to local rather than systemic therapies, but several factors must be taken into account when considering the need for local therapy. These include how widespread the cancer is, the location of the metastases, and the urgency of treating disease at that specific site.
As an example, if a bone metastasis is threatening a bone that is important for weight bearing, (eg, the thigh bone), surgery may be the best option to prevent a fracture. In these situations, local therapy (surgery followed by radiation) is generally accompanied by, or followed by systemic therapy.
BISPHOSPHONATE THERAPY — In addition to systemic therapy with either chemotherapy or hormone therapy, women who have breast cancer metastases to bone also benefit from therapy with bone-strengthening drugs called bisphosphonates. When combined with systemic therapy, monthly injections of a bisphosphonate (eg, pamidronate or zoledronic acid) can reduce the likelihood of complications from the bone metastases, such as bone fractures. For women with metastatic breast cancer and pain due to bone metastasis, intravenous bisphosphonate may also be of benefit to relieve pain when used in conjunction with systemic chemotherapy or hormone therapy.
MONITORING DURING THERAPY — Regular monitoring is essential for women who are receiving therapy for metastatic breast cancer. This monitoring determines the effectiveness of therapy and aids in monitoring for side effects.
Medical history and physical examination — A periodic medical history and physical examination are useful for monitoring symptoms, treatment-related side effects, and the response to treatment of any obvious signs of breast cancer, such as nodules beneath the skin. However, in 50 percent of women with metastatic breast cancer, a medical history and physical examination do not provide helpful information about the response of the cancer to treatment.
Imaging tests — Imaging tests, including x-rays, CT scans, magnetic resonance imaging scans (MRIs), bone scans, and sometimes PET scans are useful for viewing changes in the location and size of breast cancer metastases. Selected tests are often performed periodically during treatment to assess the response to therapy.
Bone scans are imaging tests that help determine if bone metastases are present, and if they are responding to treatment or progressing. However, the amount of tumor involvement on a bone scan is difficult to measure or quantitate. Thus, bone scans are not as useful as x-rays, CT scans, or MRI studies to characterize the treatment response.
Tumor markers — In women who do not have detectable outward signs of metastatic breast cancer, blood levels of tumor markers (such as CA15-3 and/or carcinoembryonic antigen [CEA]) may be used to measure the cancer's response to treatment. Blood levels of these tumor markers correlate with the course (ie, the clinical behavior) of breast cancer in 60 to 70 percent of women with metastatic breast cancer. However, treatment decisions are rarely, if ever made on the basis of a tumor marker alone, and their use is currently reserved for women with no areas of disease that can be followed to assess the response to treatment.
Circulating tumor cells — Another blood test that may be used to monitor the response to a specific treatment in women with metastatic breast cancer is an assay (the CellSearch assay) that determines the number of breast cancer cells circulating in the blood (termed circulating tumor cells). Although some studies suggest that the persistence of a larger number of tumor cells in the blood after a new treatment is started predicts that the treatment may not be effective [5], it is unknown whether changing the treatment in response to a large number of circulating tumor cells results in a better outcome. Trials are underway to answer this question. Until then, many oncologists restrict the use of the CellSearch assay to patients who lack measurable disease (eg, those with bone-only metastases), in whom the time of disease progression is particularly difficult to determine.
WHERE TO GET MORE INFORMATION — Your healthcare provider is the best source of information for questions and concerns related to your medical problem. Because no two patients are exactly alike and recommendations can vary from one person to another, it is important to seek guidance from a provider who is familiar with your individual situation.
This discussion will be updated as needed every four months on our web site (www.patients.uptodate.com). Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.
A number of web sites have information about medical problems and treatments, although it can be difficult to know which sites are reputable. Information provided by the National Institutes of Health, national medical societies and some other well-established organizations are often reliable sources of information, although the frequency with which they are updated is variable. People Living With Cancer: The official patient information
website of the American Society of Clinical Oncology
(http://www.plwc.org/portal/site/PLWC)
National Comprehensive Cancer Network
(www.nccn.org/patients/patient_gls.asp)
National Cancer Institute
1-800-4-CANCER
(www.nci.nih.gov)
American Cancer Society
1-800-ACS-2345
(www.cancer.org)
National Library of Medicine
(www.nlm.nih.gov/medlineplus)
Susan G. Komen Breast Cancer Foundation
(www.komen.org)
Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Greenberg, PA, Hortobagyi, GN, Smith, TL, et al. Long-term follow-up of patients with complete remission following combination chemotherapy for metastatic breast cancer. J Clin Oncol 1996; 14:2197.
2. Gennari, A, Conte, P, Rosso, R, et al. Survival of metastatic breast carcinoma patients over a 20-year period. Cancer 2005; 104:1742.
3. Giordano, SH, Buzdar, AU, Smith, TL, et al. Is breast cancer survival improving?. Cancer 2004; 100:44.
4. Fossati, R, Confalonieri, C, Torri, V, et al. Cytotoxic and hormonal treatment for metastatic breast cancer: a systematic review of published randomized trials involving 31,510 women. J Clin Oncol 1998; 16:3439.
5. Cristofanilli, M, Budd, GT, Ellis, MJ, et al. Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J Med 2004; 351:781.
General principles of treatment for metastatic breast cancer
INTRODUCTION — Breast cancer is the most common female cancer in the United States, the second most common cause of cancer death in women (after lung cancer), and the main cause of death in women ages 45 to 55. Every year, approximately 205,000 American women are diagnosed with breast cancer and more than 40,000 die from this disease. Early detection and treatment can improve survival by removing the breast tumor before it has a chance to spread (metastasize).
Despite early diagnosis and treatment, breast cancer can reappear at a later time (termed a recurrence or a relapse). Recurrence can occur even if the cancer was confined to the breast at the time of detection. A recurrence can be either local (confined to the breast area or nearby tissues) or at a distant site (beyond the breast and nearby tissues). Areas of distant tumor involvement are called metastases. The vast majority of women with metastatic breast cancer have a recurrent or relapsed tumor. However, 1 to 5 percent of women newly diagnosed with breast cancer already have metastatic disease at the time their cancers are discovered.
Metastatic breast cancer can be treated with surgery, radiation therapy, chemotherapy, hormone therapy, targeted therapies, or some combination of these options. These treatments rarely lead to long-term survival without disease recurrence (termed relapse-free survival), although they 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 specific features of the woman's breast cancer, the extent and location of metastases, the expected response of the cancer to the various types of therapy, treatment-related side effects, and a woman's personal preferences. Each woman should carefully discuss the many available treatment options to determine which is the best choice for her.
GENERAL TREATMENT PRINCIPLES — Some general principles of treating metastatic breast cancer can help a woman to understand the options that are available and the goals of therapy.
Confirming the diagnosis — It is important to confirm that a suspicious finding or symptom is indeed metastatic breast cancer, because other conditions may produce signs and symptoms that mimic those of breast cancer.
Metastatic breast cancer is usually confirmed by a biopsy (collection of a small sample of tissue or a body fluid for laboratory evaluation). If the biopsy reveals breast cancer, the laboratory evaluation can also help identify alterations in the cancer that may have occurred over time. These changes can impact treatment. Furthermore, the sample may also be tested for the presence of a protein called HER2, which can indicate a higher chance of responding to a specific "targeted" treatment called Herceptin (see "Herceptin (Trastuzumab)" below).
Goals of treatment — For many cancers, cure is the expected goal of treatment, particularly if the cancer is diagnosed at an early stage. However, cure is an unlikely outcome for women with metastatic breast cancer; as a result, other goals are of greater importance. These include relief of symptoms, improved QOL, longer survival, and a longer progression-free or relapse-free survival.
Cure — Breast cancer is considered cured when there is no remaining evidence of the cancer (called a remission) for a defined period of time, and a woman is able to live out a normal life span. However, it is difficult to define the period of time that must pass before a woman is considered cured of breast cancer because this disease can recur many years after initial diagnosis and treatment. For women with early breast cancer, a recurrence is most likely within the first five years after treatment, but can still occur up to 30 years later.
Cure is possible, but it is very uncommon in women with metastatic breast cancer. A few women in whom treatment leads to a complete remission may be long-term survivors. However, further tumor progression is prevented for prolonged periods (five to ten years) in only 2 to 5 percent of cases [1].
Prolonged survival — Despite the disappointing cure rate, treatment prolongs survival in women with metastatic breast cancer. The average survival duration for women treated for metastatic breast cancer has improved over the last 20 years [2,3], and is approximately 24 months, although the range extends from a few months to many years. Survival tends to be slightly longer (by months rather than years) for women whose cancers respond to treatment, compared to those who do not respond (nonresponders).
Improved QOL — Treatment can improve QOL in women with metastatic breast cancer by minimizing symptoms that are caused by the cancer. Studies suggest that chemotherapy effectively improves QOL despite its associated side effects.
Response rates — The response rate for a given treatment is a measure of that treatment's effectiveness. It refers to the proportion of women receiving a specific form of treatment who have a measurable decrease in the amount of breast cancer, either by physical examination or x-ray studies (eg, computed tomography (CT) scan or chest x-ray). Generally, the response to treatment is considered to be an objective, measurable indication of benefit from therapy. It is a commonly used endpoint in many clinical trials to assess the activity of new treatments.
Oncologists classify responses to therapy into four categories: Complete response — no further evidence of the tumor can be detected Partial response — more than 50 percent decrease in the amount of measurable breast cancer Minor response — less than 50 percent decrease in the amount of breast cancer Stable disease — no measurable decrease in the amount of tumor, but no increase in tumor size during treatment.
Sometimes, treatments that do not objectively decrease the amount of breast cancer can stabilize tumor growth; in other words, the tumor persists, but does not progress. Women with stable disease in response to a specific treatment tend to survive longer than women whose breast cancer grows despite treatment (called progressive disease), particularly if tumor size is stable for at least six months.
Clinical benefit — Although response rates in published studies usually include only the patients who have a complete or partial response to a specific therapy, patients with minor responses and stable disease also benefit from therapy, albeit to a lesser degree (see above). More recently, several clinical trials have designated a new term, "clinical benefit" to encompass complete and partial responders as well as those with minor responses and stable disease.
Both the response rate and the clinical benefit rate give an estimate of the likelihood of a woman benefiting from a specific therapy. As an example, if a treatment has a response rate of 60 percent, 60 of every 100 treated women can expect to have a measurable decrease (50 percent or greater decrease) in the amount of breast cancer, as long as treatment is administered on time and in the appropriate doses. Whenever possible, the treatment of metastatic breast cancer is aimed at achieving the highest possible response or clinical benefit rate with the least possible toxicity. When this is achieved, quality of life should be improved.
Disease progression — Even if there is a good response to initial therapy, metastatic breast cancer eventually becomes resistant to treatment and continues to grow despite therapy. This is called progressive disease, and indicates the need to switch to a different therapy. Since there are many different treatments available, it is not uncommon for women with metastatic breast cancer to receive many different therapies.
CHOOSING THE BEST TREATMENT OPTION — Multiple factors are considered when choosing among treatment options, including prognostic factors, response rates, the priorities of treatment, and the balance between the relative benefits and risks (side effects) of each therapy. An important factor is whether a woman's breast cancer makes hormone receptors (indicating that the tumor may be responsive to hormone treatments) or the protein HER2, which indicates that the targeted therapy Herceptin may be beneficial.
Several of the factors that are taken into account when selecting among the many treatment options are discussed in detail below.
Prognostic factors — As noted above, the range of survival for women with metastatic breast cancer ranges from several months to several years. Certain factors can help to determine the likely course of metastatic breast cancer over time (the prognosis). Relapse-free interval — The relapse-free interval refers to the time from initial diagnosis to the first disease recurrence. The prognosis of metastatic breast cancer is usually better when several five years have elapsed between the initial treatment and recurrence. Number of metastatic sites — Tests can help identify the number of locations affected by metastases. Women with metastases involving fewer sites usually have a better prognosis than those with many sites. Vital (visceral) organ involvement — The prognosis of metastatic breast cancer is usually better when metastases are located in the chest wall, lymph nodes, or bones rather than in organs such as the liver or lung. Hormone receptor status — Laboratory tests can determine if the breast cancer cells have hormone receptors such as estrogen receptors (ERs) or progesterone receptors (PRs). Besides indicating which tumors are likely to respond to hormone treatments, the presence of hormone receptors on breast cancer cells is also associated with a better prognosis. HER2 — Some breast cancers express high levels of a protein called HER2. Although controversial, overexpression of HER2 may be associated with a worse prognosis. More importantly, overexpression of this protein is a powerful predictor of a response to the targeted agent Herceptin (trastuzumab), which allows the physician to select those women who stand to benefit from this drug. (See "Herceptin (Trastuzumab)" below).
Predictive factors — Other factors, called predictive factors, can help predict the likelihood that breast cancer will respond to a specific type of therapy.
Hormone therapy — As noted above, the presence of hormone receptors indicates that a breast cancer may respond to hormone treatment. Hormone therapy is often recommended as the initial treatment for women with ER or PR-positive metastatic breast cancer, because it typically has fewer associated side effects than does chemotherapy. (See "Patient information: Endocrine therapy for metastatic breast cancer").
If there is a reasonable doubt that hormone therapy will be effective, then chemotherapy is often recommended as the initial systemic treatment. Several factors decrease the chances of responding to hormone therapy: A short interval between initial treatment and recurrence The presence of metastases in visceral organs like the lung or liver; women who have isolated metastases in bones or soft tissues such as lymph nodes or skin are more likely to respond to hormone therapy. A lower number of ER receptors. Between 50 and 60 percent of breast cancers with high or moderate numbers of ERs respond to hormone therapy, compared with only 10 percent of breast cancers with few ERs The absence of PR receptors
Chemotherapy — Unlike hormone therapy, there are no well-defined factors that predict whether a breast cancer will respond to chemotherapy. Chemotherapy rather than hormone therapy is chosen when a tumor lacks both ERs and PRs. Among women with metastatic breast cancer who have not previously received chemotherapy for metastatic breast cancer, between 50 and 75 percent of women will respond to the initial course of chemotherapy. (See "Patient information: Chemotherapy and Herceptin (trastuzumab) for metastatic breast cancer").
Chemotherapy may also be recommended as the initial therapy (even in women with hormone receptor-positive tumors) when the breast cancer is progressing rapidly, when metastases are present in vital organs, when a woman has many cancer-related symptoms, or when a rapid response to therapy is needed (eg, if the cancer is close to or pushing against the spinal cord). In vitro drug assays — There are laboratory tests of the sensitivity or resistance of tumor cells to chemotherapy drugs, called in vitro drug assays. In these tests, breast cancer cells, which are obtained by biopsy, are combined with a chemotherapy drug (in a laboratory, not in the patient) to determine if the drug could be of benefit.
While these tests are accurate in predicting "extreme drug resistance" (ie, if the cancer is very resistant to a certain chemotherapy drug in the laboratory, it is not likely to be effective in the patient), they do not accurately predict response (ie, if the tumor cells in the laboratory are killed by the drug, this does not always indicate whether the tumor in the patient will respond to that drug). Thus, use of these assays is controversial. Chemotherapy plus hormone therapy — Although simultaneous treatment with chemotherapy and hormone therapy improves the likelihood that hormone receptor-positive metastatic breast cancer will respond to therapy, no studies have shown that such combination therapy improves survival [4]. Furthermore, combined therapy is more likely to cause additional side effects than either treatment alone; these side effects can reduce a woman's QOL.
For these reasons, women with hormone-receptor-positive breast cancer are usually treated sequentially, with hormone therapy first, followed by chemotherapy when the patient becomes refractory to hormone treatment. Occasionally, if a patient has extensive visceral organ involvement, it is appropriate to induce a remission with chemotherapy first, and then follow this therapy with less toxic hormone therapy.
Herceptin (Trastuzumab) — As noted above, whether a breast cancer produces high levels of HER2 is a powerful predictor of benefit from treatment with Herceptin (trastuzumab). At present, Herceptin use is restricted to individuals whose tumors are strongly HER2-positive. (See "Patient information: Chemotherapy and Herceptin (trastuzumab) for metastatic breast cancer").
Herceptin alone is a reasonable choice for women with minimal symptoms and no rapidly progressing disease involving the internal organs (eg, liver, lungs). However, symptomatic women or those with internal organ involvement are often offered Herceptin in combination with a chemotherapy drug such as paclitaxel; there is evidence that both drugs work better together than either one taken alone.
Local versus systemic therapy — The treatments described above are all systemic (or bodywide) therapy; the drug is distributed throughout the body, and the benefit may be seen in metastases, no matter where they are located. In most cases, the treatments are administered into the vein, although most hormone therapies and some chemotherapy drugs (eg, Xeloda [capecitabine]) are given by mouth.
In contrast to systemic therapy, local therapy refers to surgery and/or radiation therapy that is directed specifically at areas affected by breast cancer. Such therapy benefits only the site at which the treatment is directed, and areas of disease elsewhere in the body are not affected.
Women with a breast cancer recurrence that is limited to the breast or chest wall are the most appropriate candidates for local therapy. However, surgery or radiation may also be considered for selected women with metastatic disease. In general, areas of metastatic breast cancer respond better to local rather than systemic therapies, but several factors must be taken into account when considering the need for local therapy. These include how widespread the cancer is, the location of the metastases, and the urgency of treating disease at that specific site.
As an example, if a bone metastasis is threatening a bone that is important for weight bearing, (eg, the thigh bone), surgery may be the best option to prevent a fracture. In these situations, local therapy (surgery followed by radiation) is generally accompanied by, or followed by systemic therapy.
BISPHOSPHONATE THERAPY — In addition to systemic therapy with either chemotherapy or hormone therapy, women who have breast cancer metastases to bone also benefit from therapy with bone-strengthening drugs called bisphosphonates. When combined with systemic therapy, monthly injections of a bisphosphonate (eg, pamidronate or zoledronic acid) can reduce the likelihood of complications from the bone metastases, such as bone fractures. For women with metastatic breast cancer and pain due to bone metastasis, intravenous bisphosphonate may also be of benefit to relieve pain when used in conjunction with systemic chemotherapy or hormone therapy.
MONITORING DURING THERAPY — Regular monitoring is essential for women who are receiving therapy for metastatic breast cancer. This monitoring determines the effectiveness of therapy and aids in monitoring for side effects.
Medical history and physical examination — A periodic medical history and physical examination are useful for monitoring symptoms, treatment-related side effects, and the response to treatment of any obvious signs of breast cancer, such as nodules beneath the skin. However, in 50 percent of women with metastatic breast cancer, a medical history and physical examination do not provide helpful information about the response of the cancer to treatment.
Imaging tests — Imaging tests, including x-rays, CT scans, magnetic resonance imaging scans (MRIs), bone scans, and sometimes PET scans are useful for viewing changes in the location and size of breast cancer metastases. Selected tests are often performed periodically during treatment to assess the response to therapy.
Bone scans are imaging tests that help determine if bone metastases are present, and if they are responding to treatment or progressing. However, the amount of tumor involvement on a bone scan is difficult to measure or quantitate. Thus, bone scans are not as useful as x-rays, CT scans, or MRI studies to characterize the treatment response.
Tumor markers — In women who do not have detectable outward signs of metastatic breast cancer, blood levels of tumor markers (such as CA15-3 and/or carcinoembryonic antigen [CEA]) may be used to measure the cancer's response to treatment. Blood levels of these tumor markers correlate with the course (ie, the clinical behavior) of breast cancer in 60 to 70 percent of women with metastatic breast cancer. However, treatment decisions are rarely, if ever made on the basis of a tumor marker alone, and their use is currently reserved for women with no areas of disease that can be followed to assess the response to treatment.
Circulating tumor cells — Another blood test that may be used to monitor the response to a specific treatment in women with metastatic breast cancer is an assay (the CellSearch assay) that determines the number of breast cancer cells circulating in the blood (termed circulating tumor cells). Although some studies suggest that the persistence of a larger number of tumor cells in the blood after a new treatment is started predicts that the treatment may not be effective [5], it is unknown whether changing the treatment in response to a large number of circulating tumor cells results in a better outcome. Trials are underway to answer this question. Until then, many oncologists restrict the use of the CellSearch assay to patients who lack measurable disease (eg, those with bone-only metastases), in whom the time of disease progression is particularly difficult to determine.
WHERE TO GET MORE INFORMATION — Your healthcare provider is the best source of information for questions and concerns related to your medical problem. Because no two patients are exactly alike and recommendations can vary from one person to another, it is important to seek guidance from a provider who is familiar with your individual situation.
This discussion will be updated as needed every four months on our web site (www.patients.uptodate.com). Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.
A number of web sites have information about medical problems and treatments, although it can be difficult to know which sites are reputable. Information provided by the National Institutes of Health, national medical societies and some other well-established organizations are often reliable sources of information, although the frequency with which they are updated is variable. People Living With Cancer: The official patient information
website of the American Society of Clinical Oncology
(http://www.plwc.org/portal/site/PLWC)
National Comprehensive Cancer Network
(www.nccn.org/patients/patient_gls.asp)
National Cancer Institute
1-800-4-CANCER
(www.nci.nih.gov)
American Cancer Society
1-800-ACS-2345
(www.cancer.org)
National Library of Medicine
(www.nlm.nih.gov/medlineplus)
Susan G. Komen Breast Cancer Foundation
(www.komen.org)
Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Greenberg, PA, Hortobagyi, GN, Smith, TL, et al. Long-term follow-up of patients with complete remission following combination chemotherapy for metastatic breast cancer. J Clin Oncol 1996; 14:2197.
2. Gennari, A, Conte, P, Rosso, R, et al. Survival of metastatic breast carcinoma patients over a 20-year period. Cancer 2005; 104:1742.
3. Giordano, SH, Buzdar, AU, Smith, TL, et al. Is breast cancer survival improving?. Cancer 2004; 100:44.
4. Fossati, R, Confalonieri, C, Torri, V, et al. Cytotoxic and hormonal treatment for metastatic breast cancer: a systematic review of published randomized trials involving 31,510 women. J Clin Oncol 1998; 16:3439.
5. Cristofanilli, M, Budd, GT, Ellis, MJ, et al. Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J Med 2004; 351:781.
Despite early diagnosis and treatment, breast cancer can reappear at a later time (termed a recurrence or a relapse). Recurrence can occur even if the cancer was confined to the breast at the time of detection. A recurrence can be either local (confined to the breast area or nearby tissues) or at a distant site (beyond the breast and nearby tissues). Areas of distant tumor involvement are called metastases. The vast majority of women with metastatic breast cancer have a recurrent or relapsed tumor. However, 1 to 5 percent of women newly diagnosed with breast cancer already have metastatic disease at the time their cancers are discovered.
Metastatic breast cancer can be treated with surgery, radiation therapy, chemotherapy, hormone therapy, targeted therapies, or some combination of these options. These treatments rarely lead to long-term survival without disease recurrence (termed relapse-free survival), although they 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 specific features of the woman's breast cancer, the extent and location of metastases, the expected response of the cancer to the various types of therapy, treatment-related side effects, and a woman's personal preferences. Each woman should carefully discuss the many available treatment options to determine which is the best choice for her.
GENERAL TREATMENT PRINCIPLES — Some general principles of treating metastatic breast cancer can help a woman to understand the options that are available and the goals of therapy.
Confirming the diagnosis — It is important to confirm that a suspicious finding or symptom is indeed metastatic breast cancer, because other conditions may produce signs and symptoms that mimic those of breast cancer.
Metastatic breast cancer is usually confirmed by a biopsy (collection of a small sample of tissue or a body fluid for laboratory evaluation). If the biopsy reveals breast cancer, the laboratory evaluation can also help identify alterations in the cancer that may have occurred over time. These changes can impact treatment. Furthermore, the sample may also be tested for the presence of a protein called HER2, which can indicate a higher chance of responding to a specific "targeted" treatment called Herceptin (see "Herceptin (Trastuzumab)" below).
Goals of treatment — For many cancers, cure is the expected goal of treatment, particularly if the cancer is diagnosed at an early stage. However, cure is an unlikely outcome for women with metastatic breast cancer; as a result, other goals are of greater importance. These include relief of symptoms, improved QOL, longer survival, and a longer progression-free or relapse-free survival.
Cure — Breast cancer is considered cured when there is no remaining evidence of the cancer (called a remission) for a defined period of time, and a woman is able to live out a normal life span. However, it is difficult to define the period of time that must pass before a woman is considered cured of breast cancer because this disease can recur many years after initial diagnosis and treatment. For women with early breast cancer, a recurrence is most likely within the first five years after treatment, but can still occur up to 30 years later.
Cure is possible, but it is very uncommon in women with metastatic breast cancer. A few women in whom treatment leads to a complete remission may be long-term survivors. However, further tumor progression is prevented for prolonged periods (five to ten years) in only 2 to 5 percent of cases [1].
Prolonged survival — Despite the disappointing cure rate, treatment prolongs survival in women with metastatic breast cancer. The average survival duration for women treated for metastatic breast cancer has improved over the last 20 years [2,3], and is approximately 24 months, although the range extends from a few months to many years. Survival tends to be slightly longer (by months rather than years) for women whose cancers respond to treatment, compared to those who do not respond (nonresponders).
Improved QOL — Treatment can improve QOL in women with metastatic breast cancer by minimizing symptoms that are caused by the cancer. Studies suggest that chemotherapy effectively improves QOL despite its associated side effects.
Response rates — The response rate for a given treatment is a measure of that treatment's effectiveness. It refers to the proportion of women receiving a specific form of treatment who have a measurable decrease in the amount of breast cancer, either by physical examination or x-ray studies (eg, computed tomography (CT) scan or chest x-ray). Generally, the response to treatment is considered to be an objective, measurable indication of benefit from therapy. It is a commonly used endpoint in many clinical trials to assess the activity of new treatments.
Oncologists classify responses to therapy into four categories: Complete response — no further evidence of the tumor can be detected Partial response — more than 50 percent decrease in the amount of measurable breast cancer Minor response — less than 50 percent decrease in the amount of breast cancer Stable disease — no measurable decrease in the amount of tumor, but no increase in tumor size during treatment.
Sometimes, treatments that do not objectively decrease the amount of breast cancer can stabilize tumor growth; in other words, the tumor persists, but does not progress. Women with stable disease in response to a specific treatment tend to survive longer than women whose breast cancer grows despite treatment (called progressive disease), particularly if tumor size is stable for at least six months.
Clinical benefit — Although response rates in published studies usually include only the patients who have a complete or partial response to a specific therapy, patients with minor responses and stable disease also benefit from therapy, albeit to a lesser degree (see above). More recently, several clinical trials have designated a new term, "clinical benefit" to encompass complete and partial responders as well as those with minor responses and stable disease.
Both the response rate and the clinical benefit rate give an estimate of the likelihood of a woman benefiting from a specific therapy. As an example, if a treatment has a response rate of 60 percent, 60 of every 100 treated women can expect to have a measurable decrease (50 percent or greater decrease) in the amount of breast cancer, as long as treatment is administered on time and in the appropriate doses. Whenever possible, the treatment of metastatic breast cancer is aimed at achieving the highest possible response or clinical benefit rate with the least possible toxicity. When this is achieved, quality of life should be improved.
Disease progression — Even if there is a good response to initial therapy, metastatic breast cancer eventually becomes resistant to treatment and continues to grow despite therapy. This is called progressive disease, and indicates the need to switch to a different therapy. Since there are many different treatments available, it is not uncommon for women with metastatic breast cancer to receive many different therapies.
CHOOSING THE BEST TREATMENT OPTION — Multiple factors are considered when choosing among treatment options, including prognostic factors, response rates, the priorities of treatment, and the balance between the relative benefits and risks (side effects) of each therapy. An important factor is whether a woman's breast cancer makes hormone receptors (indicating that the tumor may be responsive to hormone treatments) or the protein HER2, which indicates that the targeted therapy Herceptin may be beneficial.
Several of the factors that are taken into account when selecting among the many treatment options are discussed in detail below.
Prognostic factors — As noted above, the range of survival for women with metastatic breast cancer ranges from several months to several years. Certain factors can help to determine the likely course of metastatic breast cancer over time (the prognosis). Relapse-free interval — The relapse-free interval refers to the time from initial diagnosis to the first disease recurrence. The prognosis of metastatic breast cancer is usually better when several five years have elapsed between the initial treatment and recurrence. Number of metastatic sites — Tests can help identify the number of locations affected by metastases. Women with metastases involving fewer sites usually have a better prognosis than those with many sites. Vital (visceral) organ involvement — The prognosis of metastatic breast cancer is usually better when metastases are located in the chest wall, lymph nodes, or bones rather than in organs such as the liver or lung. Hormone receptor status — Laboratory tests can determine if the breast cancer cells have hormone receptors such as estrogen receptors (ERs) or progesterone receptors (PRs). Besides indicating which tumors are likely to respond to hormone treatments, the presence of hormone receptors on breast cancer cells is also associated with a better prognosis. HER2 — Some breast cancers express high levels of a protein called HER2. Although controversial, overexpression of HER2 may be associated with a worse prognosis. More importantly, overexpression of this protein is a powerful predictor of a response to the targeted agent Herceptin (trastuzumab), which allows the physician to select those women who stand to benefit from this drug. (See "Herceptin (Trastuzumab)" below).
Predictive factors — Other factors, called predictive factors, can help predict the likelihood that breast cancer will respond to a specific type of therapy.
Hormone therapy — As noted above, the presence of hormone receptors indicates that a breast cancer may respond to hormone treatment. Hormone therapy is often recommended as the initial treatment for women with ER or PR-positive metastatic breast cancer, because it typically has fewer associated side effects than does chemotherapy. (See "Patient information: Endocrine therapy for metastatic breast cancer").
If there is a reasonable doubt that hormone therapy will be effective, then chemotherapy is often recommended as the initial systemic treatment. Several factors decrease the chances of responding to hormone therapy: A short interval between initial treatment and recurrence The presence of metastases in visceral organs like the lung or liver; women who have isolated metastases in bones or soft tissues such as lymph nodes or skin are more likely to respond to hormone therapy. A lower number of ER receptors. Between 50 and 60 percent of breast cancers with high or moderate numbers of ERs respond to hormone therapy, compared with only 10 percent of breast cancers with few ERs The absence of PR receptors
Chemotherapy — Unlike hormone therapy, there are no well-defined factors that predict whether a breast cancer will respond to chemotherapy. Chemotherapy rather than hormone therapy is chosen when a tumor lacks both ERs and PRs. Among women with metastatic breast cancer who have not previously received chemotherapy for metastatic breast cancer, between 50 and 75 percent of women will respond to the initial course of chemotherapy. (See "Patient information: Chemotherapy and Herceptin (trastuzumab) for metastatic breast cancer").
Chemotherapy may also be recommended as the initial therapy (even in women with hormone receptor-positive tumors) when the breast cancer is progressing rapidly, when metastases are present in vital organs, when a woman has many cancer-related symptoms, or when a rapid response to therapy is needed (eg, if the cancer is close to or pushing against the spinal cord). In vitro drug assays — There are laboratory tests of the sensitivity or resistance of tumor cells to chemotherapy drugs, called in vitro drug assays. In these tests, breast cancer cells, which are obtained by biopsy, are combined with a chemotherapy drug (in a laboratory, not in the patient) to determine if the drug could be of benefit.
While these tests are accurate in predicting "extreme drug resistance" (ie, if the cancer is very resistant to a certain chemotherapy drug in the laboratory, it is not likely to be effective in the patient), they do not accurately predict response (ie, if the tumor cells in the laboratory are killed by the drug, this does not always indicate whether the tumor in the patient will respond to that drug). Thus, use of these assays is controversial. Chemotherapy plus hormone therapy — Although simultaneous treatment with chemotherapy and hormone therapy improves the likelihood that hormone receptor-positive metastatic breast cancer will respond to therapy, no studies have shown that such combination therapy improves survival [4]. Furthermore, combined therapy is more likely to cause additional side effects than either treatment alone; these side effects can reduce a woman's QOL.
For these reasons, women with hormone-receptor-positive breast cancer are usually treated sequentially, with hormone therapy first, followed by chemotherapy when the patient becomes refractory to hormone treatment. Occasionally, if a patient has extensive visceral organ involvement, it is appropriate to induce a remission with chemotherapy first, and then follow this therapy with less toxic hormone therapy.
Herceptin (Trastuzumab) — As noted above, whether a breast cancer produces high levels of HER2 is a powerful predictor of benefit from treatment with Herceptin (trastuzumab). At present, Herceptin use is restricted to individuals whose tumors are strongly HER2-positive. (See "Patient information: Chemotherapy and Herceptin (trastuzumab) for metastatic breast cancer").
Herceptin alone is a reasonable choice for women with minimal symptoms and no rapidly progressing disease involving the internal organs (eg, liver, lungs). However, symptomatic women or those with internal organ involvement are often offered Herceptin in combination with a chemotherapy drug such as paclitaxel; there is evidence that both drugs work better together than either one taken alone.
Local versus systemic therapy — The treatments described above are all systemic (or bodywide) therapy; the drug is distributed throughout the body, and the benefit may be seen in metastases, no matter where they are located. In most cases, the treatments are administered into the vein, although most hormone therapies and some chemotherapy drugs (eg, Xeloda [capecitabine]) are given by mouth.
In contrast to systemic therapy, local therapy refers to surgery and/or radiation therapy that is directed specifically at areas affected by breast cancer. Such therapy benefits only the site at which the treatment is directed, and areas of disease elsewhere in the body are not affected.
Women with a breast cancer recurrence that is limited to the breast or chest wall are the most appropriate candidates for local therapy. However, surgery or radiation may also be considered for selected women with metastatic disease. In general, areas of metastatic breast cancer respond better to local rather than systemic therapies, but several factors must be taken into account when considering the need for local therapy. These include how widespread the cancer is, the location of the metastases, and the urgency of treating disease at that specific site.
As an example, if a bone metastasis is threatening a bone that is important for weight bearing, (eg, the thigh bone), surgery may be the best option to prevent a fracture. In these situations, local therapy (surgery followed by radiation) is generally accompanied by, or followed by systemic therapy.
BISPHOSPHONATE THERAPY — In addition to systemic therapy with either chemotherapy or hormone therapy, women who have breast cancer metastases to bone also benefit from therapy with bone-strengthening drugs called bisphosphonates. When combined with systemic therapy, monthly injections of a bisphosphonate (eg, pamidronate or zoledronic acid) can reduce the likelihood of complications from the bone metastases, such as bone fractures. For women with metastatic breast cancer and pain due to bone metastasis, intravenous bisphosphonate may also be of benefit to relieve pain when used in conjunction with systemic chemotherapy or hormone therapy.
MONITORING DURING THERAPY — Regular monitoring is essential for women who are receiving therapy for metastatic breast cancer. This monitoring determines the effectiveness of therapy and aids in monitoring for side effects.
Medical history and physical examination — A periodic medical history and physical examination are useful for monitoring symptoms, treatment-related side effects, and the response to treatment of any obvious signs of breast cancer, such as nodules beneath the skin. However, in 50 percent of women with metastatic breast cancer, a medical history and physical examination do not provide helpful information about the response of the cancer to treatment.
Imaging tests — Imaging tests, including x-rays, CT scans, magnetic resonance imaging scans (MRIs), bone scans, and sometimes PET scans are useful for viewing changes in the location and size of breast cancer metastases. Selected tests are often performed periodically during treatment to assess the response to therapy.
Bone scans are imaging tests that help determine if bone metastases are present, and if they are responding to treatment or progressing. However, the amount of tumor involvement on a bone scan is difficult to measure or quantitate. Thus, bone scans are not as useful as x-rays, CT scans, or MRI studies to characterize the treatment response.
Tumor markers — In women who do not have detectable outward signs of metastatic breast cancer, blood levels of tumor markers (such as CA15-3 and/or carcinoembryonic antigen [CEA]) may be used to measure the cancer's response to treatment. Blood levels of these tumor markers correlate with the course (ie, the clinical behavior) of breast cancer in 60 to 70 percent of women with metastatic breast cancer. However, treatment decisions are rarely, if ever made on the basis of a tumor marker alone, and their use is currently reserved for women with no areas of disease that can be followed to assess the response to treatment.
Circulating tumor cells — Another blood test that may be used to monitor the response to a specific treatment in women with metastatic breast cancer is an assay (the CellSearch assay) that determines the number of breast cancer cells circulating in the blood (termed circulating tumor cells). Although some studies suggest that the persistence of a larger number of tumor cells in the blood after a new treatment is started predicts that the treatment may not be effective [5], it is unknown whether changing the treatment in response to a large number of circulating tumor cells results in a better outcome. Trials are underway to answer this question. Until then, many oncologists restrict the use of the CellSearch assay to patients who lack measurable disease (eg, those with bone-only metastases), in whom the time of disease progression is particularly difficult to determine.
WHERE TO GET MORE INFORMATION — Your healthcare provider is the best source of information for questions and concerns related to your medical problem. Because no two patients are exactly alike and recommendations can vary from one person to another, it is important to seek guidance from a provider who is familiar with your individual situation.
This discussion will be updated as needed every four months on our web site (www.patients.uptodate.com). Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.
A number of web sites have information about medical problems and treatments, although it can be difficult to know which sites are reputable. Information provided by the National Institutes of Health, national medical societies and some other well-established organizations are often reliable sources of information, although the frequency with which they are updated is variable. People Living With Cancer: The official patient information
website of the American Society of Clinical Oncology
(http://www.plwc.org/portal/site/PLWC)
National Comprehensive Cancer Network
(www.nccn.org/patients/patient_gls.asp)
National Cancer Institute
1-800-4-CANCER
(www.nci.nih.gov)
American Cancer Society
1-800-ACS-2345
(www.cancer.org)
National Library of Medicine
(www.nlm.nih.gov/medlineplus)
Susan G. Komen Breast Cancer Foundation
(www.komen.org)
Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Greenberg, PA, Hortobagyi, GN, Smith, TL, et al. Long-term follow-up of patients with complete remission following combination chemotherapy for metastatic breast cancer. J Clin Oncol 1996; 14:2197.
2. Gennari, A, Conte, P, Rosso, R, et al. Survival of metastatic breast carcinoma patients over a 20-year period. Cancer 2005; 104:1742.
3. Giordano, SH, Buzdar, AU, Smith, TL, et al. Is breast cancer survival improving?. Cancer 2004; 100:44.
4. Fossati, R, Confalonieri, C, Torri, V, et al. Cytotoxic and hormonal treatment for metastatic breast cancer: a systematic review of published randomized trials involving 31,510 women. J Clin Oncol 1998; 16:3439.
5. Cristofanilli, M, Budd, GT, Ellis, MJ, et al. Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J Med 2004; 351:781.
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