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In This Report

•	Highlights
•	Introduction
•	Risk Factors
•	Lifestyle Changes
•	Symptoms
•	Diagnosis
•	Prognosis
•	Treatment
•	Surgery
•	Radiation
•	Medications
•	Chemotherapy
•	Hormone Therapy
•	Resources
•	References

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Breast Cancer

Highlights

Drug Approvals

• Letrozole (Femara), an aromatase inhibitor, is now approved for extended use in postmenopausal women with early breast cancer who have received five years of tamoxifen therapy.
• Gemcitabine (Gemzar) has been approved for combination use with paclitaxel (Taxol) as a first-line treatment for metastatic breast cancer.
• Abraxane, a new form of paclitaxel, has been approved for treatment-resistant metastatic breast cancer or relapse within six months of post-surgical chemotherapy with an anthracycline cancer drug.

Investigative Drugs

• Trastuzumab (Herceptin) showed outstanding results in Phase III clinical trials for treatment of early-stage breast cancer. Results released in 2005 indicated that trastumuzab plus standard chemotherapy significantly improved disease-free survival for women with lymph-node positive cancer. Trastumuzab targets the HER-2 protein and is currently approved for treatment of advanced breast cancer.
• Bevacizumab (Avastin), in combination with paclitaxel (Taxol), is showing promise for prolonging progression-free survival in women with metastatic breast cancer. Bevacizumab targets the vascular endothelial growth factor (VEGF).

Risk Factor Research

• Breast cancer is more common among Jewish women of Eastern European (Ashkenazi) descent. Mutations in the BRCA1 and BRCA2 genes have been identified as genetic factors for this population. New research suggests that the variations in the estrogen receptor genes ESR1 and ESR2 may also increase breast cancer susceptibility in Ashkenazi women.
• Although African-American women have lower overall rates of breast cancer, they represent the highest proportion of women who are diagnosed with the disease before age 45. Sub-Saharan African women also tend to get breast cancer at a younger age, which may indicate a genetic component. The tumor suppressor gene p53 is being investigated as a possible gene candidate.
• Breast cancer is rare in men, but an increasing number of men are being diagnosed with the disease.

Introduction

Breast cancers are potentially life-threatening malignancies that develop in one or both breasts. The structure of the female breast is important in understanding this cancer:

• The interior of the female breast consists mostly of fatty and fibrous connective tissues.
• It is divided into about 20 sections called lobes.
• Each lobe is further subdivided into a collection of lobules, which are structures that contain small milk-producing glands.
• These glands secrete milk into a complex system of tiny ducts. The ducts carry the milk through the breast and converge in a collecting chamber located just below the nipple.
• Breast cancer is either noninvasive (generally known as in situ, that is, confined to the site of origin) or invasive (spreading).

The female breast is either of two mammary glands (organs of milk secretion) on the chest.

Noninvasive Breast Cancer

Noninvasive breast cancers include the following:

• Ductal carcinoma in situ (also called intraductal carcinoma or DCIS). DCIS consist of cancer cells in the lining of the duct. DCIS is a non-invasive, early cancer, but if left untreated, it may sometimes progress to an invasive, infiltrating ductal breast cancer.
• Lobular carcinoma in situ, or LCIS. Although noninvasive, lobular carcinoma in situ is a marker for an increased risk of invasive cancer in both breasts. (Some experts prefer to call this condition lobular neoplasia rather than refer to it as a cancer.) According to a 2001 report, for patients with LCIS the risk for developing invasive cancer in the same breast is about 18% and in the other breast is 14% after 20 years. These invasive cancers can either be lobular or ductal.

At the time of diagnosis of these early cancers (i.e., DCIS and LCIS), there is no evidence of invasion.

Invasive Breast Cancer

Invasive cancer occurs when cancer cells spread beyond the basement membrane, which covers the underlying connective tissue in the breast. This tissue is rich in blood vessels and lymphatic channels that are capable of carrying cancer cells beyond the breast. Invasive breast cancers include the following:

• Infiltrating ductal carcinoma. This is invasive breast cancer that penetrates the wall of a duct. It comprises between 70% and 80% of all breast cancer cases.
• Infiltrating lobular carcinoma. This invasive cancer has spread through the wall of a lobule. It accounts for between 10% and 15% of all breast cancers. It may sometimes appear in both breasts, sometimes in several separate locations.

Click the icon to see an image of the breast.

There are other less common breast cancers that are not discussed in this report.

Risk Factors

Experts estimate that about 211,240 new cases of invasive female breast cancer will be diagnosed in the United States in 2005. About 1,690 breast cancer cases will be diagnosed in men during the year. Although breast cancer in men is rare, the incidence has been increasing and men are diagnosed at a later stage than women. An estimated 40,410 women and 460 men will die from breast cancer in 2005. The earlier breast cancer is diagnosed, the earlier the opportunity for treatment. According to the American Cancer Society, over 2 million women who have been treated for breast cancer are alive today.

At this time, age is a major identifiable risk factor. More than 80% of breast cancer cases occur in women over 50. The odds by age are as follows:

• Cancer in women younger than 30 is very rare, accounting for only 1.5% of all breast cancer cases.
• At age 40, a woman's chances for breast cancer are one in 217.
• At age 50, they are one in 50.
• If a woman lives to be 85, the odds of her having breast cancer are one in eight.

Ethnicity and Race

Breast cancer is more prevalent among Jewish women of Eastern European (Ashkenazi) descent. In terms of race, African American women tend to get breast cancer at an earlier age than Caucasians. Although African American women have lower overall rates of breast cancer, they represent the highest proportion of women who are diagnosed with the disease before age 45 years. Comparative studies of breast cancer rates among sub-Saharan Africans suggest a genetic component, as African women are diagnosed most frequently between age 35 and 45 years.

The mortality rate in African Americans is twice that of Caucasians, although it is declining. Social and economic factors make it less likely that African American women will be screened, so they are more likely to be diagnosed at a later stage. They are also less likely to have access to effective treatments. When they do have equal treatment, outcomes are the same as in Caucasian patients.

Inherited Genetic Factors and Family History

An estimated 10% of all women with breast cancer have a very strong family history of the disease, which often appears in young women under the age of 50. In such families, some members may also have developed ovarian cancer as well.

Prior to menopause, a mass on the ovary that is smaller than 2 centimeters is probably a follicle cyst that will go away on its own. However, if the growth is larger and doesn't go away over the course of a few menstrual cycles, then it may need to be removed.

Certain known genes predispose women to this cancer are as follows:

BRCA Genes. Inherited mutations in genes known as BRCA1 or BRCA2 are now believed to be responsible for 30% to 50% of hereditary breast cancers, ovarian cancers, or both in families with a history of these cancers. According to some studies, the risk each carries appears to be as follows:

• Between 25% and 35% of BRCA1 carriers will develop breast cancer by age 70.
• Between 35% and 50% of BRCA2 carriers develop the disease. BRCA2 genes may confer an increased risk of breast cancer in men as well as in women (which is extremely low).

These mutations can be passed down to the daughter by either the mother or the father.

These mutations are present in only about 0.5% of the U.S. or U.K. population overall but occur in about 2.5% of all Jewish women of Eastern European (Ashkenazi) descent. This prevalence in a relatively large population makes mutations to BRCA1 and BRCA2 the most common serious genetic disease known in any population group. These mutations are not restricted to the Ashkenazi population and may occur in women of any ethnicity, including women of Asian and African descent. It should be noted, however, that these mutations still account for a minority of breast cancer cases overall -- only 7% of all breast cancer cases in Eastern European Jewish women, and far fewer in the general population.

ESR Genes. Genetic variations in estrogen receptor genes (ESRs) may increase the risk for some women but offer protection to others. Mutations in the ESR1 and ESR2 genes may be associated with breast cancer susceptibility for Ashkenazi women over age 50 years.

Other Genetic Factors. Mutations in the tumor suppressor gene p53 are more common in the breast cancer tumors of African-American women than Caucasian women. Researchers have also identified other defective genes that contribute to breast cancer, such as NOEY2 (which is inherited from the father) and a mutant gene for the rare disorder ataxia-telangiectasia. (The disease itself is rare, but 1% of the population carries a single copy which is enough to increase the risk for breast cancer.) Finally, Cowden's syndrome is an inherited disorder caused by a defective PTEN gene that is associated with a higher risk of breast cancer.

Over-Exposure to Estrogen

Because growth of breast tissue is highly sensitive to estrogens, the more a woman is exposed to estrogen over her lifetime, the higher the risk for breast cancer.

Role of Estrogen Metabolism. A 2000 study suggested that the chance of estrogen increasing breast cancer risk in premenopausal women is related to how it is metabolized. In some women, very powerful estrogen products, or metabolites, are generated when metabolism takes place at a site on the estrogen molecule called C-16. These metabolites appear to pose a higher risk for breast cancer. (This metabolic effect does not appear to occur in postmenopausal women.) Fortunately, the study suggests that healthy diet and exercise may be able to alter this process.

Timing of Estrogen Exposure. Women's risk for breast cancer appears to be greater at specific times of estrogen exposure. For example, there is some evidence that starting one's period at an early age may be protective, in spite of the fact that this indicates a longer lifetime duration of estrogen exposure. Higher exposure in the womb (perhaps suggested by high birth weight), during pregnancy, or at menopause, however, does appear to increase risk.

Pregnancy and Abortion. Over the long term, women who have given birth even once have a lower risk than those who have not given birth. (Additional births do not seem to have any added impact.) It should be noted that there may be a higher risk for breast cancer in the immediate years after birth, particularly in older women.

Although a few studies have suggested a slightly increased risk for breast cancer in women who have had abortions, the weight of evidence does not support an association between abortion and breast cancer. However, interrupting a pregnancy does reduce the protective features of a full-term pregnancy.

Oral Contraception. Studies have been conflicting about whether estrogen in oral contraception increases the chances for breast cancer. A 2002 study supported an earlier major study, with both finding no evidence that OC use increases the risk for breast cancer, even in women who have taken them for 15 years of more or had taken them at young ages. In contrast, other studies have reported a higher risk in women who are current or recent users and in women who take them for more than four years before a first full-term pregnancy. Still, the risk for women taking OCs around menopause (ages 45 to 64) is unclear. Earlier research found a higher risk in women who used earlier forms of the pill containing high-dose estrogens and progestins (before 1975) and who had a family history of breast cancer.

Hormone Replacement Therapy. A number of studies have now reported a higher risk for breast cancer in postmenopausal women taking hormone replacement therapy (HRT), particularly with prolonged use and with formulations containing both estrogen and progestin. (Progestin has been more strongly implicated in the risk for breast cancer than estrogen.) Prolonged use increases the risk. A major study on HRT was stopped because of a slightly higher risk for breast cancer, although it should be noted the absolute risk is still quite small. There was no effect on mortality rates from breast cancer in HRT users. There has been some evidence to suggest that breast cancer in HRT users may have a more favorable outlook, including a lower recurrence rate, than nonusers. Breast tissue density increases with HRT, making mammograms more difficult to read.

Breast Abnormalities

Abnormalities or Breast Conditions Suggesting a Higher Risk. Some breast formations or abnormalities should be watched and include the following:

• Dense breast tissue is associated with a higher risk for breast cancer. Studies suggest that in women with highly dense tissue have two to six times the risk of women with the least dense tissue. Genetic factors play a large role in breast density. Hormone replacement therapy also increases breast density.
• Benign proliferative breast disease or atypical cell growth, known as atypical hyperplasia, is a significant risk factor for breast cancer.

Benign Breast Conditions. Benign breast conditions are much more commonly seen on mammograms than cancer. And in the great majority of cases they pose no risk. Some common benign breast abnormalities that pose few or no risks include the following:

• Cysts. These mostly occur in women in their middle to late reproductive years and can be eliminated simply by aspirating fluid from them.

Click the icon to see an image of cysts in the breast.

• Fibroadenoma. These are solid benign lumps that occur in women between the ages of 15 and 30.
• Breast abscesses during breastfeeding.

Click the icon to see an image of a breast abscess.

• Nipple discharge. Discharge from the nipple is worrisome to patients, but is unlikely to be a sign of cancer. Unexplained discharge still warrants evaluation, however.

Click the icon to see an image of nipple discharge.

• Mastalgia. This is breast pain that occurs in association with or independently from the menstrual cycle. About 8% to 10% of women experience moderate to severe breast pain associated with their menstrual cycle. In general, breast pain does not need assessment unless it is severe and prolonged.

Physical Characteristics

The following physical characteristics have been associated with greater or lesser risk:

• A number of studies have linked obesity to breast cancer after (but not before) menopause. The risk appears to be greater in women who began to gain weight after age 18. One study, in fact, suggested that being heavier as a child conferred a lower risk for breast cancer after menopause. (Estrogen levels are lower in the presence of high fat levels in premenopausal women.)
• Estrogen is involved in building bone mass. Therefore, women with heavy, dense bones are likely to have higher estrogen levels and be at greater risk for breast cancer.
• Some studies have found a greater risk for breast cancer in taller women, possibly due to the higher estrogen levels associated with greater bone growth. In one study, regardless of their actual height, women who reached their full height at 13 or younger had a higher risk than those who attained maximum height at age 18, reflecting higher estrogen levels at an earlier age.

Environmental Factors

Exposure to Estrogen-like Industrial Chemicals. Chemicals with estrogen-like effects, called xenoestrogens, have been under suspicion for years. There has been particular concern with pesticides containing organochlorines (e.g., DDT and its metabolites, such as dieldrin) and pyrethroids (e.g., permethrin), but at this time evidence of any causal association is very weak.

Exposure to Diethylstilbestrol (DES). Women who took diethylstilbestrol (DES) to prevent miscarriage have a slightly increased risk for breast cancer. To date, this risk has not been seen in their daughters (commonly called "DES daughters"), who were exposed to the drug when their mothers took it during pregnancy.

Radiation Exposure. Heavy exposure to radiation is a significant risk factor for breast cancer. Children receiving high-dose radiation therapy face an increased risk for breast cancer in adulthood.

Viruses

Researchers theorize that viruses may be involved in some types of breast cancers. A study of breast cancer samples taken from Tunisian women in North Africa found similarities with a virus known to cause breast cancer in mice. The samples were compared with those taken from women living in other global regions. The researchers suggested that a human breast cancer virus may be more prevalent in specific parts of the world.

Insulin-Like Growth Factor

Insulin-like growth factor 1 is an important growth hormone during development in the womb and childhood. It has powerful properties that increase cell proliferation, and high concentrations have now been linked to cancers, including premenopausal breast cancer. In fact, it may be one of the factors that are responsible for the association between height and breast cancer. More research is needed to verify a possible role of insulin-like growth factor 1 in breast cancer development.

Lifestyle Changes

A number of studies have suggested that regular exercise, particularly if it is vigorous, offers some modest protection against breast cancer by modulating estrogen. (Exercise may also be helpful for women with early stage breast cancer by improving physical function and blunting some of the negative effects of treatments, notably fatigue.)

Physical activity contributes to health by reducing the heart rate, decreasing the risk for cardiovascular disease, and reducing the amount of bone loss that is associated with age and osteoporosis. Physical activity also helps the body use calories more efficiently, thereby helping in weight loss and maintenance. It can increase basal metabolic rate, reduces appetite, and helps in the reduction of body fat.

Dietary Factors

Much research has targeted the role of diet in breast cancer, either as a risk factor or as a factor for patients already diagnosed with cancer.

Fats. Although some studies have found an association between high-fat intake and breast cancer, the most recent data suggest that fat from any source (vegetable oils or animal products) plays an insignificant role in increasing the risk for breast cancer. According to some other studies, in fact, monounsaturated fats (found in olive, peanut, and canola oils) may even be protective. Of some note, a 2003 study reported that young girls who modestly lowered their fat intake also changed their balance of estrogen and other sex hormones to one that theoretically could protect them against breast cancer.

Vitamins and Chemicals in Fruits and Vegetables. Many fresh fruits and vegetables contain chemicals that may be cancer fighters. Experts are investigating whether any specific vitamins, nutrients, or teams of them may be specifically valuable. Examples include the following:

• Isothiocyanates stimulate enzymes that convert estrogen to a more benign form and may block steroid hormones that promote breast and prostate cancers. They are found in broccoli, cabbage, Brussels sprouts, cauliflower, collards, kale, kohlrabi, mustard greens, rutabaga, turnips, and bok choy.

Click the icon to see an image of prostate cancer.

• Polyphenols, found in apples, onions, and green tea, may be beneficial, although this is controversial. (Chemicals in green tea in particular have been studied for cancer-fighting effects in breast cancer.)
• Lycopene, found in tomatoes may have cancer-fighting properties.

Click the icon to see an image of phytochemicals.

• There is some evidence that foods containing folate (folic acid) may be protective. It is found in avocado, bananas, orange juice, asparagus, fruits, green leafy vegetables, dried beans and peas, and yeast. It is also added to commercial grain products.

Click the icon to see an image of folate sources.

• Low levels of vitamin D may increase breast cancer risk, especially in older women. Vitamin D is activated by sunlight and obtained from fortified milk.

Click the icon to see an image of vitamin D sources.

• Foods high in vitamin C have also been associated with a lower risk (although there is not evidence of protection from any vitamin supplements, including C or E).

Click the icon to see an image of vitamin C sources.

Estrogen-like compounds (called phytoestrogens) require a special discussion. Such compounds are found in soybeans, black cohosh (an herb), whole wheat, berries, and flaxseed. Results are mixed.

Dairy Products and Other Protein Foods. Studies suggest that dairy products may also play a protective role in premenopausal women. If this is eventually verified, it is not clear if protection comes from calcium and vitamin D in these foods or if there are others factors involved. Women who increase their intake should choose low- or no-fat dairy products.

A 1999 study also reported that women with breast cancer who had a high intake of protein from both poultry and dairy products had a better outlook than those with a lower intake of these foods. In this study, red meat appeared to have no effect one way or the other. Other studies, however, have found a higher risk of breast cancer in women who consume higher quantities of flame-broiled meats, particularly women who are sensitive to chemicals released during the process. Fish may offer some protection.

Iron. Animal studies have linked a higher incidence of breast cancer with iron-rich diets, and in humans, high iron stores have been associated with a higher risk for breast cancer. Estrogen appears to increase iron levels in cells, and iron produces oxidants (damaging particles) that are associated with cancer. More research is needed to confirm these findings, however.

Avoiding Alcohol

A number of studies have now reported a higher risk for breast cancer with alcohol consumption. A well-conducted 2003 analysis of many of these studies suggested that for every daily drink there was a 7.1% increase in breast cancer. By age 80, women who consumed two drinks a day, have a 10% risk for developing breast cancer. The experts in the study suggested that based on these findings about 4% of breast cancer cases in developed nations may be attributed to alcohol. (Women who drink and who take hormone replacement therapy compound this risk.) Some research indicates that alcohol in such amounts increases levels of growth factors that can stimulate breast cancer cells. It should be noted, that light to moderate drinking has benefits for the heart that most likely outweigh the cancer risk in most women who have no other risk factors for breast cancer or alcohol abuse. (Folic acid may help reduce the risk for breast cancer among women who regularly drink alcohol. More research is needed.)

Breastfeeding

Several studies have reported that breastfeeding is associated with a lower risk for cancer in premenopausal women, and two 1999 studies suggest that some protective effect from breastfeeding may last beyond menopause. Some studies also indicate that the longer the mother breastfeeds the better. In fact, some experts believe the high rates of breast cancer in developed countries may be partly due to a lack of or shorter duration of breastfeeding.

Specific Preventive Measures for High-Risk Women

Lifestyle Factors. Premenopausal women at elevated risk, usually because of family history, should take as many preventive measures as possible, starting at an early age. The following life-style choices may be beneficial (although this is an area subject to change as more information becomes available):

Exercising and eating healthily is the first essential rule.

• High-risk premenopausal women may choose alternatives to oral contraceptives and, if feasible, consider having children early in their life.
• High-risk postmenopausal women may want to forego hormone replacement therapy.
• Any woman at high risk for breast cancer might consider avoiding alcohol or drinking it sparingly.

In spite of some rumors published in the popular press, antiperspirants or use of deodorants after shaving have not been linked with any higher risk for breast cancer.

Tamoxifen and Other SERMs. Drugs known as selective estrogen-receptor modulators (SERMs) act like estrogen in some tissues but behave like estrogen blockers (antiestrogens) in others. Tamoxifen, the most studied of these, is currently used treat breast cancer and is the only drug to date approved for prevention. In spite of some negative European studies, most evidence now strongly suggests that it reduces the risk for estrogen-receptor positive cancers by nearly half in high-risk women, including those with BRCA2 mutations (although possibly not BRCA1). It also helps prevent recurrence in women who have been treated for breast cancers. (It has no protective effects against estrogen-receptor negative cancers.)

Raloxifene, another SERM, is also proving to be protective against breast cancer and osteoporosis and has a lower risk than tamoxifen of causing uterine cancer. As with tamoxifen, it increases the risk for blood clots and hot flashes. A major comparison study is underway to compare raloxifene with tamoxifen.

Unfortunately, it is not clear how long SERMs should be taken or if even they actually save lives. Research is needed to resolve these issues. Although tamoxifen protects postmenopausal women from osteoporosis, it poses a risk for serious adverse effects, notably blood clots and uterine cancer. This makes it a better choice for younger women who have a lower risk for these complications than older women. None of these agents is recommended for any woman who is not at high risk for breast cancer or its recurrence. Meanwhile, high-risk women should discuss all the risks and benefits of SERMs with their physician.

Investigative Agents. The following investigative drugs are showing promise as preventive agents:

• Aromatase inhibitors are proving to be effective treatments for hormone-receptor positive breast cancer. Like tamoxifen, they are also being investigated for protection in high-risk women.
• Retinoids. Analogues of vitamin A called retinoids are being studied for protection against breast cancer. One retinoid, fenretinide, appears to offer some protection against a second breast cancer in previously diagnosed, premenopausal women (but not in postmenopausal women, who in fact may do worse).

Prophylactic Mastectomies and Oophorectomies. Studies suggest that preventive breast removal (called prophylactic mastectomy) reduces the risk of breast cancer by about 90% in women who harbor the BRCA genetic mutations. In one study, only three women who chose mastectomies developed breast cancer, whereas 40 would ordinarily have been expected to develop the disease. Shutting down estrogen production with preventive oophorectomy (ovary removal) is proving to be an effective alternative in reducing the risk of breast cancer in women in the BRCA genes.

Click the icon to see an image of the uterus and ovaries.

Still, the decision is not easy. Having the genes does not mean that cancer will always occur, meaning that mastectomy might not be necessary in all such women. Furthermore, even after mastectomy, some precancerous cells may persist that can activate the disease later on. Nevertheless, in one 2000 study, 70% of women were satisfied with their decision to have prophylactic breast removal. Women should discuss all options with their physician, including oophorectomy and close monitoring. The use of other options such as tamoxifen is described below.

Symptoms

Breast cancers in their early stages usually are painless. Often the first symptom is the discovery of a hard lump. Fifty percent of such masses are found in the upper outer quarter of the breast. The lump may make the affected breast appear elevated or asymmetric. The nipple may be retracted or scaly. Sometimes the skin of the breast is dimpled like the skin of an orange. In some cases there is a bloody or clear discharge from the nipple. Many cancers, however, produce no symptoms and cannot be felt on examination; they can be detected only with the use of a mammogram.

Monthly breast self-exams should always include: visual inspection (with and without a mirror) to note any changes in contour or texture; and manual inspection in standing and reclining positions to note any unusual lumps or thicknesses.

Diagnosis

Breast Examination by a Health Professional. Early detection of breast cancer significantly reduces the risk of death. Every woman between the ages of 20 and 49 should have a physical examination by a health professional every one to two years. Those over 50 should be examined annually. A breast exam by a health professional can find 10% to 25% of breast cancers that are missed by mammograms. Between 6% to 46% of the lumps detected by examination are malignant. (The yield is lowest in younger women and highest in older women.)

Self-Examinations. Woman have been encouraged to perform a self-examination each month, but well-conducted studies in 2002 reported no difference in mortality rates between women who were intensively instructed in self-examination and those who were not. For one, they are difficult to perform and women are often not very proficient. Most women also stop doing them. This does not mean women should stop attempting self-examinations, but they should not replace the annual examination done by a health professional, which evidence suggests is beneficial.

Monthly breast self-exams should always include: visual inspection (with and without a mirror) to note any changes in contour or texture; and manual inspection in standing and reclining positions to note any unusual lumps or thicknesses.

Click the icon to see an image of a breast self-exam.

Mammograms

Current Recommendations for Screening. Mammograms are very effective low-radiation screening methods for breast cancer. At this time, the U.S. Preventive Services Task Force recommends screening mammograms, with or without breast examination every one to two years for all women over 40.After age 50 screening should be annual. (Women over 65 account for most new cases of breast cancer.) Women with risk factors for breast cancer, including a close family member with the disease, should consider having annual mammograms starting 10 years earlier than the age at which the relative was diagnosed. (Uninsured women or those who have not been referred to a mammogram center can contact their local American Cancer Society for available low-cost programs.)

Click the icon to see an image of a mammogram.

Issues Involved with Screening. Mammograms are not foolproof, however. In general, they still miss up to 25% of cancers (which can sometimes be caught on a physical examination). And, furthermore, between 80% and 90% of suspicious mammograms turn out to be benign. According to one study, by the time a woman has nine mammograms, she has a 43% chance of having a false-positive mammogram (one that suggests cancer that isn't really there). This means many women are requiring biopsies who do not have cancer (but the only way to be sure is to perform the biopsy). Digital mammography is a recent technique that converts the image of the breast so it can be viewed and manipulated on a computer screen. It is improving accuracy but no screening technique is perfect yet.

Even given current recommendations, there are a number of issues as to who should screen and when to screen.

For Women between Ages 50 and 60. Evidence suggests that annual mammograms save lives in this age group. Furthermore, according to one study, because regular screening tends to find cancers in earlier stages there has also been a decline in the number of mastectomies (surgical removal of the breast).

For Women between Ages 40 and 49. Whether premenopausal women should have routine mammograms is controversial. The areas of debate are as follows:

• Arguments against Regular Screening. A number of studies have now reported that any survival benefits from regular mammography in this group are likely to be small compared to breast examinations alone. Most of the arguments against mammography in this population are due its inefficiencies in this age group. The probability that woman in this age group with a suspicious mammogram will actually have breast cancer is only 2% to 4%; so frequent screening becomes very cost-inefficient and produces many unnecessary biopsies. In addition, breast tissue is dense in premenopausal women and mammography often fails to detect breast cancers that are present. Breast cancers in this age group are also often aggressive and two-year intervals may not detect them early enough to affect survival.
• Arguments for Regular Screening. Breast cancer fatality rates are highest in women between ages 40 and 49. And in spite of some negative studies, recent ones are finding some survival benefits for screening every one or two years. Advances in imaging techniques are helping to improve accuracy.

For Women Over 69. Most breast cancers appear in women over 70 and such women are more likely to be diagnosed at a later stage, most often because of less frequent screenings. Still, experts disagree about the benefits of regular screening in older women. Some evidence suggests that regular screening would prevent only about one death per 1,000 women screened. Elderly women are also particularly likely to have non-malignant abnormalities in their breasts and so undergo unnecessary biopsies.

Other Imaging Techniques

Magnetic Resonance Imaging (MRI) and Ultrasound. MRI and ultrasound techniques can detect very small tumors (less than half an inch). However, they are expensive and are time-consuming procedures. Nevertheless, some experts believe they are important in identifying small tumors missed on mammography in women who are receiving lumpectomy or breast-conserving surgeries. Such findings would allow the surgeons to remove the optimal amount of abnormal tissue. Ultrasound may also be particularly important for women with dense breast tissue who show signs of breast cancer.

Scintimammography. Scintimammography employs a radioactive chemical injected into the circulatory system, which is then selectively taken up by the tumor and revealed on mammograms. This method is very accurate in detecting the presence or absence of breast cancer, and some experts hope that it might eventually reduce the number of unnecessary invasive biopsies.

Biopsy

A definitive diagnosis of breast cancer can be made only by a biopsy (a microscopic examination of a tissue sample of the suspicious area).

• When a lump can be felt and is suspicious for cancer on mammography, an excisional biopsy may be recommended. This biopsy is a surgical procedure for removing the suspicious tissue and typically requires general anesthetic.

Click the icon to see an image of breast biopsy.

• A core biopsy involves a small incision and the insertion of a spring-loaded hollow needle that removes a number of samples. The patient only requires local anesthetic.
• A wire localization biopsy may be performed if mammography detects abnormalities but there is no lump. With this procedure, using mammography as a guide, the physician inserts a small wire hook through a hollow needle and into the suspicious tissue. The needle is withdrawn and the hook is used by the surgeon to locate the lesion and to remove it. The patient may be given local or general anesthetic.
• A new vacuum-assisted device may be useful for some biopsies. This employs a single probe through which a vacuum is used to draw out tissue. It allows several samples to be taken without having to remove and re-insert the probe.

Final analysis of the breast tissue may take several days.

Lymphadenectomy

If breast cancer has been determined, the next diagnostic step is to find out how far it has spread. To do this, the physician performs a procedure called an axillary lymphadenectomy, which partially or completely removes the lymph nodes in the armpit beside the affected breast (called axillary lymph nodes). It may require a hospital stay of a day or two.

Click the icon to see an image of the axillary lymph nodes..

Once the lymph nodes are removed, they are analyzed to determine whether subsequent treatment needs to be more or less aggressive:

• If no cancer is found in the lymph nodes, then the condition is referred to as node negative breast cancer. The chances are good, then, that the cancer has not spread and is still local.
• If cancer cells are present in the lymph nodes, the cancer is called node positive. Their presence increases the possibility that the cancer has spread microscopically to other areas of the body. In such cases, however, it is still not known if the cancer has metastasized beyond the lymph nodes or, if so, to what extent. The physician may then perform further tests to see if the cancer has spread to the bone (bone scan), lungs (x-ray or CT scan) or brain (MRI or CT scan).

Side effects of the procedure include increased risk for infection and pain, swelling in the arm from fluid build-up, and impaired sensation and restricted movement in the affected arm. Patients might ask their physician about the availability of physical therapy or upper-body exercises after treatment. In two studies, such programs resulted in quicker recovery and no fluid build-up in the arm.

Sentinel Node Biopsy

A technique known as a sentinel node biopsy is increasingly performed by experienced surgeons in selected patients. This procedure is used to determine if cancer has spread beyond the nodes and so possibly reduce the need for complete axillary lymphadenectomies.

Click the icon to see an image of a sentinel node biopsy.

It involves the following:

• The procedure uses an injection of a tiny amount of a tracer, either a radioactively-labeled substance (radioisotope) or a blue dye, into the tumor site.
• The tracer or dye then flows via the lymphatic system into the so-called sentinel node. This is the first lymph node to which any cancer would spread.
• The sentinel lymph node and possibly one or two others are then removed.
• If they do not show any signs of cancer, it is highly likely that the remainder of the lymph nodes will be cancer free, and further surgery becomes unnecessary.

It is still not known if the sentinel node biopsy has any survival advantages compared to the standard procedures with lymph nodes removal.

Prognosis

In the U.S., about 39,800 women will die from breast cancer this year. (Lung cancer is the leading cancer killer in women, however.) The good news is that major international studies are now reporting improved long-term survival and lower rates of recurrence with new treatments and approaches. Unfortunately, women in lower social and economic groups still have significantly lower survival rates than women in higher groups.

A number of factors are used to determine successful treatment and the possibility for a cure. The include the following:

• The location of the tumor and how far it has spread.
• Whether the tumor is hormone receptor-positive or negative.
• Genetic factors.
• Tumor size and shape.
• Rate of cell division.
• Certain biologic markers.

The good news is that women are living longer with breast cancer, and at this time more than two million American are survivors. Survivors must live with the uncertainties of possible recurrent and some risk for complications from the treatment itself.

If the cancer recurs after treatment, most develop within five years. However, 25% of recurrences and half of new cancers in the opposite breast occur after five years. It should be noted that one study suggested that the risk factors for a first breast cancer do not necessarily place a woman at any higher risk for recurrence. (Women with a first cancer, however, do have a higher risk for a new cancer in the opposite breast. The outlook for such new cancers is independent from those of the first one.)

Location of the Tumor

The location of the tumor is a major factor in outlook:

• If the cancer is ductal carcinoma in situ (DCIS) or has not spread to the lymph nodes (i.e., is node-negative), the five-year survival rates with treatment are up to 98%. It should be noted, however, that the cancer recurs in between 9% and 30% of such node-negative cancers. Recurrence is a potentially life-threatening problem, even if the disease relapses locally in the same breast. Nevertheless, in one study, among DCIS patients with locally invasive recurrence eight-year mortality rates were still only 12%.
• If the lymph nodes contain cancer cells (i.e., are node positive) then survival rates fall. If the tumor is larger than 5 cm or there is widespread involvement in the lymph nodes, it is sometimes referred to as locally advanced. In such cases, the survival rate drops to about 75% and below.
• If the cancer has metastasized and spread through the blood stream to other sites (most often the lung, liver and bone), the average survival time for patients treated with chemotherapy is between one and two years (with some patients living for many years). And new combinations of drugs are improving these averages.

The location of the tumor within the breast is an important prognostic factor. Tumors that develop toward the outside of the breast tend to be less serious than those that occur more toward the middle of the breast.

Hormone Receptor-Positive or -Negative

Breast cancer cells may contain receptors, or binding sites, for hormones like estrogen or progesterone. Cells containing these binding sites are known as hormone receptor-positive cells and if they lack them are called hormone receptor-negative cells.

Hormone receptor-positive cells grow more slowly than receptor negative cells. Women have a better prognosis if their tumors are receptor-positive because these cells grow more slowly than receptor-negative cells and they have more treatment options. (Hormone receptor-negative tumors can only be treated with chemotherapy.)

The Influence of Genes

Determining a "genetic signature" for a tumor may prove to be a very powerful predictor of the aggressive nature of a breast cancer. Researchers have focused on 70 genes whose activity patterns may help make such predictions.

The relevance of the inherited BRCA1 or BRCA2 mutations to survival is controversial. Some studies have suggested that these mutations offer a survival advantage, while others suggest that they make no difference or even worsen prognosis. Women with these genetic mutations do have a greater risk for a new cancer to develop. Patients with BRCA1 mutations tend to develop tumors that are hormone receptor negative, which can behave more aggressively.

Tumor Markers

Researchers are investigating a number of substances in the tumor cells that will indicate whether a cancer is likely to spread or not. Such chemical markers may help physicians determine treatments, and some may even prove to be targets for future drugs. The following are only a few of the more well-researched markers.

HER-2. The HER-2 protein is part of the epidermal growth factor receptor family and is becoming an important marker in breast cancer. It is involved in the growth and spread of breast cancer cells, and about 25% to 30% of breast cancer patients have high levels of this protein. The presence of HER-2 may suggest aggressive cancer. It is proving to be important in determining treatment choices. For example, women who have HER-2 positive cancers tend to benefit from anthracycline-based chemotherapy and to Herceptin.

Angiogenesis Factors. Angiogenesis is the growth of new blood vessels. High levels of angiogenesis factors indicate that the tumor is developing its own supply of blood vessels, which enable the tumor to send colonies of cancer cells into the blood stream and spread to other parts of the body. Specific angiogenesis factors, such as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF), may turn out to be important markers for determining treatment and prognosis. The monoclonal antibody bevacizumab (Avastin) targets VEGF. The drug is showing promise in clinical trials for prolonging progression-free survival in women with metastatic breast cancer.

Others. Many other markers are being investigated, including p53, cathepsin-D, protein c-erbB-2, bcl-2, Ki-67, telomerase, thymidylate synthase, CA 15-3, and carcinogenic embryonic antigen (CEA). The American Society of Clinical Oncology (ASCO) cautions, however, that the value of many of these factors has not yet been confirmed.

Other Factors for Predicting Outlook

Tumor Size and Shape. Large tumors pose a higher risk than small tumors. Undifferentiated tumors, which have indistinct margins, are more dangerous than those with well-defined margins.

Rate of Cell Division. The more rapidly a tumor grows, the more dangerous it is. A number of tests measure aspects of cancer cell division and may eventually prove to predict the disease. For example, the mitotic index (MI) is a measurement of the rate at which cells divide. The higher the MI, the more aggressive the cancer. Another measures cells at a certain phase of their division.

Treatment

The three major treatments of breast cancer are surgery, radiation, and drug therapy. No one treatment fits every patient, and some combination therapy is virtually always required. The choice is determined by many factors, including the age of the patient and (among women) menopausal status, the kind of cancer (e.g., ductal vs. lobular), its stage, and whether the tumor contains hormone-receptors or not.

Breast cancer treatments are defined as local or systemic:

• Local Treatment. Surgery and radiation are considered local therapies because they directly treat the tumor, breast, lymph nodes, or other specific regions. Surgery is usually the standard initial treatment.
• Systemic Treatment. Drug treatment is called systemic therapy, because it affects the whole body.

Any or all of these therapies may be used separately or, most often, in different combinations. For example, radiation alone or with chemotherapy or hormone therapy may be beneficial before surgery, if the tumor is large or not easily removed at prevention. The optimal sequence for these therapies is being investigated. [Specific treatments and combinations are discussed in the sections below.]

Stage 0

This stage is also called noninvasive carcinoma or carcinoma in situ.

Treatment Options for Lobular Carcinoma in Situ. These are abnormal cells that pose a long-term risk for invasive cancer. (1) Careful monitoring with or without preventive use of tamoxifen or other selective estrogen-receptor modulators (SERMs). (2) In selected cases, consideration of removal of both breasts, since if the cancer does develop, it tends to do so in both breasts or to be invasive. In one study, chance for invasive cancer over a 25-year period was 25%.

Treatment Options for Ductal Carcinoma in Situ. These are cancer cells in the lining of a duct that have not invaded the surrounding breast tissue. (1) Mastectomy previously was the commonly recommended treatment. (2) Breast-sparing surgery (typically without lymph-node removal) followed by radiation therapy is reasonable for many women. Note that the risk for recurrence sometimes with a more invasive cancer is higher in women under 45 than in older women with this approach. (3) Use of tamoxifen or other SERMs after surgery and radiation to prevent recurrence in selected patients.

Stage I and Stage II

• Stage I. Cancer cells have not spread beyond the breast and the tumor is no more than 2 cm (about 3/4 of an inch) across.
• Stage II. One of the following conditions apply: the tumor is less than 2 cm across, and the cancer has spread to the lymph nodes under the arm; the tumor is between 2 and 5 cm (about 3/4 inch to 2 inches) with or without spreading to the lymph nodes under the arm; the tumor is larger than 5 cm but has not spread to the lymph nodes under the arm.

Primary Treatment Options for Stage I and II Breast Cancers. Choice of (1) Breast-sparing surgery (typically lumpectomy, usually with lymph node sampling) followed by external beam radiation therapy. (2) Modified or radical mastectomy with or without breast reconstruction. (3) Removal or radiation of lymph nodes. Choice between (1) and (2) depends mostly on the size and location of the tumor, the size of the breast, certain features of the cancer, and how the woman feels about preserving her breast. Considerations by tumor size are as follows:

• Tumors under 2 cm: Women can generally choose lumpectomy followed by radiation.
• Tumors between 2 cm and 5 cm. Even if tumors are up to 5 cm, a 2000 international study suggested that lumpectomy and mastectomy offer equivalent survival rates (about 66%) and time to metastasis at 10 years. In the study, however, local recurrence occurred in 20% of lumpectomy and 12% mastectomy patients.
• Tumors over 5 cm: Women generally choose mastectomy.

Other considerations: If women choose breast-sparing procedures, the risk for recurrence is lower with removal of as much breast tissue as possible. In women who experience a local recurrence after treatment, those who have chosen lumpectomy and radiation tend to have a better outlook than women who chose mastectomy, since cancers in the latter case would develop in the chest wall.

Adjuvant and Neoadjuvant Treatment Options. Adjuvant therapy is administered in addition to surgery or radiation therapy to prevent recurrence. (1) Combination chemotherapy can be considered for hormone receptor-negative cancers. Trastuzumab (Herceptin) plus standard chemotherapy has shown outstanding promise in several Phase III trials in increasing disease-free survival for patients with lymph-node positive cancer. (2) Hormonal therapy with or without chemotherapy for hormone receptor-positive cancers. Tamoxifen is the standard agent and is administered for about five years. Aromatase inhibitors (letrozole, anastrozole, and exemestane) are showing promise in adjuvant treatment. In 2004, letrozole was approved for extended adjuvant treatment of postmenopausal women with early breast cancer who have received 5-year post-surgical tamoxifen therapy. Ovarian ablation using goserelin alone or in combination with tamoxifen plus goserelin is also showing specific benefits.

Assessing Risk of Recurrence. A new genetic test (Oncotype DX) can help determine the likelihood of late recurrence (for example, recurrence in 5 or 10 years) in newly diagnosed patients whose breast cancer is stage I or II, node negative, estrogen receptor positive, and who will be treated with tamoxifen. Knowing whether their tumor has a low, moderate, or high risk of recurrence may help women determine the best course of treatment. Importantly, it may help those with low-risk tumors avoid overly aggressive treatment.

Stage III (Locally Advanced)

In this stage, the tumor in the breast is more than 5 cm across, and

• It has spread (sometimes extensively) to the underarm lymph nodes.
• It has spread to other lymph nodes or tissues near the breast.

A condition called inflammatory breast cancer is also treated as a Stage III cancer.

Treatment Options for Stage III. (1) Standard therapy is mastectomy usually with radiation therapy and systemic treatment (combination chemotherapy, hormonal therapy, or both). (In very advanced Stage III, systemic drug therapy, radiation, or both sometimes achieve a response that allows a woman to avoid mastectomy, although this approach does not increase survival rates.) (2) Radiation after surgery is now recommended for women with four or more involved lymph nodes or an extensive primary tumor. It is not yet clear if radiation would benefit women with one to three involved lymph nodes. (3) Clinical trials: high-dose chemotherapy and stem cell transplantation; new chemotherapeutic, hormonal, or biologic agents; neoadjuvant therapies using taxanes alone or concurrent taxane and radiation treatment; post surgical radiation for women with one to three involved lymph nodes.

Stage IV (Metastasized Cancer)

In stage IV the cancer has spread from the breast to other parts of the body. In about 75% of cases, the cancer has spread to the bone. The cancer at this stage is considered to be chronic and incurable and the usefulness of treatments available is limited. The goals of treatment for Stage IV can be a complete or partial response, stabilization of the disease, or slowing of its progression. Unlike many other cancers, stage IV breast cancer patients have responded to as many as five rounds of intervention drug treatments.

Treatment Options for Stage IV. (1) Surgery or radiation for any localized tumors in the breast. (2) Chemotherapy, hormonal agents, or both are appropriate for most patients (durable and complete remission possible in 10% to 20% of cases but cure is very rare). Chemotherapy in patients with hormone receptor-negative disease or who have extensive metastasis that requires rapid tumor shrinkage. Ovarian ablation (in premenopausal women) or other hormonal therapies in patients with hormone receptor-positive cancer and no or minimal organ involvement. (Aromatase inhibitors, taxanes, and other agents used in combination or in innovative schedules are improving results.) .) In 2004, the cancer drug gemcitabine (Gemzar) was approved for use in combination with paclitaxel (Taxol) as a first-line treatment option for women with metastatic breast cancer. (3) Metastasis to the brain may require radiation and high-dose steroids. (4) Metastasis to the bone (which occurs in 75% of cases) may be helped with radiation and bisphosphonates. Such treatments relieve and pain and help prevent bone fractures. (5) Clinical trials: standard hormonal or chemotherapy agents used as initial treatment, newly developed chemotherapeutic or hormonal agents, monoclonal antibodies, total hormone blockade using surgery, high-dose chemotherapy with stem-cell support, immune cell transplant.

Recurrent Breast Cancer

Recurrent breast cancer is considered to be an advanced cancer. In such cases, the disease has come back in spite of the initial treatment. Most recurrences appear within the first two or three years after treatment, but breast cancer can recur many years later. Treatment options are based on the stage at which the cancer reappears, whether the tumor is hormone responsive or not, and the age of the patient. Between 10% to 20% of recurring cancers are local; most are metastatic at presentation. All patients with recurring cancer are candidates for clinical trials.

The Effects of Emotions and Psychological Support

Recent evidence has not supported early reports of actual survival benefits for women with metastatic breast cancer who engage in support groups. However, studies have suggested that psychotherapy, group support, or both can relieve pain and reduce stress, particularly in women who are suffering emotionally.

Stress has been ruled out as a risk factor either for breast cancer itself or for recurrence in breast cancer patients. The role of depression, however, is unclear. A 2000 study suggested that women who had a history of major depression were four times as likely to develop breast cancer as those without clinical depression. One expert suggested the association may be based on common hormonal factors that affect both conditions. A 2003 study, however, reported a slightly higher risk for a poorer outcome in breast cancer patients who had pre-existing depression. Those with bipolar disorder had the highest risk. Such findings are unlikely to be related to hormonal issues. More research is needed to determine if treating depression in such women will improve their outlook.

Surgery

Surgery forms a part of nearly every patient's treatment for breast cancer. The initial surgical intervention is often a lumpectomy, the removal of the tumor itself. In the past, mastectomy (the removal of the breast) was the standard treatment for nearly all breast cancers. Now many patients with early-stage cancers can choose breast-conserving treatment, or lumpectomy followed by radiation, with or without chemotherapy.

Note: Local control rates using lumpectomy are comparable to those of mastectomy only when radiation therapy is also used for lumpectomy patients. A patient should carefully discuss all options with the physician or physician team.

Breast-Conserving Procedures

Breast-conserving procedures are now appropriate and as successful as mastectomy in most women with early stage breast cancer. All women should discuss these options fully with their physician. Recurrence rates with conservative surgery are highest in women under 45. Some women choose mastectomy over breast-conserving treatment even if the latter is appropriate because it gives them a greater sense of security and allows them to avoid radiation therapy.

Lumpectomy. Lumpectomy is the removal of the tumor, often along with lymph nodes in the armpit. It serves as an opportunity for biopsy, a diagnostic tool, and a primary treatment for small local breast tumors. If invasive cancer is found, the physician will decide to proceed with breast radiation therapy, to remove additional tissue (should the margins of the specimen show signs of cancer), or to perform a mastectomy. Lumpectomy followed by radiation therapy is appropriate and as effective as mastectomy in most women with stage I or II breast cancers.

Click the icon to see an illustrated series detailing breast lump removal surgery.

Breast-Conserving Surgery (Quadrantectomy). Breast-conserving surgery (sometimes referred to as quadrantectomy) removes the cancer and a large area of breast tissue, occasionally including some of the lining over the chest muscles. It is less invasive than a full mastectomy but the cosmetic results are less satisfactory than with a lumpectomy. Excellent studies have found that breast-conserving surgeries plus postoperative radiotherapy offer the same survival rates as radical mastectomy in women with early breast cancer. A new technology called partial breast radiation (MammoSite), FDA approved in 2002, confines radiation to the tumor site rather than delivering it to the whole breast, and reduces treatment time from five weeks to five days in women who undergo breast conserving surgery.

Mastectomy

Surgery to remove the breast (mastectomy) is important for women with operable breast cancer who are not candidates for breast conserving surgeries. There are different variations on the procedure:

• A total/simple mastectomy involves removal of the whole breast and sometimes lymph nodes under the armpit.
• A radical mastectomy removes the breast, chest muscles, all of the lymph nodes under the arm, and some additional fat and skin. (A modified radical mastectomy removes the entire breast and armpit lymph nodes, with the underlying chest wall muscle.) A 25-year study supported other research that observed no survival advantages from radical mastectomy compared to the less invasive mastectomies for the great majority of patients. It is rarely used anymore except when cancer is very advanced.

Click the icon to see an illustrated series detailing mastectomy surgery.

Complications and Side Effects of Surgery. Short-term pain and tenderness occur in the area of the procedure, and pain relievers may be necessary.

The most frequent complication of extensive lymph node removal is edema, or swelling, of the arm, which is usually mild and rarely painful but does increase the risk for infection. The likelihood of edema can be lessened by removing only some of the lymph nodes instead of all of them.

Infrequent complications include poor wound healing, bleeding, or a reaction to the anesthesia.

After mastectomy and lymph node removal, women may experience numbness, tingling, and difficulty in extending the arm fully. These effects can last for months or years afterward.

Breast Reconstruction

After a mastectomy, some women choose a breast prosthesis or opt for breast reconstruction, which can be performed during the mastectomy itself, if desired. Several studies have indicated that women who take advantage of cosmetic surgery after breast cancer have a better sense of well-being and a higher quality of life than women who do not choose reconstructive surgery. The breast is reshaped using a saline implant or, for a more cosmetic result, a muscle flap is taken from elsewhere in the body. Muscle flap procedures are more complicated, however, and blood transfusions may be required. (It should be noted that implants, including silicone implants, do not appear to put a woman at risk for breast cancer recurrence.) If the nipple is removed, it is rebuilt from other body tissues and color is applied using tattoo techniques. It is nearly impossible to rebuild a breast that is identical to its partner, and additional operations may be necessary to achieve a desirable effect.

Click the icon to see an illustrated series detailing breast reconstruction surgery.

Investigative Minimally Invasive Procedures

A number of studies are investigating minimally invasive techniques that employ lasers, deep-freezing of cancer cells (cryosurgery), high-intensity ultrasound, and other experimental approaches to kill cancer cells and reduce severe complications of surgery. Radiofrequency ablation, for example, is an interesting approach that uses an electrode inserted into the tumor. It emits radio waves that produce enough heat to destroy cancer cells. Early trials are promising. None of these procedures is considered standard at the present time.

Axillary Versus Sentinel Node Removal

Results of the largest prospective, randomized trial of surgical lymph node removal are expected in late 2004. The results will show whether, in clinically node-negative breast cancer patients, removal of the sentinel nodes (those closest to the tumor) alone provides the same survival and tumor control benefits that are seen when the axillary nodes (those in the armpit) are also removed. Removing the sentinel nodes alone greatly reduces the side effects of breast cancer surgery.

Follow-Up Care

After breast cancer surgery, women often undergo frequent testing to ensure immediate diagnosis of any recurrence. In general, annual mammograms and physical examinations, with additional tests as necessary based on clinical signs and symptoms, are reliable approaches. Patients, however, should discuss with their physician a follow-up plan that alleviates as much anxiety as possible.

Radiation

Radiation therapy uses x-rays to kill cancer cells or to shrink the size of a tumor in the breast or surrounding tissue. Radiation therapy after mastectomy can reduce local recurrences in many high-risk patients, particularly those with four or more positive lymph nodes or an advanced primary cancer. Whether it adds benefits for women post mastectomy with one to three positive nodes is uncertain. Radiation is also important in advanced stages for relief of symptoms and to slow progression.

Administration of Radiation Therapy

Radiation is generally administered in the following ways:

External Beam Radiation. It is usually administered four to six weeks after surgery and delivered externally by an x-ray machine that targets radiation to the whole breast. It may be delivered to the chest wall in high-risk patients (e.g., large tumors, close surgical margins, or lymph node involvement). The treatment is generally given daily (except for weekends) for about six weeks. A follow-up boost of radiation therapy in patients with lumpectomies appears to reduce the risk for recurrence.

Brachytherapy. Less commonly radiation is delivered in implants (called brachytherapy). Implants are most often used as a radiation boost after whole breast radiation, and studies suggest they improve survival in patients at high risk for local recurrence. Some evidence suggests that implants alone can reduce treatment time and may be as effective as external beam radiation in some patients with early stage breast cancer. A new technology for breast brachytherapy (MammoSite) was approved in 2002. The technique provides 5-year local tumor control rates similar to those of whole-breast radiation for selected patients, with much shorter treatment time and good cosmetic results.

Investigators are also testing other approaches to radiation treatment. One uses a combination of neutrons and protons (mixed-beam) or proton beams rather than the standard photon radiation therapy. Intensity-modulated radiation therapy is a promising technique that delivers different doses to multiple target areas using images of specific regions. Such an approach may improve the coverage of breast cancers while reducing the toxic effects to the heart and lungs.

Side Effects of Radiation Therapy

Side effects of radiation include the following:

• Fatigue is very common and increases with subsequent treatments, but most women are able to continue with normal activities. Exercise may be helpful.
• Nausea and lack of appetite may develop and worsen as treatment progresses.
• Skin changes and burns can occur on the breast skin. Using a cream that contains a corticosteroid, such as mometasone furoate (MMF) may be helpful. After repeated sessions, the skin may become moist and "weepy." Exposing the treated skin to air as much as possible helps healing. (Washing the affected skin with soap and water does not seem to be harmful and in one study was associated with a lower risk for this side effect.)
• Uncommonly, the breast may change color, size, or become permanently firm.
• Rarely, the nearest arm may swell and develop impaired mobility or even paralysis.

Long-Term Complications

Future complications include the following:

• Radiation to the left breast may increase the risk for future heart attack in younger women, but the risk is still low (only 2% over 20 years).
• There is a very small risk (less than 1%) of lung irritation and scarring.
• One study reported a higher risk for future cancer in the opposite breast in younger women who have been given radiation to the chest wall.
• Radiation therapy also can increase the risk of developing other cancers, such as soft tissue malignancies known as sarcomas.

Current procedures that employ precise targeting of the radiation using advanced imaging techniques reduce exposure and are likely to reduce the risks for heart disease and other serious complications.

Medications

The most important advances in the cure of breast cancer have come through the use of drug therapy, also called systemic therapy. Surgery and radiation therapy are effective for treating tumors confined to the breast but not for cancer cells that have spread. In such cases, drug therapy is needed. Drugs works systemically. That is, they kill cancer cells throughout the body rather than just in the breast or nearby tissue.

Agents Used for Breast Cancer

Systemic treatments for breast cancer include the following:

• Chemotherapy. Chemotherapy employs drugs called cytotoxic agents. They are given orally or by injection that kill cancer cells throughout the body. It plays a role in a very wide range of breast cancer cases.
• Hormone Therapy. The goal of hormone therapy is to prevent estrogen from stimulating breast cancer cells. It is now recommended for women of any age whose breast cancers are hormone-receptor positive (either estrogen or progesterone), regardless of the size of the tumor and whether or not it has spread to the lymph nodes.

Considerations for Drug Therapies

Drug therapy, either hormonal agents or chemotherapies, may be used as follows:

• As primary therapy for patients for whom surgery or radiation therapy is not appropriate.
• With surgery, radiation or both (adjuvant therapy). Adjuvant therapy is particularly beneficial for women who have microscopic evidence of the spread of cancer at the time of diagnosis. The use of drug therapy is designed to kill these residual breast cancer cells before they have a chance to become clinically evident.
• Prior to local treatments (neoadjuvant therapy). The goal in such cases is usually to shrink locally advanced tumors (Stage III) to a size small enough for surgical or radiological therapy.

In metastatic cancer: Drugs are used in such cases not to cure but to improve quality of life and possibly prolong survival.

Chemotherapy

Chemotherapy regimens are designed to kill cancer cells throughout the body. It has advantages for nearly every breast cancer patient regardless of whether the cancer is hormone receptor-positive or negative.

Adjuvant and Neoadjuvant Regimens

Adjuvant chemotherapy is used with surgery, radiation or both. Its goal is to eradicate microscopic disease in other parts of the body. Neoadjuvant chemotherapy, which is given before other treatments, is also proving to be useful for women with locally advanced breast cancer (Stage III). In such cases, it may reduce the tumor size so that it is operable.

Candidates for Adjuvant Chemotherapy. Adjuvant chemotherapy is an appropriate consideration for most women with invasive breast cancer, regardless of menopausal status. Studies are also reporting the adjuvant therapy may be beneficial for women with early stage cancers. Chemotherapy can reduce risk of relapse and prolong survival whether the tumor is node-negative or positive, or whether it is hormone-receptor positive or negative.

Chemotherapy Regimens and Drug Combinations. Adjuvant chemotherapy is usually administered after initial surgery in combination regimens in four to six courses of treatment over three to six months and usually before follow-up radiation therapy to the breast.

The following are some important agents used in combination treatments:

• Anthracyclines. Anthracyclines include doxorubicin (Adriamycin) or epirubicin (Ellence). To date, combinations using these agents have the best survival benefits. Patients who overexpress the HER-2/neu gene and have hormone receptor-negative tumors may particularly benefit from anthracyclines. The drug may have toxic effects on the heart, however.
• Cyclophosphamide, 5-fluorouracil (5-FU), and methotrexate (CMF). This was the standard regimen for years, but its use has declined with the introduction of anthracyclines. A variation in which mitoxantrone (Novantrone) replaced methotrexate may offer better survival rates than CMF.
• Taxanes include paclitaxel (Taxol) and docetaxel (Taxotere). Two studies published in 2003 suggest that women should strongly consider taxane-based therapy for node-positive breast cancer. The first study compared the standard regimen of 5-fluorouracil, doxorubicin, and cyclophosphomide (FAC) to the combination of docetaxel (Taxotere), doxorubicin (Adriamycin), and cyclophosphomide (Cytoxan) (TAC). After 55 months of follow-up, TAC-treated patients had a 28% lower risk of relapse and and 30% lower mortality rate than FAC-treated patients. In the second study, TAC therapy given on a dose-dense schedule (every two weeks) was shown to be superior to a standard schedule (every three weeks).
• A new injectable suspension form of paclitaxel (Abraxane) uses a novel technology to deliver chemotherapy to the tumor site. In a 2003 study, Abraxane increased the efficacy of paclitaxel by doubling the response rate (33% vs. 19%) and significantly prolonging the time to tumor progression. Abraxane is associated with fewer side effects than paclitaxel, and does not require pretreatment with a steroid. It was approved by the FDA in 2005 and is expected to be on the market this year.
• Trastuzamab (Herceptin). Results from several Phase III clinical trials show that trastuzumab, a drug used to treat metastatic breast cancer, may be an effective treatment for early-stage, HER-2 positive breast cancer when combined with other drugs. Data released in 2005 showed that  trastuzumab plus standard chemotherapy prolonged disease-free survival for early-stage, HER-2 positive breast cancer patients. Most of the study patients had cancer that had spread to the lymph nodes (lymph-node positive cancer). Patients in the trastuzumab treatment group had a 52% reduction in disease recurrence compared with those not treated with the drug. The main chemotherapy regimen used in the trials was doxorubicin and cyclophosphamide followed by paclitaxel and trastuzumab. Trastuzumab is a humanized monoclonal antibody that targets the HER-2 protein. Targeted therapies are increasingly showing promise for treating many forms of cancer.

Chemotherapy and Other Agents Used in Metastatic Cancer

Patients who develop metastatic disease (i.e., who relapse at distant sites) are generally not curable. Combination therapies, however, are often effective at shrinking tumors and improving quality of life and may even be improving survival rates.

Agents Used to Treat Metastatic Cancer. Combination agents that are most effective are the following:

• Docetaxel (Taxotere) and taxanes, paclitaxel (Taxol).
• Anthracyclines, doxorubicin (Adriamycin) or epirubicin (Ellence).

Combinations that include both anthracyclines and taxanes are showing high response rates although it is not clear whether such combinations improve overall survival compared to these drugs used as single agents.

Other promising combinations or agents used alone or in combinations are the following:

• Cyclophosphamide, 5-fluorouracil (5-FU), and methotrexate (CMF) with a corticosteroid (e.g., prednisone).
• Capecitabine (Xeloda). This is a unique oral agent that may be a good substitute for 5-FU and when used alone may an effective alternative to CMF in older patients. Studies have reported response rates of up to 26% in patients previously treated with chemotherapy and of 30% when used as the first treatment for metastatic breast cancer. A combination of capecitabine and docetaxel may prove to be particularly important.
• Trastuzumab (Herceptin). Trastuzumab (Herceptin) is a monoclonal antibody, a genetically designed agent that binds only to cells that have a specific marker on the cell surface. Trastuzumab destroys cells carrying the HER-2 protein, and is being used in women who tests positive for the gene that regulates this protein. HER-2 plays a role in cancer cell growth in about 30% of breast cancer patients. This agent is producing longer survival rates in metastatic breast cancer patients when it is used in combination with paclitaxel. (This agent is useful only in women who test positive for HER-2 gene overexpression.) Trastuzumab was approved in 1998 for treatment of late-stage breast cancer. Of concern are reports of toxic effects on the heart with this combination. Other agents are also showing promise in combination with Herceptin.

Other drugs showing some promise in chemotherapeutic regimens for metastatic cancer include bevacizumab (Avastin), vinorelbine (Navelbine), pemetrexed (Alimta), gemcitabine (Gemzar) and platinum-based agents (cisplatin, carboplatin, oxaplatin), edatrexate, and losoxantrone.

Bisphosphonates: Supportive Agents. Bisphosphonates (Zometa, Aredia) are supportive important agents for preventing fractures and reducing pain in people whose cancer has spread to the bones. Clodronate and pamidronate are the agents currently used and newer bisphosphonates (ibandronate and zoledronate) are being studied. To date, evidence strongly supports their use for reducing pain and improving quality of life. Bisphosphonates are also being investigated in early stage breast cancer, with some studies suggesting that they may help prevent metastasis in the bone and improve survival rates.

Side Effects of Chemotherapy

Side effects occur with all chemotherapeutic drugs. They are more severe with higher doses and increase over the course of treatment.

Common side effects include the following:

• Nausea and vomiting. Drugs known as serotonin antagonists, especially ondansetron (Zofran), can relieve these side effects in nearly all patients given moderate drugs and most patients who take more powerful drugs. In one study, a combination of dexamethasone (a corticosteroid) with ondansetron taken within 24 hours of chemotherapy achieved either a major or complete reduction in nausea and vomiting.
• Diarrhea.
• Temporary hair loss.
• Weight loss.
• Fatigue.
• Depression.

Serious short- and long-term complications can also occur and may vary depending on the specific agents used. They include the following:

• Anemia. The erythropoetins epoetin alfa (Epogen, Procrit) and darbepoetin alfa (Aranesp) stimulate red blood cell production age and can help reduce or prevent anemia, resulting in significant improvement in quality of life. Aranesp persists longer in the blood than epoetin alfa and may therefore require fewer injections.
• Increased chance for infection from severe reduction in white blood cells (neutropenia). The addition of a drug called granulocyte colony-stimulating factor (filgrastim and lenograstim) is very helpful in reducing the risk for severe infection.
• Liver and kidney damage.
• Abnormal blood clotting (thrombocytopenia).
• Allergic reaction, particularly to platinum-based agents.
• Menstrual abnormalities and infertility. Premature menopause occurs in about 30% of women, particularly in those over 40. A natural hormone medication called a gonadotropin-releasing hormone analogue that puts women in a temporary pre-pubescent state during chemotherapy may preserve fertility in some women.
• Sexual dysfunction.
• Rarely, secondary cancers such as leukemia.
• Between a quarter and a third of women report problems in concentration, motor function, and memory, which can be long-term. In one study, women were experiencing such symptoms two years after treatment, although by four years they had resolved.
• Cumulative doses of anthracyclines can damage heart muscles over time and increase the risk for heart failure. An encapsulated form doxorubicin (Myocet, Doxil) may reduce the risk for toxic effects on the heart, but has not been approved for breast cancer use as of the date of this report.
• Taxanes can cause a drop in white blood cells and possible problems in the heart and central nervous system. Allergic reactions can occur, more often in Taxol than Taxotere. Taking a steroid before taxane administration can help prevent such reactions. Taxane therapy may also cause severe joint and muscle pain in some patients, relievable with corticosteroids.

High-Dose Chemotherapy with Bone Marrow or Peripheral-Blood Stem-Cell Transplantation

High-dose chemotherapy along with peripheral-blood stem-cell rescue or bone marrow transplantation procedures have been used for cancer that has metastasized and, in some cases, for earlier stages of breast cancer in high-risk patients. The objective of this treatment is to be able to give patients very high toxic doses of cell-killing drugs. Transplantation procedures are based on stem cells, which are produced in the bone marrow. Stem cells are the early forms for all blood cells in the body (including red, white, and immune cells). Cancer treatments can harm these growing cells as well as cancer cells. Transplantation procedures, then, first removes these stem cells either directly (peripheral blood stem cell transplantation) or from bone marrow (bone marrow transplantation).

Despite the initial enthusiasm over the use of high dose therapy for treatment of high risk breast cancer, this approach can no longer be generally recommended and should not be used outside of a clinical trial setting. The results of three randomized studies failed to show a convincing advantage for the use of high dose therapy. (A fourth study that was originally thought to show an advantage was subsequently found to be flawed.) Nevertheless, some experts believe this approach can still be useful in selected patients and studies continue. In general, however, transplantation has a limited role in breast cancer management, and its use should be restricted to clinical trials.

Hormone Therapy

Hormone therapy works by blocking estrogen that causes cell-proliferation. They are used for adjuvant therapy and for advanced cancers in patients with hormone receptor positive tumors. Over the past few years, many new anti-estrogen agents have become available. Generally they do one or more of the following:

• Block the hormone receptor itself.
• Suppress estrogen production.
• Destroy the ovaries (which produce estrogen).

Tamoxifen and Selective Estrogen Receptor Modulators (SERMs)

Tamoxifen (Nolvadex) has been the standard hormonal agent used for breast cancer. It is the prototype for a growing class of compounds called selective estrogen receptor modulators (SERMs). SERMs chemically resemble estrogen and trick the breast cancer cells into accepting it in place of estrogen. Unlike estrogen, however, they do not stimulate breast cancer cell growth. Other SERMs being studied for breast cancer include toremifene (which is very similar to tamoxifen), idoxifene, and droloxifene.

Candidates. Tamoxifen is used for any cancer stage in women of all ages who have hormone receptor-positive cancers. In addition, it is being used protect against cancer in high-risk women.

Tamoxifen as Adjuvant Therapy. When used as adjuvant therapy for early stage hormone receptor positive breast cancer, tamoxifen is for a total of five years as tolerated. Evidence now shows that taking it for five years significantly improves survival rates and reduces recurrence. Taking it longer appears to confer no additional advantages. Patients whose tumors are convincingly hormone receptor-negative do not benefit. Comparisons between tamoxifen and other SERMs used for adjuvant therapy are underway.

Side Effects. Hormone therapy with SERMs has fewer side effects than chemotherapy, but can still cause hot flashes, vaginal bleeding and discharge, and visual disturbances.

Of concern is an increased risk for blood clots, which can, in rare cases, be life-threatening. Tamoxifen, and possibly toremifene pose a long-term increased risk for uterine (endometrial), cancer, though not enough to offset the benefits from breast cancer prevention. Any woman on tamoxifen with vaginal bleeding should see her physician immediately to rule out uterine cancer. Although early evidence indicates that some of the newer SERMs may not increase the risk for uterine cancer. Long-term studies are needed.

Endometrial cancer is a cancerous growth of the endometrium (lining of the uterus). It is the most common uterine cancer.

Aromatase Inhibitors

Aromatase inhibitors block aromatase, an enzyme that is a major source of estrogen in many major body tissues, including the breast, muscle, liver, and fat. These agents are showing great promise for breast cancer and do not have the potentially severe complications of tamoxifen: blood clots and uterine cancer. Aromatase inhibitors are classified as either nonsteroidal or steroidal agents. (A steroid in this case does not refer to the drugs known as corticosteroids. The term here refers to one of a family of hormones that include male and female reproductive hormones and which have a specific chemical structure.)

• Nonsteroidal Aromatase Inhibitors. Anastrozole (Arimidex) and letrozole (Femara) are now important treatments for advanced breast cancer patients with hormone-receptor positive tumors. Anastrozole is also approved for early breast cancer treatment in postmenopausal women. Letrozole has been approved for extended adjuvant treatment, following five years of tamoxifen therapy, in postmenopausal women with early breast cancer. Both agents are proving to be at least as effective as tamoxifen and have fewer side effects, including vaginal bleeding and blood clots. A five-year study published in 2002 comparing anastrozole to tamoxifen also reported lower risks for uterine cancer with anastrozole. (Tamoxifen was more bone-protective, however.) Another newer nonsteroidal agent, vorozole (R83842) is under investigation.
• Steroidal Aromatase Inhibitors. The steroidal aromatase inhibitors include exemestane (Aromasin) and formestane (Lentaron). Exemestane is the only oral aromatase inhibitor to date. In one 2000 study, exemestane was more effective than tamoxifen in sustained response. It is now used in metastatic breast cancer for postmenopausal women who do not respond to tamoxifen, but it may have wider benefits. Formestane is given by injection and is also effective, although is still under investigation in the U.S. One study suggested it might be particularly beneficial for elderly breast cancer patients.

One study suggested that using a nonsteroidal and steroidal aromatase inhibitor sequentially (e.g., formestane followed by anastrozole at the time of treatment failure) may extend the time to disease progression more than therapy with one agent.

Selective Estrogen Receptor Downregulators (SERDs)

Selective estrogen receptor downregulators (SERDs) block estrogen in all tissues in the body. Fulvestrant (Faslodex) is one such agent, which is proving to be at least as effective as anastrozole in delaying time to disease progression in women with advanced breast cancer. Side effects are generally gastrointestinal problems and hot flashes.

Progestins

Progestins, particularly megestrol (Megace), have been used as second- or third-line treatment of advanced breast cancer when tamoxifen fails. Some of the aromatase inhibitors, however, are proving to be more effective and some have fewer side effects, such as weight gain.

Ovarian Ablation

Ovarian ablation literally shuts down estrogen production from the ovaries. This can be accomplished chemically with medications or it can be done by destroying the ovaries with surgery or radiation. Note: osteoporosis is one serious side effect of this approach, but a number of therapies are available that can help prevent bone loss.

Chemical Ovarian Ablation. Drug treatment (nonchemotherapy agents) used to completely block ovarian production of estrogen is called chemical ovarian ablation. It is often reversible. The primary agents used are luteinizing hormone-releasing hormone (LHRH) agonists, such as goserelin (Zoladex). (They are also sometimes called GnRH agonists). These drugs block the release of the reproductive hormones LH-RH, which results in the cessation of ovulation and estrogen production. Studies are now suggesting that women with estrogen-positive early stage cancer who take goserelin have similar survival rates to those who take standard chemotherapy and they experience fewer serious side effects. A major analysis of four trials using LHRH agonists plus tamoxifen also suggested that this combination should be the standard for patients with advanced breast cancers that are hormone-receptor positive, although this is an area of controversy. (Chemotherapy is still more effective in women with estrogen-negative tumors.)

Ovariectomy. Ovariectomy, the removal of the ovaries, has modestly improved breast cancer survival rates in some premenopausal women whose tumors are hormone receptor-positive. In these women, combining this procedure with tamoxifen may improve results beyond those of standard chemotherapies. Ovariectomy does not benefit women after menopause, and its advantages can be blunted in women who have received adjuvant chemotherapy. The procedure causes sterility and can have a major negative emotional impact on many younger patients.

Resources

• www.cancer.gov -- National Cancer Institute
• www.cancer.org -- American Cancer Society
• www.aacr.org -- American Association for Cancer Research
• www.asco.org -- American Society of Clinical Oncology
• www.oncolink.org -- Oncolink
• www.aicr.org -- American Institute for Cancer Research
• www.nccn.org -- National Comprehensive Cancer Network
• www.wcn.org -- Women's Cancer Network
• www.sistersnetworkinc.org -- Sisters Network
• www.cancer.gov/clinicaltrials -- Find clinical trials

References

Goss PE, Ingle JN, Martino S, Robert NJ, Muss HB, Piccart MJ, et al. A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med. 2003;349(19):1793-1802.

Paik S, Shak S, Tang G, Kim C, Baker J, Cronin M, et al. A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med. 2004;351(27):2817-2826.

Robson M, Svahn T, McCormick B, Borgen P, Hudis CA, Norton L, et al. Appropriateness of breast-conserving treatment of breast carcinoma in women with germline mutations in BRCA1 or BRCA2: a clinic-based series. Cancer. 2005;103(1):44-51.

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