Breast cancer is the most common malignancy in women in the Western world, affecting about one woman in eight over their lifetime. About 215,000 women will develop breast cancer in the United States every year, and about 41,000 die of it. Breast cancer is most treatable when detected in its earliest stages, and there is great interest in screening healthy women—beginning when they are between forty and fifty years old—with mammography and periodic physical examinations. These measures will help detect breast cancers at an earlier stage, resulting in earlier treatment and a better chance for cure. The proper instruction in breast self-examination beginning at an even earlier age may also help with early detection, although this has not been proven in clinical studies. In the United States and western Europe, breast cancer is most often diagnosed at an early stage due to increased awareness and availability of screening and treatment, and hence is most often cured with surgery. The incidence of breast cancer has been rising in industrialized countries for reasons that are still not fully understood. In the United States, this rise has finally leveled off for the last few years, while the death rate due to breast cancer has begun to fall somewhat, due to both screening and improvements in treatment.
Advances in operative techniques and radiation therapy have led to less invasive surgery. Newer medical treatments following surgery for early-stage breast cancer and the wider application of these have led to improvement in curability and survival. The spread of breast cancer, which happens to a minority of breast cancer patients in the United States, still remains incurable, but newer therapies have begun to emerge that can prolong life and improve the quality of life. Revolutions in the biological sciences have the potential to further this trend and also to be used for new strategies in earlier detection and better individualization of treatment.
Normal breast structures in which cancers may develop
What Causes It No definite cause has been established, although genetic factors, lifestyle, and diet all play a role. Most women with breast cancer do not have a clear risk factor and in any given case of breast cancer, it is not possible to pinpoint a specific cause.
Types Breast cancers are divided generally into two types: invasive cancers and noninvasive (or in situ) cancers. Invasive cancers have the capacity to spread to lymph nodes under the arm or to distant sites such as the lungs and bone, whereas in situ cancers rarely spread even though they can return both as in situ or invasive cancers within the breast after they are removed. Invasive cancers are generally divided into lobular and ductal cancers. Lobular cancers start in the many small sacs in the breast that produce milk. The much more common ductal cancers start in the tubes that carry milk from the lobules to the nipple. Within these broad categories, there are over thirty histologic types as seen under the microscope. About half are infiltrating ductal cancers, meaning that they spread through the duct wall. Another 28 percent are combinations of infiltrating ductal cancers and other types, including mucinous, papillary, and lobular. For the most part, these different types of invasive cancers are treated similarly, as outlined later in this post.
Infiltrating lobular carcinoma (5 to 10 percent of breast cancers), which is often detected as a thickening of the breast tissue rather than as a lump, can sometimes involve several areas throughout the breast. Other infiltrating cancers include Paget’s disease, a cancer that begins in the area of the nipple and is associated with bleeding, redness, itching, and burning (this is not the same as Paget’s disease of the bone, which is a chronic benign process); and inflammatory breast cancer, which shows up as a hot, red, swollen area having the appearance of an infection or inflammation. This subtype has a worse prognosis, because the red color and warmth of the skin indicate that tumor cells have already spread into many lymphatic vessels.
Regional lymph nodes important in breast cancer
In situ cancers are confined within the lining of the ducts or lobules. These are early cancers or precancerous lesions that have not developed the ability to spread beyond the breast. They are generally of two types:
• Ductal in situ carcinomas (also called intraductal or ductal carcinoma in situ [DCIS]) do have the ability over a long period to lead to invasive cancer if untreated, so these tumors are treated with complete surgical removal. In many cases, radiation therapy and hormonal therapy (tamoxifen [Nolvadex] for five years) are used to lower the risk of the cancer returning in the breast when breast-conserving surgery (like a lumpectomy) is used. Even without these treatments, the risks of spread of DCIS and death due to breast cancer are very remote.
• In situ lobular cancers (also called lobular carcinoma in situ [LCIS]) are best understood as markers for the risk of developing cancer. Since LCIS tends to reflect risk in both breasts, it is not usually possible to remove all lobular carcinomas in situ without removing all of both breasts. This is excessive treatment in most situations, although it is sometimes considered in younger patients who have many years of risk ahead. Careful follow-up is recommended (see “Screening,” in this post) when this diagnosis is made. In a similar vein, the entity of atypical ductal hyperplasia is sometimes found on pathology after a biopsy of a lump or an abnormal finding on a mammogram. This is also a marker of higher risk, especially if accompanied by a family history of breast cancer, and may therefore warrant closer surveillance.
Nearly all breast cancers arise from glandular tissue (adenocarcinomas), although other types also occur, including squamous cell carcinomas, sarcomas, carcinosarcomas, phyllodes tumor, sweat gland carcinomas, and lymphomas, and these are treated differently. There are several less common types, which have a generally better prognosis than infiltrating ductal cancer, such as medullary carcinoma (6 percent of cases), mucinous (2.5 percent), and tubular (1 percent). Each type has prognostic and therapeutic implications.
How It Spreads After cancer starts, it may be several years before a lump appears. It may remain confined to the breast for a long time, or, in other cases, spread to nearby lymph nodes and distant organs early in the disease. In general, more aggressive cancers tend to spread to lymph nodes more readily and this is also an indicator of a higher chance of spread to a distant site. Very little is known about the mechanisms that a cancer cell uses to facilitate spread. Cancer cells are known to be less “sticky” to one another than normal cells, and also to make enzymes that can help dissolve tissue barriers. Oftentimes, spread can occur years after the initial diagnosis of localized cancer. Much less commonly, distant spread is found at the time that a breast cancer is initially diagnosed, but in less developed countries where patients present later in the course of their disease, such a presentation is more common. As will be discussed later, several medical therapies can be used to lower the risk of spread after surgery for early-stage breast cancer.
Risk Factors
At Higher Risk
• Increasing age. Breast cancer is uncommon under the age of forty and increases in frequency after the age of fifty.
• Family history of breast or ovarian cancer, primarily in parents, daughters, and sisters. This is true for relatives on the father’s side as well as on the mother’s. The risk is higher if there are multiple family members and cancer(s) at a younger age. This is due to the fact that this increases the chances that there may be an inherited genetic predisposition for breast and ovarian cancer. Several genes, including BRCA1 and BRCA2, have been identified that can contain mutations and confer a risk for these and other cancers.
• History of previous cancer in one breast, especially if it occurred before menopause.
• Some noncancerous or precancerous lesions of the breast may be associated with development of breast cancer, including multiple papillomatosis, atypical hyperplasia, and lobular carcinoma in situ (LCIS).
• Excessive radiation, with an increased risk for women who were given radiation for postpartum mastitis, received prolonged fluoroscopic X-ray evaluations for tuberculosis, or were exposed to therapeutic radiation therapy for other cancers before the age of thirty. Mammography does not expose the breasts to excessive radiation, and to date, there is no evidence that mammography or periodic diagnostic X-rays increase the risk of breast cancer.
At Slightly Higher Risk
• Family history of breast cancer in more distant relatives, such as aunts, grandmothers, and cousins.
• Women with a family history of cancer of the uterus or colon have a slightly increased risk of developing breast cancer (with multiple family members or if of Jewish background, the risk may even be higher).
• Some large breast cysts, especially if accompanied by early atypical hyperplasia (not the more common fibrocystic condition).
• Taking postmenopausal estrogens with progesterone for more than ten years. In general, taking estrogen replacement after menopause remains an individual decision, since there are benefits in terms of lowering osteoporosis risks and improving symptoms of menopause. It may be best, however, to limit exposure to brief durations (less than five years) in women at higher-than-average risk for breast cancer. Also, recent studies have shown that estrogen and progesterone replacement increase the risk of heart attacks and stroke. Of note, oral contraceptives at today’s doses do not appear to elevate breast cancer risk.
• Never having carried a term pregnancy or first pregnancy after age thirty.
• Use of alcohol, with a slight increase in risk with even moderate use (one to two drinks per day) and increasing risk with higher alcohol use.
• Early onset of menstruation and late onset of menopause.
• Individuals of European Jewish background have a higher-than-normal risk.
• Higher body weight increases the risk, especially among postmenopausal women.
At Lower Risk
• Term pregnancy under age eighteen.
• Early menopause.
• Surgical removal of the ovaries before age thirty-five.
• Asian ancestry (but not if born in America and adopting American dietary habits).
• Exercise and physical activity at a younger age.
Factors That May Affect Risk, but Whose Role Is Unclear
• A low-calorie, low-fat (especially animal fat), high-fiber or Asian-style diet may decrease risk. This may pertain mostly to the diet early in life, since the majority of studies on adult diet have not uncovered consistent associations with breast cancer risk. There have been numerous studies examining diet and breast cancer risk, and most have been inconclusive. The most definitive study to date shows a slight decrease with a low-fat, high-vegetable/fruit diet, but as of yet, the difference is not statistically significant.
• Controversy continues regarding breast-feeding. Some studies suggest that breast-feeding may reduce the risk of breast cancer, particularly in cultures where prolonged breast-feeding (several years for each child) is the norm.
Factors Not Related to Breast Cancer
• Fibrocystic breasts.
• Multiple pregnancies.
• Coffee or caffeine intake.
Screening
A thorough breast examination should be part of every routine physical and be included with a yearly gynecologic checkup. There are three well-accepted methods for detecting early breast cancer.
• Mammography for Apparently Healthy Women There is now widespread agreement that mammography (low-dose X-ray imaging of the breasts) can discover some cancers at least a year before—and sometimes as much as four years before—they can be felt. The scientific evidence that this earlier detection translates to a reduction in the death rate from breast cancer is most convincing for screening women ages fifty and older, but there is evidence that it is also beneficial for women in their forties, although to a somewhat lesser degree. Still, mammography does not detect all cancers, and a positive mammography test does not always mean a cancer is present. Digital mammography may provide clearer images and allows for computer enhancement for detection as well as for sending the images long distance for expert reading. Currently, it appears to be a little more effective for younger (less than age fifty) or premenopausal women and those whose breasts appear more dense on mammogram.
• Many health organizations recommend that women have mammography every year beginning at age forty. There is some controversy as to whether mammograms are not as accurate in younger women, since the breast is denser and may make a lump harder to discern on film. Since younger women have a lower chance of having breast cancer in the first place, they are more likely to have a higher number of benign biopsies for every cancer detected when they undergo screening mammograms. Yearly mammograms are recommended beginning at age thirty or perhaps even earlier when the risk of breast cancer is very high (because of prior breast cancer, very strong family history, hereditary predisposition, or a breast biopsy showing atypical hyperplasia or LCIS).
• The smallest lump usually felt is about 1/2 inch (1 cm) and contains about 1 billion cancer cells. Routine mammography can detect smaller cancers, some even less than 1/4 inch (0.5 cm). It is estimated that five-year survival is 20 to 25 percent better for cancers detected by mammography than for those diagnosed after a lump has appeared. Women screened regularly with modern mammography (after 1985) have only a 10 to 30 percent rate of axillary node metastasis, compared to 50 percent for women who do not undergo screening.
• Some concern has been expressed about the risk of frequent X-ray imaging, but the benefits far outweigh any potential risks. The X-ray dose of a mammogram today is considered to be negligible. It is about one-tenth that of twenty-five years ago and is about the same as the cosmic radiation received during a transcontinental airplane flight. However, it is true that most biopsies (about two in three) done because of abnormal mammograms end up being negative for cancer.
• Magnetic resonance imaging (MRI) has gained much attention as a screening tool, but it is currently recommended only in patients with very high risk, such as those who carry a BRCA1 or BRCA2 mutation. It is sometimes also used in individuals who have breast implants or those who are higher risk but have dense breasts that are harder to screen by mammogram. Even with MRI, mammography should also be done, since some cancers may be seen only by one of the tests. Because it can pick up so many benign changes, ultrasound for screening is still being studied and is currently recommended only to pursue a specific area that may be abnormal on mammogram or MRI or on physical examination.
• Breast Self-Examination Monthly breast self-examination (BSE) is widely advocated and taught, although studies have not shown that this actually lowers the breast cancer death rate. BSE can be taught by trained physicians and nurses, and most communities have centers to teach women how to perform this examination. BSE also identifies a large number of breast lumps that are not cancer, more so than either mammography or physical examination. Even though formal studies are negative, it makes sense that women should be familiar with the nature of their breasts so that they can report any changes to their doctor.
• Breast Examination by a Physician or Trained Health Care Provider Examination of the breasts is a component of routine physical checkups. Benign lumps and masses as well as areas of thickening occur from time to time in most women, and repeated examinations by a physician may call attention to areas that deserve further testing. Physicians often draw in their records diagrams of areas of change or concern, which makes it easier to detect small changes at the next examination.
Although mammography is the most effective screening method, 10 to 15 percent of cancers will be missed by mammography yet found by physical examination, including BSE. Complete breast cancer screening involves all three methods.
Common Signs and Symptoms
A breast lump, usually discovered by the individual, is the most common presenting sign. Sometimes, a mass or speckles of calcium seen on a mammogram may appear suspicious for a cancer but no lump can be felt. When felt, the cancer is often hard and irregular and may feel different from the rest of the breast. There may also be a persistent lump in the armpit (axilla), a symptom of enlarged lymph glands. Pain in the breast is more often due to a benign condition, but medical evaluation is advised, since 5 to 10 percent of breast cancers can also present as pain.
Spontaneous discharge from the nipple of one breast may indicate breast cancer, but most discharges are from benign conditions and most cancers do not have a discharge. Discharges that contain blood or greenish fluid are of more concern. There may be irregularity or retraction of the breast skin or nipple. Scaling of the nipple may indicate Paget’s disease, a form of breast cancer that starts in the nipple.
In advanced cases, there may be significant swelling or distortion of the skin or breast. Skin pores may be accentuated because of lymphatic involvement, creating an appearance resembling the skin of an orange, known medically as peau d’orange. This may indicate a rare type of cancer termed inflammatory breast carcinoma, which may also be signaled by redness, swelling, or increased heat in the skin.
Breast cancer may occasionally first appear as metastatic disease, with signs or symptoms related to whatever other organ is involved—pain in an area of bony metastasis, swelling in the neck, lung nodules seen on chest X-rays, or liver enlargement.
Breast Cancer Prevention
In earlier trials of the hormonal therapy tamoxifen (Nolvadex) used for early-stage breast cancer, it was noted that fewer new cancers in the other breast developed in women taking tamoxifen. Therefore, a large trial was initiated to compare five years of tamoxifen to a placebo (an inactive drug) in preventing the development of breast cancer in women who were at higher risk based on their age, family history, and other factors. This trial showed that in the short term (about five years), the number of breast cancer cases was cut in half by the use of tamoxifen. In terms of actual numbers, this translated into going from 40 cases of breast cancer for every 1,000 women over five years to 20 cases with the use of tamoxifen. Complications of tamoxifen, which include the risk of blood clots, stroke, and uterine cancer, are more prevalent in older women and the benefits of tamoxifen are greater in women at high risk of getting breast cancer. A balanced decision of risks and benefits must therefore be undertaken in considering the use of tamoxifen in women at higher breast cancer risk. Raloxifene (Evista), another drug in the same class as tamoxifen, is used to prevent osteoporosis and may have a lower risk of uterine cancer induction (a known side effect of tamoxifen). Preliminary evidence supports that raloxifene may also reduce breast cancer risk and have fewer side effects, particularly less clotting and uterine cancer risk.
Inherited Risk of Breast Cancer
About 5 to 10 percent of all breast cancer cases are associated with a familial inherited predisposition. In these cases, there is usually a strong family history of breast or ovarian cancer and it can be either on the father’s or the mother’s side. The probability of carrying an inherited predisposition is higher in women with a family history of cancer. You can ask yourself the following questions: Do I have a paternal or maternal family history that includes
• two or more female relatives diagnosed with breast cancer before they reached menopause (or before the age of fifty)?
• any family member diagnosed with bilateral breast cancer, or breast cancer in both breasts?
• any family member diagnosed with ovarian cancer at any age?
• any family member with breast and ovarian cancers or more than one primary cancer (e.g., prostate and colon, or breast and pancreatic cancers)?
• a pattern of certain types of cancers among close relatives? (In addition to breast and ovarian cancers, there are other types of cancers that may suggest the presence of a hereditary cancer syndrome; for example, colon, uterine [endometrial], and ovarian cancers diagnosed before age fifty may suggest hereditary nonpolyposis colorectal cancer [HNPCC]).
There are several known genes that increase risk for breast cancer, but a majority of women with inherited susceptibility to breast cancer have mutations in the BRCA1 or BRCA2 gene. Tests for mutations in these genes are now available. If an individual carries a BRCA1 or BRCA2 mutation, he or she has a 50 percent chance of passing it to each offspring or sharing it with a sibling. There are still many unanswered questions about the risks associated with a positive test.
Not every woman who carries a mutation in the BRCA1 or BRCA2 gene will develop breast and/or ovarian cancer, but the risk is high for these women. A female carrier of a BRCA1 mutation has a 55 to 85 percent lifetime risk of developing breast cancer, a 20 to 40 percent lifetime risk of developing ovarian cancer, and a 6 percent risk of developing colon cancer, by age seventy. This is compared to the 10 to 12 percent lifetime risk of developing breast cancer and the 1 to 2 percent risk of developing ovarian cancer in the general population. The lifetime risk for breast cancer in the second breast, after cancer has developed on one side, is 40 to 60 percent. Males who carry a mutation in BRCA1 are at higher risk of developing prostate and colon cancer.
Women who carry a mutation in the BRCA2 gene have the same risk of developing breast cancer as women who carry a BRCA1 mutation, 55 to 85 percent by age seventy. However, they have a slightly lower risk of developing ovarian cancer, 15 to 30 percent risk by age seventy. Males who carry a mutation in the BRCA2 gene have a 5 to 10 percent risk of developing breast cancer in their lifetime and a risk of prostate cancer of 20 percent by age eighty. The pattern of cancers seen with BRCA2 can also include pancreatic, fallopian tube, and laryngeal (throat) cancers.
This risk may vary somewhat depending on other inherited factors or on lifestyle factors. Furthermore, there is very little information on how closer monitoring or even preventive surgery in BRCA1 and BRCA2 mutation carriers will affect the risk of developing cancer or dying of cancer.
There are other genes that can be involved in the predisposition to breast cancer and other cancers; these include Chk 1, p53, PTEN (Cowden syndrome), and p16.
When there is a strong family history suggestive of the possibility of an inherited predisposition, a session with a genetic counselor or an appropriately trained specialist should occur prior to any testing. This session is designed to verify the family history and then see if the risk of carrying a BRCA1 or BRCA2 mutation or other gene mutation is in the range of warranting genetic testing. A balanced discussion that covers the accuracy of the test, the meaning of the test results, and the options for surveillance, prophylactic surgery, and other risk-reduction strategies needs to be held prior to a decision to proceed with testing.
Individual initiation is an important aspect of genetic testing, and a cancer risk assessment and genetic counseling provide vital information and support to address decisions such as genetic testing, treatment, drug therapy for prevention (such as tamoxifen [Nolvadex] therapy), and surveillance. The information from genetic counseling and gene-testing results has implications for the individual and for many other at-risk family members. Often one family member takes on the task of searching out this information for the rest of the family. The individual who is seeking BRCA1 and BRCA2 testing may or may not have a personal history of breast or ovarian cancer. It is always more informative to first test a family member who has cancer.
If no one in the family has yet been tested, the initial genetic testing should ideally be done on the individual that already has (or had) cancer. In some cases, other cancers in the family, such as colon cancer, may prompt the testing for other genes that confer risk for other cancers. If the results of genetic testing are negative in the presence of a very strong family history, it is possible that there is still a familial risk that is carried on a gene other than BRCA1 and BRCA2. There is still active research to discover other cancer susceptibility genes. In individuals of Jewish background, 90 to 95 percent of the mutations are clustered within two sites on the BRCA1 gene and one site on the BRCA2 gene. Testing for only three mutations is cheaper and less time-consuming. Otherwise full sequencing of the BRCA1 and BRCA2 genes, a more laborious test, is necessary. If one family member is known to carry a mutation, then only that specific site of the BRCA1 or BRCA2 gene needs to be tested in other family members. Direct relatives of the involved person (parent, child, or sibling) will have a 50 percent chance of having the same mutation.
For individuals testing positive for BRCA1 or BRCA2 mutations, the options are as follows:
• Frequent surveillance: mammograms yearly beginning at age twenty-five to thirty. Breast exams every six months. For ovarian cancer, a bimanual pelvic exam, transvaginal ultrasound with color-flow Doppler ultrasound, and CA-125 serum marker blood tests are recommended every six months.
• Prophylactic (preventive) surgery. Because these surgeries do not completely remove breast or ovarian tissue, there is still a small risk of developing cancer. Prophylactic mastectomy is estimated to lower the risk by 90 percent (that is, from 60 to 85 percent lifetime to 6 to 10 percent). Prophylactic oophorectomy, or removal of the ovaries, at age thirty-five or when childbearing is complete, can also be considered. This is estimated to cut the risk of ovarian cancer significantly and can also reduce the risk of breast cancer in premenopausal women because estrogen levels are lowered.
Numerous uncertainties still exist in the field of cancer genetics and genetic testing. Over time, better estimates of the benefits of surveillance, prophylactic surgery, and new experimental screening and prevention options will be available. Ethical issues such as protection against insurance discrimination and confidentiality of records are still not completely resolved and will need special policies and laws.
Diagnosis
It may be difficult to clinically distinguish malignant from benign breast masses such as fibrous tumors (fibroadenomas), fatty collections, inflammatory masses, infections, and cysts. In premenopausal patients, it is common for benign lesions to enlarge just before menstrual periods and then shrink.
It is often helpful for the physician to draw an exact diagram with a description of a newly detected mass. Mammography and/or biopsy may be useful, but if these are not done, the mass should be reexamined one or two months later if there is any suspicion that it might be cancer. If the mass persists, mammography and biopsy should be considered as outlined below.
Physical Examination
• Physical examination of the breast is conducted with the patient in various positions and with careful recording of any suspicious masses or abnormal findings.
• This should be accompanied by a complete physical, including a pelvic examination and evaluation for signs of cancer in other locations such as the skin, lymph nodes, and liver.
Blood and Other Tests
The following tests are commonly done as part of the evaluation before or after biopsy or surgical treatment. Not all tests need to be done in all situations, since the results may sometimes not be needed to make optimal treatment decisions (this process is outlined in “How Prognostic Factors Affect Treatment Choices,” in this post).
• Blood counts and a chemistry panel to determine organ function and detect metastases, including liver function and bone enzyme (alkaline phosphatase, LDH, SGOT, and SGPT) tests.
• Tumor marker blood tests—including serum carcinoembryonic antigen (CEA), CA 15-3, and CA 27-29—may be performed to help determine prognosis and response to therapy. The use of these markers in treatment decisions still remains controversial. In patients with advanced metastatic breast cancer, these markers may help determine response (or lack of response) to treatment.
• Tumor tissue tests, including hormone receptors (estrogen and progesterone receptors), DNA, and other protein markers with potential diagnostic and prognostic value.
• Chest X-rays will assess lungs, ribs, and the spine for metastases. Specialized X-rays of other areas may be done if there are specific bodily complaints.
• A bone scan will help exclude bone metastases. This is often not necessary with small cancers but should be done if there is new bone or joint pain.
• An abdominal CT scan may be done to evaluate the liver, especially if the serum alkaline phosphatase (a bone and liver enzyme) is elevated. This test is not done routinely in someone without symptoms or with normal blood tests, unless the cancer is of very high risk (such as many positive lymph nodes).
Imaging
• Mammography is helpful in evaluating a suspicious mass, especially if it is new or persistent. It is also useful in women whose breasts are large and difficult to examine or who have had implants. Mammography is also used to locate precisely the position and extent of a known tumor. A standard two-view mammogram and specialized views, including magnified images, can provide vital information, but mammography is not a definitive diagnostic test, since 10 to 15 percent of cancers are not detectable by this technique. A biopsy should be done of any suspicious palpable (able to be felt) mass even if mammography does not suggest the presence of cancer.
• Mammograms may detect an abnormality elsewhere in the same or opposite breast. These images may show microcalcifications suspicious for cancer (even if no mass is palpable) or a smaller, nonpalpable but still suspicious mass. In this situation, a biopsy must be done, usually guided by mammography, to determine whether the lesion is cancer.
• Mammography may also be used to evaluate women with precancerous breast conditions, to evaluate yearly the opposite breasts of women with known breast cancer (as there is a higher risk of developing cancer there), and to evaluate women with metastatic adenocarcinoma of an unknown primary site. Sometimes the primary site is a hidden breast cancer. This last point is especially important because breast cancer may respond to chemotherapy or hormonal therapy not used to treat other forms of metastatic cancer.
• Ultrasound evaluation (breast ultrasonography) may be used to diagnose cysts. Ultrasonography is fairly accurate in determining whether a mass is cystic (containing fluid) or solid. This may eliminate the need for more complex procedures, including needle aspiration and biopsy. Some physicians prefer to withdraw the fluid from some cysts with a simple needle and syringe (aspiration), especially if the cysts are painful. If nonbloody fluid is removed and the mass completely disappears, no further treatment or evaluation is needed. Solid masses are more suspicious for cancer and therefore will usually be evaluated with a biopsy.
• Ultrasound imaging, like mammography, can also be used to locate precisely the position of a known but nonpalpable tumor to guide biopsy.
• Tissue should be removed by biopsy for microscopic examination if a mass is still present after fluid is removed, if blood is removed, if abnormal cells are found in the fluid, if no fluid can be aspirated, or if the mass returns two weeks later.
• Magnetic resonance imaging (MRI) may be done to evaluate breast implants if there are signs or symptoms suggestive of implant rupture. MRI may also help determine the extent of cancer or DCIS once a diagnosis is made, to help better plan for surgery. Since cancer may rarely be found in a completely different area of the breast or in the opposite breast when a known cancer is diagnosed, MRI is being studied to see if diagnosing and treating “incidentally detected” breast cancer will improve a patient’s chances of remaing free of recurrence over time.
Biopsy Almost all biopsies of suspicious breast masses used to be open surgical biopsies—removing a lump or part of a lump after cutting through the skin. This typically left behind a scar and a defect of varying size in the breast tissue. Now more options are available. Fine needle aspiration (FNA) biopsy is frequently used and entails placing a very thin needle inside the mass and extracting cells for microscopic evaluation. The procedure itself takes only seconds and the discomfort is comparable to a blood test. In order to make FNA reliable, it is important that the sampling as well as the interpretation of the specimens is done by specially trained physicians who use the procedure frequently.
Another option is a core needle biopsy, which uses a larger bore needle that extracts a thin core of tissue. This latter procedure requires local anesthesia and is more likely than FNA to be associated with significant bruising of the area. Bruising may be associated with temporary soreness in the breast but subsides gradually on its own.
In cases where a mass lesion is not palpable but can be seen by imaging studies such as mammography, ultrasound, or MRI, any one of these three imaging techniques can be used to guide fine needle aspiration or core needle biopsy. Generally, if ultrasound is able to visualize the target, it is the preferred method, because of ease of use and minimized discomfort for the patient.
If a fine needle aspirate or a core needle aspirate is nondiagnostic (does not contain enough material for the diagnosis) or indeterminate (does not allow a definitive benign or malignant diagnosis), then either a repeat attempt at needle biopsy is done or an open surgical biopsy is carried out.
The accuracies of FNA and core biopsies are similar when carried out by specifically trained practitioners. In large studies, two to five palpable breast cancers in one hundred are not identified as cancers. Because of this limitation, biopsy results are looked at in combination with palpation (what the mass feels like) and any image study, including mammogram and ultrasound. This is called the triple test. If any of the three indicate a high degree of concern for cancer, then an open biopsy is carried out. By using this combination, the frequency of missed cancers can be brought to 1 percent or less, which is comparable to the miss rate when using open biopsy alone.
Mammography may help guide the surgeon to do an open biopsy of the correct area. This is especially important for nonpalpable lesions. A needle is placed within or adjacent to the lesion under X-ray guidance (needle localization). An X-ray of the removed specimen (mass) is done during the surgery to be certain all the abnormal findings, including calcifications if present, seen on the mammogram have been removed.
Staging and Prognosis
Once a diagnosis of cancer is made, it is important to know the exact location and the extent of cancer and any possible sites of spread—this is referred to as the tumor stage. Some of this information comes from the surgical treatment itself and examination of the tissue removed, while other information is gathered from X-ray and blood tests. Stage is directly related to prognosis and determines the type of treatment to be offered, especially when several therapies are available. The main aspects of prognosis include the risk of recurrence and death due to breast cancer. There are two general types of recurrences. Local recurrences are those that occur in the same breast, in the chest wall at or near the surgical incision, or in the remaining lymph nodes under the arm of the involved side. These are considered curable with surgery, sometimes with radiation, although this usually does portend a higher later risk of recurrence. Distant recurrences (also called metastases) refer to the spread of tumor to distant organs, most commonly the bone, lungs, and liver, or to nodes other than those under the same arm. Distant recurrences are generally not curable and account for most of the deaths due to breast cancer, even though some individuals can live a normal life for a long time with metastases.
The TNM classification system is used to stage breast cancer according to the size of the primary tumor (T), the involvement of the lymph nodes in the armpit (axillary nodes) next to the affected breast (N), and the presence or absence of metastasis to distant organs or nodes other than the same side axilla (M). The clinical stages range from Stage I to IV. Stage 0 (or Tis) is in situ cancer, which is still localized to the point of origin and has not yet begun to invade outward or spread. The presence of axillary nodal involvement with tumor and the number of nodes involved constitute the most powerful prognostic factor. Tumor size, along with several other features, can also predict risk, but to a lesser extent. The appearance of the tumor under the microscope can also help determine prognosis. Tumor grade refers to several qualities of the cancer cells, such as the amount of glandular formation, the size of the cell nucleus (center of the cell, where the genes and cell division functions reside), and the fraction of cells that are actively dividing (referred to as the mitotic index). A higher grade is associated with a higher risk of both local and distant recurrence, and other microscopic features such as the presence of tumor cells in the lymphatic and blood vessels of the tumor itself.
How Prognostic Factors Affect Treatment Choices
Most treatments like chemotherapy and hormonal therapy tend to have a greater effect when the risk of recurrence is higher. If the risk of recurrence is very low, such as would be seen in a small tumor of low grade with negative nodes, then the amount by which the risk could be further reduced would be very small indeed. For this reason, staging and analysis of the above-mentioned prognostic factors is important. Also, some tumor tissue tests can help determine which type of treatment would be most effective. In addition to lymph node status, tumor size, and grade, other factors can help in determining prognosis and deciding what treatments are most important following surgery. It is important to remember that none of the markers listed below should be looked at singly, but rather should be put together with all the prognostic factors. For example, someone with a small node-negative tumor has a low risk of recurrence, and even though one of the markers below may indicate higher levels of aggressiveness, this may raise the risk of recurrence only by a small amount. These tumor tissue tests include the following:
• The measurement of protein receptors for two types of female hormones that affect breast cancer tissue—estrogen and progesterone receptors. The tumor content of these receptors—positive or negative—correlates with prognosis and response to hormonal therapy. Therefore, most patients with either estrogen- or progesterone-receptor-positive (ER or PR) tumors will derive a reduction in the future risk of recurrence with the use of the hormonal therapy tamoxifen (Nolvadex; covered in more detail in “Hormonal Therapy for Early-Stage Breast Cancer,” in this post).
• Cell cycle analysis. Both normal and malignant cells go through a complete cell cycle known as mitosis. During one phase of the cycle (the S-phase), new DNA is synthesized in preparation for the division of one cell into two. Flow cytometry as well as other techniques is used to measure the S-phase fraction, or growth rate. The percentage of tumor cells in this S-phase is an indication of how rapidly a tumor is dividing. As might be expected, tumors with a high S-phase fraction are more aggressive and have a less favorable prognosis. Ki-67 (or MIB-1) correlates with the S-phase and the growth rate, and high levels of staining for this protein also indicate a higher risk of recurrence.
• Immunohistochemical detection of abnormal tumor proteins, including secreted enzymes and stress proteins, are under investigation. Lower levels of the enzyme cathepsin-D or specific “heat-shock” proteins, for example, are associated with better survival in some studies.
• There are also abnormal oncogene and growth-factor-related products. The product of the HER-2/neu oncogene, a growth factor receptor protein, is overproduced in about one-quarter of breast cancers. The overproduction appears to be associated with earlier tumor relapses and lower survival rates. There is preliminary evidence that this marker may also influence the degree of benefit that might be seen with certain chemotherapy and hormonal drugs. There is preliminary evidence that overexpression of HER-2/neu may render cancer more sensitive to doxorubicin (Adriamycin)–based therapy (see “Adjuvant Chemotherapy for Early-Stage Breast Cancer,” in this post). Most important, it has been shown that patients with HER-2–positive tumors can derive a significant benefit from therapy with an antibody against HER-2 (trastuzumab [Herceptin]) and this is discussed further in the section on adjuvant chemotherapy.
• More recently, multigene assays, or tests that look at many genes at a time, have been able to use the patterns of actively expressed genes to predict how well someone might respond to chemotherapy. These tests have been applied primarily in situations where the average benefit of chemotherapy might be very small and possibly confined to a subgroup of patients that could be identified by multigene analysis. In the future, this approach may also help determine which of several treatment options would be ideal for a specific patient and allow for tailored therapy based on individual tumor and “host” characteristics.
Further clinical testing will be needed to confirm how many of these tests add to our ability to identify individuals with a higher risk of relapse and to better individualize therapy. It is expected, however, that during the next few years, many additional tests will be discovered and routinely performed on all breast tumors. At the current time, the most important markers that are used in treatment decisions are nodal status, tumor size, tumor grade, estrogen/progesterone receptor, and HER-2/neu receptor.
Treatment Overview
It is now standard practice for primary physicians, surgeons, radiation oncologists, and medical oncologists to work together to plan and carry out each patient’s treatment. Any one of these physicians can assume the role of “quarterback,” serving as the leader for decision making and conveying information to the patient and family and other members of the medical team.
Surgery The basic principle of breast cancer treatment is to remove the identifiable cancer and a rim of surrounding normal tissue to make sure that there is a “margin” of safety around the tumor. The degree of excision depends on the individual. The surgeon and the pathologist evaluate the extent of the cancer and its location within the tissue that has been removed. Fortunately, most cases of breast cancer, especially those detected on a mammogram, can be treated with breast-conserving surgery.
Types of limited surgery, showing typical incisions and amount of tissue removed
Smaller tumors can be treated with lumpectomy, which consists of removal of the lump and a surrounding normal rim of tissue (in this case, radiation to the breast is recommended). Only larger tumors require a quadrantectomy. If a tumor is advanced or has spread throughout the breast, complete removal of the cancer will remove a large portion of the breast itself and it may be advisable to proceed with a mastectomy. The judgment as to the amount of tissue that can be removed before it is wiser to do a mastectomy must be discussed between a patient and her surgeon. Radical operations such as the Halsted radical mastectomy (which removes muscles on the chest wall) should be used only in very advanced situations where a cancer is attached to the muscle. In some cases where the tumor is large, or in those that might require a mastectomy instead of a lumpectomy, chemotherapy may be given before surgery to shrink the tumor and improve the chances of being able to perform breast-conserving surgery.
Lymph nodes are generally removed as part of the surgical procedure to determine the extent of the cancer, although it is possible that their removal can also contribute to lowering the risk of subsequent recurrence. Cancer present in the lymph nodes indicates a significant risk of microscopic (and therefore undetectable) metastases outside the breast and the axillary (armpit) area, possibly in the lungs, liver, or bone. The finding of positive lymph nodes usually means that additional adjuvant therapy—hormonal or chemotherapy following surgery—will be recommended to lower the risk of spread. If the lymph nodes do not contain cancer, the likelihood of distant metastases is lower. Removal of the lymph nodes per se does not seem to make a difference to survival. Following lymph node dissection, there may be a small risk of lymphedema, or chronic swelling of the arm, that can develop after surgery—sometimes even many years later. This risk is higher if nodes in the upper part of the axilla are removed or if radiation to the upper lymph nodes is used (sometimes these procedures are necessary because of suspicious changes noted at the time of surgery or the finding of multiple lymph nodes involved with tumor).
It is now also recognized that axillary lymph nodes are not an effective barrier to tumor spread. The nodes are removed not as a curative measure, but mainly to provide information about the risk of recurrence and metastasis and to better define the need for adjuvant therapy. In the past, most women with invasive cancer underwent removal of many lymph nodes at the time of their surgery, a procedure termed axillary lymph node dissection. Today, for patients who do not have nodes that are suspicious for containing cancer, either on physical examination or on an imaging test, a sentinel lymph node biopsy is done. In this procedure, the surgeon uses a blue dye, sometimes with a radioactive tracer, to mark the first axillary node that may receive cancer cells. The blue dye and/or tracer are injected into the breast beside the tumor. They then travel through normal lymphatic channels to one or more sentinel nodes, which are identified by the surgeon visually and, if applicable, with a radioactive probe. The surgeon may also remove additional nodes that feel hardened or enlarged at the time of surgery. If the sentinel node or nodes have no cancer, it is unlikely that other nodes contain cancer. If the sentinel node contains cancer, there is concern that other nodes may also contain cancer and this is usually followed by a full lymph node dissection. Surgery to find the sentinel node is 90 percent successful, and its ability to predict if any nodes contain cancer is 90 to 95 percent accurate. This means there are three possible outcomes of the procedure. You should discuss the plan for each outcome with your surgeon. The three possibilities are as follows:
1. Your surgeon finds the sentinel node, and a pathologist examines the node during your surgery. If it does not contain cancer, there is a 90 to 95 percent chance that you do not have cancer in the remaining nodes, and no further surgery may be needed. The final pathology analysis, which sometimes includes the use of antibodies to help detect cancer cells in the nodes, is available a few days after surgery.
2. Your surgeon finds the sentinel node, the node is evaluated by a pathologist during surgery, and the node contains cancer. This happens 20 to 30 percent of the time and may not be evident until the final pathologic examination after surgery. Because of the possible spread of cancer from a positive sentinel node to other nodes, the usual plan is to remove additional nodes, which converts the operation to a standard node dissection or is done as a separate surgery later. Studies are currently under way to determine whether it is necessary to remove additional nodes when the sentinel node contains cancer. Sometimes the specific situation involves a detailed discussion with your surgeon and others on your team as to exactly what findings should form the basis for the need of a follow-up axillary node dissection.
3. Your surgeon may not be able to identify the sentinel node. This happens less than 10 percent of the time. In this situation, the usual plan is to remove the lymph nodes as would be done in a standard axillary dissection.
When a very small amount of cancer (less than 2 mm) is found in the sentinel or other nodes, it is called a micrometastasis (not to be confused with distant metastasis) and is still considered a marker of higher risk. However, if the amount of tumor is less than 0.2 mm, this is at the current time considered to portend the same risk as negative nodes and also may not require subsequent axillary nodal dissection.
If only the sentinel node—and possibly a few additional nodes—are removed, there is less chance of long-term lymphedema, nerve injury, or loss of motion in the shoulder after surgery. Sentinel node removal is a relatively new procedure, and information changes frequently. Ask your surgeon for a time to discuss the plan for your surgery.
Breast Reconstruction Another role for surgery is reconstructing a breast after one has been removed. This is being done more often than it used to be. It is also being done earlier and with techniques that produce a more cosmetically acceptable result. An experienced plastic or reconstructive surgeon may see the patient before primary surgery to give advice and assistance but is more often consulted near the end of therapy if the patient wants her breast reconstructed.
Postmastectomy Breast ReconstructionWomen who have had a mastectomy have a number of options to restore their normal physical appearance, including wearing a breast prosthesis. In many cases, however, breast reconstruction greatly improves an overall feeling of wholeness, elevating a sense of well-being and body image. This also eliminates the need for an external prosthesis and decreases the number of clothing restrictions. Reconstruction almost never interferes with monitoring for recurrence, and also can be coordinated around other needed treatments such as chemotherapy.
Postmastectomy breast reconstruction is one of the most significant advances in plastic surgery over the past two decades. There are now several ways to reconstruct the breast, each with its advantages and disadvantages. Improved techniques are now also available for reconstructing the nipple. The opposite breast may have to be reshaped or have its size altered to provide the best symmetry. A team approach in which the plastic surgeon works with the primary care physician, general surgeon, and radiation and/or medical oncologist generally leads to the most satisfactory result.
The first question to be decided is whether to reconstruct the breast immediately, at the time of the mastectomy, or to delay the procedure. The immediate approach of creating a breast mound at the same time as the mastectomy has the advantage of being less psychologically disruptive (“mourning” for the lost breast) and has a superior aesthetic result to delayed reconstruction. Immediate reconstruction is appropriate for women with smaller cancers or for those women with tumors that do not closely approach the chest wall or skin of the breast. If the tumor is larger than 2 inches (5 cm), or if the general surgeon is not confident that the cancer can be removed with clear margins, reconstruction of the breast is usually delayed. The primary goal is always curing the cancer. Breast reconstruction is always a secondary goal and should not interfere with the cancer treatment.
The delayed approach has few advantages. It allows the surgical wound to heal completely, so the reconstruction does not compound possible postmastectomy healing problems in those women who are at high risk for complications (diabetics, smokers, and those who have had previous radiation to the breast). These days, an experienced reconstructive surgeon can perform a successful reconstruction in most patients, even those at high risk. There will always be some women who do not want their breasts reconstructed or who are unable to decide whether they want reconstruction prior to their mastectomies. For these women, it is better to leave the decision to a later date.
Some consideration should be given to the timing of radiation therapy when it is needed. For example, this may affect the cosmetic outcome when using implants, due to increased fibrosis (scarring). For patients that need radiation to the chest wall, it may be best to avoid using implants immediately after surgery and to consider other reconstructive options.
In the early 1990s, isolated cases of possible reaction to silicone gel leading to autoimmune disease received a great deal of attention. Scientific studies were launched and the routine use of silicone gel for breast augmentation was suspended until more was known about this. However, the use of silicone implants for breast-reconstruction patients was never suspended. Now that the scientific studies have been done showing “no link” between silicone and autoimmune disease, silicone implants are being reintroduced rapidly into the marketplace for both reconstructive and cosmetic patients. In addition, alternative materials are being studied that may have advantages over both silicone and saline. These new materials are undergoing rigorous investigation, and it will be several more years before they are available in the United States.
The most common complication following silicone breast implantation has historically been capsular contracture. In up to half of women, the normally thin layer of scar tissue surrounding the smooth surface of the implant thickens and contracts. This creates an abnormal firmness and sometimes pain and/or distortion of the breast. Capsular contracture can often be corrected with additional surgery.
One-Stage Implant Breast Reconstruction
After a “skin-sparing mastectomy,” in which the breast tissue is most commonly removed along with the nipple and biopsy site, there is usually enough skin left on the chest to reconstruct the breast mound with an implant in “one stage.” In the case of immediate reconstruction, postoperatively adjustable implants are commonly being employed instead of tissue expanders. These implants do not need to be replaced at a later date like tissue expanders. The implant is inserted at the time of the mastectomy under general anesthesia. Minor adjustments in the volume of the implant may be made in the doctor’s office following this surgery. A few months later, a small injection dome is removed and the nipple is made with local anesthesia. It is also possible in some patients to achieve excellent results by preserving the nipple and entire skin envelope, reconstructing the breast with an adjustable implant with only a scar under the breast.
Advantages
• Reestablishes the completed breast mound with minimal additional surgery.
• Patients may also be less psychologically stressed, since they have an immediately visible result of the reconstruction procedure rather than the absence of a breast. Some studies have shown this leads to faster recovery and return to work.
• This may also be done in the delayed situation, occasionally using a permanent, nonadjustable implant for small-breasted women.
Disadvantages
• The general and plastic surgeons must schedule the surgery together in the case of immediate reconstruction. This can be logistically challenging in some cases.
• The opposite breast generally needs a small procedure (such as a breast reduction or a breast lift) at the same time to provide symmetry. (Many surgeons are able to accomplish this in the initial operation.)
• As with any implant, there is a low but definite risk of complications, which could lead to further surgery.
• There is a higher risk of complications with this procedure if the patient has undergone prior radiation therapy.
• If radiation is needed at a later date, the implant may become hard and uncomfortable.
Tissue Expansion Technique
When there is not enough skin available on the chest wall, or in the case of delayed reconstruction, an inflatable prosthesis is placed under the skin and sometimes the muscles of the chest wall and is gradually inflated with saline. This is usually done weekly in the doctor’s office. Several months are generally required before the breast reaches the size needed to match the opposite breast. The expander is then exchanged for a permanent prosthesis in an additional operation. A postoperatively adjustable implant may also be used instead of a tissue expander. This implant does not need to be replaced at a later date.
Advantages
• As a delayed procedure (done after the mastectomy has healed), this technique is simple and can be done on an outpatient basis under local or general anesthesia.
• This technique may afford the shortest recovery and time off work when done after the mastectomy has healed.
Disadvantages
• This is a multistaged procedure and often requires many months to complete.
• The opposite breast generally needs a small procedure (such as a breast reduction or a breast lift) at the same time to provide symmetry.
• As with any implant, there is a low but definite risk of complications, which could lead to further surgery.
• There is a higher risk of complications with this procedure if the patient has undergone prior radiation therapy.
• If radiation is needed at a later date, the implant may become hard and uncomfortable.
Breast reconstruction using adjustable implant/tissue expander
Latissimus (LATS) Flap Technique
This technique became very popular in the late 1970s and early 1980s. Today, it is most useful when the TRAM or DIEP flap is not an option or when an implant/expander alone does not suffice (e.g., when there has been localized radiation damage after the mastectomy). A breast implant is generally used along with the broad, fan-shaped back muscle (latissimus dorsi) and a segment of overlying skin, which is rotated around to the chest wall to replace tissue removed during the mastectomy.
Advantages
• Adds fullness to the lower portion of the breast, where it is most needed to produce a natural-looking breast.
• Offers an option for additional healthy skin if the skin on the chest wall has been irradiated.
Disadvantages
• An implant is needed as well as the flap in most cases.
• Creates an additional chest scar and a visible scar on the back.
• Transferring this back muscle may impair muscle power for some athletic activities.
• Skin from the back may be a different shade or texture.
LATS breast reconstruction, using skin flap from back muscle
TRAM (Transverse Rectus Abdominus Myocutaneous) Flap Technique
This is one of the more complex of the commonly used techniques and is not appropriate for all patients. A portion of one or both of the vertical muscles in the center of the abdomen (rectus abdominus) and a large ellipse of skin and fat from the lower abdomen are transferred through a subcutaneous tunnel onto the chest wall and shaped into the form of a breast.
In some areas of the country, this technique is currently being replaced by the DIEP flap, which does not harvest the muscle for blood supply. The TRAM is still an excellent option and in skilled hands is a shorter, less complex operation with a lower complication rate.
DIEP and Microsurgical Free-Flap Technique
Just as with the standard TRAM flap, this technique uses a similar skin and fat ellipse from the lower abdomen transferred to the chest wall and shaped into a breast mound. When the free flap is transferred to the chest wall, the divided blood vessel ends are joined directly to an appropriate chest wall artery and vein by microsurgical technique. This eliminates the need for the full length of rectus muscle (which surrounds the nourishing vessels) to be twisted and turned upward as the flap is repositioned onto the chest wall. The free (microsurgical) TRAM surgery is a longer operation than the standard TRAM. The added advantage of the DIEP (deep inferior epigastric perforator flap) is that the muscles of the abdomen remain intact; thus there is in the majority of cases no loss of abdominal function. Today it is the microsurgical flap of choice and, in experienced hands, has a relatively low complication rate and equal or better cosmetic outcomes.
Patients who have had their abdominal muscles cut during previous surgery (a gallbladder operation, for example) would not be acceptable candidates for a standard TRAM flap, but a DIEP or a free TRAM flap could safely be used in such cases.
The DIEP flap is the most complex of the commonly used techniques and is not appropriate for all patients. Other microsurgical flaps, such as the TUG (inner thigh) flap or gluteal (buttock) flap, may be used if the DIEP or TRAM are not available, but because of donor site issues should not be the first choice for breast reconstruction.
Advantages
• Cosmetic results are usually more natural than implants and more often match the opposite breast in and out of clothing.
• No further maintenance surgery on the breast is needed at a later date as in the case of implant reconstruction.
• An implant is not required.
• In the case of a TRAM flap, a “tummy tuck” follows the transfer of skin and fat from the lower abdomen. A patient must request that the DIEP surgeon repair her muscles if necessary.
• Sparing the rectus muscles in the case of the DIEP flap.
Disadvantages
• Possible weakness or hernia of the abdominal wall.
• Additional scar across the lower abdomen.
• Involves a lengthy surgical procedure under general anesthesia.
• A plastic surgeon with microsurgery skills is required for the free-flap technique. Always ask your surgeon how many DIEP flaps he/she has personally done.
• There may be a higher risk of complications.
Radiation Radiotherapy is often part of standard treatment for early-stage breast cancer to treat the remaining breast tissue after the primary tumor has been removed as part of breast-conserving surgery (such as a lumpectomy). This is based on the frequent risk of microscopic (and undetectable) cancer cells remaining in the breast. For smaller breast cancers, the combined treatment of surgery (lumpectomy or segmental resection) and subsequent radiotherapy has been shown to be equivalent to the modified radical mastectomy.
Another use of radiation therapy as primary treatment is in postmastectomy radiation to the chest wall. This may be done if the tumor was found at surgery or after tissue examination to invade the skin or chest wall muscles, if it was very large, or if many lymph nodes were involved. The assumption is that there may be hidden tumor cells in the chest wall or armpit (axilla) after surgery that can be eradicated effectively by radiation. In addition to the chest wall, the area treated (the radiation field or port) sometimes includes the lymph nodes in the armpit or over the collarbone (supraclavicular nodes). If chemotherapy is being used for early-stage breast cancer (see section below), then radiation is usually given after all of the chemotherapy.
In patients who later develop chest wall recurrence, radiation therapy is often used (if the area was not previously treated with radiation), usually with a wide margin to kill the presumed microscopic tumor implants that could also be nearby. This therapy to localized recurrences may achieve permanent control over the cancer in up to half of patients.
Radiation is given daily, usually five days a week, over about six weeks. The usual technique involves external-beam radiation to the entire involved breast, sometimes with an additional booster dose to the tumor area. This boost may be given by an external beam or with radiation seeds surgically implanted directly into the tumor area (brachytherapy). There is no increased risk of a secondary malignancy or a breast cancer on the opposite side as a result of radiotherapy. Radiation is also used in certain situations for advanced metastatic breast cancer, and this is further described in the section on treatment for advanced breast cancer.
More recently, partial breast irradiation has been given in certain cases of smaller, node-negative tumors, and this technique spares the whole breast from radiation and can be given over a small period of time, typically a few days, or even less. Different techniques for partial breast irradiation include brachytherapy as described above but given without whole breast radiation, the use of a balloon that is inflated inside the tumor cavity and filled with a radioactive material and then deflated and removed after your last radiation session (MammoSite balloon), and the use of focused and tailored radiation beams (conformal radiation). These techniques are currently being tested in higher-risk cancer, such as cases with positive nodes, and being compared to standard radiation.
Systemic or Medical Therapy Systemic therapy refers to drugs that circulate throughout the body and include chemotherapy, hormonal therapy, and, more recently, biological therapy such as antibodies as well as a combination of these types of therapies. These can be given as adjuvant therapy, which refers to therapy after surgery for early-stage breast cancer and which is designed to lower the future risk of distant recurrences (metastases) and thereby improve survival. It can also be given to patients with metastatic advanced breast cancer to shrink or prevent growth of cancer and to improve the quality of life, but generally is not curative in this situation.
Adjuvant Systemic Therapy for Early-Stage Breast Cancer Adjuvant or prophylactic chemotherapy, hormonal therapy, and antibody therapy, are now given to many patients after surgery for early-stage breast cancer (Stages I, II, and III) to try to prevent or minimize the growth of microscopic deposits of tumor cells that might grow into a recurrent tumor. It is believed that recurrence of breast cancer in the years following initial surgery is due to growth of these microscopic deposits of breast cancer cells that are undetectable by current standard tests. Treating some patients who have no obvious metastases at the time of surgery, but who are at high risk for recurrence or spread due to the size of the tumor, the presence of metastases in axillary lymph nodes, and other factors, has been shown to result in improvements in long-term survival without cancer. Although in the past, chemotherapy was primarily used to treat cancers in premenopausal women, and hormonal therapy to treat cancers in postmenopausal women, there is growing evidence that both types of treatment are effective regardless of menopausal status (see Table 1 below). Chemotherapy appears to be most effective in premenopausal women; however, chemotherapy may still be quite effective for treating postmenopausal women at higher risk of recurrence, for example, those with positive nodes. In some cases, such as larger tumors or Stage III breast cancer, chemotherapy or hormonal therapy may be given before surgery. A rough approximation as to how much chemotherapy and hormonal therapy can reduce the risk of breast cancer recurring in the future is shown below.
Table 1. Benefits of Adjuvant TherapyChemotherapy in women under age 50 Lowers the risk by about one-thirdChemotherapy in women over age 50 Lowers the risk by about one-fifthHormonal therapy for estrogen-receptor Lowers the risk by about one-half or progesterone-receptor-positive breast cancerTherefore, one can estimate the benefit for a specific case depending on what the recurrence would be in the first place. For example, a sixty-year-old woman with a 3/4-inch (2 cm) breast cancer with negative nodes would have about a 25 percent (one in four) chance of developing metastases over the next five years without any systemic adjuvant therapy. With tamoxifen (Nolvadex), this would be cut in half, to about 12 or 13 percent (one in eight). Chemotherapy would then lower the remaining risk by another 2 to 3 percent (one-fifth of the remaining 12 to 13 percent risk) to 10 percent (1 in 10). A general schematic that outlines the types of adjuvant systemic therapy used based on the overall risk of the cancer is shown in Table 2, “Types of Adjuvant Systemic Therapy.”
Table 2. Types of Adjuvant Systemic TherapyCyclophosphamide (Cytoxan), methotrexate (Mexate), and 5-fluorouracil (5-FU)Doxorubicin (Adriamycin) and cyclophosphamide (Cytoxan)Docetaxel (Taxotere) and cyclophosphamide (Cytoxan)5-Fluorouracil (5-FU), doxorubicin (Adriamycin), and cyclophosphamide (Cytoxan)5-Fluorouracil (5-FU), epirubicin (Ellence), and cyclophosphamide (Cytoxan)Doxorubicin (Adriamycin), cyclophosphamide (Cytoxan), and paclitaxel (Taxol)8 (4 of AC, 4 of paclitaxel [Taxol])Doxorubicin (Adriamycin), cyclophosphamide (Cytoxan), and docetaxel (Taxotere)8 (4 of AC, 4 of docetaxel [Taxotere])Docetaxel (Taxotere), doxorubicin (Adriamycin), and cyclophosphamide (Cytoxan)FEC as described above followed by either taxane or Taxol** Both docetaxel (Taxotere) and paclitaxel (Taxol) are classified as taxanes.
Adjuvant Chemotherapy for Early-Stage Breast Cancer Chemotherapy for early-stage breast cancer is usually given in combination, rather than as a single drug, in order to overcome any resistance the cancer cells may have to a specific agent. Details on commonly used regimens are provided in Table 2. Common drug combinations include the following:
• Cyclophosphamide (Cytoxan) + methotrexate + 5-fluorouracil (5-FU). This regimen is abbreviated CMF and is given on an outpatient basis over six months, requiring twelve visits to the clinic. Common side effects include nausea, vomiting, fatigue, moderate to complete hair loss, mouth sores, diarrhea, and lowering of the white blood cell count with a small risk of infection. This is an older regimen not used much today, but it is not associated with the small risk of heart problems as described with the regimens below.
• Doxorubicin (Adriamycin) + cyclophosphamide (this is abbreviated AC) given on an outpatient basis over three months, requiring four treatment visits to the clinic. Common side effects include nausea, vomiting, fatigue, complete hair loss, mouth sores, diarrhea, and lowering of the white blood cell count with a small risk of infection. Doxorubicin can on rare occasions cause weakness of the heart muscle (cardiomyopathy).
• Cyclophosphamide + doxorubicin + 5-fluorouracil (this is abbreviated CAF). This regimen is given over four to six months and has the same side effects as AC chemotherapy listed above, with perhaps more chance of mouth sores and diarrhea.
• Taxane drugs, which include paclitaxel (Taxol) and docetaxel (Taxotere), are increasingly used in combination with doxorubicin or following AC to treat higher-risk cancers, particularly with positive lymph nodes. These are given every three weeks for four cycles. Common side effects include fatigue, moderate to complete hair loss, numbness and tingling of hands and feet, mouth sores, diarrhea, allergic reactions, and lowering of the white blood cell count with a small risk of infection. For higher-risk cancers such as node-positive, higher grade, or hormone receptor–negative, therapy should include an anthracycline drug (doxorubicin or epirubicin [Ellence]) and a taxane (paclitaxel or docetaxel) in patients who are in good enough health to receive these drugs.
Ideally, chemotherapy is given within three to twelve weeks following the final surgery, provided all healing from surgery is nearly complete. If doxorubicin (Adriamycin) is going to be used, a scan of the heart (either a multiple gated acquistion [MUGA] scan or an echocardiogram) is first done to make sure there is no preexisting heart muscle weakness. Blood counts are also checked before each cycle of chemotherapy to make sure they have adequately recovered from the prior cycle. Many of the side effects listed above affect different individuals to different extents. Newer drugs can help minimize these side effects. For example, newer antinausea drugs can cut down on the chance of nausea and vomiting from the AC regimen from 80 percent to 20 percent. These drugs are often given preventively before chemotherapy to avoid nausea altogether. If recovery of the white blood cell counts delays the next cycle of chemotherapy, or if an infection or fever develops due to low white cell counts, then a self-injectable drug called a granulocyte colony-stimulating factor, or G-CSF (filgrastim [Neupogen] or pegfilgrastim [Neulasta]), is given with subsequent chemotherapy cycles. Also, drugs including epoetin alfa (Procrit) and darbepoetin alfa (Aranesp) can be given to help minimize drops in the red blood count and to lower the rare need for blood transfusions. Most side effects resolve after completing chemotherapy but can sometimes linger for several months. However, some effects are permanent, such as transition into menopause and loss of ovarian function and fertility. This is more likely in women who are closer to menopausal age. Long-term side effects of chemotherapy rarely cause major problems that interfere with life or normal activities. However, there are reports of changes in cognitive function (ability to think, remember, and reason) in women who have received chemotherapy for early-stage breast cancer. There is also an increase in the chance of developing leukemia, although this is very rare, about 1 in 300 or 400.
High-dose chemotherapy with bone marrow or stem cell transplant is being investigated for high-risk patients. Currently, this approach has not been proven to be superior to the standard chemotherapy regimens described above, but clinical trials to address this are still ongoing.
Hormonal Therapy The lining of the ducts and lobules in the breast change under the influence of hormones, and breast cancer cells also can be responsive to hormones. It has been known for some time that removing the ovaries can sometimes make breast cancers regress. In many cases, breast cancer treatment today includes drugs that affect the ovaries, otherwise affect production of estrogen, or interfere with the way that estrogen stimulates cancer cells. These treatments are used when the tumor cells test positive for the presence of the estrogen receptor (ER) or progesterone receptor (PR). ER and PR are proteins that bind to hormones like estrogen and progesterone and are present not only in some breast cancers but also in normal breast and many other tissues such as the lining of the vagina, uterus, liver, and bone. When estrogen binds to ER, it causes many different cellular activities depending on the type of cell as well as the presence of other hormones and factors. Tamoxifen (Nolvadex) is the most widely used hormonal drug and works by binding to the estrogen receptor and interfering with its function. Short-term side effects of tamoxifen include hot flashes, mild nausea, occasional changes in mood, and slight weight gain. These side effects usually improve or resolve over one to three months after starting therapy. Other side effects include an increased risk of blood clots, thickening of the lining of the uterus, and an increased risk of developing cancer of the lining of the uterus (endometrial cancer), about 1 in 100 over five years. The risk of blood clots is similar to the risk of blood clots caused by estrogen use, or during pregnancy. Regular gynecologic examinations are recommended for women taking tamoxifen, and a biopsy of the lining of the uterus (done in the office) should be performed if vaginal bleeding develops.
Other hormonal treatments involve removing the function of the ovaries, since in women who are still menstruating, removing the ovarian source of estrogen can have an impact both in early-stage and advanced breast cancer. This can be done by surgical removal of the ovaries (oophorectomy) or by using an injectable monthly drug that stops the ovaries from cycling and producing estrogen (sometimes termed chemical or medical oophorectomy).
A newer form of hormonal therapy, aromatase inhibitors (AIs), are now commonly used for postmenopausal women. After menopause, when the ovaries no longer make estrogen, the only source of estrogen is what is converted from androgens by a chemical reaction mediated by an enzyme termed aromatase. AIs lower the already low estrogen levels but work only after the ovaries have stopped making estrogen and should not be used in premenopausal women or immediately after periods have stopped. AIs have been shown to be slightly better than tamoxifen and in addition do not have the side effects of increasing the risk of uterine cancer or blood clots. However, they can sometimes cause joint and muscle pains and can also accelerate bone loss and osteoporosis over time.
Hormonal Therapy for Early-Stage Breast Cancer Some form of hormonal therapy is recommended for all patients with ER- or PR-positive breast cancer unless medically contraindicated. This can be omitted altogether in very low risk cancers, such as those that are node-negative, low grade, and less than 1/4 to 1/2 inch (0.5 to 1 cm), if the risk-benefit ratio favors no therapy. In patients who also receive chemotherapy, recent studies indicate that the best outcomes are obtained when hormonal therapy is given after all the chemotherapy.
For premenopausal women, tamoxifen (Nolvadex) is given daily for five years to most women whose tumors are positive for estrogen or progesterone receptors, whether chemotherapy is added or not. It can be begun either during chemotherapy (if given) or following chemotherapy, or following radiation therapy (if given). The use of tamoxifen for more than five years is being studied in clinical trials. Even though tamoxifen is discontinued after five years, the effect on lowering mortality persists for at least ten years.
Medical or surgical oophorectomy (described above) can also be effective in lowering the risk of recurrence for premenopausal women with estrogen-receptor-positive tumors. Prior to the advent of chemotherapy and tamoxifen, it was used fairly commonly. It appears to be as effective as chemotherapy but has never been compared alone to chemotherapy plus tamoxifen. Furthermore, it is not clear if oophorectomy adds to the effect of tamoxifen (in the absence or presence of chemotherapy). For these reasons, it is not commonly used in routine practice, but results of ongoing studies may in the future resurrect the use of this treatment.
Aromatase inhibitors (AIs) are slightly better than tamoxifen for postmenopausal women in lowering recurrence risk and are generally favored, although sometimes tamoxifen is used if significant side effects are seen with these drugs. The approved AIs include anastrozole (Arimidex), letrozole (Femara), and exemestane (Aromasin). Studies have also shown that two to five years of an AI following two to five years of tamoxifen is slightly more effective than tamoxifen for five years, so sequential therapy is also being used, especially in women who have just undergone menopause, or do so slightly after beginning tamoxifen. For premenopausal women who have contraindications to tamoxifen, such as a history of a blood clot, oophorectomy (either medical or surgical) along with an AI can be considered, but this is not a routine recommendation and this approach is still being studied in clinical trials.
HER-2 Antibody Therapy for Early-Stage Breast Cancer The antibody trastuzumab (Herceptin) works against breast cancer cells that make high levels of the HER-2 protein or that make extra copies of the HER-2 gene. Tumor tissue is tested for HER-2 and if the test is positive, then trastuzumab is added to the therapy, especially for higher-risk breast cancer. So far, all the studies have used trastuzumab either after chemotherapy or with overlap with the taxane part of the chemotherapy regimen, and the overall duration of treatment is currently recommended for one year. If radiation and/or hormonal therapy is used, trastuzumab can overlap with this treatment. Trastuzumab can cause heart muscle weakness (cardiomyopathy), which is usually temporary and responds to cardiac medication. Heart function needs to be tested before and periodically during trastuzumab therapy. As with other therapies, your doctor will need to balance the benefits and risks of trastuzumab for your specific case prior to making this decision.
Follow-Up After Treatment for Early-Stage Breast Cancer
Monitoring for Recurrence Following therapy for early-stage breast cancer, there remains a risk for recurrence. Local recurrences refer to those in the breast or in the remaining lymph nodes under the arm that are still curable (see “Recurrent Cancer,” in this post), hence follow-up with physical examinations every six months (or more frequently in the first year after treatment) as well as mammograms is recommended. In some centers, a recommendation is given for mammograms every six months for five years on the side of the involved breast if breast-conserving surgery was used, since most recurrences in the breast tend to happen in this frame of time. Annual mammograms on the other breast should continue, since there is a higher chance of a new cancer in the other breast (10 to 20 percent lifetime risk) compared to women who have never had a diagnosis of breast cancer.
Monitoring for distant recurrences (metastases) is primarily done by evaluating new symptoms or findings on physical examination that could be indicative of recurrence. These include an enlarged lymph node, new unexplained bone pain (such as in the back, hips, or ribs), chest tightness, shortness of breath, and headaches. Such signs should be investigated by the appropriate X-rays and biopsies depending on the findings.
In patients with no symptoms or abnormalities on physical examination, it is controversial whether or not routine blood tests or X-rays are useful in detecting metastases. Blood tests such as chemistry panels (especially liver function tests) and tumor marker tests (e.g., CEA, CA 15-3, CA 27-29) can oftentimes detect a distant recurrence months or even years before it may cause symptoms. However, even when detected very early, advanced metastatic breast cancer cannot be cured, even though some patients can respond to treatment and live a very long time. Therefore, it is not clear that such testing is really beneficial. In fact, serum markers are not always accurate and can lead to a false alarm and numerous tests and biopsies. Therefore, most expert organizations do not recommend the use of serum markers or routine X-rays or scans for follow-up after treatment of early-stage breast cancer if there are no symptoms or abnormalities on physical examination. On the other hand, these tests are used by many oncologists, and many patients feel a sense of reassurance when these are negative. There always remains the possible scenario of detecting a resectable recurrence even though it is not clear that this would be curative or affect long-term survival. This controversial area is best addressed by discussing the pros and cons with your oncologist.
Postmenopausal Symptoms and Health Maintenance Many women go through menopause after chemotherapy. Estrogen replacement is generally avoided in women with a history of breast cancer or those who are at increased risk for breast cancer because of the theoretical increase in the risk of cancer recurrence. Some studies have actually demonstrated a higher recurrence risk in patients with hormone-receptor-positive breast cancer who take estrogen replacement therapy.
Hot flashes can be a problem with menopause or when women who are already postmenopausal and on estrogen replacement discontinue estrogen when they are diagnosed with breast cancer. Hot flashes can also be a problem with taking tamoxifen (Nolvadex) even in premenopausal women. There has been interest in the use of soy (found in tofu, soybeans, and tempeh) to treat hot flashes, although a recent study did not find it to be helpful in this regard. Antidepressants like venlafaxine (Effexor) have also been found to be helpful, although they may have side effects such as dry mouth and loss of appetite. The progesterone drug megestrol acetate (Megace) at low doses also helps with hot flashes but can be accompanied by weight gain.
Vaginal dryness and thinning of the vaginal wall can sometimes be a problem. Local preparations such as testosterone and vaginal estrogens can help even though there is a potential that these treatments could affect the risk of recurrence. This has not been studied extensively in women with breast cancer; however, a local slow-release estrogen (estradiol) ring (Estring) has been shown not to result in estrogen entering into the bloodstream.
Osteopenia (thinning of the bone mineral) can occur after menopause and may be more of a problem in women who enter early menopause due to chemotherapy or loss of ovary function. Postmenopausal women on tamoxifen may actually have less bone loss. Periodic measurement of bone mineral density can be done with a simple test. If bone mineral density is well below normal, nonestrogen drug treatment options to prevent osteoporosis are alendronate (Fosamax), risedronate (Actonel), ibandronate (Boniva), and raloxifene (Evista). Since raloxifene is similar to tamoxifen, these drugs would not be used together or sequentially.
Recurrent Cancer
Local or Locoregional Recurrences Recurrent breast cancer can be classified as a local recurrence if it occurs in the same breast after breast-conserving surgery, in the skin or chest wall near the breast, or in the axillary nodes on the same side. This is usually treated with mastectomy, resection of the skin/chest wall tumor, or lymph node excision. It is controversial as to whether further hormonal therapy, chemotherapy, or radiation therapy can influence the risk of another local recurrence or distant recurrence. If several years have passed since chemotherapy was used for the original cancer, a different chemotherapy regimen may be considered, but clinical trials have not been done to show that this is effective. Alternatively, if the tumor is hormone receptor–positive, changing hormone therapy from tamoxifen (Nolvadex) to an aromatase inhibitor (or initiating tamoxifen if it was not used initially) may also be an option. These types of local recurrences may portend a higher risk of later recurrence. When local recurrences involve the chest wall, skin, or muscle, this tends to be a more ominous sign of future risk for distant recurrence. If surgically removable, these recurrences are excised with attempts to obtain clear surgical margins (no tumor cells seen microscopically at the edges of the specimen). Radiation therapy to the area may also be used. If local recurrences cannot be removed surgically or are not amenable to treatment with radiation due to their extent, location, or prior radiation (which usually precludes further radiation), then systemic therapy (hormonal, chemotherapy, or biological therapy) can be used as described in “Systemic Medical Therapy for Advanced Breast Cancer,” in this post. Recurrences should be evaluated with X-rays to check for the possibility of distant recurrences (CT scan of the chest and abdomen and bone scan, or PET scan).
Distant Recurrences Distant recurrences, or metastases, refer to the spread of tumor to sites beyond the breast and lymph nodes under the arm (to the bone, liver, or lungs, for example) or to skin and chest wall involvement beyond the breast area. This can either be the initial presentation of the cancer or be a recurrence that can develop even years after early-stage breast cancer. Upon diagnosis of Stage IV breast cancer, a biopsy (either with a needle or a surgical excision) may be needed to confirm that the metastases seen on X-rays or on examination is indeed a recurrence of breast cancer. For example, a single spot seen on a chest X-ray could be a scar from an old infection, or a primary lung cancer, in which case the treatment may be different. In addition, it is important to know if the cancer is positive for the estrogen or progesterone receptor as well as HER-2/neu in order to choose the proper therapy (discussed in the following sections). Full-staging X-rays are done at the time of diagnosis of Stage IV breast cancer, and this usually includes a CT scan of the chest and abdomen and a bone scan. A brain scan may be performed if there are signs of possible brain metastases, such as headaches, visual changes, weakness, numbness, and dizziness. In rare cases, such as a single metastasis to the lung, liver, or brain, surgical removal can be contemplated, since occasionally this will result in long-term cure with no further metastases developing. However, in almost all cases, there is likely to be progression or new sites of involvement over time. Therefore, advanced metastatic breast cancer is generally not considered to be curable. However, systemic therapy (discussed in the next sections) can be effective in controlling cancer progression and maintaining normal or near-normal quality of life for some period of time. In contrast to treatment for early-stage breast cancer, the choice of drugs and length of treatment depend on the individual case. Decisions need to be made on an ongoing basis depending on the response of the cancer to treatment and the side effects of both the cancer and the treatment.
Systemic Therapy for Advanced Breast Cancer Advanced metastatic breast cancer cannot be cured, although cancer shrinkage, or remissions, can be seen with therapy. It is very difficult to predict if a remission will be seen at all, or how long it will last before the cancer becomes resistant to therapy. Treatment of advanced breast cancer is felt to have only a modest impact on the length of life on the average, but when used appropriately, it can improve symptoms or delay the onset of symptoms, and thereby improve the quality of life. The subset of patients who are very sensitive to treatment and have long remissions are those that get a better-than-average prolongation of life—on the order of months or even many years in some cases.
An examination and X-rays or scans that assess known areas of tumor are repeated periodically during therapy; the interval of these assessments depends on the rapidity of growth and the type of treatment used. Response (shrinkage of cancer) is usually associated with an improvement in symptoms and quality of life. Responses can last from a few months to several years, with the average being around one year (perhaps longer in the case of hormonal therapy). The goals of treating advanced metastatic breast cancer are different from those for early stage. The type and length of therapy depends on how the tumor is responding to treatment, what effect this is having on symptoms and quality of life, and how the therapy itself may be adversely affecting quality of life. In general, treatment is continued as long as there is regression of cancer and the side effects appear to be acceptable, such that the improvement in symptoms (or the calculated prevention of the onset of symptoms) outweighs the side effects of therapy. If there is progression (growth) of cancer, then another therapy can be tried. In hormone-receptor-positive cancer, hormonal therapies are tried first (this is described in more detail in the next section). If there was initially a response to the first hormonal therapy before the cancer progressed, then there is a better chance that the second hormonal approach will temporarily shrink the cancer or prevent growth. Using combinations of two or more hormonal therapies at the same time has not generally been shown to be better than using these drugs alone.
Chemotherapy is generally used if it is felt further hormonal treatment is not likely to work. If chemotherapy is being used, treatment can be stopped when it is felt the best response has been attained as opposed to simply continuing indefinitely, since there has not been shown to be a difference in survival from either approach. Decisions about changing chemotherapy are made when there is progression of cancer. This is discussed further in “Chemotherapy for Advanced Breast Cancer,” in this post.
Hormonal Therapy for Advanced Breast Cancer Hormonal therapy is typically used as a first option for treatment of metastatic advanced breast cancer if the cancer is positive for either the estrogen or progesterone receptor. In some cases, if there is organ involvement (like lungs or liver) that is extensive and appears to be rapidly growing, then chemotherapy might be used initially. Hormonal therapy is continued until there is progression of cancer or intolerable side effects of treatment. Tamoxifen (Nolvadex) is often used in patients who did not receive this drug as part of adjuvant therapy for early-stage breast cancer. In this case, tamoxifen is continued until the cancer shows signs of growing. A newer class of hormonal agents, called aromatase inhibitors or inactivators, block the production of estrogen in postmenopausal women. Three agents are currently approved for use in advanced cancer: anastrozole (Arimidex), letrozole (Femara), and exemestane (Aromasin). It now appears that anastrozole and letrozole may be as effective as or even more effective than tamoxifen when used as the first hormonal treatment for advanced disease. Aromatase inhibitors have few side effects, primarily hot flashes and joint aching. For premenopausal women, oophorectomy can also be used, either as first hormonal therapy or after progression on tamoxifen. This can be accomplished by surgical removal of the ovaries or by medical (or chemical) oophorectomy using drugs called gonadotropin-releasing hormone analogues (e.g., goserelin [Zoladex]), which are given by injection once a month or once every three months. Patients whose tumors lack both estrogen and progesterone receptors are not candidates for hormonal therapy.
Chemotherapy for Advanced Breast Cancer Several chemotherapeutic agents are used for advanced breast cancer. The most common of these are doxorubicin (Adriamycin), paclitaxel (Taxol), and docetaxel (Taxotere). Sometimes these drugs are used as combinations (e.g., doxorubicin + cyclophosphamide [Cytoxan], or paclitaxel + doxorubicin). Other chemotherapy drugs with activity against breast cancer include capecitabine (Xeloda), vinorelbine (Navelbine), gemcitabine (Gemzar), and doxorubicin liposomal (Doxil). Table 3 outlines the dosing schedule and some of the side effects of these drugs.
Table 3. Commonly Used Chemotherapy Agents for Advanced Breast CancerEvery 3 weeks or weekly by veinHair loss, nausea, vomiting, low white count/risk of infection, mouth sores, diarrheaEvery 3 weeks or weekly by veinHair loss, numbness/tingling, low white count/risk of infection, mouth sores, diarrheaEvery 3 weeks or weekly by veinHair loss, low white count/risk of infection, swelling, mouth sores, diarrheaPill by mouth twice a day for 2 weeks, every 3 weeksDiarrhea, redness and peeling of the palms of the hands and soles of the feet, mouth soresLow white and red cell count, fatigue, numbness/tingling, constipation, muscle painLow white and red cell count, fatigueRedness and peeling of the palms of the hands and soles of the feet, mouth sores
Of the numerous chemotherapy agents available, it is not clear that a particular sequence of which drug is used first is better than any other. There is still controversy as to whether it is better to use combinations of chemotherapy agents or to use these drugs one at a time. There are also conflicting results as to whether combinations of certain chemotherapies are better than using them as single drugs in sequence as needed at the time of progression. While combinations may increase the chance of a response compared to single drugs, they have not always been shown to improve survival time and are also accompanied by more side effects. Some combinations such as docetaxel + capecitabine and paclitaxel + gemcitabine have actually shown slightly improved survival times, but it is still not clear if it is better to use these drugs in sequence (switch from one to the other if the cancer grows) than to use them in combination. High-dose chemotherapy with bone marrow or stem cell transplant currently does not appear to be better than standard-dose therapy. In patients who have already shown resistance (growth of cancer while on treatment) to several chemotherapy drugs, the chance of responding becomes less, as does the expected length of the remission.
The difficult choice of stopping all therapy and focusing on end-of-life care needs to be addressed when it is very unlikely that the treatment will result in a response and an improvement in the quality of life and will only cause toxic side effects.
Trastuzumab (Herceptin) for Advanced Breast Cancer New biological agents are more fully discussed in “Investigational Agents,” in this post. Many of these are being tested to see if they are effective in ongoing trials. The only currently approved biological agent for breast cancer is trastuzumab (Herceptin), which is useful both as a single drug and in combination with chemotherapy. This drug is an antibody to the HER-2/neu protein. It is effective only in patients whose tumors are positive for HER-2/neu (at a level of 3+ by an antibody, or immunohistochemistry, test; or when positive by a gene test called fluorescence in situ hybridization, or FISH). Trastuzumab has actually been shown to improve survival when added to chemotherapy. Although it is not a curative drug, some patients have had long responses. Side effects of trastuzumab are a chance of a reaction (usually to the first dose only) that includes fevers and chills as well as uncommon mild diarrhea, cough, and a small chance of weakness of the heart muscle (cardiomyopathy). When given in combination with chemotherapy (usually paclitaxel [Taxol]), it is common practice to give the two together until after the best response has been seen and then to continue trastuzumab alone as long as there is no progression. Trastuzumab is also effective with other chemotherapy drugs such as vinorelbine (Navelbine), docetaxel (Taxotere), carboplatin (Paraplatin), cisplatin (Platinol), gemcitabine (Gemzar), and capecitabine (Xeloda).
Newer Biological Drugs for Advanced Breast Cancer Two drugs are in the process of being approved for breast cancer in combination with chemotherapy. An antibody against tumor-associated blood vessels, bevacizumab (Avastin) has been shown to delay progression of tumor growth when added to chemotherapy. For HER-2/neu–positive advanced breast cancer that has progressed on trastuzumab (Herceptin), a new drug that blocks the enzyme activity of the HER-2/neu receptor, lapatinib (Tykerb), has also been shown to delay progression when added to the chemotherapy capecitabine (Xeloda). Many newer drugs are being tested in clinical trials and even before this latest edition of Everyone’s Guide to Cancer Therapy is out, it is likely that newer drugs will be approved for specific biological subtypes of breast cancer, in many cases combined with standard or with other biological agents.
Radiation Therapy for Advanced Breast Cancer Radiation is often used in treating metastatic disease, both to shrink tumors and to relieve local symptoms such as pressure and pain. If metastatic bone lesions occur in a weight-bearing bone such as the leg, for example, the bone may fracture with very little provocation. This is called a pathologic fracture. Such areas are usually given radiation to help heal the bone (usually after being surgically repaired), decrease pain, and control local spread of the tumor. If a bone lesion is extensive, there may be a significant risk of pathologic fracture during the next several months it might take to complete radiation therapy and healing. An orthopedic surgeon is often called in to determine if a fixation device—such as a rod or plate surgically placed over the cancerous bone to stabilize it—should be used to minimize the risk of fracture during this time.
Similarly, pain in the spine or spinal lesions seen on a bone scan or X-ray should be promptly investigated. If a metastatic tumor is present, there may be a risk of compression fractures of the vertebrae (even on simple walking) or of pressure on the spinal cord by the tumor, which can result in paralysis. Tumors that spread to the neck are especially worrisome because compression and fractures there can lead to paralysis of both arms and legs (quadriplegia) as well as loss of bladder and bowel control (incontinence).
Pain is often produced by tumors pressing on nerves, and radiation may help relieve the pain by shrinking these tumors. As is true in other types of cancer, the radiation dosage has to be kept low in some locations because of the limited tolerance of normal tissues.
Side effects of radiotherapy may include tiredness and skin changes, but with modern techniques major complications are infrequent.
Other Treatments Used in Advanced Breast Cancer Patients with bone metastases may benefit from treatment with the bisphosphonate pamidronate (Aredia) or zoledronic acid (Zometa), which may reduce pain, the need for radiation to control pain, and the risk of fractures and other complications. Bisphosphonates are given intravenously every month for two hours. Sometimes fever and bone pain can be seen after the treatment, but this usually becomes less of a problem or disappears altogether upon subsequent doses. Rarely, drops in calcium levels or interference with kidney function can be a problem. Monitoring of kidney function and calcium levels should be done periodically. Very rare problems with damage to the jawbone have been reported and it is recommended any needed dental procedures be done before starting these drugs.
G-CSF (filgrastim [Neupogen]), long-acting pegylated G-CSF (pegfilgratim [Neulasta]), and granulocyte macrophage–colony-stimulating factor, or GM-CSF (sargramostim [Leukine]), are growth factors that stimulate the white blood cells to grow. These medications are given by injection under the skin and are used to either prevent or minimize low white blood counts, which can result in serious infections or delays in chemotherapy. These growth factors stimulate the rapid production of blood cells and can lower the risk and duration of serious infections associated with chemotherapy. Rather than using these factors, sometimes a reduction in the dose of chemotherapy may be more prudent, since there is little evidence to suggest that attempting to maintain higher doses of chemotherapy is more effective in delaying progression or improving the length or quality of life.
Another significant side effect from chemotherapy, especially for metastatic cancer, is anemia (lowering of the red blood cell count) and can be associated with fatigue. The growth factor erythropoietin and synthetic derivatives (epoetin alfa [Procrit] and darbepoetin [Aranesp]) are given by injection under the skin every one to three weeks and can improve a low red blood cell count, resulting in less need for transfusions, less fatigue, and an improved quality of life. The use of these drugs is reserved for anemia associated with chemotherapy use. It is important to make sure that there is enough iron in the body to make red blood cells when erythropoietin is used.
Monitoring Response to Treatment For either recurrent or metastatic disease, appropriate studies are done to determine response to treatment. Before any significant change in therapy—a new chemotherapy program, for example—it is essential to establish baseline information, documenting current status by examinations, tumor measurements, X-rays (including CT scans and sometimes MRI and/or PET scans), and blood tests. Any abnormal studies, such as bone scans, X-rays (including CT), and blood tests, are repeated at appropriate intervals. Tumor markers such as carcinoembryonic antigen (CEA), CA 15-3, and CA 27-29 can be used when scans or physical examinations are not reliable in assessing tumor response.
Objective clinical response (partial remission, or PR) is ordinarily defined as at least a 30 percent shrinkage in the greatest diameter of a metastatic lesion or the sum of these measurements—this classification is more important to define response for clinical trials than in clinical management of patients. A metastatic tumor in the lung 1?1/4 inches (3 cm) in diameter would have to shrink to about 3/4 inch (2 cm) for this to be called a significant response, with such shrinkage being classified as a partial response. A complete response or remission occurs when all visible and detectable disease disappears. Disease progression means that measurable tumors increase in size during treatment by more than 20 percent or new tumors appear. “Stable disease” suggests disease that does not grow in any area and that does not meet the definition of response or progression.
It is easier to assess metastases in certain areas such as lymph nodes and the lung. Measurements can be made with a ruler held against a chest X-ray. Smaller, multiple lung metastases must be visualized by CT scan. Tumors in the liver can be monitored by liver function tests, especially the alkaline phosphatase, but also by direct measurement of metastatic tumors seen on abdominal CT, MRI, or ultrasound images. Measuring response in bone lesions is more difficult. Most metastatic breast cancers produce a softening or dissolving of the bone with the appearance of a “lytic” spot that looks like a hole. If treatment is successful, the lytic lesion will fill in with new bone, but this takes many months. Other cancers cause an increase in the density of the affected bone (blastic lesion) that may not be visible on bone scan and may require both CT scans and plain bone X-rays to be seen.
For determining the response to chemotherapy or hormonal therapy, a bone lesion that has not received radiation therapy has to be chosen as a marker. Obviously, if a lesion given radiation heals and chemotherapy or hormonal therapy is also being given, it would be impossible to know which treatment brought about the healing.
Bone lesions seen on bone scan sometimes require that an X-ray be done before treatment and another as soon as the treatment has been given an adequate trial. Following bone scans for evidence of response to treatment may not be as useful as conventional X-rays of lytic bone lesions. Scans may show “hot spots” in any abnormal area, and these spots may also indicate healing. They may also be produced by inflammation, metabolic diseases, or severe arthritis. The area could remain positive for months or a few years with successful therapy. Other types of bone lesions may not be visible on bone scan (see above). In a few patients with positive bone scans but without any lesions on X-rays, response may be signified by no new lesions developing. If the bone scan is unchanged after six months, especially if pain lessens, the positive areas can be presumed to indicate healing.
Positron-emission tomography (PET) scans are being increasingly utilized to assess the extent of metastatic disease and to follow the status following cancer therapy. Sometimes if something is seen on a CT scan but it is not definitive for cancer, a PET scan might help determine if it is likely to be cancer. Not all breast cancers can be seen on a PET scan, and sometimes a finding on a PET scan might be a “false alarm” and not represent cancer. It is important that this scan be used by knowledgeable physicians and in the right setting.
The “Flare” Response Hormone treatment and also chemotherapy can sometimes produce worse bone pain during the first few weeks of therapy, and the serum calcium level may also rise. This endocrine “flare” may be early evidence that the cancer is responding to the hormone treatments. If possible, pain medication is given to allow therapy to continue while the elevated calcium level is evaluated and treated. Usually the calcium returns to normal and the pain decreases, confirming a response.
Similarly, the bone scan sometimes becomes temporarily worse in a patient who is clinically improving. The increased uptake on the scan may represent healing of the destroyed bone. The X-ray appearance may not change for several months even in patients with a good response to treatment and whose pain has decreased. Likewise, blood tumor markers (see “Monitoring Response to Treatment,” above) may rise temporarily in patients whose cancers are responding to treatment.
Treatment by Stage
Stage 0 (Carcinoma In Situ)
TNM Tis, N0, M0
Noninvasive or in situ cancers consist of lobular carcinoma in situ (LCIS) and ductal carcinoma in situ (intraductal carcinoma, or DCIS). These cancers are often small and may be discovered incidentally by mammography before a mass can be felt. They may also be in several locations in one or both breasts. In situ cancer can also be found in the presence of invasive cancer, in which case the cancer is staged and treated according to the invasive cancer.
Standard Treatment
• For DCIS, conventional therapy is a wide excision of the tumor. It is critical to remove an additional area around the initial biopsy if the edges of the biopsy showed tumor cells. Axillary lymph nodes do not need to be removed in most cases, as the risk of positive nodes is quite low in most situations. Axillary sampling may occasionally be performed when the intraductal carcinoma is very aggressive (high grade) and extensively involves the breast. Following surgical excision of the tumor, radiation therapy is given to the remaining breast tissue, since this significantly reduces the chances of additional cancer developing in the same breast. Another option is to remove the entire breast tissue (total mastectomy). This is done if the intraductal carcinoma is very large or involves several different areas of the breast or when it is desirable to avoid radiation. It has also been shown that treatment with tamoxifen (Nolvadex) following surgery and radiation can further reduce the risk of recurrence of both intraductal and invasive cancers. The use of tamoxifen is generally reserved for cancers with a high risk of recurrence. Studies are ongoing to see if radiation can be omitted when the intraductal carcinoma is small and low grade and there is a wide area of normal breast tissue around the cancer removed at the time of surgery.
• In situ lobular cancer—a form that more commonly occurs in both breasts—is thought by some to be less malignant. However, patients with this lesion have a 25 percent risk of developing some form of invasive cancer in either breast over many years. There are some differences of opinion about management of patients with LCIS. Standard treatment can include periodic examinations (including mammography) and follow-up without any additional therapy. This may be adequate if the patient is aware of the long-term risk of developing invasive cancer and will participate in the frequent evaluations. Axillary lymph node sampling is not necessary. A very aggressive alternative is total mastectomy on both sides. This choice may be appealing to women who don’t want to have examinations several times a year, mammograms once or twice a year, and the constant worry that invasive cancer may be found during their next visit to the doctor. Also, tamoxifen can be used to lower the risk of breast cancer development in patients who have LCIS.
Five-Year Survival 98 to 100 percent*
Stage I
TNM T1, N0, M0
The tumor is 3/4 inch (2 cm) or less in size, without any evidence of spread to nearby lymph nodes or distant sites.
Standard Treatment This stage is most often curable with surgery. The treatment plan may use radiotherapy (if breast-conserving surgery is done) and chemotherapy or hormone therapy as well as surgery and has to be tailored to the individual, taking the risks and benefits of each plan into account. (See “Surgery” and “Adjuvant Systemic Therapy for Early-Stage Breast Cancer,” earlier in this post) For many years, it was not customary to treat Stage I breast cancer with chemotherapy or hormone therapy. These patients generally have a good prognosis, with only about one chance in four of developing recurrent cancer. For most cancers smaller than 1/2 inch (1 cm) in diameter, the chance of recurrence is less than 10 to 20 percent within ten years of diagnosis. Studies now have proven that there is a small benefit from the use of hormonal therapy and chemotherapy for Stage I breast cancer. A careful discussion with each patient regarding these issues is very important. For example, a premenopausal woman with a 1.9 cm aggressive HER-2/neu–positive, ER-positive cancer might have a five- to ten-year risk of recurrence of 20 percent or higher. Chemotherapy might reduce her risk of recurrence by as much as 5 to 6 percent, and hormonal therapy by about 8 percent. In this situation, chemotherapy may add a significant benefit to hormonal therapy. In contrast, a postmenopausal woman with a 0.8 cm slow-growing cancer that is HER-2/neu–negative and ER-positive might have a five- to ten-year risk of recurrence of less than 10 percent. Tamoxifen (Nolvadex) could reduce this risk further to less than 5 percent, but chemotherapy would be expected to provide only a 2 percent reduction in risk of recurrence. In this situation, tamoxifen (or no therapy for older women at higher risk for tamoxifen-related side effects) would be the appropriate choice of adjuvant therapy.
Five-Year Survival 85 to 97 percent
Stage II
TNM T0, N1, M0 or T1, N1, M0 or T2, N0, M0 (IIA)
T2, N1, M0 or T3, N0, M0 (IIB)
Stage IIA consists of a small primary lesion (less than 3/4 inch [2 cm]) and positive axillary lymph nodes, or a larger primary lesion between 3/4 inch and 2 inches (2 to 5 cm) without positive nodes.
Stage IIB consists of a primary lesion between 3/4 inch and 2 inches (2 to 5 cm) and positive axillary nodes, or a very large tumor (greater than 2 inches [5 cm]) with no axillary nodes involved.
Five-Year Survival 70 to 90 percent
Stage III
TNM Any T, N3, M0 or T4, any N, M0
Standard Treatment This stage includes patients with large tumors that may be more difficult to treat with surgery first. Studies have shown that using neoadjuvant (preoperative) chemotherapy will yield equal results compared to chemotherapy after surgery, but more patients can have breast-conserving surgery. This stage also includes inflammatory carcinoma (Stage T4d), which is generally regarded as inoperable. The breast is usually enlarged and may be red and warm. Surgery is usually limited to the initial diagnostic biopsy, with treatment of the local tumor by chemotherapy or radiation. Neoadjuvant chemotherapy is often given first. If a good response is obtained with chemotherapy and/or radiation, surgery may be helpful to remove residual tumor. Chemotherapy regimens may include any of those listed in “Adjuvant Chemotherapy for Early-Stage Breast Cancer,” earlier in this post. It is becoming increasingly common to give all the chemotherapy prior to surgery.
Because all three therapies are used, but their best sequence has not yet been determined, newly diagnosed patients with Stage IIIB cancer should be considered for clinical trials. Complex treatment programs involving integrated chemotherapy and radiotherapy followed by surgery are under study. If a clinical trial is not available, consideration should be given to one of the commonly used aggressive combined treatment plans.
Five-Year Survival 40 to 70 percent
Stage IV
TNM Any T, any N, M1
This stage applies to the presence of any distant metastases (to the bone, liver, or lungs, for example) or skin and chest wall involvement beyond the breast area. This can either be the initial presentation of the cancer or be a recurrence. Upon diagnosis of Stage IV breast cancer, a biopsy (either with a needle or a surgical excision) may be needed to confirm that the metastases seen on X-rays or on examination are indeed a recurrence of breast cancer. For example, a single spot seen on a chest X-ray could be a scar from an old infection, or a primary lung cancer, in which case, the treatment may be different. In addition, it is important to know if the cancer is positive for estrogen and progesterone receptor as well as HER-2/neu in order to choose the proper therapy. Full-staging X-rays are done at the time of diagnosis of Stage IV breast cancer, and this usually includes a CT scan of the chest and abdomen and a bone scan, or a PET scan. If there are signs of possible brain metastases, such as headaches, visual changes, weakness, numbness, or dizziness, then a CT scan or MRI of the brain should be done to exclude metastases to the brain. Once information about the tumor markers (estrogen/progesterone receptors, HER-2/neu) and X-rays/scans is complete, decisions can be made about starting the treatment plan as outlined in the sections on therapy for advanced breast cancer, earlier in this post.
Five-Year Survival 5 to 20 percent
Breast Cancer In Men
Male breast cancer is rare, but 1 out of every 125 cases of breast cancer involves a man, usually one over sixty years old. There is a higher frequency of Stage III disease, principally because of skin involvement by the tumor. Although a painless breast lump is the most common sign, most breast lumps in men are benign and are related to some other cause, such as medications or liver disease. Sometimes there is delay in seeking therapy, which is perhaps due to low awareness by the public and doctors of the possibility of this diagnosis.
Standard Treatment Both simple and radical mastectomies have been done, but no statement can be made about a standard method. Skin grafting may be required for advanced disease. Radiation therapy is sometimes used postoperatively to decrease the risk of local recurrence. Treatment with chemotherapy, hormonal therapy, and/or biological therapy is used following the same criteria discussed in prior sections of this post.
Investigational Agents
Patients with advanced or metastatic breast cancer (Stage IV) are often eligible for clinical trials involving newly developed agents not yet approved for breast cancer treatment. These new agents span all of the types of treatments used for breast cancer and include new chemotherapies, new hormonal therapies, and new biological or immunological therapies. By definition, investigational agents are not yet proven to be effective for the particular clinical situation in which they are being tested, and that is why a clinical trial has been organized.
New chemotherapies include drugs that are similar to existing chemotherapies but are potentially improved in terms of effectiveness, side effects, and/or convenience. These drugs usually affect how cancer cells divide, so can have many side effects on normal cells. Examples include versions that can be taken as a pill at home rather than requiring intravenous infusion. Other investigational chemotherapies are completely new and include drugs that are designed to attack particular aspects of cancer cells. In this respect, they are similar to many of the biological agents (see below), in that they are designed using our improved understanding of how cancer develops.
New hormonal or endocrine therapies include drugs that block the effects of estrogen, since estrogen can stimulate breast cancer growth. Examples include drugs that are “pure antiestrogens,” which always block estrogen throughout the body. Tamoxifen (Nolvadex), the most commonly used hormonal therapy, blocks estrogen in many but not all tissues. It is possible that these new versions may be more effective in some patients, and are also likely to avoid the important but rare side effect of increased uterine cancer risk. Others may work in situations where other hormonal agents are no longer effective.
Biological agents comprise the largest group of new agents in clinical trials and include new monoclonal antibodies and antibody-based agents; cancer vaccines; inhibitors of tumor invasion; and inhibitors of tumor angiogenesis (blood vessel formation that is necessary for tumor growth). A milestone in breast cancer therapy was the approval of trastuzumab (Herceptin) as the first monoclonal antibody treatment for breast cancer with high levels of HER-2/neu. Newer types of monoclonal antibodies and antibody-based agents are in development and include antibodies linked to drugs and other toxins for greater potency against cancer cells, as well as antibodies against other molecular targets besides HER-2/neu. Several drugs called kinase inhibitors are being tested in many types of cancers, as these drugs inhibit enzymes called kinases, which propagate several signaling pathways that mediate important cancer cell activities such as growth and development. One such drug, lapatinib (Tykerb), has just been approved in HER-2/neu–positive breast cancer that has progressed on trastuzumab. Vaccines against cancer have been studied for many years and with recent improvements in design may become useful in breast cancer treatment. A number of cancer vaccines are in clinical trials for breast cancer at advanced and even early stages.
Alternative Medicine for Breast Cancer
Alternative medicine refers to approaches that are not mainstream and sometimes not accepted by the conventional medical community. These include mind-body techniques, herbal medicine, nutritional therapy, megavitamin supplementation, homeopathy, prayer, and many other modalities. Very little information exists from well-done clinical trials to make definitive recommendations in this area. Some studies have shown that vitamin C or E as well as an antioxidant like selenium might be associated with a lower risk of cancer, but none have shown that these can actually treat cancer. Herbal therapies are often used for side effects, cancer treatment, and improving the immune system. While some studies have shown these effects in the laboratory, no clear conclusions can be made about how effective these might be in actual practice. Acupuncture can be helpful in some cases of pain and nausea that may not respond to other treatments. The National Institutes of Health issued a consensus statement supporting acupuncture for these indications. The use of megavitamins and antioxidants during radiation therapy or chemotherapy to alleviate side effects remains very controversial. Proponents say that this can help with symptoms and even effectiveness, while detractors state that this could diminish the effect of treatment. Certainly, there is a need to perform serious research in the area of alternative medicine, since there is the potential to uncover therapies of use as well as to dispel useless treatments that could be harmful or expensive. For individuals interested in seeking alternative medicine, it is recommended that an experienced practitioner be sought who can clearly articulate the reasons for the therapy and give a balanced assessment of the pros and cons and of the information upon which this is based. Careful attention to possible improvements or side effects should be tracked, and all the information should be shared with both practitioner and physician.
The Most Important Questions You Can Ask
• Can I save my breast? Is this wise?
• When can I have breast reconstruction done and what are my choices? What will I look like afterward?
• Will I need radiation therapy?
• Will the radiation therapy produce any damage to the skin or any deformity? What are the other side effects?
• If I need chemotherapy, what are the choices? How long will it last and what are the side effects (both short-term and long-term)? By how much will it lower my risk of recurrence and risk of dying of breast cancer? Is there a role for hormonal therapy or biological therapy?
• Why do I have to stop taking female hormones?
• What can you give me to help me with my hot flashes?
• Will I lose my hair? When will I start losing it and how long will it take to come back?
• How often do I need to be examined afterward? What tests will I have?
• How often should I have a mammogram?
• When will I be sure that my cancer will not come back?
• If I have advanced, or metastatic, breast cancer, what are the expectations of therapy?
• How will the treatment regimen be chosen, how will I be monitored, and what adjustments or changes will be made over time?
* Survival times listed are averages from large population studies and significant variability exists in these estimates.
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