GoogleNews.com, NYTimes.com, ScienceDaily.com, February 10, 2011 — Among patients with early-stage breast cancer that had spread to a nearby lymph node and who received treatment that included lumpectomy and radiation therapy, women who just had the sentinel lymph node removed (the first lymph node to which cancer is likely to spread from the primary tumor) did not have worse survival than women who had more extensive axillary lymph node dissection (surgery to remove lymph nodes found in the armpit), according to a study in the February 9 issue of JAMA.
Axillary lymph node dissection (ALND) has been part of breast cancer surgery since the use of radical mastectomy and reliably identifies nodal metastases. “Sentinel lymph node dissection (SLND) accurately identifies nodal metastasis of early breast cancer, but it is not clear whether further nodal dissection [removal] affects survival,” the authors write. “ALND, as a means for achieving local disease control, carries an indisputable and often unacceptable risk of complications such as seroma [a mass or swelling caused by the localized accumulation of serum within a tissue or organ], infection, and lymphedema [condition in which excess fluid called lymph collects in tissues and causes swelling].”
Armando E. Giuliano, M.D., of the John Wayne Cancer Institute at Saint John’s Health Center, Santa Monica, Calif., and colleagues conducted a study to determine the effects of ALND on overall survival in patients with SLN metastases treated with lumpectomy (surgical removal of a tumor without removing much of the surrounding tissue or lymph nodes) and radiation therapy. The trial was conducted at 115 sites and enrolled patients from May 1999 to December 2004. Patients were women with T1-T2 (stage of tumor) invasive breast cancer, no palpable adenopathy (enlarged lymph nodes), and 1 to 2 SLNs containing metastases.
Patients with SLN metastases identified by SLND were randomized to undergo ALND or no further axillary treatment. Those randomized to ALND underwent dissection of 10 or more nodes. Of 891 patients, 445 were randomly assigned to the ALND group and 446 to the SLND-alone group.
As expected, there was a difference between ALND and SLND-alone treatment groups in total number of removed lymph nodes and total number of tumor-involved nodes; the median (midpoint) total number of nodes removed was 17 in the ALND group and 2 in the SLND-alone group. At a median follow-up of 6.3 years, there were 94 deaths (SLND-alone group, 42; ALND group, 52). The use of SLND alone compared with ALND did not appear to result in statistically inferior survival, with the 5-year over all survival rates being 92.5 percent in the SLND-alone group and 91.8 percent in the ALND group. Disease-free survival did not differ significantly between treatment groups, with 5-year disease-free survival being 83.9 percent for the SLND-alone group and 82.2 percent for the ALND group.
The rate of wound infections, axillary seromas, and paresthesias (prickly, tingling sensations) among patients in the trial was higher for the ALND group than for the SLND-alone group (70 percent vs. 25 percent).
The authors note that these results suggest that breast cancer patients, such as those in this study, do not benefit from the addition of ALND in terms of local control, disease-free survival, or overall survival, and that ALND may no longer be justified for certain patients. “Implementation of this practice change would improve clinical outcomes in thousands of women each year by reducing the complications associated with ALND and improving quality of life with no diminution in survival.”
Editorial: Management of Axillary Lymph Node Metastasis in Breast Cancer — Making Progress
Grant Walter Carlson, M.D., and William C. Wood, M.D., of Emory University, Atlanta, write in an accompanying editorial that the adage that less is more may be applicable regarding surgery for breast cancer.
“Giuliano and colleagues have made an important contribution to the surgical management of SLN metastasis in breast cancer,” they write. Following the lead of other clinical investigators, “these randomized clinical trials have shown that less surgery combined with more radiation and chemotherapy have improved survival for women with breast cancer. Taken together, findings from these investigators provide strong evidence that patients undergoing partial mastectomy, whole-breast irradiation, and systemic therapy for early breast cancer with microscopic SLN metastasis can be treated effectively and safely without ALND.”
1. Grant Walter Carlson, William C. Wood. Management of Axillary Lymph Node Metastasis in Breast Cancer: Making Progress. JAMA, 2011; 305 (6): 606-607 DOI: 10.1001/jama.2011.131
2. Armando E. Giuliano, Kelly K. Hunt, Karla V. Ballman, Peter D. Beitsch, Pat W. Whitworth, Peter W. Blumencranz, A. Marilyn Leitch, Sukamal Saha, Linda M. Mccall, Monica Morrow. Axillary Dissection vs No Axillary Dissection in Women With Invasive Breast Cancer and Sentinel Node Metastasis: A Randomized Clinical Trial. JAMA, 2011; 305 (6): 569-575 DOI: 10.1001/jama.2011.90
The New York Times Special Report
Breast Cancer In-Depth Report
Breast cancers are potentially life-threatening malignancies that develop in one or both breasts. The structure of the female breast is important in understanding this cancer:
- The interior of the female breast consists mostly of fatty and fibrous connective tissues.
- It is divided into about 20 sections called lobes.
- Each lobe is further subdivided into a collection of lobules, structures that contain small milk-producing glands.
- These glands secrete milk into a complex system of tiny ducts. The ducts carry the milk through the breast and converge in a collecting chamber located just below the nipple.
- Breast cancer is either noninvasive (referred to as in situ , confined to the site of origin) or invasive (spreading).
The female breast is either of two mammary glands (organs of milk secretion) on the chest.
Noninvasive Breast Cancer
Noninvasive breast cancers include:
- Ductal carcinoma in situ (DCIS; also called intraductal carcinoma). DCIS consist of cancer cells in the lining of the duct. DCIS is a non-invasive, early cancer, but if left untreated, it may sometimes progress to an invasive, infiltrating ductal breast cancer. DCIS is the most common type of noninvasive breast cancer.
- Lobular carcinoma in situ (LCIS). Although it is technically not a cancer, lobular carcinoma in situ is a marker for an increased risk of invasive cancer the same or both breasts.
A diagnosis of these early cancers (DCIS and LCIS) is made when there is no evidence of invasion.
Invasive Breast Cancer
Invasive cancer occurs when cancer cells spread beyond the basement membrane, which covers the underlying connective tissue in the breast. This tissue is rich in blood vessels and lymphatic channels that are capable of carrying cancer cells beyond the breast. Invasive breast cancers include:
- Invasive (also called infiltrating) ductal carcinoma. This is invasive breast cancer that penetrates the wall of a milk-passage duct. It comprises between 70 – 80% of all breast cancer cases.
- Invasive (also called infiltrating) lobular carcinoma. This is invasive cancer that has spread through the wall of a milk-producing lobule. It accounts for 10 – 15% of all breast cancers. It may sometimes appear in both breasts, sometimes in several separate locations.
There are other less common breast cancers that are not discussed in this report.
In-Depth From A.D.A.M. Risk Factors
About 12% of women develop breast cancer in their lifetime. Each year in the United States, about 192,000 women are diagnosed with invasive breast cancer and about 68,000 women are diagnosed with pre-invasive breast cancer. (Although breast cancer in men is rare, about 2,000 American men are diagnosed each year with invasive breast cancer.)
About 40,000 American women die from breast cancer each year. Breast cancer death rates have declined significantly since the 1990s, especially for women younger than age 50. The earlier breast cancer is diagnosed, the earlier the opportunity for treatment. In the United States, there are currently more than 2.5 million breast cancer survivors.
Risk factors for breast cancer include:
Most cases of breast cancer occur in women older than age 60. According to the American Cancer Society, about 1 in 8 cases of invasive breast cancer are found in women younger than age 45, while 2 in 3 cases of invasive breast cancer occur in women age 55 and older.
Race and Ethnicity
Breast cancer is slightly more common among white woman than African-American, Asian, Latina, or Native American women. However, African-American women tend to have more aggressive types of breast cancer tumors and are more likely to die from breast cancer than women of other races. It is unclear whether this is mainly due to biologic or socioeconomic reasons. Social and economic factors make it less likely that African-American women will be screened, so they are more likely to be diagnosed at a later stage. They are also less likely to have access to effective treatments.
Breast cancer is also more prevalent among Jewish women of Eastern European (Ashkenazi) descent (see Genetic Factors, below).
Family and Personal History
Women who have a family history of breast cancer are at increased risk for developing breast cancer themselves. Having a first-degree relative (mother, sister, or daughter) who has been diagnosed with breast cancer doubles the risk for developing breast cancer.
Women who have had ovarian cancer are at increased risk for developing breast cancer. And, a personal history of breast cancer increases the risk of developing a new cancer in the same or other breast.
About 5 – 10% of breast cancer cases are due to inherited genetic mutations.
BRCA Genes. Inherited mutations in genes known as BRCA1 or BRCA2 are responsible for most cases of hereditary breast cancers, ovarian cancers, or both in families with a history of these cancers.
BRCA gene mutations are present in only about 0.5% of the overall population. However, certain ethnic groups — such as Jewish women of Eastern European (Ashkenazi) descent — have a higher prevalence (2.5%) of BRCA gene mutations. BRCA gene mutations are also seen in some African-American and Hispanic women.
Screening Guidelines for BRCA Genes. The U.S. Preventive Services Task Force (USPSTF) recommends that women at high risk should be tested for BRCA genes, but does not recommend routine genetic counseling or testing in low-risk women (no family history of BRCA 1 or 2 genetic mutations). Risk assessment is based on a woman’s family history of breast and ovarian cancer (on both the maternal and paternal sides).
In general, a woman is considered at high risk for BRCA genes if she has a first-degree relative (mother, daughter, or sister) or several second-degree relatives (grandmother, aunt) diagnosed with breast or ovarian cancer. Women who do not have a family history of breast cancer have a low probability of inheriting BRCA genes and do not need to be tested.
The relevance of the inherited BRCA1 or BRCA2 mutations to survival is controversial. Some studies have suggested that these mutations are linked to less lethal breast cancer. Others suggest that they do not change prognosis or may worsen it. Women with these genetic mutations do have a greater risk for a new cancer to develop. Patients with BRCA1 mutations tend to develop tumors that are hormone receptor negative, which can behave more aggressively.
Other Genetic Mutations. Other genes associated with increased hereditary breast cancer risk include p53, CHEK2, ATM, and PTEN.
Exposure to Estrogen
Because growth of breast tissue is highly sensitive to estrogens, the more estrogen a woman is exposed to over her lifetime, the higher her risk for breast cancer.
Duration of Estrogen Exposure . Early age at menarche (first menstrual period) or later age at menopause may slightly increase a woman’s risk for breast cancer.
Pregnancy . Women who have never had children or who had their first child after age 30 may have a slightly increased breast cancer risk. Having children at an early age, and having multiple pregnancies, reduces breast cancer risk. Scientific evidence shows there is no association between abortion and increased breast cancer risk.
Studies have been mixed on whether breast-feeding decreases breast cancer risk. Breast-feeding reduces a woman’s total number of menstrual cycles, and thereby estrogen exposure, which may account for its possible protective effects. Some studies suggest that the longer a woman breast-feeds, the lower her risk, and that breast-feeding may be most protective for women with a family history of breast cancer.
Birth Control Pills . Although studies have been conflicting about whether estrogen in oral contraceptives increase the chances for breast cancer, the most recent research indicates that current or former oral contraceptive use does not significantly increase breast cancer risk. Women who have used oral contraceptives may have slightly more risk for breast cancer than women who have never used them, but this risk declines once a woman stops using birth control pills.
Hormone Replacement Therapy . Many studies have reported a higher risk for breast cancer in postmenopausal women who take combination hormone replacement therapy (HRT), which contains both estrogen and progesterone. Combination HRT is used by women who have a uterus, because estrogen alone can increase the risk of uterine cancer. Estrogen-only hormone replacement therapy is prescribed for women who have had a hysterectomy.
According to the most recent studies, long-term use (about 5 years or more) of combination HRT increases the risk of developing and dying from breast cancer. This risk then decreases within 5 years of stopping combination HRT.
The North American Menopause Society recommends that women who are at risk for breast cancer should avoid hormone therapy and try other options to manage menopausal symptoms such as hot flashes. Most doctors recommend that women use HRT only for short-term relief of menopausal symptoms. In recent years, rates of breast cancer have decreased as fewer women have opted for HRT.
Women who take HRT should be aware that they need regular mammogram screenings, because HRT increases breast cancer density, making mammograms more difficult to read. <!–[For more information, see
In-Depth Report #40: Menopause .]–>
Infertility and Infertility Treatments . Despite some concerns that infertility treatments using the drug clomiphene may increase the risk for breast cancer, most studies do not show an association. Some studies indicate that ovulation induction with clomiphene may actually decrease breast cancer risk. (Clomphine is related to tamoxifen, a drug that is used for breast cancer prevention in high-risk women.)
Certain breast conditions may increase the risk for breast cancer:
- Dense breast tissue is associated with a higher risk for breast cancer. Studies suggest that women with highly dense tissue have 2 – 6 times the risk of women with the least dense tissue. Genetic factors play a large role in breast density. Hormone replacement therapy also increases breast density. In addition, dense breasts make mammograms more difficult to read, which increases the likelihood of missing early signs of cancer.
- Benign proliferative breast disease, or unusual cell growth known as atypical hyperplasia, is a significant risk factor for breast cancer.
Some common benign breast abnormalities that pose very little or no risks for breast cancer include:
- Cysts. These mostly occur in women in their middle-to-late reproductive years and can be eliminated simply by aspirating fluid from them.
Click the icon to see an image of cysts in the breast.
- Fibroadenoma. These are solid benign lumps that occur in women ages 15 – 30.
- Breast abscesses during breast-feeding.
Click the icon to see an image of a breast abscess.
- Nipple discharge. Discharge from the nipple is worrisome to patients, but it is unlikely to be a sign of cancer. Unexplained discharge still warrants evaluation, however.
Click the icon to see an image of nipple discharge.
- Mastalgia. This is breast pain that occurs in association with, or independently from, the menstrual cycle. About 8 – 10% of women experience moderate-to-severe breast pain associated with their menstrual cycle. In general, breast pain does not need assessment unless it is severe and prolonged.
The following physical characteristics have been associated with increased risk:
- Obesity increases the risk for all types of estrogen receptor-positive breast cancers. Women who gain weight after menopause are most at risk. (On a positive note, losing weight after menopause decreases breast cancer risk.) In postmenopausal women, estrogen is produced in fat tissue. High amounts of fatty tissue increase levels of estrogen in the body, leading to faster growth of estrogen-sensitive cancers.
- Estrogen is involved in building bone mass. Therefore, women with heavy, dense bones are likely to have higher estrogen levels and to be at greater risk for breast cancer.
- Some studies have found a greater risk for breast cancer in taller women, possibly due to the higher estrogen levels associated with greater bone growth.
Exposure to Estrogen-like Industrial Chemicals. Chemicals with estrogen-like effects, called xenoestrogens, have been under suspicion for years. There has been particular concern with pesticides containing organochlorines (DDT and its metabolites, such as dieldrin) and pyrethroids (permethrin), but at this time evidence of any causal association is very weak.
Exposure to Diethylstilbestrol. Women who took diethylstilbestrol (DES) to prevent miscarriage have a slightly increased risk for breast cancer. There may also be a slightly increased risk for their daughters (commonly called “DES daughters”), who were exposed to the drug when their mothers took it during pregnancy .
Radiation Exposure. Heavy exposure to radiation is a significant risk factor for breast cancer. Girls who receive high-dose radiation therapy for cancer face an increased risk for breast cancer in adulthood. Low-dose radiation exposure before age 20 may increase the risk for women with BRCA genetic mutations.
Disproven Risk Factors
Antiperspirants or use of deodorants after shaving have not been linked with any higher risk for breast cancer. There is also no evidence that bras increase breast risk. Abortion does not increase risk.
In-Depth From A.D.A.M. Prevention and Lifestyle Factors
Regular exercise, particularly vigorous exercise, appears to offer protection against breast cancer. Exercise can help reduce body fat, which in turn lowers levels of cancer-promoting hormones such as estrogen. The American Cancer Society recommends engaging in 45 – 60 minutes of physical activity at least 5 days a week.
Exercise can also help women who have been diagnosed with breast cancer and may help reduce the risk of breast cancer recurrence. Studies indicate that both aerobic and weight training exercises benefit the body and the mind, and improve quality of life for breast cancer survivors.
Physical activity contributes to health by reducing the heart rate, decreasing the risk for cardiovascular disease, and reducing the amount of bone loss that is associated with age and osteoporosis. Physical activity also helps the body use calories more efficiently, thereby helping in weight loss and maintenance. It can increase basal metabolic rate, reduces appetite, and helps in the reduction of body fat.
Despite much research on the association between diet and breast cancer, there is still little consensus. The best advice is to eat a well-balanced diet and avoid focusing on one “cancer-fighting” food. The American Cancer Society’s dietary guidelines for cancer prevention recommend that people:
- Choose foods and amounts that promote a healthy weight.
- Eat 5 or more servings of fruits and vegetables each day.
- Choose whole grains instead of refined grain products.
- Limit consumption of processed and red meat.
- Women should limit alcohol consumption to 1 drink per day (women at high risk for breast cancer should consider not drinking alcohol at all).
For breast cancer survivors, the American Cancer Society recommends diets that include lots of fruits and vegetables, low amounts of saturated fat (from meat and high-fat dairy products), moderation in soy foods, and moderate or no alcohol consumption.
Here are results from recent studies evaluating diet and breast cancer, for preventing both the development of cancer and its recurrence:
Fats . Research is still mixed on the role that fats, and which specific types of fats, play in breast cancer risk and prevention. According to results from the Women’s Health Initiative study of dietary fat and breast cancer, there is no definite evidence that a low-fat diet will help prevent breast cancer. However, the study suggested that women who normally eat a very high-fat diet may benefit by reducing their fat intake.
Fruits and Vegetables . Fruits and vegetables are important sources of antioxidants, which may help protect against the tissue damage linked to increased cancer risk. Antioxidants include vitamin C, vitamin E, and carotenoids such as beta-carotene and lycopene. Richly colored fruits and vegetables — not supplements — are the best sources for these nutrients. These fiber-rich foods are an essential part of a healthy diet. However, it is not clear whether fruits and vegetables can specifically prevent breast cancer development or recurrence.
Calcium and Vitamin D . Eating lots of foods rich in calcium and vitamin D (such as yogurt and milk) may modestly reduce the risk of breast cancer for premenopausal women. Low-fat or non-fat dairy products are a healthier choice than high-fat ones.
Soy . The American Cancer Society recommends that women with breast cancer eat only moderate amounts of soy foods and avoid taking dietary supplements that contain high amounts of isoflavones. Isoflavones are a type of phytoestrogen (estrogen-like plant chemical). There have been concerns that high intakes of soy may increase the risk of estrogen-responsive cancers such as breast cancer.
Specific Preventive Measures for High-Risk Women
Lifestyle Factors. Premenopausal women at higher risk, usually because of family history, should take as many preventive measures as possible, starting at an early age. The following lifestyle choices may be beneficial:
- Exercising and eating healthily is the first essential rule.
- High-risk premenopausal women may choose alternatives to oral contraceptives and, if feasible, consider having children early in their life.
- High-risk postmenopausal women should consider not taking hormone replacement therapy.
- Any woman at high risk for breast cancer should consider avoiding alcohol or drink it very sparingly.
Tamoxifen and Raloxifene. Drugs known as selective estrogen-receptor modulators (SERMs) act like estrogen in some tissues but behave like estrogen blockers (anti-estrogens) in others. Two SERMs — tamoxifen (Nolvadex) and raloxifene (Evista) — are approved for breast cancer prevention for high-risk women. Tamoxifen and raloxifene are not recommended as prevention for women at low risk for breast cancer or its recurrence. Women at high risk for breast cancer should discuss with their doctors the risks and benefits of SERMs.
Tamoxifen (Nolvadex) is the most studied of these drugs. It is currently used to treat breast cancer and was the first drug approved for prevention. There is strong evidence that it halves the risk for estrogen receptor-positive cancers in high-risk women, including those with BRCA2 mutations (although possibly not BRCA1). It also helps prevent recurrence in women who have been treated for breast cancers. However, it has no protective effects against estrogen receptor-negative (hormone-insensitive) cancers.
Tamoxifen can increase the risk for uterine (endometrial) cancers. It can also increase the risk for blood clots, strokes, and endometriosis. Less serious side effects include hot flashes and vaginal discharge.
Raloxifene (Evista) is approved for prevention of breast cancer in postmenopausal women with osteoporosis and postmenopausal women at high risk for invasive breast cancer. (It is also approved for prevention and treatment of osteoporosis in postmenopausal women.) Studies indicate that it works as well as tamoxifen in reducing the risk of invasive breast cancer
One of raloxifene’s main benefits is that it has a lower risk than tamoxifen of causing uterine cancer and blood clots. However, women with a history of blood clots in the legs, lungs, or eyes should not take raloxifene. Although studies indicate raloxifene does not increase the risk of stroke, it can increase the risk of dying from a stroke. Women with a history of or current risk factors for stroke or heart disease should discuss with their doctors whether raloxifene is an appropriate choice.
Less serious side effects of raloxifene include hot flashes, leg cramps, swelling of the legs and feet, flu-like symptoms, joint pain, and sweating. Raloxifene can cause birth defects and is approved only for postmenopausal women. It should not be taken with the cholesterol-lowering drug cholestyramine (Questran) or with estrogens.
In-Depth From A.D.A.M. Symptoms
Breast cancers in their early stages are usually painless. Often the first symptom is the discovery of a hard lump. Fifty percent of such masses are found in the upper outer quarter of the breast. The lump may make the affected breast appear elevated or asymmetric. The nipple may be retracted or scaly. Sometimes the skin of the breast is dimpled like the skin of an orange. In some cases there is a bloody or clear discharge from the nipple.
Many cancers, however, produce no symptoms and cannot be felt on examination. With an increase in the use of mammogram screening programs during the last several decades, more breast cancers are being discovered before there are any symptoms.
Monthly breast self-exams should always include: visual inspection (with and without a mirror) to note any changes in contour or texture, and manual inspection in standing and reclining positions to note any unusual lumps or thicknesses.
In-Depth From A.D.A.M. Diagnosis
Breast Examination by a Health Professional. Women ages 20 – 49 should have a physical examination by a health professional every 1 – 2 years. Those over age 50 should be examined annually.
Self-Examinations. Women have been encouraged to perform a self-examination each month, but some studies have reported no difference in mortality rates between women who do self-examination and those who do not. This does not mean women should stop attempting self-examinations, but they should not replace the annual examination done by a health professional.
1. Pick a time of the month that is easy to remember and perform self-examination at that time each month. The breast has normal patterns of thickness and lumpiness that change within a monthly period, and a consistently scheduled examination will help differentiate between what is normal from abnormal. Many doctors recommend “breast awareness” rather than formal monthly self-examinations.
2. Stand in front of a mirror. Breasts should be basically the same size (one may be slightly larger than the other). Check for changes or redness in the nipple area. Look for changes in the appearance of the skin. With hands on the hips, push the pelvis forward and pull the shoulders back and observe the breasts for irregularities. Repeat the observation with hands behind the head. Move each arm and shoulder forward.
3. Lie down on the back with a rolled towel under one shoulder. Apply lotion or bath oil over the breast area. Using the 2nd, 3rd, and 4th finger pads (not tips) held together, make dime-sized circles. Press lightly first to feel the breast area, then press harder using a circular motion.
Using this motion, start from the collarbone and move downward to underneath the breast. Shift the fingers slightly over, slightly overlapping the previously checked region, and work upward back to the collarbone. Repeat this up-and-down examination until the entire breast area has been examined. Be sure to cover the entire area from the collarbone to the bottom of the breast area and from the middle of the chest to the armpits. Move the towel under the other shoulder and repeat the procedure.
Examine the nipple area, by gently lifting and squeezing it and checking for discharge.
4. Repeat step 3 in an upright position. (The shower is the best place for this, using plenty of soap.)
Note: A lump can be any size or shape and can move around or remain fixed. Of special concern are specific or unusual lumps that appear to be different from the normal varying thicknesses in the breast.
Monthly breast self-exams should always include: visual inspection (with and without a mirror) to note any changes in contour or texture, and manual inspection in standing and reclining positions to note any unusual lumps or thicknesses.
Current Recommendations for Screening. Mammograms are very effective low-radiation screening methods for breast cancer. There is, however, debate on when women should begin to have mammograms and how frequently they should have them.
Most major professional groups, including The American Cancer Society and The American College of Obstetrics and Gynecology recommend that women have a mammogram every 1 – 2 years starting at age 40.
The U.S. Preventive Services Task Force made the following recommendations in November 2009:
- The USPSTF recommended against routine screening mammography in women ages 40 to 49 years and stated that the decision to screen women in this age group should be made on a case-by-case basis, taking the patient’s values regarding specific benefits and harms into account.
- The USPSTF recommended screening mammography be performed for women ages 50 to 74 years every other year.
Given the confusion and recommendations, women, (particularly those in their 40s), should discuss the risks and benefits of mammography with their doctors, and then base their decisions on family history, general health, and personal values.
Since mammographies in younger women produce a relatively high rate of false-positive results (when the test falsely indicates breast cancer), there is a risk of radiation exposure and potentially unnecessary biopsies or surgeries. However, mammograms can help catch tumors while they are in their earliest and most treatable stages. The most deadly types of breast cancer tend to occur in women in their 40s.
After a woman reaches age 50, her risk for developing breast cancer increases. (Women over age 65 account for most new cases of breast cancer.) Women with risk factors for breast cancer, including a close family member with the disease, should consider having annual mammograms starting 10 years earlier than the age at which the relative was diagnosed.
Other Imaging Techniques
Magnetic Resonance Imaging and Ultrasound. Magnetic resonance imaging (MRI) and ultrasound techniques can detect very small tumors (less than half an inch). However, they are expensive and time-consuming procedures, and ultrasound may yield more false-positive results. Nevertheless, some doctors believe they are important in identifying small tumors missed on mammography in women who are receiving lumpectomy or breast-conserving surgeries. Such findings allow surgeons to remove the optimal amount of abnormal tissue. Ultrasound may be particularly helpful for women with dense breast tissue who show signs of breast cancer.
In 2007, the American Cancer Society recommended that high-risk women have an MRI of their breast with their annual mammogram, including those who have:
- A BRCA1 or BRCA2 mutation
- A first-degree relative (parent, sibling, child) with a BRCA1 or BRCA2 mutation, even if they have yet to be tested themselves
- A lifetime risk of breast cancer that has been scored at 20 – 25% or greater based on various risk assessment tools that evaluate family history and other factors
- Had radiation to the chest between ages 10 – 30
- Li-Fraumeni syndrome, Cowden syndrome, or Bannayan-Riley-Ruvalcaba syndrome, or may have one of these genetic syndromes based on a history in a first-degree relative
For women who have had cancer diagnosed in one breast, MRIs can also be very helpful for detecting hidden tumors in the other breast. An important study reported that MRI scans of women who were diagnosed with cancer in one breast detected over 90% of cancers in the other breast that had been previously missed by mammography or clinical breast exam. Currently, few women who are diagnosed with cancer in one breast are offered an MRI of the other breast. Some doctors advocate MRIs for all women newly diagnosed with breast cancer; others oppose this view. MRI scans may be most useful for younger women with breast cancer who have dense breast tissue that may obscure tumors from mammography readings. MRIs are less likely to be helpful for older women with early tumors in one breast and clear mammography readings in the other.
It is very important that women have MRIs at qualified centers that perform many of these procedures each year. MRI is a complicated procedure and requires special equipment and experienced radiologists. MRI facilities should also be able to offer biopsies when suspicious findings are detected.
Scintimammography. In scintimammography, a radioactive chemical is injected into the circulatory system, which is then selectively taken up by the tumor and revealed on mammograms. This method is used for women who have had abnormal mammograms or for women who have dense breast tissue. It is not used for regular screening or as an alternative to mammography.
A definitive diagnosis of breast cancer can be made only by a biopsy (a microscopic examination of a tissue sample of the suspicious area).
- When a lump can be felt and is suspicious for cancer on mammography, an excisional biopsy may be recommended. This biopsy is a surgical procedure for removing the suspicious tissue and typically requires general anesthetic.
- A core biopsy involves a small incision and the insertion of a spring-loaded hollow needle that removes several samples. The patient needs only local anesthetic.
- A wire localization biopsy may be performed if mammography detects abnormalities, but there is no lump. With this procedure, using mammography as a guide, the doctor inserts a small wire hook through a hollow needle and into the suspicious tissue. The needle is withdrawn, and the hook is used by the surgeon to locate and remove the lesion. The patient may receive local or general anesthetic.
- A vacuum-assisted device may be used for some biopsies. This uses a single probe through which a vacuum is used to draw out tissue. It allows several samples to be taken without having to remove and re-insert the probe.
Final analysis of the breast tissue may take several days.
Sentinel Node Biopsy
The sentinel lymph node is the first lymph node that cancer cells are likely to spread to from the primary tumor (the original site of the cancer). Sentinel node biopsy is a procedure that examines the sentinel node to determine if cancer has spread.
Sentinel node biopsy involves:
- The procedure uses an injection of a tiny amount of a tracer, either a radioactively-labeled substance (radioisotope) or a blue dye, into the tumor site.
- The tracer or dye then flows through the lymphatic system into the sentinel node. This is the first lymph node to which any cancer would spread.
- The sentinel lymph node and possibly one or two others are then removed.
- If they do not show any signs of cancer, it is highly likely that the remaining lymph nodes will be cancer free, making further surgery unnecessary.
Patients who have a sentinel node biopsy tend to have better arm function and a shorter hospital stay than those who have an axillary node biopsy. The American Society of Clinical Oncology’s guidelines recommend sentinel node biopsy instead of axillary lymph node dissection for women with early stage breast cancer who do not have nodes that can be felt during a physical exam.
If the sentinel node biopsy finds evidence that cancer has spread, the next diagnostic step is to find out how far it has spread. To do this, the doctor performs a procedure called an axillary lymphadenectomy , which partially or completely removes the lymph nodes in the armpit beside the affected breast (called axillary lymph nodes). It may require a hospital stay of 1 – 2 days.
Once the lymph nodes are removed, they are analyzed to determine whether subsequent treatment needs to be more or less aggressive:
- If no cancer is found in the lymph nodes, the condition is referred to as node negative breast cancer. The chances are good that the cancer has not spread and is still local.
- If cancer cells are present in the lymph nodes, the cancer is called node positive . Their presence increases the possibility that the cancer has spread microscopically to other areas of the body. In such cases, however, it is still not known if the cancer has metastasized beyond the lymph nodes or, if so, to what extent. The doctor may perform further tests to see if the cancer has spread to the bone (bone scan), lungs (x-ray or CT scan) or brain (MRI or CT scan).
Side effects of the procedure may include increased risk for infection and pain, swelling in the arm from fluid build-up, and impaired sensation and restricted movement in the affected arm.
In-Depth From A.D.A.M. Prognosis
Breast cancer is the second most lethal cancer in women. (Lung cancer is the leading cancer killer in women.) The good news is that early detection and new treatments have improved survival rates. The 5-year survival rate for women diagnosed with cancer is 80%. About Unfortunately, women in lower social and economic groups still have significantly lower survival rates than women in higher groups.
Several factors are used to determine the risk for recurrence and the likelihood of successful treatment. They include:
- Location of the tumor and how far it has spread
- Whether the tumor is hormone receptor-positive or -negative
- Tumor markers
- Gene expression
- Tumor size and shape
- Rate of cell division
The good news is that women are living longer with breast cancer. Due to better treatment options, breast cancer mortality rates declined by about 25% since 1990. However, survivors must live with the uncertainties of possible recurrent cancer and some risk for complications from the treatment itself.
Recurrences of cancer usually develop within 5 years of treatment. About 25% of recurrences and half of new cancers in the opposite breast occur after 5 years.
Location of the Tumor
The location of the tumor is a major factor in outlook:
- If the cancer is ductal carcinoma in situ (DCIS) or has not spread to the lymph nodes (node negative), the 5-year survival rates with treatment are up to 98%.
- If the cancer has spread to the lymph nodes or beyond the primary tumor site (node positive), the 5-year survival rate is about 84%.
- If the cancer has spread (metastasized) to other sites (most often the lung, liver, and bone), the average 5-year survival rate is 27%. New drug therapies, particularly aromatase inhibitors, have helped prolong survival for women with metastatic (stage IV) cancer.
The location of the tumor within the breast is an important predictor. Tumors that develop toward the outside of the breast tend to be less serious than those that occur more toward the middle of the breast.
Hormone Receptor-Positive or -Negative
Breast cancer cells may contain receptors, or binding sites, for the hormones estrogen and progesterone. Cells containing these binding sites are known as hormone receptor-positive cells. If cells lack these connectors, they are called hormone receptor-negative cells. About 75% of breast cancers are estrogen receptor-positive (ER-positive, or ER+). About 65% of ER-positive breast cancers are also progesterone receptor-positive (PR-positive, or PR+). Cells that have receptors for one of these hormones, or both of them, are considered hormone receptor-positive.
Hormone receptor-positive cancer is also called “hormone sensitive” because it responds to hormone therapy such as tamoxifen or aromatase inhibitors. Hormone receptor-negative tumors are referred to as “hormone insensitive” or “hormone resistant.”
Women have a better prognosis if their tumors are hormone receptor-positive because these cells grow more slowly than receptor-negative cells. In addition, women with hormone receptor-positive cancer have more treatment options. (Hormone receptor-negative tumors can be treated only with chemotherapy.) Recent declines in breast cancer mortality rates have been most significant among women with estrogen receptor-positive tumors, due in part to the widespread use of post-surgical hormone drug therapy.
Tumor markers are proteins found in blood or urine when cancer is present. Although they are not used to diagnose cancer, the presence of certain markers can help predict how aggressive a patient’s cancer may be and how well the cancer may respond to certain types of drugs.
Tumor markers relevant for breast cancer prognosis include:
HER2 . The American Cancer Society recommends that all women newly diagnosed with breast cancer get a biopsy test for a growth-promoting protein called HER2/neu. HER2-positive cancer usually occurs in younger women and is more quickly-growing and aggressive than other types of breast cancer. The HER2 marker is present in about 20% of cases of invasive breast cancer. Two types of tests are used to detect HER2:
- Immunohistochemistry (IHC)
- Fluorescence in-situ hybridization (FISH)
Either test may be used as long as it is performed by an accredited laboratory. Tests that are not clearly positive or negative should be repeated.
Treatment with trastuzumab (Herceptin) or lapatinib (Tykerb) may help women who test positive for HER2. In 2008, the FDA approved a new genetic test (Spot-Light) that can help determine which patients with HER2-positive breast cancer may be good candidates for trastuzumab treatment.
Other Markers . Other markers that may be evaluated include CA 15-3, CA 27.29, CEA, ER, PgR, uPA, and PAI-1.
Gene Expression Profiling
Gene expression profiling tests (Oncotype DX, MammaPrint) examine a set of genes in tumor tissue to determine the likelihood of breast cancer recurrence. These tests are also used to help determine whether adjuvant (following surgery) drug treatments should be given. The American Society of Clinical Oncology and the National Comprehensive Cancer Network now recommend that gene expression profiling tests be administered to newly diagnosed patients with node-negative, estrogen-receptor-positive breast cancer. Based on the results, a doctor can decide whether a patient who has had surgery may benefit from chemotherapy.
Other Factors for Predicting Outlook
Tumor Size and Shape . Large tumors pose a higher risk than small tumors. Undifferentiated tumors, which have indistinct margins, are more dangerous than those with well-defined margins.
Rate of Cell Division . The more rapidly a tumor grows, the more dangerous it is. Several tests measure aspects of cancer cell division and may eventually prove to predict the disease. For example, the mitotic index (MI) is a measurement of the rate at which cells divide. The higher the MI, the more aggressive the cancer. Other tests measure cells at a certain phase of their division.
Effect of Emotions and Psychological Support
Recent evidence has not supported early reports of survival benefits for women with metastatic breast cancer who engage in support groups. However, some studies have suggested that psychotherapy, group support, or both may relieve pain and reduce stress, particularly in women who are suffering emotionally.
Stress has been ruled out as a risk factor either for breast cancer itself or for its recurrence.
In-Depth From A.D.A.M. Treatment
The three major treatments of breast cancer are surgery, radiation, and drug therapy. No one treatment fits every patient, and combination therapy is usually required. The choice is determined by many factors, including the age of the patient, menopausal status, the kind of cancer (ductal verses lobular), its stage, and whether or not the tumor contains hormone-receptors.
Breast cancer treatments are defined as local or systemic:
- Local Treatment . Surgery and radiation are considered local therapies because they directly treat the tumor, breast, lymph nodes, or other specific regions. Surgery is usually the standard initial treatment.
- Systemic Treatment . Drug treatment is called systemic therapy, because it affects the whole body. Drugs may include either chemotherapy or hormone therapy. Drug therapy may be used as primary therapy for patients for whom surgery or radiation therapy is not appropriate, neoadjuvant therapy (before surgery or radiation) to shrink tumors to a size that can be treated with local therapy, or as adjuvant therapy (following surgery or radiation) to reduce the risk of cancer recurrence. For metastatic cancer, drugs are used not to cure but to improve quality of life and prolong survival.
Any or all of these therapies may be used separately or, most often, in different combinations. For example, radiation alone or with chemotherapy or hormone therapy may be beneficial before surgery, if the tumor is large. Surgery followed by radiation and hormone therapy is usually recommended for women with early-stage, hormone-sensitive cancer. There are numerous clinical trials investigating new treatments and treatment combinations. Patients, especially those with advanced stages of cancer, may wish to consider enrolling in a clinical trial.
Cancer Stage and Treatment Options
Treatment strategies depend in part on the stage of the cancer.
Stage 0 (Carcinoma in Situ). Stage 0 breast cancer is considered non-invasive (‘in situ”), meaning that the cancer is still confined within breast ducts or lobules and has not yet spread to surrounding tissues. Stage 0 cancer is classified as either:
- Ductal carcinoma in situ (DCIS). These are cancer cells in the lining of a duct that have not invaded the surrounding breast tissue.
- Lobular carcinoma in situ (LCIS). These are cancer cells in the lobules of the breast. LCIS rarely develops into invasive breast cancer, but having it in one breast increases the risk of developing cancer in the other breast.
Treatment options for DCIS include:
- Breast-conserving surgery and radiation therapy (followed by hormone therapy for women with hormone-sensitive cancer). Many doctors recommend this approach.
- Total mastectomy (followed by hormone therapy for women with hormone-sensitive cancer)
- Breast-conserving surgery without radiation therapy
Treatment options for LCIS include:
- Regular exams and mammograms to monitor any potential changes (observation treatment)
- Hormone therapy to prevent development of breast cancer (for women with hormone-sensitive cancer)
- Mastectomy of both breasts was previously used as treatment, but is now rarely recommended
Stage I and II (Early-Stage Invasive). In stage I cancer, cancer cells have not spread beyond the breast, and the tumor is no more than 2 cm (about 3/4 of an inch) across.
Stage II cancer is classified as either stage IIA or stage IIb.
In stage IIA cancer the tumor is either:
- No more than 2 centimeters and has spread to the underarm lymph nodes (axillary lymph nodes)
- Between 2 – 5 centimeters and has not spread to the underarm lymph nodes
In stage IIB cancer the tumor is either:
- Larger than 2 centimeters and less than 5 centimeters and has spread to 1 – 3 axillary lymph nodes
- Larger than 5 centimeters but has now spread to lymph nodes
Treatment options for stage I and stage II breast cancer may include:
- Breast-conserving surgery (such as lumpectomy) followed by radiation therapy
- Modified radical mastectomy with or without breast reconstruction
- Post-surgical therapy (adjuvant therapy), including radiation of lymph nodes, chemotherapy, or hormone therapy
- Trastuzumab (Herceptin) given along with or following adjuvant chemotherapy for women with HER2-positive cancer
Stage III (Locally Advanced). Stage III breast cancer is classified into several sub-categories: Stage IIIA, stage IIIB, and stage IIIC (operable or inoperable).
In stage IIIA breast cancer, the tumor is either of the following:
- Not more than 5 centimeters and has spread to 4 – 9 axillary lymph nodes
- Larger than 5 centimeters and has spread to 1 – 9 axillary nodes or to internal mammary nodes.
Treatment options for stage IIIA breast cancer are the same as those for stages I and II.
In stage IIIB breast cancer, the tumor has spread to either of the following:
- Tissues near the breast (including the skin or chest wall)
- Lymph nodes within the breast or under the arm
Stage IIIB treatment options may include:
- Chemotherapy, and possibly hormone therapy (sometimes in combination with chemotherapy)
- Chemotherapy followed by surgery (breast-conserving surgery or total mastectomy) with lymph node dissection followed by radiation therapy and possibly more chemotherapy or hormone therapy
- Clinical trials
Stage IIIC breast cancer is classified as either operable or inoperable.
In operable stage IIIC, the cancer may be found in:
- 10 or more of the underarm lymph nodes
- Lymph nodes beneath the collarbone and near the neck on the same side of the body as the affected breast
- Lymph nodes within the breast as well as underarm lymph nodes
Treatment options for operable stage III breast cancer are the same as those for stage I and II breast cancers.
In inoperable stage III breast cancer, the cancer has spread to lymph nodes above the collarbone and near the neck on the same side of the body as the affected breast. Treatment options are the same as those for stage IIIB.
Stage IV (Advanced Cancer). In stage IV, the cancer has spread (metastasized) from the breast to other parts of the body. In about 75% of cases, the cancer has spread to the bone. The cancer at this stage is considered to be chronic and incurable, and the usefulness of treatments is limited. The goals of treatment for stage IV cancer are to stabilize the disease and slow its progression, as well as to reduce pain and discomfort.
Treatment options for stage IV cancer include:
- Surgery or radiation for any localized tumors in the breast.
- Chemotherapy, hormone therapy, or both. Targeted therapy with trastuzumab (Herceptin) or lapatinib (Tykerb) should be considered for women with HER2-positive cancer.
- Cancer that has spread to the brain may require radiation and high-dose steroids.
- Cancer that has spread to the bone may be helped by radiation or bisphosphonate drugs. Such treatments can relieve pain and help prevent bone fractures.
- Clinical trials of new drugs or drug combinations, or experimental treatments such as high-dose chemotherapy with stem cell transplant.
The American Society of Clinical Oncology (ASCO) recommends follow-up care for patients who have been treated for breast cancer:
- Visit your doctor every 3 – 6 months for the first 3 years after your first cancer treatment, every 6 – 12 months during the fourth and fifth year, and once a year thereafter.
- Have a mammogram 1 year after the mammogram that diagnosed your cancer (but no earlier than 6 months after radiation therapy), and every 6 – 12 months thereafter.
- Perform a breast self-exam every month (however, this is no substitute for a mammogram).
- See your gynecologist regularly (women taking tamoxifen should be sure to report any vaginal bleeding).
- A year after diagnosis, you can either continue to see your oncologist or transfer your care to your primary care physician.
- If you are on hormone therapy, discuss with your oncologist how often to schedule follow-up visits for re-evaluation of your treatment.
ASCO does not recommend the use of laboratory blood tests (complete blood counts, carcinoembryonic antigen) or imaging tests (bone scans, chest x-rays, liver ultrasound, FDG-PET scan, CT scan) for routine breast cancer follow-up.
Genetic counseling may be helpful if you have:
- Ashkenazi Jewish heritage
- Personal or family history of ovarian cancer
- Personal or family history of cancer in both breasts
- Any first-degree female relative (mother, sister, daughter) diagnosed with breast cancer before age 50
- Two or more first-degree or second-degree (grandparent, aunt, uncle) diagnosed with breast cancer
- History of breast cancer in a male relative
Pregnancy after Breast Cancer Treatment . There are no definite recommendations on how long a woman should wait to become pregnant after breast cancer treatment. Because of the connection between estrogen levels and breast cancer cell growth, some doctors recommend delaying pregnancy until 2 years after treatment in order to reduce the risk of cancer recurrence and improve odds for survival. However, other studies indicate that conceiving 6 months after treatment does not negatively affect survival. Discuss with your doctor your risk for recurrence, and when it may be safe to attempt pregnancy.
Recurrent Breast Cancer
Recurrent breast cancer is considered to be an advanced cancer. In such cases, the disease has come back in spite of the initial treatment. Most recurrences appear within the first 2 – 3 years after treatment, but breast cancer can recur many years later. Treatment options are based on the stage at which the cancer reappears, whether or not the tumor is hormone responsive, and the age of the patient. Between 10 – 20% of recurring cancers are local. Most recurrent cancers are metastatic. All patients with recurring cancer are candidates for clinical trials.
Because most breast cancer recurrences are discovered by patients in between doctor visits, it is important to notify your doctor if you experience any of the following symptoms. These symptoms may be signs of breast cancer recurrence:
- New lumps in the breast
- Bone pain
- Chest pain
- Abdominal pain
- Shortness of breath or difficulty breathing
- Persistent headaches or coughing
- Rash on breast
- Nipple discharge
In-Depth From A.D.A.M. Surgery
Surgery forms a part of nearly every patient’s treatment for breast cancer. The initial surgical intervention is often a lumpectomy, the removal of the tumor itself. In the past, mastectomy (the removal of the breast) was the standard treatment for nearly all breast cancers. Now, many patients with early-stage cancers can choose breast-conserving treatment, or lumpectomy followed by radiation, with or without chemotherapy.
For invasive breast cancer, studies indicate that lumpectomy or partial mastectomy combined with radiation therapy works as well as a modified radical mastectomy.
Breast-conserving procedures are now appropriate and as successful as mastectomy in most women with early stage breast cancer. All women should discuss these options fully with their doctor. Recurrence rates with conservative surgery are highest in women under age 45. Some women choose mastectomy over breast-conserving treatment even if the latter is appropriate because it gives them a greater sense of security and allows them to avoid radiation therapy.
Lumpectomy. Lumpectomy is the removal of the tumor, often along with lymph nodes in the armpit. It serves as an opportunity for biopsy, a diagnostic tool, and a primary treatment for small local breast tumors. If invasive cancer is found, the doctor will decide to proceed with breast radiation therapy, to remove additional tissue (should the margins of the specimen show signs of cancer), or to perform a mastectomy. Lumpectomy followed by radiation therapy is appropriate and as effective as mastectomy for most women with Stage I or II breast cancers.
Breast-Conserving Surgery (Quadrantectomy). Breast-conserving surgery (sometimes referred to as quadrantectomy) removes the cancer and a large area of breast tissue, occasionally including some of the lining over the chest muscles. It is less invasive than a full mastectomy, but the cosmetic results are less satisfactory than with a lumpectomy. Studies have found that breast-conserving surgeries plus postoperative radiotherapy offer the same survival rates as radical mastectomy in most women with early breast cancer.
Surgery to remove the breast (mastectomy) is important for women with operable breast cancer who are not candidates for breast conserving surgeries. There are different variations on the procedure:
- A total mastectomy involves removal of the whole breast and sometimes lymph nodes under the armpit.
- A radical mastectomy removes the breast, chest muscles, all of the lymph nodes under the arm, and some additional fat and skin. (A modified radical mastectomy removes the entire breast and armpit lymph nodes, with the underlying chest wall muscle.) For most patients, there are no survival advantages from radical mastectomy compared to less invasive mastectomies.
Complications and Side Effects of Surgery. Short-term pain and tenderness occur in the area of the procedure, and pain relievers may be necessary.
The most frequent complication of extensive lymph node removal is lymphedema, or swelling, of the arm. The likelihood of edema can be lessened by removing only some of the lymph nodes instead of all of them.
Infrequent complications include poor wound healing, bleeding, or a reaction to the anesthesia.
After mastectomy and lymph node removal, women may experience numbness, tingling, and difficulty in extending the arm fully. These effects can last for months or years afterward.
After a mastectomy, some women choose a breast prosthesis or opt for breast reconstruction, which can be performed during the mastectomy itself, if desired. Several studies have indicated that women who take advantage of cosmetic surgery after breast cancer have a better sense of well-being and a higher quality of life than women who do not choose reconstructive surgery. The breast is reshaped using a saline implant or, for a more cosmetic result, a muscle flap is taken from elsewhere in the body. Muscle flap procedures are more complicated, however, and blood transfusions may be required. (It should be noted that implants, including silicone implants, do not appear to put a woman at risk for breast cancer recurrence.) If the nipple is removed, it is rebuilt from other body tissues and color is applied using tattoo techniques. It is nearly impossible to rebuild a breast that is identical to its partner, and additional operations may be necessary to achieve a desirable effect.
In-Depth From A.D.A.M. Radiation
Radiation therapy uses high-energy x-rays to kill cancer cells or to shrink the size of a tumor in the breast or surrounding tissue. It is used for several weeks following lumpectomy or partial mastectomy, and sometimes after full mastectomy. Radiation therapy can help reduce the chance of breast cancer recurrence in the breast and chest wall. Radiation is also important in advanced stages of cancer for relief of symptoms and to slow progression. Research shows that radiation therapy is helpful for women of all ages, including those over age 65.
Administration of Radiation Therapy
Radiation is generally administered in the following ways:
External Beam Radiation. This type of radiation is administered 4 – 6 weeks after surgery and delivered externally by an x-ray machine that targets radiation to the whole breast. It may be delivered to the chest wall in high-risk patients (large tumors, close surgical margins, or lymph node involvement). The treatment is generally given daily (except for weekends) for about 6 weeks. Some hospitals offer a shortened course of 3 weeks of radiation for patients with early-stage breast cancer.
Brachytherapy. Less commonly, radiation is delivered in implants (called brachytherapy). Implants are most often used as a radiation boost after whole breast radiation.
Side Effects of Radiation Therapy
Side effects of radiation include:
- Fatigue is very common and increases with subsequent treatments, but most women are able to continue with normal activities. Exercise may be helpful.
- Nausea and lack of appetite may develop and worsen as treatment progresses.
- Skin changes and burns can occur on the breast skin. Using a cream that contains a corticosteroid, such as mometasone furoate (MMF), may be helpful. After repeated sessions, the skin may become moist and “weepy.” Exposing the treated skin to air as much as possible helps healing. Washing the affected skin with soap and water is not harmful.
- Uncommonly, the breast may change color, size, or become permanently firm.
- Rarely, the nearest arm may swell and develop impaired mobility or even paralysis.
Future complications include:
- Radiation to the left breast may increase the long-term risk for developing heart disease and heart attacks.
- There is a very small risk (less than 1%) of lung irritation and scarring.
- Some studies have reported a higher risk for future cancer in the opposite breast in younger women who have been given radiation to the chest wall.
- Radiation therapy can increase the risk of developing other cancers, such as soft tissue malignancies known as sarcomas.
Current advanced imaging techniques use precise radiation that reduces exposure. These newer techniques are likely to reduce the risks for heart disease and other serious complications.
In-Depth From A.D.A.M. Chemotherapy
Chemotherapy drugs are “cytotoxic” (cell-killing) drugs. They are given orally or by injection. They work systemically by killing cancer cells throughout the body. (Unfortunately, they also kill normal cells, which accounts for many of their side effects.) Chemotherapy is always used for advanced breast cancer, but may also be used to treat types of early-stage breast cancer.
Newer biologic drugs target specific proteins involved in cancer. Treatment with these drugs is called targeted therapy. Because targeted therapy drugs do not work as systemically as chemotherapy or hormone therapy drugs, they tend to cause fewer widespread side effects, although they also carry risks of their own
Chemotherapy needs to be tailored to the type of cancer involved. Women require different treatments depending on whether the tumor is node-negative or -positive, hormone receptor-positive or -negative, or HER2-positive or -negative. Different treatment approaches are also used for early-stage cancer and advanced cancer.
Adjuvant chemotherapy is administered following surgery and before radiation therapy. Delaying chemotherapy until more than 12 weeks after surgery may increase the risk for breast cancer recurrence and reduce the odds for survival.
Chemotherapy Drug Classes
Many different types of chemotherapy drugs are used to treat breast cancer. Common types of chemotherapy drug classes include:
- Anthracyclines include doxorubicin (Adriamycin) and epirubicin (Ellence). Anthracycline-based combination regimens are often used to treat early-stage breast cancer, as well as advanced cancer.
- Taxanes include paclitaxel (Taxol) and docetaxel (Taxotere). These drugs may be particularly helpful for node-positive breast cancer. A newer formulation of paclitaxel (Abraxane) is used as a secondary treatment for advanced breast cancer.
- Platinum-based drugs include oxaliplatin (Eloxatin) and carboplatin (Paraplatin). These drugs may be used in combination regiments for advanced cancer or for cancers associated with BRCA genes.
Chemotherapy Regimens for Early-Stage Breast Cancer
Some of the abbreviations used for chemotherapy drug combinations (regimens) refer to drug classes rather than drug names. For example, regimens that contain an anthracycline drug (such as doxorubicin) use the letter “A,” and regimens that contain a taxane drug (such as docetaxel) use the letter “T.” Cyclophosphamide (Cytoxan), fluorouracil (5-FU), and methotrexate (MTX) are standard cancer drugs used in many breast cancer chemotherapy regimens.
Chemotherapy regimens usually consist of 4 – 6 cycles of treatment given over 3 – 6 months. Common chemotherapy regimens for early-stage breast cancer include:
- AC (Doxorubicin and cyclophosphamide)
- AC followed by T (Doxorubicin and cylophosphamide followed by paclitaxel)
- CAF (Cyclophosphamide, doxorubicin, and 5-FU)
- CMF (Cyclophosphamide, methotrexate, and 5-FU)
- TAC (Docetaxel, doxorubicin, and cyclophosphamide)
Targeted Therapy for Early-Stage HER2-Positive Breast Cancer
Trastuzumab (Herceptin). Trastuzumab is a monoclonal antibody that targets the HER2 protein on cancer cells. HER2-positive cancers account for 15 – 25% of early-stage breast cancer and are associated with more aggressive disease. Younger women tend to be most affected. In 2006, the Food and Drug Administration approved trastuzumab for treatment of HER2-positive, early-stage breast cancer (cancer confined to the breasts or lymph nodes that has been surgically removed).
Trastuzumab is given along with other chemotherapy drugs following lumpectomy or mastectomy. Research indicates that trastuzumab can help prevent cancer recurrence and death among women with early-stage breast cancer, but it increases the risk of heart problems. Trastuzumab can cause heart failure. Women who have heart failure or weak heart muscle (cardiomyopathy) should not use this drug. Women who take trastuzumab need to have regular heart monitoring, especially if they have already have heart problems.
Chemotherapy for Advanced (Metastatic) Cancer
Patients who develop metastatic disease (cancer that spreads throughout the body) are generally not curable. New advances in drug therapies, however, can help shrink tumors, prolong survival, and improve quality of life.
Chemotherapy regimens for advanced cancer may use a single drug or a combination of drugs. Many chemotherapy regimens used for early-stage breast cancer are also used for advanced breast cancer. Some specific combinations for advanced cancer include:
- Gemcitabine and paclitaxel. Gemcitabine (Gemzar) is used in combination with paclitaxel (Taxol) as a first-line treatment option for women with metastatic breast cancer.
- Capecitabine (Xeloda) and docetaxel (Taxotere). Capecitabine is an oral drug that is chemically related to 5-FU. In addition to combination treatment with docetaxel, it is used in combination with a new type of drug, ixabepilone (Ixempra), for patients with advanced breast cancer who have not responded to other types of chemotherapy. It is also being studied in combination with other drugs.
Numerous chemotherapy drugs and drug combinations are being tested in clinical trials. Patients with advanced breast cancer may also receive other types of drug treatments. For example, bisphosphonate drugs, such as zoledronic acid (Zometa) and pamidronate (Aredia), are important supportive drugs for preventing fractures and reducing pain in people whose cancer has spread to the bones.
Targeted Therapy for Advanced HER2-Positive Breast Cancer
Three targeted therapy drugs are approved for the treatment of HER2-positive advanced breast cancer
- Trastuzumab (Herceptin) was approved in 1998 for treatment of metastatic breast cancer. It is used after chemotherapy, along with drugs such as paclitaxel.
- Lapatinib (Tykerb) was approved in 2007 for patients who have not been helped by other cancer drugs, including an anthracycline, a taxane, or trastuzumab. Lapatinib is used in combination with capecitabine (Xeloda). Research suggests it may have fewer risks for heart problems than trastuzumab.
- Bevacizumab (Avastin) was approved in 2008 for treatment of patients who have not received chemotherapy for metastatic HER2-negative breast cancer. Studies indicate that bevacizumab does not help prolong overall survival, but may help slow tumor growth. Bevacizumab is used in combination with paclitaxel. Bevacizumab targets vascular endothelial growth factor (VEGF), a protein involved in tumor blood vessel formation (angiogenesis).
Promising new treatments for breast cancer include:
- Zoledronic acid (Zometa) is an intravenous bisphosphonate drug that is used to help prevent or delay bone fractures in patients with breast cancer that has spread to the bones. Recent research suggests that the drug may also help reduce the risk for cancer recurrence in patients with early-stage breast cancer.
Side Effects of Chemotherapy
Side effects occur with all chemotherapeutic drugs. They are more severe with higher doses and increase over the course of treatment.
Common side effects include:
- Nausea and vomiting. Drugs such as ondansetron (Zofran) and aprepitant (Emend) can help relieve these side effects.
- Temporary hair loss
- Weight loss
Serious short- and long-term complications can also occur and may vary depending on the specific drugs used. They may include:
- Anemia. Chemotherapy-induced anemia is usually treated with erythropoiesis-stimulating drugs, which include epoietin alfa (Epogen, Procrit) and darberpetin alfa (Aranesp). Erythropoiesis-stimulating drugs should not be used unless a patient’s hemoglobin level drops to below 10 g/dL. These drugs may pose serious health risks when they are used to achieve a hemoglobin level of 12 g/dL or greater. Doctors need to follow strict dosing guidelines when administering these drugs. Patients should discuss the risks and benefits of erythropoiesis-stimulating drugs with their oncologists. <!–[For more information, see
In-Depth Report #57: Anemia .]–>
- Increased chance for infection from severe reduction in white blood cells (neutropenia). The addition of a drug called granulocyte colony-stimulating factor (filgrastim and lenograstim) can help reduce the risk for severe infection.
- Liver and kidney damage.
- Abnormal blood clotting ( thrombocytopenia ).
- Allergic reaction, particularly to platinum-based drugs.
- Menstrual abnormalities and infertility. Premature menopause occurs in about 30% of women who have chemotherapy, particularly in those over 40. A hormone medication called a gonadotropin-releasing hormone analogue, which puts women in a temporary pre-pubescent state during chemotherapy, may preserve fertility in some women. Women may also wish to consider embryo cryopreservation — the harvesting of eggs, followed by in vitro fertilization and freezing of embryos for later use. The American Society of Clinical Oncology recommends that women being treated for cancer see a reproductive specialist to discuss all available fertility preservation options.
- Sexual dysfunction.
- Rarely, secondary cancers such as leukemia.
- A quarter to a third of women report problems in concentration, motor function, and memory, which can be long-term.
- Heart problems. Trastuzumab (Herceptin) may increase the risk for heart failure, particularly in women with pre-existing risk factors. Cumulative doses of anthracyclines (doxorubicin, epirubicin) can also damage heart muscles over time and increase the risk for heart failure.
- Taxanes can cause a drop in white blood cells and possible problems in the heart and central nervous system. Allergic reactions can occur, more often in taxol than taxotere. Taking a steroid before taxane administration can help prevent such reactions. Taxane therapy may also cause severe joint and muscle pain in some patients, relievable with corticosteroids.
High-Dose Chemotherapy with Bone Marrow or Peripheral-Blood Stem Cell Transplantation
High-dose chemotherapy along with peripheral-blood stem cell rescue or bone marrow transplantation procedures have been used for cancer that has metastasized and, in some cases, for earlier stages of breast cancer in high-risk patients. The objective of this treatment is to be able to give patients very high toxic doses of cell-killing drugs.
Transplantation procedures are based on stem cells , which are produced in the bone marrow. Stem cells are the early forms for all blood cells in the body (including red, white, and immune cells). Cancer treatments can harm these growing cells as well as cancer cells.
Despite the initial enthusiasm over the use of transplantation therapy for treatment of high risk breast cancer, this approach is no longer generally recommended and is rarely used outside of a clinical trial setting.
In-Depth From A.D.A.M. Hormone Therapy
The goal of hormone therapy is to prevent estrogen from stimulating breast cancer cells. It is recommended for women whose breast cancers are hormone-receptor positive (either estrogen or progesterone), regardless of the size of the tumor and whether or not it has spread to the lymph nodes. Like chemotherapy, hormone therapy works systemically.
Hormone therapy works by blocking estrogen that causes cell proliferation. It is used only for patients with hormone receptor-positive (“hormone sensitive”) tumors. Different types of hormone therapy work in different ways by:
- Blocking estrogen receptors in cancer cells (Tamoxifen)
- Suppressing estrogen production in the body (Aromatase inhibitors)
- Destroying ovaries, which produce estrogen (Ovarian ablation)
Tamoxifen was the first widely used hormonal therapy drug, but today it is mainly used as adjuvant therapy for premenopausal women with hormone-sensitive breast cancer. Postmenopausal women are now generally prescribed aromatase inhibitors.
Tamoxifen and Selective Estrogen Receptor Modulators (SERMs)
Tamoxifen (Nolvadex) has been the standard hormonal drug used for breast cancer. It belongs to a class of compounds called selective estrogen receptor modulators (SERMs). SERMs chemically resemble estrogen and trick the breast cancer cells into accepting it in place of estrogen. Unlike estrogen, however, they do not stimulate breast cancer cell growth. Because SERMs block estrogen’s effects on cancer cells, they are sometimes referred to as “anti-estrogen” drugs.
Tamoxifen is used for all cancer stages in (mainly premenopausal) women with hormone receptor-positive cancers. In addition, it is used to prevent breast cancer in high-risk women. Another SERM drug, toremifene (Fareston), is an option for women with advanced cancer, but this drug is rarely used in the United States. A third drug, fulvestrant (Faslodex), works in a similar anti-estrogen way to tamoxifen but belongs to a different drug class. Fulvestrant is approved only for postmenopausal women with hormone-sensitive advanced breast cancer in which tamoxifen or aromatase inhibitors no longer work.
To prevent cancer recurrence, women should take tamoxifen for 5 years following surgery and radiation. Tamoxifen is an effective cancer treatment, but it can cause unpleasant side effects and has small (less than 1%) but serious risks for blood clots and uterine (endometrial) cancer. Immediately report any signs of vaginal bleeding to the doctor, as this may be a symptom of uterine cancer.
Less serious, but discomforting, side effects include hot flashes and mood swings. According to one study, nearly 25% of women stop taking tamoxifen within 1 year because of these symptoms. By 3.5 years, over 33% stop treatment. Taking tamoxifen for fewer than 5 years, however, increases the risk for cancer recurrence and death. Talk with your doctor about antidepressants or other therapies that may help you cope with tamoxifen’s side effects.
Many doctors now recommend that postmenopausal women switch to an aromatase inhibitor after 2 – 3 years of tamoxifen therapy. Several recent studies have indicated that switching from tamoxifen to an aromatase inhibitor significantly improves survival rates and reduces the risk of death from breast cancer as well as other causes.
Endometrial cancer is a cancerous growth of the endometrium (lining of the uterus). It is the most common uterine cancer.
Aromatase inhibitors block aromatase, an enzyme that is a major source of estrogen in many major body tissues, including the breast, muscle, liver, and fat. Aromatase inhibitors work differently than tamoxifen. Tamoxifen interferes with tumors’ ability to use estrogen by blocking their estrogen receptors. Aromatase inhibitors reduce the overall amount of estrogen in the body.
Because these drugs cannot stop the ovaries of premenopausal women from producing estrogen, they are recommended only for postmenopausal women.
There are currently three aromatase inhibitors approved for treating early-stage, hormone receptor-positive breast cancer in postmenopausal women:
- Anastrazole (Armidex) for treatment after surgery
- Exemestane (Aromasin) for women who have taken tamoxifen for 2 – 3 years
- Letrozole (Femara) for treatment after surgery or for women who have completed 5 years of tamoxifen therapy
All of these drugs are also approved for women with advanced (metastatic) hormone-sensitive breast cancer. Studies indicate that the introduction of aromatase inhibitors has helped greatly in prolonging survival for women with advanced cancer.
Compared to tamoxifen, aromatase inhibitors are less likely to cause blood clots and uterine cancer. However, these drugs are more likely to cause osteoporosis, which can lead to bone loss and fractures. In general, recent studies indicate that aromatase inhibitors are better than tamoxifen in improving survival and reducing the risk of cancer recurrence. Unfortunately, like tamoxifen, they can cause hot flashes, as well as joint pain.
Ovarian ablation is a treatment that stops estrogen production from the ovaries. Medications can accomplish ovarian ablation. Destroying the ovaries with surgery or radiation can also shut down estrogen production. (Osteoporosis is one serious side effect of this approach, but several therapies are available to help prevent bone loss.)
Chemical Ovarian Ablation . Drug treatment to block ovarian production of estrogen is called chemical ovarian ablation. It is often reversible. The primary drugs used are luteinizing hormone-releasing hormone (LHRH) agonists, such as goserelin (Zoladex). (They are also sometimes called GnRH agonists). These drugs block the release of the reproductive hormones LH-RH, therefore stopping ovulation and estrogen production.
Bilateral Oophorectomy . Bilateral oophorectomy, the surgical removal of both ovaries, is a surgical method of ovarian ablation. It may modestly improve breast cancer survival rates in some premenopausal women whose tumors are hormone receptor-positive. In these women, combining this procedure with tamoxifen may improve results beyond those of standard chemotherapies. Oophorectomy does not benefit women after menopause, and its advantages can be blunted in women who have received adjuvant chemotherapy. The procedure causes sterility.
In-Depth From A.D.A.M. Resources
- www.cancer.gov — National Cancer Institute
- www.cancer.org — American Cancer Society
- www.asco.org — American Society of Clinical Oncology
- www.breastcancer.org — BreastCancer.Org
- www.komen.org — Susan G. Komen Breast Cancer Foundation
- www.nccn.org — National Comprehensive Cancer Network
- www.cancer.net — Cancer.Net
- www.cancer.gov/clinicaltrials — Find clinical trials
Breast cancer’s spread to the bone relies on interactions among tumor cells (blue); specialized bone cells that break down the bone, called osteoclasts (pink); specialized cells that rebuild bone tissue, called osteoblasts (brown); and the bone matrix. A “signaling protein” called Jagged1 sends destructive instructions that activate a group of molecules that work together, one molecule activating the next, in what’s called called the “Notch signaling pathway” (green flash) in the bone cells. Notch signaling stimulates the bone degrading activity of osteoclasts, releasing tumor growth factors such as the TGF-beta protein (red bubbles) from the bone matrix. Meanwhile, Notch signaling in bone-building osteoblasts increases the expression of another secreted protein, IL-6 (orange bubbles), which feeds back to tumor cells to promote their growth, forming a vicious cycle in bone metastasis. (Credit: Illustration by Stephen Cheng)
Princeton University (Princeton, NJ) — In a discovery that may lead to a new treatment for breast cancer that has spread to the bone, a Princeton University research team has unraveled a mystery about how these tumors take root.
Cancer cells often travel throughout the body and cause new tumors in individuals with advanced breast cancer — a process called metastasis — commonly resulting in malignant bone tumors. What the Princeton research has uncovered is the exact mechanism that lets the traveling tumor cells disrupt normal bone growth. By zeroing in on the molecules involved, and particularly a protein called “Jagged1″ that sends destructive signals to cells, the research team has opened the door to drug therapies that could block this disruptive process. Doctors at other medical centers who have reviewed the research have found it promising.
“Right now we don’t have many treatments to offer these patients,” said Yibin Kang, an associate professor of molecular biology at Princeton who led the research team. “Doctors can manage the symptoms of this bone cancer, but they can’t do much more. Our findings suggest there could be a new way of treatment,” one that could slow or halt these bone tumors.
Breast cancer spreads to the bone in 70 to 80 percent of patients with advanced breast cancer, and it can also spread to the brain, lung and liver. Metastatic bone cancer is also a frequent occurrence among patients with advanced prostate, lung and skin cancers. In findings that will be published online in the journal Cancer Cell on Feb. 3, the team’s research shows that breast tumor cells are able to give bone cells the wrong instructions through a process known as cell signaling — with disastrous effects for the patient.
The billions of cells in a living human body must communicate to develop, repair tissue, and effectively maintain normal physiological functions. Cell signaling is part of a complex system that enables them to do that but, in patients with cancer, the relationship between signaling molecules and the molecules that communicate with them has gone awry.
Signaling molecules are those that can be received and read by a cell through a receptor molecule on its surface. Once the signaling molecules connect with a receptor, their union sets off a process that leads to the receiving cell changing its behavior. The sequence of events that follows involves a signaling pathway, which is a group of molecules that work together, one molecule activating the next until a specific function is carried out, such as renewing an organ’s cells. There are many such signaling pathways.
But in the case of metastatic breast cancer, a disruptive pathway is formed. The signaling molecule, also known as a ligand, connects with a receptor molecule on certain bone cells and activates a cellular pathway that ultimately disrupts healthy bone renewal. Kang’s team identified the signaling molecule as Jagged1, and the receptor molecule as one that activates a cellular pathway known as the “Notch pathway.”
This finding gives cancer researchers a specific target, Kang said — that of developing ways “to neutralize Jagged1’s destructive power” and keeping it from interfering with normal bone growth.
At the Memorial Sloan-Kettering Cancer Center in New York City, Jacqueline Bromberg, a physician who also studies breast cancer, said the findings of Kang’s team are promising.
“The bone is the most common site for metastasis in patients with breast cancer,” said Bromberg, who met Kang several years ago while he was a postdoctoral fellow at Sloan Kettering. She noted that although there are treatments that can slow these tumors, such as estrogen-blockers, radiation and chemotherapy, “we have few therapies which effectively eradicate bone metastasis.”
At the University of Indiana School of Medicine in Indianapolis, oncology professor Theresa Guise said the Princeton discoveries “show critical interactions between the tumor cells and bone cells.” She added that the team has made a valuable contribution to research in that it “has dissected the contribution of the tumor and the micro-environment in this process.”
Finding Has Link to Earlier Breast Cancer Work
The research builds on earlier work begun six years ago by Kang’s laboratory that looked at how several different signaling pathways promote the spread of cancer to the bone. In a study published in the journal Nature Medicine in 2009, Kang showed that a pathway known as TGF beta plays a role in the growth of bone tumors. But until the recent study, it was not clear that Jagged1 plays a crucial role in that process. Before the current work focused on identifying the series of interconnected events that create the network of destructive pathways, Kang and Nilay Sethi, a dual degree student who recently finished his Ph.D. in molecular biology at Princeton, worked to find first which of the signaling molecules were at work in patients with breast cancer that had metastasized to the bone.
“It turned out that tumor samples from patients with breast cancer that had spread to the bone had higher levels of Jagged1,” said Sethi, who is now completing his medical degree at the University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School.
The current research shows that, when the Jagged1 signaling molecule binds to its receptor molecule on the bone-producing cells, the interaction turns on the signaling pathway called Notch, and that leads to dramatic changes in bone growth. “It’s like a key finding its matching lock, and opens a floodgate of information,” Kang said. “Unfortunately, in this case, the Jagged1-Notch signaling is misused by cancer cells to serve a destructive purpose.”
In healthy bone, specialized bone cells called osteoclasts scour the bone surface and use a combination of enzymes and acids to break down the old bone. Then another group of bone cells called osteoblasts deposit a new layer of bone matrix to rebuild the bone tissue. Working just like cellular excavators and paving machines, the bone-scrubbing osteoclasts and bone-building osteoblasts work in sync every day to renew the bone and maintain its strength. When these cells’ activity gets out of balance, bone diseases can result.
While tumor cells lack the specialized tools that osteoclasts have to break down the bone, they are able to use the destructive Jagged1 molecule to disrupt the balanced activity of bone renewal, forcing the osteoclasts and osteoblasts to behave in a way that allows the tumor cells to invade the bone, Kang explained.
For example, by activating Notch signaling in osteoclasts, Jagged1 makes osteoclasts mature more quickly from their precursor cells, known as monocytes. A massive accumulation of these bone-scouring osteoclasts becomes the front line of the invasive force of tumor cells. That speeds up the breakdown of bone tissue and clears the way for tumor cells to expand into a malignant mass in the bone.
“Meanwhile, Jagged1 instructs the osteoblasts to secrete elevated levels of Interleukin-6, a tumor growth factor, so the cancer grows even faster,” Kang said. “It’s a one-two punch.”
Creating further damage, the breakdown of the bone matrix releases a large quantity of another protein called TGF-beta, another signaling molecule that is embedded in the bone matrix during the bone-building process. In their earlier work published in 2009, Kang and colleagues showed that the TGF-beta protein derived from bones fuels the malignant growth of bone metastasis.
In the current study, some experiments conducted by Sethi established a surprising new link between TGF-beta and the Jagged1 molecule in bone metastasis.
“When tumor cells use the hijacked osteoclasts to break down the bone and release TGF-beta, it signals back to tumor cells to further stimulate the expression in Jagged1 in tumor cells,” Sethi said. “The link between the Jagged1/Notch and TGF-beta pathways establishes a vicious cycle, essentially driving the unstoppable expansion of tumor and the destruction of skeletal tissues.”
As a medical student, Sethi said he is acutely aware of the consequence of bone metastasis. “These patients suffer a lot. They have fractures, severe bone pain and debilitating nerve compression,” he said. In addition, as the bone breaks down, calcium builds up in the blood, causing other life-threatening complications.
Blocking Destructive Pathway a Potential Treatment Path
The key to stopping the process appears to be finding a way to neutralize the Jagged1 signaling molecule or its receptor Notch.
Kang has several ideas on how scientists may learn how to do just that. One way to interrupt the destructive process is to put a roadblock in the Notch pathway. There is a way to do that by halting the activity of gamma secretase — an enzyme that plays a key role when the Notch pathway is activated –because without it the delivery of instructions to bone cells cannot be completed. The pharmaceutical firm Merck & Co. has developed one such experimental drug that stops gamma secretase, known as a gamma secretase inhibitor or GSI, and the company has provided it to Kang’s lab to support his team’s work.
The drug has already shown promise treating metastatic bone cancer, Kang said. In animal experiments, the inhibitors have been proven to block the disease-causing signaling between tumor cells and bone cells, communication mediated by Jagged1 and Notch. Kang said GSI can reduce bone metastasis significantly, along with a dramatic reduction of bone destruction.
He hopes his team’s new data showing that GSIs appear to work to halt the spread of cancer to the bone will result in clinicians starting a clinical trial of GSI to fight breast cancer metastases in the near future.
According to Kang, there are few drugs currently available to relieve symptoms associated with bone metastases, and none is able to completely stop the cancer. If Kang’s findings lead to a drug that can halt or slow this process, it could affect the 200,000 patients that the NCI estimates are diagnosed every year with breast cancer. It might work for some other cancer patients as well, Kang said.
Sloan-Kettering’s Bromberg said Kang’s recent discovery “underlies the importance of targeting the environmental milieu” in which disease develops, in this case the activity of the Notch signaling pathway and specific interactions between cancer cells and the specialized cells that break down and rebuild bone.
Kang’s work was funded by the New Jersey Commission on Cancer Research, the San-Francisco-based Brewster Foundation founded by 1969 Princeton alumnus Leonard Schaeffer, U.S. Department of Defense, American Cancer Society, Merck & Co., the National Institutes of Health and the Champalimaud Foundation in Lisbon, Portugal.
1. Nilay Sethi, Xudong Dai, Christopher G. Winter, Yibin Kang. Tumor-Derived Jagged1 Promotes Osteolytic Bone Metastasis of Breast Cancer by Engaging Notch Signaling in Bone Cells. Cancer Cell, 03 February 2011 DOI: 10.1016/j.ccr.2010.12.022
Princeton University (2011, February 4). Mechanism involved in breast cancer’s spread to bone discovered.
ScienceDaily.com — Vitamins and calcium supplements appear to reduce the risk of breast cancer, according to findings presented at the American Association for Cancer Research 101st Annual Meeting 2010.
“It is not an immediate effect. You don’t take a vitamin today and your breast cancer risk is reduced tomorrow,” said Jaime Matta, Ph.D., professor in the Ponce School of Medicine in Puerto Rico. “However, we did see a long-term effect in terms of breast cancer reduction.”
Matta said the findings suggest that the calcium supplements are acting to enhance DNA repair capacity, a complex biological process involving more than 200 proteins that, if disrupted, can lead to cancer.
“This process involves at least five separate pathways and is critical for maintaining genomic stability,” said Matta. “When the DNA is not repaired, it leads to mutation that leads to cancer.”
The study included 268 women with breast cancer and 457 healthy controls. Women were more likely to have breast cancer if they were older, had a family history of breast cancer, had no history of breastfeeding and had lower DNA repair capacity.
Vitamin supplements appeared to reduce the risk of breast cancer by about 30 percent. Calcium supplements reduced the risk of breast cancer by 40 percent. After controlling for the level of DNA repair capacity, calcium supplements were no longer as protective, but the link between vitamin supplements and breast cancer reduction remained.
“We’re not talking about mega doses of these vitamins and calcium supplements, so this is definitely one way to reduce risk,” said Matta.
ScienceDaily (Feb. 10, 2011) — Scientists discovered a new way breast cancer cells dodge the immune system and promote tumor growth, providing a fresh treatment target in the fight against the disease. While comparable mechanisms to avoid the immune system have been identified in mice with breast and other cancers, the study tested human breast tumor cells, putting researchers closer to understanding how the disease progresses in real patients.
The study, published in the journal Cancer Research, found high levels of the protein Hsp27 (heat shock protein 27) are released from human breast cancer cells and may not only render immune cells unresponsive to the tumor, but increase blood flow to the tumor as well, both of which fuel tumor growth.
“Our study is very unique because we used human breast cancer cells, which are extremely difficult to get,” said Asit De, Ph.D., lead author and research associate professor in the Department of Surgery at the University of Rochester Medical Center, who worked closely with physicians at the Wilmot Cancer Center. “The way tumor cells operate in mice is not identical to humans, so we need to do more of these types of human studies to confirm or reject cancer-related discoveries in mice.”
Past research reports Hsp27 is present in high levels inside breast tumor cells and is associated with resistance to chemo and radiation therapy. De and his team discovered Hsp27 is also released, or pushed out of breast tumor cells, into the area surrounding the tumor, known as the breast tumor microenvironment.
Once outside the cells, Hsp27 may transform circulating white blood cells called monocytes that enter the tumor into cells known as macrophages, which do the opposite of what they are meant to do. Usually, macrophages work to wipe out tumor cells, but in this case they help, rather than hurt, tumor cells. These particular macrophages may make human T cells — the main immune cells that attack and kill foreign invaders, like tumors — totally indifferent to the tumor and the body’s call to destroy it.
In addition to suppressing the immune response to the tumor, these macrophages encourage rapid formation of extra blood vessels that can help in supplying blood to the tumor — a process known as angiogenesis — essentially feeding the tumor so it can continue to grow.
Elevated levels of Hsp27 have been found in the blood of cancer patients with other solid tumors, such as liver and pancreatic cancer tumors, leading study authors to believe the protein may play a role in tumor progression beyond breast cancer.
“Our finding that Hsp27 aids tumor progression is just the start — we know there are several other molecules that help breast tumor cells suppress the immune system and we hope to identify more of them in future research,” noted De.
Hsp27 is a ubiquitous protein that is important in all the body’s cells. When it remains inside cells at normal levels it acts as a chaperone, protecting cells from stress, such as exposure to high heat or chemicals. Only when the protein is let loose outside cells does it appear to have a detrimental effect on the immune system.
To carry out the study, De worked closely with clinicians in surgical oncology and plastic surgery at the Medical Center to obtain and analyze tumor-containing breast tissue samples from breast cancer patients undergoing surgery and normal breast tissue samples from healthy volunteers undergoing breast reduction. He also collected and tested blood samples from untreated breast cancer patients and age-matched healthy women.
Besides skin cancer, breast cancer is the most commonly diagnosed cancer among women in the United States. It is also the second leading cause of cancer-related death in American women, behind lung cancer. The development of treatment strategies that stop a tumor’s ability to silence or circumvent the immune system require a better understanding of tumors’ various avoidance mechanisms, such as the one identified by De.
De plans to continue research on Hsp27 in breast cancer, studying whether blocking Hsp27 slows tumor growth.
The study was funded by the American Cancer Society. In addition to De, the work was performed by Sanjib Banerjee, Ph.D., Chuen-Fu Lin, M.D., and Jennifer Strickland. The team also received collaborative support from basic scientists Eileen Redmond, Ph.D., David Morrow, Ph.D. and Carol Miller-Graziano, Ph.D., and clinicians Kristin Skinner, M.D., James Peacock, M.D., Linda Schiffhauer, M.D., David Hicks, M.D., Alissa Huston, M.D., Michelle Shayne, M.D., and Howard Langstein, M.D., from the University of Rochester Medical Center. Clinical coordinator Lauren O’Donoghue contributed to the study as well.
Broccoli. Scientists are reporting discovery of a potential biochemical basis for the apparent cancer-fighting ability of broccoli and its veggie cousins. They found for the first time that certain substances in the vegetables appear to target and block a defective gene associated with cancer. (Credit: iStockphoto)
National Cancer Institute of the National Institutes of Health — Scientists are reporting discovery of a potential biochemical basis for the apparent cancer-fighting ability of broccoli and its veggie cousins. They found for the first time that certain substances in the vegetables appear to target and block a defective gene associated with cancer.
Their report, which could lead to new strategies for preventing and treating cancer, appears in ACS’ Journal of Medicinal Chemistry.
Fung-Lung Chung and colleagues showed in previous experiments that substances called isothiocyanates (or ITCs) — found in broccoli, cauliflower, watercress, and other cruciferous vegetables — appear to stop the growth of cancer. But nobody knew exactly how these substances work, a key to developing improved strategies for fighting cancer in humans. The tumor suppressor gene p53 appears to play a key role in keeping cells healthy and preventing them from starting the abnormal growth that is a hallmark of cancer. When mutated, p53 does not offer that protection, and those mutations occur in half of all human cancers. ITCs might work by targeting this gene, the report suggests.
The scientists studied the effects of certain naturally-occurring ITCs on a variety of cancer cells, including lung, breast and colon cancer, with and without the defective tumor suppressor gene. They found that ITCs are capable of removing the defective p53 protein but apparently leave the normal one alone. Drugs based on natural or custom-engineered ITCs could improve the effectiveness of current cancer treatments or lead to new strategies for treating and preventing cancer.
The authors acknowledged funding from the Ruth L. Kirschstein National Research Service Award and a grant from the National Cancer Institute of the National Institutes of Health.