Breast Cancer

Most women share a common fear: developing breast cancer. This is not an unfounded fear when considering that, except for lung cancer, breast cancer is the most common cancer found in women, accounting for one of every three diagnoses. However, men are also affected by breast cancer. In 2002 the American Cancer Association estimate that 1500 men will be diagnosed with breast cancer, and 400 will die as a result. In 2001 an estimated 192,200 American women were diagnosed with breast cancer and 39,600 women died of the disease (The American Cancer Association). In 2004 an estimated 203,500 new cases of breast cancer will be diagnosed in America.

WHAT IS BREAST CANCER?

Breast cancer occurs when cells in the breast tissue divide and grow without control. The cell cycle is the natural mechanism that regulates the growth and death of cells. When the normal cell regulators malfunction and cells do not die at the proper rate, there is a failure of cell death (apoptosis) therefore cell growth goes unchecked. As a result, cancer begins to develop as cells divide without control, accumulating into a mass of extra tissue called a tumor. A tumor can be either non-cancerous (benign) or cancerous (malignant). As a tumor grows, it elicits new blood vessel growth from the surrounding normal healthy tissues and diverts blood supply and nutrients away from this tissue to feed itself. This process is termed “angiogenesis”- the development (genesis) of new blood vessels (angio). Unregulated tumor angiogenesis facilitates the growth of cancer throughout the body.

Cancer cells have the ability to leave the original tumor site, travel to distant locations, and recolonize. This process is called metastasis and it occurs in organs such as the liver, lungs, and bones. Both the bloodstream and lymphatic system (the network connecting lymph nodes throughout the body) serve as ideal vehicles for the traveling cancer. Although, these traveling cancer cells do not always survive beyond the tumor, if they do survive, the cancer cells will again begin to divide abnormally and will create tumors in each new location. A person with untreated or treatment-resistant cancer may eventually die of the disease if vital organs such as the liver or lungs are invaded, overtaken, and destroyed.

Cancerous tumors in the breast usually grow slowly. It is thought that by the time a tumor is large enough to be felt as a lump, it may have been growing for as long as 10 years. This has lead to the belief that undetectable spread of tumor cells (micrometastasis) may have already occurred by the time of the diagnosis. Therefore, preventive measures such as a healthy balanced diet and lifestyle, nutritional supplementation, and exercise are of primary importance against the development of cancer. Early diagnosis is the best way to reduce the risk of dying from breast cancer. This can be accomplished by monthly self-breast exams, annual clinical breast exams and screening mammography. If breast cancer is detected, a multimodality approach incorporating nutritional supplementation, dietary modification, detoxification, and one or more of the following may be considered: surgery, chemotherapy, radiation, hormone therapy, or vaccine therapy.

RISK FACTORS

A wide variety of factors may influence an individual's likelihood of developing breast cancer; these factors are referred to as risk factors. The established risk factors for breast cancer include: female gender, age, previous breast cancer, benign breast disease, hereditary factors (family history of breast cancer), early age at menarche (first menstrual period), late age at menopause, late age at first full-term pregnancy, obesity, low physical activity, use of postmenopausal hormone replacement therapy, use of oral contraceptives, exposure to low-dose ionizing radiation in midlife and exposure to high-dose ionizing radiation early in life.

Correlated risk factors for breast cancer include never having been pregnant, having only one pregnancy rather than many, not breast feeding after pregnancy, diethylstilbestrol (DES), certain dietary practices (high intake of fat and low intakes of fiber, fruits, and vegetables), tobacco, smoking, abortion, breast trauma, breast augmentation, large breast size, synthetic estrogens, electromagnetic fields, use of nonsteroidal anti-inflammatory drugs (NSAIDs), and alcohol consumption. Alcohol is known to increase estrogen levels. Alcohol use appears to be more strongly associated with risk of lobular carcinomas and hormone receptor-positive tumors than it is with other types of breast cancer (Li et al. 2003).

A novel growth inhibitor recently identified as estrogen down-regulated gene 1 (EDG1) was found to be switched off (down-regulated) by estrogens. Inhibiting EDG1 expression in breast cells resulted in increased breast cell growth, whereas over-expression of EDG1 protein in breast cells resulted in decreased cell growth and decreased anchorage-independent growth, supporting the role of EDG1 in breast cancer (Wittmann et al. 2003).

ANATOMY OF THE BREAST

The breast is composed mainly of fat (adipose tissue) and breast tissue, along with connective tissue, nerves, veins, and arteries. Breast tissue is a complex network known as the mammary gland. Within the mammary gland, there are 15-20 lobes or compartments separated by adipose tissue. Within each lobe are several smaller compartments called lobules.

Lobules are composed of grapelike clusters of milk-secreting glands termed alveoli, which are found embedded in connective tissue. Spindle-shaped cells called myoepithelial cells, whose contractions help propel milk toward the nipple, surround the alveoli. There are about one million lobules contained within each breast (Spratt et al. 1995). The lobules are connected by tiny ducts that are joined together (much like a grape stem) into increasingly larger ducts. Within each breast there are between five and ten ductal systems, each with its own opening at the nipple.

Surrounding the nipple is a darkly shaded circle of skin called the areola. The areola appears rough because it contains modified sebaceous (oil) glands. These glands secrete small amounts of fluid to lubricate the nipple during breast-feeding.

Of all breast cancers, about 80% originate in the mammary (lactiferous) ducts, while about 20% arise in the lobules (IOM 1997). One of the most important distinctions to understand is the difference between invasive breast cancer and carcinoma in situ.

TYPES OF BREAST CANCER

Invasive Cancer
When abnormal cells from within the lobules or mammary ducts break out into the surrounding tissue the condition is referred to as invasive breast cancer. However, this term does not necessarily mean that metastases have been found anywhere beyond the breast.

Carcinoma In Situ
Carcinoma in situ is referred to as precancerous condition because it can increase the risk of developing cancer. When abnormal cells grow within the lobules or mammary ducts and there is no sign that the cells have spread into the surrounding tissue or beyond, the condition is called carcinoma in situ. The term in situ means “in place”. There are two main categories of carcinoma in situ: ductal carcinoma in situ (DCIS) and lobular carcinoma in situ (LCIS).

Non-invasive cancer is grouped into four subcategories, based on how the cancer cells grow relative to each other within the center of the milk duct:

Solid: There is wall-to-wall cell growth

Cribiform: There are holes between groups of cancer cells, making it look like Swiss cheese.

Papillary: The cells grow in fingerlike projections, toward the inside of the duct.

Comedo: There are areas of "necrosis," which is debris from dead cancer cells; this indicates that a tumor is growing so fast that some tumor cells die because there is insufficient blood supply.

Carcinoma in situ is generally considered a slow-growing cancer. The solid, cribiform, and papillary growth patterns are also referred to as "low-grade" cancers. However, Comedo is considered a faster growing cancer and is referred to as a "high-grade" non-invasive cancer, but is more likely than other categories to become invasive.

Ductal Carcinoma In Situ
Mammary ducts are hollow to allow fluid to pass through. However, with ductal carcinoma in situ (DCIS) excess cells grow inside the mammary ducts. DCIS is not invasive cancer. It is a precancerous condition that has the potential to develop into breast cancer. DCIS is, however, a risk factor for breast cancer.

Lobular Carcinoma In Situ
The lobules of the breast tissue have open space inside them much like the mammary ducts. Lobular carcinoma in situ (LCIS) is the growth and accumulation of large numbers of abnormal cells within the lobules. LCIS is often referred to as lobular neoplasia in situ. LCIS is not a direct cancer precursor. The abnormal cells found inside the lobules are not likely to mutate into cancer. LCIS is, however, a risk factor for breast cancer.

SPECIAL MANIFESTATIONS OF CANCER

Paget's Disease of the Nipple
Paget's disease is a rare, slowly growing cancer of the nipple. Paget's disease is usually associated with in situ or invasive cancer. One of the biggest problems with Paget's disease of the nipple is that its symptoms appear to be harmless. It is frequently thought to be a skin inflammation or infection, leading to unfortunate delays in disease detection, diagnosis and treatment. Symptoms of Paget's disease include persistent redness, itching, oozing, crusting, and fluid discharge from the nipple or a sore on the nipple that does not heal. Typically, only one nipple is affected. Treatment and prognosis for the disease are directly related to the type and extent of the underlying cancer.

Inflammatory Breast Cancer (IBC)
Inflammatory breast cancer (IBC) is a rare and aggressive form of invasive breast cancer that is usually not detected by mammograms or ultrasounds. IBC usually grows in nests or sheets rather than as a confined solid tumor and can be diffuse throughout the breast with no palpable mass. The cancer cells clog the lymphatic system just below the skin, resulting in lymph node involvement. Increased breast density compared to prior mammograms should be considered suspicious.

However, the main symptoms of IBC are breast swelling, inflammation, pink, red, or a dark colored area (erythema), sometimes with texture similar to the skin of an orange (peau d'orange), ridges and thickened areas of the breast skin, an area of the breast that is warm to the touch, what appears to be a persistent bruise, itching (pruritus) that is unrelenting and unaffected by medicated creams and ointments, increase in breast size over a short period of time, nipple flattening, retraction, or discharge, breast pain that is not cyclic in nature and may be constant or stabbing, or swollen lymph nodes in the armpit or above the collar bone. Since many of these symptoms mimic a breast infection, doctors frequently treat inflammatory breast cancer merely as an infection. When symptoms do not improve after antibiotic treatment for the suspected “infection” only then is the inflammatory breast cancer diagnosed.

IBC has an extremely high risk of recurrence and a very poor prognosis. It is the most lethal form of breast cancer. To improve the chances of survival it is important that symptoms are recognized early, resulting in an immediate diagnosis and treatment. Chemotherapy is usually begun within days of diagnosis. Without treatment, chances of 5-year survival for individuals with inflammatory breast cancer are very poor. With treatment, about 50% of patients will be living 5 years after diagnosis.

BREAST DISEASES

There are a variety of breast diseases, ranging from infections to excessive cell growth (neoplasms). Unfortunately, many breast diseases mimic the symptoms of cancer and therefore require tests and possibly surgical biopsy to obtain an accurate diagnosis. The majority of biopsies are found to be benign (non-cancerous) forms of breast disease. While most breast diseases are not dangerous in themselves, they may increase the risk of developing breast cancer. Hyperplasia, cysts, fibroadenomas, and calcifications are the common benign breast diseases.

Calcifications
Calcifications are randomly scattered residues of calcium that in older women may have left the bones to appear in other parts of the body, such as the joints or breasts. Microcalcifications are small, tight clusters of tiny calcifications in the ducts that can be seen on a mammogram and may indicate a precancerous or cancerous condition.

Cysts
Cysts are sacs filled with fluid; they are almost always benign. Although most are too small to feel, approximately a third of women between the ages of 35-50 have cysts in their breasts. If large enough, cysts may feel like lumps in the breast. Normally, cysts are left untreated. However, if a cyst becomes painful, it can be aspirated or drained of its fluid. Some women may prefer to have a cyst removed if, after being aspirated repeatedly, it continues to recur.

Cysts are not associated with an increased risk of cancer; yet, they are more common in women as they approach menopause and occur much less frequently after menopause (Donegan 1995). What causes cysts to develop is unknown; however, certain dietary factors, such as the intake of caffeine have been proposed as possible risk factors for the development of breast cysts.

Fibroadenomas
Fibroadenomas are a type of benign lump most commonly found in younger women. They are usually not removed since they pose no risk. If a fibroadenoma is large, uncomfortable, and produces a lump, it may be removed. In older women, fibroadenomas are generally removed to ensure that they are not malignant tumors. Fibroadenomas do not pose an increased risk of cancer.

Hyperplasia
Hyperplasia is not a precancerous condition. It is the excessive accumulation or proliferation of normal cells typically found on the inside of the lobules or the ducts in the breast tissue. Hyperplasia is associated with approximately a two-fold risk of breast cancer.

Atypical Hyperplasia
Atypical hyperplasia occurs when excess cells in the lobules or ducts are abnormal. This condition falls between hyperplasia (too many normal cells) and carcinoma in situ (too many abnormal cells). However, atypical hyperplasia is associated with an approximately 3.5-5 times increased risk of developing breast cancer (Page et al. 1985; Colditz 1993; Marshall et al. 1997).

TYPES OF STANDARD SCREENING TECHNIQUES

In order to detect breast cancer at its earliest, most treatable stage, the importance of regular monthly breast self-exams, and yearly clinical breast exams, cannot be overemphasized. Mammography, sonography, contrasting magnetic resonance imaging (MRI) and digital infrared thermal imaging are all viable diagnostic tools, which will be discussed later in this article. Having regular breast-cancer screening exams is considered the single most effective way to lower the risk of dying from breast cancer.

"Early-stage" invasive cancer is considered very treatable because the tumor is relatively small and the cancer cells have not spread to the lymph nodes. However, when a tumor has become very large or has spread to other organs (such as the liver, lungs, or bones), it is considered "advanced-stage" invasive cancer and is far less treatable.

Breast cancer was thought to grow in an orderly progression from a small tumor in the breast tissue to a larger tumor. The cancer was believed to then travel from the breast into the adjacent lymph nodes, spreading throughout the distant nodes and finally metastasizing in other areas of the body. However, a growing body of research now contends that cancer cells are capable of traveling from the breast throughout the blood and lymphatic systems very early in the course of the disease. This strengthens the rationale for early detection and treatment.

Breast Self-Exam
A breast self-exam provides an opportunity to detect tumors that may develop in the time between yearly clinical breast exams. To increase a woman's chances of detecting a small tumor at a time when it may be more responsive to treatment, a breast self-exam should be performed monthly, usually 2-3 days after menstruation. For women with irregular periods, it is important to remember to perform a monthly exam on the same day each month. Keep in mind that prior to menstruation or during pregnancy, breasts may be somewhat lumpy or more tender than usual.

By performing self-exams once a month, women can become familiar with the normal appearance and "feel" of their breasts, increasing the likelihood of recognizing changes such as thickening, lumps, or spontaneous nipple discharge. Because breast tissue normally has a bumpy texture, it may feel lumpy. However, there can be a great deal of individual variation. If a breast has lumpiness throughout, then it is probably just the normal contours of the breast tissue and in most cases is no cause to worry. Dominant lumps are firmer than the rest of the breast and are of more concern. When a dominant lump is found, there is an increased risk that it may be cancer, even though cysts and fibroadenomas can cause similar lumps. Any time a woman discovers a lump that feels dominant, it should be checked by a medical professional.

How to Do Breast Self-Exam

1. Lie down. Flatten your right breast by placing a pillow or towel under your right shoulder. Place your right arm behind your head. Examine your right breast with your left hand.
2. Use the pads, not the tips, of the middle three fingers on your left hand. With fingers flat, press gently using a circular, rubbing motion and feel for lumps. In small, dime-sized circles without lifting the fingers, start at the outermost top edge of your breast and spiral in toward the nipple.
3. Press firmly enough to feel the different breast tissues, using three different pressures. First, light pressure to just move the skin without jostling the tissue beneath, then medium pressure pressing midway into the tissue, and finally deep pressure to probe more deeply down to the ribs or to the point just short of discomfort.
4. Completely feel all of the breast and chest area up under your armpit, up to the collarbone, and all the way over to your shoulder to cover breast tissue that extends toward the shoulder.
5. Gently squeeze both nipples and look for discharge.

After you have completely examined your right breast, examine your left breast using the same method with your right hand. You may want to examine your breasts or do an extra exam while showering. It's easy to slide soapy hands over your skin and to feel anything unusual. You should also check your breasts in a mirror, looking for any change in size or contour, dimpling of the skin, or spontaneous nipple discharge.

Clinical Breast Exam
Clinical breast exams are physical examinations to check the appearance and "feel" of the breasts for signs of lumps. A physician, nurse practitioner, or other trained medical staff person will examine the breasts, both when the woman is sitting upright and when she is lying down.

Clinical breast exams are an important part of breast cancer screening. For younger women, clinical breast exam may have an advantage over mammography; mammography images can be more difficult to read in some younger women because of their dense breast tissue. For this reason, clinical breast exams are generally started much earlier than mammograms.

Mammography
Mammography is an x-ray technique used to locate small or indistinctly shaped breast lumps that may not be felt during an exam. A mammogram takes about 15 minutes and consists of compressing each breast individually between two plates to makean x-ray image. Afterwards, a radiologist will read the film and look for any signs of abnormal tissue.

X-ray images appear in gradations of black, gray, and white depending on the density or hardness of the tissue. For example, since bone is especially dense, it appears white on an x-ray, while fat appears dark gray. Cancerous tumors and some other noncancerous abnormalities appear as a lighter shade of gray. Unfortunately, this may pose a problem because normal, dense breast tissue may appear light gray on a mammogram. Breast density changes with age. Younger women have proportionately more breast tissue than fat and therefore denser breasts, making mammograms difficult to interpret. In older women's breasts, density dissipates with age, leaving breasts that are composed mostly of fat. A mammogram that shows the light gray patch of a tumor or lesion surrounded by the dark gray image of fat tissue is most easily recognized.

Cysts and fibroadenomas appear as circular or oval patches with stark outer edges on x-rays, allowing a radiologist to identify where the border of the benign abnormal tissue ends and the surrounding normal tissue begins. On an x-ray, the core cancerous cells appear as a light patch, while the cancer cells that invade the surrounding tissue create a fuzzy or spiky appearance along the outer edge (called "spiculated"), producing an image with no clear borders.

There is growing controversy regarding the safety and efficacy of mammography. The National Cancer Institute clearly states on their website “Being exposed to radiation is a risk factor for breast cancer” (National Cancer Institute 2003). Further, both low-filtered (30 kVp) x-rays and mammography x-rays have mutagenic effect on mammalian cells. A re-evaluation of the risk assessment of mammography, especially for familial predisposed women is recommended. People with known increased risk of breast cancer, particularly those with a familial predisposition, are advised to be cautious and avoid early and frequent mammography exposure. Alternative examination methods should be considered for women with an inherited increased risk of breast cancer (Frankenberg-Schwager et al. 2002).

There is evidence that high-quality mammography may reduce breast cancer mortality in women aged 50 to 69. In fact, the risk of radiation-induced breast cancer decreases with increasing age at radiation exposure (Jung 2001). There has been difficulty in establishing the benefit of screening mammography in younger women. This difficulty has been attributed to both the technical limitations introduced by younger women’s dense breast tissue and to differences in breast cancer biology in younger women. Equally, women with inherited increased risk for breast cancer may gain no benefits from early screening.

The false positive rate ranges from 2.6% to 15.9% (Elmore et al. 2002). False positives usually result in additional diagnostic tests, which can include an additional x-ray examination, or a biopsy, which is the removal of a small portion of breast tissue for microscopic examination. A portion of the population’s mammograms are misread as false negatives. A false negative mammogram occurs when the mammogram is read as “normal” or “negative” although a malignancy is present. Screening mammograms from a population-based screening registry estimated a missed detectable cancer rate of 29% (Yankaskas et al. 2001). Other studies report a missed detectable cancer rate by mammograms of approximately 12% to 37% (Woolf 2001).

Regardless of the high rates of false-positives and false-negatives, x-ray mammography is still considered the gold standard of breast cancer screening since it can detect tumors at an early stage when they are small and responsive to treatment. Most physicians recommend annual mammograms for women over 40, and for those at high risk with a family history of breast cancer.

Ultrasound
Ultrasound, also known as sonography, is an imaging method that utilizes very-high frequency sound waves to produce a picture that outlines the breast without exposure to ionizing radiation. During a sonogram, (also known as echogram) sound waves are transmitted through the breast. Depending on the nature of the breast tissue, the sound waves are reflected back or are transmitted through the tissue being examined. The pictures generated are the results of such echoes; they are picked up and translated by a computer resulting in the ultrasound image. Breast ultrasonography can be used to evaluate breast problems found during a mammogram or a physical exam.

Ultrasound is useful for some breast masses. It can be used to determine if a breast mass is solid (and more likely to be malignant) or if it is cystic and filled with fluid (and more likely to be benign). The ultrasound facilitates analysis by enabling the radiologist to guide a needle to biopsy a solid mass or to remove fluid if it is a cystic fluid-filled mass. The limitation of both mammography and ultrasound is that both have diagnostic features, which depend primarily on structural distinction and anatomical variation of a tumor from the surrounding breast tissue. These limitations make distinguishing benign microcalcifications from malignancies nearly impossible.

MRI
Magnetic Resonance Imaging (MRI) of the breast, also known as a breast MRI, is an imaging method consisting of a high field (1.5 Tesla) magnet with dedicated breast coils linked to a computer. The most useful MRI breast examination combines a contrast material, known as Gadolinium DTPA, magnetization, and radio waves to provide detailed pictures of an area inside the breast by a computer without the use of radiation. Every MRI produces hundreds of images of the breast from side-to-side, top-to-bottom, and front-to-back.

MRI is the most sensitive imaging modality for detection of breast cancer (Kuhl et al. 2000; Warner et al. 2001). Unfortunately, an MRI cannot always accurately distinguish between cancer and benign (noncancerous) breast conditions. Like ultrasound, MRI cannot detect microcalcifications. MRI is, however, effective in evaluating dense breast tissue and may be useful in screening younger women at high risk for breast cancer due to a predisposing family history of breast cancer.

MRI can be used to evaluate women who have had augmentation or breast enlargement surgery using implants. In such context, MRI is an excellent tool for imaging the augmented breast, including the breast implants itself, and the surrounding tissue, since abnormalities or signs of breast cancer are sometimes obscured by the implant. In contrast, the x-rays used in mammography are not able to penetrate silicone or saline implants sufficiently to image the overlying or underlying breast tissue. Compared to mammography or ultrasound, MRI is more accurate in women with augmented breasts.

Thermography
Digital Infrared Thermal Imaging, also known as thermography, is a painless, non-invasive diagnostic technique, which does not involve any radiation exposure. This technology at one time appeared promising but lost favor about 20 years ago. However, with new ultra-sensitive high-resolution digital infrared devices, its efficacy has been improved. Infrared imaging software utilizes high precision pixel temperature measurements which can detect minute temperature variations related to blood flow and can demonstrate abnormal blood flow patterns associated with the initiation and progression of a chaotic tumor vasculature (blood flow system). Angiogenesis is a key factor that facilitates the growth of cancer and it is this biological feature of cancer on which thermography is based. Due to thermography’s sensitivity to blood flow and metabolic changes, it can detect tumors at a smaller size than mammography.

Unfortunately, there are no studies involving the detection of breast cancer that compare the accuracy of Digital Infrared Thermal Imaging to that of mammography, ultrasound, and MRI. However, studies have been conducted to evaluate the accuracy of mammography versus ultrasound versus MRI. In a study that screened 192 women at high risk for breast cancer, cancer was detected in nine patients. Mammography and ultrasound detected 6 of the nine cases of cancer whereas MRI detected all nine cases of breast cancer (Kuhl et al. 2000).

Another study comparing the accuracy of these three modalities screened 196 women at high risk for hereditary breast cancer and detected a total of six cases of invasive breast cancer. Mammography detected 2 of the 6 cases, ultrasound detected 3 of the 6, and MRI detected all 6 cases(Warner et al. 2001).

High-Risk Screening
Regular screening is especially important for women who are at high risk of breast cancer. A woman can be placed in a high-risk category if she possesses either a single factor that greatly increases her risk or a combination of lesser factors that together increase her risk.

Single factors that can place a woman in a high-risk category include a personal history of breast cancer, carcinoma in situ, atypical hyperplasia, and exposure to high doses of ionizing radiation in childhood or young adulthood (for instance, for treatment of Hodgkin's disease) (Hancock et al. 1993; USPSTF 1996; Harris et al. 1997). A family history of breast cancer, especially in a mother, sister, or daughter, or a particular genetic mutation can also place a woman at high risk of breast cancer. In addition, research on genetic markers for breast-cancer risk has pinpointed a number of genes, two of which, BRCA1 and BRCA2, are associated with a markedly elevated risk of breast and ovarian cancer. As many as 60-80% of women with mutations in either of these two genes may develop breast cancer in their lifetimes (Alberg et al. 1997; Struewing et al. 1997; Whittemore 1997).

There are also several moderate risk factors for breast cancer, which occurring together can place a woman at high risk. They include having a first period (menarche) before age 12, not bearing a child, and having a first child after age 30. It is recommended that women at high risk for breast cancer have annual clinical breast examinations more frequently than women at average risk.

TYPES OF ABNORMAL SCREENING FINDINGS

Typically, a clinical breast exam or mammogram will show no sign of disease. However, for some women, the test results will prove to be abnormal, and they will need to have additional tests to determine whether they have cancer. Which tests are performed depends on a number of factors, such as the type of abnormality found and the age of the woman. Usually the follow-up tests begin with the least invasive methods, such as an ultrasound or second mammogram, and progress, if necessary, to the more invasive methods, such as a needle or surgical biopsy. A biopsy should spare the tissue, removing just enough tissue to make a diagnosis without being unnecessarily invasive. A woman should not rush from one abnormal screening mammogram or clinical breast exam to a major invasive surgical procedure or to treatment for breast cancer. Following the series of tests outlined below may help avoid unnecessary procedures.

From a Clinical Breast Exam
A lump called a palpable mass is the most common abnormal finding from a clinical breast exam. The first determination that must be made is whether the mass is solid or fluid-filled. Most likely, if it is fluid-filled, the mass is a cyst. Simple fluid-filled cysts are not cancerous and can be left untreated in many cases. However, complex cysts contain both solid tissue and fluid and may need additional examination to assure they are not cancerous. Solid masses, on the other hand, are potentially cancerous.

For Individuals Age 30 and Older
The general approach to follow up a palpable mass involves further examination of the mass with a diagnostic mammogram, ultrasound, or needle biopsy. Mammography with or without an ultrasound is often the first choice. However, a person with a mass that is likely not cancerous may choose to begin follow-up with a needle biopsy. Instead of an initial needle biopsy, most individuals with a palpable mass begin follow-up tests with a mammogram and/or ultrasound of the mass. This imaging may help avoid a needle biopsy by identifying a mass as a simple cyst, complex cyst, or a suspicious mass that could be cancerous.

Needle Biopsy
A needle biopsy is the insertion of a thin, hollow needle into a breast mass to ascertain if fluid can be drawn out (aspirated). If fluid can be aspirated, this indicates that the mass is a cyst. If the cyst is completely reduced after being aspirated and does not return after 2-3 months, then no further treatment is required. If the mass is not completely reduced after being aspirated or if it later returns, then additional steps are necessary to rule out cancer, including another needle biopsy, an ultrasound examination, or surgical removal of the mass.

If fluid is not aspirated during the initial needle biopsy, this is an indication that the mass is solid, and an examination of the tissue removed during the needle biopsy will determine the next step. If the mass is found to be a fibroadenoma, then the woman has a choice to make: Have it removed or have it closely monitored. Removal involves surgery, but can determine definitively whether or not there is any cancer present.

If the initial needle biopsy results are unclear, then the mass will be examined with mammography and/or ultrasound, followed by either another needle biopsy or a surgical biopsy. However, if the initial needle biopsy reveals cancer, then treatment should begin at once.

For Individuals Under Age 30
In this age group, the follow-up is slightly different because most individuals with a palpable mass have a very low rate of breast cancer. Follow-up of a palpable mass usually begins with observing the mass for a duration of 1-2 menstrual cycles (in women) to see if it persists or disappears. During this follow-up period, clinical breast exams should not be performed in the week before or during a woman's menstrual period because cysts can become enlarged during menstruation. If the mass remains after the observation period, then an ultrasound or needle biopsy will be performed. If a woman has a strong family history of cancer (e.g., two or more immediate family members with cancer), there is increased risk of breast cancer, and an ultrasound or needle biopsy may be performed without waiting.

Other Abnormal Findings from a Clinical Breast Exam
In addition to a palpable mass, other potentially abnormal findings during a clinical breast exam include thickening within the breast, changes to the skin, and nipple discharge. Any of these abnormal findings require a follow-up to assure that they are not signs of cancer.

Abnormal Findings from a Mammogram
Nonpalpable lesions are tissue abnormalities that generally are either too small to be detected during a clinical breast exam or are spread out in such a way that there is no lump even if the mass is large. Nonpalpable lesions are typically found by mammogram.

First, the radiologist compares the mammogram with previous (or baseline) abnormal mammograms. Next, the radiologist will perform a diagnostic mammogram, focusing on the area where there appears to be abnormal tissue. An ultrasound of the area may also be performed.

The next step will be determined based upon the findings from the diagnostic mammogram and ultrasound. If the lesion is clearly not cancer (e.g., a simple cyst), there is no further follow-up necessary. If the lesion appears likely to be benign (e.g., a fibroadenoma), a repeat mammogram at 6 months and follow up at the physician's discretion is required.

A suspicious lesion can be cancerous; therefore, the next step is to perform a biopsy of the lesion, using stereotactic fine needle aspiration or core needle biopsy (both will be discussed later in this protocol). If the biopsy findings do not agree with the mammogram findings, both procedures must be repeated. If the findings are in agreement, a diagnosis can be made. If the lesion is found to be cancerous, treatment should commence immediately. If the lesion is benign, a follow-up mammogram should be performed within a year. If the follow-up mammogram reveals nothing abnormal, then a woman can return to her normal schedule of mammograms and clinical breast exams. If a lesion is a particular type of benign breast disease (e.g., atypical hyperplasia), the lesion should be excised and examined for the presence of cancer. If cancer is found, treatment should commence immediately. If no cancer is found, then a woman can return to her normal screening schedule.

TYPES OF BIOPSIES

Two general categories of biopsies are used to diagnose breast cancer. These are:

1. Needle biopsies, which include core needle biopsy and fine needle aspiration.
2. Open biopsies, which include excisional biopsy (including wire localization) and incisional biopsy.

Core Needle Biopsy
Core needle biopsy, or cutting needle biopsy, is a method of procuring tissue samples from the breast using a thin, hollow needle. Palpable lumps can be biopsied in a doctor's office using local anesthetic. Using the fingertips to isolate the lump, the doctor makes a small nick in the skin, inserts a needle, and removes a sample of the tissue from the suspicious area. A pathologist, who microscopically evaluates the breast tissue and/or lymph nodes removed during biopsy or surgery for cancer, then examines the tissue sample.

For nonpalpable areas that cannot be felt to be sampled, the procedure is more involved and will likely be performed in a hospital or outpatient clinic because of the need for special equipment to locate and accurately sample the correct area. An ultrasound or special three-dimensional mammography, called stereotactic mammography is used.

A core needle biopsy using stereotactic mammography entails first placing a woman on her stomach on a mammography table with the affected breast fitted through a hole in the table. The breast is compressed so that it will remain in place to record an accurate image. Calculations are made based on this image, and a biopsy device containing a needle automatically takes a number of tissue samples from the affected area in the breast. Multiple samples increase the chances of an accurate diagnosis. This procedure involves little pain because the device inserts and removes the needle very quickly.

A core needle biopsy using ultrasound entails a women lying on her back and the doctor holding an ultrasound transducer against the breast. The transducer makes an image of the area to be sampled, allowing the doctor to follow the needle as it enters the breast and reaches the abnormal area. The needle is then inserted by hand and a sample of tissue is removed.

The core needle biopsy provides several advantages. It supplies specific information about a tumor, such as whether it is in situ or invasive. It is accurate, quick, relatively inexpensive, only mildly uncomfortable, and does not involve surgery.

There are disadvantages to the core needle biopsy. The most important is that the core needle biopsy can produce false negative results. False negatives may occur if the needle misses the tumor and instead takes a sample of normal tissue. This can impact a woman's chances for long-term survival because the undiagnosed cancer may go untreated. Furthermore, the samples taken may not provide complete information about a tumor; a tumor may be diagnosed as being in situ instead of invasive. Taking multiple tissue samples can help limit this potential problem.

Fine Needle Aspiration (FNA)
Fine needle aspiration (FNA), also known as fine needle biopsy, is a method of procuring cell samples using a very thin needle. Although FNA can be performed on both palpable lumps as well as nonpalpable areas found by mammogram, FNA is recommended only for use on palpable lumps. The key to an accurate diagnosis is the removal of an adequate number of cells from the suspicious area. With nonpalpable lesions, however, FNA can frequently remove insufficient samples of cells, especially compared to core needle biopsy.

For palpable lumps, FNA can be done in a doctor's office. During the procedure, the doctor will locate and isolate the lump with the fingertips, insert a very thin needle attached to a syringe, and draw out (or aspirate) a sample of cells. The needle is so thin that there is little pain, and no anesthetic is needed. The whole procedure takes only a few minutes. Then the sample cells will be sent to a doctor or a cytopathologist who specializes in examining individual cells for a diagnosis.

The advantages of FNA are that it is quick, relatively inexpensive, only mildly uncomfortable, and does not involve surgery. FNA is an excellent method of diagnosing cancer when it is performed on a palpable lump by an experienced doctor and is analyzed by an experienced cytopathologist.

There are several disadvantages to using the FNA procedure. FNA is not recommended for nonpalpable lesions. Even for palpable masses, FNA may not remove enough cells for the cytopathologist to be able to make an accurate diagnosis. In addition, false negatives occur in about 0-4% of FNA procedures performed on palpable lesions (Harris et al. 1997). As a result, a woman having an FNA may need to have a more definitive biopsy, such as a core needle or excisional biopsy, to ensure that the palpable lesion is not cancerous.

Another drawback of FNA is that while it can be used to determine if cells are cancerous, it cannot distinguish in situ cancers from invasive cancers. However, these two types of cancers are generally treated differently via surgery. Finally, FNA requires an experienced breast cytopathologist to accurately analyze the sample of cells, a type of physician that not all hospitals or medical centers will have on staff.

Excisional Biopsy
An excisional biopsy is the most accurate method for diagnosing breast cancer. It is also referred to as "lumpectomy" or "partial mastectomy." An excisional biopsy is performed by a surgeon and is generally done under a local anesthetic, meaning that the area to be operated on is desensitized, but the patient remains awake. During the procedure, the surgeon makes an incision in the breast and removes the entire suspicious area and a small amount of surrounding normal tissue. Most women are able to have a biopsy and return home the same day.

Wire Localization for Nonpalpable Lesions
A nonpalpable lesion is difficult to locate during an excisional biopsy. Therefore, a radiologist uses a mammography or ultrasound image for direction and a surgeon inserts a very thin wire into the breast as a guide to identify the breast tissue that requires removal. The surgeon then removes the abnormal tissue. This procedure is called wire localization or needle localization.

Once the nonpalpable mass is removed, the tissue is x-rayed immediately. This allows the surgeon and radiologist to match the suspicious areas on a woman's mammogram with those in the biopsy tissue. If the areas do not match, the surgeon has two options. One option is for the surgeon to make an additional attempt to remove the correct tissue. The other option is to wait and rebiopsy at another time when the area has been targeted a second time using the wire localization technique.

Frozen Sections
Immediately after the tumor is removed from the breast, a frozen section is usually performed. This process entails freezing a portion of the biopsied tissue and then quickly cutting a thin slice for the pathologist to analyze under the microscope. In the past, if a biopsy came back as positive for cancer, surgical treatment was performed immediately. Currently, biopsies are prior to and separate from the definitive surgery. However, immediate results using frozen sections can help alleviate a woman's anxiety.

A high percentage of false negatives may be produced with frozen sections. Therefore, frozen section results are only preliminary and need to be confirmed by a routine fixed sample, which takes about 2 working days to analyze (Harris et al. 1997).

Excisional Biopsy as a Surgical Treatment
The primary function of an excisional biopsy is to diagnose cancer. However, it can also serve as definitive surgery by removing the cancerous tumor from the breast. Definitive surgery consists of the removal of the entire tumor plus a surrounding amount of normal tissue (a margin) and possibly the axillary lymph nodes.

The pathologist will then inspect the tumor margins. If normal tissue surrounds the entire tumor (which is termed clean or uninvolved or negative margins), the surgery is considered definitive and no additional surgery is needed. If there is insufficient normal tissue surrounding the tumor ("dirty" or involved or positive margins), additional surgery is required to remove the remaining tumor.

The excisional biopsy has many advantages over a needle biopsy. It provides a larger sample size, ensuring far fewer false negative results, and provides accurate information on factors such as tumor size, tumor grade, and the presence of estrogen receptors, all of which are key factors in deciding on a treatment plan.

The excisional biopsy has some disadvantages. It is a far more extensive procedure than a needle biopsy. If a large amount of tissue is removed, the appearance and feel of the breast may also be changed. An excisional biopsy is also expensive and has a longer, more painful recovery period.

Incisional Biopsy
Incisional biopsy is a surgical procedure done most often on women with advanced-stage cancer whose tumors are too large to be removed as an initial treatment. Only a portion of the tumor is removed, providing a sufficient amount of tissue to procure information essential for developing a treatment plan.

PROGNOSTIC AND PREDICTIVE FACTORS

Once cancer is diagnosed, there are several tests performed on lymph node or tumor tissue that can be useful in determining a woman's prognosis and for assessing the type of treatment that will be most effective for her specific breast cancer. The issue of which factors are the most reliable at determining a woman's prognosis and predicting her outcome to certain treatments is perpetually under study. As research progresses, certain factors will fall in and out of favor. Only when found to be accurate and reliable does a factor become a part of standard practice. Commonly assessed prognostic and predictive factors include lymph node status, tumor size, and tumor grade, type of cancer, hormone receptor status, proliferation rate, and HER2/neu (also known as erbB2 expression).

Axillary Lymph Nodes
Lymph nodes are simply small clumps of immune cells acting as filters for the lymphatic system. Like the circulatory system, the lymphatic system runs throughout the body carrying fluid, cells, and other material. When breast cancer spreads, the first places it usually goes is to the axillary lymph nodes in the armpit. The best prognosis is when the cancer remains localized within the breast. Once the cancer spreads beyond the breast, the prognosis worsens.

There are two ways to determine node status. The first method consists of palpating the axillary lymph nodes during a physical examination. If the nodes are enlarged, it is possible that cancer has spread. This method, while fast and convenient, is not very accurate. It has both a 30% false negative and a 30% false positive rate (Harris et al. 1997).

The second method is removal of the nodes from under the armpit in a procedure called an axillary dissection. The nodes are then examined to determine whether or not they contain cancer. This procedure may be performed at different stages of a woman's treatment. However, a standard axillary dissection is typically performed during removal of the breast tumor, and approximately 10-25 lymph nodes are also removed from tissue layers under the armpit.

When an excisional biopsy serves as definitive surgery, the axillary dissection may be performed at the same time or as a separate procedure. Many surgeons now try to perform both procedures together to eliminate the need for separate surgery, anesthesia, and recovery. However, regardless of when the procedure is performed, the node samples are sent to a pathologist for analysis. If the samples do contain cancer, the pathologist will carefully note the number of cancerous nodes and their order and location, from proximal (closest to the breast) to distal (farthest away from the breast).

The Sentinel Node Biopsy
The sentinel node biopsy is a procedure that finds and removes the first (or sentinel) node from the tumor site and examines it to see if it contains cancer cells. If the sentinel node is cancer free, it's likely that the other axillary nodes are cancer free as well (Turner et al. 1997). However, if the sentinel node is positive for cancer, there is a strong likelihood that other nodes may also be involved, and a standard axillary dissection may be required (Weaver et al. 2000).

In order to locate the sentinel node, a colored dye and/or radioactive-labeled tracer is injected into the breast near the tumor. A device called a scintillation counter determines which lymph node is the first node to take up the dye or tracer. This node is then surgically removed and sent to a pathologist for examination.

The advantages of this procedure are that, when done correctly, it is accurate, less traumatic, and it allows axillary dissections to be done on only those women whose sentinel nodes present positive for cancer.

The disadvantages of the procedure are that it is fairly new, not widely available, and its accuracy depends in large part on the training of the surgeon doing the procedure (Haigh et al. 2000). Several ongoing clinical trials will ultimately determine whether sentinel node biopsy becomes part of the standard diagnostic procedure for breast cancer (Barnwell et al. 1998; Krag et al. 1998; McNeil 1998; Haigh et al. 2000). However, the integration of sentinel node biopsy into contemporary clinical practice is underway (Schwartz et al. 2001).

Tumor Size and Lymph Node Status
Based on numerous studies, there appears to be a strong correlation between tumor size and lymph node involvement. Research demonstrates that the larger the breast tumor, the more likely it is that the lymph nodes will be positive for cancer (Carter et al. 1989). One study of 644 women with tumors 2 cm or smaller found that only 11% of the women with tumors 0.1-0.5 cm in size had axillary lymph node involvement. However, when tumors 1.7-2.0 cm were found, more than 40% of the women had axillary lymph node involvement. The prognosis for breast cancer is related to the size of the tumor. Tumor size can be determined by touch during a physical examination, through imaging with an ultrasound or mammography, or most accurately through post-surgical examination of the tumor. In general, the larger the tumor size, the poorer the prognosis.

Tumor Grade
The grade of a tumor is used to determine how fast a cancer may spread to the lymph nodes or other areas of the body. A pathologist microscopically examines biopsied tissue, determining how closely the cancer cells resemble normal tissue. The less the tumor cells resemble normal tissue, the higher the tumor grade. The pathologist will also assess the rate of cancer cell division. Rapidly dividing cells indicate accelerated tumor growth and therefore a higher tumor grade. Tumor grades are determined as Grade I, or low; Grade II, or medium; and Grade III, or high. Tumor grade is considered directly related to prognosis: the higher the grade, the poorer the prognosis.

Hormone Receptors
An important aspect in any reproductive cancer is whether the tumor growth is hormonally driven. Often breast tumors require hormones for growth, i.e., hormonally responsive tumor. The hormones attach to their receptor sites and promote cell proliferation. Hormone receptor-positive tumors consist of cancer cells with receptor sites for estrogen, progesterone, or both. The receptor status of a tumor is determined by testing tissue removed during a biopsy. Breast cancer can be categorized by its receptor status, which can be estrogen receptor-positive (ER+), estrogen receptor-negative (ER -), progesterone receptor-positive (PR+), progesterone receptor-negative (PR-) or any combination thereof. Both estrogen and progesterone are naturally occurring hormones that the body produces in varying amounts throughout one's lifetime. These hormones are essential for many other physiological functions, such as bone integrity, which will be discussed later in this protocol.

Treatment to block the hormones from attaching to the tumor receptor sites may slow or stop the cancer's growth. The drug most often used in this type of treatment is tamoxifen, which is very effective against receptor-positive cancers. Tamoxifen will be discussed extensively later in this protocol.

HER2 Gene Overexpression
HER2 (human epidermal growth factor receptor 2) is a gene found in every cell of the human body, and its purpose is to help a cell divide. The HER2 gene tells a cell to form the HER2 protein on the cell surface. HER2 protein then receives a signal to send a message to the center of the cell, known as the nucleus, that it is time to divide. The HER2 protein is also called the HER2 receptor.

Each healthy breast cell contains two copies of the HER2 gene, which contribute to normal cell function. When a change occurs that causes too many copies of the HER2 gene to appear in a cell, the gene, in turn, causes too many HER2 proteins, or receptors, to appear on the cell surface. This is referred to as HER2 protein overexpression. Patients who are considered HER2-positive have cancer that grows and spreads more rapidly.

HER2 protein overexpression affects about 25% of breast cancer patients and results in a more aggressive form of the disease and earlier disease reappearance; in these cases the disease may not be as responsive to standard therapies. The HER2 status of a tumor is determined by testing tissue removed during a biopsy.

Herceptin may be considered by breast cancer patients whose tumors over-express the HER2 gene (Nihira 2003).

p53 Gene Mutation
The p53 protein is a tumor suppressor encoded by the p53 gene, whose mutation is associated with approximately 50-60% of human cancers. The p53 gene acts as the guardian of DNA and, in the event of DNA damage, it performs several crucial functions. The p53 gene acts as a checkpoint in the cell cycle inducing growth arrest (halting the cell cycle) by increasing the expression of the p21 gene. It initiates DNA repair. If the DNA can be repaired, the p53 gene prevents apoptosis (programmed cell death), or if the DNA cannot be repaired, it initiates apoptosis. The p53 protein also plays a role in the transcription ("reading") of DNA by binding to and initiating the expression of multiple genes.

When a mutation in the p53 gene occurs, one amino acid is substituted for another and p53 loses its ability to block abnormal cell growth. Indeed, some mutations produce a p53 molecule that actually stimulates cell division and promotes cancer. These cancers are more aggressive, more apt to metastasize, and more often fatal.

People inheriting only one functional copy of the p53 gene from their parents are predisposed to cancer in early adulthood. Usually several independent tumors develop in a variety of tissues. This is a rare condition known as Li-Fraumeni syndrome. The p53 gene has been mapped to chromosome 17p13, and mutations in the p53 gene are found in most tumor types and contribute to the molecular events that lead to tumor formation.

Since the hallmark of cancer is the unchecked proliferation of cells, the role of p53 is critical. The question then becomes, if the p53 gene is a built-in tumor suppressor, why does cancer still develop? The answer is that the p53 molecule can be inactivated in several ways. As discussed earlier, in some families p53 mutations are inherited and family members have a high incidence of cancer. More often, the p53 molecule is inactivated by an outside source.

In the cell, p53 protein binds DNA, which in turn stimulates another gene to produce a protein called p21 that interacts with a cell division-stimulating protein (cdk2). When p21 binds with cdk2, the cell cannot pass through to the next stage of cell division. Mutant p53 can no longer bind DNA in an effective way, and as a consequence the p21 protein is not made available to act as the "stop signal" for cell division. Thus, cells divide uncontrollably and form tumors. DNA tumor viruses, such as the human adenovirus and the human papilloma virus can bind to and inactivate the p53 protein function, altering cells and initiating tumor growth. In addition, some sarcomas amplify another gene, called mdm-2, which produces a protein that binds to p53 and inactivates it, much the way the DNA tumor viruses do.

The amount of information that exists on all aspects of p53 normal function and mutant expression in human cancers is vast, reflecting its key role in the pathogenesis of human cancers. It is clear that p53 is just one component of a network of events that culminate in tumor formation.

ras Mutation
The ras oncogenes often governs the regulation of cancer cell growth. The ras family is responsible for modulating the regulatory signals (mitogen activated protein kinase (MAPK) signal transduction cascade) that govern the cancer cell cycle and proliferation. The Ras protein also plays a role in initiating a number of other signal transduction cascades, including phosphoinositide (PI) kinase, and the activation of protein kinase C (PKC). Inhibition of Ras protein action is important because ras induces the expression of the MDM2 gene, whose protein serves to inhibit the activity of the p53 protein. In this way, ras activity reduces the ability of the p53 protein to induce cell death (apoptosis) in cancer cells. Mutations in genes encoding ras proteins have been intimately associated with unregulated cell proliferation of cancer. Further, since ras protein plays an important role in multiple signal transduction pathways and is overexpressed in a large number of cancers, the inhibition of ras is now considered a goal in cancer treatment (Rowinsky et el. 1999).

BRCA1 and BRCA2 Mutations
BRCA1 and BRCA2 are familial (inherited) gene mutations that have been linked to breast cancer. BRCA1 is a tumor suppressor gene located on the long arm of chromosome 17, and BRCA2 is located on chromosome 13. Tumor suppressor genes play a role in regulating cell growth. When one copy of BRCA1 is inherited in a defective (mutant) form, a woman is predisposed to breast and ovarian cancer. However, BRCA1 mutations do not appear critical for the development of the majority of breast and ovarian cancers. Development of cancer in either organ involves a number of additional mutations, at least one of which involves the other copy (allele) of BRCA1. A woman who inherits one mutant allele of BRCA1 from either her mother or father has a greater than 80% risk of developing breast cancer during her life. While it appears that a high number of currently identified high-risk families have mutations in either the BRCA1 or BRCA2 genes, hereditary breast cancer accounts for only about 5% of all cases of breast cancer.

Testing tumors in women with breast cancer for the BRCA1 gene could increase the effectiveness of chemotherapy dramatically. Cancer cells with functional BRCA1 are highly resistant to one type of chemotherapy but extremely sensitive to another. In laboratory tests tumor cells react differently to anti-cancer agents depending on the BRCA1 gene activity. A functioning BRCA1 gene made tumor cells more than 1,000 times more sensitive to drugs such as Taxol and Taxotere, which work by blocking the final stage of cell division. The same cells, however, were between 10 and 1,000 times more resistant to drugs like cisplatin that work by damaging DNA within tumors. Assessing a tumor's BRCA1 status may be invaluable in deciding which type of chemotherapy to use.

The BRCA1 gene plays an important role in stopping the development of cancer, and women who inherit a damaged version of this gene have a high risk of developing breast cancer. BRCA1 may also get "switched off" in as many as 30 percent of tumors, even in patients who inherit a normal version of the gene.

Aggressive Tumors
Certain tumors may be classified as aggressive based on a number of prognostic factors, such as tumor type, size, and grade. Typically, an aggressive tumor is one that under microscopic examination shows signs of fast growth and has a high grade. Because aggressive tumors have a greater chance of spreading to other areas of the body and returning after treatment, they are often treated more intensively. One example of an aggressive tumor is inflammatory breast cancer.

Staging
Cancer is classified into stages, which determine treatment and prognosis. There are a number of methods for staging breast cancer. The most widely used is the TNM classification (Tumor, Nodes, Metastases). TNM takes into account the size of the tumor (T), the number of cancerous lymph nodes (N), and whether or not the cancer has spread to other areas of the body (metastasis) (M). The stage of cancer is usually determined twice. The first is clinical staging, which is based on results from a physician's physical exam and tests such as mammography. The second is pathologic staging based on a direct examination of the lymph nodes and a tumor removed during surgery.

TESTS FOR DISTANT METASTASES

Cancer cells have the ability to leave the original tumor site, travel to distant locations, and metastasize in organs such as the liver, lungs, or bones. The process of metastasis is dynamic and requires an optimal environment in order for a tumor cell to proliferate, invade surrounding tissues, be released into the circulation, adhere to blood vessels in the liver, invade the liver, proliferate, and establish its own blood supply (tumor angiogenesis). This complex process requires interaction of tumor cells with the microenvironment of the liver to the extent that the tumor cell can utilize the growth factors and blood vessels of the liver in order to grow.

In addition to tests for prognostic and predictive factors, women diagnosed with node-positive breast cancer will require a number of tests to confirm that the cancer has not spread to other organs, such as the lungs, liver, and bone. Only about 6% of women when first diagnosed with breast cancer have distant metastases (Ries et al. 2000). Most women found to have metastases have previously been treated for the disease and are experiencing a recurrence.

Symptoms such as shortness of breath, a chronic cough, weight loss, and bone pain may indicate distant metastases. However, only after specific tests can the occurrence of distant metastasis be confirmed or ruled out. The three primary tests performed are blood tests that check for liver and/or bones metastasis, bone scans to test for bone metastasis, and x-ray/CT scans to test for chest, abdomen, and liver metastasis. Based on the results of the primary tests and the symptoms the woman experiences, further testing may be required.

Common Tests for Distant Metastases

1. X-rays. An x-ray is a test in which an image is created using low doses of radiation reflected on film paper or fluorescent screens providing an image of specific areas. The films created by x-rays show different features of the body in various shades of gray. The darkest images are those areas that do not absorb x-rays well; the lighter images are dense areas (like bones) that absorb more of the x-rays. To enhance visibility, some x-ray exams will use a contrasting solution that can be swallowed, injected intravenously into the circulatory system, or given by an enema to locate or confirm possible metastases.
2. Computer Axial Tomography (CAT or CT) scan. This procedure combines the use of a digital computer together with a rotating x-ray device to create detailed cross-sectional images, or "slices," of the different organs and body parts. This procedure may or may not involve injecting an intravenous contrasting solution into the circulatory system. It does, however, always involve exposure to ionizing radiation. A CAT scan has the unique ability to image a combination of soft tissue, bone, and blood vessels and can assist in locating possible metastasis.
3. Magnetic Resonance Imaging (MRI). MRIs involve no ionizing radiation and can be used for precise imaging of any organ suspected of having metastases. This is a special imaging technique used to image internal structures of the body, particularly the soft tissues. An MRI image is often superior to a normal x-ray image. In an MRI exam, the patient passes through a tunnel surrounded by a magnet, which polarizes hydrogen atoms in the tissues and then monitors the summation of the energies within living cells. A computer tracks the magnetism and produces a clear picture of the tissues, particularly soft tissues. Images are very clear and are particularly good for soft tissue, brain, and spinal cord, joints, and abdomen. These scans may be used for detecting some cancers or for following their progress.
4. Positron Emission Tomography (PET). A highly specialized imaging technique using short lived substances such as simple sugars (glucose), which are labeled with signal emitting tracers (18-fluoro-deoxyglucose (18-FDG)) and injected into the patient. A scanner records the signals these tracers emit as they travel through the body and collect in various organs targeted for examination. Although all cells use glucose, more glucose is used by cells with increased metabolism such as tumor cells, which use more glucose than neighboring cells, and thus, they are easily seen on the PET scan. PET uses a camera that produces powerful images to reveal metastasis that other imaging techniques simply cannot detect. This technique is very sensitive in deciphering and picking up active cancer cells or tumor tissue but does not measure size. PET can follow the course of cancer through the body and accurately show the extent of the disease. PET can differentiate between normal tissue, scar tissue, and malignant cancerous tissue.
5. Ultrasound. Very high frequency sound waves are used to produce an image of many of the internal structures in the body without exposure to ionizing radiation. This is highly operator-dependent and is thought to be useful in diagnosis but not particularly accurate in the assessment of tumor response. For the latter, CT or MRI scans are more accurate. Intraoperative ultrasonography is useful in the detection of liver metastases.
6. Bone Scan. A bone scan is a nuclear medicine study of the body skeleton used to look for cancer, stress fractures, and other bone or joint problems. It does not measure bone density and is not used to diagnose osteoporosis. This procedure uses a radioisotope tracer (Technetium-99m MDP or HDP) injected intravenously into the circulatory system. This radioactive compound localizes in the bone and the distribution of the radioactivity in the body is recorded by the radionuclide scanner (better known as a gamma or scintillation camera), producing an image of the tracer's distribution in the skeletal system. This recording can reveal the presence of bone metastases.
7. Bone Density. Since excessive bone breakdown releases tumor growth factors into the bloodstream that can fuel cancer growth, a bone density scan and a test that can be used to assess bone resorption rates should be regularly performed for cancer patients. All bone density scan measurements with the exception of ultrasound use small doses of radiation to determine the amount of bone present.
8. DPD. The deoxypyridinoline (DPD) cross-links urine test (Pyrilinks-D) can be used to assess bone resorption rates; this test should be done every 60-90 days to detect bone loss in patients with cancer that has a proclivity to spread to bone. A QCT bone density scan should be done annually. Every cancer patient should take a bone-protecting supplement to protect against excess bone breakdown. For information regarding maintaining bone integrity refer to the protocol Cancer Treatment: The Critical Factors.
9. QCT. Quantitative Computed Tomography, or QCT Densitometry (often referred to as a QCT bone density scan) is a method used to measure bone mass. The principle underlying QCT densitometry and other bone mass measurements (such as DXA) is that calcified tissue will absorb more x-rays than surrounding tissue so that the CT density measurement can be used to measure total bone mass within a sample of tissue. With proper technique, precision for the conventional (2D) method is 2-3%, and about 1% for 3D QCT, so monitoring patients at yearly intervals yields clinically useful results. Only QCT isolates the metabolically active bone for analysis. The QCT examination is performed on any modern CT scanner and takes approximately 10 minutes. Insurance companies and Medicare may reimburse for QCT examinations.
10. DXA. DXA stands for dual x-ray absorptiometry. It was previously known as DEXA, dual energy x-ray absorptiometry. Low dose x-rays of two different energies are used to distinguish between bone and soft tissue, giving an accurate measurement of bone density at these sites. However, DXA also includes aortic calcification and osteophytes in the calculation of bone mineral. Lateral DXA, has been shown to have a sensitivity intermediate between the high sensitivity of QCT and the somewhat lower one of conventional DXA (used for detection of osteoporosis), but it uses 4-10 times the radiation exposure, is less precise, and the study time is increased compared to conventional DXA/QDR.
11. Blood Tests. A variety of blood tests can assess the health of different organs and systems in your body. "Cancer marker" tests can detect possible cancer activity in the body. If cancer is present, it can produce specific protein in the blood that can serve as a "marker" for the cancer. CA 15.3 is the name of a protein used to find breast and ovarian cancers, although it is important to note that there may be insufficient quantities of this protein present in the blood to ensure early stage breast cancer detection. Creatine-kinase-BB serves as a marker for breast, ovarian, colon, and prostate cancers. CEA (carcinoembryonic antigen) is a marker for the presence of colon, lung, and liver cancers and a marker for secondary breast and ovarian cancer sites. CA125 may signal ovarian cancer and secondary breast and colorectal cancer sites. TRU-QUANT and CA 27.29 are other examples of proteins associated with the recurrence of breast cancer (more information on tumor markers will follow). Blood tests should evaluate for the presence of anemia or hepatic dysfunction, both of which can be consequences of the patient’s underlying cancer.

TREATMENT OF BREAST CANCER

In the past 20 years, many strides have been made to improve the treatment of breast cancer. Some of the trauma associated with breast cancer treatment has been reduced because of increased early detection through mammography, surgery options that conserve much of the breast, and the increasing long-term survival rate. The treatment goal is to rid the body of the cancer as completely as possible and to prevent the cancer from returning. This is usually accomplished by utilizing multimodalities, including surgery, anticancer drugs (chemotherapy), irradiation, hormone therapy, nutritional supplementation, and diet modification.

Surgery and radiation therapy are considered local treatments. They focus on eliminating cancer from a limited or local area - such as the breast, chest wall, and axillary nodes. Chemotherapy, hormone therapy, nutritional supplementation, and diet modification are considered systemic therapy. In systemic therapy, the entire body is treated in order to eradicate any cancer cells that may have spread from the breast tumor to other areas of the body.

Treatment depends on many factors, such as age, tumor stage, and estrogen-receptor status. However, deciding on a particular treatment is both a personal and a medical choice. Each treatment option has risks and benefits. Therefore, the type of treatment a woman chooses should be based on an understanding of how these risks and benefits relate to one's personal values and lifestyle.

LOCALIZED TREATMENT

Surgery
Breast cancer surgery strives to completely remove the tumor from the breast. However, surgery may also include the removal of one, some, or all of the axillary lymph nodes. Following surgery, both the tumor and/or lymph nodes are sent to a pathologist for examination to determine the stage of the breast cancer so the physician and patient can decide what additional treatment may be required after surgery.

There are two basic types of surgery for breast cancer: breast-conserving surgery and total mastectomy.

Breast-Conserving Surgery
Breast-conserving surgery consists of the removal of the breast tumor and some surrounding normal tissue. This procedure can be referred to as a lumpectomy, wide excision, or partial-radical mastectomy. During the operation, axillary lymph nodes may also be removed.

During breast-conserving surgery, the patient is usually given general anesthetic, causing unconsciousness. The surgeon then opens the breast and removes the tumor and a small amount of normal tissue. The surgeon then sutures together the edges of the incision, trying to keep the breast as normal looking as possible.

If axillary lymph nodes are removed, the surgeon will also open the area under the armpit on the same side as the affected breast, removing about 10-15 lymph nodes. However, if a sentinel node biopsy is performed only 1-3 lymph nodes are removed and used to assess node status.

Breast-conserving surgery can be done on palpable tumors (tumors that the physician is able to feel), as well as tumors that are not palpable but that can be located by mammography. In the case of tumors that are not palpable, a radiologist will insert a very thin wire into the area of the tumor in the breast during a mammogram. This procedure is called wire-localization or needle-localization (and was discussed earlier). The wire remains in the breast until the surgery and serves as a guide for the surgeon.

The tumor and lymph nodes removed during surgery are sent to a pathologist, who will assess the tumor margins to determine whether there is an adequate amount of normal tissue surrounding the tumor. This margin of normal tissue helps indicate whether or not the entire tumor was removed. If clean, uninvolved, or negative margins are found, this indicates that only normal tissue remains at the edges of the tissue removed and no additional surgery is needed. If normal tissue does not completely surround the tumor, the margins are considered "dirty," "involved," or "positive." Additional surgery will then be done to obtain adequate margins (Love et al. 1997).

A second breast-conserving operation is usually done if the tumor margins are found to be "dirty." This surgery is called a re-excision. If it does not achieve negative margins, a total mastectomy may be recommended.

Total Mastectomy
A total mastectomy procedure entails the removal of the entire breast. This may include an axillary dissection as well. For women who have decided to have breast reconstruction, this procedure will directly follow the mastectomy surgery.

A total mastectomy is done under general anesthetic. During the operation, all of the breast tissue is removed, including the nipple. For women considering breast reconstruction during or sometime after surgery, as much skin as possible is left intact in order to cover the implant. If a woman is not having reconstruction or is having it at a later time, the skin in the area is sewn together and a drainage tube is inserted so fluid from the healing wound can drain away.

The pathologist will evaluate the breast tissue and lymph nodes. The results of these tests will help determine which adjuvant therapy will be used.

Luteal Phase Surgery
Studies have suggested that premenopausal women who have their breast-conserving procedure or mastectomy done during the later part of their menstrual cycle (during the luteal phase) may have a better outcome after surgery. However, researchers are still assessing the benefits to "timing surgery" (Senie et al. 1997; NCI 1998).

Radiation Therapy
Radiation therapy (also known as radiotherapy) is considered a local treatment for breast cancer that uses targeted, high-energy x-rays to impede cancer cells' ability to grow and divide. The aim of radiation therapy is to rid the breast, chest, and axillary lymph nodes of cancer by using high-energy x-rays. For women with early-stage breast cancer, radiation therapy is most often performed following breast-conserving surgery. It is believed that after conserving surgery, there may still be microscopic cancer in the breast undetectable to the naked eye. Therefore, to reduce the chance of recurrence, radiation therapy is necessary to eliminate any remaining cancer.

Radiation therapy may also be used on the axillary lymph nodes and the chest wall following total mastectomy. Radiation therapy usually commences several weeks after surgery. However, it may be postponed if a patient is receiving chemotherapy first. (For more information regarding radiation therapy, please see the Cancer Radiation Therapy protocol.)

ADJUVANT TREATMENT

The goal of an adjuvant treatment is to systemically eliminate any cancer cells or micrometastases that may have spread from the breast tumor to other parts of the body as well as to eliminate any microscopic cancer cells that may remain in the local breast/lymph node area. These therapies are referred to as adjuvant, meaning "in addition to," because they are used with surgery and radiation. It is called adjuvant systemic therapy because the entire system of the body is treated. Several types of adjuvant systemic treatments are used for early-stage breast cancer: chemotherapy and hormone therapy are well established conventional adjuvant therapies; nutritional supplementation and diet modification may be incorporated in any conventional adjuvant treatment plan.

Except for some women with very small tumors (less than 1 cm) and with lymph nodes that do not have cancer, adjuvant therapy is usually recommended for women with early-stage breast cancer. Which therapies, and in what combination, depends on many things, such as the woman's age, whether the tumor has estrogen receptors, and the number of positive lymph nodes.

Chemotherapy
Chemotherapy uses drugs that can be taken in oral form or injected intravenously to kill cancer cells; sometimes, a combination is used. However, intravenous drugs are usually given in a hospital or doctor's office. Depending on the drugs used, chemotherapy is administered once or twice a month for 3-6 months. Sometimes the range might be extended to 7 or 8 months. Chemotherapy usually begins 4-6 weeks after the final surgery and is administered in a combination of 2-3 drugs that have been found to be the most effective. Unfortunately, chemotherapy drugs have many side effects that can damage or destroy normal healthy tissues throughout the body.

Although the exact schedule depends on the specific drugs used, drugs may be given on day 1 of a 3-week cycle or there may be a period of a week or two on the drugs, followed by a period of about 2 weeks off the drugs. This cycling allows the body a chance to rest and recover between treatments; however, it also gives the cancer cells an opportunity to rest, recover, and possibly mutate into a type of cancer that is chemotherapy-resistant. An entire course of chemotherapy lasts about 4-6 months, depending on the drugs used. Recent studies indicate that a more efficacious approach would be to lower the dose of conventional chemotherapy agents, reschedule their application, and combine them with agents designed to interfere with cancer's ability to produce new blood vessels (anti-angiogenic agents) (Holland et al. 2000).

This lower-dose approach, known as "metronomic dosing," uses a dosing schedule as often as every day. An amount as low as 25% of the maximum tolerated dose (MTD) in combination with anti-angiogenesis agents targets the tumor endothelial cells making up the blood vessels and microvessels feeding the tumor. Tumor endothelial cells can be killed with much less chemotherapy than tumor cells, and the side effects to healthy tissue and the patient in general are dramatically reduced (Hanahan et al. 2000).

While chemotherapy is an effective treatment for many women, it is associated with a number of well-known and traumatic side effects, such as hair loss, and exhausting bouts of nausea and vomiting, which many patients find difficult to tolerate. (For more information on chemotherapy, please refer to the Cancer Chemotherapy protocol.)

Hormone Therapy
Breast tumors often require hormones for growth, which poses a unique problem because the hormones involved in tumor growth are either estrogen, progesterone, or both. Estrogen and progesterone are naturally occurring and necessary hormones, produced mainly in the ovaries and adrenal glands in varying amounts throughout a woman's lifetime. These hormones are essential for many physiological functions, such as bone integrity, which will be discussed later in this protocol.

Hormone receptor-positive tumors can consist of cancer cells with receptor sites for estrogen, progesterone, or both. The hormones attach to receptor sites and promote cell proliferation. Hormone therapy blocks the hormones from attaching to the tumor receptor sites and may slow or stop the cancer's growth. The drug most often used in this type of endocrine therapy is tamoxifen, with a response rate from 30-60%. Other therapies are sometimes used, such as aromatase inhibitors (that inhibit the conversion of precursors to estrogens) or oophorectomy (the removal of the ovaries).

The effective role of some newer hormonal therapies in the treatment of both pre- and post-menopausal women with early breast cancer has been studied. Hormonal therapy with goserelin, either with or without tamoxifen, has been endorsed as an alternative to chemotherapy for young women with hormone-sensitive disease since it is equally effective and better tolerated. Twenty-five percent of all women diagnosed with breast cancer are premenopausal; of these women approximately 60% have hormone-sensitive tumors.

While chemotherapy kills cancer cells by destroying all rapidly dividing cells in the body, goserelin suppresses the supply of estrogen from the ovaries, which stimulates the cancer cells to grow. This is achieved by inhibiting production of another hormone called luteinizing hormone (LH), which stimulates the ovaries to make estrogen. Since many breast cancers grow more rapidly in the presence of estrogen, this can help to reduce tumor growth.

Tamoxifen prevents estrogen from stimulating cancer cell growth by blocking the estrogen receptors in the cancer cells. Cutting off the cancer's supply of estrogen provides an effective alternative method of combating the disease and avoids the distressing side effects of chemotherapy. Based upon evidence from adjuvant studies, hormonal therapy with goserelin is better-tolerated and equally effective as an alternative to chemotherapy. This gives physicians and patients a real choice in treatment following initial surgery (Goldhirsch et al. 2003).

Tamoxifen (Nolvadex)
Tamoxifen is an anti-estrogenic drug used to treat women whose tumors are estrogen or progesterone receptor-positive. This endocrine therapy blocks the female hormone estrogen from binding to the tumor cells. Tamoxifen has been the gold standard hormonal agent used for the treatment of breast cancer for more than 8 years. It is a prototype for a class of compounds called selective estrogen receptor-modulators (SERMs) of breast cancer but is also an effective primary treatment for advanced disease. Women with early-stage breast cancer who take tamoxifen have, on average, a 25% proportional increase in their chances of surviving 5 years after diagnosis.

Tamoxifen does not work equally well in all women. As the name implies, estrogen receptor-negative tumors do not have estrogen receptors, and therefore do not respond to tamoxifen. A Phase III study of 2691 high-risk cancer patients tested the effectiveness of tamoxifen with both pre- and postmenopausal subsets of receptor-negative and receptor-positive tumors. Both the 5-year disease-free and overall survival in patients with receptor-positive tumors treated with the addition of tamoxifen to chemotherapy was significantly higher than with chemotherapy alone, while no such advantage in disease-free or overall survival was found in receptor-negative patients. Further, in the receptor-positive postmenopausal group, the addition of tamoxifen showed a significant improvement in both disease-free and overall survival. However, in the premenopausal receptor-negative patients, tamoxifen led to a worse outcome, as indicated by the significantly reduced survival rate (ONI 2000). Women with estrogen receptor-negative tumors may receive chemotherapy instead of tamoxifen.

Therefore, for the patient whose breast cancer's growth is estrogen-dependent, tamoxifen can keep estrogen from these cells, slowing or stopping their growth. Tamoxifen is a pill taken daily for 5 years. To date, studies do not show any benefit to taking tamoxifen for longer than 5 years (NCI 1998). Studies show that the use of tamoxifen as a post-surgical adjuvant therapy can reduce the chances of the cancer reoccurring.

Tamoxifen has a host of side effects, including hot flashes, weight gain, mood swings, abnormal secretions from the vagina, fatigue, nausea, depression, loss of libido, headache, swelling of the limbs, decreased number of platelets, vaginal bleeding, blood clots in the large veins (deep venous thrombosis), blood clots in the lungs (pulmonary emboli), cataracts (Fisher et al. 1998), and--the side effect of the greatest concern--endometrial cancer (Harris et al. 1997).

Studies have shown an increase of early-stage endometrial cancer (cancer of the lining of the uterus) among women taking tamoxifen, and the risk increases if the drug is taken for more than 5 years. Endometrial cancer is usually diagnosed at a very early stage and is usually curable by surgery. The studies have also shown an increased risk of uterine sarcoma (a rare cancer of the connective tissues of the uterus) among women taking tamoxifen. Unusual vaginal bleeding is a common symptom of both of these cancers. The treating physician should be notified immediately if vaginal bleeding occurs.

Raloxifene
Raloxifene is a drug similar to tamoxifen. It is a selective estrogen receptor-modulator (SERM) that blocks the effect of estrogen on breast tissue and breast cancer. It is currently in the testing phase to assess its effectiveness in reducing the risk of developing breast cancer. Pending testing completion, this drug is not recommended as hormonal therapy for women who have been diagnosed with breast cancer.

Toremifene (Fareston)
Toremifene (Fareston) is an anti-estrogen drug closely related to tamoxifen that may be an option for postmenopausal women with breast cancer that has metastasized. Fareston is a type of anti-estrogen medication that is used in tumors that are estrogen-receptor-positive or estrogen receptor-unknown.

Some patients treated with anti-estrogens who have bone metastasis may experience a tumor flare with pain and inflammation in the muscles and bones that will usually subside quickly. Blood calcium level should be monitored because tumor flare can cause a raised level of calcium in the blood (hypercalcemia) with symptoms of nausea, vomiting, and thirst. Often a short stay in the hospital is necessary until the calcium levels have been reduced or treatment may need to be stopped. Fareston is being studied in clinical trials for use in earlier stages of breast cancer.

Anastrozole (Arimidex), Femara (Letrozole), and Aromasin (Exemestane)
Anastrozole (Arimidex), Femara (Letrozole), and Aromasin (Exemestane) are three hormonal therapy drugs referred to as aromatase inhibitors. Aromatase is the enzyme that converts male hormones (testosterone) into female hormones (estrogens) in postmenopausal women. Premenopausal women get most of their estrogen from the ovaries. But postmenopausal women still have estrogen in their bodies, and it is this conversion to estrogen of androgens coming from adrenal glands in the body that needs to be interrupted so the breast cancer cells no longer have estrogen to stimulate their growth. Unlike tamoxifen, which slows the growth of breast cancer by preventing estrogen from activating its receptor, anastrozole blocks an enzyme needed for the production of estrogen, inhibiting the conversion of precursors to estrogens, and is effective in hormone receptor-positive breast cancers. Anastrozole is currently an option for women whose advanced breast cancer continues to grow during or after tamoxifen treatment.

Studies are ongoing to compare tamoxifen and anastrozole as adjuvant hormonal therapies. Anastrozole (Arimidex) was better than tamoxifen at preventing the recurrence of breast cancer in a study conducted in 381 centers in 21 countries, involving 9366 patients, and examining three treatment arms: tamoxifen alone, tamoxifen in combination with other therapy, and anastrozole alone. The trial results showed that women taking anastrozole experienced fewer side effects than women taking tamoxifen. However, women taking tamoxifen experienced fewer musculoskeletal disorders. The study was only conducted for a relatively short period of time, 2 years, and the long-term effects (5 years and beyond) are not yet known. Longer-term studies are needed to assess both the benefits and risks of this therapy. However, most recent studies have showed anastrozole to be slightly superior to tamoxifen (Susman 2001).

In a primary trial of 33 months, anastrozole was superior to tamoxifen in terms of disease-free survival (DFS), time to recurrence (TTR), and incidence of contra-lateral breast cancer (CLBC) in adjuvant endocrine therapy for postmenopausal patients with early-stage breast cancer. After an additional follow-up period of 47 months, anastrozole continued to show superior efficacy.

When compared with tamoxifen, anastrozole has numerous advantages in terms of tolerability. Endometrial cancer, vaginal bleeding and discharge, cerebrovascular events, venous thromboembolic events, and hot flashes all occurred less frequently in the anastrozole group. However, musculoskeletal disorders and fractures continued to occur less frequently in the tamoxifen group. The study concluded that the benefits of anastrozole are likely to be maintained in the long term and provide further support for the status of anastrozole as a valid treatment option for postmenopausal women with hormone-sensitive early-stage breast cancer (Baum 2003).

The biological basis for the superior efficacy of neoadjuvant letrozole versus tamoxifen for postmenopausal women with estrogen receptor (ER)-positive locally advanced breast cancer was investigated. Letrozole inhibited tumor proliferation more than tamoxifen. While the molecular basis for this advantage was complex, it appeared to include a possible tamoxifen agonist effect on the cell cycle in both HER1/2+ and HER1/2- tumors. Letrozole seems to inhibit tumor proliferation more effectively than tamoxifen independent of HER1/2 expression status (Ellis et al. 2003).

Letrozole (2.5 mg per day) and anastrozole (1 mg per day) were compared as endocrine therapy in postmenopausal women with advanced breast cancer previously treated with an anti-estrogen. Letrozole was significantly superior to anastrozole in the overall response rate (ORR) and both agents were well tolerated. Advanced breast cancer is more responsive to letrozole than anastrozole as a second-line endocrine therapy, as letrozole has the greater aromatase-inhibiting activity (Rose et al. 2003). These results support previous studies which showed that letrozole (Femara) was significantly more potent than anastrozole (Arimidex) in inhibiting aromatase activity in vitro and in inhibiting total body aromatization in patients with breast cancer.

A once a day oral dose of Femara lowered the risk of breast cancer recurrence by 43% in 5000 older women who had already completed 5 years of treatment with tamoxifen. After just over 2 years, 207 women had a recurrence of cancer - 75 in the Femara group and 132 in the placebo group. There were 31 deaths in women receiving Femara and 42 deaths in women receiving placebo. Compared with placebo, Femara therapy after the completion of standard tamoxifen treatment significantly improved disease-free survival. This is a significant finding because in more than 50% of women treated for breast cancer, the cancer recurs 5 or more years after the original diagnosis (Goss et al. 2003).

Possible side effects of aromatase-inhibitor drugs include those associated with menopausal-like estrogen deficiency, such as hot flashes, night sweats, menstrual irregularity, depression, bone or tumor pain, pulmonary embolism (a blood clot in the lung), musculoskeletal disorders, and generalized weakness.

Megestrol Acetate
Megestrol acetate (Megace) is another drug used for hormonal treatment of advanced breast cancer, usually for women whose cancers do not respond to tamoxifen or have stopped responding to tamoxifen. Megestrol acetate is a man-made substance called progestin that is similar to the female hormone progesterone.

As with other therapies, there are reported side effects, including an increase in appetite causing weight gain, fluid retention causing ankle swelling, and nausea at the onset of therapy, which usually subsides. In rare cases, allergic reactions, jaundice, and raised blood pressure have been reported.

Trastuzumab (Herceptin Genentech)
Trastuzumab (Herceptin Genentech) is an anticancer drug therapy for women with HER2-positive metastatic breast cancer. This monoclonal antibody therapy differs from traditional treatments, such as chemotherapy and hormone-blocking therapy. Herceptin works by specifically targeting tumor cells that overexpress the HER2 protein. A monoclonal antibody blocks the receptors and prevents activation of genes that induce cell division, thereby slowing the growth of the tumor.

The reported side effects are chills, diarrhea, nausea, weakness, headache, vomiting, and possibly damage of the heart muscle, anemia, and nerve pain. Trastuzumab can be used alone or in combination with the drug paclitaxel (Taxol) and is prescribed for metastatic breast cancer.

Paclitaxel (Taxol)
Paclitaxel (Taxol) belongs to the group of medicines called antineoplastics (anticancer drugs) that interfere with the growth of cancer cells and eventually destroy them. Because the growth of normal cells may also be affected by paclitaxel, side effects can occur. Some side effects may not occur until months or years after the medicine was used.

Side effects include neutropenia (decreased white blood cell count), anemia (decreased red blood cell count), thrombocytopenia (decreased platelet count), increased risk of infection, fatigue, bruising, hemorrhage, rash, itching, redness, hives, facial flushing, chest pain, difficulty breathing, high or low blood pressure, decreased heart rate, lightheadedness, dizziness, increased perspiration, shortness of breath, headache, numbness or tingling of the hands and/or feet, muscle aches, bone pain, mouth ulcers (sores), alopecia (loss or thinning of scalp and body hair), decreased appetite, diarrhea, nausea, vomiting, skin burns and ulcers, nail changes, hot flashes, and vaginal dryness.

Oophorectomy
Oophorectomy is surgery in which the ovaries are removed, therefore eliminating the body's main source of estrogen and progesterone in premenopausal women. Prior to the advent of anti-estrogen drugs, an oophorectomy was commonly used to treat breast cancer in premenopausal women.

Occasionally this procedure is still used in premenopausal women. However, chemotherapy drugs can alter the ovaries and reduce estrogen production. Tamoxifen may block any remaining estrogen effect on cancer cells, allowing many women to avoid surgery.

NATURAL THERAPIES

Protecting Breast Cells Against Dangerous Estrogens
The stronger form of estrogen, estradiol, can be converted into the weaker form, estriol, in the body without using drugs. Estriol is considered to be a more desirable form of estrogen. It is less active than estradiol, so when it occupies the estrogen receptor, it blocks estradiol's strong "growth" signals. Using a natural substance the conversion of estradiol to estriol increased by 50% in 12 healthy people (Michnovicz et al. 1991). Furthermore, in female mice prone to developing breast cancer the natural substance reduced the incidence of cancer and the number of tumors significantly. The natural substance was indole-3-carbinol (I3C).

Indole-3-carbinol (I3C) is a phytochemical isolated from cruciferous vegetables (broccoli, cauliflower, Brussels sprouts, turnips, kale, green cabbage, mustard seed, etc.). I3C given to 17 men and women for 2 months reduced the levels of strong estrogen, and increased the levels of weak estrogen. But more importantly, the level of an estrogen metabolite associated with breast and endometrial cancer, 16--a-hydroxyestrone, was reduced by I3C (Bradlow et al. 1991).

When I3C changes "strong" estrogen to "weak" estrogen, the growth of human cancer cells is inhibited by 54-61% (Telang et al. 1997). Moreover, I3C provoked cancer cells to self-destruct (kill themselves via apoptosis). Induction of cell death is an approach to suppress carcinogenesis and is the prime goal of cytotoxic chemotherapy. The increase in apoptosis induced by I3C before initiation of new tumor development may contribute to suppression of tumor progression. Nontoxic I3C can reliably facilitate apoptosis (12 week treatment in rats); thus, this phytonutrient may become a standard adjunct in the treatment of breast cancer (Zhang et al. 2003)

I3C inhibits human breast cancer cells (MCF7) from growing by as much as 90% in culture; growth arrest does not depend on estrogen receptors (Cover et al. 1998). Furthermore, I3C induces apoptosis in tumorigenic (cancerous) but not in nontumorigenic (non-cancerous) breast epithelial cells (Rahman et al. 2003).

I3C does more than just turn strong estrogen to weak estrogen. 16-a-Hydroxyestrone (16-OHE) and 2-hydroxyestrone (2-OHE) are metabolites of estrogen in addition to estriol and estradiol. 2-OHE is biologically inactive, while 16-OHE is biologically active; that is, like estradiol, it can send "growth" signals. In breast cancer, the dangerous 16-OHE is often elevated, while the protective 2-OHE is decreased. Cancer-causing chemicals change the metabolism of estrogen so that 16-OHE is elevated. Studies show that people who take I3C have beneficial increases in the "weak" estriol form of estrogen and also increases in protective 2-OHE.

African-American women who consumed I3C, 400 mg for 5 days, experienced an increase in the "good" 2-OHE and a decrease of the "bad" 16-OHE. However, it was found that the minority of women who did not demonstrate an increase in 2-OHE, had a mutation in a gene that helps metabolize estrogen to the 2-OHE version. Those women had an eight times higher risk of breast cancer (Telang et al. 1997).

I3C Stops Cancer Cells from Growing
Tamoxifen is a drug prescribed to reduce breast cancer metastases and improve survival. I3C has modes of action similar to tamoxifen. I3C inhibited the growth of estrogen-receptor-positive breast cancer cells by 90% compared to 60% for tamoxifen. The mode of action attributed to I3C's impressive effect was interfering with the cancer cell growth cycle. Adding tamoxifen to I3C gave a 5% boost (95% total inhibition) (Cover et al. 1999).

In estrogen-receptor-negative cells, I3C stopped the synthesis of DNA by about 50%, whereas tamoxifen had no significant effect. I3C also restored p21 and other proteins that act as checkpoints during the synthesis of a new cell. Tamoxifen showed no effect on p21. Restoration of these growth regulators is extremely important. For example, tumor suppressor p53 works through p21 that I3C restores. I3C also inhibits cancers caused by chemicals. If animals are fed I3C before exposure to cancer-causing chemicals, DNA damage and cancer are virtually eliminated (Cover et al. 1999).

A study on rodents shows that damaged DNA in breast cells is reduced 91% by I3C. Similar results are seen in the liver (Devanaboyina et al. 1997). Female smokers taking 400 mg of I3C significantly reduced their levels of a major lung carcinogen. Cigarette chemicals are known to adversely affect estrogen metabolism (Taioli et al. 1997).

There is no proven way to prevent breast cancer, but the best and most comprehensive scientific evidence so far supports phytochemicals such as I3C (Meng et al. 2000). The results from a placebo-controlled, double-blind dose-ranging chemoprevention study on 60 women at increased risk for breast cancer demonstrated that I3C at a minimum effective dosage 300 mg per day is a promising chemopreventive agent for breast cancer prevention (Wong et al. 1997). The results of a single-blind phase I trial which studied the effectiveness of I3C in preventing breast cancer in nonsmoking women who are at high risk of breast cancer are awaited. The rationale for this study is that I3C, ingested twice daily, may be effective at preventing breast cancer.

I3C was found to be superior to 80 other compounds, including tamoxifen, for anticancer potential. Indoles, which down-regulate estrogen receptors, have been proposed as promising agents in the treatment and prevention of cancer and autoimmune diseases such as multiple sclerosis, arthritis, and lupus. Replacement of all the chemically altered estrogen drugs, such as tamoxifen, with a new generation of chemically altered indole drugs that fit in the aryl-hydrocarbon (Ah) receptor and regulate estrogen indirectly may prove beneficial to cancer patients (Bitonti et al. 1999). An I3C tetrameric derivative (chemically derived) is currently a novel lead inhibitor of breast cancer cell growth, considered a new, promising therapeutic agent for both ER+ and ER- breast cancer (Brandi et al. 2003).

A summary of studies shows that indole-3-carbinol (I3C) can:

• Increase the conversion of estradiol to the safer estriol by 50% in healthy people in just 1 week (Michnovicz et al. 1991)
• Prevent the formation of the estrogen metabolite, 16,alpha-hydroxyestrone, that prompts breast cancer cells to grow (Chen et al. 1996), in both men and women in 2 months (Michnovicz et al. 1997)
• Stop human cancer cells from growing (54-61%) and provoke the cells to self-destruct (apoptosis) (Telang et al. 1997)
• Inhibit human breast cancer cells (MCF7) from growing by as much as 90% in vitro (Ricci et al. 1999)
• Inhibit the growth of estrogen-receptor-positive breast cancer cells by 90%, compared to tamoxifen's 60%, by stopping the cell cycle (Cover et al. 1999)
• Prevent chemically induced breast cancer in rodents by 70-96%. Prevent other types of cancer, including aflatoxin-induced liver cancer, leukemia, and colon cancer (Grubbs et al. 1995)
• Inhibit free radicals, particularly those that cause the oxidation of fat (Shertzer et al. 1988)
• Stop the synthesis of DNA by about 50% in estrogen-receptor-negative cells, whereas tamoxifen had no significant effect (Cover et al. 1998)
• Restore p21 and other proteins that act as checkpoints during the synthesis of a new cancer cell. Tamoxifen has no effect on p21 (Cover et al. 1998)
• Virtually eliminate DNA damage and cancer prior to exposure to cancer-causing chemicals (in animals fed I3C) (Grubbs et al. 1995)
• Reduce DNA damage in breast cells by 91% (Devanaboyina et al. 1997)
• Reduce levels of a major nitrosamine carcinogen in female smokers (Taioli et al. 1997)

How to Use I3C
While the evidence is compelling, it is too soon to know exactly how effective I3C will be as an adjuvant breast cancer therapy (see the Breast Cancer References for citations pertaining specifically to I3C).

Suggested dosage: Take one 200-mg capsule of I3C twice a day, for those under 120 pounds. For those who weigh more than 120 pounds, three 200-mg capsules a day are suggested. Women who weigh over 180 pounds should take four 200-mg I3C capsules a day.

Note: A little is good; a lot is not necessarily better. Too much I3C can have the opposite effect; therefore, do not exceed the suggested dosage.

Caution: Pregnant women should not take I3C because of its modulation of estrogen. I3C appears to act both at the ovarian and hypothalamic levels, whereas tamoxifen appears to act only on the hypothalamic-pituitary axis as an anti-estrogen. Both I3C and tamoxifen block ovulation by altering preovulatory concentrations of luteinizing hormone (LH) and follicle stimulating hormone (FSH) (Gao et al. 2002). The reported aversion to cruciferous vegetables by pregnant women may be associated with their ability to change estrogen metabolism. Estrogen is a necessary growth factor for the fetus.

Curcumin
Curcumin is extracted from the spice turmeric and is responsible for the orange/yellow pigment that gives the spice its unique color. Turmeric is a perennial herb of the ginger family and a major component of curry powder. Chinese and Indian people, both in herbal medicine and in food preparation, have safely used it for centuries.

Curcumin has a number of biological effects in the body. However, one of the most important functions is curcumin's ability to inhibit growth signals emitted by tumor cells that elicit angiogenesis (growth and development of new blood vessels into the tumor).

Curcumin inhibits the epidermal growth factor receptor and is up to 90% effective in a dose-dependent manner. It is important to note that while curcumin has been shown to be up to 90% effective in inhibiting the expression of the epidermal growth factor receptor on cancer cell membranes, this does not mean it will be effective in 90% of cancer patients or reduce tumor volume by 90%. However, because two-thirds of all cancers overexpress the epidermal growth factor receptor and such overexpression frequently fuels the metastatic spread of the cancer throughout the body, suppression of this receptor is desirable.

Other anticancer mechanisms of curcumin include:

• Inhibition of the induction of basic fibroblast growth factor (bFGF). bFGF is both a potent growth signal (mitogen) for many cancers and an important signaling factor in angiogenesis (Arbiser et al. 1998).
• Antioxidant activity. In vitro it has been shown to be stronger than vitamin E in prevention of lipid peroxidation (Sharma 1976; Toda et al. 1985).
• Inhibition of the expression of COX-2 (cyclooxygenase 2), the enzyme involved in the production of prostaglandin E2 (PGE-2), a tumor-promoting hormone-like agent (Zhang et al. 1999).
• Inhibition of a transcription factor in cancer cells known as nuclear factor-kappa B (NF-KB). Many cancers overexpress NF-KB and use this as a growth vehicle to escape regulatory control (Bierhaus et al. 1997; Plummer et al. 1999).
• Increased expression of nuclear p53 protein in human basal cell carcinomas, hepatomas, and leukemia cell lines. This increases apoptosis (cell death) (Jee et al. 1998).
• Increases production of transforming growth factor-beta (TGF-beta), a potent growth inhibitor, producing apoptosis (Park et al. 2003; Sporn et al. 1989).
• TGF-beta is known to enhance wound healing and may play an important role in the enhancement of wound healing by curcumin (Mani H et al. 2002; Sidhu et al. 1998).
• Inhibits PTK (protein tyrosine kinases) and PKC (protein kinase C). PTK and PKC both help relay chemical signals through the cell. Abnormally high levels of these substances are often required for cancer cell signal transduction messages. These include proliferation, cell migration, metastasis, angiogenesis, avoidance of apoptosis, and differentiation (Reddy et al. 1994; Davidson et al. 1996).
• Inhibits AP-1 (activator protein-1) through a non-antioxidant pathway. While curcumin is an antioxidant (Kuo et al. 1996), it appears to inhibit signal-transduction via protein phosphorylation thereby decreasing cancer-cell activity, regulation, and proliferation (Huang et al. 1991).

Based on the favorable, multiple mechanisms listed above, higher-dose curcumin would appear to be useful for cancer patients to take. However, as far as curcumin being taken at the same time as chemotherapy drugs, there are contradictions in the scientific literature. Therefore, caution is advised. Please refer to the Cancer Chemotherapy protocol before considering combining curcumin with chemotherapy.

Curcumin's effects are a dose dependent response, and a standardized product is essential. The recommended dose is four 900-mg capsules 3 times per day, preferably with food.

Green Tea
As a tumor grows it elicits new capillary growth (angiogenesis) from the surrounding normal tissues and diverts blood supply and nutrients away from the tissue to feed itself. Unregulated tumor angiogenesis can facilitate the growth of cancer throughout the body. Antiangiogenesis agents, including green tea, inhibit this new tumor blood vessel (capillary) growth.

Green tea contains epigallocatechin gallate EGCG, a polyphenol that helps to block the induction of vascular endothelial growth factor (VEGF). Scientists consider VEGF essential in the process of angiogenesis and tumor endothelial cell survival. It is the EGCG fraction of green tea that makes it a potentially effective adjunct therapy in the treatment of breast cancer. In vivo studies have shown green tea extracts to have the following actions on human cancer cells (Jung et al. 2001b; Muraoka et al. 2002):

• Inhibition of tumor growth by 58%
• Inhibition of activation of nuclear factor-kappa beta
• Inhibition of microvessel density by 30%
• Inhibition of tumor-cell proliferation in vitro by 27%
• Increased tumor-cell apoptosis 1.9-fold
• Increased tumor endothelial-cell apoptosis threefold

The most current research shows that green tea may have a beneficial effect in treating cancer. While drinking green tea is a well-documented method of preventing cancer, it is difficult for the cancer patient to obtain a sufficient quantity of EGCG anticancer components in that form. Standardized green tea extract is more useful then green tea itself because the dose of EGCG can be precisely monitored and greater doses can be ingested without excessive intake of liquids. A suggested dose for a person with breast cancer is 5 capsules of 350-mg lightly caffeinated green tea extract 3 times a day with each meal. Each capsule should provide at least 100 mg of EGCG. It may be desirable to take a decaffeinated version of green tea extract in the evening to ensure that the caffeine does not interfere with sleep. Those sensitive to caffeine may also use this decaffeinated form.

However, there are benefits to obtaining some caffeine. Studies show that caffeine potentiates the anticancer effects of tea polyphenols, including the critical EGCG. Caffeine will be discussed in further detail later in this protocol. Green tea extract is available in a decaffeinated form for those sensitive to caffeine or those who want to take the less-stimulating decaffeinated green tea extract capsules for their evening dose.

Conjugated Linoleic Acid (CLA)
Conjugated linoleic acid (CLA) found naturally, as a component of beef and milk, refers to isomers of octadecadienoic acid with conjugated double bonds. CLA is essential for the transport of dietary fat into cells, where it is used to build muscle and produce energy. CLA is incorporated into the neutral lipids of mammary fat (adipocyte) cells, where it serves as a local reservoir of CLA. It has been proposed that CLA may be an excellent candidate for prevention of breast cancer (Ip et al. 2003). Low levels of CLA are found in breast cancer patients but these do not influence survival. Nevertheless, it has been hypothesized that a higher intake of CLA might have a protective effect on the risk of metastasis (Chajes et al. 2003).

CLA was shown to prevent mammary cancer in rats if given before the onset of puberty. CLA ingested during the time of the "promotion" phase of cancer development conferred substantial protection from further development of breast cancer in the rats by inducing cell kill of pre-cancerous lesions (Ip et al. 1999b). It was determined that feeding CLA to female rats while they were young and still developing conferred life-long protection against breast cancer. This preventative action was achieved by adding enough CLA to equal 0.8% of the animal's total diet (Ip et al. 1999a).

CLA inhibits the proliferation of human breast cancer cells (MCF-7), induced by estradiol and insulin (but not EGF). In fact, CLA caused cell kill (cytotoxicity) when tumor cells were induced with insulin (Chujo et al. 2003). The antiproliferative effects of CLA are partly due to their ability to elicit a p53 response that leads to growth arrest (Kemp et al. 2003). CLA elicits cell killing effects in human breast tumor cells through both p53-dependent and p53 independent pathways according to the cell type (Majumder et al. 2002). Refer to Cancer Treatment The Critical Factors, for more information on determining the p53 status of cancer. The effects of CLA are mediated by both direct action (on the epithelium) as well as indirect action through the stroma.

The growth suppressing effect of CLA may be partly due to changes in arachidonic distribution among cellular lipids and an altered prostaglandin profile (Miller et al. 2001). Intracellular lipids may become more susceptible to oxidative stress to the point of producing a cytotoxic effect (Devery et al. 2001). CLA has the ability to suppress arachidonic acid. Since arachidonic acid can produce inflammatory compounds that can promote cancer proliferation, this may be yet another explanation for CLA's anticancer effects.

Life Extension's recommendation for CLA is a dose of 3000-4000 mg daily, which is approximately 1% of the average human diet. The suggested amount required to obtain the overall cancer-preventing effects is only 3000-4000 mg daily in divided doses.

CLA may work via a mechanism similar to that of antidiabetic drugs not only by enhancing insulin-sensitivity but also by increasing plasma adiponectin levels, alleviating hyperinsulinemia (Nagao et al. 2003) protecting against cancer. A number of human cancer cell lines express the PPAR-gamma transcription factor, and agonists for PPAR-gamma can promote apoptosis in these cell lines and impede their clonal expansion both in vitro and in vivo. CLA can activate PPAR-gamma in rat adipocytes, possibly explaining CLA's antidiabetic effects in Zucker fatty rats. A portion of CLA's broad-spectrum anticarcinogenic activity is probably mediated by PPARgamma activation in susceptible tumor (McCarty 2000). However, CLA’s anticarcinogenic effects could not be confirmed in one epidemiologic study in humans (Voorips et al. 2002). (Note: The term PPAR-gamma is an acronym for peroxisome proliferator-activatedreceptor-gamma. A PPAR-gamma agonist such as Avandia, Actos, or CLA activates the PPAR-gamma receptor. This class of drug is being investigated as a potential adjuvant therapy against certain types of cancer.)

Note: A combination product called Super CLA with Guarana may be used instead of CLA alone. Guarana is an herb that contains a form of caffeine called guaranine, which is 2.5 times stronger than the caffeine found in coffee, tea, and caffeinated soft drinks. What makes guaranine a unique source of caffeine is its slower release due to the guarana seed, which is fatty (even in powder form) as opposed to water-soluble. Caffeine has an inhibitory effect on the growth of cancer and is synergistic with other natural anticancer compounds.

Caffeine
Caffeine occurs naturally in green tea and has been shown to potentiate the anticancer effects of tea polyphenols. Caffeine is a model radio-sensitizing agent that is thought to work by abolishing the radiation-induced G2-phase checkpoint in the cell cycle. Caffeine can induce apoptosis of a human lung carcinoma cell line by itself and it can act synergistically with radiation to induce tumor cell kill and cell growth arrest. The cancer cell killing effect of caffeine is dependent on the dose (Qi et al. 2002).

Caffeine enhances the tumor cell killing effects of anticancer drugs and radiation. A preliminary report on radiochemotherapy combined with caffeine for high-grade soft tissue sarcomas in 17 patients, (treated with cisplatin, caffeine, and doxorubicin after radiation therapy) determined complete response in six patients, partial response in six and no change in five patients. The effectiveness rate of caffeine-potentiated radiochemotherapy was therefore 17%, and contributed to a satisfactory local response and the success of function-saving surgery for high-grade soft tissue sarcomas (Tsuchiya et al. 2000).

In a randomized, double blind placebo-controlled crossover study, the effects of caffeine as an adjuvant to morphine in advanced cancer patients was found to benefit the cognitive performance and reduce pain intensity (Mercadente et al. 2001).

Cancer patients should note that one study demonstrated that caffeine reduced the cytotoxic effect of paclitaxel on human lung adenocarcinoma cell lines (Kitamoto et al. 2003).

To ascertain the inhibitory effects of caffeine, mice at high risk of developing malignant and nonmalignant tumors (SKH-1), received oral caffeine as their sole source of drinking fluid for 18-23 weeks. Results revealed that caffeine inhibited the formation and decreased the size of both nonmalignant tumors and malignant tumors (Lou et al. 1999).

In cancer cells, p53 gene mutations are the most common alterations observed (50-60%) and are a factor in both carcinomas and sarcomas. Caffeine has been shown to potentiate the destruction of p53-defective cells by inhibiting p53's growth signal. The effects of this are to inhibit and override the DNA damage-checkpoint and thus kill dividing cells. Caffeine uncouples cell-cycle progression by interfering with the replication and repair of DNA(Sakurai et al. 1999; Ribeiro et al. 1999; Jiang et al. 2000; Valenzuela et al. 2000).

Caffeine inhibits the development of Ehrlich ascites carcinoma in female mice (Mukhopadhyay 2001). Topical application of caffeine inhibits the occurrence of cancer and increases tumor cell death in radiation-induced skin tumors in mice (Lu et al. 2002). Caffeine inhibits solid tumor development and lung experimental metastasis induced by melanoma cells (Gude et al. 2001).

Consumption of coffee, tea, and caffeine was not associated with breast cancer incidence in a study of 59,036 Swedish women (aged 40-76 years) (Michels et al. 2002).

Melatonin
One of the most important supplements for a breast cancer patient is the hormone melatonin. Melatonin inhibits human breast cancer cell growth (Cos et al. 2000) and reduces tumor spread and invasiveness in vitro (Cos et al.1998). Indeed, it has been suggested that melatonin acts as a naturally occurring anti-estrogen on tumor cells, as it down-regulates hormones responsible for the growth of hormone-dependent mammary tumors (Torres-Farfan 2003).

A high percentage of women with estrogen-receptor-positive breast cancer have low plasma melatonin levels (Brzezinski et al. 1997). There have been some studies demonstrating changes in melatonin levels in breast cancer patients; specifically, women with breast cancer were found to have lower melatonin levels than women without breast cancer (Oosthuizen et al. 1989). Normally, women undergo a seasonal variation in the production of certain hormones, such as melatonin. However, it was found that women with breast cancer did not have a seasonal variation in melatonin levels, as did the healthy women (Holdaway et al. 1997).

Low levels of melatonin have been associated with breast cancer occurrence and development. Women who work predominantly at night and are exposed to light, which inhibits melatonin production and alters the circadian rhythm, have an increased risk of breast cancer development (Schernhammer et al. 2003). In contrast, higher melatonin levels have been found in blind and visually impaired people, along with correspondingly lower incidences of cancer compared to those with normal vision, thus suggesting a role for melatonin in the reduction of cancer incidence (Feychting et al. 1998).

Light at night, regardless of duration or intensity, inhibits melatonin secretion and phase-shifts the circadian clock, possibly altering the cell growth rate that is regulated by the circadian rhythm (Travlos et al. 2001). Disruption of circadian rhythm is commonly observed among breast cancer patients (Mormont et al. 1997; Roenneberg et al. 2002) and contributes to cancer development and tumor progression. The circadian rhythm alone is a statistically significant predictor of survival time for breast cancer patients (Sephton et al. 2000).

Melatonin differs from the classic anti-estrogens such as tamoxifen in that it does not seem to bind to the estrogen receptor or interfere with the binding of estradiol to its receptor (Sanchez-Barcelo 2003). Melatonin does not cause side effects, such as those) caused by the conventional anti-estrogen drug tamoxifen. Furthermore, when melatonin and tamoxifen are combined, synergistic benefits occur. Moreover, melatonin can increase the therapeutic efficacy of tamoxifen (Lissoni et al.1995) and biological therapies such as IL-2 (Lissoni et al. 1994).

How melatonin interferes with estrogen signaling is unknown, though recent studies suggest that it acts through a cyclic adenosine monophosphate (cAMP)-independent signaling pathway (Torres-Farfan 2003). It has been proposed that melatonin suppresses the epidermal growth factor receptor (EGF-R) (Blask et al. 2002) and exerts its growth inhibitory effects by inducing differentiation (“normalizing” cancer cells)(Cos et al. 1996). Melatonin directly inhibits breast cancer cell proliferation (Ram et al. 2000) and boosts the production of immune components, including natural killer cells (NK cells) that have an ability to kill metastasized cancer cells.

In tumorigenesis studies, melatonin reduced the incidence and growth rate of breast tumors and slowed breast cancer development (Subramanian et al. 1991). Furthermore, prolonged oral melatonin administration significantly reduced the development of existing mammary tumors in animals (Rao et al. 2000).

In vitro experiments carried out with the ER-positive human breast cancer cells (MCF-7 cells), demonstrated that melatonin, at a physiological concentration (1 nM) and in the presence of serum or estradiol (a) inhibits, in a reversible way, cell proliferation, (b) increases the expression of p53 and p21WAF1 proteins and modulates the length of the cell cycle, and (c) reduces the metastatic capacity of these cells and counteracts the stimulatory effect of estradiol on cell invasiveness. Further, this effect is mediated, at least in part, by a melatonin-induced increase in the expression of the cell surface adhesion proteins E-cadherin and beta (1)-integrin (Sanchez-Barcelo et al. 2003).

Melatonin can be safely taken for an indefinite period of time. The suggested dose of melatonin for breast cancer patients is 3-50 mg at bedtime. Initially, if melatonin is taken in large doses vivid dreams and morning drowsiness may occur. To avoid these minor side effects melatonin may be taken in low doses nightly and the dose slowly increased over a period of several weeks.

Se-Methylselenocysteine
Se-methylselenocysteine (SeMSC), a naturally occurring organic selenium compound found to be an effective chemopreventive agent is a new and better form of selenium. SeMSC is a selenoamino acid that is synthesized by plants such as garlic and broccoli. Methylselenocysteine (MSC) has been shown to be effective against mammary cell growth both in vivo and in vitro (Sinha et al. 1999) and has significant anticancer activity against mammary tumor development (Sinha et al. 1997). Moreover, Se-methylselenocysteine was one of the most effective selenium chemoprevention compounds and induced apoptosis in human leukemia cells (HL-60) in vitro (Jung et al. 2001a). Exposure to MSC blocks expansion of cancer colonies and premalignant lesions at an early stage by simultaneously modulating pathways responsible for inhibiting cell proliferation and enhancing apoptosis (Ip et al. 2000a).

Se-methylselenocysteine has been shown to:

• Produce a 33% better reduction of cancerous lesions than selenite.
• Produce a 50% decrease in tumor development.
• Induce cell death (apoptosis) in cancer cells.
• Inhibit cancer-cell growth (proliferation).
• Reduce density and development of tumor blood vessels.
• Down-regulate VEGF (vascular endothelial growth factor).

(Ip et al. 1992; Sinha et al. 1997; Sinha et al. 1999; Ip et al. 2000a, b; Dong et al. 2001)

Unlike MSC, which is incorporated into protein in place of methionine, SeMSC is not incorporated into any protein, thereby offering a completely bioavailable compound. In animal studies, SeMSC has been shown to be 10 times less toxic than any other known form of selenium. Breast cancer patients may consider taking 400 mcg of SeSMC daily.

CoQ10
Coenzyme Q10 (CoQ10) is synthesized in humans from tyrosine through a cascade of eight aromatic precursors. These precursors require eight vitamins, which are vitamin C, B2, B3 (niacin) B6, B12, folic acid, pantothenic acid, and tetrahydrobiopterin as their coenzymes.

Since the 1960s, studies have shown that cancer patients often have decreased blood levels of coenzyme Q10 (Lockwood et al. 1995; Folkers 1996; Ren et al. 1997). In particular, breast cancer patients (with infiltrative ductal carcinoma) who underwent radical mastectomy were found to have significantly decreased tumor concentrations of CoQ10 compared to levels in normal surrounding tissues. Increased levels of reactive oxygen species may be involved in the consumption of CoQ10 (Portakal et al. 2000). These findings sparked interest in the compound as a potential anticancer agent (NCCAM 2002). Cellular and animal studies have found evidence that CoQ10 stimulates the immune system and can increase resistance to illness (Bliznakov et al. 1970; Hogenauer et al. 1981; NCCAM 2002).

CoQ10 may induce protective effect on breast tissue and has demonstrated promise in treating breast cancer. Although there are only a few studies, the safe nature of CoQ10 coupled with this promising research of its bioenergetic activity suggests that breast cancer patients should take 100 mg up to 3 times a day. It is important to take CoQ10 with some kind of oil, such as fish or flax, because dry powder CoQ10 is not readily absorbed.

In a clinical study, 32 patients were treated with CoQ10 (90 mg) in addition to other antioxidants and fatty acids; six of these patients showed partial tumor regression. In one of these cases the dose of CoQ10 was increased to 390 mg and within one month the tumor was no longer palpable, within two months the mammography confirmed the absence of tumor. In another case, the patient took 300 mg of CoQ10 for residual tumor (post non-radical surgery) and within 3 months there was non residual tumor tissue (Lockwood et al. 1994). This overt complete regression of breast tumors in the latter two cases coupled with further reports of disappearance of breast cancer metastases (liver and elsewhere) in several other case (Lockwood et al. 1995) demonstrates the potential of CoQ10 in the adjuvant therapy of breast cancer.

There are promising results for the use of CoQ10 in protecting against heart damage related to chemotherapy. Many chemotherapy drugs can cause damage to the heart (UTH 1998; ACS 2000; NCCAM 2000; Dog et al. 2001), and initial animal studies found that CoQ10 could reduce the adverse cardiac effects of these drugs (Combs et al. 1977; Choe et al. 1979; Lubawy et al. 1980; Usui et al. 1982; Shinozawa et al. 1993; Folkers 1996).

Caution: Some studies indicate that CoQ10 should not be taken at the same time as chemotherapy. If this were true, it would be disappointing, because CoQ10 is so effective in protecting against adriamycin-induced cardiomyopathy. Adriamycin is a chemotherapy drug sometimes used as part of a chemotherapy cocktail. Until more research is known, it is not possible to make a definitive recommendation concerning taking CoQ10 during chemotherapy. For more information please see the Cancer Chemotherapy protocol.

EPA and DHA
Dietary polyunsaturated fatty acids (PUFAs) of the omega-6 (n-6) class, found in corn oil and safflower oil, may be involved in the development of breast cancer, whereas long chain (LC) omega-3 (n-3) PUFAs, found in fish oil can inhibit breast cancer (Bagga et al. 2002).

A case control study examining levels of fatty acids in breast adipose tissue of breast cancer patients has shown that total omega-6 PUFAs may be contributing to the high risk of breast cancer in the United States and that omega-3 PUFAs, derived from fish oil, may have a protective effect (Bagga et al. 2002).

A higher omega-3:omega-6 ratio ((n-3)):(n-6) ratio) may reduce the risk of breast cancer, especially in premenopausal women (Goodstine et al. 2003). In a prospective study of 35,298 Singapore Chinese women aged 45-74 years, it was determined that high levels of dietary omega-3 fatty acids from marine sources (fish/shellfish) were significantly associated with reduced risk of breast cancer. Furthermore, women who consumed low levels of marine omega-3 fatty acids had a statistically significant increased risk of breast cancer (Gago-Dominguez et al. 2003).

Omega-3 fatty acids, primarily eicosapentanoic acid (EPA) and docosahexaneoic acid (DHA) found naturally in oily fish and fish oil, have been consistently shown to retard the growth of breast cancer in vitro and in animal experiments, inhibit tumor development and metastasis. Fish oils have antiproliferative effects at high doses, which means they can inhibit tumor cell growth, through a free radical-mediated mechanism, while at more moderate doses omega-3 fatty acids inhibit, Ras protein activity, angiogenesis, and inflammation. The production of pro-inflammatory cytokines can be modified by dietary omega-3 PUFAs (Mancuso et al. 1997).

High consumption of fatty fish is weakly associated with reduced breast cancer risk (Goodstine et al. 2003). Flaxseed, the richest source of alpha-linoleic acid inhibited the established growth and metastasis of human breast cancer implanted in mice. This effect was found to be due to its down-regulation of insulin-like growth factor I (IGF-1) and epidermal growth factor receptor (EGF-R) expression (Chen et al. 2002). The recommended dosage is to consume a fish-oil concentrate supplement that provides 3200 mg of EPA and 2400 mg of DHA a day taken in divided doses.

Vitamins A, D, and E
Vitamin A and vitamin D3 inhibit breast cancer cell division and can induce cancer cells to differentiate into mature, noncancerous cells. Vitamin D3 works synergistically with tamoxifen (and melatonin) to inhibit breast cancer cell proliferation. The vitamin D-3 receptor as a target for breast cancer prevention was examined. Pre-clinical studies demonstrated that vitamin D compounds could reduce breast cancer development in animals. Furthermore, human studies indicate that both vitamin D status and genetic variations in the vitamin D-3 receptor (VDR) may affect breast cancer risk. Findings from cellular, molecular and population studies suggest that the VDR is a nutritionally modulated growth-regulatory gene that may represent a molecular target for chemoprevention of breast cancer (Welsh et al. 2003).

Daily doses of vitamin A, 350,000 to 500,000 IU were given to 100 patients with metastatic breast carcinoma treated by chemotherapy. A significant increase in the complete response was observed; however, response rates, duration of response and projected survival were only significantly increased in postmenopausal women with breast cancer (Israel et al. 1985).

Breast cancer patients may take between 4000 to 6000 IU, of vitamin D3 every day. Water-soluble vitamin A can be taken in doses of 100,000-300,000 IU every day. Monthly blood tests are needed to make sure toxicity does not occur in response to these high daily doses of vitamin A and vitamin D3. After 4-6 months, the doses of vitamin D3 and vitamin A can be reduced.

Vitamin E is the term used to describe eight naturally occurring essential fat-soluble nutrients: alpha-, beta-, delta-, and gamma-tocopherols plus a class of compounds related to vitamin E called alpha-, beta-, delta-, and gamma-tocotrienols. Vitamin E from dietary sources may provide women with modest protection from breast cancer.

Vitamin E succinate, a derivative of fat-soluble vitamin E, has been shown to inhibit tumor cell growth in vitro and in vivo (Turley et al. 1997; Cameron et al. 2003). In estrogen receptor-negative human breast cancer cell lines vitamin E succinate, inhibited growth and induced cell death. Since vitamin E is considered the main chain breaking lipophilic antioxidant in plasma and tissue, its role as a potential chemopreventative agent and its use in the adjuvant treatment of aggressive human breast cancers appears reasonable. Those with estrogen-receptor-negative breast cancers should consider taking 800-1200 IU of vitamin E succinate a day. Vitamin E supplementation, 800 IU daily for 4 weeks, was shown to significantly reduce hot flashes in breast cancer survivors (Barton et al. 1998).

Caution: Refer to the symptoms of vitamin A toxicity in Appendix A: Avoiding Vitamin A Toxicity. When taking doses of vitamin D3 in excess of 1400 IU a day, regular blood chemistry tests should be taken to monitor kidney function and serum calcium metabolism. Vitamin E has potential blood thinning properties, individuals taking anticoagulant drugs should inform their treating physician if supplementing with vitamin E and have their clotting factors monitored regularly.

Tocotrienols
When vitamin E was isolated from plant oils, the term tocopherols was used to name the initial four compounds that shared similar structures. Their structures have two primary parts--a complex ring and a phytyl (long-saturated) side chain--and have been designated as alpha, beta, delta, and gamma tocopherol. Tocopherols (vitamin E) are important lipid-soluble antioxidants that can protect the body against free radical damage.

However, there are four additional compounds related to tocopherols--called tocotrienols?that are less widely distributed in nature. The tocotrienol structure, three double bonds in an isoprenoid (unsaturated) side chain, differs from that of tocopherols. While tocopherols are found in corn, olive oil, and soybeans, tocotrienols are concentrated in palm, rice bran, and barley oils.

Tocotrienols elicit powerful anticancer properties, and studies have confirmed tocotrienol activity is much stronger than that of tocopherols (Schwenke et al. 2002).

Tocotrienols provide more efficient penetration into tissues such as the brain and liver. Because of the double bonds in the isoprenoid side chain, tocotrienols move freely and more efficiently within cell membranes than tocopherols, giving tocotrienols greater ability to counteract free radicals. This greater mobility also allows tocotrienols to recycle more quickly than alpha-tocopherol. Tocotrienols are better distributed in fatty cell membranes and demonstrate greater antioxidant and free-radical-scavenging effects than that of vitamin E (alpha-tocopherol) (Serbinova et al. 1991; Theriault et al. 1999).

Tocotrienol's antioxidant function is associated with lowering DNA damage, tumor formation, and of cell damage. Animals exposed to carcinogens that were fed corn oil- or soybean oil-based diets had significantly more tumors than those fed a tocotrienol-rich palm oil diet. Tocotrienol-rich palm oil did not promote chemically induced breast cancer (Sundram et al. 1989).

Tocotrienols possess the ability to stimulate the selective killing of cancer cells through programmed cell death (apoptosis) and to reduce cancer cell proliferation while leaving normal cells unaffected (Kline et al. 2001). Tocotrienols are thought to suppress cancer through the isoprenoid side chain.

Isoprenoids are plant compounds that have been shown to suppress the initiation, growth, and progression of many types of cancer in experimental studies (Block et al. 1992). They are common in fruits and vegetables, which may explain why diets rich in these foods have consistently been shown to reduce the incidence of cancer.

Isoprenoids induce cell death (apoptosis) and arrest cell growth in human breast adenocarcinoma cells (MCF-7) (Mo et al.1999). Isoprenoids may suppress the mevalonate pathway, through which mutated Ras proteins transform healthy cells into cancer cells. Mutated ras is the most common cellular defect found in human cancers. The mevalonate pathway escapes regulatory control in tumor tissue but remains highly sensitive to regulation by tocotrienols. Tocotrienols are at least five times more powerful than farnesol, the body's regulator of the mevalonate pathway. Interestingly, human breast cancer cells have been shown to respond very well to treatment with tocotrienols (Parker et al. 1993).

Tocotrienols cause growth inhibition of breast cancer cells in culture independent of estrogen sensitivity and have great potential in the prevention and treatment of breast cancer (Nesaretnam et al. 1998).

In vitro studies have demonstrated the effectiveness of tocotrienols as inhibitors of both estrogen-receptor-positive (estrogen-responsive) and estrogen-receptor-negative (nonestrogen-responsive) cell proliferation. The effect of palm tocotrienols on three human breast cancer cells lines, estrogen-responsive and estrogen-nonresponsive (MCF7, MDA-MB-231, and ZR-75-1), found that tocotrienols inhibited cell growth strongly in both the presence and absence of estradiol. The gamma- and delta-fractions of tocotrienols were most effective at inhibiting cell growth, while alpha-tocopherol was ineffective. Tocotrienols were found to enhance the effect of tamoxifen (Nesaretnam et al. 2000).

Delta-tocotrienol was shown to be the most potent inducer of apoptosis (programmed cell death) in both estrogen-responsive and estrogen-nonresponsive human breast cancer cells, followed by gamma- and alpha-tocotrienol (beta-tocotrienol was not tested). Interestingly, delta-tocotrienol is more plentiful in palm tocotrienols than in tocotrienols derived from rice. Of the natural tocopherols, only delta-tocopherol showed any apoptosis-inducing effect, although it was less than one tenth of the effect of palm and rice delta-tocotrienol (Yu et al. 1999).

Tocotrienols effectively arrested the cell cycle and triggered cell death of mammary cancer cells (from mice) whereas tocopherols (alpha, gamma, and delta) did not cause inhibition of tumor cell growth. Highly malignant cells were most sensitive to the antiproliferative effects of tocotrienols, whereas less aggressive precancerous cells were the least sensitive (McIntyre et al. 2000).

Tocotrienols were found to be far more effective than alpha-tocopherol in inhibiting breast cancer cell growth. Tocotrienols in combination with tamoxifen proved more effective than either compound alone in both estrogen-responsive and nonresponsive breast cancer cells. The synergism between tamoxifen and tocotrienols may reduce the risk of adverse side effect from tamoxifen (Guthrie et al. 1997).

Tocotrienols are considered important lipid-soluble antioxidants, with potent anticancer and anti-inflammatory activity. Therefore, a daily dose of 240 mg of tocotrienols should be considered as an adjuvant breast cancer therapy.

PREVENTING BREAST CANCER CELL METASTASIS

Breast cancer cells frequently metastasize to the bone, where they cause severe degradation of bone tissue. Metastatic cancer affects more than half of all women during the course of their disease. Bone metastases are a significant cause of morbidity due to pain, pathological fractures, hypercalcemia (abnormally high levels of calcium in blood plasma), and spinal cord compression. The bisphosphonates, including alendronate (Fosamax), tiludronate (Skelid), pamidronate (Aredia), etidronate (Didronel), risedronate (Actonel), ibandronate, and zoledronic acid (Zometa), are a class of drugs that protect against the degradation of bone, primarily by inhibiting osteoclast-mediated bone resorption (bone breakdown).

Bisphosphonates are analogs of a naturally occurring compound, called pyrophosphate, which serves to regulate calcium and prevent bone breakdown. Bisphosphonates are a major class of drugs used for the treatment of bone diseases as they have a marked ability to inhibit bone resorption. Bisphosphonates are considered standard care for tumor-associated hypercalcemia and have been shown to reduce bone pain, improve quality of life, and to delay and reduce skeletal events (Hortobagyi 1996; Roemer-Becuwe et al. 2003).

Bone Remodeling
The renewal of bone is responsible for bone strength throughout our life. Old bone is removed (resorption) and new bone is created (formation). This process is called bone remodeling. Healthy bone is continually being remodeled. Two main types of cells are responsible for bone renewal: the osteoblasts involved in bone formation and the osteoclasts involved in bone resorption. There are several stages involved in bone remodeling. The first is activation. This process involves preosteoclasts that are stimulated and differentiated under the influence of cytokine and growth factors to mature into active osteoclasts. The next step is resorption, in which osteoclasts digest mineral matrix (old bone). The third step is reversal, which ends resorption and signals for the final phase, formation. During this stage, osteoblasts are responsible for bone matrix synthesis (collagen production). Two other noncollagenous proteins are also formed: osteocalcin and osteonectin, together they form new bone.

Bone Metastases Affects Remodeling
In patients with bone metastases, bone resorption by the osteoclasts is increased and exceeds bone reformation. Calcium lost from the bones appears in increased amounts in the patient's blood serum and urine. This increase in bone resorption may result in pain, bone fractures, spinal cord compression, and hypercalcemia.

Normally, the activity of the osteoclasts and osteoblasts is well-balanced, with the osteoclasts cleaning out the fatigued bone and the osteoblasts rebuilding new bone. In metastatic cancer, there is - increased osteoclast activity caused by factors called osteoclastic activating factors (OAFs). These OAFs released by tumor cells and include parathyroid hormone-related peptide (PTHrP), growth factors, and cytokines.

Among the known inhibitors of osteoclast activity, the bisphosphonates are the most promising drugs available ( by prescription) to women with breast cancer who have a high risk of advancing cancer. Bisphosphonates interrupt the "vicious cycle" of bone metastases. Bisphosphonates inhibit bone turnover directly by decreasing resorption of bone and inhibiting the recruitment and function of osteoclasts.

Bisphosphonates may stop bone metastases from occurring if they are included at the onset of cancer diagnosis and treatment (ONI 2000). Bisphosphonates may delay the occurrence of bone metastases in women with breast cancer who do not have metastases.

In patients with bone metastases, bisphosphonates are useful as an adjuvant therapy to decrease bone pain, fractures, hypercalcemia, and progression of bone metastases (Delmas 1996). Treatment with bisphosphonates can also prevent the destruction of bone by cancer metastases and reduce the progression of metastatic tumors. A new bisphosphonate, risedronate, slows the progression of bone metastases in breast cancer patients, either by inhibiting the resorption of bone, which reduces the release of tumor growth factors, or by inhibiting the adhesion of breast cancer cells to bone matrix (Delmas 1996).

In women with early and advanced breast cancer and bone metastases the use of bisphosphonates (oral or intravenous) in addition to hormone therapy or chemotherapy reduced bone pain, the risk of developing a fracture, and increased the time to a fracture (Pavlakis et al. 2002). Monthly infusions of pamidronate in 382 women with Stage IV breast cancer and bone metastases significantly reduced the incidence and prolonged the median time of skeletal complications (Hortobagyi et al. 1996).

Bisphosphonates are now third generation and are often used in the treatment of lytic bone metastasis. They inhibit the osteoclast activity that causes elevation of the blood calcium level and osteolytic bone weakening. Osteolytic holes form as the cancer degrades the bone, making it prone to fracture (Cristfanilli et al. 1999)., The bisphosphonates, zoledronate and ibandronate, manage tumor-induced hypercalcemia, Paget's disease of the bone, and multiple myeloma-associated bone resorption. These bisphosphonate drugs are three orders of magnitude more potent than the first-generation drugs etidronate, clodronate, and tilundronate. Patients newly diagnosed with lytic bone metastasis of breast cancer are offered bisphosphonate therapy, such as intravenous zoledronate or pamidronate every 3 or 4 weeks, as long as it proves effective. Oral clodronate offers equivalent results but is less well-tolerated.

Women with primary breast cancer who receive chemotherapy, hormone therapy, aromatase therapy, or oophorectomy may experience ovarian failure or early menopause, leading to a loss of bone mineral density.

The mechanisms by which tumor cells degrade bone involve tumor-cell adhesion to bone, as well as the release of compounds from tumor cells that stimulate osteoclast-induced bone degradation. Bisphosphonates inhibit cancer-cell adhesion and inhibit osteoclast activity. By preventing tumor-cell adhesion, bisphosphonates are useful agents for the prophylactic treatment of patients with cancer that is known to preferentially metastasize to bone.

There is evidence that growth factors, such as insulin-like growth factor and transforming growth factor, are released when the bone matrix is degraded. These growth factors could stimulate tumor-cell proliferation throughout the body and mayactivate cancer cells to the degraded bone ripe for clonal development, which may be a reason that early use of bisphosphonates significantly improved survival and may ward off metastasis.

Based upon the mounting research, it is strongly recommended that the use of bisphosphonates be considered at onset of breast cancer treatment to potentially stop bone metastases from developing. Patients are urged to discuss the use of bisphosphonates with their physicians.

Note: Administration of bisphosphonate therapy should be accompanied by an adequate intake of a bone supplement that supplies all the raw materials to make healthy bone. These include calcium, magnesium, boron, silica, vitamin D, and vitamin K. Do not take vitamin K with Coumadin or other anticoagulant drugs or blood thinners.

Bone Loss and Fatty Acids
While people often use omega-3 fatty acids to reduce the inflammation associated with arthritis, these fatty acids may actually help prevent bone loss. French researchers found in a group of 105 patients that high levels of pro-inflammatory omega-6 fatty acids were strongly associated with bone loss. However, the use of omega-3 supplements--360 mg a day of eicosapentanoic acid (EPA) and 240 mg a day of docosahexaneoic acid (DHA) - appeared to decrease production of pro-inflammatory prostaglandin E2 in bone and significantly stopped bone loss (Requirand et al. 2000).

Hormone Therapy and Metastasis
In primary breast cancer the estrogen receptor (ER) status represents an important prognostic factor and therefore, has a profound impact on the type of therapy employed. Yet, there is little research into the ER expression of disseminated breast cancer cells even though these cells are the main targets in adjuvant therapy.

A small pilot study involving 17 patients evaluated the ER expression profile on disseminated epithelial cells in bone marrow, one of the preferential organs for manifestation of distant metastases in breast cancer. Eleven patients (64.7%) were found to have ER-positive primary carcinomas. Of those eleven, only two patients revealed ER-positive epithelial cells in bone marrow. Additionally, one of these two patients expressed both ER-positive and ER-negative epithelial cells in bone marrow. Although in both of these cases the ER-positive epithelial cells in bone marrow derived from ER-positive primary tumors, in this small patient cohort none of the prognostic ally relevant clinical and pathological factors tested (i.e., TNM-classification, grading, and ER status in primary breast cancer) correlated with the ER status in bone marrow. A striking discrepancy between ER expression in primary breast cancers and the corresponding disseminated epithelial cells in bone marrow was found. This suggests either the selective dissemination of ER-negative tumor cells into the bone marrow or a negative impact of the bone marrow microenvironment on epithelial ER expression. While further research is required before conclusions can be drawn, this phenomenon might influence therapeutic effects of anti-hormonal treatment (Ditsch et al. 2003).

Diet
Cancer has an appetite for sugar and requires sugar for survival. Sugar plays an active role in reducing the immune response and energizes cancer, as tumors are primarily obligate glucose metabolizers.

There is a relationship between lactic acid, insulin, and angiogenesis. In tumors, hypoxic conditions occur through both inflammation, which reduces blood flow, and the chaotic development of blood vessels within tumors. These hypoxic conditions alter the pathways by which immune cells and tumor cells burn fuel (glucose) for energy, creating excessive lactic acid. In an oxygen-rich (aerobic) environment, glucose is burned in an efficient process that produces a maximum amount of energy and a minimal amount of lactic acid. However, tumor cells in chronic hypoxic conditions produce excessive lactic acid and inefficient utilization of glucose. Thus, there is a vicious cycle in which the reduced energy output stimulates the tumor cells to burn more glucose, which in turn produces more lactic acid. Tumor cells consume glucose at a rate three to five times higher than normal cells, creating a highly stimulated glycolysis (glucose-burning) pathway.

This glucose consumption can waste the cancer patient's energy reserves, and the increased production of lactic acid can stimulate increased production of angiogenic factors. The macrophage-mediated angiogenesis creates a complex interplay between opposing regulators. Insulin plays an active roll in promoting angiogenesis. Insulin is a growth factor that stimulates glycolysis and the proliferation of many cancer-cell lines through tyrosine kinase growth factors (Boyd 2003). In cancer patients, elevated levels of insulin are common in cancerous tissue and blood plasma. Obesity, and early stages of Type-II noninsulin-dependent diabetes mellitus (NIDDM), has been implicated as risk factors in a variety of cancers.

Based upon cancer's sugar dependency, a sugar-deprivation diet is strongly recommended. An effective tool in eliminating sugar from the diet is through following the Glycemic Index. The index is a list that rates the speed at which foods are digested and raise blood sugar levels. The ratings are based upon the rate at which a measured amount of pure glucose affects the body's blood sugar curve. Glucose itself has a rating of 100, and the closer a food item is to a rating of 100, the more rapidly it raises blood glucose levels. Foods with a low Glycemic Index, such as vegetables, protein, and grains, are suggested (please refer to the Obesity protocol for specific information about low glycemic foods).

With regard to depleting sugar from the diet, the following should be considered:

• Limit or avoid all white foods, including (but not limited to) sugar, flour, rice, pasta, breads, crackers, cookies, etc.
• Read labels. Sugar has many names (brown sugar, corn syrup, honey, molasses, maple syrup, high-fructose corn syrup, dextrin, raw sugar, fructose, polyols, dextrose, hydrogenated starch, galactose, glucose, sorbitol, fruit juice concentrate, lactose, brown rice syrup, xylitol, sucrose, mannitol, sorghum, maltose, and turbinado, to mention only a few).
• Limit all fruit juices; per glass they contain the juice of many pieces of fruit and a large amount of fructose (fruit sugar) but no fiber. Instead, infrequently eat low glycemic-rated fruit in small portions.

Natural compounds have also been reported to inhibit the cancer-promoting effects of insulin. For example, vitamin C has been reported to increase oxygen consumption and reduce lactic acid production in tumor cells. In addition, some natural compounds may help reduce insulin production by reducing insulin resistance. Insulin resistance occurs when cells are no longer sensitive to insulin and thus more insulin is produced in an effort to reduce glucose levels. Insulin resistance has been implicated as a risk factor for breast cancer, and diets high in saturated fats and omega-6 fatty acids promote insulin resistance. Although the exact pathway is unknown, it is thought that the mechanism of action is via chronic activation of PKC. Some of the known natural compounds that can reduce insulin resistance include omega-3 fatty acids, curcumin, flavonoids, selenium, and vitamin E.

As discussed earlier in the protocol, estrogen is a growth factor for most breast cancers. High-fat diets and associated increases in fat tissue can increase estrogen availability in a number of ways:

• Fat tissue is a major source of estrogen production in postmenopausal women. Therefore, there is an association between high body weight and decreased survival in breast cancer patients.
• Obesity and possibly insulin resistance can decrease the levels of sex hormone binding globulin (SHBG) in both men and women and increase breast cancer risk or cancer progression. This is an important factor in estrogen-dependent breast cancer cells because it is adequate levels of SHBG that act as an anti-proliferative and provides an anti-estrogenic effect.
• Obesity can alter liver metabolism of estrogen, allowing the retention of high estrogen byproducts with high estrogenic activity within the body.
• High-fat diets may reduce the amount of estrogen excreted in the feces. In contrast, low-fat/high-fiber diets can reduce circulating estrogen.

Another consideration when discussing diet and breast cancer is the reduction of dietary estrogen. Several foods contain naturally occurring hormones (found in animal sources); synthetic hormones that can mimic estrogen in the human body (found in commercially packaged meat, poultry, and dairy products); or naturally estrogenic properties that can encourage the body's production of estrogens (natural foods such as soy). Regardless of the source, try to avoid all commercial animal products (including, but not limited to, meats, poultry, and dairy). Also avoid the use of soft plastic food-storage products that can give off large amounts of polymers (e.g., by leaching into food contents), thought by environmentalists and some researchers to be a possible cause of breast cancer.

In order to reduce estrogen, a breast cancer patient should consider increasing dietary intake of fish high in omega-3 fatty acids, whey, eggs, and nuts, occasionally including hormone-free poultry and hormone-free, low-fat dairy products.

BLOOD TESTING

Monthly blood tests should include complete blood chemistry, with tests for liver function and serum calcium levels, prolactin, parathyroid hormone, and the tumor marker CA 27.29 (or CA 15.3). Additional blood tests to consider are the CEA and GGTP tests. These tests monitor the progress of therapies used and also detect toxicity from high doses of vitamin A and vitamin D3. The patient should insist on obtaining a copy of their blood workups every month.

SUMMARY

When considering breast cancer treatment options, physicians and patients alike must sort through an overwhelming amount of information. This protocol attempts to simplify complicated scientific research and bring to the forefront the most up-to-date, multimodality approach to cancer treatment. It integrates surgery, anticancer drugs, irradiation, hormone therapy, nutritional supplementation, and diet modification in a comprehensive approach to counteract breast cancer.

As discussed in this protocol, cancer growth is based on many complicated interactions via numerous physiological pathways within the body. Despite the huge strides in scientific research, there are still many unanswered questions regarding cancer's growth and development. What we do know is that there is overwhelming research supporting an integrated approach to the treatment of cancer. Additionally, research supports using nutritional supplementation to improve the efficacy of chemotherapy drugs and radiotherapy (see the Cancer Chemotherapy and Cancer Radiation protocols for more information). In fact, combining certain supplements can create a synergism that can effectively block or impede certain cancer pathways.

Therefore, the supplementation regimen following is suggested. Please read the entire protocol before considering this regimen because there are certain cautions to consider. As always, consult your physician before beginning any nutritional supplementation regimen.

1. Indole-3-carbinol (I3C), a 200-mg capsule twice daily, if you weigh under 120 lbs or three 200-mg capsules daily in two divided doses if you weigh over 120 lbs. Take two 200-mg capsules twice daily, if you weigh over 180 lbs.
   Caution: Pregnant women should not take indole-3-carbinol because of its modulation of estrogen.
2. Curcumin, four 900 mg capsules, 3 times daily on an empty stomach for a total of 10.8 g per day. Note the caution earlier in this protocol.
3. Lightly caffeinated green tea extract, five 350 mg capsules, 3 times daily with meals for a total of 5.25 g per day. Use decaffeinated green tea extract if you are sensitive to caffeine or want to use the less-stimulating version with the evening dosage.
4. CLA or CLA with Guarana, 3000 to 4000 mg daily of CLA and about 300 mg of guarana, early in the day.
5. Melatonin, 3 to 50 mg at bedtime.
6. PhytoFood Powder (broccoli, cabbage, and other cruciferous vegetables that provide sulphoraphane and other cancer-fighting plant extracts), 1-2 tbsp daily.
7. Se-methylselenocysteine, 200 to 400 mcg daily.
8. CoQ10, three 100 mg softgels in divided doses. Note the caution stated in this protocol.
9. Mega EPA (with DHA), 8 capsules daily, supplying 3200 mg of EPA and 2400 mg of DHA. Take with nonfiber meals.
10. Vitamin D3, 4000 to 6000 IU taken daily with monthly blood testing to monitor for toxicity. Reduce dosage at 6 months.
11. Water-soluble vitamin A, 100,000 to 300,000 IU daily with monthly blood testing to monitor for toxicity. Reduce dosage at 6 months (refer to vitamin A precautions in Appendix A).
12. Vitamin E succinate (tocopheryl succinate), 1200 IU daily.
13. Gamma E Tocopherol/Tocotrienol, 1 capsule daily. Take an additional 200 mg of palm-oil tocotrienols as an adjuvant therapy.
14. Vitamin C, 4000 to 12,000 mg throughout the day.
15. Gamma linolenic acid, 1200 mg a day (4 capsules of a borage oil supplement called Mega GLA will supply this amount).
16. Whey protein concentrate-isolate, 30 to 60 grams daily in divided doses.
17. Bone Assure provides calcium, magnesium, and bone-protecting nutrients. Take 6 capsules at bedtime.
18. Vitamin K, 10 mg daily.
19. Silicon, 6 mg daily. (Jarrow's Biosil is recommended.)
20. Life Extension Mix without Copper (multinutrient formula), 3 tablets 3 times daily.

Reminder: Bisphosphonate (injectable Zometa or Aredia) drug therapy is strongly encouraged for all breast cancer patients as well as aromatase-inhibitor therapy (Arimidex, Femara, or Aromasin) if appropriate.

Note: If chemotherapy and/or radiation are being considered, refer to the Cancer Chemotherapy and Cancer Radiation protocols. Also refer to the protocols titled Cancer Treatment: The Critical Factors and Cancer Adjuvant Therapy.

FOR MORE INFORMATION

Contact the American Cancer Society, 1 (800) ACS-2345.

Sources for National Cancer Institute Information.

• Cancer Information Service, (800) 4-CANCER
  (1-800-422-6237); TTY (for hearing impaired callers), (800) 332-8615
• NCI Online /Internet, use http://cancer.gov to reach the NCI website.
• CancerMail Service, to obtain a contents list, send e-mail to cancermail@cips.nci.nih.gov with the word "help" in the body of the message.

PRODUCT AVAILABILITY

Indole-3-carbinol (I3C), curcumin, green tea, CLA, CLA with guarana, melatonin, SeMsc (Se-methylselenocysteine), CoQ10, Mega EPA/ DHA, vitamin D3 caps, water-soluble vitamin A liquid, vitamin E succinate, Gamma E Tocopherol/Tocotrienols, vitamin C, Mega GLA, enhanced whey protein, Bone Assure, Phyto Food, vitamin K, Biosil, and Life Extension Mix can be ordered by calling (800) 544-4440 or by ordering online.

STAYING INFORMED

The information published in this protocol is only as current as the day the manuscript was sent to the printer. This protocol raises many issues that are subject to change as new data emerge. Furthermore, cancer is still a disease with unacceptably high mortality rates, and none of our suggested regimens can guarantee a cure.

The Life Extension Foundation is constantly uncovering information to provide to cancer patients. A special website has been established for the purpose of updating patients on new findings that directly pertain to the published cancer protocols. Whenever Life Extension discovers information that may benefit cancer patients, it will be posted on the website www.lefcancer.org.

Before utilizing this cancer protocol, we suggest that check www.lefcancer.org to see if any substantive changes have been made to the recommendations described herein. Based on the sheer number of newly published findings, there could be significant alterations to the information you have just read.