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Breast cancer is the most common form of malignant disease in women , it is the most common cause of death in women between 40 and 55 years of age. The incidence of breast cancer is increasing, especially in older women, but the cause of the increase is not known. This disease will develop in about 12 percent of women ; about 70 percent of this group can be cured.

A guide to the screening or assessment of women who have breast complaints can come from knowledge of which groups are at greatest risk for the development of breast cancer. The characteristics most associated with increased relative risk of breast cancer include (1) first-degree female family members (mothers and sisters) who had breast cancer, (2) prior breast cancer, (3) nulliparity, (4) age greater than 30 years at first pregnancy, (5) early menarche or late menopause, and (6) radiation exposure, especially in the pubertal years or in women heterozygous for ataxia-telangiectasia. Many variables acting together appear to determine whether breast cancer develops in an individual.

Genetic analyses of families with a high incidence of breast cancer suggest that specific mutations within the genome are responsible for breast cancer. The BRCA1 and the BRCA2 genes, when mutated within the germ line, are associated with an approximately 85 percent risk of breast cancer development in the lifetime of individuals with such a mutation. Those with the BRCA1 mutation are also at high risk for ovarian cancer. A specific mutation within the BRCA1 gene, called l85delAG, is found in as many as one percent of Ashkenazi Jewish individuals. The BRCA1 gene encodes a large protein that may be excreted from cells and appears to control cell proliferation. Whereas perhaps only eight percent of all breast cancers can be attributed to these two genes, it is likely that other genetic defects will be found in families in which cancer of the breast and ovary are prevalent. Primary breast cancer in extremely young women without a family history of breast cancer is frequently not associated with mutations in the BRCA1 and BRCA2 genes. Screening of women and their children for the presence of mutations in the BRCA1 and BRCA2 genes poses important ethical, legal, and privacy issues that need to be addressed before screening becomes widespread. Analyses of individuals with the Li-Fraumeni syndrome, a condition that is associated with the development of multiple cancers (including breast cancers) at a young age, indicate that germ line mutations in the tumor suppressor gene p53 are responsible for breast cancer in these individuals. About 60 percent of breast cancers during their formation have acquired mutations in the p53 gene or other genes on chromosome 17. These acquired mutations, either alone or in conjunction with the overexpression of other oncogenes or the loss of tumor suppressor genes, are likely to play an important role in the progression of breast cancer.

Studies that examine the actual intake of fat by individual women have not supported the correlation between fat consumption and the risk of breast cancer, but international studies have demonstrated a positive correlation between per capita consumption of animal fat and the incidence of breast cancer. So-called central obesity rather than peripheral obesity appears to increase the risk of breast cancer. The combination of obesity, low parity or late first pregnancy, and a family history of breast cancer is associated with a pronounced increased risk of breast cancer. Several studies have linked the consumption of alcohol, even in modest amounts, with an increased risk of breast cancer.

Radiation is a cause of breast cancer. The likelihood of breast cancer is increased in women who received thymic irradiation as infants, irradiation for acne as teenagers, or therapeutic irradiation at a young age, particularly to the chest, as in mediastinal irradiation for Hodgkin's disease. Scatter from therapeutic irradiation does not appear to increase the risk of breast cancer in the contralateral (uninvolved) breast in women older than 35 years. Screening mammography does not increase the incidence of breast cancer.

Controversy surrounds the question of whether the use of hormonal birth control pills increases the risk of breast cancer. The difficulty in interpreting these data arises from differences in age at first use, relation of use to previous pregnancies, formulations of hormones, duration of use, and underlying breast cancer risk. Very long term use or use at a young age before first pregnancy may increase risk. However, at this time, birth control pills containing estrogen plus progestational agents do not appear to alter the risk of breast cancer.

The risk of breast cancer associated with estrogen replacement in postmenopausal women has been extensively studied. An overview analysis of replacement therapy showed that the use of conjugated estrogens at a dosage of 0.065 mg/day was not associated with an increased risk of breast cancer, but investigators report that the long-term use of estrogens (more than 10 years) is associated with small increases in relative risk. However, any increased risk is outweighed by the benefits of estrogen replacement on reduction in the incidence of hip fracture, cardiovascular disease, and sexual dysfunction. Age-adjusted mortality from all causes is reduced in women receiving estrogen replacement. Estrogen replacement is associated with an increased risk of endometrial cancer.

Breast augmentation does not lower or raise the risk of breast cancer fibrocystic disease does not predispose an individual to breast cancer unless it is associated with atypical ductal hyperplasia; and women with cysts are not at higher risk for breast cancer unless they have a family history of breast cancer. Silicone-containing implants have not been shown to increase the risk of breast cancer. Breast-feeding does not appear to lower the risk of breast cancer, although this finding has been disputed in studies of women younger than 50 years who develop breast cancer.

There are few interventions that will reduce the risk of breast cancer. The exceptions may be having a first pregnancy before age 35, reducing consumption of alcohol, and reducing body weight. These matters of lifestyle have value in general health maint enance even if they do not have great influence on the risk of breast cancer. In adjuvant therapy trials for early breast cancer, it was noted that the appearance of new cancers in the contralateral breast was reduced in those patients receiving the antiestrogen tamoxifen. This observation led to the initiation in the United States and in England of the first breast cancer prevention trials using tamoxifen. The projections are that the use of tamoxifen for five years in a woman whose risk of breast cancer is comparable to that of a 60-year-old woman could reduce this relative risk by 30 percent. Because tamoxifen is associated with toxicity, including development of endometrial carcinoma , it is premature to introduce this agent into clinical practice for prevention of breast cancer. Studies are also assessing the possible impact of tamoxifen on cardiovascular disease and osteoporosis, because the drug has been shown to lower low-density lipoprotein (LDL) cholesterol levels and to decrease the rate of calcium loss from bone.

Most breast cancers are still detected by patients themselves, although the percentage of mammographically detected cancers has increased. Mammographic screening is important because it can detect smaller lesions and breast cancers that are noninvasive-findings that are favorable and more likely to lead to cure. Forty-two percent of the cancers detected by screening are not detectable by physical examination, and about one third are either noninvasive or small ( 1 cm in diameter) invasive cancers. Seventy-five to 80 percent of patients whose invasive cancers are detected by screening have negative axillary lymph nodes, which is associated with the best prognosis. For these reasons, breast cancer screening is now an important aspect of health care for all women 40 years of age and older. Physical examination and mammography complement each other in breast evaluation; used together, they detect more than 96 percent of diagnosed breast cancer lesions and have proved to be effective in reducing mortality from breast cancer by 25 to 30 percent. Physical examination combined with mammography remains the standard method of assessing the breast. In the evaluation of data from screening programs, it is necessary to distinguish between screening mammography and diagnostic mammography, because the incidence of breast cancer is higher in women referred for mammography because of breast complaints. Breast cancer can exist despite a normal mammogram; thus, a biopsy should be performed for all suspicious breast masses. Equipment now being used to perform mammography has greatly reduced radiation exposure during this procedure.

Screening programs detect breast cancers in patients of all ages, but a reduction in mortality in women who have undergone screening has been established only for those between 50 and 69 years of age. Long-term follow-up, however, reveals reduced mortality in screened women compared with unscreened women between 40 and 49 years of age who develop breast cancer. The sensitivity of mammography has improved considerably since the time that many of the trials were performed that found no overall reduction in mortality for women younger than 50 years. Whether mammography should be used in asymptomatic women younger than 40 years depends on their breast cancer risk; the procedure is indicated, regardless of age, for any woman in whom a suspicious breast mass is detected on examination. The following recommendations apply to asymptomatic women with no significant risk factors: (1) monthly self-examination and annual physical examination for women younger than 40 years, (2) monthly self-examination, annual physical examination, and mammography at one- to two-year intervals for women between 40 and 49 years of age, and (3) monthly self-examination, annual mammography, and physical examination for women 50 years of age and older. Women who perform regular self-examination tend to have better prognoses if breast cancer develops. All women should be taught how to perform breast self-examination and encouraged to do so monthly.

In most patients, other methods of breast evaluation, such as thermography, computed tomography, and magnetic resonance imaging, have not been shown to be of value except to supplement mammography. MRI may prove valuable, but its role in breast assessment is in its developmental phase. Ultrasonography supplements mammography in defining a mass as either solid or cystic and can aid in the aspiration of fluid from cystic masses, but it is not a screening technique in its own right.

There are three methods with which to establish a diagnosis of breast cancer: fine-needle aspiration (FNA), core- or cutting-needle biopsy, and excisional biopsy. Bilateral mammography should always be performed before breast biopsy of a mass to determine the size of the mass, whether the contralateral breast contains abnormalities that may also require biopsy, and whether more than a single lesion exists in the breast with the suspicious mass. Edema and hemorrhage make it difficult to evaluate a mammogram performed in the immediate postbiopsy period. An increasingly common sequence for breast mass assessment is the following: (1) FNA or core-needle biopsy is used to establish a diagnosis of breast cancer, (2) primary treatment options are discussed with the patient, and (3) the management plan for the appropriate local treatment is implemented [see Management of Primary Breast Cancer, Local-Regional Treatment of Invasive Breast Cancer, below]. FNA provides a rapid cytologic diagnosis, and core-needle biopsy provides a rapid histologic diagnosis. Although FNA and core-needle biopsies can aid in the planning of treatment if breast preservation is desired, they do not establish the size of the tumor, provide tissue for an estrogen receptor (ER) assay, or eliminate the need for subsequent surgical removal of T1 or T2 tumors. FNA of breast masses performed in the office can also be used to determine quickly whether the masses are filled with fluid. If no fluid is obtained from aspiration or if a mass remains after fluid aspiration, excisional biopsy is required. Suspicious lesions that are found on mammography but are not palpable can be evaluated by stereotactically guided FNA or core-needle biopsy under mammographic guidance or by open biopsy after a guide wire is placed in the breast lesion under mammographic guidance. FNA infrequently yields false positive results.

Excisional biopsy, with the use of local anesthesia, on an outpatient basis can be performed on palpable masses that clearly are cancers. When technically feasible, an excisional biopsy is always preferable to an incisional biopsy because excisional biopsy removes the entire tumor, permits accurate assessment of the size of the tumor, and allows microscopic evaluation of the entire tumor. Excisional biopsy can also be a definitive surgical procedure for women who have small primary tumors and who subsequently receive radiation therapy as their principal treatment [see Management of Primary Breast Cancer, Local-Regional Treatment of Invasive Breast Cancer, below]. Excisional biopsy should always be performed with the intention of completely removing the tumor, and the surface of the biopsy specimen should always be inked before fixation so that it can be determined whether its margins are free of tumor. The procedure should be performed separately from definitive surgical treatment of the breast because this approach can permit study of permanent sections rather than frozen sections to determine whether a breast-preserving approach would be indicated and can permit discussion with the patient before the definitive therapeutic decision is made. When cancers that contain microcalcifications are excised, short-term follow-up mammography (two to four months) of the involved breast should be performed to confirm that all the microcalcifications were excised. Mammography of the biopsy specimen at the time of excision should be used to confirm that the entire tumor was removed during surgery.

The TNM classification is used for staging breast cancer and serves as a basis for establishing a prognosis, although a number of factors other than the anatomic extent of disease are important in the prognosis. The primary tumor (T) is classified on a scale of 0 to 4 on the basis of tumor size, extension of the tumor to the chest wall, and the presence of skin edema or peau d'orange, skin or breast ulceration, or satellite nodules. The regional lymph nodes (N) are classified on the basis of palpability, suspicion of malignant disease, and location. Distant metastases (M) are assessed by physical examination and clinical studies. Prognoses for the four stages of breast cancer vary widely Staging should be based on pathological rather than purely clinical findings whenever possible.

After a histopathologic diagnosis of breast cancer is made, studies are performed to complete staging, detect clinically apparent distant spread, and provide baseline values against which comparisons can be made during follow-up. For stage I and stage II patients, these studies include chest x-rays, leukocyte and platelet count, and blood chemistry tests, including serum alkaline phosphatase serum, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and bilirubin levels. Liver scan, radionuclide bone scan, brain CT scan, and CT scan of other body regions are not indicated in the primary assessment of most stage I and stage II breast cancer patients, because the yield is so low. Bone or bone marrow biopsy is of little value in determining stage I and stage II primary breast cancer, even though cancer cells in some patients can be detected using special immunostaining. The whole body technetium bone scan is extremely sensitive for detecting bone metastases and is indicated for patients with advanced stage II and stage III breast cancer.

Prognosis is an assessment of the risk of relapse of breast cancer on the basis of anatomic, histologic, cytologic, and biologic factors . If there is no evidence of systemic spread, the number of involved axillary lymph nodes, the grade of the tumor, and, to a lesser extent, the size of the primary tumor and the hormone receptor status of the tumor are the most important indicators of prognosis. These factors suggest whether residual cancer cells at distant sites may remain after local-regional treatment.Therefore, it is important to determine at diagnosis the size of the primary tumor, the extent of axillary lymph node involvement, the grade of the tumor, and whether the tumor is positive for hormone receptors. An ER assay and a progesterone receptor (PR) assay of the tumor should be obtained at the time of diagnosis of breast cancer and when biopsies of metastases are performed.

More than 60 percent of stage IIB patients with one to three involved axillary lymph nodes will relapse within 10 years after radical mastectomy if they are not given adjuvant therapy. Those with more than three involved axillary lymph nodes have relapse rates greater than 85 percent by the 10th year. A relapse rate as high as 25 percent is observed even among patients with no axillary lymph node involvement. About nine percent of patients will have internal mammary node involvement without the involvement of axillary lymph nodes; such patients have a 50 percent risk of relapse. Primary tumor location within the breast does not appear to determine the sites of nodal spread.

The average time to relapse is three to four years in patients with one to three involved axillary nodes and one to two years in patients with more than three involved axillary nodes. Patients with tumors of 2 to 5 cm have a risk of at least 30 percent of relapse even with no node involvement, whereas those with tumors 5 cm or greater have a relapse rate that exceeds 70 percent by the 10th year. A breast cancer patient is not free of the risk of relapse for about 20 years after mastectomy. As important as axillary involvement and primary tumor size are in determining prognosis, there are patients who have extended survival (cure) in spite of ominous findings at diagnosis. However, with few exceptions, patients who experience relapse die of breast cancer.

Other features of the tumor are useful for determining the risk of relapse, especially for patients without lymph node involvement. Prognosis is worse for patients whose tumors are poorly differentiated or have a poor nuclear grade than for those whose tumors are well differentiated or have a good nuclear grade. Other factors indicating a greater risk of relapse include vascular or lymphatic invasion in the breast biopsy specimen, cancer cells that contain more than the diploid number of chromosomes (a high DNA index), a large percentage of cancer cells in the S phase of the cell cycle (i.e., undergoing DNA synthesis), and tumors containing additional copies of the HER-2/neu oncogene or other oncogenes . The accumulation of p53 or c-erbB-2 protein in breast cancer sections, which can be detected by immunostaining, may be an indicator of shortened survival. A higher number and greater density of microvessels, called angiogenesis, and expression of cathepsin D at elevated levels within an invasive breast cancer specimen correlate with an increased risk of development of distant metastases. On the other hand, expression of high levels of the nm23 protein or the detection of mucinlike molecules in tumor tissue signals breast cancers that are less likely to metastasize.

The ER and PR assays are also important tools in the assessment, prognosis, and treatment of breast cancer. ER and PR are many times more concentrated in breast cancer tissue than in normal mammary tissue. Many breast cancers and all normal estrogen-responsive tissues contain labile cytoplasmic proteins that bind estrogen and progesterone. These proteins combine with estrogen and progesterone and shuttle between the cytoplasm and the nucleus to activate the target cell genome to perform hormone-dependent functions. About 60 percent of tumors are ER+, and 40 percent are either borderline positive or ER-. The assay is considered positive when 10 femtomoles (fmol) or more of estrogen or progesterone are bound per milligram of protein extracted from the tumor tissue. Estrogen-binding or progesterone-binding values below 3 fmol/mg of protein are considered negative, and values of 3 to 9 fmol/mg of protein are borderline positive. Estrogen receptors can also be detected by immunostaining tissue sections with monoclonal antibodies. The data are frequently reported in grades (1+ to 3+) or percentage of positive cells. Different receptors bind each steroid hormone; many breast cancers contain proteins for binding glucocorticoids and androgens as well.

The ER and PR assays have therapeutic as well as prognostic importance. Patients with positive assays have an objective response rate to hormone treatment of about 50 to 60 percent; patients with negative assays have an objective response rate of less than 10 percent. The higher the content of estrogen-binding receptor protein, the higher the likelihood of response to hormone treatment. The presence of a positive PR assay in addition to a positive ER assay may increase the likelihood of response. The concordance of progesterone and estrogen receptors is relatively high (70 percent). Patients with positive assays have a longer relapse-free survival after mastectomy and live longer from both the time of diagnosis and the time of relapse than those with n egative assays. More than 50 percent of premenopausal patients with high-grade breast cancers and a negative ER assay will have a relapse of breast cancer even with no axillary lymph node involvement. The ER assay is most likely to be positive in patient s with metastatic breast cancer who by clinical assessment have a good prognosis. These patients include the elderly, those with well-differentiated tumors, those with invasive lobular carcinomas, those with favorable sites of relapse (e.g., bone or skin), and those with a long relapse-free interval (two years or more). Nearly all breast cancers in males have ER+ assays. As with all clinical laboratory data, the hormone receptor assay should be only one factor in determining whether to use hormone therapy. The assay is subject to a significant number of false negative reports, and ER+ metastases can emerge, even though the primary tumor is ER-. Therefore, the clinical setting and the hormone receptor assay form the basis for determining when hormone therapies are indicated.

Serum markers, such as carcinoembryonic antigen and C15-23, have been used to detect the early relapse of breast cancer during and after adjuvant chemotherapy or hormone therapy. Such analyses should be discouraged as they rarely aid in the treatment of breast cancer in relapse, because the goal of such treatment is palliation rather than cure and early detection of relapse does not offer a therapeutic advantage [see Management of Breast Cancer at Relapse, below].

The two components of primary breast cancer management are local-regional treatment and systemic treatment. Both components of management in stage I, stage II, and stage III patients have undergone changes.

The objectives of the local-regional treatment of stage I and stage II patients are (1) to eliminate the primary cancer and thus prevent local-regional recurrence, with the expectation of increasing the chances of prolonged survival or cure, and (2) to reduce tumor mass and thus increase the effectiveness of systemic therapy.

There is no single local-regional protocol that can be used to treat all breast cancer patients. Controlled clinical trials demonstrate that the selection of an appropriate local-regional treatment should be based on a careful assessment of the size, location, and histologic features of the tumor; the feasibility of complete excision of the tumor; the extension of the tumor to the chest wall or skin; and the involvement of axillary lymph nodes. Although mastectomy remains the most commonly used local treatment for primary breast cancer, breast preservation should be offered to most stage I and stage II patients.

Complete excision of the primary tumor (sometimes called a lumpectomy) and axillary dissection followed by irradiation of the entire breast, with or without a boost to the tumor bed, are now the standard treatment for T1 and T2 patients. Irradiation of the breast is not a new concept, and this approach has produced results comparable to those achieved with total mastectomy, particularly in patients with T1 and small T2 lesions. Controlled trials have shown that in patients with clinically involved nodes and tumors that are 4 cm or smaller, local-regional control and disease-free survival are comparable with excision plus irradiation and with mastectomy. The best results of primary radiation therapy are achieved when the tumor is small and completely excised (with tumor-free margins) and when a high dose of radiation is administered to the entire breast, perhaps with a boost to the tumor bed. The axilla is not irradiated in patients who have had an axillary dissection. Poor candidates for excision or a lumpectomy followed by primary radiation therapy are patients with tumors larger than 4 cm, patients whose breasts contain multiple sites of cancer, and patients with widespread microcalcifications, subareolar cancer, histologically positive margins on the tumor specimen, bloody nipple discharge, or collagen vascular diseases. Patients younger than 35 years may also be poor candidates for this procedure because of the risk posed by radiation scatter to the contralateral breast. Studies suggest that several cycles of chemotherapy before local treatment (neoadjuvant chemotherapy) can reduce tumor size, so that patients with tumors larger than 3 cm in diameter can become candidates for excision plus primary radiation therapy rather than mastectomy. Because cosmesis is the principal reason to employ excision followed by radiation therapy, it is important that the biopsy incision be placed on the breast to optimize cosmesis and that the axillary dissection be done through an incision separate from the biopsy incision. Although approaches that avoid mastectomy are to be encouraged, the use of excision alone (i.e., not followed by irradiation) to treat T1 and T2 tumors should be discouraged because it carries a high risk of local-regional relapse. When relapse occurs in the breast that was treated with excision and radiation therapy, total mastectomy is nearly always indicated. Prognosis is not altered by such a relapse, because controlled trials suggest that a relapse at the site of the original cancer serves as a marker of the risk of distant spread rather than as a source of distant spread.

Currently, virtually all mastectomies are of the modified type, in which the breast tissue, the overlying skin, the nipple-areolar complex, and the low and midaxillary lymph nodes are removed. Continued clinical research that focuses on minimizing the need for removal of the breast or the axillary lymph nodes is needed. According to the National Institutes of Health Consensus Development Panel, the recommended standard therapy for stage I and stage II patients is breast preservation with wide excision, axillary dissection, and radiation therapy rather than mastectomy. Total mastectomy with axillary dissection (modified radical mastectomy) and preservation of the pectoral muscles should be reserved for patients who are poor candidates for primary radiation therapy. The Halsted, or standard, radical mastectomy is not recommended at any stage of breast cancer.

Mastectomy has been compared with breast-conserving procedures in controlled clinical trials. In studies comparing excision alone with excision plus irradiation or total mastectomy, there was no difference in survival among these three groups of patients at 12 years of follow-up, although there was an unacceptable rate of local relapse in the group that received excision alone. all patients, whether they undergo a mastectomy or a procedure that preserves the breast, the level I and level II axillary lymph nodes (i.e., the nodes lateral and inferior, respectively, to the pectoralis minor muscle) should be removed to determine the prognosis and the need for adjuvant therapy. This procedure is especially important in determining prognosis for those patients younger than 50 years. Some investigators have reported that in premenopausal women, undergoing mastectomy or biopsy for breast cancer during menstruation can reduce the risk of relapse, but other investigators have disputed this claim. This unsettled question requires a prospective trial that includes an accurate determination of the phase of the menstrual cycle and a random timing of biopsy or surgery.

Although radiation therapy is now commonly used in the breast-preserving procedure of excision and irradiation, it is less commonly used after mastectomy (postoperative radiation therapy). Postoperative radiation therapy of the regional lymph node areas and chest wall after mastectomy is not recommended as a routine measure for stage I and stage II patients, because there is little evidence in controlled trials that it increases survival or decreases the percentage of patients in whom distant metastases develop, although this conclusion has recently been questioned. Radiation therapy of the chest wall and supraclavicular region after mastectomy does reduce local-regional recurrence, but only a small percentage of T1 and T2 patients are at risk for such local recurrence. However, postoperative radiation therapy should be considered for patients who have extensive lymph node involvement (i.e., more than four to seven positive nodes), tumors larger than 5 cm, or extension of the primary tumor to the chest wall, nipple, or breast skin. In such cases the radiation should be delivered to the chest wall, internal mammary nodes, and supraclavicular nodes because these patients are at high risk for relapse in these sites. The merits of postoperative radiation therapy have been reviewed.

Methods for the initial treatment of locally advanced primary breast cancer (stage IIIB) have also changed. When the primary tumor is very large or fixed to the chest wall or when there is extensive lymphatic or skin involvement (i.e., T3N2, T4, or inflammatory breast cancer), there is a very high risk that uncontrolled local-regional disease and distant metastases will result. In such cases, these complications are unlikely to be prevented by radiation therapy or surgery alone. Combined-modality approaches are indicated. Those studies that demonstrated the highest likelihood of local-regional disease control and a lengthening of long-term disease-free survival in this group of patients used programs that combined intensive chemotherapy (neoadjuvant chemotherapy) with radiation therapy or surgery. For such patients, a diagnosis should be obtained by the least invasive method (FNA or core-needle biopsy), and a number of cycles of neoadjuvant chemotherapy should be used before local therapy is initiated to enhance the technical feasibility of local-regional radiation or mastectomy.

For most patients, the difficulty with invasive breast cancer is not local-regional control: in at least one third of all patients who receive appropriate local treatment, relapse occurs at distant sites, whereas a local-regional relapse occurs in fewer than 10 percent. Therefore, survival in breast cancer patients is determined by relapse at distant rather than local sites. Wide excision followed by irradiation or modified radical mastectomy produces comparable rates of local-regional disease control in stage I and stage II patients. However, because breast cancer cells may have metastasized before the start of local treatment, many of these patients will not be cured. If relapse occurs, it will most likely be at a distant site. If the relapse occurs locally after mastectomy, a distant site of metastasis will soon appear. Thus, the entire population of cancer cells must be treated by multidisciplinary approaches.

Noninvasive breast cancer, which includes ductal carcinoma in situ (DCIS, also termed intraductal carcinoma) and lobular carcinoma in situ (LCIS, also termed lobular neoplasia), is now detected more readily because of improvements in mammography techniques and constitutes about 30 percent of breast cancer diagnosed by mammography. The natural history and management of DCIS and of LCIS are different.

Because the cure rate of breast cancer approaches 100 percent with total mastectomy, it has been the standard treatment of DCIS, but there is concern that mastectomy may be excessive for some patients with these lesions. Treatment approaches to DCIS must take into consideration the possibility that DCIS in the involved breast may be multifocal or multicentric or that undetected invasion may be present. As in patients with invasive breast cancer, consideration should first be given to breast preservation in patients with DCIS. Excision and radiation therapy to preserve the breast should be considered in patients with DCIS when there is a single defined area of involvement, the lesion has been excised with tumor-free margins, there is no mammographic or pathological evidence of DCIS in other areas of the breast, and the patient is willing to undergo the required follow-up examinations during her lifetime. If any of these conditions is not met, total mastectomy is indicated. In controlled trials, patients with DCIS were randomized to excision alone or excision plus radiation therapy. The relapse rate was seven percent for those who received excision plus radiation therapy and 18 percent for those who received excision alone. It appears that the prognosis of patients with DCIS is influenced by whether the DCIS is low, intermediate, or high grade as well as by size of the involved area, but the subtype of DCIS should not preclude breast preservation. Axillary node dissection should be considered only for those patients who have extensive DCIS of high grade or those with tumors that are found to have an invasive component during biopsy or mastectomy.

The treatment of LCIS differs from that of DCIS. LCIS is more often multifocal in the involved breast and more frequently involves the contralateral breast than does intraductal carcinoma. Wide excision alone rather than mastectomy should be considered for patients with LCIS because mortality from invasive breast cancer after wide excision alone is relatively low (< 11 percent) after long-term follow-up. Although LCIS can be bilateral, there is no convincing evidence that routine bilateral mastectomy is indicated in such cases, and contralateral, prophylactic, subcutaneous mastectomy should not be encouraged. Unlike the situation with invasive breast cancers, there is no role for adjuvant therapy in the management of DCIS or LCIS.

Local-regional management should include consideration of cosmesis for all patients with breast cancer. Patients undergoing total mastectomy or modified radical mastectomy can, during the procedure or subsequently, have reconstructive surgery that establishes near-normal chest wall contours. Discussion of the feasibility and timing of reconstruction should be part of any primary treatment program in which the breast will be removed. Because the issue is systemic spread rather than local recurrence, patients who had a mastectomy should not be discouraged from undergoing reconstruction. Impaired detection by mammography should not be used as an argument against reconstruction. Today, because of the health controversy regarding breast implants, TRAM (transverse rectus abdominis muscle) flap reconstructions are more commonly used. However, the use of implants remains the simplest form of reconstruction. There is no evidence that implants produce breast cancer.

Systemic treatment of invasive primary breast cancer consists of adjuvant chemotherapy or hormone therapy beginning at the time of local-regional therapy. The objective of adjuvant chemotherapy or hormone therapy is to enhance the chances for long-term survival without local, regional, and distant metastases after local treatment. The use of adjuvant therapy is based on the concept that the probability of residual local, regional, and distant microscopic metastases can be estimated in properly staged patients and that systemic therapy for prolonged periods can eradicate these small deposits of cells, thus reducing the risk of relapse. It is clear that adjuvant therapy has altered the outcome for women with breast cancer.

There are two forms of adjuvant systemic treatment for patients with axillary nodes involved with metastatic breast cancer: adjuvant chemotherapy and adjuvant hormone therapy.

Adjuvant chemotherapy Patients with one or more positive axillary lymph nodes have a risk of relapse of breast cancer that exceeds 50 percent; therefore, with few exceptions, these patients should be considered for adjuvant chemotherapy or hormone therapy. Many studies of adjuvant therapy have been conducted, and many are still under way. Studies with long-term follow-up include those employing melphalan (l-phenylalanine mustard, or l-PAM), chemotherapy, or CMF (a combination of cyclophosphamide, methotrexate, and fluorouracil [5-FU]). These studies have demonstrated that women who receive adjuvant chemotherapy have significantly better overall survival than control subjects and that drug combinations are superior to single drugs. Both regimens have been shown to be effective in reducing relapse. The trials of melphalan or CMF after modified radical mastectomy demonstrated that the use of adjuvant chemotherapy significantly prolonged relapse-free survival or both relapse-free survival and total survival in premenopausal patients who at the time of mastectomy had one to three positive axillary lymph nodes . In neither study was there improvement in survival in the postmenopausal group. Both postmenopausal and premenopausal women derive the greatest benefit from CMF therapy when relatively full dosages of the drugs are given.

In more recent trials, the duration of chemotherapy was shortened, and four to six cycles, usually given over three to six months, maximally lengthened relapse-free survival. These trials demonstrate that both premenopausal and postmenopausal patients benefit from adjuvant chemotherapy. The melphalan trials are now principally of scientific and historical interest because melphalan is no longer used as adjuvant therapy for patients with primary breast cancer.

The CMF regimen and the combination of cyclophospamide and doxorubicin (Adriamycin) (CA) or cyclophosphamide, doxorubicin, and 5-FU (CAF) are the most commonly used regimens for premenopausal breast cancer patients with positive axillary lymph nodes. They are equally efficacious in increasing relapse-free survival in premenopausal women with involved axillary lymph nodes. Some investigators consider doxorubicin-containing adjuvant chemotherapy to be the preferred treatment for premenopausal women, but there is little evidence that it is superior to CMF in promoting relapse-free survival. Concern over the potential for the cardiac toxicity seen with cumulative doses of doxorubicin higher than those used in the adjuvant setting has led to caution in its use. A recent study of patients with more than three positive nodes suggested that CAF followed by CMF is superior to alternating cycles of these two regimens. The trend today in the adjuvant treatment of women with involved axillary lymph nodes is to increase dose intensity (the amount of drug given per unit of time). Controlled trials at this time do not provide good evidence, except that in patients with c-erbB-2-positive tumors, standard to high doses produce differences in disease-free survival rates. However, trials testing this hypothesis are under way using new agents such as paclitaxel in combination with cyclophosphamide and doxorubicin.

A meta-analysis of trials in which 18,400 node-positive and node-negative premenopausal and postmenopausal women were randomized to multidrug adjuvant chemo therapy or no adjuvant therapy demonstrated a relative reduction of 21 percent in relapse and 11 percent in mortality in patients of any age who received chemotherapy. For women 50 years of age or younger, the relative reduction was 27 percent in relapse and 17 percent in mortality. For women older than 50 years, the relative reduction was 17 percent in relapse and nine percent in mortality. With follow-up approaching 20 years in some trials, the reductions in relapse of and mortality from breast cancer in women younger than 50 years appear durable. Individual trials clearly show that relapse and death are prevented in women younger than 50 years with involved axillary lymph nodes who are given multidrug chemotherapy. There is less agreement that chemotherapy is preferred over tamoxifen as the adjuvant therapy for women older than 50 years with involved axillary lymph nodes.

High-dose chemotherapy and peripheral blood stem cell infusion Peripheral blood stem cell infusions have completely replaced autologous bone marrow transplantation after intensive adjuvant chemotherapy in patients with 10 or more involved axillary lymph nodes. Usually, several cycles of standard-dose chemotherapy are given over three to four months. This is followed by a single dose or several large doses of chemotherapy, resulting in bone marrow aplasia. Stem cells harvested from the peripheral blood of the patient are then infused. There have been continued reductions in the mortality from this procedure, and the results of controlled trials of patients with primary breast cancer are being awaited. Such therapy should be used only in specialized centers until controlled trials show whether chemotherapy doses that require stem cell rescue produce outcomes superior to those of chemotherapy doses that do not require stem cell rescue.

Adjuvant hormone therapy Because hormone therapy has been a mainstay in the treatment of advanced breast cancer, it has been applied in the adjuvant setting. Tamoxifen used alone as an adjuvant to mastectomy for breast cancer, principally in stage II patients with axillary node involvement, shows benefit in extending relapse-free and total survival when compared with no adjuvant therapy. These benefits are most clearly demonstrated in women older than 50 years, but relapse-free survival is extended in younger women as well. In postmenopausal patients, the benefit from tamoxifen given for two years appears to be greater than that from multidrug adjuvant chemotherapy. In an overview using meta-analysis, a 20 percent relative reduction in relapse and an eight percent absolute reduction in mortality were reported for postmenopausal women treated with adjuvant tamoxifen. The optimal duration of adjuvant tamoxifen treatment is undergoing study, but tamoxifen is currently given at 20 mg/day for five years after the completion of primary treatment. Because the absolute benefit of tamoxifen in women older than 50 years with involved axillary lymph nodes is as great as that of adjuvant chemotherapy, many specialists advocate the use of the less demanding tamoxifen therapy, even though the duration of therapy with this agent is very long (five years), whereas it is only two to six months with chemotherapy. Tamoxifen therapy places women at increased risk for endometrial cancer.

Ovarian ablation as an adjuvant therapy has not been studied as extensively as chemotherapy or tamoxifen in women with node-positive tumors. Its role in adjuvant treatment needs to be better defined through controlled trials. Ovarian ablation is not commonly employed as an adjuvant treatment, because it is not superior to chemotherapy alone in premenopausal patients. However, a meta-analysis revealed that there is significant benefit associated with ovarian ablation in patients younger than 50 years but no benefit in patients older than 50 years. Node-positive patients appear to benefit more than node-negative patients, and differences in absolute benefit tend to appear only many years after treatment. By 15 years after treatment, there is a mean difference of about 10 percent in relapse and 13 percent in mortality when ovarian ablation is compared with no adjuvant treatment. A meta-analysis suggests that there is no more benefit from the combination of ovarian ablation and chemotherapy than there is from chemotherapy alone, although long-term follow-up may eventually show benefit of the combined treatment in premenopausal patients with ER+ tumors and four or more involved axillary nodes.

Chemotherapy has been combined with tamoxifen on various schedules. Some studies of postmenopausal women with ER+ or ER- tumors who have positive nodes have shown that the combination of chemotherapy and tamoxifen is superior to either treatment used alone, but other trials have failed to support this finding. In overview analyses, direct comparisons of chemotherapy, chemotherapy plus tamoxifen, and tamoxifen alone for treating postmenopausal women with positive axillary lymph nodes show that tamoxifen or chemotherapy plus tamoxifen may be superior to chemotherapy alone, although the absolute differences are not great. The addition of tamoxifen to chemotherapy in premenopausal women does not appear to be superior to chemotherapy alone, and in fact, it may be detrimental. The administration of tamoxifen for several years after completion of adjuvant chemotherapy, rather than concurrent use of chemotherapy and tamoxifen, may lengthen relapse-free survival for both premenopausal and postmenopausal women with positive nodes and ER+ tumors.

There has been increasing use of adjuvant chemotherapy or hormone therapy in women with primary breast cancer and no node involvement. This trend reflects the fact that about 20 to 25 percent of women with tumors larger than 1 cm in diameter will experience relapse even though no axillary lymph nodes are involved. In certain subsets of node-negative premenopausal patients, the risk of relapse may approach 50 percent. Because only about one third of node-negative patients have a high risk of relapse, advocating chemotherapy or hormone therapy for all patients without node involvement is more controversial than it is for patients with involved axillary lymph nodes. The issues to be resolved concerning the use of adjuvant therapy in node-negative patients are the importance of tumor size, tumor grade, tumor markers, and findings on flow cytometry (DNA index and S phase) for assessing the prognosis and benefit from adjuvant therapy.

Adjuvant chemotherapy Overview analysis and five controlled trials with relatively short-term follow-up have assessed the value of adjuvant treatment in node-negative patients. They principally demonstrate benefit in disease-free survival in this group of patients. In all of the studies, only women with invasive cancers were analyzed; thus, none of the conclusions from these studies can be applied to patients with DCIS or LCIS who have negative axillary lymph nodes. Chemotherapy with CMF, CMF plus prednisone (CMFP), or methotrexate plus 5-FU (MF) for six to 12 cycles was associated with longer relapse-free survival in premenopausal and postmenopausal women with no node invo lvement. Premenopausal women with either ER- or ER+ tumors and postmenopausal women with ER- tumors benefited from multiple courses of chemotherapy. The magnitude of increase in either relapse-free or overall survival varies considerably from trial to trial. In most trials, the follow-up was too short to discern which form of chemotherapy was best. In node-negative premenopausal and postmenopausal patients, the benefit of a single cycle of chemotherapy given at the time of mastectomy (perioperative chemotherapy) was small: only a four to five percent reduction in risk of relapse. Therefore, longer courses of treatment should be given.

Adjuvant hormone therapy Adjuvant tamoxifen therapy is beneficial for both premenopausal and postmenopausal women with no axillary node involvement. Overviews of the studies of adjuvant tamoxifen therapy in node-negative patients reveal both a significant increase in relapse-free survival and a reduction in mortality compared with no adjuvant treatment. The magnitude of benefit, however, is small (a difference of five percent for relapse and 3.5 percent for mortality after 10 years of follow-up). Although most studies have been confined to those patients with ER+ tumors, some trials have included patients with ER- tumors and have shown that benefit occurs in patients with ER- and ER+ tumors. Too few patients in controlled trials are available to be certain of the value of adjuvant ovarian ablation, alone or in addition to chemotherapy or tamoxifen, in node-negative patients.

Not all women with invasive, node-negative breast cancer should receive adjuvant therapy, because in controlled trials the magnitude of benefit was small, follow-up was short, women with very small primary tumors and negative nodes were not included, and the vast majority of women who did not receive adjuvant therapy in these studies (i.e., the control subjects) probably will never experience relapse. There is the need to identify among the control groups those characteristics most associated with the risk of relapse. Until those characteristics are known, the group of women with node-negative breast cancer who are at risk cannot be better identified, and the differences in outcome in such studies are likely to remain small.

Results from controlled trials support treatment of women with no axillary lymph node involvement with six months of combination chemotherapy if they have ER- invasive tumors. In node-negative patients with ER+ tumors, there is no scientific basis for selecting chemotherapy over tamoxifen; therefore, tamoxifen would be a tentative selection because it would be the least toxic treatment. However, the benefits in relapse-free survival with this treatment are small, and only the postmenopausal group has shown improved overall survival. It is common practice to use chemotherapy (CMF or CMFP) in a premenopausal patient with an invasive breast tumor larger than 1 cm in diameter and negative axillary lymph nodes, especially if the estrogen receptor is negative, the tumor is of high grade, or both. In postmenopausal patients with such cancers, either chemotherapy or tamoxifen is used. Before one can confidently use adjuvant chemotherapy or tamoxifen to treat patients without axillary node involvement, improved overall survival as a result of the treatment should be demonstrated. There is a need for clinical trials based on comparisons of node-negative women with poor prognostic factors

Conclusions about the Use of Adjuvant Therapy for Patients with Primary Breast Cancer

Making judgments about the use of adjuvant therapy for patients with primary breast cancer has not necessarily become easier with the reporting of new trials and longer follow-up of older trials, but there are some conclusions that appear to be warranted:

1. The entry of patients into controlled adjuvant therapy trials remains important even though adjuvant therapy already has an established role in the treatment of node-positive patients and of many node-negative patients. Such trials will make it possible to distinguish between those patients who can benefit from adjuvant therapy and those who cannot.

2. Results of adjuvant chemotherapy and hormone therapy should be evaluated in terms of the subsets of patients treated.

3. There should not be an extensive delay between the completion of local-regional treatment and the initiation of adjuvant treatment; ideally, adjuvant therapy should be initiated within 14 days, but patients can benefit from it even if the delay is a matter of months. Once adjuvant treatment is initiated, it should be given for multiple cycles.

4. Adjuvant chemotherapy is indicated for premenopausal women with positive axillary lymph nodes who cannot participate in controlled trials. It should be given according to schedules from published trials.

5. Adjuvant tamoxifen alone or chemotherapy plus tamoxifen is indicated for postmenopausal patients with positive axillary lymph nodes and receptor-positive cancers who cannot participate in controlled trials.

6. Adjuvant chemotherapy is indicated for postmenopausal patients with positive axillary lymph nodes and receptor-negative cancers. The difficulty in translating overview analysis into a treatment recommendation is that chemotherapy plus tamoxifen or tamoxifen alone may produce comparable or greater benefit in this group. At this time, the best treatment of postmenopausal women who are axillary node-positive, receptor-negative is not established.

7. Adjuvant chemotherapy is indicated for premenopausal and postmenopausal patients with negative axillary lymph nodes and ER- tumors greater than 1 cm, but it is not clear what impact such therapy will have on mortality.

8. Adjuvant tamoxifen in node-negative premenopausal and postmenopausal patients, especially those with ER+ tumors, produces both an increase in relapse-free survival and a reduction in mortality.

9. Ovarian ablation alone has been shown to increase relapse-free survival and decrease mortality only in node-positive patients younger than 50 years. Ovarian ablation as the sole adjuvant therapy has not displaced chemotherapy as the standard adjuvant therapy for premenopausal patients.

10. Adjuvant chemotherapy alters ovarian function in premenopausal women; in most of these women, permanent loss of ovarian function and sterility develops after treatment.

11. There is no evidence that combination adjuvant chemotherapy containing cyclophosphamide increases the incidence of second primary breast cancers. There is evidence of an increase in the risk of leukemia in women receiving adjuvant chemotherapy with l-PAM.

12. Most patients who have axillary node involvement will experience a relapse of breast cancer whether or not they receive adjuvant chemotherapy, whereas most patients who have no axillary node involvement will not experience relapse.

After a patient has completed local and adjuvant treatment, there is a need for follow-up care to detect relapse and new breast cancers. Follow-up care should consist of obtaining the patient's history; physical examination at three- to four-month intervals for two years and every six months thereafter; annual mammography; and a general serum analysis at regular intervals. Controlled trials have shown that this approach leads to the same absolute survival and duration of survival as follow-up with a battery of imaging studies. Imaging studies are indicated if symptoms develop.

There is a curative intent to therapy when primary breast cancer is confined to the breast and axilla, but the appearance of metastases changes the intent from curative to palliative. Thus, it is very important that the first metastases be confirmed by biopsy and that management be viewed as a chronic rather than an acute undertaking. The toxicity of treatment becomes of paramount importance when the objective of care is to minimize symptoms and optimize patient function. Balance is needed between treatment-related toxicity and response rate if satisfactory palliation is to be achieved. Radiation therapy, hormone manipulation, chemotherapy, and, to a very minor degree, surgery are the local and systemic methods of palliation. In designing a treatment program for patients with metastatic breast cancer, several factors must be considered:

1. Extent of the recurrence. Is it limited to a single site, or are there multiple sites?

2. Organ site of involvement. Are physiologically important organs (i.e., liver, brain, and lung parenchyma) the principal sites of metastases?

5. Duration of time from original diagnosis to relapse (i.e., the free interval).

6. Presence of physiologically significant or life-threatening consequences resulting from relapse.

7. Performance status of the patient. Is the patient asymptomatic, symptomatic, ambulatory, bedridden, or hospitalized?

Localized relapse should be treated with local methods whenever possible, whether metastases appear alone or in conjunction with distant metastases. For example, metastases confined to a single region (e.g., bone, chest wall, skin, or lymph node group) are best treated initially with radiation therapy or with excision and radiation therapy. Brain and retinal metastases are common in breast cancer and are best managed by radiation therapy. Treatment of simultaneous local and distant relapse is more complex, but the principle remains the same; radiation therapy can provide prolonged periods of local-regional control. Systemic and local therapy can be combined for such patients, and evidence suggests that patients treated with both do best. Systemic treatment alone is the usual therapy when multiple sites are involved or when liver or lung parenchymal metastases impair organ function.

The two forms of systemic therapy for breast cancer in relapse are hormone therapy (additive and ablative) and chemotherapy.

All patients with metastatic breast cancer or breast cancer in relapse should first be considered for hormone therapy because it is the least toxic systemic treatment. The likelihood of objective response is enhanced if the patient (1) is postmenopausal, especially if she is older than 60 years, (2) had a primary tumor or has an ER+ or PR+ metastatic tumor, (3) has had a long relapse-free interval (one or more years), and (4) principally has involvement of bone, skin, lymph nodes, breast, or pleura (pleural effusion). The likelihood of objective response to hormone manipulation is very low in patients who are younger than 40 years; in those who have experienced relapse shortly after primary treatment; and in those who have ER- tumors, impaired liver function caused by metastases to the liver, metastases to the lung parenchyma (especially lymphangitic spread), or central nervous system involvement alone.

Several methods of additive hormone treatment can be used for patients in relapse. Tamoxifen is the treatment of choice for the first recurrence in premenopausal and postmenopausal women. Tamoxifen is thought to act by depleting estrogen receptors in breast cancer cells, but it may have another mechanism of cytotoxicity. In postmenopausal women, an objective response as high as 50 to 60 percent that lasts from nine to 16 months can be expected in those patients with the favorable characteristics mentioned. Fewer than 10 percent of patients with unfavorable characteristics will respond.

Tamoxifen is associated with little toxicity. Patients given tamoxifen may promptly and transiently experience bone pain and, occasionally, hypercalcemia; such symptoms indicate that metastases will objectively improve. The most common side effect of tam oxifen is exacerbation of hot flashes; retinopathy is an extremely rare side effect. An increase in endometrial cancer has also been observed in breast cancer patients who are given tamoxifen. Endometrial cancer develops in approximately 1.6 per 1,000 women who are treated with tamoxifen, compared with 0.2 per 1,000 women who are not treated with tamoxifen. In patients who experience vaginal bleeding while taking tamoxifen, measurement of endometrial thickness by ultrasonography and endometrial biopsy are indicated. It would be imprudent not to recommend tamoxifen as an adjuvant therapy for mastectomy or lumpectomy and irradiation for primary breast cancer when indicated, because the benefits of tamoxifen are substantially greater than the risk of endometrial cancer. It is not clear whether the dosage of tamoxifen should be 20 or 40 mg/day in premenopausal women. There has been concern that tamoxifen may accelerate osteoporosis. However, studies have shown that tamoxifen, if anything, retards the normal loss of bone density. Tamoxifen has also been shown to lower LDL cholesterol levels, and it may reduce the incidence of second primary breast cancers.

Use of tamoxifen instead of oophorectomy as the initial therapy for premenopausal women who have had a relapse has become the standard practice. A randomized trial that compared oophorectomy with tamoxifen in premenopausal women whose tumors were ER+ or of unknown ER status showed no significant difference in response rate, duration of disease control, or survival. Failure to respond to tamoxifen does not preclude a response to subsequent oophorectomy, but the chance of a response to oophorectomy is low. However, it is not known whether oophorectomy is more effective than tamoxifen for the initial treatment of premenopausal women with ER+ metastases and visceral involvement with impaired organ function.

Several hormonal approaches, including progestational agents, aromatase inhibitors, or diethylstilbestrol, can be considered for postmenopausal patients who initially respond to tamoxifen but subsequently relapse. There are also a number of new agents that produce estrogen-receptor blockade that will be used to compete clinically with tamoxifen, but it is not yet clear whether these agents will be superior to tamoxifen. Progestational agents are nontoxic and are most effective in postmenopausal patients who are older than 60 years. Diethylstilbestrol is also effective in the initial treatment of postmenopausal women who experience a recurrence of breast cancer. However, this therapy is associated with serious complications (e.g., thromboembolic disease and congestive heart failure) and with less serious side effects (e.g., urinary incontinence, nausea, fluid retention, and vaginal bleeding). There is generally no advantage in duration of response or survival when hormones are used in combination rather than sequentially.

Aminoglutethimide is an agent that blocks the synthesis of cholesterol in the adrenal glands and thus inhibits the synthesis of steroid hormones, including estrogen. It is likely to be replaced by aromatase inhibitors, which, like aminoglutethimide, block the conversion of androgen precursors to estrogen in adipose tissues and other tissues throughout the body. Controlled trials show that the objective response and duration of response to aminoglutethimide plus hydrocortisone and to surgical adrenalectomy plus hydrocortisone are the same. Trials comparing new aromatase inhibitors with aminoglutethimide show that the new agents produce comparable responses and that one agent, anastrozole, is comparable to megestrol in treating metastatic breast cancer in postmenopausal women. The newer aromatase inhibitors are associated with fewer side effects and are to be used only in women with no ovarian function.

Gonadotropin-releasing hormone analogues show promise in the treatment of premenopausal females and males with recurrent breast cancer. These agents produce a so-called medical oophorectomy in women because, it is thought, they suppress ovarian steroid hormone production by reducing follicle-stimulating hormone (FSH) stimulation of the ovary. Leuprolide, one such agent, may also directly inhibit breast cancer growth in addition to suppressing FSH release.

All patients, both premenopausal and postmenopausal, who relapse after an initial response to any hormone therapy become candidates for further additive or ablative forms of hormone treatment. Premenopausal women who initially improve with tamoxifen but subsequently experience relapse become candidates for oophorectomy. Aminoglutethimide plus hydrocortisone, or other aromatase inhibitors, is becoming a preferred therapy for premenopausal women after oophorectomy. Androgens are now rarely used because they are associated with a low objective response rate; furthermore, virilization nearly always accompanies their use at the doses required for response.

At present, surgical ablative procedures in the hormone management of metastatic breast cancer have been supplanted by additive hormone strategies because of the emergence of tamoxifen and gonadotropin-releasing hormone analogues and the growing evidence that progestational agents and aromatase inhibitors are effective as second- and third-line hormone therapies. However, oophorectomy should still be considered as a treatment for breast cancer relapse in premenopausal women who have had a prior favorable response to tamoxifen.

Chemotherapy is indicated for patients with metastatic breast cancer who have short disease-free intervals and ER- tumors, who have disease progression despite hormone treatment, or who have metastases that have resulted in life-threatening complications, such as compromise of hepatic or respiratory function. Many chemotherapeutic agents can produce objective responses in such patients. These chemotherapeutic drugs include alkylating agents (cyclophosphamide and thiotepa), antimetabolites (5-FU and methotrexate), alkaloids (vincristine, vinblastine, paclitaxel, and vinorelbine), antibiotics (doxorubicin, mitomycin, and mitoxantrone), and other agents (e.g., cisplatin). In contrast to hormone therapy, there are few indicators that can be used to determine which patients who develop metastases will respond to chemotherapy on initial administration. Patients with ER+ tumors and patients with ER- tumors have the same objective response rate to chemotherapy. As with hormone manipulations, the most responsive site of involvement with chemotherapy is soft tissue. However, life-threatening complications such as hepatic dysfunction and respiratory compromise associated with liver or lung metastases are generally more responsive to chemotherapy than to hormone therapy.

In general, combination drug programs, rather than single-agent chemotherapy, are the initial treatments of choice when chemotherapy is indicated for patients with metastatic breast cancer. When compared with results of single-agent chemotherapy, the objective response and duration of response to combination chemotherapy are usually superior. There is also some evidence that chemotherapy combinations containing doxorubicin have a higher objective response rate than combinations lacking doxorubicin. It is controversial whether this increased response rate is more durable than that achieved by regimens that lack doxorubicin and whether it leads to an increased duration of survival. There are innumerable combinations and schedules of chemotherapeutic agents used in the treatment of metastatic breast cancer. Most combination chemotherapies have response rates of 50 to 80 percent for durations of seven to 13 months. CMF or CAF, in which doxorubicin replaces methotrexate, is usually recommended as the initial form of chemotherapy. The toxicity of chemotherapy can cause leukopenia, thrombocytopenia, nausea, diarrhea, alopecia, changes in skin pigmentation, and sterility; doxorubicin can cause cardiotoxicity. Vomiting is rare with these combinations because of the use of newer antinausea medications.

Chemotherapy has a role in the treatment programs for nearly all patients with metastatic breast cancer. Partial responses are the rule; usually, fewer than 20 percent of patients have complete responses. However, the objective response rate is high (50 to 80 percent), and CMF or CAF produces meaningful palliation in patients with severe pain, respiratory distress, discomfort and weight loss from hepatic failure, and other debilitating complications of progressive metastatic breast cancer. Patients should be aware of the potential for the development of cardiomyopathy from doxorubicin. This uncommon complication usually develops in patients in whom the total cumulative dose of doxorubicin exceeds 400 mg/m², especially in those with prior myocardial infarction or irradiation of the heart. Studies suggest that dexrazoxane can protect against concentration-dependent doxorubicin-induced car diotoxicity. Because the cardiac effects of doxorubicin are poorly monitored by electrocardiography, it is better to monitor cardiac function with ventricular angiography or cardiac biopsy. Mitoxantrone, which is an anthracyclic antibiotic similar to doxorubicin, has activity nearly as favorable as doxorubicin and is associated with less nausea and hair loss; however, it also is associated with cardiac toxicity.

Until recently, there was no clear-cut evidence that intensive, or high-dose (so-called bone marrow transplant), chemotherapy regimens improved the survival of patients who had experienced relapse with metastatic breast cancer. A controlled trial, in which patients were given combination chemotherapy at doses that required peripheral blood stem cell rescue, versus chemotherapy at doses that did not, showed increases in objective response rate, disease-free survival, and total survival. Although provocative, this trial needs confirmation by additional controlled trials because the chemotherapy used in the lower-dose arm of the study is not a standard therapy.

Chemotherapy combined with additive or ablative hormone therapy increases the response rate but does not contribute to increased survival in patients with metastatic disease. For example, CAF plus oophorectomy is superior to CAF alone in premenopausal women who relapse with ER-responsive tumors. Evidence suggests that continuous chemotherapy is better than intermittent chemotherapy for enhancing both response and quality of life in patients who have breast cancer and relapse.

There is no rigid standard for the sequence of chemotherapy regimens that are used when either CMF or CAF treatment fails. For example, patients who progress on CMF and who have not previously been treated with anthracyclines can be treated with doxorubicin or paclitaxel alone or with mitoxantrone plus 5-FU and leucovorin. Because both doxorubicin and paclitaxel are so effective, most patients with metastatic disease should have a trial of doxorubicin and paclitaxel. Paclitaxel has been found to be the most useful new agent in the treatment of patients with metastatic breast cancer. It acts by binding to tubulin, the building block of cytoplasmic microtubules involved in cell shape, transport of nutrients and organelles, and mitosis. It is subjectively less toxic than the anthracyclines but produces alopecia and peripheral neuropathy. Other drugs used in treating such patients include mitomycin, vinblastine, vinorelbine, cisplatin, infusions of 5-FU or vinblastine, and combinations of 5-FU infusion and the other agents listed. Vinorelbine is another new drug that, when used as a single agent, has activity in breast cancer patients for whom standard therapies have failed. Unfortunately, in all patients with metastatic disease, prior treatment with any chemotherapy reduces the likelihood of objective response to all subsequent chemotherapy.

The use of interferons does not show promise in patients previously treated with chemotherapy. As with primary breast cancer, there are no controlled trials demonstrating that immunotherapy is beneficial for patients with metastatic breast cancer. However, there are trials in which monoclonal antibodies directed to the HER-2/neu antigen located on the surface of breast cancer cells produced objective responses in patients with metastatic breast cancer previously treated with chemotherapy in whom this antigen was overexpressed. Localized hyperthermia in combination with radiotherapy or chemotherapy shows promise in controlling local recurrences but is not useful as systemic therapy.

Although the treatment of metastatic breast cancer can be schematized there is no single sequence for all patients. In general, survival after relapse can be long (the average is one to three years, with many patients living four years or longer) regardless of the treatment used. However, because the disease can be fulminant as well as indolent, the choice of treatment should be indicated by the progression of the disease. Attention to the course of the illness, to the objectives of correcting complications and enhancing function, and to the emotional needs and adjustment problems characteristic of women with breast cancer can improve the quality of survival.