Breast Cancer

2006-Jul-20
by JACK DANIELS

Definition Breast cancer
Breast cancer is caused (See Causes of Breast Cancer) by the development of malignant cells in the breast. The malignant cells often originate in the lining of the milk glands or ducts of the breast (ductal epithelium). 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 of Breast cancer
Breast cancer often 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.

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 can result from compromise of these vital organs' functions.

Demographics of Breast cancer
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 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. 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 probably 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 and 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.

Diagnosis of Breast cancer
The diagnosis of breast cancer is accomplished through biopsy of a 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. The 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 of Breast cancer
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 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) 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.

Breast cancer stages
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, some or all of these nodes may be removed at the time of surgical treatment. 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 of Breast cancer
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.

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 4 cm (1.5 in) 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 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 be 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 only treats the exposed tissue. 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 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.

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) as an alternative to tamoxifen. 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, 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 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 CMF, or cytoxan, methotrexate, and fluorouracil, is given for six months and is well tolerated. The regimen of cytoxan, adriamycin (doxorubicin), and fluorouracil, (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 certain prognostic factors, some patients with stage II or III disease can be predicted to do poorly. If their performance status allows, they may 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.

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 do 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.

Breast cancer treatment
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.

Prevention of Breast Cancer
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.