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	Introduction
	Risk Factors
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Breast cancer

Highlights

Screening

Women at high risk for breast cancer should have an MRI scan along with their annual mammogram, according to new guidelines from the American Cancer Society.

Guidelines from the American College of Physicians recommend women with a low risk for breast cancer talk to their doctor before starting to have mammogram screening at age 40.

Tamoxifen and Raloxifene for Prevention

• Raloxifene (Evista) works as well as tamoxifen (Nolvadex) in reducing the risk of invasive breast cancer in women with BRCA gene mutations, indicates an important study in the Journal of the American Medical Association (JAMA).
• Raloxifene may pose less risk for blood clots than tamoxifen, suggests the JAMA study. However, a New England Journal of Medicine (NEJM) study notes that raloxifene still produces a small increase in the risk for blood clots and stroke.
• These drugs may not be safe for women with pre-existing heart problems. In any case, only women at high risk for inherited types of breast cancer should consider taking these drugs for prevention.

Trastuzumab

• Trastuzumab (Herceptin) has emerged as an important treatment for women with HER2-positive breast cancer, a particularly aggressive type of cancer. Several NEJM studies report that trastuzumab given along with or after adjuvant chemotherapy significantly improves survival and prevents cancer recurrence.
• Trastuzumab can cause heart failure and other heart problems, especially for women with pre-existing heart conditions. Patients who take this drug need to have regular heart check-ups.

Aromatase Inhibitors

Aromatase inhibitors may be better than tamoxifen in improving survival and preventing recurrence in postmenopausal women with estrogen-sensitive breast cancers. These drugs are less likely to cause blood clots than tamoxifen, but may be more likely to cause osteoporosis, the thin bone condition that can lead to bone fractures.

Hormone Replacement Therapy (HRT)

• Long-term combination (progestin and estrogen) HRT increases the risk for breast cancer. New research indicates that women who use estrogen-alone HRT for 10 years or more also have an increased risk. Combined estrogen and testosterone doubles breast cancer risk.
• Short-term (less than 3 years) HRT is safe for high-risk women who have had their ovaries removed.

Obesity

Women who gain weight after menopause increase their risk of developing breast cancer. Losing weight after menopause can reduce risk.

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, 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 (referred to as in situ, 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 cancers include:

• 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 14% in the other breast -- after 20 years. These invasive cancers can be either lobular or ductal.

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

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 - 80% of all breast cancer cases.
• Infiltrating lobular carcinoma. This invasive cancer has spread through the wall of a lobule. It accounts for 10 - 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.

Age is a major identifiable risk factor. More than 80% of breast cancer cases occur in women over age 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 1 in 217.
• At age 50, they are 1 in 50.
• If a woman lives to be 85, the odds of her having breast cancer are 1 in 8.

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.

An estimated 10% of all women with breast cancer have a very strong family history of the disease. Inherited forms of breast cancer often appear in young women under the age of 50. In such families, some members may also be at higher risk for ovarian cancer. These mutations can be inherited from either a mother or father.

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.

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

• Between 25 - 35% of BRCA1 carriers develop breast cancer by age 70.
• Between 35 - 50% of BRCA2 carriers develop the disease. BRCA2 genes also increase the lifetime risk of breast cancer in men.

These mutations are present in only about 0.5% of the overall population. However, certain ethnic groups -- such as Jewish women of Eastern European (Ashkenazi) descent -- have a higher prevalence (2.5%) of BRCA gene mutations.

Screening Guidelines for BRCA Genes. In 2005, the U.S. Preventive Services Task Force (USPSTF) released updated guidelines for BRCA testing. While women at high risk should be tested, the USPSTF does not recommend routine genetic counseling or testing for BRCA genes in low-risk women (no family history of BRCA 1 or 2 genetic mutations).

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), CHEK2, and a mutant gene for the rare disorder ataxia-telangiectasia. (The disease itself is rare, but 1% of the population carries a single copy -- 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.

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 suggested 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.) However, 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 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. Several studies have 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. The longer a woman uses HRT, the higher her risk for breast cancer. HRT increases breast cancer density, making mammograms more difficult to read. This can cause cancer to be diagnosed at a later stage.

Progestin has been more strongly associated with risk for breast cancer than estrogen. However, some studies suggest that estrogen-alone HRT can pose a risk for breast cancer when women use it for longer than 10 years. A 2006 study also indicated that combined estrogen and testosterone therapy can double a womans risk for breast cancer.

At this time, most experts recommend that women use HRT only for short-term relief of menopausal symptoms. [For more information, see In-Depth Report #40: Menopause]

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 - 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.

The following physical characteristics have been associated with increased risk:

• Obesity increases the risk for all types of estrogen receptor-positive breast cancers. Women who gain weight after menopause are most at risk. (On a positive note, losing weight after menopause decreases breast cancer risk.) In postmenopausal women, estrogen is produced in fat tissue. High amounts of fatty tissue increase levels of estrogen in the body, leading to faster growth of estrogen-sensitive cancers.
• Estrogen is involved in building bone mass. Therefore, women with heavy, dense bones are likely to have higher estrogen levels and to 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 age 13 or younger had a higher risk than those who attained maximum height at age 18, reflecting higher estrogen levels at an earlier age.

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 (DDT and its metabolites, such as dieldrin) and pyrethroids (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. Low-dose radiation exposure before age 20 may increase the risk for women with BRCA genetic mutations.

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 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.

Prevention and Lifestyle Factors

Several studies suggest that regular exercise, particularly vigorous exercise, may offer some modest protection against breast cancer. Exercise can help reduce body fat, which in turn lowers levels of cancer-promoting hormones such as estrogen. Exercise can also help women who have been diagnosed with breast cancer. Studies indicate that both aerobic and weight training exercises benefit the body and the mind, and improve quality of life for breast cancer survivors. Even moderate exercise can help improve survival. A 2005 study in the Journal of the American Medical Association reported survival benefits for women diagnosed with breast cancer who walked 3 5 hours per week at an average pace.

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.

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 studies, monounsaturated fats (found in olive, peanut, and canola oils) may even be protective.

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:

• 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.

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.

One study 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.

Several studies have reported a higher risk for breast cancer in women who consume alcohol. A well-conducted 2003 analysis of many of these studies suggested that for every daily drink there was a 7% increase in breast cancer. By age 80, women who consumed two drinks a day had a 10% increased risk for developing breast cancer. Based on these findings, researchers suggested that about 4% of breast cancer cases in developed nations may be attributed to alcohol. (Women who drink and who take hormone replacement therapy have an even greater risk.) Some research indicates that alcohol in such amounts increases levels of growth factors that can stimulate breast cancer cells. However, 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.

Several studies have reported that breastfeeding is associated with a lower risk for cancer in premenopausal women. Some studies also suggest that some protective effect from breastfeeding may last beyond menopause. 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.

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:

• 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 (anti-estrogens) in others. Tamoxifen (Nolvadex) is the most studied of these drugs. It is currently used to treat breast cancer and is the only drug to date approved for prevention. Evidence strongly suggests that it halves the risk for estrogen receptor-positive cancers 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. However, it has no protective effects against estrogen receptor-negative cancers.

Raloxifene (Evista), another SERM, also protects against breast cancer and osteoporosis and has a lower risk than tamoxifen of causing uterine cancer. Results from a major comparison trial, Study of Tamoxifen and Raloxifene (STAR), were published in 2006. This study enrolled nearly 20,000 postmenopausal women at high risk for breast cancer. The data indicated that raloxifene worked as well as tamoxifen in reducing the risk of invasive breast cancer, and had a lower risk of causing blood clots. Side effects varied between the two drugs. Tamoxifen caused problems with gynecological symptoms, hot flashes, leg cramps, and bladder control. Women who received raloxifene tended to experience more musculoskeletal problems, sexual dysfunction, and weight gain.

Although the STAR study suggested that raloxifene is less likely to cause blood clots than tamoxifen, a 2006 study in the New England Journal of Medicine indicated that raloxifene carries its own risks for blood clots and fatal strokes. The researchers suggested that raloxifene may not be a safe choice for women at high risk of heart disease.

Tamoxifen and raloxifene are not recommended as prevention for women at low risk for breast cancer or its recurrence. Women at high risk for breast cancer should discuss with their doctors the risks and benefits of SERMs.

Investigational Drugs. The following investigative drugs are showing promise for prevention:

• 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).

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 BRCA genetic mutations. Shutting down estrogen production with preventive oophorectomy (ovary removal) is also proving to be an effective alternative in reducing the risk of breast cancer in women with BRCA1 gene mutations, and possibly BRCA2.

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 doctors, including oophorectomy and close monitoring.

Oophorectomy causes immediate menopause. Women who have a surgical menopause often experience more severe symptoms of hot flashes, sleep disturbances, and vaginal dryness than women who have a natural menopause. Hormone replacement therapy (HRT) is sometimes prescribed to help ease these menopausal symptoms. However, long-term use of HRT is a risk factor for breast cancer. A 2005 study suggested that short-term (less than 3 years) HRT is safe for women who have had preventive oophorectomy and will not increase their risk of developing breast cancer.

Symptoms

Breast cancers in their early stages are usually 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 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. Women between the ages of 20 and 49 should have a physical examination by a health professional every 1 -2 years. Those over age 50 should be examined annually. A breast exam by a health professional can find 10 - 25% of breast cancers that are missed by mammograms. Between 6 - 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. 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.

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 1 - 2 years for all women over age 40.

Guidelines from the American College of Physicians, however, debate whether women with a low risk for breast cancer should begin mammogram screening at age 40. The 2007 guidelines, instead, recommend that women in their 40s ask their doctor when they should begin having the test.

After age 50, experts recommend annual screenings. (Women over age 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. They miss up to 25% of cancers (which can sometimes be caught on a physical examination). Furthermore, between 80 - 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 who receive biopsies 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.

Even given current recommendations, there are several issues as to who should screen be screened 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. Numerous studies report 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 - 4%. 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 2-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. In spite of some negative studies, recent ones find some survival benefits for screening every 1 - 2 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 1 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.

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 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.

In a report published in 2007, the American Cancer Society recommended that high-risk women have an MRI of their breast with their annual mammogram, including those who have:

• A BRCA1 or BRCA2 mutation
• A first-degree relative (parent, sibling, child) with a BRCA1 or BRCA2 mutation, even if they have yet to be tested themselves
• A lifetime risk of breast cancer that has been scored at 20 - 25% or greater
• Had radiation to the chest between ages 10 - 30
• Li-Fraumeni syndrome, Cowden syndrome, or Bannayan-Riley-Ruvalcaba syndrome, or may have one of these syndromes based on a history in a first-degree relative

Scintimammography. In scintimammography, a radioactive chemical is 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.

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 several 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 doctor 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 and remove the lesion. The patient may receive local or general anesthetic.
• A new vacuum-assisted device may be useful for some biopsies. This uses 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.

If breast cancer has been determined, the next diagnostic step is to find out how far it has spread. To do this, the doctor 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 1 - 2 days.

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 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 doctor may 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 doctor 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.

A technique known as a sentinel node biopsy is a less invasive alternative to axillary lymph node dissection. This procedure can help determine if cancer has spread beyond the nodes. If the doctor finds no evidence of cancer, the patient may not need to have a complete axillary lymphadenectomy.

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

Sentinal node biopsy involves:

• 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 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 remaining lymph nodes will be cancer free, making further surgery unnecessary.

Patients who have a sentinel node biopsy tend to have better arm function and a shorter hospital stay than those who have an axillary node biopsy. The American Society of Clinical Oncologys 2005 guidelines recommend sentinel node biopsy instead of axillary lymph node dissection for women with early stage breast cancer who do not have nodes that can be felt during a physical exam. It is still not known if the sentinel node biopsy has any survival advantages compared to standard lymph node removal procedures.

Prognosis

In the U.S., about 40,410 women will die from breast cancer this year, making it the second most lethal cancer in women. (Lung cancer is the leading cancer killer in women.) The good news is that early detection and new treatments have improved survival rates. The 5-year survival rate for women diagnosed with cancer is 80%. About 88% of women diagnosed with breast cancer will survive at least 10 years. Unfortunately, women in lower social and economic groups still have significantly lower survival rates than women in higher groups.

Several factors are used to determine successful treatment and the possibility for a cure. They include:

• 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
• Biologic markers

The good news is that women are living longer with breast cancer, and at this time more than 2 million American women are survivors. Survivors must live with the uncertainties of possible recurrent cancer and some risk for complications from the treatment itself.

Recurrences of cancer usually develop within 5 years of treatment. However, 25% of recurrences and half of new cancers in the opposite breast occur after 5 years. 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.)

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 (is node-negative), the 5-year survival rates with treatment are up to 98%. However, cancer recurs in 9 - 30% of such node-negative cancers. Recurrence is a potentially life-threatening problem, even if the disease relapses locally in the same breast. In one study of DCIS patients with locally invasive recurrence, 8-year mortality rates were only 12%.
• If the lymph nodes contain cancer cells (are node positive) then survival rates fall. If the tumor is larger than 5 cm or there is widespread involvement in the lymph nodes, the cancer is sometimes referred to as locally advanced. In such cases, the survival rate drops to about 75% and below.
• If the cancer has spread to other sites (most often the lung, liver, and bone), the average survival time for patients treated with chemotherapy is 1 - 2 years (with some patients living for many years). 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.

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 be treated only with chemotherapy.)

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.

Researchers are investigating numerous substances in tumor cells that may indicate whether or not a cancer is likely to spread. Such chemical markers may help doctors 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 - 30% of patients with breast cancer 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.

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.

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. Several 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 test 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 combination therapy is usually required. The choice is determined by many factors, including the age of the patient, menopausal status, the kind of cancer (ductal vs. lobular), its stage, and whether or not the tumor contains hormone-receptors.

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.)

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. The risk for recurrence 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. 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% of 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.

• Hormone receptor-negative cancers. Combination chemotherapy is often used. Trastuzumab (Herceptin) plus standard chemotherapy has shown outstanding promise in increasing disease-free survival for patients with lymph-node positive cancer.
• Hormone receptor-positive cancers. Tamoxifen is the standard drug and is administered for about 5 years. Aromatase inhibitors (letrozole, anastrozole, and exemestane) are showing promise in adjuvant treatment. Some studies indicate that they are more effective than tamoxifen. 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.

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 drugs; neoadjuvant therapies using taxanes alone or concurrent taxane and radiation treatment; post surgical radiation for women with one to three involved lymph nodes.

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 is limited. The goals of treatment for Stage IV are a complete or partial response, stabilization of the disease, or slowing disease progression.

Treatment Options for Stage IV. (1) Surgery or radiation for any localized tumors in the breast. A 2006 study indicated that surgical removal of the primary tumor immediately after metastatic cancer diagnosis can dramatically improve survival.

(2) Chemotherapy, hormonal drugs, or both are appropriate for most patients (durable and complete remission possible in 10 - 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 drugs 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 can relieve pain and help prevent bone fractures.

(5) Clinical trials: Standard hormonal or chemotherapy drugs used as initial treatment, newly developed chemotherapeutic or hormonal drugs, monoclonal antibodies, total hormone blockade using surgery, high-dose chemotherapy with stem-cell support, immune cell transplant.

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 2 - 3 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 - 20% of recurring cancers are local. Most are metastatic at presentation. All patients with recurring cancer are candidates for clinical trials.

Recent evidence has not supported early reports of 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. 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 patients with breast cancer 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 prognosis.

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 surgical team.

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 doctor. Recurrence rates with conservative surgery are highest in women under age 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 doctor 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 5 weeks to 5 days in women who undergo breast conserving surgery.

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 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.

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.

Numerous studies are investigating minimally invasive techniques that use 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 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. These procedures, however, are not considered standard at the present time.

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 doctor 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.

Radiation is generally administered in the following ways:

External Beam Radiation. This type of radiation is administered 4 - 6 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 (large tumors, close surgical margins, or lymph node involvement). The treatment is generally given daily (except for weekends) for about 6 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. 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 include:

• 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.

Future complications include:

• Radiation to the left breast may increase the long-term risk for developing heart disease and heart attacks.
• There is a very small risk (less than 1%) of lung irritation and scarring.
• Some studies have 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 can increase the risk of developing other cancers, such as soft tissue malignancies known as sarcomas.

Current advanced imaging techniques use precise radiation that reduces exposure. These newer techniques 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 work systemically. That is, they kill cancer cells throughout the body rather than just in the breast or nearby tissue.

Systemic treatments for breast cancer include the following:

• Chemotherapy. Chemotherapy drugs are called cytotoxic drugs. They are given orally or by injection and kill cancer cells throughout the body. Chemotherapy 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.

Drug therapy, either hormonal drugs 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 (chemotherapy after surgery or radiation) 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.

For metastatic cancer, drugs are used 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 patient regardless of whether the cancer is hormone receptor-positive or negative.

Adjuvant chemotherapy is used after 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. Chemotherapy after surgery (adjuvant chemotherapy) is an appropriate consideration for most women with invasive breast cancer, regardless of menopausal status. Studies report that adjuvant therapy may also benefit women with early-stage cancers. Chemotherapy needs to be tailored to the type of cancer involved. Women require different treatments depending on whether the tumor is node-negative or -positive, and whether the cancer is hormone receptor-positive or -negative.

A 2006 study in the Journal of the American Medical Association indicated that women with hormone receptor-negative cancers respond better to chemotherapy than women with hormone receptor-positive cancer. However, some women with hormone receptor-positive cancer do benefit from chemotherapy. Adjuvant hormonal therapy is also an important treatment for women with hormone receptor-positive cancer.

Chemotherapy Regimens and Drug Combinations. Adjuvant chemotherapy is usually administered after initial surgery in combination regimens in four to six courses of treatment over 3 - 6 months and usually before follow-up radiation therapy to the breast.

The following are some important drugs used in combination treatments:

• Anthracyclines. Anthracyclines include doxorubicin (Adriamycin) or epirubicin (Ellence). To date, combinations using these drugs 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 suggested 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 cyclophosphamide (FAC) to the combination of docetaxel (Taxotere), doxorubicin (Adriamycin), and cyclophosphamide (Cytoxan) (TAC). After 55 months of follow-up, TAC-treated patients had a 28% lower risk of relapse and a 30% lower mortality rate than FAC-treated patients. In the second study, TAC therapy given on a dose-dense schedule (every 2 weeks) was shown to be superior to a standard schedule (every 3 weeks).
• An 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.
• Trastuzumab (Herceptin). Trastuzumab is a humanized monoclonal antibody that targets the HER2 protein. (Targeted therapies are increasingly showing promise for treating many forms of cancer.) Research supports that trastuzumab, a drug used to treat metastatic breast cancer, is also an important treatment for early-stage, HER 2-positive breast cancer. Trastuzumab is given either along with or following adjuvant chemotherapy. Data from 2005 and 2006 indicate that trastuzumab and paclitaxel plus standard adjuvant chemotherapy (such as doxorubicin and cyclophosphamide) prolongs disease-free survival and reduces the risk of cancer recurrence for these patients. Most of the study patients had cancer that had spread to the lymph nodes (lymph-node positive cancer). In a 2005 study, patients in the trastuzumab treatment group had a 52% reduction in disease recurrence compared with those not treated with the drug. Trastuzumab can cause heart failure and other heart function problems, which can usually be controlled with medication. Women who take trastuzumab need to have regular cardiac monitoring, especially if they have pre-existing heart problems.

Patients who develop metastatic disease (cancer that spreads throughout the body) are generally not curable. Combination therapies, however, are often effective at shrinking tumors and improving quality of life. In some cases, such therapies may improve survival. These drug regimens usually combine a taxane drug, such as docetaxel (Taxotere) or paclitaxel (Taxol), with an anthracycline drug, such as doxorubicin (Adriamycin) or epirubicin (Ellence).

Other promising combinations and single drugs include:

• Cyclophosphamide, 5-fluorouracil (5-FU), and methotrexate (CMF) with a corticosteroid (such as prednisone).
• Capecitabine (Xeloda). This is an oral drug that is sometimes used as a substitute for 5-FU or CMF, especially 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. Capecitabine is also showing good results in combination with lapatinib (Tykerb) in treating women with advanced HER2 positive cancer that did not improve with trastuzumab therapy. As a result, in March 2007, the Food and Drug Administration approved this combination treatment for patients whose cancer failed to respond to trastuzumab.
• Trastuzumab (Herceptin). Trastuzumab destroys cells carrying the HER2 protein, and is being used in women who test positive for the gene that regulates this protein. HER2 plays a role in cancer cell growth in about 30% of patients. This drug helps improve survival rates in patients with HER2 positive metastatic breast cancer when it is used in combination with paclitaxel.

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

Bisphosphonates. Bisphosphonates (Zometa, Aredia) are important supportive drugs for preventing fractures and reducing pain in people whose cancer has spread to the bones. Clodronate and pamidronate are the drugs 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 occur with all chemotherapeutic drugs. They are more severe with higher doses and increase over the course of treatment.

Common side effects include:

• Nausea and vomiting. Drugs known as serotonin antagonists, especially ondansetron (Zofran), can relieve these side effects. 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. Aprepitant (Emend), a new drug for preventing chemotherapy-caused nausea and vomiting, was approved in 2006.
• Diarrhea
• Temporary hair loss
• Weight loss
• Fatigue
• Depression

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

• Anemia. The erythropoietins epoetin alfa (Epogen, Procrit) and darbepoetin alfa (Aranesp) stimulate red blood cell production 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 drugs.
• 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, which puts women in a temporary pre-pubescent state during chemotherapy, may preserve fertility in some women. Women may also wish to consider embryo cryopreservation -- the harvesting of eggs, followed by in vitro fertilization and freezing of embryos for later use. The American Society of Clinical Oncology recommends that women being treated for cancer see a reproductive specialist to discuss all available fertility preservation options.
• 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 2 years after treatment, although by 4 years they had resolved.
• Heart problems. Trastuzumab (Herceptin) may increase the risk for heart failure, particularly in women with pre-existing risk factors. Cumulative doses of anthracyclines (doxorubicin, epirubicin) can also damage heart muscles over time and increase the risk for heart failure.
• 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 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.

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 several randomized studies have failed to show a convincing advantage for the use of high-dose therapy. 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. It is used for adjuvant therapy and for advanced cancers in patients with hormone receptor-positive tumors. Over the past few years, many new anti-estrogen drugs 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 (Nolvadex) has been the standard hormonal drug 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 to 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 well-tolerated for 5 years. Evidence shows that taking it for 5 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 doctor immediately to rule out uterine cancer. 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 block aromatase, an enzyme that is a major source of estrogen in many major body tissues including the breast, muscle, liver, and fat. These drugs are showing great promise for treating hormone receptor-positive (also called estrogen-sensitive, hormone-sensitive, or hormone-responsive) breast cancer.

There are currently three aromatase inhibitors approved for treating early-stage, hormone receptor-positive breast cancer in postmenopausal women:

• Anastrazole (Armidex)
• Exemestane (Aromasin)
• Letrozole (Femara)

Armidex and Letrozole are approved for treatment after surgery. Exemestane is approved for women who have taken tamoxifen for 2 - 3 years. These drugs are also approved for women with advanced (metastatic) hormone-sensitive breast cancer.

Tamoxifen is another drug used to treat estrogen-sensitive breast tumors, but it works in a different way than aromatase inhibitors. Tamoxifen interferes with tumors ability to use estrogen by blocking their estrogen receptors. Aromatase inhibitors reduce the overall amount of estrogen in the body.

Compared to tamoxifen, aromatase inhibitors are less likely to cause blood clots and uterine cancer. However, these drugs are more likely to cause osteoporosis, which can lead to bone loss and fractures. In general, recent studies indicate that aromatase inhibitors may be better than tamoxifen in improving survival in women with hormone-sensitive breast cancer (especially for those with node-positive cancer) and reducing the risk of cancer recurrence.

Selective estrogen receptor downregulators (SERDs) block estrogen in all tissues in the body. Fulvestrant (Faslodex) is one such drug, 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 generally include gastrointestinal problems and hot flashes.

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 literally shuts down estrogen production from the ovaries. Medications can accomplish ovarian ablation, or it can be done by destroying the ovaries with surgery or radiation. (Osteoporosis is one serious side effect of this approach, but several therapies are available to help prevent bone loss.)

Chemical Ovarian Ablation. Drug treatment (non-chemotherapy drugs) to block ovarian production of estrogen is called chemical ovarian ablation. It is often reversible. The primary drugs 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 suggest 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 younger patients.

Resources

• www.cancer.gov -- National Cancer Institute
• www.cancer.org -- American Cancer Society
• www.asco.org -- American Society of Clinical Oncology
• www.oncolink.org -- Oncolink
• www.womenshealth.gov -- National Women's Health Information Center
• www.nccn.org -- National Comprehensive Cancer Network
• www.plwc.org -- People Living With Cancer
• www.cancer.gov/clinicaltrials -- Find clinical trials

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