12 - Blood Vessels Lymphatics
Tierney, Lawrence M., McPhee, Stephen J., Papadakis, Maxine A.
Current Medical Diagnosis & Treatment, 45th Edition
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16
Breast
Armando E. Giuliano MD
See http://www.cmdtlinks.com
BENIGN BREAST DISORDERS
FIBROCYSTIC CONDITION
ESSENTIALS OF DIAGNOSIS
Painful, often multiple, usually bilateral masses in the breast.
Rapid fluctuation in the size of the masses is common.
Frequently, pain occurs or increases and size increases during premenstrual phase of cycle.
Most common age is 30–50. Rare in postmenopausal women not receiving hormonal replacement.
General Considerations
Fibrocystic condition is the most frequent lesion of the breast. Although commonly referred to as “fibrocystic disease,” it does not, in fact, represent a pathologic or anatomic disorder. It is common in women 30–50 years of age but rare in postmenopausal women who are not taking hormonal replacement medications. Estrogen hormone is considered a causative factor. There may be an increased risk in women who drink alcohol, especially women between 18 and 22 years of age. Fibrocystic condition encompasses a wide variety of histologic changes. These lesions are always associated with benign changes in the breast epithelium, some of which are found so commonly in normal breasts that they are probably variants of normal breast histology but have nonetheless been termed a “condition.”
The microscopic findings of fibrocystic condition include cysts (gross and microscopic), papillomatosis, adenosis, fibrosis, and ductal epithelial hyperplasia. Although fibrocystic condition has generally been considered to increase the risk of subsequent breast cancer, only the variants in which proliferation (especially with atypia) of epithelial components is demonstrated represent true risk factors.
Clinical Findings
A. SYMPTOMS AND SIGNS
Fibrocystic condition may produce an asymptomatic lump in the breast that is discovered by accident, but pain or tenderness often calls attention to the mass. There may be discharge from the nipple. In many cases, discomfort occurs or is increased during the premenstrual phase of the cycle, at which time the cysts tend to enlarge. Fluctuation in size and rapid appearance or disappearance of a breast mass are common with this condition. Multiple or bilateral masses are common, and many patients will give a history of a transient lump in the breast or cyclic breast pain.
B. DIAGNOSTIC TESTS
Because a mass due to fibrocystic condition is frequently indistinguishable from carcinoma on the basis of clinical findings, suspicious lesions should be biopsied. Fine-needle aspiration cytology may be used, but if a suspicious mass that is nonmalignant on cytologic examination does not resolve over several months, it must be excised. Surgery should be conservative, since the primary objective is to exclude cancer. Occasionally, core needle biopsy will suffice. Simple mastectomy or extensive removal of breast tissue is rarely, if ever, indicated for fibrocystic condition.
Differential Diagnosis
Pain, fluctuation in size, and multiplicity of lesions are the features most helpful in differentiating fibrocystic condition from carcinoma. If a dominant mass is present, the diagnosis of cancer should be assumed until disproved by biopsy. Final diagnosis often depends on excisional biopsy. Mammography may be helpful, but the breast tissue in these young women is usually too radiodense to permit a worthwhile study. Sonography is useful in differentiating a cystic from a solid mass.
Treatment
When the diagnosis of fibrocystic condition has been established by previous biopsy or is likely because the history is classic, aspiration of a discrete mass suggestive of a cyst is indicated to alleviate pain and, more importantly, to confirm the cystic nature of the mass. The patient is reexamined at intervals thereafter. If no
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fluid is obtained or if fluid is bloody, if a mass persists after aspiration, or if at any time during follow-up a persistent lump is noted, biopsy is performed.
Breast pain associated with generalized fibrocystic condition is best treated by avoiding trauma and by wearing (night and day) a brassiere that gives good support and protection. A topical nonsteroidal anti-inflammatory gel may be of value. Hormone therapy is not advisable, because it does not cure the condition and has undesirable side effects. Danazol (100–200 mg twice daily orally), a synthetic androgen, has been used for patients with severe pain. This treatment suppresses pituitary gonadotropins, but androgenic effects (acne, edema, hirsutism) usually make this treatment intolerable; in practice, it is rarely used. Similarly, tamoxifen reduces some symptoms of fibrocystic condition, but because of its side effects it is not useful for young women unless it is given to reduce the risk of cancer. Postmenopausal women receiving hormone replacement therapy may stop hormones to reduce pain.
The role of caffeine consumption in the development and treatment of fibrocystic condition is controversial. Some studies suggest that eliminating caffeine from the diet is associated with improvement. Many patients are aware of these studies and report relief of symptoms after giving up coffee, tea, and chocolate. Similarly, many women find vitamin E (400 international units daily) helpful. However, these observations remain anecdotal.
Prognosis
Exacerbations of pain, tenderness, and cyst formation may occur at any time until the menopause, when symptoms usually subside, except in patients receiving hormonal replacement therapy. The patient should be advised to examine her own breasts each month just after menstruation and to inform her physician if a mass appears. The risk of breast cancer in women with fibrocystic condition showing proliferative or atypical changes in the epithelium is higher than that of women in general. These women should be followed carefully with physical examinations and mammography.
Byrne C et al: Alcohol consumption and incidence of benign breast disease. Cancer Epidemiol Biomarkers Prev 2002; 11:1369.
Lucas JH et al: Breast cyst aspiration. Am Fam Physician 2003; 68:1983.
Marchant DJ: Benign breast disease. Obstet Gynecol Clin North Am 2002;29:1.
Morrow M: The evaluation of common breast problems. Am Fam Physician 2000;61:2371.
Norlock FE: Benign breast pain in women: a practical approach to evaluation and treatment. J Am Med Womens Assoc 2002;57:85.
FIBROADENOMA OF THE BREAST
This common benign neoplasm occurs most frequently in young women, usually within 20 years after puberty. It is somewhat more frequent and tends to occur at an earlier age in black women. Multiple tumors are found in 10–15% of patients.
The typical fibroadenoma is a round or ovoid, rubbery, discrete, relatively movable, nontender mass 1–5 cm in diameter. It is usually discovered accidentally. Clinical diagnosis in young patients is generally not difficult. In women over 30 years, fibrocystic condition of the breast and carcinoma of the breast must be considered. Cysts can be identified by aspiration or ultrasonography. Fibroadenoma does not normally occur after the menopause, but may occasionally develop after administration of hormones.
No treatment is usually necessary if the diagnosis can be made by needle biopsy or cytologic examination. Excision or vacuum-assisted core needle removal with pathologic examination of the specimen is performed if the diagnosis is uncertain. Cryoablation is being attempted as an alternative to excision. It is usually not possible to distinguish a large fibroadenoma from a phyllodes tumor on the basis of needle biopsy results.
Phyllodes tumor is a fibroadenoma-like tumor with cellular stroma that grows rapidly. It may reach a large size and if inadequately excised will recur locally. The lesion can be benign or malignant. If benign, phyllodes tumor is treated by local excision with a margin of surrounding breast tissue. The treatment of malignant phyllodes tumor is more controversial, but complete removal of the tumor with a rim of normal tissue avoids recurrence. Because these tumors may be large, simple mastectomy is sometimes necessary. Lymph node dissection is not performed, since the sarcomatous portion of the tumor metastasizes to the lungs and not the lymph nodes.
Barbosa ML et al: Cytogenetic findings in phyllodes tumor and fibroadenomas of the breast. Cancer Genet Cytogenet 2004; 154:156.
El-Wakeel H et al: Systematic review of fibroadenoma as a risk factor for breast cancer. Breast 2003;12:302.
Fine RE et al: Percutaneous removal of benign breast masses using a vacuum-assisted hand-held device with ultrasound guidance. Am J Surg 2002;184:332.
Kaufman CS et al: Cryoablation treatment of benign breast lesions with 12-month follow-up. Am J Surg 2004;188:340.
NIPPLE DISCHARGE
In order of decreasing frequency, the following are the commonest causes of nipple discharge in the nonlactating breast: duct ectasia, intraductal papilloma, and carcinoma. The important characteristics of the discharge and some other factors to be evaluated by history and physical examination are as follows:
Nature of the discharge (serous, bloody, or other).
Association with a mass.
Unilateral or bilateral.
Single or multiple duct discharge.
Discharge is spontaneous (persistent or intermittent) or must be expressed.
Discharge is produced by pressure at a single site or by general pressure on the breast.
Relation to menses.
Premenopausal or postmenopausal.
Patient is taking contraceptive pills or estrogen.
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Unilateral, spontaneous serous or serosanguineous discharge from a single duct is usually caused by an intraductal papilloma or, rarely, by an intraductal cancer. A mass may not be palpable. The involved duct may be identified by pressure at different sites around the nipple at the margin of the areola. Bloody discharge is suggestive of cancer but is more often caused by a benign papilloma in the duct. Cytologic examination may identify malignant cells, but negative findings do not rule out cancer, which is more likely in women over age 50 years. In any case, the involved duct—and a mass if present—should be excised. Ductography is of limited value since excision of the bloody duct system is indicated regardless of findings. Ductoscopy is being evaluated as a means of identifying intraductal lesions but is not yet practical.
In premenopausal women, spontaneous multiple duct discharge, unilateral or bilateral, most marked just before menstruation, is often due to mammary dysplasia. Discharge may be green or brownish. Papillomatosis and ductal ectasia are usually seen on biopsy. If a mass is present, it should be removed.
A milky discharge from multiple ducts in the nonlactating breast occurs in certain endocrine syndromes, as a result of hyperprolactinemia. Serum prolactin levels should be obtained to search for a pituitary tumor. Thyroid-stimulating hormone (TSH) helps exclude causative hypothyroidism. Numerous antipsychotic drugs and other drugs may also cause a milky discharge that ceases on discontinuance of the medication.
Oral contraceptive agents or estrogen replacement therapy may cause clear, serous, or milky discharge from a single duct, but multiple duct discharge is more common. The discharge is more evident just before menstruation and disappears on stopping the medication. If it does not stop and is from a single duct, exploration should be considered.
A purulent discharge may originate in a subareolar abscess and require removal of the abscess and the related lactiferous sinus.
When localization is not possible, no mass is palpable, and the discharge is nonbloody, the patient should be reexamined every 2 or 3 months for a year, and mammography should be done. Although most discharge is from a benign process, patients may find it annoying or disconcerting. To eliminate the discharge, proximal duct excision can be considered both for treatment and diagnosis. Cytologic examination of the nipple discharge for exfoliated cancer cells may rarely be helpful in diagnosis. However, the duct may be catheterized and lavage performed to evaluate cells for atypia. Ductoscopy, evaluation of the ductal system with a small scope inserted through the nipple, is also being studied to help identify intraductal lesions that may be causing the discharge.
Dietz JR et al: Directed duct excision by using mammary ductoscopy in patients with pathologic nipple discharge. Surgery 2002;132:582.
Dooley WC et al: Office-based breast ductoscopy for diagnosis. Am J Surg 2004;188:415.
Mokbel K et al: Mammary ductoscopy: current status and future prospects. Eur J Surg Oncol 2005;31:3.
Pritt B et al: Diagnostic value of nipple cytology: study of 466 cases. Cancer 2004;102:233.
Sauter ER et al: Fiberoptic ductoscopy findings in women with and without spontaneous nipple discharge. Cancer 2005; 103:914.
Simmons R et al: Nonsurgical evaluation of pathologic nipple discharge. Ann Surg Oncol 2003;10:113.
FAT NECROSIS
Fat necrosis is a rare lesion of the breast but is of clinical importance because it produces a mass, often accompanied by skin or nipple retraction, that is indistinguishable from carcinoma. Trauma is presumed to be the cause, though only about 50% of patients give a history of injury. Ecchymosis is occasionally present. If untreated, the mass effect gradually disappears. The safest course is to obtain a biopsy. Needle biopsy is often adequate, but frequently the entire mass must be excised, primarily to exclude carcinoma. Fat necrosis is common after segmental resection, radiation therapy, or flap reconstruction after mastectomy.
Pui MH et al: Fatty tissue breast lesions. Clin Imaging 2003; 27:150.
BREAST ABSCESS
During nursing, an area of redness, tenderness, and induration may develop in the breast. The organism most commonly found in these abscesses is Staphylococcus aureus. In the early stages, the infection can often be treated while nursing is continued from that breast by administering an antibiotic such as dicloxacillin or oxacillin, 250 mg four times daily for 7–10 days (see Puerperal Mastitis, Chapter 18). If the lesion progresses to form a localized mass with local and systemic signs of infection, surgical drainage is performed and nursing is discontinued.
A subareolar abscess may develop (rarely) in young or middle-aged women who are not lactating. These infections tend to recur after incision and drainage unless the area is explored during a quiescent interval, with excision of the involved lactiferous duct or ducts at the base of the nipple. Otherwise, infection in the breast is very rare unless the patient is lactating. In the nonlactating breast, inflammatory carcinoma is always considered. Thus, findings suggestive of abscess
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or cellulitis in the nonlactating breast are an indication for incision and biopsy of any indurated tissue. If the abscess can be percutaneously drained and completely resolves, the patient may be followed conservatively.
Dener C et al: Breast abscesses in lactating women. World J Surg 2003;27:130.
DISORDERS OF THE AUGMENTED BREAST
At least 4 million American women have had breast implants. Breast augmentation is performed by placing implants usually under the pectoralis muscle or, less desirably, in the subcutaneous tissue of the breast. Most implants are made of an outer silicone shell filled with a silicone gel, saline, or some combination of the two. About 15–25% of the patients develop capsule contraction or scarring around the implant, leading to a firmness and distortion of the breast that can be painful. Some require removal of the implant and capsule.
Implant rupture may occur in as many as 5–10% of women, and bleeding of gel through the capsule is noted even more commonly. Although silicone gel may be an immunologic stimulant, there is no increase in autoimmune disorders in patients with such implants. The Food and Drug Administration (FDA) has advised symptomatic women with ruptured implants to discuss possible surgical removal with their physicians. However, women who are asymptomatic and have no evidence of rupture of a silicone gel prosthesis should probably not undergo removal of the implant. Women with symptoms of autoimmune illnesses should address the possibility of removal.
Studies have failed to show any association between implants and an increased incidence of breast cancer. However, breast cancer may develop in a patient with a silicone gel prosthesis, as it does in women without them. Detection in patients with implants is made more difficult since mammography is less able to detect early lesions. However, local recurrence after breast reconstruction for cancer is usually cutaneous or subcutaneous and is easily detected by palpation. If a cancer develops, it should be treated in the same manner as in women without implants. Such women should be offered the option of mastectomy or breastconserving therapy, which may require removal or replacement of the implant. Radiotherapy of the augmented breast often results in marked capsular contracture. Adjuvant treatments should be given for the same indications as for women who have no implants.
Brinton LA et al: Risk of connective tissue disorders among breast implant patients. Am J Epidemiol 2004;160:619.
Englert H et al: Augmentation mammoplasty and “silicone-osis.” Intern Med J 2004;34:668.
Fryzek JP et al: Silicone breast implants. J Rheumatol 2005;32:201.
CARCINOMA OF THE FEMALE BREAST
ESSENTIALS OF DIAGNOSIS
Risk factors include delayed childbearing, positive family history of breast cancer or genetic mutations (BRCA1, BRCA2), and personal history of breast cancer or some types of mammary dysplasia.
Most women with breast cancer do not have identifiable risk factors.
Early findings: Single, nontender, firm to hard mass with ill-defined margins; mammographic abnormalities and no palpable mass.
Later findings: Skin or nipple retraction; axillary lymphadenopathy; breast enlargement, redness, edema, pain; fixation of mass to skin or chest wall.
INCIDENCE & RISK FACTORS
Next to skin cancer, breast cancer is the most common type of cancer in women, second only to lung cancer as a cause of death. The probability of developing breast cancer increases throughout life. The mean and the median age of women with breast cancer is between 60 and 61 years.
There will be about 211,240 new cases of breast cancer and about 40,410 deaths from this disease in women in the United States in the year 2005. An additional 59,000 cases of ductal carcinoma in situ will be detected, principally by screening mammography. One out of every eight or nine American women will develop breast cancer during her lifetime. The incidence of breast cancer continues to increase, but recently mortality has appeared to decrease slightly. This reflects both early detection and increased use of systemic therapy. Women whose mothers or sisters had breast cancer are three to four times more likely to develop the disease. Risk is further increased in patients whose mothers' or sisters' breast cancers occurred before menopause or were bilateral and in those with a family history of breast cancer in two or more first-degree relatives. However, there is no history of breast cancer among female relatives in over 75% of patients. Nulliparous women and women whose first full-term pregnancy was after age 35 have a 1.5 times higher incidence of breast cancer than multiparous women. Late menarche and artificial menopause are associated with a lower incidence, whereas early menarche (under age 12) and late natural menopause (after age 50) are associated with a slight increase in risk. Fibrocystic condition, when accompanied by proliferative changes,
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papillomatosis, or atypical epithelial hyperplasia, is associated with an increased incidence. A woman who has had cancer in one breast is at increased risk of developing cancer in the other breast. Such women develop a contralateral cancer at the rate of 1% or 2% per year. Women with cancer of the uterine corpus have a risk of breast cancer significantly higher than that of the general population, and women with breast cancer have a comparably increased risk for endometrial cancer. In the United States, breast cancer is more common in whites. The incidence of the disease among nonwhites (mostly blacks) is increasing, especially in younger women. In general, rates reported from developing countries are low, whereas rates are high in developed countries, with the notable exception of Japan. Some of the variability may be due to underreporting in the developing countries, but a real difference probably exists. Dietary factors, particularly increased fat consumption, may account for some differences in incidence. Oral contraceptives do not appear to increase the risk of breast cancer. There is evidence that administration of estrogens to postmenopausal women may result in a slightly increased risk of breast cancer, but only with higher, long-term doses of estrogens. Concomitant administration of progesterone and estrogen may markedly increase the incidence of breast cancer compared with the use of estrogen alone. The Women's Health Initiative prospective randomized study of hormone replacement therapy stopped treatment with estrogen and progesterone early because of an increased risk of breast cancer compared with untreated controls or women treated with estrogen alone. Alcohol consumption increases the risk slightly. Some inherited breast cancers have been found to be associated with a gene on chromosome 17. This gene, BRCA1, is mutated in families with early-onset breast cancer and ovarian cancer. As many as 85% of women with BRCA1 gene mutations will develop breast cancer in their lifetime. Other genes are associated with increased risk of breast and other cancers, such as BRCA2, ataxia-telangiectasia mutation, and p53, the tumor suppressor gene. p53 mutations have been found in approximately 1% of breast cancers in women under 40 years of age. Genetic testing is now commercially available for women at high risk of breast cancer. Women with genetic mutations who develop breast cancer may be treated in the same way as women who do not have mutations (ie, lumpectomy), though data are emerging to suggest an increased recurrence rate for these women. Such women with mutations often elect bilateral mastectomy as treatment. Some states have enacted legislation to prevent insurance companies from considering mutations as “preexisting conditions,” preventing insurability.
Women at greater than normal risk of developing breast cancer (Table 16-1) should be identified by their physicians, taught the techniques of breast selfexamination, and followed carefully. Those with an exceptional family history should be counseled and given the option of genetic testing. Some of these high-risk women may consider prophylactic mastectomy or tamoxifen.
Table 16-1. Factors associated with increased risk of breast cancer.1 | ||||||||||||||||
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The National Surgical Adjuvant Breast Project (NSABP) conducted the Breast Cancer Prevention Trial (BCPT), which studied the efficacy of tamoxifen as a preventive agent in women who had never had breast cancer but were at high risk for developing the disease. Women who received tamoxifen for 5 years had about a 50% reduction in noninvasive and invasive cancers compared with women taking placebo. However, women above the age of 50 years who received the drug had an increased incidence of endometrial cancer and deep venous thrombosis. Unfortunately, no survival data will be produced from this trial. The selective estrogen receptor modulator (SERM) raloxifene, effective in preventing osteoporosis, has also shown some promise in preventing breast cancer. This, however, requires further investigation. Several large studies examining this hypothesis are underway. Recently, considerable data have become available regarding the efficacy and success of using aromatase inhibitors to treat breast cancer. Based upon this compelling body of evidence, large multicenter studies, International Breast Cancer Intervention Study II (IBIS-II) and MAP-3, of aromatase inhibitors to prevent breast cancer are currently underway.
Andrews L et al: Psychological impact of genetic testing for breast cancer susceptibility in women of Ashkenazi Jewish background: a prospective study. Genet Test 2004;8:240.
Colditz GA: Estrogen, estrogen plus progestin therapy, and risk of breast cancer. Clin Cancer Res 2005;11(2 Pt 2):909s.
Cuzick J: Aromatase inhibitors for breast cancer prevention. J Clin Oncol 2005;23:1636.
Dite GS et al: Familial risks, early-onset breast cancer, and BRCA1 and BRCA2 germline mutations. J Natl Cancer Inst 2003;95:448.
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Ettinger B et al: Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. Multiple Outcomes of Raloxifene Evaluation (MORE) Investigators. JAMA 1999;282:637.
Euhus DM: Understanding mathematical models for breast cancer risk assessment and counseling. Breast J 2001;7:224.
Fabian CJ et al: Selective estrogen-receptor modulators for primary prevention of breast cancer. J Clin Oncol 2005;23:1644.
Freedman AN et al: Estimates of the number of US women who could benefit from tamoxifen for breast cancer chemoprevention. J Natl Cancer Inst 2003;95:526.
Hedenfalk I: Gene-expression profiles in hereditary breast cancer. N Engl J Med 2001;344:539.
Jemal A et al: Cancer Statistics, 2005. CA Cancer J Clin 2005;55:10.
King MC et al: Tamoxifen and breast cancer incidence among women with inherited mutations in BRCA1 and BRCA2: National Surgical Adjuvant Breast and Bowel Project (NSABPP1) Breast Cancer Prevention Trial. JAMA 2001;286:2251.
Narod SA et al: Oral contraceptives and the risk of breast cancer in BRCA1 and BRCA2 mutation carriers. J Natl Cancer Inst 2002;94:1773.
Narod SA et al: Prevention and management of hereditary breast cancer. J Clin Oncol 2005;23:1656.
Rebbeck TR et al: Bilateral prophylactic mastectomy reduces breast cancer risk in BRCA1 and BRCA2 mutation carriers: the PROSE Study Group. J Clin Oncol 2004;22:1055.
Rossouw JE et al: Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. JAMA 2002;288:321.
Scott CL et al: Average age-specific cumulative risk of breast cancer according to type and site of germline mutations in BRCA1 and BRCA2 estimated from multiple-case breast cancer families attending Australian family cancer clinics. Hum Genet 2003;112:542.
Wrensch MR et al: Breast cancer risk in women with abnormal cytology in nipple aspirates of breast fluid. J Natl Cancer Inst 2001;93:1791.
EARLY DETECTION OF BREAST CANCER
Screening Programs
A number of mass screening programs consisting of physical and mammographic examination of the breasts of asymptomatic women have been conducted. Such programs frequently identify about 10 cancers per 1000 women older than age 50 years and about two cancers per 1000 women younger than age 50 years. About 80% of these women have negative axillary lymph nodes at the time of surgery, whereas only 50% of nonscreened women found in the course of usual medical practice have uninvolved axillary nodes. Detecting breast cancer before it has spread to the axillary nodes greatly increases the chance of survival, and about 85% of such women will survive at least 5 years.
Both physical examination and mammography are necessary for maximum yield in screening programs, since about 35–50% of early breast cancers can be discovered only by mammography and another 40% can be detected only by palpation. About one-third of the abnormalities detected on screening mammograms will be found to be malignant when biopsy is performed. The probability of cancer on a screening mammogram is directly related to the Breast Imaging and Reporting Data System (BIRADS) assessment, and work-up should be performed based on this classification. Women 20–40 years of age should have a breast examination as part of routine medical care every 2–3 years. Women over age 40 years should have yearly breast examinations. The sensitivity of mammography varies from approximately 60% to 90%. This sensitivity depends on several factors, including patient age (breast density) and tumor size, location, and mammographic appearance. In young women with dense breasts, mammography is less sensitive than in older woman with fatty breasts, in whom mammography can detect at least 90% of malignancies. Smaller tumors, particularly those without calcifications, are more difficult to detect, especially in dense breasts. The lack of sensitivity and the low incidence of breast cancer in young women have led to questions concerning the value of mammography for screening in women 40–50 years of age. The specificity of mammography in women under 50 years varies from about 30% to 40% for nonpalpable mammographic abnormalities to 85% to 90% for clinically evident malignancies.
Doubt exists about the beneficial effect of screening, especially in women under age 50 years. Questions such as the potential harmful effects of x-rays in a large population of young women and the general value of early detection were raised and largely ignored as various groups supported screening between ages 40 and 50 years. Although the Health Insurance Plan Project study did show a beneficial effect of screening in such women, reducing breast cancer mortality 25% between 10 and 18 years after entry into the study, a Canadian trial demonstrated an unexplained shortening of survival from time of random assignment to death in the screening group. The small number of patients in this study experienced no beneficial effect, but the 95% confidence interval included a potential lifesaving effect as well as a potential harmful effect. A very large number of patients is necessary to show a beneficial effect of screening among patients aged 40–49 years, in whom the incidence of breast cancer is low. In addition, the problems of crossover of patients in the control group with women undergoing physician examination and nonscreening mammograms, problems with mammography quality, and problems in recruitment, randomization, and compliance make the interpretation of such trials difficult. The beneficial effect of screening in women aged 50–69 years is undisputed and has been confirmed by all clinical trials. The efficacy of screening in older women—those older than 70 years—is inconclusive and is difficult to determine because few women were screened.
More recent studies showing a beneficial effect of screening young women and the recommendation of a
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Swedish consensus panel led the National Cancer Institute (NCI) to reconsider its position on screening mammography for women in their 40s. Two Swedish trials that had shown a 13% decrease in breast cancer mortality (not statistically significant) now showed a statistical advantage for screening women in their 40s, and a metaanalysis similarly revealed a statistical survival advantage for screened women with longer follow-up. In March 1997, the National Cancer Advisory Board recommended that women in their 40s with average risk factors should have screening mammography every 1–2 years and that women at higher risk should seek medical advice on when to begin screening. The American Cancer Society then recommended screening every year for asymptomatic women starting at age 40 years. Studies continue to support the value of screening mammography.
Self-Examination
Breast self-examination (BSE) has not been shown to improve survival. Despite this and despite possible increased biopsy rates, it is a useful technique since many patients do detect their own cancer, and women often feel more in control and proactive by using the procedure. Because of the absence of strong evidence supporting the value of BSE, the American Cancer Society no longer recommends monthly BSE beginning at age 20 years. The recommendation is that patients be made aware of the potential benefits, limitations, and harms (increased biopsies or false-positive results) associated with BSE. Women who chose to perform BSE should be advised regarding the proper technique. Premenopausal women should perform the examination 7–8 days after the menstrual period. The breasts should be inspected initially while standing before a mirror with the hands at the sides, overhead, and pressed firmly on the hips to contract the pectoralis muscles. Masses, asymmetry of breasts, and slight dimpling of the skin may become apparent as a result of these maneuvers. Next, in a supine position, each breast should be carefully palpated with the fingers of the opposite hand. Some women discover small breast lumps more readily when their skin is moist while bathing or showering. Physicians should instruct women in the technique of self-examination and advise them to report a mass or other abnormality.
Imaging
Mammography is the most useful technique for the detection of early breast cancer. Film screen mammography delivers less than 0.4 cGy to the mid breast per view and has largely replaced the older xeromammographic technique, which delivers more radiation.
Mammography is the most reliable means of detecting breast cancer before a mass can be palpated. Slowly growing cancers can be identified by mammography at least 2 years before reaching a size detectable by palpation. Although full-field digital mammography provides an easier method to maintain and review mammograms, it has not been proven that it provides better images or increases detection rates more than film mammography. New computer-assisted detection (CAD) has not shown any increase in detection of cancers and is not routinely performed at centers with experienced mammographers.
Calcifications are the most easily recognized mammographic abnormality. The most common findings associated with carcinoma of the breast are clustered polymorphic microcalcifications. Such calcifications are usually at least five to eight in number, aggregated in one part of the breast and differing from each other in size and shape, often including branched or Vor Y-shaped configurations. There may be an associated mammographic mass density or, at times, only a mass density with no calcifications. Such a density usually has irregular or ill-defined borders and may lead to architectural distortion within the breast. A small mass or architectural distortion, particularly in a dense breast, may be subtle and difficult to detect.
Indications for mammography are as follows: (1) to screen at regular intervals women at high risk for developing breast cancer (see above); (2) to evaluate each breast when a diagnosis of potentially curable breast cancer has been made, and at yearly intervals thereafter; (3) to evaluate a questionable or ill-defined breast mass or other suspicious change in the breast; (4) to search for an occult breast cancer in a woman with metastatic disease in axillary nodes or elsewhere from an unknown primary; (5) to screen women prior to cosmetic operations or prior to biopsy of a mass, to examine for an unsuspected cancer; and (6) to follow those women with breast cancer who have been treated with breast-conserving surgery and radiation.
Patients with a dominant or suspicious mass must undergo biopsy despite mammographic findings. The mammogram should be obtained prior to biopsy so that other suspicious areas can be noted and the contralateral breast can be checked. Mammography is never a substitute for biopsy because it may not reveal clinical cancer in a very dense breast, as may be seen in young women with fibrocystic changes, and may not reveal medullary cancers.
Communication and documentation among the patient, the referring physician, and the interpreting physician are critical for high-quality screening and diagnostic mammography. The patient should be told about how she will receive timely results of her mammogram; that mammography does not “rule out” cancer; and that she may receive a correlative examination such as ultrasound at the mammography facility if referred for a suspicious lesion. She should also be aware of the technique and need for breast compression and that this may be uncomfortable. The mammography facility should be informed in writing of abnormal physical examination findings. It is strongly recommended in the Agency for Health Care Policy and Research (AHCPR) Clinical Practice Guidelines that all mammography reports be communicated with the patient as well as the health care provider in writing. Additional phone communication about any abnormal findings should take place between the interpreting
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and referring physicians. Magnetic resonance imaging (MRI) and ultrasound are currently being studied as screening tools for breast cancer. They may be useful modalities in women who are at high risk for breast cancer, but not for the general population. The sensitivity of MRI is much higher than mammography; however, the specificity is significantly lower and this results in multiple unnecessary biopsies. The increased sensitivity despite decreased specificity may be considered a reasonable trade-off for those at increased risk for developing breast cancer, but not for normal-risk population. Additionally, positron emission tomography (PET) may play a role in imaging atypical lesions, but only after diagnostic mammography has been performed.
Baxter N: Canadian Task Force on Preventive Health Care: Preventive health care, 2001 update: should women be routinely taught breast self-examination to screen for breast cancer? CMAJ 2001;164:1837.
Elmore JG et al: Screening for breast cancer. JAMA 2005;293: 1245.
Humphrey LL et al: Breast cancer screening: a summary of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med 2002;137(5 Part 1):347.
Kosters JP et al: Regular self-examination or clinical examination for early detection of breast cancer. Cochrane Database Syst Rev 2003;(2):CD003373.
Kriege M et al: the Magnetic Resonance Imaging Screening Study Group: Efficacy of magnetic resonance imaging and mammography for breast cancer screening in women with a familial or genetic predisposition. Obstet Gynecol Surv 2005;60: 107.
Nystrom L et al: Long-term effects of mammography screening: updated overview of the Swedish randomised trials. Lancet 2001;359:909.
Reddy DH et al: Incorporating new imaging models in breast cancer management. Curr Treat Options Oncol 2005;6: 135.
Smith RA et al: American Cancer Society guidelines for the early detection of cancer, 2005. CA Cancer J Clin 2005;55:31.
Taylor P et al: Impact of computer-aided detection prompts on the sensitivity and specificity of screening mammography. Health Technol Assess 2005;9:1.
Clinical Clues to Early Detection of Breast Cancer
A. SYMPTOMS AND SIGNS
The presenting complaint in about 70% of patients with breast cancer is a lump (usually painless) in the breast. About 90% of breast masses are discovered by the patient herself. Less frequent symptoms are breast pain; nipple discharge; erosion, retraction, enlargement, or itching of the nipple; and redness, generalized hardness, enlargement, or shrinking of the breast. Rarely, an axillary mass or swelling of the arm may be the first symptom. Back or bone pain, jaundice, or weight loss may be the result of systemic metastases, but these symptoms are rarely seen on initial presentation.
The relative frequency of carcinoma in various anatomic sites in the breast is shown in Figure 16-1.
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Figure 16-1. Frequency of breast carcinoma at various anatomic sites. |
Inspection of the breast is the first step in physical examination and should be carried out with the patient sitting, arms at her sides and then overhead. Abnormal variations in breast size and contour, minimal nipple retraction, and slight edema, redness, or retraction of the skin can be identified. Asymmetry of the breasts and retraction or dimpling of the skin can often be accentuated by having the patient raise her arms overhead or press her hands on her hips to contract the pectoralis muscles. Axillary and supraclavicular areas should be thoroughly palpated for enlarged nodes with the patient sitting (Figure 16-2). Palpation
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of the breast for masses or other changes should be performed with the patient both seated and supine with the arm abducted (Figure 16-3). Palpation with a rotary motion of the examiner's fingers as well as a horizontal stripping motion has been recommended.
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Figure 16-2. Palpation of axillary region for enlarged lymph nodes. |
Breast cancer usually consists of a nontender, firm or hard mass with poorly delineated margins (caused by local infiltration). Slight skin or nipple retraction is an important sign. Minimal asymmetry of the breast may be noted. Very small (1–2 mm) erosions of the nipple epithelium may be the only manifestation of Paget's carcinoma. Watery, serous, or bloody discharge from the nipple is an occasional early sign but is more often associated with benign disease.
A lesion smaller than 1 cm in diameter may be difficult or impossible for the examiner to feel and yet may be discovered by the patient. She should always be asked to demonstrate the location of the mass; if the physician fails to confirm the patient's suspicions, the examination should be repeated in 2–3 months, preferably 1–2 weeks after the onset of menses. During the premenstrual phase of the cycle, increased innocuous nodularity may suggest neoplasm or may obscure an underlying lesion. If there is any question regarding the nature of an abnormality under these circumstances, the patient should be asked to return after her period. Ultrasound is often valuable and mammography essential when an area is felt by the patient to be abnormal but the physician feels no mass.
Metastases tend to involve regional lymph nodes, which may be palpable. One or two movable, nontender, not particularly firm axillary lymph nodes 5 mm or less in diameter are frequently present and are generally of no significance. Firm or hard nodes larger than 1 cm are typical of metastases. Axillary nodes that are matted or fixed to skin or deep structures indicate advanced disease (at least stage III). Microscopic metastases are present in about 30% of patients with clinically negative nodes. On the other hand, if the examiner thinks that the axillary nodes are involved, that impression will be borne out by histologic section in about 85% of cases. The incidence of positive axillary nodes increases with the size of the primary tumor. Noninvasive cancers do not metastasize.
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Figure 16-3. Palpation of breasts. Palpation is performed with the patient supine and arm abducted. |
In most cases no nodes are palpable in the supraclavicular fossa. Firm or hard nodes of any size in this location or just beneath the clavicle are suggestive of metastatic cancer and should be biopsied. Ipsilateral supraclavicular or infraclavicular nodes containing cancer indicate that the tumor is in an advanced stage (stage III or IV). Edema of the ipsilateral arm, commonly caused by metastatic infiltration of regional lymphatics, is also a sign of advanced cancer.
B. LABORATORY FINDINGS
A consistently elevated sedimentation rate may be the result of disseminated cancer. Liver or bone metastases may be associated with elevation of serum alkaline phosphatase. Hypercalcemia is an occasional important finding in advanced cancer of the breast. Carcinoembryonic antigen (CEA) and CA 15-3 or CA 27-29 may be used as markers for recurrent breast cancer but are not helpful in diagnosing early lesions. Many scientists are further investigating breast cancer biomarkers through proteomics and hormone assays. These studies are ongoing and may prove to be helpful in early detection or evaluation of prognosis.
C. IMAGING FOR METASTASES
Chest x-ray may show pulmonary metastases. Computed tomographic (CT) scanning of the liver and brain is of value only when metastases are suspected in these areas. Bone scans utilizing 99mTc-labeled phosphates or phosphonates are more sensitive than skeletal x-rays in detecting metastatic breast cancer. Bone scanning has not proved to be of clinical value as a routine preoperative test in the absence of symptoms, physical findings, or abnormal alkaline phosphatase or calcium levels. The frequency of abnormal findings on bone scan parallels the status of the axillary lymph nodes on pathologic examination. PET may prove to be an effective single scan for bone and soft tissue or visceral metastases in patients with symptoms or signs of metastatic disease.
D. DIAGNOSTIC TESTS
1. Biopsy
The diagnosis of breast cancer depends ultimately upon examination of tissue or cells removed by biopsy. Treatment should never be undertaken without an unequivocal histologic or cytologic diagnosis of cancer. The safest course is biopsy examination of all suspicious masses found on physical examination and of suspicious lesions demonstrated by mammography. About 60% of lesions clinically thought to be cancer prove on biopsy to be benign, and about 30% of lesions believed to be benign are found to be malignant. These findings demonstrate the fallibility of clinical judgment and the necessity for biopsy. A breast mass should not be followed without histologic diagnosis, except perhaps in the premenopausal woman with a nonsuspicious mass presumed to be a fibrocystic
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condition. A lesion such as this could be observed through one or two menstrual cycles. However, if the mass does not completely resolve during this time, it must be biopsied. Figure 16-4 and Figure 16-5 present algorithms for management of breast masses in premenopausal and postmenopausal patients.
The simplest method is needle biopsy, either by aspiration of tumor cells (fine-needle aspiration cytology) or by obtaining a small core of tissue with a hollow needle.
Fine-needle aspiration cytology is a useful technique whereby cells are aspirated with a small needle and examined by the pathologist. This technique can be performed easily with no morbidity and is much less expensive than excisional or open biopsy. The main disadvantages are that it requires a pathologist skilled in the cytologic diagnosis of breast cancer and that it is subject to sampling problems, particularly because deep lesions may be missed. Furthermore, noninvasive cancers usually cannot be distinguished from invasive cancers. The incidence of false-positive diagnoses is extremely low, perhaps 1–2%. The false-negative rate is as high as 10%. Most experienced clinicians would not leave a suspicious dominant mass in the breast even when fine-needle aspiration cytology is negative unless the clinical diagnosis, breast imaging studies, and cytologic studies were all in agreement.
Large-needle (core needle) biopsy removes a core of tissue with a large cutting needle. Hand-held biopsy devices make large-core needle biopsy of a palpable mass easy and cost effective in the office with local anesthesia.
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As in the case of any needle biopsy, the main problem is sampling error due to improper positioning of the needle, giving rise to a false-negative test result.
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Figure 16-4. Evaluation of breast masses in premenopausal women. (Modified from Giuliano AE: Breast disease. In: Practical Gynecologic Oncology, 3rd ed. Berek JS, Hacker NF [editors]. Williams & Wilkins, 2000.) |
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Figure 16-5. Evaluation of breast masses in postmenopausal women. (Modified from Giuliano AE: Breast disease. In: Practical Gynecologic Oncology, 3rd ed. Berek JS, Hacker NF [editors]. Williams & Wilkins, 2000.) |
Open biopsy under local anesthesia as a separate procedure prior to deciding upon definitive treatment is the most reliable means of diagnosis. Needle biopsy or aspiration, when positive, offers a more rapid approach with less expense and morbidity, but when nondiagnostic it must be followed by open biopsy. Open biopsy consists of either an incisional biopsy or an excisional biopsy. An incisional biopsy is one in which an incision is made and a portion of the breast abnormality is removed for histologic evaluation. An excisional biopsy is also done through an incision in the skin, but with the intent to remove the entire abnormality, not simply a sample. Incisional biopsies are rarely performed now.
Additional evaluation for metastatic disease and therapeutic options can be discussed with the patient after the histologic or cytologic diagnosis of cancer has been established. This approach has the advantage of avoiding unnecessary procedures, since cancer is found in the minority of patients biopsied for a breast lump. In situ cancers are not easily diagnosed cytologically and usually require excisional biopsy.
As an alternative in highly suspicious circumstances, the patient may be admitted to the hospital, where the diagnosis is made on frozen section of tissue obtained by open biopsy under general anesthesia. If the frozen section is positive, the surgeon can proceed immediately with operation. This one-step method is rarely used today except when a cytologic study has suggested cancer but is not diagnostic and there is a high clinical suspicion of malignancy.
In general, the two-step approach—outpatient biopsy followed by definitive operation at a later date— is preferred in the diagnosis and treatment of breast cancer, because patients can be given time to adjust to the diagnosis of cancer, can consider alternative forms of therapy, and can seek a second opinion if they wish. There is no adverse effect from the short (1–2 weeks) delay of the two-step procedure, and this is the current recommendation of the NCI.
2. Ultrasonography
Ultrasonography is performed primarily to differentiate cystic from solid lesions. Though not diagnostic, ultrasound may reveal features highly suggestive of malignancy such as irregular margins on a new solid mass. Ultrasonography may show an irregular mass within a cyst in the rare case of intracystic carcinoma. If a tumor is palpable and feels like a cyst, an 18-gauge needle can be used to aspirate the fluid and make the diagnosis of cyst. If a cyst is aspirated and the fluid is nonbloody, it does not have to be examined cytologically. If the mass does not recur, no further diagnostic test is necessary. Nonpalpable mammographic densities that appear benign should be investigated with ultrasound to determine whether the lesion is cystic or solid. These may even be needle biopsied with ultrasound guidance.
3. Mammography
When a suspicious abnormality is identified by mammography alone and cannot be palpated by the clinician, the lesion should be biopsied by a computerized stereotactic guided core needle technique. These units have been added to mammographic suites to localize abnormalities and perform needle biopsy without surgery. Under mammographic guidance, a biopsy needle can be inserted into the lesion by the mammographer, and a core of tissue for histologic examination or cells for cytology can then be examined. Vacuum assistance increases the amount of tissue obtained and improves diagnosis.
Mammographic localization biopsy is performed by obtaining a mammogram in two perpendicular views and placing a needle or hook-wire near the abnormality so that the surgeon can use the metal needle or wire as a guide during operation to locate the lesion. After mammography confirms the position of the needle in relation to the lesion, an incision is made and the subcutaneous tissue is dissected until the needle is identified. Using the films as a guide, the abnormality can then be localized and excised. It often happens that the abnormality cannot even be palpated through the incision—this is the case with microcalcifications—and thus it is essential to obtain a mammogram of the specimen to document that the lesion was excised. At that time, a second marker needle can further localize the lesion for the pathologist. Stereotactic core needle biopsies have proved equivalent to mammographic localization biopsies. Core biopsy is preferable to mammographic localization for accessible lesions.
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4. Other imaging modalities
Other modalities of breast imaging have been investigated. Automated breast ultrasonography is useful in distinguishing cystic from solid lesions but should be used only as a supplement to physical examination and mammography. Ductography may be useful to define the site of a lesion causing a bloody discharge, but since biopsy is always indicated, ductography may be omitted and the blood-filled nipple system excised. Ductoscopy has shown some promise in identifying intraductal lesions, especially in the case of pathologic nipple discharge, but the utility of this procedure is still being studied. MRI is highly sensitive but not specific and should not be used for screening, but it may be of value in highly selective cases. It is useful, for example, in differentiating scar from recurrence postlumpectomy and may be valuable to screen high-risk women (eg, women with BRCA mutations) and to examine for multicentricity when there is a known primary cancer or to examine the contralateral breast in women with cancer. PET scanning does not appear useful in evaluating the breast but may prove to be of value in examining regional lymphatics.
5. Cytology
Cytologic examination of nipple discharge or cyst fluid may be helpful on rare occasions. As a rule, mammography (or ductography) and breast biopsy are required when nipple discharge or cyst fluid is bloody or cytologically questionable. Ductal lavage, a technique that washes individual duct systems with saline and loosens epithelial cells for cytologic evaluation, is being evaluated as a risk assessment tool but appears to be of little value.
Baker JA et al: Breast US: assessment of technical quality and image interpretation. Radiology 2002;223:229.
Dooley WC: Routine operative breast endoscopy for bloody nipple discharge. Ann Surg Oncol 2002;9:920.
Hollingsworth AB: Perspectives on preoperative staging with breast MRI. J Am Coll Surg 2004;199:173.
Lenahan C et al: The role of tumor markers in breast cancer management. Curr Surg 2004;61:532.
Ljung BM et al: Cytology of ductal lavage fluid of the breast. Diagn Cytopathol 2004;30:143.
van der Hoeven JJ et al: Determinants of diagnostic performance of [F-18] fluorodeoxyglucose positron emission tomography for axillary staging in breast cancer. Ann Surg 2002;236: 619.
DIFFERENTIAL DIAGNOSIS
The lesions to be considered most often in the differential diagnosis of breast cancer are the following, in descending order of frequency: mammary dysplasia (fibrocystic condition of the breast), fibroadenoma, intraductal papilloma, lipoma, and fat necrosis.
STAGING
Currently, the American Joint Committee on Cancer and the International Union Against Cancer have agreed on a TNM (tumor, regional lymph nodes, distant metastases) staging system for breast cancer. The use of this uniform TNM staging system enhances communication between investigators and clinicians. Table 16-2 sets forth the TNM classification.
PATHOLOGIC TYPES
Numerous pathologic subtypes of breast cancer can be identified histologically (Table 16-3). These types are distinguished by the histologic appearance and growth pattern of the tumor. In general, breast cancer arises either from the epithelial lining of the large or intermediate-sized ducts (ductal) or from the epithelium of the terminal ducts of the lobules (lobular). The cancer may be invasive or in situ. Most breast cancers arise from the intermediate ducts and are invasive (invasive ductal, infiltrating ductal), and most histologic types are merely subtypes of invasive ductal cancer with unusual growth patterns (colloid, medullary, scirrhous, etc). Ductal carcinoma that has not invaded the extraductal tissue is intraductal or in situ ductal. Lobular carcinoma may be either invasive or in situ.
Except for the in situ cancers, the histologic subtypes have only a slight bearing on prognosis when outcomes are compared after accurate staging. Various histologic parameters, such as invasion of blood vessels, tumor differentiation, invasion of breast lymphatics, and tumor necrosis have been examined, but they too seem to have little prognostic value.
The noninvasive cancers by definition are confined by the basement membrane of the ducts and lack the ability to spread. However, in patients whose biopsies show noninvasive intraductal cancer, associated invasive ductal cancers metastasize to lymph nodes in about 1–3% of cases.
SPECIAL CLINICAL FORMS OF BREAST CANCER
Paget's Carcinoma
The basic lesion is usually an infiltrating ductal carcinoma, usually well differentiated, or a ductal carcinoma in situ (DCIS). The ducts of the nipple epithelium are infiltrated, but gross nipple changes are often minimal, and a tumor mass may not be palpable. The first symptom is often itching or burning of the nipple, with superficial erosion or ulceration. The diagnosis is established by biopsy of the erosion.
Paget's carcinoma is not common (about 1% of all breast cancers), but it is important because the nipple changes appear innocuous. These are frequently diagnosed and treated as dermatitis or bacterial infection, leading to delay in detection. When the lesion consists of nipple changes only, the incidence of axillary metastases is less than 5%, and the prognosis is excellent. When a breast mass is also present, the incidence of axillary metastases rises, with an associated marked
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decrease in prospects for cure by surgical or other treatment.
Table 16-2. TNM staging for breast cancer. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Inflammatory Carcinoma
This is the most malignant form of breast cancer and constitutes less than 3% of all cases. The clinical findings consist of a rapidly growing, sometimes painful mass that enlarges the breast. The overlying skin becomes erythematous, edematous, and warm. Often there is no distinct mass, since the tumor infiltrates the involved breast diffusely. The diagnosis should be made when the redness involves more than one-third of the skin over the breast and biopsy shows infiltrating carcinoma with invasion of the subdermal lymphatics. The inflammatory changes, often mistaken for an infection, are caused by carcinomatous invasion of the subdermal lymphatics, with resulting edema and hyperemia. If the physician suspects infection but the lesion does not respond rapidly (1–2 weeks) to antibiotics, biopsy is performed. Metastases tend to occur early and widely, and for this reason inflammatory carcinoma is rarely curable. Mastectomy is seldom indicated unless chemotherapy and radiation have resulted in clinical remission with no evidence of distant metastases. In these cases, residual disease in the breast may be eradicated. Radiation, hormone therapy, and chemotherapy are the measures most likely to be of value rather than operation.
Table 16-3. Histologic types of breast cancer. | ||||
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Breast Cancer Occurring during Pregnancy or Lactation
Breast cancer complicates approximately one in 3000 pregnancies. The diagnosis is frequently delayed, because physiologic changes in the breast may obscure the lesion. This results in a tendency of both patients and physicians to misinterpret findings and to delay biopsy. When the cancer is confined to the breast, the 5-year survival rate after mastectomy is about 70%. Axillary metastases are already present in 60–70% of patients, and for them the 5-year survival rate after mastectomy is only 30–40%. Pregnancy (or lactation) is not a contraindication to operation, and treatment should be based on the stage of the disease as in the nonpregnant (or nonlactating) woman. Overall survival rates have improved, since cancers are now diagnosed in pregnant women earlier than in the past. Breast-conserving surgery may be performed—and radiation and chemotherapy given—even during the pregnancy.
Bilateral Breast Cancer
Clinically evident simultaneous bilateral breast cancer occurs in less than 1% of cases, but there is a 5–8% incidence of later occurrence of cancer in the second breast. Bilaterality occurs more often in familial breast cancer, in women under age 50 years, and when the tumor in the primary breast is lobular. The incidence of second breast cancers increases directly with the length of time the patient is alive after her first cancer—about 1% per year.
In patients with breast cancer, mammography should be performed before primary treatment and at regular intervals thereafter, to search for occult cancer in the opposite breast. Routine biopsy of the opposite breast is usually not warranted even for lobular cancer.
Noninvasive Cancer
Noninvasive cancer can occur within the ducts (ductal carcinoma in situ, DCIS) or lobules (lobular carcinoma in situ, LCIS). LCIS, although thought to be a premalignant lesion or a risk factor for breast cancer, in fact behaves like other carcinomas in situ. In a recent study, patients with LCIS not only went on to develop invasive lobular breast cancer, but some developed it in the same breast and indexed location of the original LCIS. Although more research needs to be done in this area, the invasive potential of LCIS is being reconsidered. DCIS tends to be unilateral and most often progresses to invasive cancer if untreated. Approximately 40–60% of women who have DCIS treated with biopsy alone develop invasive cancer within the same breast.
The treatment of intraductal lesions is controversial. DCIS can be treated with total mastectomy or by wide excision with or without radiation therapy. Conservative management, excision only, is advised in this patient population until further data are developed. Although research is defining the malignant potential of LCIS, it may be well managed with observation, but patients unwilling to accept the increased risk of breast cancer may be offered surgical excision of the area in question or even bilateral total mastectomy. Currently, accepted standards of care offer the alternative of chemoprevention, using agents such as tamoxifen, which is effective in preventing invasive breast cancer from developing in both LCIS and intraductal carcinoma in situ. Axillary metastases from in situ cancers should not occur unless there is an occult invasive cancer.
Anderson WF et al: Inflammatory breast carcinoma and noninflammatory locally advanced breast carcinoma: distinct clinicopathologic entities? J Clin Oncol 2003;21:2254.
Fisher ER et al: Pathologic findings from the National Surgical Adjuvant Breast and Bowel Project: twelve-year observations concerning lobular carcinoma in situ. Cancer 2004;100: 238.
Khan A et al: Diagnosis and management of ductal carcinoma in situ. Curr Treat Options Oncol 2004;5:131.
Lerebours F et al: Update on inflammatory breast cancer. Breast Cancer Res 2005;7:52.
Marcus E: The management of Paget's disease of the breast. Curr Treat Options Oncol 2004;5:153.
Saunders C et al: Breast cancer during pregnancy. Int J Fertil Womens Med 2004;49:203.
HORMONE RECEPTOR SITES
The presence or absence of estrogen and progesterone receptors in the cytoplasm of tumor cells is of paramount importance in managing patients with breast cancer. Patients whose primary tumors are receptor positive have a more favorable course than those whose tumors are receptor negative. Receptors are of value in determining adjuvant therapy and for treatment of advanced disease. Up to 60% of patients with metastatic breast cancer will respond to hormonal manipulation if their tumors contain estrogen receptors. Fewer than 5% of patients with metastatic, estrogen receptor-negative tumors can be treated successfully in this fashion.
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Receptor status is valuable not only in managing metastatic disease but also in helping select patients for adjuvant therapy. Adjuvant hormonal therapy (tamoxifen) with receptor-positive tumors and adjuvant chemotherapy with receptor-negative tumors improve survival rates even in the absence of lymph node metastases (see Adjuvant Therapy, below).
Progesterone receptors may be a more sensitive indicator than estrogen receptors of patients who may respond to hormonal manipulation. Up to 80% of patients with metastatic progesterone receptor-positive tumors improve with hormonal manipulation. Receptors have no relationship to response to chemotherapy.
The estrogen, progesterone, and HER-2/neu receptor status and proliferative indices of the tumor should be determined at the time of initial biopsy. This is performed on paraffin-fixed tissue by immunohistochemistry. HER-2/neu assessment in breast cancer by immunohistochemistry is appropriate for patients with tumors that score 3+. Fluorescence in situ hybridization (FISH) is recommended for women with 2+ immunohistochemistry scores to more accurately assess HER-2/neu amplification and provide better prognostic information. Receptor status may change after hormonal therapy, radiotherapy, or chemotherapy.
Konecny G et al: Quantitative association between HER-2/neu and steroid hormone receptors in hormone receptor-positive primary breast cancer. J Natl Cancer Inst 2003;95:142.
CURATIVE TREATMENT
Treatment may be curative or palliative. Curative treatment is advised for clinical stage I, II, and III disease (Table 16-2). Patients with locally advanced (T3, T4) and even inflammatory tumors may be cured with multimodality therapy, but in most palliation is all that can be expected. Palliative treatment is appropriate for all patients with stage IV disease and for previously treated patients who develop distant metastases or who have unresectable local cancers.
The growth potential of tumors and host resistance factors vary widely from patient to patient and may be altered during the course of the disease. The doubling time of breast cancer cells ranges from several weeks in a rapidly growing lesion to a year in a slowly growing one. Assuming that the rate of doubling is constant and that the neoplasm originates in one cell, a carcinoma with a doubling time of 100 days may not reach clinically detectable size (1 cm) for about 8 years. Rapidly growing cancers have a much shorter preclinical course and a greater tendency to metastasize by the time a breast mass is discovered.
The long preclinical growth phase and the tendency of breast cancers to metastasize have led clinicians to believe that most breast cancer is a systemic disease at the time of diagnosis. Although it may be true that breast cancer cells are released from the tumor prior to diagnosis, variations in the host–tumor relationship prohibit the growth of disseminated disease in many patients. Clearly, not all breast cancer is systemic at the time of diagnosis. For this reason, a pessimistic attitude concerning the management of breast cancer is unwarranted. Most patients can be cured.
Controversy surrounds the timing of surgery with respect to the menstrual cycle. Some suggest that operation during the time of unopposed estrogen adversely affects survival, but most studies support no such effect. Several randomized trials are currently examining this question.
Choice of Primary Therapy
The extent of disease and its biologic aggressiveness are the principal determinants of the outcome of primary therapy. Clinical and pathologic staging help in assessing extent of disease (Table 16-2), but each is to some extent imprecise. Other factors such as DNA flow cytometry, tumor grade, hormone receptor assays, and oncogene amplification may be of prognostic value but are not important in determining the type of local therapy.
Controversy surrounds the choice of primary therapy of stage I, II, and III breast carcinoma. A number of states require physicians to inform patients of alternative treatment methods in the management of breast cancer. Currently, the standard of care for stage I, stage II, and most stage III cancer is surgical resection.
Breast-Conserving Therapy
Many nonrandomized trials, the randomized Milan trial, and a large randomized trial conducted by the National Surgical Adjuvant Breast and Bowel Project (NSABP) in the United States show that disease-free survival rates are similar for patients treated by partial mastectomy plus axillary dissection followed by radiation therapy and for those treated by modified radical mastectomy (total mastectomy plus axillary dissection). All patients whose axillary nodes contained tumor received adjuvant chemotherapy.
In the NSABP trial, patients were randomized to three treatment types: (1) “lumpectomy” (removal of the tumor with confirmed tumor-free margins) plus whole breast irradiation, (2) lumpectomy alone, and (3) total mastectomy. All patients underwent axillary lymph node dissection, and some had tumors as large as 4 cm with (or without) palpable axillary lymph nodes. With 20 years of follow-up, the lowest local recurrence rate was among patients treated with lumpectomy and postoperative irradiation; the highest—nearly 40% at 20 years of follow-up—was among patients treated with lumpectomy alone. However, no statistically significant differences were observed in overall or disease-free survival among the three treatment groups. This study shows that lumpectomy and axillary dissection with postoperative radiation therapy are as effective as modified radical mastectomy for the management of patients with stage I and stage II breast cancer.
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The results of these and other trials have demonstrated that much less aggressive surgical treatment of the primary lesion than has previously been thought necessary gives equivalent therapeutic results and may preserve an acceptable cosmetic appearance.
Tumor size is a major consideration in determining the feasibility of breast conservation. The lumpectomy trial of the NSABP randomized patients with tumors as large as 4 cm. To achieve an acceptable cosmetic result, the patient must have a breast of sufficient size to enable excision of a 4-cm tumor without considerable deformity. Therefore, large size is only a relative contraindication. Subareolar tumors, also difficult to excise without deformity, are not contraindications to breast conservation. Clinically detectable multifocality is a relative contraindication to breast-conserving surgery, as is fixation to the chest wall or skin or involvement of the nipple or overlying skin. The patient—not the surgeon—should be the judge of what is cosmetically acceptable.
Axillary dissection is valuable in preventing axillary recurrences, in staging cancer, and in planning therapy. Intraoperative lymphatic mapping and sentinel node dissection identify lymph nodes most likely to harbor metastases if present in the axillary nodes. Numerous studies have confirmed the validity of this technique. Ongoing trials are examining the replacement of formal axillary dissection with sentinel node dissection. A trial from Milan with very short followup showed no difference between axillary dissection and sentinel node biopsy in node-negative women. Results to date suggest that sentinel node biopsy can safely replace axillary dissection for staging and treatment in histopathologically node-negative women at experienced centers. At an international consensus conference in Philadelphia in April 2001, participants recommended sentinel node biopsy as an alternative to axillary dissection in selected patients with invasive cancer. A trial by the American College of Surgeons Oncology Group is examining the role of sentinel node dissection without axillary dissection for nodepositive women. Bone marrow biopsy with examination by immunocytochemistry to detect early metastases may be as sensitive a staging procedure as axillary dissection and may identify patients at high risk for disseminating disease.
Recommendations
Earlier consensus held that breast-conserving surgery with radiation was the preferred form of treatment for patients with early-stage breast cancer. Despite the numerous randomized trials showing no survival benefit of mastectomy over breast-conserving partial mastectomy and irradiation, breast-conserving surgery appears underutilized and mastectomy remains the more common treatment. About 25% of patients in the United States with stage I or stage II breast cancer are treated with breast-conserving surgery and radiation therapy, compared with 75% treated with mastectomy. Use of breast-conserving surgery and radiation therapy varies by region of the country, ranging from 15% in the South Central United States to 30% in the Pacific Region.
Modified radical mastectomy (total mastectomy plus axillary lymph node dissection) has been the standard therapy for most patients with breast cancer. This operation removes the entire breast, overlying skin, nipple, and areolar complex as well as the underlying pectoralis fascia with the axillary lymph nodes in continuity. The major advantage of modified radical mastectomy is that radiation therapy may not be necessary. The disadvantage, of course, is the psychological impact associated with breast loss. Radical mastectomy, which removes the underlying pectoralis muscle, should be performed rarely, if at all. Axillary node dissection is not indicated for noninfiltrating cancers, because nodal metastases are rarely present. Skin-sparing mastectomy is currently gaining favor but is appropriate in only a small subgroup of patients. Radiotherapy after partial mastectomy consists of 5–6 weeks of five daily fractions to a total dose of 5000–6000 cGy. Some radiation oncologists use a boost dose. Currently several studies are underway examining the utility and recurrence rates after intraoperative radiation or dose dense radiation in which the course of radiation is shortened. Current studies suggest that radiotherapy after mastectomy may improve survival and meta-analyses suggest radiation after lumpectomy may improve survival. The use of radiation in mastectomy patients is being further researched in a large cooperative trial to better identify which subgroups will benefit. Researchers are also examining the utility of axillary irradiation as an alternative to axillary dissection in the clinically node-negative patient with sentinel node metastases.
Preoperatively, full discussion with the patient regarding the rationale for operation and various alternative forms of treatment is essential. Breast-conserving surgery and radiation should be offered whenever possible, since most patients would prefer to save the breast. Breast reconstruction, immediate or delayed, should be discussed with patients who choose or require mastectomy. Patients should have an interview with a reconstructive plastic surgeon to discuss options prior to making a decision regarding reconstruction. Time is well spent preoperatively in educating the patient and family about these matters.
Adjuvant Systemic Therapy
Following surgery and radiation therapy, chemotherapy or hormonal therapy is advocated for most patients with curable breast cancer. The objective of adjuvant systemic therapy is to eliminate the occult metastases responsible for late recurrences while they are microscopic and most vulnerable to anticancer agents. In addition, adjuvant chemotherapy may decrease local recurrence in patients treated with breast conservation, whereas adjuvant hormonal manipulation decreases contralateral breast cancer occurrence.
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Even the earliest studies comparing placebo with chemotherapy drugs having minimal activity such as L-phenylalanine mustard showed an improvement in both disease-free and overall survival for women disease free postoperatively. The landmark study from Milan evaluating the effect of 1 year of adjuvant cyclophosphamide, methotrexate, and fluorouracil (CMF) given on days 1 and 8 of each month for 12 months showed a significant improvement in survival for premenopausal women with node-positive disease. After 20 years of follow-up, significant improvement in survival persisted among those receiving chemotherapy. CMF rapidly became the standard management for premenopausal women with node-positive breast cancer. Subsequently, the use of chemotherapy for postmenopausal women and those at less risk than node-positive women was evaluated. Systemic chemotherapy improved survival in all groups of women treated. The improvement in survival for patients treated appears to be about 30% of the patients' risk of death; that is, a woman with a 30% chance of recurrence and death derives about a 10% overall improvement in survival. This risk reduction analysis has been confirmed in numerous studies and meta-analyses.
On the basis of the superiority of anthracyclinecontaining regimens in metastatic breast cancer, both doxorubicin and epirubicin have been studied extensively in the adjuvant setting and have been compared to CMF regimens. Studies comparing Adriamycin (doxorubicin) and cyclophosphamide (AC) or epirubicin and cyclophosphamide (EC) with CMF have shown that treatment with anthracycline-containing regimens are at least as effective, and perhaps more effective, as treatment with CMF. The NSABP B-23 compared four cycles of AC with six cycles of CMF and demonstrated the equivalence of these two regimens in node-negative, estrogen receptor (ER)-negative disease. Whereas four cycles of AC or EC have not demonstrated improved survival compared to CMF, the use of six cycles of fluorouracil plus AC (FAC) or fluorouracil plus EC (FEC) has shown improved survival compared to CMF alone. For node-negative patients, most oncologists offer four cycles of AC or six cycles of CMF in the adjuvant setting.
For node-positive patients, taxanes are now frequently combined with anthracycline-based regimens. The Cancer and Leukemia Group B (CALGB) study comparing four cycles of AC to four cycles of AC followed by four cycles of paclitaxel showed about a 20% proportional reduction in recurrence and a 4% absolute improvement in disease-free survival with the use of paclitaxel. Paclitaxel is now approved for and increasingly employed as adjuvant therapy in node-positive breast cancer.
Unfortunately, a subsequent study by the NSABP failed to show any benefits of the use of paclitaxel except in ER-negative patients with positive nodes. A 2002 National Institutes of Health (NIH) consensus panel felt that firm conclusions about the use of taxanes could not be drawn and recommended that patients receive adjuvant taxanes only in the context of a clinical trial. However, based on trends in improved survival, many oncologists add a taxane to AC for node-positive women. A trial comparing six cycles of FAC to six cycles of docetaxel, doxorubicin, and cyclophosphamide (TAC) showed an improvement in disease-free survival for patients receiving the addition of paclitaxel. This benefit was most marked for patients with positive nodes and was seen in both ER-negative and ER-positive tumors. Until more information is obtained, the role of taxanes in the adjuvant setting remains unclear.
Controversy exists as to whether patients whose tumors overexpress the HER-2/neu oncogene benefit more from anthracycline regimens than from CMF regimens. Retrospective analysis of randomized trials suggests that patients with HER-2/neu overexpression may benefit more from doxorubicin than patients with HER-2/neu-negative disease. These retrospective studies have numerous problems including the analysis of HER-2/neu on paraffin tissue blocks.
The overall duration of adjuvant chemotherapy still remains uncertain. However, based on the metaanalysis performed in the Oxford Overview (Early Breast Cancer Trialists' Collaborative Group), the current recommendation is for 3–6 months of the commonly used regimens. The addition of taxanes required an additional duration of therapy of up to 6 months. Recently, increasing the frequency of chemotherapy administration (dose dense chemotherapy) has been shown to be superior to standard dosing.
Adjuvant hormonal therapy is also highly effective in decreasing recurrence and mortality in women with ER-positive tumors. The standard regimen has been tamoxifen for 5 years. Hormonal therapy decreases the risk of mortality by approximately 25%. This appears to be effective regardless of age and may be used in both premenopausal and postmenopausal women. More recently, the aromatase inhibitors have been shown to be effective in the adjuvant setting. The large Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial in postmenopausal women with ER-positive disease showed improved disease-free survival in patients treated with anastrozole compared to those treated with tamoxifen alone or even with the combination of tamoxifen and anastrozole. In addition, anastrozole showed a decrease of over 50% in the recurrence of contralateral breast tumors and fewer side effects such as endometrial cancers, hot flushes, and thromboembolic events. Anastrozole is increasingly being used in the adjuvant setting in postmenopausal women. The American Society of Clinical Oncology, however, has recommended the use of tamoxifen for adjuvant hormonal therapy in the absence of significant contraindications; anastrozole is recommended when there are contraindications to tamoxifen.
Use of high-dose chemotherapy with stem cell support has not demonstrated a consistent, favorable impact on survival and should not be used outside of clinical trials. Although it is clear that dose intensity to a specific threshold is essential, there is no clear benefit to high-dose therapy with stem cell support.
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An NIH consensus conference has reexamined the standards for adjuvant therapy of breast cancer. Since the last conference on this topic in 1990, the long-term advantage of systemic therapy has been further established. In the past 10 years, no new prognostic factors have been validated to aid in the selection of patients for adjuvant treatment. Its use should be based on the patient's age; on the size, histopathologic grade, and hormone receptor status of the breast tumor; and on the status of the regional lymph nodes. The value of HER-2/neu, p53, angiogenesis factors, and vascular invasion is being investigated, but as yet they are not proven prognostic factors. Studies are being conducted evaluating trastuzumab in the adjuvant setting in a group of patients whose tumors overexpress HER-2/ neu. The panel concluded that regardless of other factors, adjuvant systemic chemotherapy with drug combinations improves survival and should be used for most women who have potentially curable breast cancer. The use of anthracyclines is superior to combinations without anthracyclines. Tamoxifen should be used as a systemic agent in all women whose tumors are hormone receptor positive—regardless of age, menopausal status, or other prognostic factors. HER-2/ neu status should not affect the choice of agents or the use of hormone therapy. Ovarian ablation in premenopausal patients with estrogen receptor-positive tumors may produce a benefit similar to that of adjuvant systemic chemotherapy. Taxanes have demonstrated benefit in patients with metastatic cancer and are being used in node-negative patients. Adjuvant systemic therapy should not be given to women who have small nodenegative breast cancers with favorable histologic subtypes, such as mucinous or tubular carcinoma.
In practice, most medical oncologists are currently using systemic adjuvant therapy for patients with either node-negative or node-positive breast cancer. Prognostic factors other than nodal status being used to determine the patient's risks are tumor size, estrogen and progesterone receptor status, nuclear grade, histologic type, proliferative rate, and oncogene expression (Table 16-4). The assumption is made that all patients with node-negative aggressive tumors should receive adjuvant therapy except those who have serious coexistent medical problems. In general, systemic chemotherapy decreases the chance of recurrence by about 30%. Most patients tolerate at least tamoxifen. The use of chemotherapy prior to resection of the primary tumor (neoadjuvant) is gaining popularity. This enables the assessment of in vivo chemosensitivity. A complete tumor response in vivo prior to operation appears to be associated with improvement in survival. Neoadjuvant chemotherapy also permits breast conservation by shrinking the primary tumor in women who would otherwise need mastectomy for local control.
Important questions remaining to be answered are the timing and duration of adjuvant and neoadjuvant chemotherapy, which chemotherapeutic agents should be applied for which subgroups of patients, the use of combinations of hormonal therapy and chemotherapy, and the value of prognostic factors other than hormone receptors in predicting response to adjuvant therapy. Adjuvant systemic therapy is not generally used in patients with small tumors and those with negative lymph nodes who have favorable tumor markers. However, a small disease-free survival benefit, even in patients with small favorable tumors, has been suggested. It appears that adjuvant systemic therapy benefits all breast cancer patients, but the clinician must decide if the benefits outweigh the risks, complications, and expense.
Table 16-4. Prognostic factors in node-negative breast cancer. | |||||||||||||||||||||||||||||||||
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Cady B et al: The surgeon's role in outcome in contemporary breast cancer. Surg Oncol Clin North Am 2000;9:119.
Delaney G: Recent advances in the use of radiotherapy to treat early breast cancer. Curr Opin Obstet Gynecol 2005;17:27.
Early Breast Cancer Trialists' Collaborative Group: Favourable and unfavourable effects on long-term survival of radiotherapy for early breast cancer: an overview of the randomised trials. Lancet 2000;355:1757.
Fisher B et al: Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. N Engl J Med 2002;347:1233.
Fisher B et al: Treatment of axillary lymph node-negative, estrogen receptor-negative breast cancer: updated findings from National Surgical Adjuvant Breast and Bowel Project clinical trials. J Natl Cancer Inst 2004;96:1823.
Howell A et al: ATAC Trialists' Group: Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years' adjuvant treatment for breast cancer. Lancet 2005;365:60.
Love RR: Meeting highlights: international consensus panel on the treatment of primary breast cancer. J Clin Oncol 2002;20:1955.
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Muller V et al: Bone marrow micrometastases and circulating tumor cells: current aspects and future perspectives. Breast Cancer Res 2004;6:258.
Rouzier R et al: Incidence and prognostic significance of complete axillary downstaging after primary chemotherapy in breast cancer patients with T1 to T3 tumors and cytologically proven axillary metastatic lymph nodes. J Clin Oncol 2002;20:1304.
Sokolowicz LE et al: Hormonal therapy for primary breast cancer: scientific rationale and status of clinical research. Curr Oncol Rep 2005;7:31.
The National Institutes of Health Consensus Development Conference: Adjuvant Therapy for Breast Cancer. Bethesda, Maryland, USA. November 1-3, 2000. Proceedings. J Natl Cancer Inst Monogr 2001;(30):1.
Veronesi U et al: Twenty-year follow-up of randomized study comparing breast-conserving surgery with radical mastectomy for early breast cancer. N Engl J Med 2002;347:1227.
Veronesi U et al: Full-dose intraoperative radiotherapy with electrons during breast-conserving surgery. Arch Surg 2003;138:1253.
Vinh-Hung V et al: Breast-conserving surgery with or without radiotherapy: pooled-analysis for risks of ipsilateral breast tumor recurrence and mortality. J Natl Cancer Inst 2004;96:115.
Vogel C et al: Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer. J Clin Oncol 2002;3:719.
Wilke LG et al: Sentinel lymph node biopsy in patients with early-stage breast cancer: status of the National Clinical Trials. Surg Clin North Am 2003;83:901.
PALLIATIVE TREATMENT
This section covers palliative therapy of disseminated disease incurable by surgery (stage IV).
Radiotherapy
Palliative radiotherapy may be advised for primary treatment of locally advanced cancers with distant metastases to control ulceration, pain, and other manifestations in the breast and regional nodes. Irradiation of the breast and chest wall and the axillary, internal mammary, and supraclavicular nodes should be undertaken in an attempt to cure locally advanced and inoperable lesions when there is no evidence of distant metastases. A small number of patients in this group are cured in spite of extensive breast and regional node involvement.
Palliative irradiation is of value also in the treatment of certain bone or soft tissue metastases to control pain or avoid fracture. Radiotherapy is especially useful in the treatment of isolated bony metastasis, chest wall recurrences, brain metastases, and acute spinal cord compression.
Hormone & Targeted Therapy
Disseminated disease may shrink—or grow less rapidly—after endocrine therapy such as administration of hormones (eg, estrogens, androgens, progestins; see Table 16-5); ablation of the ovaries, adrenals, or pituitary; or administration of drugs that block hormone receptor sites (eg, antiestrogens) or drugs that block the synthesis of hormones (eg, aromatase inhibitors). Hormonal manipulation is usually more successful in postmenopausal women even if they have received estrogen replacement therapy. Treatment should be based on the presence of estrogen receptor protein in the primary tumor or metastases. The rate of response is nearly equal in premenopausal and postmenopausal women with ER-positive tumors. A favorable response to hormonal manipulation occurs in about one-third of patients with metastatic breast cancer. Of those whose tumors contain estrogen receptors, the response is about 60% and perhaps as high as 80% for patients whose tumors contain progesterone receptors as well. Because only 5–10% of women whose tumors do not contain estrogen receptors respond, they should not receive hormonal therapy except in unusual circumstances,
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eg, in an older patient who cannot tolerate chemotherapy. Because the quality of life during a remission induced by endocrine manipulation is often superior to a remission following cytotoxic chemotherapy, it is usually best to try endocrine manipulation first in cases in which the estrogen receptor status is unknown. Additionally, women with ER-positive tumors who fail hormone therapy or experience progression should be placed on a different form of hormonal manipulation. Women who have failed tamoxifen and gone on to a third-generation aromatase inhibitor have shown equal if not better response than those who respond to tamoxifen. When receptor status is unknown but the disease is progressing rapidly or involves visceral organs, however, endocrine therapy is rarely successful, and introducing it may waste valuable time.
Table 16-5. Agents commonly used for hormonal management of metastatic breast cancer. | ||||||||||||||||||||||||||||||||
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In addition to radiotherapy, bisphosphonate therapy has shown excellent results in delaying and reducing skeletal events in women with bony metastases. Bisphosphonates are also sometimes used in conjunction with aromatase inhibitors to decrease the potential bony events associated with those drugs. Further research is being conducted examining the utility of bisphosphonates in conjunction with other therapies and in early breast cancer treatment.
In general, only one type of therapy should be given at a time unless it is necessary to irradiate a destructive lesion of weight-bearing bone while the patient is on another regimen. The regimen should be changed only if the disease is clearly progressing. This is especially important for patients with destructive bone metastases, since changes in the status of these lesions are difficult to determine radiographically. A plan of therapy that would simultaneously minimize toxicity and maximize benefits is often best achieved by hormonal manipulation.
The choice of endocrine therapy depends on the menopausal status of the patient. Women within 1 year of their last menstrual period are arbitrarily considered to be premenopausal, whereas women whose menstruation ceased more than a year ago are postmenopausal. If endocrine therapy is the initial choice, it is referred to as primary hormonal manipulation; subsequent endocrine treatment is called secondary or tertiary hormonal manipulation.
Trastuzumab is a monoclonal antibody that binds to HER-2/neu receptors on the cancer cell and has been shown to be highly effective in HER-2/neu-expressive cancers. In metastatic disease, for patients with HER-2/neu oncogene overexpression, trastuzumab has been shown to increase survival when combined with AC or paclitaxel. Ongoing studies are evaluating trastuzumab in combination with other agents for adjuvant chemotherapy regimens.
A. THE PREMENOPAUSAL PATIENT
1. Primary hormonal therapy
The potent antiestrogen tamoxifen is the endocrine treatment of choice in the premenopausal patient. Tamoxifen is usually given orally in a dose of 20 mg daily. There is no significant difference in survival or response between tamoxifen therapy and bilateral oophorectomy. Tamoxifen is by far the most common and preferred method of hormonal manipulation for both premenopausal and postmenopausal women. The average remission is about 12 months. Tamoxifen can be given with little morbidity and few side effects. Toremifene, a tamoxifen analog, is currently available and has similar side effects but is less likely to cause uterine cancer. Controversy continues about whether a response to tamoxifen is predictive of probable success with other forms of endocrine manipulation.
Bilateral oophorectomy is less desirable than primary hormonal manipulation in premenopausal women because tamoxifen is so well tolerated. Oophorectomy can be achieved rapidly and safely by surgery, however, or, if the patient is a poor operative risk, by irradiation of the ovaries. Chemical ovarian ablation using a gonadotropin-releasing hormone (GnRH) analog can also be utilized. Oophorectomy presumably works by eliminating estrogens, progestins, and androgens, which stimulate growth of the tumor.
2. Secondary or tertiary hormonal therapy
Although patients who do not respond to tamoxifen or oophorectomy should be treated with cytotoxic drugs, those who respond and then relapse may subsequently respond to another form of endocrine treatment (Table 16-5). The initial choice for secondary endocrine manipulation has not been clearly defined.
Patients who improve after oophorectomy but subsequently relapse should receive tamoxifen or an aromatase inhibitor. If one fails, the other may be tried but is not likely to succeed. Megestrol acetate may be considered. Megestrol is a progestational agent. Both drugs cause less morbidity and mortality than surgical adrenalectomy, can be discontinued once the patient improves, and are not associated with the many problems of postsurgical hypoadrenalism, so that patients who require chemotherapy are more easily managed. Adrenalectomy or hypophysectomy used in the past induced regression in 30–50% of patients who previously responded to oophorectomy, but these procedures are rarely done today. Pharmacologic hormonal manipulation has in large part replaced these invasive procedures. Toremifene has shown no added value in women whose tumors no longer respond to tamoxifen. Aromatase inhibitors are of value in patients who responded to tamoxifen or oophorectomy but then progress.
B. THE POSTMENOPAUSAL PATIENT
1. Primary hormonal therapy
Tamoxifen, 20 mg daily, or anastrozole, 1 mg daily, is the initial therapy of choice for postmenopausal women with metastatic breast cancer amenable to endocrine manipulation. Anastrozole (an aromatase inhibitor) has fewer side effects than tamoxifen, the former therapy of choice, and is at least equally as effective. The main side effects of tamoxifen are nausea, vomiting, skin rash, and
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hot flushes. Rarely, it may induce hypercalcemia in patients with bony metastases. The main side effects of anastrozole are similar but lower in incidence; however, osteoporosis can occur.
2. Secondary or tertiary hormonal therapy
Postmenopausal patients who do not respond to tamoxifen or anastrozole should be given cytotoxic drugs such as CMF or AC. Postmenopausal women who respond initially to tamoxifen or anastrozole but later manifest progressive disease may be crossed over. Aromatase inhibitors have been available for the treatment of advanced breast cancer in postmenopausal women who fail tamoxifen treatment. Recent trials comparing an aromatase inhibitor, anastrozole, with tamoxifen suggest that the former is just as effective and has fewer side effects. Aromatase inhibitors recently have achieved the status of primary hormonal therapy in postmenopausal women. Clinical trials have proved the efficacy of anastrozole and toremifene for such purposes. Androgens have many toxicities and should rarely be used. As in premenopausal patients, neither hypophysectomy nor adrenalectomy is still being performed.
Chemotherapy
Cytotoxic drugs should be considered for the treatment of metastatic breast cancer (1) if visceral metastases are present (especially brain or lymphangitic pulmonary), (2) if hormonal treatment is unsuccessful or the disease has progressed after an initial response to hormonal manipulation, or (3) if the tumor is ER negative. The most useful single chemotherapeutic agent to date is doxorubicin (Adriamycin), with a response rate of 40–50%. Single agents are rarely used but rather are given in combination with other cytotoxic drugs.
Combination chemotherapy using multiple agents has proved to be more effective, with objectively observed favorable responses achieved in 60–80% of patients with stage IV disease. Various combinations of drugs have been used, and clinical trials are continuing in an effort to improve results and reduce undesirable side effects. Nausea and vomiting are well controlled with drugs that directly affect the central nervous system, such as ondansetron and granisetron. These drugs are selective antagonists of serotonin receptors in the central nervous system and block nausea caused by cytotoxic chemotherapy. Doxorubicin (40 mg/m2 intravenously on day 1) and cyclophosphamide (200 mg/m2 orally on days 3–6) produce an objective response in about 85% of patients so treated. Other chemotherapeutic regimens have consisted of various combinations of drugs, including cyclophosphamide, vincristine, methotrexate, fluorouracil, and taxanes with response rates ranging up to 60–70%. Prior adjuvant chemotherapy does not seem to alter response rates in patients who relapse. Growth factors such as erythropoietin (epoetin alfa), which stimulates red blood cell production and mimics the effect of erythropoietin, and filgrastim (granulocyte colony-stimulating factor; G-CSF), which stimulates proliferation and differentiation of hematopoietic cells, prevent lifethreatening anemia and neutropenia seen commonly with high doses of chemotherapy. These agents greatly diminish the incidence of infections that may complicate the use of myelosuppressive chemotherapy.
The taxanes (paclitaxel and docetaxel) have been shown to be very effective for patients with metastatic breast cancer. They have usually been given after failure of combination chemotherapy for metastatic disease or relapse shortly after completion of adjuvant chemotherapy. However, they are becoming more important in both the management of metastatic disease and even adjuvant therapy. These drugs have response rates of 30–40% in patients with metastatic disease. They may be especially valuable in treating anthracycline-resistant tumors. Both agents are currently being used after treatment with anthracyclines in patients with advanced disease as well as in adjuvant and neoadjuvant settings. High-dose chemotherapy and autologous bone marrow or stem cell transplantation aroused widespread interest for the treatment of metastatic breast cancer. With this technique, the patient receives high doses of cytotoxic agents, eradicating the marrow, for which the patient subsequently undergoes autologous bone marrow or stem cell transplantation. Complete response rates are as high as 30–35%—considerably better than what can be achieved with conventional chemotherapy. Most randomized trials, however, comparing high-dose chemotherapy with stem cell support show no improvement in survival over conventional chemotherapy. A study purporting to show a survival advantage to high-dose chemotherapy in South Africa was found to be falsified and discredited. Enthusiasm for high-dose chemotherapy with stem cell support has waned, but additional studies continue and recently showed a beneficial effect in some high-risk women. The technique is extremely costly, and the treatment itself is associated with a mortality rate of about 3–7%.
Bernard-Marty C et al: Facts and controversies in systemic treatment of metastatic breast cancer. Oncologist 2004;9:617.
Cristofanilli M et al: New horizons in treating metastatic disease. Clin Breast Cancer 2001;1:276.
Fricker J: Letrozole better than tamoxifen in postmenopausal women. Lancet Oncol 2005;6:137.
Harvey HA: Optimizing bisphosphonate therapy in patients with breast cancer on endocrine therapy. Semin Oncol 2004;31 (6 Suppl 12):23.
Hussain SA et al: Endocrine therapy and other targeted therapies for metastatic breast cancer. Expert Rev Anticancer Ther 2004;4:1179.
Mouridsen HT: Aromatase inhibitors in advanced breast cancer. Semin Oncol 2004;31(6 Suppl 12):3.
Pandit-Taskar N et al: Radiopharmaceutical therapy for palliation of bone pain from osseous metastases. J Nucl Med 2004; 45:1358.
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Slamon DJ et al: Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 2001;344:783.
Stadtmauer EA et al: Conventional-dose chemotherapy compared with high-dose chemotherapy plus autologous hematopoietic stem-cell transplantation for metastatic breast cancer. N Engl J Med 2000;342:1069.
PROGNOSIS
Stage of breast cancer is the most reliable indicator of prognosis (Table 16-6). Patients with disease localized to the breast and no evidence of regional spread after microscopic examination of the lymph nodes have by far the most favorable prognosis. Axillary lymph node status is the best-analyzed prognostic factor and correlates with survival at all tumor sizes. In addition, increased number of axillary nodes involved correlates directly with lower survival rates. Estrogen and progesterone receptors are prognostic variables because patients with hormone receptor-negative tumors and no evidence of metastases to the axillary lymph nodes have a much higher recurrence rate than do patients with hormone receptor-positive tumors and no regional metastases. The histologic subtype of breast cancer (eg, medullary, lobular, colloid) seems to have little significance in prognosis once these tumors are truly invasive. Flow cytometry of tumor cells to analyze DNA index and S-phase frequency aid in prognosis. Tumors with marked aneuploidy have a poor prognosis (Table 16-4). HER-2/neu oncogene amplification, epidermal growth factor receptors, and cathepsin D may have some prognostic value, but no markers are as significant as lymph node metastases in predicting outcome.
The mortality rate of breast cancer patients exceeds that of age-matched normal controls for nearly 20 years. Thereafter, the mortality rates are equal, though deaths that occur among breast cancer patients are often directly the result of tumor. Five-year statistics do not accurately reflect the final outcome of therapy.
Table 16-6. Approximate survival (%) of patients with breast cancer by TNM stage. | |||||||||||||||||||||||||||
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When cancer is localized to the breast, with no evidence of regional spread after pathologic examination, the clinical cure rate with most accepted methods of therapy is 75% to greater than 90%. Exceptions to this generalization may be related to the hormonal receptor content of the tumor, tumor size, host resistance, or associated illness. Patients with small mammographically detected estrogen and progesterone receptor-positive tumors and no evidence of axillary spread have a 5-year survival rate greater than 95%. When the axillary lymph nodes are involved with tumor, the survival rate drops to 50–70% at 5 years and probably around 25–40% at 10 years. In general, breast cancer appears to be somewhat more malignant in younger than in older women, and this may be related to the fact that fewer younger women have ER-positive tumors.
For those patients whose disease progresses despite treatment, supportive group therapy may improve survival. As they approach the end of life, such patients will require meticulous efforts at palliative care (see Chapter 5).
Hayes DF: Prognostic and predictive factors for breast cancer: translating technology to oncology. J Clin Oncol 2005;23: 1596.
FOLLOW-UP CARE
After primary therapy, patients with breast cancer should be followed for life for at least two reasons: to detect recurrences and to observe the opposite breast for a second primary carcinoma. Local and distant recurrences occur most frequently within the first 2 years. During this period, the patient should be examined every 6 months. Thereafter, examination is done annually. Special attention is paid to the contralateral breast, because 10–20% of patients will develop a new primary breast malignancy. The patient should examine her own breast monthly, and a mammogram should be obtained annually. In some cases, metastases are dormant for long periods and may appear 10–15 years or longer after removal of the primary tumor. Estrogen and progestational agents are rarely used for a patient free of disease after treatment of primary breast cancer, particularly if the tumor was hormone receptor positive. Studies nevertheless have failed to show an adverse effect of hormonal agents in patients who are free of disease. Even pregnancy has not been clearly associated with shortened survival of patients rendered disease free—yet most oncologists are reluctant to advise a young patient with breast cancer that she may become pregnant, and most are less than enthusiastic about prescribing hormone replacement therapy for the postmenopausal breast cancer patient. The use of estrogen replacement therapy may be considered for a woman with a history of breast cancer after discussion of the benefits and risks of such therapy for conditions such as osteoporosis and hot flushes, but is not recommended.
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Local Recurrence
The incidence of local recurrence correlates with tumor size, the presence and number of involved axillary nodes, the histologic type of tumor, the presence of skin edema or skin and fascia fixation with the primary tumor, and the type of initial local (breast) therapy. As many as 8% of patients develop local recurrence on the chest wall after total mastectomy and axillary dissection. When the axillary nodes are not involved, the local recurrence rate is less than 5%, but the rate is as high as 25% when they are heavily involved. A similar difference in local recurrence rate was noted between small and large tumors. Factors such as multifocal cancer, in situ tumors, positive resection margins, chemotherapy, and radiotherapy have an effect on local recurrence in patients treated with breast-conserving surgery.
Chest wall recurrences usually appear within the first 2 years but may occur as late as 15 or more years after mastectomy. All suspicious nodules and skin lesions should be biopsied. Local excision or localized radiotherapy may be feasible if an isolated nodule is present. If lesions are multiple or accompanied by evidence of regional involvement in the internal mammary or supraclavicular nodes, the disease is best managed by radiation treatment of the entire chest wall including the parasternal, supraclavicular, and axillary areas and usually by systemic therapy.
Local recurrence after mastectomy usually signals the presence of widespread disease and is an indication for studies to search for evidence of metastases. Most patients with locally recurrent tumor will develop distant metastases within 2 years. When there is no evidence of metastases beyond the chest wall and regional nodes, irradiation for cure or complete local excision should be attempted. Patients with local recurrence may be cured with local resection and radiation. After partial mastectomy, local recurrence may not have as serious a prognostic significance as after mastectomy. However, those patients who do develop a breast recurrence have a worse prognosis than those who do not. It is speculated that the ability of a cancer to recur locally after radiotherapy is a sign of aggressiveness and resistance to therapy. Completion of the mastectomy should be done for local recurrence after partial mastectomy; some of these patients will survive for prolonged periods, especially if the breast recurrence is DCIS or more than 5 years after initial treatment. Systemic chemotherapy or hormonal treatment should be used for women who develop disseminated disease or those in whom local recurrence occurs.
Edema of the Arm
Significant edema of the arm occurs in about 10–30% of patients after axillary dissection with or without mastectomy. It occurs more commonly if radiotherapy has been given or if there was postoperative infection. Partial mastectomy with radiation to the axillary lymph nodes is followed by chronic edema of the arm in 10–20% of patients. Because axillary dissection is more accurate for staging operation than axillary sampling, it is recommended that at least level I and II lymph nodes be removed, in combination with partial mastectomy. Sentinel lymph node dissection offers accurate staging without the removal of level I and II nodes and has a much lower risk of lymphedema for node-negative patients. Judicious use of radiotherapy, with treatment fields carefully planned to spare the axilla as much as possible, can greatly diminish the incidence of edema, which will occur in only 5% of patients if no radiotherapy is given to the axilla after a partial mastectomy and lymph node dissection.
Late or secondary edema of the arm may develop years after treatment, as a result of axillary recurrence or of infection in the hand or arm, with obliteration of lymphatic channels. Infection in the arm or hand on the dissected side should be treated with antibiotics, rest, and elevation. When edema develops, careful examination of the axilla for recurrence should be done. If there is no sign of recurrence, the swollen extremity should be treated with rest and elevation. A mild diuretic may be helpful. If there is no improvement, a compressor pump or manual decompression decreases the swelling, and the patient is then fitted with an elastic glove or sleeve. Most patients are not bothered enough by mild edema to wear an uncomfortable glove or sleeve and will treat themselves with elevation or manual decompression alone. Benzopyrones have been reported to decrease lymphedema but are not approved for this use in the United States. Rarely, edema may be severe enough to interfere with use of the limb.
Breast Reconstruction
Breast reconstruction is usually feasible after standard or modified radical mastectomy. Reconstruction should be discussed with patients prior to mastectomy, because it offers an important psychological focal point for recovery. Reconstruction is not an obstacle to the diagnosis of recurrent cancer. The most common breast reconstruction has been implantation of a silicone gel prosthesis in the subpectoral plane between the pectoralis minor and pectoralis major muscles. Although the FDA has placed a moratorium on the purely cosmetic use of silicone gel implants because of possible leakage of silicone and possible associated autoimmune phenomena, they can be used in the reconstructed patient with appropriate prior consent. Most plastic surgeons currently would place a saline-filled prosthesis rather than a silicone gel implant. Alternatively, autologous tissue can be used for reconstruction.
Autologous tissue flaps are aesthetically superior to implant reconstruction in most patients. They also have the advantage of not feeling like a foreign body to the patient. The most popular autologous technique currently is the trans-rectus abdominis muscle flap (TRAM flap), which is done by rotating the rectus abdominis
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muscle with attached fat and skin cephalad to make a breast mound. The free TRAM flap is done by completely removing the rectus with overlying fat and skin and using microvascular surgical techniques to reconstruct the vascular supply on the chest wall. A latissimus dorsi flap can be swung from the back but offers less fullness than the TRAM flap and is therefore less acceptable cosmetically. Reconstruction may be performed immediately (at the time of initial mastectomy) or may be delayed until later, usually when the patient has completed adjuvant therapy. When considering reconstructive options, concomitant illnesses should be considered, since the ability of an autologous flap to survive depends on medical comorbidities. In addition, the need for radiotherapy may affect the choice of reconstruction.
Risks of Pregnancy
Data are insufficient to determine whether interruption of pregnancy improves the prognosis of patients who are discovered during pregnancy to have potentially curable breast cancer and who receive definitive treatment. Theoretically, the increasingly high levels of estrogen produced by the placenta as the pregnancy progresses could be detrimental to the patient with occult metastases of hormone-sensitive breast cancer. Moreover, occult metastases are present in most patients with positive axillary nodes, and treatment by adjuvant chemotherapy could be potentially harmful to the fetus, although chemotherapy may be given to pregnant women. Under these circumstances, interruption of early pregnancy seems reasonable, with progressively less rationale for the procedure as term approaches. The decision is affected by many factors, including the patient's desire to have the baby and the generally poor prognosis when axillary nodes are involved.
Equally important is the advice regarding future pregnancy (or abortion in case of pregnancy) to be given to women of child-bearing age who have had definitive treatment for breast cancer. Under these circumstances, it must be assumed that pregnancy will be harmful if occult metastases are present, though this has not been demonstrated. Patients whose tumors are ER negative (most younger women) probably would not be affected by pregnancy. To date, no adverse effect of pregnancy on survival of pregnant women who have had breast cancer has been demonstrated, though most oncologists advise against it.
In patients with inoperable or metastatic cancer (stage IV disease), induced abortion is usually advisable because of the possible adverse effects of hormonal treatment, radiotherapy, or chemotherapy upon the fetus.
Cocquyt VF et al: Better cosmetic results and comparable quality of life after skin-sparing mastectomy and immediate autologous breast reconstruction compared to breast conservative treatment. Br J Plast Surg 2003;56:462.
Langer S et al: Lymphatic mapping improves staging and reduces morbidity in women undergoing total mastectomy for breast carcinoma. Am Surg 2004;70:881.
van der Veen P et al: Lymphedema development following breast cancer surgery with full axillary resection. Lymphology 2004;37:206.
CARCINOMA OF THE MALE BREAST
ESSENTIALS OF DIAGNOSIS
A painless lump beneath the areola in a man usually over 50 years of age.
Nipple discharge, retraction, or ulceration may be present.
GENERAL CONSIDERATIONS
Breast cancer in men is a rare disease; the incidence is only about 1% of that in women. The average age at occurrence is about 60—somewhat older than the commonest presenting age in women. There may be an increased incidence of breast cancer in men with prostate cancer. The prognosis, even in stage I cases, is worse in men than in women. Blood-borne metastases are commonly present when the male patient appears for initial treatment. These metastases may be latent and may not become manifest for many years. As in women, hormonal influences are probably related to the development of male breast cancer. There is a high incidence of both breast cancer and gynecomastia in Bantu men, theoretically owing to failure of estrogen inactivation by a liver damaged by associated liver disease. It is important to note that first-degree relatives of men with breast cancer are considered to be at high risk. This risk should be taken into account when discussing options with the patient and family. In addition, BRCA2 mutations are common in men with breast cancer. Men with breast cancer, especially with a history of prostate cancer, should receive genetic counseling.
Clinical Findings
A painless lump, occasionally associated with nipple discharge, retraction, erosion, or ulceration, is the primary complaint. Examination usually shows a hard, ill-defined, nontender mass beneath the nipple or areola. Gynecomastia not uncommonly precedes or accompanies breast cancer in men. Nipple discharge is an uncommon presentation for breast cancer in men, but is an ominous finding associated with carcinoma in nearly 75% of cases.
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Breast cancer staging is the same in men as in women. Gynecomastia and metastatic cancer from another site (eg, prostate) must be considered in the differential diagnosis. Benign tumors are rare. Biopsy settles the issue.
Treatment
Treatment consists of modified radical mastectomy in operable patients, who should be chosen by the same criteria as women with the disease. Irradiation is the first step in treating localized metastases in the skin, lymph nodes, or skeleton that are causing symptoms. Examination of the cancer for hormone receptor proteins is of value in predicting response to endocrine ablation. Men commonly have ER-positive tumors. Adjuvant chemotherapy is used for the same indications as in breast cancer in women.
Because breast cancer in men is frequently a disseminated disease, endocrine therapy is of considerable importance in its management. Tamoxifen is the main drug for management of advanced breast cancer in men. Tamoxifen (20 mg daily) should be the initial treatment. There is little experience with aromatase inhibitors though they should be effective. Castration in advanced breast cancer is a successful measure and more beneficial than the same procedure in women but is rarely used. Objective evidence of regression may be seen in 60–70% of men with hormonal therapy—approximately twice the proportion in women. The average duration of tumor growth remission is about 30 months, and life is prolonged. Bone is the most frequent site of metastases from breast cancer in men (as in women), and hormonal therapy relieves bone pain in most patients so treated. The longer the interval between mastectomy and recurrence, the longer the tumor growth remission following treatment. As in women, there is correlation between estrogen receptors of the tumor and the likelihood of remission following hormonal therapy.
Aromatase inhibitors should replace adrenalectomy in men as it has in women. Corticosteroid therapy alone has been considered to be efficacious but probably has no value when compared with major endocrine ablation. Either tamoxifen or aromatase inhibitors may be primary or secondary hormonal manipulation.
Estrogen therapy—5 mg of diethylstilbestrol three times daily orally—may be effective hormonal manipulation after others have been successful and failed, just as in women. Androgen therapy may exacerbate bone pain. Chemotherapy should be administered for the same indications and using the same dosage schedules as for women with metastatic disease.
Prognosis
The prognosis of breast cancer is poorer in men than in women. The crude 5and 10-year survival rates for clinical stage I breast cancer in men are about 58% and 38%, respectively. For clinical stage II disease, the 5and 10-year survival rates are approximately 38% and 10%. The survival rates for all stages at 5 and 10 years are 36% and 17%. For those patients whose disease progresses despite treatment, meticulous efforts at palliative care are essential (see Chapter 5).
Kwiatkowska E et al: Somatic mutations in the BRCA2 gene and high frequency of allelic loss of BRCA2 in sporadic male breast cancer. Int J Cancer 2002;98:943.
Loerzel VW et al: Male breast cancer. Clin J Oncol Nurs 2004;8: 191.
Volm MD: Male breast cancer. Curr Treat Options Oncol 2003;4: 159.
Weiss JR et al: Epidemiology of male breast cancer. Cancer Epidemiol Biomarkers Prev 2005;14:20.
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- Chapter II Information Search on the Internet: A Causal Model
- Chapter IV How Consumers Think About Interactive Aspects of Web Advertising
- Chapter V Consumer Complaint Behavior in the Online Environment
- Chapter XII Web Design and E-Commerce
- Chapter XVI Turning Web Surfers into Loyal Customers: Cognitive Lock-In Through Interface Design and Web Site Usability