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.
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 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.
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 (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.)
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 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.)
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 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 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) 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 (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) 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®) 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 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.
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 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.
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.
Apigenin, a flavone (ie, a class of flavonoids) that is present in fruits and vegetables (eg, onions, oranges, tea, celery, artichoke, and parsley), has been shown to possess anti-inflammatory, antioxidant, and anticancer properties. Many studies have confirmed the cancer chemopreventive effects of apigenin (Patel 2007).
Apigenin stimulates apoptosis in breast cancer cells (Chen 2007). A 2012 study showed that apigenin slowed the progression of human breast cancer by inducing cell death, inhibiting cell proliferation, and reducing expression of a gene associated with cancer growth (Her2/neu). In another study, it was noted that blood vessels responsible for feeding cancer cells were smaller in apigenin-treated mice compared to untreated mice. This is significant because smaller vessels mean restricted nutrient flow to the tumors and may have served to starve the cancer as well as limit its ability to spread (Mafuvadze 2012).
Apigenin has been proven to have a synergistic treatment effect when combined with the chemotherapy drug paclitaxel (Xu 2011). In a study, apigenin increased the efficacy of the chemotherapy drug 5-Fluorouracil against breast cancer cells (Choi 2009).
Astragalus, an herb used for centuries in Asia, has exhibited immune-stimulatory effects. Astragalus potentiates lymphokine-activated killer cells (Chu 1988). One study found that astragalus could partially restore depressed immune function in tumor-bearing mice (Cho 2007a), while another concluded that “…astragalus could exhibit anti-tumor effects, which might be achieved through activating the…anti-tumor immune mechanism of the host” (Cho 2007b).
It was observed in a clinical trial that astragalus inhibited the proliferation of breast cancer cells. Authors of the study stated, “The antiproliferation mechanisms may be related to its effects of up-regulating the expressions of p53…” (Ye 2011). Similar findings were noted in a previous experiment (Deng 2009).
Blueberries are rich in anthocyanins (ie, dark pigments in fruits) and pterostilbenes (ie, antioxidant closely related to resveratrol). The anti-cancer effects of blueberries are mediated by multiple mechanisms:
Blueberry extracts block DNA damage. Damage to cellular DNA underlies most forms of cancer. By preventing such damage, blueberry extracts can block the malignant transformation of healthy cells (Aiyer 2008).
Blueberry extracts inhibit angiogenesis. Rapidly-growing cancers recruit new blood vessels to meet their ravenous appetites for nutrients and oxygen. Blueberry inhibits new tumor blood vessel growth, known as angiogenesis (Gordillo 2009; Liu 2011).
Blueberry extracts trigger cancer cells’ suicide. If normal cells replicate too fast, they are programmed to die through apoptosis. Cancerous cells, by contrast, ignore that programming, constantly doubling their population unchecked. Blueberry components restore normal programming and induce apoptosis in cells from a variety of cancers, putting the brakes on their rapid growth (Katsube 2003; Yi 2005; Seeram 2006; Srivastava 2007; Alosi 2010).
Blueberry extracts stop excessive proliferation. Uncontrolled cell reproduction results in formation of dangerous tumors, as cells ignore the normal signals to stop growing. By restoring normal cellular signaling, blueberry extracts stop such out-of-control proliferation (Yi 2005; Adams 2010; Nguyen 2010). In an experimental breast cancer cell line, blueberry significantly reduced breast cancer cell proliferation, leading the researchers to state that “blueberry anthocyanins … demonstrated anticancer properties by inhibiting cancer cell proliferation and by acting as cell antiinvasive factors and chemoinhibitors” (Faria 2010). In rats with experimentally induced breast cancer, the volume of new breast tumor formation was reduced by 40% in the group of rats supplemented with blueberry compared to the control group (Srinivasan 2008).
Blueberry extracts slow tumor spread by invasion and metastasis. Solid cancers produce matrix metalloproteinases, which are “protein-melting” enzymes that help them invade adjacent tissues and that enable them to metastasize. Blueberry extracts block matrix metalloproteinases, thereby inhibiting cancer invasion and metastasis (Adams 2010a; Matchett 2005). In one experiment published in 2011, blueberry extract was administered to mice with breast cancer. Compared to the control group, tumor volume was 75% lower in mice fed blueberry extract. Moreover, mice fed blueberry extract developed 70% fewer liver metastases and 25% fewer lymph node metastases compared to the control group (Adams 2011).
Breast cancers that are estrogen-receptor positive can grow and be exacerbated in the presence of estrogen in the body. One aim of drug therapy for estrogen-receptor positive breast cancer is to decrease the levels of estrogen in the body. To that end, drugs used to block the enzyme (ie, aromatase) that converts testosterone into estrogen (ie, aromatase inhibitors) are widely used in women with estrogen-receptor positive breast cancer. Chrysin, a flavonoid, is a natural aromatase inhibitor (Campbell 1993; Mohammed 2011).
Coffee, especially brews enriched with chlorogenic acid, protect cells against the DNA damage that leads to aging and cancer development (Bakuradze 2011; Hoelzl 2010; Misik 2010). Growing tumors develop the ability to invade local and regional tissue by increasing their production of “protein-melting” enzymes called matrix metalloproteinases. Chlorogenic acid—present in coffee—strongly inhibited matrix metalloproteinase activity (Jin 2005; Belkaid 2006).
A 2011 study reported that postmenopausal women who drank 5 cups of coffee dailyexhibited a 57% decreased risk of developing estrogen-receptor negative (non-hormone-responsive) breast cancer (Li 2011). Chlorogenic acid and other polyphenols are the likely beneficial agents in such cancers (Bageman 2008).
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.
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.)
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 (Mercadante 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).
Lignans are found in high concentrations in flaxseed and sesame. Once consumed, lignans are converted in the intestines into enterolactone.Enterolactone has been shown to inhibit angiogenesis and promote cancer cell apoptosis (Bergman 2007; Chen 2007).
Enterolactone inhibits the aromatase enzyme, which converts testosterone into estrogen (Brooks 2005; Wang 1994).
Researchers conducted an analysis of breast cancer risk and dietary lignan intake in 3158 women. They determined that premenopausal women with the highest lignan intake had a 44% reduced risk of developing breast cancer (McCann 2004).
Thirty-two women awaiting surgery for breast cancer were randomized to receive either a muffin containing 25 grams of flaxseeds or no flaxseed (control group). Post-operative analysis of the cancerous tissue revealed that markers of tumor growth were reduced by 30-71% in the flaxseed group versus no reduction in the control group (Thompson 2005). Scientists concluded that “dietary flaxseed has the potential to reduce tumor growth in patients with breast cancer.”
In order to examine the relationship between dietary lignan intake and breast cancer, researchers assessed the diets of 1122 women in the 1-2 years before breast cancer diagnosis. They noted that postmenopausal women with the highest dietary intake of lignans had a 71% decreased risk of death from breast cancer (McCann 2010).
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.
Pomegranate, which is rich in antioxidants, has gained widespread popularity as a functional food (ie, has health benefits). The health benefits of the fruit, juice(s), and extract(s) have been studied in realtion to a variety of chornic diseases, including cancer (Syed 2012; Johanningsmeier 2011).
Researchers discovered that consumption of whole pomegranate seed oil and juice concentrate (Kim 2002) resulted in dramatic growth inhibition of estrogen-dependent breast cancer cells. The same study showed inhibition of tumor formation in rodent cells exposed to known breast carcinogens. Using different methods, another research group found a 42% reduction in tumor formation with whole pomegranate juice polyphenols and an 87% reduction with pomegranate seed oil (Mehta 2004).
Pomegranate seed oil is a potent inhibitor of aromatase, the enzyme that converts testosterone into estrogen (Adams 2010). This enzymatic blockade contributes to pomegranate seed oil’s ability to inhibit growth of estrogen-dependent breast cancer cells. Pomegranate extract has also been shown to enhance the effects of the estrogen blocking drug tamoxifen, with the authors of a study stating that “…pomegranate combined with tamoxifen may represent a novel and a powerful approach to enhance and sensitize tamoxifen action” (Banerjee 2011). Pomegranate also increases apoptosis, even in cancer cells that lack estrogen receptors (Kim 2002).
Cancer cells need to grow new blood vessels to support their rapid growth and tissue invasion (angiogenesis). They typically do this by ramping up production of a variety of growth factors, including VEGF and inflammatory interleukins. Pomegranate seed oil powerfully inhibits production of VEGF while upregulating production of migratory inhibitory factor (MIF) in breast cancer cells. In a laboratory model of vessel growth, these modulations translated into a significant decrease in new blood vessel formation (Toi 2003). Pomegranate seed oil’s capacity to block breast cancer development was also demonstrated in an organ culture model of mouse breast cancer (Mehta 2004).Treating the glands with pomegranate seed oil prior to exposure to a powerful carcinogen resulted in a 87% reduction in the number of cancerous lesions compared with controls.
Pomegranate seed oil contains a number of unique chemical constituents with potent biological effects. Punicic acid, an omega-5 polyunsaturated fatty acid that inhibits both estrogen-dependent and estrogen-independent breast cancer cell proliferation in lab cultures (Grossmann 2010), also induced apoptosis at rates up to 91% higher than those in untreated cell cultures—effects which appear to be related to fundamental regulation of cancer cell signaling pathways (Grossmann 2010).
PSK, which is a specially prepared polysaccharide extract from the mushroom Coriolus versicolor, has been studied extensively in Japan where it is used as a non-specific biological response modifier to enhance the immune system in cancer patients (Koda 2003; Noguchi 1995; Yokoe 1997). PSK suppresses tumor cell invasiveness by down-regulating several invasion-related factors (Zhang 2000). PSK has been shown to enhance NK cell activity in multiple studies (Ohwada 2006; Fisher 2002; Garcia-Lora 2001; Pedrinaci 1999).
In a study investigating the use of PSK in women with stage 2 breast cancer, post-operative participants received Tamoxifen with PSK (3 g daily) or Tamoxifen alone. The 5-year survival was 89.9% in the PSK group compared to 86.9% in the group receiving Tamoxifen only (Morimoto 1996).
Pterostilbene, a polyphenol found in blueberries, grapes, and in the bark of the Indian Kino Tree, is closely related to resveratrol (but with unique attributes). Pterostilbene’s mechanisms of action include blocking enzymes that activate carcinogens (Mikstacka 2006, 2007), inducing apoptosis (Tolomeo 2005) and cell cycle arrest (Wang 2012), and enhancing nitric oxide-induced cell death (Ferrer 2007).
Researchers observed that pterostilbene markedly inhibited the growth of breast cancer cells in the laboratory by inducing apoptosis and cell cycle arrest (Wang 2012).
Quercetin is a flavonoid found in a broad range of foods, from grape skins and red onions to green tea and tomatoes. Quercetin’s antioxidant and anti-inflammatory properties protect cellular DNA from cancer-inducing mutations (Aherne 1999). Quercetin traps developing cancer cells in the early phases of their replicative cycle, effectively preventing further malignant development and promoting cancer cell death (Yang 2006). Furthermore, quercetin favorably modulates chemical signaling pathways that are abnormal in cancer cells (Morrow 2001; Bach 2010).
In breast cancer cells, quercetin induces apoptosis and cell cycle arrest (Choi 2001; Chou 2010). Querctin inhibited the growth of tumors (Zhong 2003) and prolonged survival of mice with breast cancer (Du 2010).
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 2001).
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. 2001; 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.
Sulforaphane, which is an isothiocyanate, is most highly concentrated in broccoli as well as in other cruciferous vegetables (eg, brussels sprouts, cabbage and cauliflower).
Sulforaphane detoxifies potential carcinogens, promotes apoptosis, blocks the cell cycle that is required for cancer cell replication, prevents tumor invasion into healthy tissue, enhances natural killer cell activity, and combats metastasis (Zhang 2007; Nian 2009; Traka 2008; Thejass 2006). Research has also demonstrated that sulforaphane is among the plant chemicals most potently capable of blocking the cancer-producing effects of ultraviolet radiation (Dinkova-Kostova 2008).
It has been observed that sulforaphane activated apoptosis (Pledgie-Tracy 2007) and inhibited the proliferation of breast cancer cells in culture (Ramirez 2009; Jo 2007). The binding of estrogen hormones to estrogen receptor alphapromotes breast cell proliferation, which can promote the progression of breast cancer. Researchers have also noted that sulforaphane down-regulates the expression of estrogen receptor alpha in breast cancer cells (Ramirez 2009).
In another clinical trial, mice injected with breast cancer cells developed 60% less tumor mass when treated with sulforaphane compared to untreated mice (Jackson 2004).
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 2002; 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 D3 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 D3 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.
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.