Breast cancer

Definition

Breast cancer is caused by the development of malignant cells in the breast. The malignant cells originate in the lining of the milk glands or ducts of the breast (ductal epithelium), defining this malignancy as a cancer. Cancer cells are characterized by uncontrolled division leading to abnormal growth and the ability of these cells to invade normal tissue locally or to spread throughout the body, in a process called metastasis .

Description

Breast cancer arises in the milk-producing glands of the breast tissue. Groups of glands in normal breast tissue are called lobules. The products of these glands are secreted into a ductal system that leads to the nipple. Depending on where in the glandular or ductal unit of the breast the cancer arises, it will develop certain characteristics that are used to sub-classify breast cancer into types. The pathologist will denote the subtype at the time of evaluation with the microscope. Ductal carcinoma begins in the ducts, and lobular carcinoma has a pattern involving the lobules or glands. The more important classification is related to the evaluated tumor's capability to invade, as this characteristic defines the disease as a true cancer. The stage before invasive cancer is called in situ, meaning that the early malignancy has not yet become capable of invasion. Thus, ductal carcinoma in situ is considered a minimal breast cancer.

How breast cancer spreads

The primary tumor begins in the breast itself but once it becomes invasive, it may progress beyond the breast to the regional lymph nodes or travel (metastasize) to other organ systems in the body and become systemic in nature. Lymph is the clear, protein-rich fluid that bathes the cells throughout the body. Lymph will work its way back to the bloodstream via small channels known as lymphatics. Along the way, the lymph is filtered through cellular stations known as nodes, thus they are called lymph nodes. Nearly all organs in the body have a primary lymph node group filtering the tissue fluid, or lymph, that comes from that organ. In the breast, the primary lymph nodes are under the armpit, or axilla. Classically, the primary tumor begins in the breast and the first place to which it is likely to spread is the regional lymph nodes. Cancer, as it invades in its place of origin, may also work its way into blood vessels. If cancer gets into the blood vessels, the blood vessels provide yet another route for the cancer to spread to other organs of the body.

Breast cancer follows this classic progression though it often becomes systemic or widespread early in the course of the disease. By the time one can feel a lump in the breast it is often 0.4 inches, or one centimeter, in size and contains roughly a million cells. It is estimated that a tumor of this size may take one to five years to develop. During that time, the cancer may metastasize, or spread by lymphatics or blood to areas elsewhere in the body.

When primary breast cancer spreads, it may first go to the regional lymph nodes under the armpit, the axillary nodes. If this occurs, regional metastasis exists. If it proceeds elsewhere either by lymphatic or blood-borne spread, the patient develops systemic metastasis that may involve a number of other organs in the body. Common sites of systemic involvement for breast cancer are the lung, bones, liver, and the skin and soft tissue. As it turns out, the presence of, and the actual number of, regional lymph nodes containing cancer remains the single best indicator of whether or not the cancer has become widely metastatic. Because tests to discover metastasis in other organs may not be sensitive enough to reveal minute deposits, the evaluation of the axilla for regional metastasis becomes very important in making treatment decisions for this disease.

If breast cancer spreads to other major organs of the body, its presence will compromise the function of those organs. Death is the result of extreme compromise of vital organ function.

Demographics

Every woman is at risk for breast cancer. If she lives to be 85, there is a one out of nine chance that she will develop the condition sometime during her life. As a woman ages, her risk of developing breast cancer rises dramatically regardless of her family history. The breast cancer risk of a 25-year-old woman is only one out of 19, 608; by age 45, it is one in 93. In fact, less than 5% of cases are discovered before age 35 and the majority of all breast cancers are found in women over age 50.

In 1999, there were 180, 000 new cases of breast cancer diagnosed. About 45, 000 women die of breast cancer each year, accounting for 16% of deaths caused by cancer in women. For the first time ever, mortality rates decreased an average of 1.7% per year from 1995 through 1999, a reflection of earlier diagnosis and improving therapies.

Causes and symptoms

There are a number of risk factors for the development of breast cancer, including:

• family history of breast cancer in mother or sister
• early onset of menstruation and late menopause
• reproductive history: women who had no children or have children after age 30 and women who have never breastfed have increased risk
• history of abnormal breast biopsies

Though these are recognized risk factors, it is important to note that more than 70% of women who get breast cancer have no known risk factors. Having several risk factors may boost a woman's chances of developing breast cancer, but the interplay of predisposing factors is complex. In addition to those accepted factors listed above, some studies suggest that high-fat diets, obesity, or the use of alcohol may contribute to the risk profile. Another factor that may contribute to a woman's risk profile is hormone replacement therapy (HRT).

HRT provides significant relief of menopausal symptoms, prevention of osteoporosis, and possibly protection from cardiovascular disease and stroke. However, studies show that there is a small increased risk of developing breast cancer with HRT use. Thus, the use of hormone replacement therapy should be based on personal risk factors.

Of all the risk factors listed above, family history is the most important. In The Biological Basis of Cancer, the authors estimate that probably about half of all familial breast cancer cases (families in which there is a high breast cancer frequency) have mutations affecting the tumor suppressor gene BRCA-1. Another gene (BRCA-2) also appears to confer inherited vulnerability to early-onset breast cancers. However, breast cancer due to heredity is only a small proportion of breast cancer cases; only 5%-10% of all breast cancer cases will be women who inherited a susceptibility through their genes. Nevertheless, when the family history is strong for development of breast cancer, a woman's risk is increased.

Not all lumps detected in the breast are cancerous. Fibrocystic changes in the breast are extremely common. Also known as fibrocystic condition of the breast , fibrocystic changes are a leading cause of non-cancerous lumps in the breast. Fibrocystic changes also cause symptoms of pain, swelling, or discharge and may become evident to the patient or physician as a lump that is either solid or filled with fluid. Complete diagnostic evaluation of any significant breast abnormality is mandatory because though women commonly develop fibrocystic changes, breast cancer is common also, and the signs and symptoms of fibrocystic changes overlap with those of breast cancer.

Diagnosis

The diagnosis of breast cancer is accomplished by the biopsy of any suspicious lump or mammographic abnormality that has been identified. (A biopsy is the removal of tissue for examination by a pathologist. A mammogram is a low-dose, 2-view, x-ray examination of the breast.) The patient may be prompted to visit her doctor upon finding a lump in a breast, or she may have noticed skin dimpling, nipple retraction, or discharge from the nipple. Or, the patient may not have noticed anything abnormal, and a lump is detected by the mammogram.

When a patient has no signs or symptoms

Screening involves the evaluation of women who have no symptoms or signs of a breast problem, so when the screening mammogram leads to the evaluation, the patient has no symptoms and may not have any abnormality on examination of the breast. Mammography has been very helpful in detecting breast cancer that one cannot identify on physical examination. However, 10%-13% of breast cancer does not show up on mammography, and a similar number of patients with breast cancer have an abnormal mammogram and a normal physical examination. These figures emphasize the need for examination as part of the screening process.

Screening

It is recommended that women get into the habit of doing monthly breast self examinations to detect any lump at an early stage. If an uncertainty or a lump is found, evaluation by an experienced physician and mammography is recommended. The American Cancer Society (ACS) has made recommendations for the use of mammography on a screening basis. There has been controversy about the timing and appropriate frequency of mammography when used as a screening tool, but the ACS recommendations are as follows: Women should get annual mammograms after age 40. Those with a significant family history (one or more first-degree relatives who have been treated for breast cancer), should start annual mammograms 10 years younger than the youngest relative was when she was diagnosed, but not earlier than 35.

Because of the greater awareness of breast cancer in recent years, screening evaluations by examinations and mammography are performed much more frequently than in the past. The result is that the number of breast cancers diagnosed increased, but the disease is being diagnosed at an earlier stage than previously. The earlier the stage of disease at the time of presentation, the better the long-term outcome after treatment, or prognosis, becomes.

When a patient has physical signs or symptoms

A very common finding that leads to diagnosis is the presence of a lump within the breast. Skin dimpling, nipple retraction, or discharge from the nipple are less frequent initial findings prompting biopsy. Though bloody nipple discharge is distressing, it is most often caused by benign disease. Skin dimpling or nipple retraction in the presence of an underlying breast mass on examination is a more advanced finding. Actual skin involvement, with edema or ulceration of the skin, are late findings.

A very common presenting sign is the presence of a breast lump. If the lump is suspicious and the patient has not had a mammogram by this point, a study should be done on both breasts prior to anything else so that the original characteristics of the lesion can be studied. The opposite breast should also be evaluated mammographically to determine if other problems exist that were undetected by physical examination.

Whether an abnormal screening mammogram or one of the signs mentioned above followed by a mammogram prompted suspicion, the diagnosis is established by obtaining tissue by biopsy of the area. There are different types of biopsy, each utilized with its own indication depending on the presentation of the patient. If signs of widespread metastasis are already present, biopsy of the metastasis itself may establish diagnosis.

Biopsy

Depending on the situation, different types of biopsy may be performed. The types include incisional and excisional biopsies. In an incisional biopsy, the physician takes a sample of tissue, and in excisional biopsy, the mass is removed. Fine needle aspiration biopsy and core needle biopsy are kinds of incisional biopsies.

FINE NEEDLE ASPIRATION BIOPSY.

In a fine needle aspiration biopsy, a fine-gauge needle may be passed into the lesion and cells from the area suctioned into the needle can be quickly prepared for microscopic evaluation (cytology ). (The patient experiencing nipple discharge can have a sample taken of the discharge for cytological evaluation, also.) Fine needle aspiration is a simple procedure that can be done under local anesthesia, and will tell if the lesion is a fluid-filled cyst or whether it is solid. The sample obtained will yield much diagnostic information. Fine needle aspiration biopsy is an excellent technique when the lump is palpable and the physician can easily hit the target with the needle. If the lesion is a simple cyst, the fluid will be evacuated and the mass will disappear. If it is solid, the diagnosis may be obtained. Care must be taken, however, because if the mass is solid and the specimen is non-malignant, a complete removal of the lesion may be appropriate to be sure.

CORE NEEDLE BIOPSY.

Core needle biopsies are also obtained simply under local anesthesia. The larger piece of tissue obtained with its preserved architecture may be helpful in confirming the diagnosis short of open surgical removal. An open surgical incisional biopsy is rarely needed for diagnosis because of the needle techniques. If there remains question as to diagnosis, a complete open surgical biopsy may be required.

EXCISIONAL BIOPSY.

When performed, the excisional, (complete removal) biopsy is a minimal outpatient procedure often done under local anesthesia.

NON-PALPABLE LESIONS.

As screening increases, non-palpable lesions demonstrated only by mammography are becoming more common. The use of x rays and computers to guide the needle for biopsy or to place markers for the surgeon performing the excisional biopsy are commonly employed. Some benign lesions can be fully removed by multiple directed core biopsies. These techniques are very appealing because they are minimally invasive; however, the physician needs to be careful to obtain a good sample.

Other tests

If a lesion is not palpable and has simple cystic characteristics on mammography, ultrasound may be utilized both to determine that it is a cyst and to guide its evacuation. Ultrasound may also be used in some cases to guide fine needle or core biopsies of the breast.

Computed tomography (CT scan, CAT scans), and magnetic resonance imaging (MRI) have only a very occasional use in the evaluation of breast lesions.

Clinical staging, treatments, and prognosis

Staging

Once diagnosis is established, before treatment is rendered, more tests are done to determine if the cancer has spread beyond the breast. These tests include a chest x ray and blood count with liver function tests. Along with the liver function measured by the blood sample, the level of alkaline phosphatase, an enzyme from bone, is also determined. A radionuclear bone scan may be ordered. This test looks at the places in the body to which breast cancer usually metastasizes. A CT scan may also be ordered. The physician will do a careful examination of the axilla to assess likelihood of regional metastasis but unfortunately this exam is not very accurate. Since the axillary node status is the best reflection of possible widespread disease, these nodes in part or all will be removed at the time of surgical treatment.

Using the results of these studies, clinical stage is defined for the patient. This helps define treatment protocol and prognosis. After surgical treatment, the final, or pathologic, stage is defined as the true axillary lymph node status is known. Detailed staging criteria are available from the American Joint Commission on Cancer Manual and are generalized here:

• Stage 1—The cancer is no larger than 2 cm (0.8 in) and no cancer cells are found in the lymph nodes.
• Stage 2—The cancer is between 2 cm and 5 cm, and the cancer has spread to the lymph nodes.
• Stage 3A—Tumor is larger than 5 cm (2 in) or is smaller than 5 cm, but has spread to the lymph nodes, which have grown into each other.
• Stage 3B—Cancer has spread to tissues near the breast, (local invasion), or to lymph nodes inside the chest wall, along the breastbone.
• Stage 4—Cancer has spread to skin and lymph nodes beyond the axilla or to other organs of the body.

Treatment

Surgery, radiation, and chemotherapy are all utilized in the treatment of breast cancer. Depending on the stage, they will be used in different combinations or sequences to effect an appropriate strategy for the type and stage of the disease being treated.

SURGERY.

Historically, surgical removal of the entire breast and axillary contents along with the muscles down to the chest wall was performed as the lone therapy, (radical mastectomy ). In the last twenty-five years, as it has been appreciated that breast cancer is often systemic early in its course, the role of surgery is still primary but of less and less magnitude.

Today, surgical treatment is best thought of as a combination of removal of the primary tumor and staging of the axillary lymph nodes. If the whole breast is removed along with the entire axillary contents, but the muscles of the chest wall are not, the modified radical mastectomy has been performed.

If the tumor is less than 4 cm (1.5 in) in size and located so that it can be removed without destroying a reasonable cosmetic appearance of the residual breast, just the primary tumor and a rim of normal tissue will be removed. The axillary nodes will still be removed for staging purposes, usually through a separate incision. Because of the risk of recurrence in the remaining breast tissue, radiation is used to lessen the chance of local recurrence. This type of primary therapy is known as lumpectomy , (or segmental mastectomy), and axillary dissection.

Currently the necessary extent of the axillary dissection is being questioned. Sentinel lymph node biopsy, a technique for identifying which nodes in the axilla drain the tumor, has been developed to provide selective sampling and further lessen the degree of surgical trauma the patient experiences.

When patients are selected appropriately based on the preoperative clinical stage, all of these surgical approaches have been shown to produce similar results. In planning primary surgical therapy, it is imperative that the operation is tailored to fit the clinical circumstance of the patient.

The pathologic stage is determined after surgical treatment absolutely defines the local parameters. In addition to stage, there are other tests that are very necessary to aid in decisions regarding treatment. Handling of the surgical specimen is thus very important. The tissue needs to be analyzed for the presence or absence of hormone receptors and a receptor called HER-2. The presence of these receptors will influence additional therapies. Microscopic evaluation may also include the assessment of lymphatic or blood vessel invasion as these predict a worse outcome. The DNA of the tumor cells is quantitatively analyzed to help decide the biologic aggressiveness of the tumor. These parameters will be utilized collectively along with the axillary lymph node status to define the anticipated aggressiveness of the cancer. This assessment, along with the age and general condition of the patient, will be considered when planning the adjuvant therapies. Adjuvant therapies are treatments utilized after the primary treatment to help ensure that no microscopic disease exists and to help prolong patients' survival time.

RADIATION.

Like surgical therapy, radiation therapy is a local modality—it treats the tissue exposed to it and not the rest of the body. Radiation is usually given post-operatively after surgical wounds have healed. The pathologic stage of the primary tumor is now known and this aids in treatment planning. The extent of the local surgery also influences the planning. Radiation may not be needed at all after modified radical mastectomy for stage I disease, but is almost always utilized when breast-preserving surgery is performed. If the tumor was extensive or if multiple nodes were involved, the field of tissue exposed will vary accordingly. Radiation is utilized as an adjunct to surgical therapy and is considered an important modality in gaining local control of the tumor. The use of radiation therapy does not affect decisions for adjuvant treatment. In the past, radiation was used as an alternative to surgery on occasion. However, now that breast-preserving surgical protocols have been developed, primary radiation treatment of the tumor is no longer performed. Radiation also has an important role in the treatment of the patient with disseminated disease, particularly if it involves the skeleton. Radiation therapy can effect pain control and prevention of fracture in this circumstance.

DRUG THERAPY.

Many breast cancers, particularly those originating in post-menopausal women, are responsive to hormones. These cancers have receptors on their cells for estrogen and progesterone. Part of primary tumor assessment after removal of the tumor is the evaluation for the presence of these estrogen and progesterone receptors. If they are present on the cancer cells, altering the hormone status of the patient will inhibit tumor growth and have a positive impact on survival. The drug tamoxifen binds up these receptors on the cancer cells so that the hormones can't have an effect and, in so doing, inhibits tumor growth. If the patient has these receptors present, tamoxifen is commonly prescribed for five years as an adjunct to primary treatment. Adjuvant hormonal therapy with tamoxifen has few side effects but they have to be kept in mind, particularly the need for yearly evaluation of the uterus. Other agents directed at altering hormone environment are under study. Because of these agents, there is rarely any need for surgical removal of hormone-producing glands, such as the ovary or adrenal gland, that was sometimes necessary in the past.

Shortly after the modified radical mastectomy replaced the radical mastectomy as primary surgical treatment, it was appreciated that survival after local treatment in stage II breast cancer was improved by the addition of chemotherapy. Adjuvant chemotherapy for an interval of four to six months is now standard treatment for patients with stage II disease. The addition of systemic therapy to local treatment in patients who have no evidence of disease is performed on the basis that some patients have metastasis that are not currently demonstrable because they are microscopic. By treating the whole patient early, before widespread disease is diagnosed, the adjuvant treatment improves survival rates from roughly 60% for stage II to about 75% at five years after treatment. The standard regimen of cytoxan, methotrexate , and fluorouracil (CMF), is given for six months and is well tolerated. The regimen of cytoxan, adriamycin (doxorubicin ), and floururacil, (CAF), is a bit more toxic but only requires four months. (Adriamycin and cytoxin may also be used alone, without the fluorouracil.) The two methods are about equivalent in results. Adjuvant hormonal therapy may be added to the adjuvant chemotherapy as they work through different routes.

As one would expect, the encouraging results from adjuvant therapy in stage II disease have led to the study of similar therapy in stage I disease. The results are not as dramatic, but they are real. Currently, stage I disease is divided into categories a, b, and c on the basis of tumor size. Stage Ia is less than a centimeter in diameter. Adjuvant hormonal or chemotherapy is now commonly recommended for stage Ib and Ic patients. The toxicity of the treatment must be weighed individually for the patient as patients with stage I disease have a survivorship of over 80% without adjuvant chemotherapy.

If patients are diagnosed with stage IV disease or, in spite of treatment, progress to a state of widespread disease, systemic chemotherapy is utilized in a more aggressive fashion. In addition to the adriamycin-containing regimens, docetaxel and paclitaxel have been found to be effective in inducing remission.

On the basis of prognostic factors such as total number of involved nodes over 10, aneuploid DNA with a high synthesis value, or aggressive findings on microscopic evaluation, some patients with stage II or III disease can be predicted to do poorly. If their performance status allows, they can be considered for treatment with highly aggressive chemotherapy. The toxicity is such that bone marrow failure will result. To get around this anticipated side effect of the aggressive therapy, either the patients will be transplanted with their own stem cells, (the cells that will give rise to new marrow), or an allogeneic bone marrow transplantation will be required. This therapy can be a high-risk procedure for patients. It is given with known risk to patients predicted to do poorly and then only if it is felt they can tolerate it. Most patients who receive this therapy receive it as part of a clinical trial. At present, it is unclear that such aggressive therapy can be justified and it is under study.

For patients who are diagnosed with advanced local disease, surgery may be preceded with chemotherapy and radiation therapy. The disease locally regresses allowing traditional surgical treatment to those who could not receive it otherwise. Chemotherapy and sometimes radiation therapy will continue after the surgery. The regimens of this type are referred to as neo-adjuvant therapy. This has been proven to be effective in stage III disease. Neo-adjuvant therapy is now being studied in patients with large tumors that are stage II in an effort to be able to offer breast preservation to these patients.

A drug known as Herceptin (trastuzumab ), a monoclonal antibody, is now being used in the treatment of those with systemic disease. The product of the Human Epidermal Growth Factor 2 gene, (HER-2) is overex-pressed in 25%-30% of breast cancers. Herceptin binds to the HER-2 receptors on the cancer, resulting in the arrest of growth of these cells.

Prognosis

The prognosis for breast cancer depends on the type and stage of cancer. Over 80% of stage I patients are cured by current therapies. Stage II patients survive overall about 70% of the time, those with more extensive lymph nodal involvement doing worse than those with disease confined to the breast. About 40% of stage III patients survive five years, and about 20% of stage IV patients do so.

Coping with cancer treatment

Surgery for breast cancer is physically well-tolerated by the patient, especially those undergoing minimal surgery in the axilla. Most patients can return to a normal lifestyle within a month or so after surgery. Exercises can help the patient regain strength and flexibility. Arm, shoulder, and chest exercises help, and complete recovery of activity is to be expected.

About 5-7% of patients undergoing complete axillary lymph node resection as part of their therapy may develop clinically significant lymphedema, or swelling in the arm on the side of involvement. If present, elevation and massage may be needed intermittently. Though usually not serious, on occasion this complication may interfere with complete physical recovery. The incidence of lymphedema is less with less axillary surgery. This is the reason for the enthusiasm for sentinel node biopsy as the surgical staging procedure in the axilla.

It is common after breast cancer treatment to be depressed or moody, to cry, lose appetite, or feel unworthy or less interested in sex. The breast is involved with a woman's identity and loss of it may be disturbing. For some, counseling or a support group can help. Many women have found a support group of breast cancer survivors to be an invaluable help during this stage. Involvement with volunteers from the local chapter of the Reach to Recovery program may be very helpful.

Nearly all patients undergo some form of adjuvant therapy for breast cancer. The magnitude of the toxicity of these adjuvant therapies is usually small and many patients receiving chemotherapy on this basis are capable of normal activity during this time. Certainly, those who progress to advanced disease are treated with more toxic chemotherapeutic regimens in an attempt to induce remission.

Clinical trials

The use of tamoxifen and other agents which alter the hormone status of the patient are under study. The National Surgical Adjuvant Breast and Bowel Project (NSABP) with support from the National Cancer Institute began a study in 1992 (called the Breast Cancer Prevention Trial, or BCPT) studying the use of tamoxifen as a breast cancer preventative for high-risk women. The results yielded from the study showed that tamoxifen significantly reduced breast cancer risk, and the U.S. Food and Drug Administration approved the use of tamoxifen to reduce breast cancer risk for high-risk patients in 1998. Another NSABP study, known as STAR, is seeking to understand if another drug, raloxifene , is as effective as tamoxifen in reducing breast cancer risk in high-risk patients. That study was begun in 1999, and participants are to be monitored for five years.

Neo-adjuvant therapies to allow the use of breast preservation in those with more advanced local disease are under investigation.

Immune therapies have not been helpful to date though there are vaccines being developed against proteins such as that produced by HER-2 that may be beneficial in the future.

High-dose chemotherapy with bone marrow rescue remains controversial. Factors can be identified that predict certain patients will develop metastatic disease. This treatment has been offered to this select group of patients but the toxicity is such that defining a clear indication for this treatment remains under study.

Prevention

As mentioned above, because of the results yielded from the BCPT clinical trial, tamoxifen can now be prescribed to high-risk women to help prevent breast cancer.

And, while most breast cancer can't be prevented, it can be diagnosed from a mammogram at an early stage when it is most treatable. The results of awareness and routine screening have allowed earlier diagnosis, which results in a better prognosis for those discovered.

Special Concerns

Though breast-preserving therapy is being done more frequently than in years past, modified radical mastectomy remains an option when selecting therapy for the primary tumor. This option may allow treatment without radiation in earlier stage patients, or may be necessary if the presentation of the tumor does not allow breast preservation. Loss of the breast is disfiguring and many patients so treated desire reconstruction of the breast. Breast reconstruction is performed either at the time of initial surgery (immediate) or it may be delayed. Alternatives include placement of implants or the rotation of muscle flaps from the abdomen or back. Most agree that breast preservation gives superior results to any form of reconstruction. When the breast is removed as part of primary therapy, these reconstructions are available and do produce very reasonable results.

See Also Breast ultrasound; Sentinel lymph node mapping; Tumor staging

Resources

BOOKS

Abelhoff, Armitage, Lichter, Niederhuber. Clinical Oncology Library. Philadelphia: Churchill Livingstone 1999.

American Joint Committee on Cancer. AJCC Clinical Staging Manual. Philadelphia: Lippincott-Raven, 1997.

Love, Susan and Karen Lindsey. Dr. Susan Love's Breast Book. Reading, MA: Addison-Wesley, 1995.

Mayers, Musa. Holding Tight, Letting Go: Living with Metastatic Breast Cancer. Sebastopol, CA: O'Reilly & Associates, 1997.

McKinnell, Robert G., Ralph E. Parchment, Alan O. Perantoni, and G. Barry Pierce. The Biological Basis of Cancer. New York: Cambridge University Press, 1998.

Schwartz, Spencer, Galloway, Shires, Daly, Fischer. Principles of Surgery. New York: McGraw Hill, 1999.

PERIODICALS

Esteva and Hortobagyi. "Adjuvant Systemic Therapy for Primary Breast Cancer." Surgical Clinics of North America Volume 79 No. 5 (October 1999) p 1075-1090.

Krag, et al, "The Sentinel Node in Breast Cancer." New England Journal of Medicine Volume 339 No. 14 (October 1, 1998), p 941-946.

Margolese, R. G., M.D. "Surgical Considerations For Invasive Breast Cancer." Surgical Clinics of North America Volume 79 No. 5 (October 1999), p 1031-1046.

Munster and Hudis. "Adjuvant Therapy for Resectable Breast Cancer." Hematology Oncology Clinics of North America Volume 13 No. 2 (April 1999) p 391-413.

Shuster, et al. "Multidisciplinary Care For Patients With Breast Cancer." Surgical Clinics of North America Volume 80 No. 2 (April, 2000) p 505-533.

ORGANIZATIONS

American Cancer Society. (800) ACS-2345. <http://www.cancer.org>.American Cancer Society's Reach to Recovery Program: <http://www2.cancer.org/bcn/reach.html>. Cancer Care, Inc. (800) 813-HOPE.<http://www.cancercareinc.org>.

Cancer Information Service of the NCI. (1-800-4-CANCER).<http://wwwicic.nci.nih.gov>.

National Alliance of Breast Cancer Organizations. 9 East 37th St., 10th floor, New York, NY 10016. (888) 80-NABCO.

National Coalition for Cancer Survivorship. 1010 Wayne Ave., 5th Floor, Silver Spring, MD 20910. (301) 650-8868.

National Women's Health Resource Center. 2425 L St. NW, 3rd floor, Washington, DC 20037. (202) 293-6045.

OTHER

Breast Cancer Online <http://www.bco.org/>

National Alliance of Breast Cancer Organizations <http://www.nabco.org/>

National Cancer Institute <http://rex.nci.nih.gov/PATIENTS/INFO_PEOPL_DOC.html>

Richard A. McCartney, M.D.

Carol A. Turkington

KEY TERMS

Adjuvant therapy

—Treatment involving radiation, chemotherapy (drug treatment), or hormone therapy, or a combination of all three given after the primary treatment for the possibility of residual microscopic disease.

Aneuploid

—An abnormal number of chromosomes in a cell.

Aspiration biopsy

—The removal of cells in fluid or tissue from a mass or cyst using a needle for microscopic examination and diagnosis.

Benign

—Not malignant, noncancerous.

Biopsy

—A procedure in which suspicious tissue is removed and examined by a pathologist for cancer or other disease. For breast biopsies, the tissue may be obtained by open surgery, or through a needle.

Estrogen-receptor assay

—A test to see if a breast cancer needs estrogen to grow.

Hormones

—Chemicals produced by glands in the body which circulate in the blood and control the actions of cells and organs. Estrogens are hormones which affect breast cancer growth.

Hormone therapy

—Treating cancers by changing the hormone balance of the body, instead of by using cell-killing drugs.

Lumpectomy

—A surgical procedure in which only the cancerous tumor in the breast is removed, together with a rim of normal tissue.

Lymph nodes

—Small, bean-shaped masses of tissue scattered along the lymphatic system that act as filters and immune monitors, removing fluids, bacteria, or cancer cells that travel through the lymph system. Breast cancer cells in the lymph nodes under the arm or in the chest are a sign that the cancer has spread, and that it might recur.

Malignant

—Cancerous.

Mammography

—X-ray imaging of the breast that can often detect lesions in the tissue too small or too deep to be felt.

Oncogene

—A gene that has to do with regulation of cell growth. An abnormality can produce cancer.

QUESTIONS TO ASK THE DOCTOR

• Has my cancer spread?
• What is the stage of my cancer? What does that mean?
• What treatment choices do I have?
• What treatment do you recommend? Why?
• What are the advantages and disadvantages of this treatment?
• Will I lose my hair? If so, what can be done about it?
• What are the chances my cancer will come back after this treatment?
• What should I do to be ready for treatment?

Breast Cancer

Definition

Breast cancer is caused by the development of malignant cells in the breast. The malignant cells originate in the lining of the milk glands or ducts of the breast (ductal epithelium), defining this malignancy as a cancer. Cancer cells are characterized by uncontrolled division leading to abnormal growth and the ability of these cells to invade normal tissue locally or to spread throughout the body, in a process called metastasis.

Description

Breast cancer arises in the milk-producing glands of the breast tissue. Groups of glands in normal breast tissue are called lobules. The products of these glands are secreted into a ductal system that leads to the nipple. Depending on where in the glandular or ductal unit of the breast the cancer arises, it will develop certain characteristics that are used to sub-classify breast cancer into types. The pathologist will denote the subtype at the time of evaluation with the microscope. Ductal carcinoma begins in the ducts, lobular carcinoma has a pattern involving the lobules or glands. The more important classification is related to the evaluated tumor's capability to invade, as this characteristic defines the disease as a true cancer. The stage before invasive cancer is called in situ, meaning that the early malignancy has not yet become capable of invasion. Thus, ductal carcinoma in situ is considered a minimal breast cancer.

How breast cancer spreads

The primary tumor begins in the breast itself but once it becomes invasive, it may progress beyond the breast to the regional lymph nodes or travel (metastasize) to other organ systems in the body and become systemic in nature. Lymph is the clear, protein-rich fluid that bathes the cells throughout the body. Lymph will work its way back to the bloodstream via small channels known as lymphatics. Along the way, the lymph is filtered through cellular stations known as nodes, thus they are called lymph nodes. Nearly all organs in the body have a primary lymph node group filtering fluid that comes from that organ. In the breast, the primary lymph nodes are under the armpit, or axilla. Classically, the primary tumor begins in the breast and the first place to which it is likely to spread is the regional lymph nodes. Cancer, as it invades in its place of origin, may also work its way into blood vessels. If cancer gets into the blood vessels, the blood vessels provide yet another route for the cancer to spread to other organs of the body.

Breast cancer follows this classic progression though it often becomes systemic or widespread early in the course of the disease. By the time one can feel a lump in the breast it is often 0.4 inches, or one centimeter, in size and contains roughly a million cells. It is estimated that a tumor of this size may take one to five years to develop. During that time, the cancer may metastasize, or spread by lymphatics or blood to areas elsewhere in the body.

When primary breast cancer spreads, it may first go to the axillary nodes. If this occurs, regional metastasis exists. If it proceeds elsewhere either by lymphatic or blood-borne spread, the patient develops systemic metastasis that may involve a number of other organs in the body. Favorite sites of systemic involvement for breast cancer are the lung, bones, liver, and the skin and soft tissue. As it turns out, the presence of, and the actual number of, regional lymph nodes containing cancer remains the single best indicator of whether or not the cancer has become widely metastatic. Because tests to discover metastasis in other organs may not be sensitive enough to reveal minute deposits, the evaluation of the axilla for regional metastasis becomes very important in making treatment decisions for this disease.

If breast cancer spreads to other major organs of the body, its presence will compromise the function of those organs. Death is the result of extreme compromise of vital organ function.

KEY TERMS

Adjuvant therapy— Treatment involving radiation, chemotherapy (drug treatment), or hormone therapy, or a combination of all three given after the primary treatment for the possibility of residual microscopic disease.

Aneuploid— An abnormal number of chromosomes in a cell.

Aspiration biopsy— The removal of cells in fluid or tissue from a mass or cyst using a needle for microscopic examination and diagnosis.

Benign— Not malignant, noncancerous.

Biopsy— A procedure in which suspicious tissue is removed and examined by a pathologist for cancer or other disease. For breast biopsies, the tissue may be obtained by open surgery, or through a needle.

Estrogen-receptor assay— A test to see if a breast cancer needs estrogen to grow.

Hormones— Chemicals produced by glands in the body that circulate in the blood and control the actions of cells and organs. Estrogens are hormones that affect breast cancer growth.

Hormone therapy— Treating cancers by changing the hormone balance of the body, instead of by using cell-killing drugs.

Lumpectomy— A surgical procedure in which only the cancerous tumor in the breast is removed, together with a rim of normal tissue.

Lymph nodes— Small, bean-shaped masses of tissue scattered along the lymphatic system that act as filters and immune monitors, removing fluids, bacteria, or cancer cells that travel through the lymph system. Breast cancer cells in the lymph nodes under the arm or in the chest are a sign that the cancer has spread, and that it might recur.

Malignant— Cancerous.

Mammography— X-ray imaging of the breast that can often detect lesions in the tissue too small or too deep to be felt.

Oncogene— A gene that has to do with regulation of cancer growth. An abnormality can produce cancer.

Demographics

Every woman is at risk for breast cancer. If she lives to be 85, there is a one out of nine chance that she will develop the condition sometime during her life. As a woman ages, her risk of developing breast cancer rises dramatically regardless of her family history. The breast cancer risk of a 25-year-old woman is only one out of 19,608; by age 45, it is one in 93. In fact, less than 5% of cases are discovered before age 35 and the majority of all breast cancers are found in women over age 50.

In 2002, 200,000 new cases of breast cancer were diagnosed. About 45,000 women die of breast cancer each year, accounting for 16% of deaths caused by cancer in women. However, deaths from breast cancer are declining in recent years, a reflection of earlier diagnosis from screening mammograms and improving therapies.

Causes and symptoms

There are a number of risk factors for the development of breast cancer, including:

• family history of breast cancer in mother or sister
• early onset of menstruation and late menopause
• reproductive history: women who had no children or have children after age 30 and women who have never breastfed have increased risk
• history of abnormal breast biopsies

Though these are recognized risk factors, it is important to note that more than 70% of women who get breast cancer have no known risk factors. Having several risk factors may boost a woman's chances of developing breast cancer, but the interplay of predisposing factors is complex. In addition to those accepted factors listed above, some studies suggest that high-fat diets, obesity, or the use of alcohol may contribute to the risk profile. Another factor that contributes to a woman's risk profile is hormone replacement therapy (HRT).

HRT provides significant relief of menopausal symptoms, prevention of osteoporosis, and possibly protection from cardiovascular disease and stroke. While physicians have long known a small increased risk for breast cancer was linked to use of HRT, a landmark study released in 2003 proved the risk was greater than thought. The Women's Health Initiative found that even relatively short-term use of estrogen plus progestin is associated with increased risk of breast cancer, diagnosis at a more advanced stage of the disease, and a higher number of abnormal mammograms. The longer a woman used HRT, the more her risk increased.

Of all the risk factors listed above, family history is the most important. In The Biological Basis of Cancer, the authors estimate that about half of all familial breast cancer cases (families in which there is a high breast cancer frequency) have mutations affecting the genes BRCA-1 or BRCA-2. In 2003, scientists discovered a third gene called EMSY. However, breast cancer due to heredity is only a small proportion of breast cancer cases; only 5%-10% of all breast cancer cases will be women who inherited a susceptibility through their genes. Nevertheless, when the family history is strong for development of breast cancer, a woman's risk is increased.

Not all lumps detected in the breast are cancerous. Fibrocystic changes in the breast are extremely common. Also known as fibrocystic condition of the breast, fibrocystic changes are a leading cause of non-cancerous lumps in the breast. Fibrocystic changes also cause symptoms of pain, swelling, or discharge and may become evident to the patient or physician as a lump that is either solid or filled with fluid. Complete diagnostic evaluation of any significant breast abnormality is mandatory because though women commonly develop fibrocystic changes, breast cancer is common also, and the signs and symptoms of fibrocystic changes overlap with those of breast cancer. Certain benign changes in the breast may now be linked to increased risk for breast cancer.

Diagnosis

The diagnosis of breast cancer is accomplished by the biopsy of any suspicious lump or mammographic abnormality that has been identified. (A biopsy is the removal of tissue for examination by a pathologist. A mammogram is a low-dose, 2-view, x-ray examination of the breast.) The patient may be prompted to visit her doctor upon finding a lump in a breast, or she may have noticed skin dimpling, nipple retraction, or discharge from the nipple. A patient may not have noticed a symptom or abnormality, and a lump was detected by a screening mammogram.

When a patient has no signs or symptoms

Screening involves the evaluation of women who have no symptoms or signs of a breast problem. Mammography has been helpful in detecting breast cancer that cannot be identified on physical examination. However, 10%-13% of breast cancer does not show up on mammography, and a similar number of patients with breast cancer have an abnormal mammogram and a normal physical examination. These figures emphasize the need for examination as part of the screening process.

Screening

It is recommended that women get into the habit of doing monthly breast self examinations to detect any lump at an early stage. If an uncertainty or a lump is found, evaluation by an experienced physician and a mammogram is recommended. The American Cancer Society (ACS) has made recommendations for the use of mammography on a screening basis. In 2003, the ACS updated its guidelines concerning screening mammograms. The most notable change was that women should begin annual screening at age 40 instead of age 50. (in the past, the ACS, recommended beginning mammograms at age 40, but only ever one or two years instead of annually.) Women at higher risk for breast cancer should benefit from beginning screenings at earlier ages and at more frequent intervals.

Because of the greater awareness of breast cancer in recent years, screening evaluations by examinations and mammography are performed much more frequently than in the past. The result is that the number of breast cancers diagnosed increased, but the disease is being diagnosed at an earlier stage than previously. The earlier the stage of disease at the time it is discovered, the better the long-term outcome (prognosis) becomes.

When a patient has physical signs or symptoms

A common finding that leads to diagnosis is the presence of a lump within the breast. Skin dimpling, nipple retraction, or discharge from the nipple are less frequent initial findings prompting biopsy. Though bloody nipple discharge is distressing, it is most often caused by benign disease. Skin dimpling or nipple retraction in the presence of an underlying breast mass on examination is a more advanced finding. Actual skin involvement, with edema or ulceration of the skin, are late findings.

The presence of a breast lump is a common sign of breast cancer. If the lump is suspicious and the patient has not had a mammogram by this point, a study should be done on both breasts prior to anything else so that the original characteristics of the lesion can be studied. The opposite breast should also be evaluated mammographically to determine if other problems exist that were undetected by physical examination.

Whether an abnormal screening mammogram or one of the signs mentioned above followed by a mammogram prompted suspicion, the diagnosis is established by obtaining tissue by biopsy of the area. There are different types of biopsy, each utilized with its own indication. If signs of widespread metastasis are already present, biopsy of the metastasis itself may establish diagnosis.

Biopsy

Depending on the situation, different types of biopsy may be performed. The types include incisional and excisional biopsies. In an incisional biopsy, the physician takes a sample of tissue, and in excisional biopsy, the mass is removed. Fine needle aspiration biopsy and core needle biopsy are kinds of incisional biopsies.

FINE NEEDLE ASPIRATION BIOPSY. In a fine needle aspiration biopsy, a fine-gauge needle may be passed into the lesion and cells from the area suctioned into the needle can be quickly prepared for microscopic evaluation (cytology). (The patient experiencing nipple discharge also can have a sample taken of the discharge for cytological evaluation.) Fine needle aspiration is a simple procedure that can be done under local anesthesia, and will tell if the lesion is a fluid-filled cyst or whether it is solid. The sample obtained will yield much diagnostic information. Fine needle aspiration biopsy is an excellent technique when the lump is palpable and the physician can easily hit the target with the needle. If the lesion is a simple cyst, the fluid will be evacuated and the mass will disappear. If it is solid, the diagnosis may be obtained. Care must be taken, however, because if the mass is solid and the specimen is non-malignant, a complete removal of the lesion may be appropriate to be sure.

CORE NEEDLE BIOPSY. Core needle biopsies also are obtained simply under local anesthesia. The larger piece of tissue obtained with its preserved architecture may be helpful in confirming the diagnosis short of open surgical removal. An open surgical incisional biopsy is rarely needed for diagnosis because of the needle techniques. If there remains question as to diagnosis, a complete open surgical biopsy may be required.

EXCISIONAL BIOPSY. When performed, the excisional (complete removal) biopsy is a minimal outpatient procedure often done under local anesthesia.

NON-PALPABLE LESIONS. As screening increases, non-palpable lesions demonstrated only by mammography are becoming more common. The use of x rays and computers to guide the needle for biopsy or to place markers for the surgeon performing the excisional biopsy are commonly employed. Some benign lesions can be fully removed by multiple directed core biopsies. These techniques are very appealing because they are minimally invasive; however, the physician needs to be careful to obtain a good sample.

Other tests

If a lesion is not palpable and has simple cystic characteristics on mammography, ultrasound may be utilized both to determine that it is a cyst and to guide its evacuation. Ultrasound may also be used in some cases to guide fine needle or core biopsies of the breast.

Computed tomography (CT) scans have only rare in the evaluation of breast lesions. Magnetic resonance imaging (MRI) has been used more often in recent years to follow up on suspicious findings from mammograms or for certain patients.

Treatment

Staging

Once diagnosis is established and before treatment is rendered, more tests are done to determine if the cancer has spread beyond the breast. These tests include a chest x ray and blood count with liver function tests. Along with the liver function measured by the blood sample, the level of alkaline phosphatase, an enzyme from bone, is also determined. A radionuclear bone scan may be ordered. This test looks at the places in the body to which breast cancer usually metastasizes. A CT scan also may be ordered. The physician will do a careful examination of the axillae to assess likelihood of regional metastasis. Sometimes, the physician removed all of the axillary lymph nodes to assess breast cancer stage. However, recent studies show great success with sentinel lymph node biopsy. This technique removes the sentinel lymph node, or that lymph node that receives fluid drainage first from the area where the cancer is located. If this node is free of cancer, staging can be assigned accordingly. This method saves women the discomfort and side effects associated with removing additional lymph nodes in her armpit.

Using the results of these studies, clinical stage is defined for the patient. This helps define treatment protocol and prognosis. After surgical treatment, the final, or pathologic, stage is defined as the true axillary lymph node status is known. Detailed staging criteria are available from the American Joint Commission on Cancer Manual and are generalized here:

• Stage 1—The cancer is no larger than 2 cm (0.8 in) and no cancer cells are found in the lymph nodes.
• Stage 2—The cancer is between 2 cm and 5 cm, and the cancer has spread to the lymph nodes.
• Stage 3A—Tumor is larger than 5 cm (2 in) or is smaller than 5 cm, but has spread to the lymph nodes, which have grown into each other.
• Stage 3B—Cancer has spread to tissues near the breast, (local invasion), or to lymph nodes inside the chest wall, along the breastbone.
• Stage 4—Cancer has spread to skin and lymph nodes beyond the axilla or to other organs of the body.

Treatment

Surgery, radiation, and chemotherapy are all utilized in the treatment of breast cancer. Depending on the stage, they will be used in different combinations or sequences to effect an appropriate strategy for the type and stage of the disease being treated.

SURGERY. Historically, surgical removal of the entire breast and axillary contents along with the muscles down to the chest wall was performed as the lone therapy, (radical mastectomy ). In the last 25 years, as it has been appreciated that breast cancer often spreads early, surgery remains a primary option but other therapies have risen in importance. Recent studies have suggested that breast conserving treatment improves the quality of life.

Today, surgical treatment is best thought of as a combination of removal of the primary tumor and staging of the axillary lymph nodes. A modified radical mastectomy involves removing the whole breast along with the entire axillary contents but not the muscles of the chest wall.

If the tumor is less than 1.5 (4 cm) in size and located so that it can be removed without destroying the reasonable cosmetic appearance of the residual breast, just the primary tumor and a rim of normal tissue will be removed. The axillary nodes will still be removed for staging purposes, usually through a separate incision. Because of the risk of recurrence in the remaining breast tissue, radiation therapy is used to lessen the chance of local recurrence. This type of primary therapy is known as lumpectomy, (or segmental mastectomy), and axillary dissection.

Sentinel lymph node biopsy, a technique for identifying which nodes in the axilla drain the tumor, has been developed to provide selective sampling and further lessen the degree of surgical trauma the patient experiences.

When patients are selected appropriately based on the preoperative clinical stage, all of these surgical approaches have been shown to produce similar results. In planning primary surgical therapy, it is imperative that the operation is tailored to fit the clinical circumstance of the patient.

The pathologic stage is determined after surgical treatment absolutely defines the local parameters. In addition to stage, there are other tests that are very necessary to aid in decisions regarding treatment such as adjuvant therapies. Adjuvant therapies are treatments utilized after the primary treatment to help ensure that no microscopic disease exists and to help prolong patients' survival time.

RADIATION THERAPY. Like surgical therapy, radiation therapy is a local modality—it treats the tissue exposed to radiation and not the rest of the body. Radiation is usually given post-operatively after surgical wounds have healed. The pathologic stage of the primary tumor is now known and this aids in treatment planning. The extent of the local surgery also influences the planning. Radiation may not be needed at all after modified radical mastectomy for stage I disease, but is almost always utilized when breast-preserving surgery is performed. If the tumor was extensive or if multiple nodes were involved, the field of tissue exposed will vary accordingly. Radiation is utilized as an adjunct to surgical therapy and is considered important to gaining local control of the tumor. The use of radiation therapy does not affect decisions for adjuvant treatment. In the past, radiation was used as an alternative to surgery on occasion. However, now that breast-preserving surgical protocols have been developed, primary radiation treatment of the tumor is no longer performed. Radiation also has an important role in the treatment of the patient with disseminated disease, particularly if it involves the skeleton. Radiation therapy can affect pain control and prevention of fracture in this circumstance.

DRUG THERAPY. Many breast cancers, particularly those originating in post-menopausal women, are responsive to hormones. These cancers have receptors on their cells for estrogen and progesterone. Part of primary tumor assessment after removal of the tumor is the evaluation for the presence of these estrogen and progesterone receptors. If they are present on the cancer cells, altering the hormone status of the patient will inhibit tumor growth and have a positive impact on survival. The drug tamoxifen binds up these receptors on the cancer cells so that the hormones can't have an effect and, in so doing, inhibits tumor growth. If the patient has these receptors present, tamoxifen is commonly prescribed for five years as an adjunct to primary treatment. Adjuvant hormonal therapy with tamoxifen has few side effects but they have to be kept in mind, particularly the need for yearly evaluation of the uterus. Other agents directed at altering hormone environment are under study. Because of these agents, there is rarely any need for surgical removal of hormone-producing glands, such as the ovary or adrenal, that was sometimes necessary in the past.

In late 2003, cancer experts were beginning to recommend a new group of drugs called aromatase inhibitors (Arimidex, common name anastrozole, or more recently Femara and Novartis, common name letrozole). New guidelines also recommend letrozole following five years of tamoxifen therapy. These drugs fight breast cancer differently, but early research shows they fight it as effectively and with fewer side effects.

Shortly after the modified radical mastectomy replaced the radical mastectomy as primary surgical treatment, survival after local treatment in stage II breast cancer was improved by the addition of chemotherapy. Adjuvant chemotherapy for an interval of four to six months is now standard treatment for patients with stage II disease. The addition of systemic therapy to local treatment in patients who have no evidence of disease is performed on the basis that some patients have metastases that are not currently demonstrable because they are microscopic. By treating the whole patient early, before widespread disease is diagnosed, the adjuvant treatment improves survival rates from roughly 60% for stage II to about 75% at five years after treatment. The standard regimen of cytoxan, methotrexate, and 5-flourouracil, (CMF), is given for six months and is well tolerated. The regimen of cytoxan, adriamycin (doxorubicin), and 5-floururacil, (CAF), is a bit more toxic but only requires four months. (Adriamycin and cytoxin may also be used alone, without the fluorouracil.) The two methods are about equivalent in results. Adjuvant hormonal therapy may be added to the adjuvant chemotherapy as they work through different routes.

The encouraging results from adjuvant therapy in stage II disease have led to the study of similar therapy in stage I disease. The results are not as dramatic, but they are real. Currently, stage I disease is divided into categories a, b, and c on the basis of tumor size. Stage Ia is less than a centimeter in diameter. Adjuvant hormonal or chemotherapy is now commonly recommended for stage Ib and Ic patients. The toxicity of the treatment must be weighed individually for the patient as patients with stage I disease have a survivorship of over 80% without adjuvant chemotherapy.

If patients are diagnosed with stage IV disease or, in spite of treatment, progress to a state of widespread disease, systemic chemotherapy is utilized in a more aggressive fashion. In addition to the adriamycin-containing regimens, the taxols (docetaxel and paclitaxel) have been found to be effective in inducing remission.

On the basis of prognostic factors such as total number of involved nodes over 10, aneuploid DNA with a high synthesis value, or aggressive findings on microscopic evaluation, some patients with stage II or III disease can be predicted to do poorly. If their performance status allows, they can be considered for treatment with highly aggressive chemotherapy. The toxicity is such that bone marrow failure will result. To get around this anticipated side effect of the aggressive therapy, either the patients will be transplanted with their own stem cells, (the cells that will give rise to new marrow), or a traditional bone marrow transplantation will be required. This therapy can be a high-risk procedure for patients. It is given with known risk to patients predicted to do poorly and only if it is felt they can tolerate it. Most patients who receive this therapy receive it as part of a clinical trial. At present, it is unclear that such aggressive therapy can be justified.

For patients who are diagnosed with advanced local disease, surgery may be preceded with chemotherapy and radiation therapy. The disease locally regresses allowing traditional surgical treatment to those who could not receive it otherwise. Chemotherapy and sometimes radiation therapy will continue after the surgery. The regimens of this type are referred to as neo-adjuvant therapy. This has been proven to be effective in stage III disease. Neo-adjuvant therapy is now being studied in patients with large tumors that are stage II in an effort to be able to offer breast preservation to these patients.

A drug known as Herceptin (trastuzumab), a monoclonal antibody, is now being used in the treatment of those with systemic disease. The product of the Human Epidermal Growth Factor 2 gene, (HER-2) is overexpressed in 25%-30% of breast cancers. Herceptin binds to the HER-2 receptors on the cancer, resulting in the arrest of growth of these cells.

Prognosis

The prognosis for breast cancer depends on the type and stage of cancer. Over 80% of stage I patients are cured by current therapies. Stage II patients survive overall about 70% of the time, those with more extensive lymph nodal involvement doing worse than those with disease confined to the breast. About 40% of stage III patients survive five years, and about 20% of stage IV patients do so. In 2003, research showed that young women who choose breast-conserving surgery are at higher risk for local recurrence and should receive indefinite follow-up care from their physicians.

Prevention

The use of tamoxifen and other agents which alter the hormone status of the patient are under study. The National Surgical Adjuvant Breast and Bowel Project (NSABP) with support from the National Cancer Institute began a study in 1992 (called the Breast Cancer Prevention Trial, or BCPT) studying the use of tamoxifen as a breast cancer preventative for high-risk women. The results yielded from the study showed that tamoxifen significantly reduced breast cancer risk, and the U.S. Food and Drug Administration approved the use of tamoxifen to reduce breast cancer risk for high-risk patients in 1998. Another NSABP study, known as STAR, is seeking to understand if another drug, raloxifene, is as effective as tamoxifen in reducing breast cancer risk in high-risk patients. That study was begun in 1999, and participants were to be monitored for five years.

And, while most breast cancer can't be prevented, it can be diagnosed from a mammogram at an early stage when it is most treatable. The results of awareness and routine screening have allowed earlier diagnosis, which results in a better prognosis for those discovered.

Resources

BOOKS

Abelhoff, Armitage, Lichter, and Niederhuber. Clinical Oncology Library. Philadelphia: Churchill Livingstone 1999.

Schwartz, Spencer, Galloway, Shires, Daly, and Fischer. Principles of Surgery. New York: McGraw Hill, 1999.

PERIODICALS

"Early Detection Saves Lives." Women's Health Weekly (November 14, 2003): 13.

Esteva and Hortobagyi. "Adjuvant Systemic Therapy for Primary Breast Cancer." Surgical Clinics of North America 79, no. 5 (October 1999): 1075-1090.

"HRT Linked to Higher Breast Cancer Risk, Later Diagnosis, Abnormal Mammograms." Women's Health Weekly (July 17, 2003): 2.

Margolese, R. G., M. D. "Surgical Considerations For Invasive Breast Cancer." Surgical Clinics of North America 79, no. 5 (October 1999): 1031-1046.

Munster and Hudis. "Adjuvant Therapy for Resectable Breast Cancer." Hematology Oncology Clinics of North America 13, no. 2 (April 1999): 391-413.

"New Human Breast and Ovarian Cancer Gene Described." Biotech Week (December 31, 2003): 89.

Pennachio, Dorothy L. "Letrozole Improves Breast Cancer Outlook." Patient Care (December 2003): 4.

"Quality of Life Seems to be Better After Conservative Treatment of Breast Cancer." Women's Health Weekly (July 17, 2003): 22.

"Revised Guidelines Show Changes for Breast Cancer Treatment." Biotech Week (December 24, 2003): 296.

"Sentinel Lymph Node Biopsy is Accurate for Staging." Women's Health Weekly (June 5, 2003): 4.

Shuster, et al. "Multidisciplinary Care For Patients With Breast Cancer." Surgical Clinics of North America 80, no. 2 (April 2000): 505-533.

Smith, Robert A., et al. "American Cancer Society Guidelines for Breast Cancer Screening: Update 2003." Cancer (May-June 2003): 141.

ORGANIZATIONS

American Cancer Society. 1599 Clifton Road NE, Atlanta, GA 30329. (800)ACS-2345. 〈http://www.cancer.org〉.

Cancer Care, Inc. 275 Seventh Ave., New York, NY 10001.(800) 813-HOPE. 〈http://www.cancercare.org〉.

Cancer Information Service of the NCI. 9000 Rockville Pike, Building 31, Suite 10A18, Bethesda, MD 20892. 1-800-4-CANCER. 〈http://wwwicic.nci.nih.gov〉.

National Alliance of Breast Cancer Organizations. 9 East 37th St., 10th floor, New York, NY 10016. (888) 80-NABCO.

National Coalition for Cancer Survivorship. 1010 Wayne Ave., 5th Floor, Silver Spring, MD 20910. (301) 650-8868.

National Women's Health Resource Center. 120 Albany St., Suite 820, New Brunswick, NJ 08901. (877) 986-9472. 〈http://www.healthywomen.org〉.

OTHER

Breast Cancer Online. 〈http://www.bco.org/〉.

National Alliance of Breast Cancer Organizations. 〈http://www.nabco.org/〉.

National Cancer Institute. 〈http://rex.nci.nih.gov/PATIENTS/INFO_PEOPL_DOC.html〉.

Breast Cancer

Breast cancer remains the most common cause of cancer among women in the United States, and it results in more deaths from cancer among women than any other type of cancer, except lung cancer. Over 40,000 women die from breast cancer in the United States each year. A long history of research, now coupled with the new information emerging from the field of molecular genetics, is beginning to explain the basic steps leading to breast cancer, and it will enable the development of novel treatment and prevention strategies.

Almost all breast cancers begin in the glandular structures in the breast that, during lactation, produce milk. These mammary glands are under the control of reproductive hormones that stimulate the monthly cycle of gland expansion and shrinkage, which is a feature of the regular menstrual cycle. Many of the factors associated with the development of breast cancer appear to have their effect through interaction with the hormonal stimulation of these glands.

The risk of developing breast cancer increases throughout a woman's lifetime, and the disease is relatively rare in very young women. The overall association of breast cancer incidence with increasing age may be explained by a model of breast cancer in which a progressive and cumulative series of genetic changes within the cells of the glands is necessary for the initiation of cancer. The longer a woman lives, the more opportunities there are for these genetic changes to accumulate and reach a stage where cells can become cancerous.

One of the most consistent epidemiological observations is the association of reproductive events with risk of breast cancer. Women who have one or more full-term pregnancies have a lower risk for breast cancer, especially if they are pregnant before age twenty. Pregnancy at an early age may help to stabilize the mammary glands and make them less vulnerable to genetic changes later in life. The risk for breast cancer is also significantly decreased among women undergoing surgical removal of the ovaries, particularly if the surgery is performed before age thirty-five. This surgery removes the major source of reproductive hormones and therefore results in less stimulation of the glands in the breast.

Conversely, the greater number of years a woman has regular menstrual cycles, the higher the risk of breast cancer. There is also a modest increase in risk associated with postmenopausal estrogen replacement therapy (especially when used more than 15 years), and with exposure to the synthetic estrogen diethylstilbestrol during pregnancy. Studies have found a significant correlation between breast cancer and levels of hormones—estradiol, estrone, estrone sulfate, prolactin, and dehydroepiandrosterone sulfate. A drug used to treat breast cancer, tamoxifen, blocks estrogen receptors.

Taken together, a significant body of research shows that reproductive hormones—produced internally and taken as medicines—are major determinants of breast cancer risk. Other factors—including genetic predisposition, environmental exposure, and lifestyle choices—may increase cancer risk via hormone regulation.

There are striking racial and ethnic differences in breast cancer incidence and resulting deaths. Overall, rates are highest for Caucasian women and lowest for Native American and Korean women. The general international pattern of breast cancer incidence reveals higher rates for Western, industrialized nations, and lower rates for less industrialized and Asian countries. Even within the United States, there is significant geographic diversity in breast cancer rates, with mortality rates highest in the Northeast and lowest in the South. Much of this variation is thought to be due to regional differences in reproductive events, such as the age when women start having children and their use of hormone medications.

There is also considerable evidence from international comparisons, migration studies, and time trends to support an important role for dietary fat in the causation of breast cancer. However when the diets of specific population groups are followed over time, no definite causal link can be demonstrated. The data on fiber and vitamins and minerals is also contradictory. Dietary studies also show a fairly consistent but weak increase in breast cancer risk with moderate to heavy alcohol consumption. Alcohol may act by stimulating the production of more internal hormones. Among postmenopausal women, body weight has also been positively correlated with both breast cancer incidence and mortality. Although exposure to large amounts of radiation is associated with an increased risk for breast cancer, there does not appear to be any risk associated with routine diagnostic imaging, such as chest X rays and mammograms.

Finally, there is limited data to support a protective role for physical activity, both during leisure time and at work, in terms of breast cancer risk. The effect is most pronounced among premenopausal and younger postmenopausal women. The known association of vigorous physical activity with decreased circulating levels of ovarian hormones may explain this finding, which could have significant public health implications.

Women undergoing breast biopsies whose tissue shows no evidence of cancer, but whose cells have atypical features or faster-than-normal rates of growth have an increased risk of breast cancer, with risks up to eightfold higher in some cases. It is thought that these atypical cells may be a precursor to the development of breast cancer, or they may act as markers for genetic instability within the glandular cells.

Population studies have documented that a history of breast cancer in first-, second-, or third-degree relatives increases cancer risk between twofold and fourfold. Recently two genes, BRCA1 and BRCA2, have, when inherited in a mutated form, been associated with a hereditary form of breast cancer. This form is characterized by early age at onset (5 to 15 years earlier than noninherited cases), cancer in both breasts, and association in the family with tumors of other organs, particularly of the ovary in women and prostate gland in men. Among the normal functions of these genes are the control of the cell cycle and the maintenance of stability of the genes. Both genes are tumor suppressor genes whose proteins help both to control the cell cycle and to repair damaged DNA. Mutations interfere with this vital function, causing damaged cells to reproduce and become cancerous.

The frequency of mutations in BRCA1 in the general population has been estimated to be 1 in 800. Carrier rates are not distributed evenly, however, and mutations tend to concentrate in families with multiple cases of breast or ovarian cancer. Different ethnic groups have unique BRCA1 and BRCA2 mutations. Most notably, three specific mutations are common in Ashkenazic Jews. Additional founder mutations have been described in Sweden and Iceland.

Individuals who have inherited a mutated BRCA1-2 gene face an estimated 36 percent to 85 percent lifetime risk for breast cancer and an estimated 16 percent to 60 percent lifetime risk for ovarian cancer. Among female BRCA1 carriers who have already developed a primary breast cancer, estimates for a second breast cancer in the opposite breast are as high as 64 percent by age seventy. Men who test positive for a mutation in the BRCA2 gene also have a higher lifetime risk for breast cancer.

The identification and location of these breast cancer genes will now permit further investigation of the precise role they play in cancer progression and, specifically, how they interact with reproductive hormones.

see also Cancer; Cell Cycle; Colon Cancer; Oncogenes; Tumor Suppressor Genes.

Mary B. Daly

Bibliography

Brody, Larry, and Barbara Biesecker. "Breast Cancer Susceptibility Genes BRCA1 and BRCA2. " Medicine 77 (1998): 208-226.

Kelsey, Jennifer, and Leslie Bernstein. "Epidemiology and Prevention of Breast Cancer." Annual Review of Public Health 17 (1996): 47-67.

Weber, Barbara L. "Genetic Testing for Breast Cancer." Scientific American Science and Medicine 3, no. 1 (1996): 12-21.

MALE BREAST CANCER

According to the National Cancer Institute, male breast cancer is most common among males between 60 and 70 years of age. Two of the major risk factors for men include: exposure to radiation, and having a family history of breast cancer (especially the BRCA2 gene). The survival rate for men with breast cancer almost equals that for women.

BREAST CANCER

Breast cancer is the most common malignancy in American women, accounting for approximately 30 percent of their new cancer cases. It is the second leading cause of cancer death in women, following lung cancer. In the year 2000, it was estimated that there were more than 180,000 new cases of breast cancer diagnosed, and over 41,000 breast cancer deaths in the United States. Breast cancer incidence rates were steady through the 1990s, although the number of breast cancer deaths declined, decreasing an average of 1.8 percent per year between 1990 and 1996.

Breast cancer can be divided into invasive and noninvasive forms. Noninvasive breast cancer is almost always cured through local control measures (surgery and radiation therapy). Tamoxifen (a selective estrogen-receptor modulator), is used to reduce the risk of a local recurrence in patients treated with breast conservation. Early-stage invasive disease is limited to the breast and axillary lymph nodes, while metastatic disease includes tumors that have spread outside the breast and local lymph nodes. Early-stage invasive breast cancer is curable, although less so than noninvasive disease.

The first step in the management of early-stage breast cancer is surgical removal of the tumor. This can be accomplished by lumpectomy (removal of the tumor and a margin of surrounding normal breast tissue) or mastectomy (removal of the entire affected breast). Following lumpectomy, patients should receive radiation to the remaining breast tissue to decrease the risk of recurrence. Studies have shown that patients with small tumors who are treated with breast conservation therapy (lumpectomy and radiation) have equivalent survival rates to patients treated with mastectomy. Ipsilateral axillary lymph nodes are removed in order to determine whether the tumor has spread via the lymphatic drainage. Involvement of the ipsilateral lymph nodes is a marker for increased risk of later distant spread of the tumor.

Once the tumor is removed, the size of the tumor, hormonal status (estrogen and progesterone receptor), and lymph node involvement is considered in aggregate to determine the overall risk of distant spread of disease. Patients at high risk for recurrent disease can be given systemic therapy in order to decrease the odds of relapse. Systematic therapy circulates throughout the entire body in order to kill microscopic tumor cells. Conventionally this therapy can consist of chemotherapy, hormonal therapy (if the tumor is estrogen- or progesterone-receptor positive), or both. Chemotherapy is typically given to patients with invasive tumors greater than 1 centimeter in largest diameter or with involved (positive) lymph nodes. Patients with hormone receptor—positive tumors or tumors in which the receptor status is unknown benefit from treatment with tamoxifen for five years. Both of these interventions have been shown to decrease both the patient's annual risk of recurrence and the risk of mortality from breast cancer. Tamoxifen also decreases the risk of a second primary breast cancer in the preserved contralateral breast.

Breast cancer can metastasize to other organs in the body. Once breast cancer has been detected in distant sites, it is no longer curable. At that stage, the goal of the treatment is to prolong survival while maintaining quality of life. Patients with hormone receptor—positive tumors who are minimally symptomatic and who have predominantly bone disease can frequently be treated with hormonal therapy. This treatment is taken orally and is generally well tolerated. Patients who have hormone receptor—negative tumors, those who have failed hormone therapy, and those who have symptomatic or rapidly progressive disease are frequently treated with chemotherapy. The specific decisions regarding hormone therapy, chemotherapy, and supportive measures require skill, compassion, and a detailed understanding of the numerous treatment options.

Established risk factors for breast cancer include older age (women over fifty have a 6.5 times higher risk of developing breast cancer than younger women), a family history of breast cancer (especially the presence of a documented genetic abnormality), early age of menarche (less than 12 versus equal to or greater than 14), late age of menopause (equal to or greater than 55 versus less than 55), age at first live birth (greater than 30 versus less than 20), history of benign breast disease, and a history of hormone replacement use. Some studies also suggest an increased breast-cancer risk associated with increased alcohol and dietary fat intake, excess body weight, and limited exercise. Further studies are needed to establish the benefit of lifestyle modification in the prevention of breast cancer.

Randomized trials have shown the benefit of chemoprevention in reducing the risk of breast cancer for women at increased risk. The National Surgical Adjuvant Breast and Bowel Project Tamoxifen Prevention Trial (NSABP-1) evaluated the benefits of tamoxifen in the prevention of breast cancer. More than three thousand women at increased risk for breast cancer (defined as a five-year risk of breast cancer of 1.66 percent or more) were followed for approximately four years. Treatment with tamoxifen reduced the overall odds of developing both invasive and noninvasive breast cancer by approximately 50 percent. This decrease in breast cancer risk was seen across all age groups. Side effects of tamoxifen include hot flashes, an increased risk of thromboembolic events, and increased risk of endometrial cancer.

Newer antiestrogens, such as raloxifene, may have fewer side effects than tamoxifen. The MORE (Multiple Outcomes of Raloxifene Evaluation) trial was a trial of 7,705 postmenopausal women who received raloxifene for the treatment of osteoporosis. Raloxifene was found to reduce the risk of invasive breast cancer by 76 percent, with no increased risk of endometrial cancer. Raloxifene is being compared directly to tamoxifen for prevention in high-risk patients in the STAR (Study of Tamoxifen and Raloxifene) trial.

Clifford Hudis

Arti Hurria

(see also: Breast Cancer Screening; Breast Self-Examination; Cancer; Clinical Breast Examination; Gender and Health; Mammography; Tamoxifen )

Bibliography

Armstrong, K.; Eisen, A.; and Weber, B. (2000). "Assessing the Risk of Breast Cancer." New England Journal of Medicine 342:564–571.

Cummings, S. R.; Eckert, S.; Krueger, K. A. et al. (1999). "The Effect of Raloxifene on Risk of Breast Cancer in Postmenopausal Women: Results from the MORE Randomized Trial. Multiple Outcomes of Raloxifene Evaluation." Journal of American Medical Association 281:2189–2197. (Published erratum appears in Journal of American Medical Association 282:2124.)

Early Breast Cancer Trialists' Collaborative Group (1998). "Tamoxifen for Early Breast Cancer: An Overview of the Randomized Trials." Lancet 351: 1451–1467.

Fisher, B.; Constantino, J. P.; Wickerman, D. L.; et al. (1998). "Tamoxifen for Prevention of Breast Cancer: Report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study." Journal of the National Cancer Institute 90:1371–1388.

Fisher, B.; Redmond, C.; Poisson, P. et al. (1989). "Eight-Year Results of a Randomized Clinical Trial Comparing Total Mastectomy and Lumpectomy With or Without Irradiation in the Treatment of Breast Cancer." New England Journal of Medicine 320:822–828.

Greenlee, R. T.; Murray, T.; Bolden, S.; and Wingo, P. A. (2000). "Cancer Statistics, 2000." CA Cancer J Clin 50:7–33.

breast cancercancer that originates in the breast. Breast cancer is the second leading cause of cancer death in women (following lung cancer ). Even allowing for improvements in detection (i.e., the introduction of routine mammography), there has been a long-term gradual increase in the incidence of breast cancer since the early 1970s, but because of the more effective treatment afforded by such early detection, overall mortality began to decrease by the mid-1990s. Breast cancers can arise in the lobes or lobules (lobular carcinoma) or in the ducts (ductal carcinoma) of the breast. Lobular carcinoma often affects both breasts.

Causes

Epidemiological study has identified certain risk factors that increase the possibility that a woman will get breast cancer, although not all women with breast cancer have these traits, and many women with all of these traits do not develop the disease. Risk factors include age (the incidence of breast cancer is rare in women under 35—most cases occur in women over 60); a history of breast cancer in a close blood relative; and a history of breast cancer or benign proliferative breast disease. A high cumulative exposure to female sex hormones (estrogen and progesterone) appears to increase the risk of some breast cancers. Hormonally related risk factors include early menarch (before age 12), late menopause (after age 55), having no children or postponing childbirth, and obesity in women over 50.

Many other possible associations are under study, such as those relating to postmenopausal estrogen replacement, alcohol and fat consumption, lack of exercise, and exposure to pesticides and other environmental chemicals. A 2002 report on the association of estrogen replacement therapy with an increased risk of breast cancer led to a large drop in prescriptions for the drugs used in such therapy; a coincident drop in the incidence of breast cancer tumors, especially estrogen-positive tumors, which apparently could not be accounted for by other causes, strongly suggested a link between the two. Tumors in women of African descent are known to be particularly aggressive.

Like all cancers, breast cancers result from changes in the structure or function of genes that are key to the regulation of cellular growth, differentiation, or repair. Acquired changes in a number of specific genes have been associated with the disease; these are changes that occur during a person's lifetime but are not inherited or passed on. About 5% of women with breast cancer have an inherited susceptibility to the disease, and most of these women have an inherited mutation in one of two genes. In 1994 it was discovered that women who inherit a mutated BRCA1 gene have an almost 85% chance of developing breast cancer and an increased chance of developing uterine cancer. BRCA1 normally acts to prevent tumors by repairing damage to the genetic material caused by oxidation, a chemical process that in the body occurs naturally during metabolism. Defective BRCA1 genes cannot repair this damage, allowing its effects to accumulate over time. Cells with oxidative damage to the genes that control their growth can proliferate, or become cancerous. The defective gene can be inherited from either parent, but appears to cause breast cancer only in women. Young women who get breast cancer often come from families that carry a BRCA1 mutation. BRCA1 mutations account for about half of known hereditary breast cancers. Another gene, named BRCA2, has also been identified. BRCA2 mutations have been associated with both female and rare male breast cancers. The two genes may also play a role in some ovarian cancers and sporadic (nonhereditary) breast cancer cases.

Early Detection and Prevention

Monthly breast self-examination and regular mammography are the recommended methods of breast cancer early detection. The first sign of breast cancer may be a lump in the breast; a thickening, swelling, or dimpling; skin irritation or scaliness; pain; or a discharge or tenderness of the nipple. A biopsy can rule out or confirm a malignancy. Tamoxifen can prevent breast cancer in women considered at high risk of developing the disease.

Treatment

In most cases, treatment for breast cancer begins with surgical excision of the tumor. Modern treatment attempts to preserve as much tissue as possible for both functional and cosmetic reasons. This may mean a lumpectomy (simple excision of only the cancerous tumor) or mastectomy (excision of part or all of the breast tissue, sometimes with adjacent muscle). The lymph nodes under the arm are often excised in a procedure known as an axillary dissection if a sentinel node (one of the first nodes to filter fluid from the portion of the breast with the cancer) shows evidence of cancer. In some cases, chemotherapy and external beam radiation therapy or radioactive isotopes implanted directly into the area of the cancer, are used in addition to or instead of surgery. Hormone therapy in the form of ovary removal or drugs such as tamoxifen and selective estrogen receptor modulators or anastrozole and other aromatase inhibitors may be used to slow the growth of or prevent recurrence of hormonally sensitive tumors; tamoxifen is also used to control the growth of metastatic breast cancer. Bone marrow transplantation is sometimes used when bone marrow that has been destroyed by large doses of chemotherapy or radiation therapy needs to be replaced.

Many women who have had a mastectomy decide to have breast reconstruction surgery. This reconstruction is done with breast implants or the patient's own tissue. Due to the controversy over silicone implants, saline-filled implants were used from 1992 to 1998, but either type may be used now. Women who have had an axillary dissection often experience chronic, progressive pain, numbness, and weakness in the affected arm. Lymphedema, painful swelling of the arm, can occur after node dissection or radiation treatment of the lymph nodes. Following surgery, chemotherapy, and radiation, women who had estrogen-sensitive tumors are given tamoxifen or, if they are postmenopausal, anastrozole or another aromatase inihibitor to help prevent a recurrence.

Bibliography

See Y. Hirshaut and P. I. Pressman, Breast Cancer: The Complete Guide (3d ed. 2000). See also publications of the National Cancer Institute, the American Cancer Society, the National Breast Cancer Association, and the National Lymphedema Network.

BREAST CANCER

DEFINITION

Breast cancer is cancer of the breast. Cancer (see cancer entry) is a disease in which cells begin to grow rapidly and out of control. Cancer cells can travel through the body by way of blood or lymph nodes. They can then come to rest and start growing in other parts of the body.

DESCRIPTION

Every woman is at risk for breast cancer. The risk varies with age. At age twenty-five, a woman's risk is about 1 in 20,000. At age forty-five, it is 1 in about 100. At age eighty-five, it is more than 1 in 10. About 80 percent of all breast cancers are found in women over the age of fifty.

CAUSES

Researchers do not know how normal cells suddenly become cancerous. Thus, the fundamental cause or causes of breast cancer are still a puzzle. Scientists do know that certain risk factors are related to the development of breast cancer. These factors include:

• Family history of breast cancer occurring in mother or sister.
• Early onset (beginning) of menstruation and late menopause. Menopause is the end of menstruation.
• Reproductive history. Women who have no children or have children late in life have increased risk. Women who have never breast-fed also have increased risk.
• History of abnormal breast biopsies. A biopsy is a medical procedure in which a small sample of tissue is removed for study under a microscope.

The acknowledged risk factors are of limited value, however. More than 70 percent of women who develop breast cancer have no known risk factors.

Breast Cancer: Words to Know

Benign:

Not harmful or cancerous.

Biopsy:

A medical procedure in which a small sample of tissue is removed so that it can be studied under a microscope.

Lumpectomy:

A procedure in which the cancerous lump is removed from the breast.

Mammogram:

An X-ray photograph of the breast.

Mastectomy:

Surgical removal of a breast.

Menopause:

The end of menstruation.

Metastasis:

The process by which cancer cells spread to other parts of the body.

Radical mastectomy:

Surgical removal of an entire breast along with the chest muscles around the breast and all the lymph nodes under the arm.

Reconstructive surgery:

A medical procedure in which an artificial breast is created to replace the breast removed during a mastectomy.

Systemic treatment:

A form of treatment that affects the whole body.

Tamoxifen:

A naturally occurring substance that has shown promise in preventing the return of breast cancer.

SYMPTOMS

The primary method of discovering the symptoms of breast cancer is self-examination. Doctors recommend that women learn how to properly examine their breasts and to do so on a regular basis. The purpose is to look for any changes in the breasts. One warning sign of breast cancer may be a lump in the breast or armpit area. The presence of a lump suggests that medical advice should be sought. A lump does not necessarily indicate breast cancer. In many cases, lumps are benign (not cancerous) and can be removed without any lasting harm to the patient.

Other symptoms that may be detected during a self-examination include:

• Thickening in the breast or armpit
• Change in the size, shape, or color of a nipple
• Dimples or redness of the skin on the breast
• Change in size or shape of the breast

DIAGNOSIS

The primary medical tool in diagnosing breast cancer is a mammogram. A mammogram is an X-ray photograph of the breast. The American Cancer Society currently recommends that women between the ages of forty and fifty have a mammogram every year or two. The society suggests a yearly mammogram for women over the age of fifty.

The purpose of a mammogram is to find any lumps or other changes in the breast. If such changes are found, additional tests may be necessary. One test is a breast biopsy. The tissue removed during a biopsy can be studied under a microscope, which allows a doctor to determine whether cells in the sample are cancerous or not.

If cancer is found, tests can also be used to determine if the cancer has metastasized (pronounced muh-TASS-tuh-sized). Metastasis (pronounced muh-TASS-tuh-sis) is the process by which cancer cells spread to other parts of the body. Testing for metastasis involves removal of lymph nodes from the armpit. The presence of cancer cells in the lymph nodes suggests that the cancer has begun to spread.

TREATMENT

The treatment used for breast cancer depends on how serious a patient's condition is. Under the best circumstances, the cancer is found at an early stage. It may consist of nothing more than a small lump in the breast. In other cases, it may have developed into a larger lump or begun to metastasize.

The simplest treatment is a lumpectomy, a procedure in which the cancerous lump is removed from the breast. The surgeon also removes some tissue around the lump and some of the lymph nodes under the arm. Removing healthy tissue around the lump ensures that all of the cancer has been removed. Removing the lymph nodes allows the doctor to test for metastasis.

A more serious form of treatment is a mastectomy (pronounced mas-TEK-tuh-mee). A mastectomy may be required if a lump has become quite large or the cancer has spread to the chest muscles. In a mastectomy, the patient's entire breast is removed. In the most extreme conditions, the surgeon may also remove the chest muscles around the breast and all the lymph nodes under the arm. This procedure is called a radical mastectomy. Radical mastectomies are rarely done.

Some women also choose to have reconstructive surgery. In reconstructive surgery, an artificial breast is created to replace the breast removed during a mastectomy. The artificial breast may provide a women with a better sense of self-esteem by restoring her natural shape.

If cancer cells are found in the lymph nodes, more aggressive treatment may be necessary. The presence of these cells suggests that the cancer has begun to spread to other parts of the body. Additional treatments are then needed to kill cancer cells in all parts of the body. Such forms of treatment are known as systemic (for "system") treatments.

Three common forms of systemic treatment include radiation, chemotherapy, and hormone therapy. In radiation treatments, some form of radiation is used to kill any remaining cancer cells in the breast or other parts of the body. The radiation used is similar to X rays, but much more powerful.

Chemotherapy involves the use of certain chemicals known to kill cancer cells. These chemicals are given to the patient either by injection or by mouth. They travel through the body and kill cancer cells wherever they are found. Both radiation and chemotherapy have some serious side effects, including nausea and vomiting, temporary hair loss, mouth or vaginal sores, fatigue, and infertility.

Hormone therapy is a special type of chemotherapy. In one form, it makes use of a natural product known as tamoxifen (pronounced tuh-MOK-sih-fen) to kill cancer cells. Patients take one pill a day for at least two years and sometimes as long as five. Studies show that the use of tamoxifen can lower the chance that breast cancer can return by between 25 and 35 percent.

PROGNOSIS

Survival rates for breast cancer depend very much on the type of cancer found and how early it was diagnosed. In general, cancers that are found earlier are more likely to be treated successfully. Patients who have surgery often return to a normal lifestyle within about a month. Exercises help patients regain strength and flexibility of the arms, shoulders, and chest.

Patients who receive treatment for breast cancer often experience emotional problems. They may become moody or depressed, lose their appetite, or feel unworthy or uninterested in sexual activities. Support groups are available to help women get through the most difficult period after diagnosis and treatment. Support groups consist of other individuals who have experienced the same medical problem and, sometimes, professional counselors.

PREVENTION

There is no way to prevent breast cancer. The best way to deal with the disease is to perform regular self-examinations and have regular mammograms. For women who have had breast cancer, tamoxifen treatments appear to be a promising factor in preventing reoccurrence of the disease.

FOR MORE INFORMATION

Books

Hirshaut, Yashar, and Peter Pressman. Breast Cancer: The Complete Handbook. New York: Bantam Books, 1996.

Kneece, Judy C. Finding a Lump in Your Breast: Where to Go, What to Do. Columbia, SC: Educate Publishing, 1996.

Lauersen, Niels, and Eileen Stukane. The Complete Book of Breast Care. New York: Fawcett Columbine, 1996

Love, Susan, and Karen Lindsey. Dr. Susan Love's Breast Book. Reading, MA: Addison-Wesley, 1995.

Mayer, Musa. Holding Tight, Letting Go: Living with Metastatic Breast Cancer. Sebastopol, CA: O'Reilly & Associates, 1997.

Porter, Margit Esser. Hope Is Contagious: The Breast Cancer Treatment Survival Handbook. New York: Simon & Schuster, 1997.

Stoppard, Miriam. The Breast Book. New York: DK Publishing, 1996.

Periodicals

"Early Detection: The Best Defense." Family Circle (October 31, 1992): p. 107.

Fackelmann, Kathy. "Refiguring the Odds." Science News (July 31, 1993): pp. 76–77.

Organizations

American Cancer Society. 1599 Clifton Road NE, Atlanta, GA 30329. (800) ACS–2345. http://www.cancer.org.

Cancer Care, Inc. 1180 Avenue of the Americas. New York, NY 10036. (800) 813–HOPE. http://www.cancercareinc.org.

National Alliance of Breast Cancer Organizations. 9 East 37th Street, 10th Floor, New York, NY 10016. (888) 80–NABCO.

National Cancer Institute. 31 Center Drive, Bethesda, MD 20892–2580. (800) 4–CANCER. http://www.nci.nih.gov.

National Coalition for Cancer Survivorship. 1010 Wayne Avenue, 5th Floor, Silver Springs, MD 20910. (301) 650–8868.

National Women's Health Resource Center. 2425 L Street NW, 3rd Floor, Washington, DC 20037. (202) 293–6045.

Web sites

Community Breast Health Project at Stanford. [Online] http://www.med.Stanford.EDU:80/CBHP (accessed on October 18, 1999).

Breast Cancer

How Does Breast Cancer Start?

Who Gets Breast Cancer?

What Happens When Women Have Breast Cancer?

Can Breast Cancer Be Prevented?

Will There Ever Be a Way of Preventing Breast Cancer?

What Is It Like to Live with Breast Cancer?

Resources

Breast cancer is a potentially dangerous tumor that develops in the cells of the breast. Cancer cells sometimes spread from the breast to other parts of the body.

KEYWORDS

for searching the Internet and other reference sources

Mammography

Oncology

Tamoxifen

In the United States, breast cancer is a very common cancer among women, second only to skin cancer. Breast cancer also occurs in men, but much more rarely. Deaths from breast cancer have been reduced in recent years because more effective treatments are now available, and because these cancers are found earlier when they are easier to treat.

How Does Breast Cancer Start?

Humans are mammals, and all mammals have breasts, which are the organs that make milk to feed babies. In the breast are lobules (LOB-yools) that look like bunches of grapes. Channels, or ducts, from the lobules enable milk to flow to the nipple. The lobules and ducts are surrounded by fatty tissue and ligaments called stroma (STRO-ma).

Cancer in Situ

Breast cancer begins when a single cell in a duct or lobule undergoes changes (mutations) that cause it to start growing out of control. At first, even though the cells are growing very rapidly, they stay within the duct or lobule. At this stage the cancer is called cancer in situ. Later, the cells may break out of the duct or lobule into the fat and surrounding tissue, where they continue to divide and multiply. Since a tumor needs nourishment to grow, it sends out signals in the form of proteins that cause new blood vessels to form and support it. Without a blood supply, a tumor will die.

Metastasis

Cancer cells may enter the bloodstream, where they may be killed by the immune system (the body’s defense against disease). If they are not killed by the immune system, the cancer cells may travel to distant organs of the body, settle there, grow, and divide. This process of spread is called metastasis (me-TAS-ta-sis).

Breast cancer cells are most likely to find their way to the lungs, liver, and bones. Cancer is named for the place where it starts. So even when breast cancer travels to the lungs or the bones, it is still called breast cancer.

Who Gets Breast Cancer?

No one knows yet exactly what causes breast cancer to start. It is impossible to catch it from another person.

Can teenagers get breast cancer?

Breast cancer in teenagers is very rare. A girl whose breasts are developing may feel some discomfort from time to time. And once her periods start, she may retain water during the last part of her cycle, which can cause her breasts to ache. But these pains are a normal part of the body’s functioning. They are not a sign of cancer.

BRCA1, BRCA2, and estrogen

Women who inherit some mutated genes from their parents are at higher risk of getting breast cancer. These genes, called BRCA1 and BRCA2, are involved in only a small fraction of breast cancer cases. Researchers suspect that natural substances called hormones, especially the female hormone estrogen, play a role in promoting some types of breast cancer.

Women, Breast Cancer, and Mammograms

• All women are at risk for breast cancer. Over 60 percent of U.S. women diagnosed with breast cancer do not have a family history of the disease.
• Currently, breast cancer occurs in one out of every eight U.S. women.
• The early detection of breast cancer by mammograms increases the chance of successful treatment.
• Some doctors believe that every woman should have her first mammogram by age 35. This first mammogram should be saved as a baseline for comparison with future mammograms.
• Women between the ages of 40 and 50 should have a mammogram every one to two years.
• Women over the age of 50 should have a mammogram every year.

Family history

A woman whose mother, sister, or daughter has had breast cancer has twice the risk of getting it as a woman with no family history of breast cancer. However, most women diagnosed with breast cancer do not (to their knowledge) have a family history of breast cancer. A woman who has already had breast cancer in one breast is at higher risk of getting it in the other breast.

Age

Age is also a risk factor. Older women have a higher risk of developing breast cancer. Another risk factor is early age for first menstrual period as well as late age for menopause. Women who have their first child after the age of 30, or who do not have any children, also have a higher risk.

Diet and life Style

Rates of breast cancer vary around the world, and it appears these differences are related to diet or life style. For example, women in Asia have only one fifth to one tenth the risk of getting breast cancer as women in North America or Western Europe. But when Asian women move to Western countries, their risk increases to the same level as the local population. The reasons why are not clear.

What Happens When Women Have Breast Cancer?

Signs and symptoms

Usually, a woman will notice a painless lump in her breast. Or her doctor may feel the lump during a routine examination. The shape, color, or texture of the breast or nipple may change or the nipple may be tender or have a discharge. Sometimes cancers are found before symptoms occur. In these cases, routine or “screening” mammography (mam-MOG-ra-fee) (x-ray examination of the breasts) shows changes that indicate a possibility of cancer, which must be checked.

Men and Breast Cancer

• About 1 percent of all cases of breast cancer occur in men.
• A family history of breast cancer is a risk factor for men as well as for women.
• Breast cancer in men is often not detected until the cancer is advanced and more difficult to treat.
• Breast cancer in men usually shows up as a lump beneath the breast area, fixation of skin to the lump, and discharge from the nipple.
• Treatment usually involves surgical removal of the lump, followed by chemotherapy or radiation therapy.
• Treatment and cure rates for men are similar to those for women.

Diagnosis

If screening tests or a woman’s symptoms suggest cancer, the doctor may request a biopsy (BY-op-see). In this procedure, a small amount of tissue is removed from the abnormal area of the breast and examined under a microscope. Most biopsies show that the woman does not have cancer. If the tissue is benign (be-NINE) (not cancer), no further treatment may be needed. But if the diagnosis is cancer, then the woman will want to learn about the disease and discuss her options for treatment with health professionals, her friends, and family.

Treatment

For tumors that do not appear to have spread, it may be possible to remove only the tumor and leave most of the breast. This is called a lumpectomy (lump-EK-to-mee). Sometimes, however, it may be necessary to perform a mastectomy (mas-TEK-to-mee), an operation that removes the breast. Whether mastectomy or lumpectomy is the best choice depends on the size and sometimes the kind of tumor.

Follow-up treatment may include radiation therapy and anti-cancer medication, called chemotherapy (kee-mo-THER-a-pee), to kill any remaining cancer cells and to prevent them from growing back. The choice of follow-up treatment depends on the kind of tumor and

3,000 Years of Breast Cancer Research and Treatment

A description of “bulging tumors” being burned or cut out of the breast can be found in the Edwin Smith papyrus from Thebes, dated 1600 B.C.E.

Ancient Greek women sought help from Aesculapius (es-ku-LA-peus), their mythical god of healing. Aesculapian temples were filled with offerings, including carvings of excised tumorous breasts. The women hoped their gifts would prompt an explanation of their disease or convey thanks to the god for his healing power.

The Greek physician Hippocrates (c. 460-c. 375 B.C.E.) emphasized the importance of diet and the environment for the management of breast cancer. During the second century, the Roman physician Galen (130-200 A.D.) focused his research on a theory that excess black bile caused cancer, and that treatment required that the bile be removed by means of bloodletting.

The bloodletting technique prevailed until the 1500s, when medieval doctors began returning to surgical treatment of breast cancer.

whether it appears to have spread to the lymph nodes* or other parts of the body.

* lymph nodes

are bean-sized round or oval masses of immune system tissue that filter bodily fluids before they enter the bloodstream, helping to keep out bacteria and other undesirable substances.

Can Breast Cancer Be Prevented?

There is no sure way to prevent breast cancer. It may be possible for women to reduce their risk of breast cancer by not drinking too much alcohol, by eating a healthy diet, and by getting regular exercise. Because detecting cancer early improves the chance of treating it with a better outcome, or even curing it, women 40 and older should have a screening mammogram and a physical exam to check their breasts every year. Women aged 20 to 39 should have a breast exam every three years. And all women aged 20 and older should learn how to examine their own breasts and check them once a month.

Will There Ever Be a Way of Preventing Breast Cancer?

Because chemotherapy kills healthy cells as well as cancer cells, research efforts in the area of drug treatment are concentrating on drugs that do less damage to healthy cells than current treatments. Researchers also are studying how best to use the information from genetic tests for breast cancer genes to help a woman lower her risk of getting breast cancer.

Support groups

For women with breast cancer, talking to other women who are living with the disease can be a very comforting experience. For women whose breast cancer has come back or spread, it may even do more than that. One study showed that women with metastatic breast cancer who participated in support groups lived an average of almost two years longer than women who did not.

Women who have just been diagnosed with breast cancer also may find it helpful to meet and to talk to women who had breast cancer 10 or 15 years earlier and who are now living happy, healthy lives.

The American Cancer Society and the National Alliance of Breast Cancer Organizations provide information about finding support groups.

Tamoxifen research

An effective treatment for many women with breast cancer is a drug called tamoxifen. This drug works against the hormones that stimulate the cells in the breast to grow and are believed to be a factor in many breast cancers. Tamoxifen is so effective that it

Imaging the Body: Wilhelm Konrad RÖntgen

In 1895, the German physics professor Wilhelm Konrad Röntgen (1845-1923) discovered a new kind of ray that he found mysterious enough to call “X.” Röntgen’s “x-rays” (later called “roentgen rays”) were an alternative to light that made it possible to see structures within the body. Among the first photographs Röntgen took were of the bones in his wife’s hand.

Today, Röntgen’s invention is used to take pictures of many parts of the body, including the breast, making early detection of breast cancer possible and saving or extending the lives of millions of women around the world. Röntgen was awarded the Nobel Prize in physics in 1901.

X-ray mammograms are far from perfect. They miss some cancers, and they return uncertain results in some healthy women, causing them to undergo the anxiety and discomfort of biopsies to rule out cancer. Scientists are continuing research efforts to improve breast imaging.

was approved in the late 1990s for use by women who do not have breast cancer but who are at a high risk of getting it. Researchers are investigating similar drugs that do not have the side effects of tamoxifen and might be safe enough for healthy women at lower risk to use as a way of preventing breast cancer.

What Is It Like to Live with Breast Cancer?

Treatment for breast cancer can be very unpleasant. Mastectomy is emotionally difficult, and some women, about 1 in 10, may get serious swelling in their arms as a result of the surgery. As with almost any kind of cancer, a person must learn to live with the fear that the cancer might return. Side effects of chemotherapy may make it impossible for a young woman with breast cancer to have children. Many women lose their hair temporarily. If the cancer has spread, it becomes important to recognize, plan for, and cope with the prospect of dying. And because breasts are a part of the body that we consider very personal and that a woman associates with many things she cherishes, including love and children, she may worry that the people closest to her see her differently. Many women who have had mastectomies are able to have breast reconstructive surgery, which can restore a more normal appearance following breast removal. Many women with breast cancer find support groups very helpful in dealing with the stresses of the illness. It is important for patients, friends, and family to remember that people are much more than the sum of their body parts. No one is to blame for cancer. Love and understanding may help to make even the most difficult situation bearable.

See also

Cancer

Tumor

Resources

Books

Love, Susan M. Dr. Susan Love’s Breast Book, second edition. Reading, Massachusetts: Addison-Wesley, 1995.

Tomlinson, Theresa. Dancing through the Shadows. London: DorlingKindersly, 1997.

Organizations

U.S. National Cancer Institute, Bethesda, MD 20892. The NCI coordinates the government s cancer research program, and provides information about cancer to patients, their families, and the public. Its fact sheet What You Need to Know About Breast Cancer is posted at its website. Telephone 800-4-CANCER http://www.nci.nih.gov/wyntk_pubs/index.html

American Cancer Society (ACS), 1599 Clifton Road NE, Atlanta, GA 30329-4251. ACS is a national, not-for-profit society whose purpose is to provide unbiased, accurate, up-to-date health information about cancer. Telephone 800-ACS-2345 http://www.cancer.org

National Alliance of Breast Cancer Organizations (NABCO). NABCO’s newsletter NABCO News publishes information about breast cancer research, and its website helps people find local support groups. Telephone 888-806-2226 http://www.nabco.org

Y-Me National Breast Cancer Hotline, 212 West Van Buren, Chicago, IL 60607. A national organization that offers information and support to anyone who has been touched by breast cancer. Telephone 800-221-2141 http://www.y-me.org

University of Pennsylvania Cancer Center. The OncoLink website at the University of Pennsylvania posts information about all aspects of cancer. http://www.cancer.med.upenn.edu

breast cancer n. a malignant tumour of the breast, usually a carcinoma, rarely a sarcoma. It is unusual in men but is the commonest form of cancer in women, in some cases involving both breasts.
www.breastcancercare.org.uk Website of the charity Breast Cancer Care