Rima J. Couzi
Michael J. Purtell
Breast cancer is the most commonly diagnosed cancer in women, accounting for 32% of all new cancer diagnoses. It is second only to lung cancer in cancer deaths. In 2005 alone, an estimated 211,240 women will be diagnosed with breast cancer, and 40,410 will die of the disease (1). The current cumulative lifetime risk for developing invasive breast cancer is one in seven. This statistic, although accurate, is often misinterpreted as being a constant risk at any age. The risk of developing breast cancer increases proportionally with age from 1 in 207 in women younger than 40 years to 1 in 13 in the 60 to 79 age group (1). Women tend to overestimate their risk of developing breast cancer, and breast-related complaints are a significant source of anxiety to patients, despite the fact that most of these are secondary to benign causes. Many women view breast cancer as the leading threat to their health, although statistically it ranks behind cardiovascular diseases and lung cancer as a cause of death in women (2,3). The primary caregiver must have a rational approach to the evaluation and treatment of breast complaints and breast masses. He or she implements the screening program for cancer and supervises the patient's referral. If cancer is found, the primary caregiver is the one to whom the patient initially turns for information. A reassuring patient–caregiver relationship is critical in dealing with this emotionally charged area of medicine.
Normal Anatomy and Physiology of the Breast
The breast is a modified sweat gland that consists of a tree-like structure with 5 to 10 primary milk ducts that originate at the nipple. These branch into segmental ducts and subsegmental ducts that end in terminal duct lobular units (see Harris, athttp://www.hopkinsbayview.org/PAMreferences). These units are embedded in loose connective tissue with a rich capillary supply. The terminal duct lobular units, which are lined by cuboidal epithelium, are sensitive to hormonal influences and are the basic lactational units of the breast. There are complex interactions between steroid hormones, peptide hormones, and growth factors that affect breast development, maturation, and differentiation. Briefly, estrogen stimulates the proliferation of ductal tissue, whereas progesterone stimulates the proliferation and differentiation of the lobules. The production of milk is regulated by prolactin. During the follicular phase of the menstrual cycle, the cuboidal epithelial cells proliferate.
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In the luteal phase, the lobular stromal cells become edematous and the ductules open up with secretions from the cuboidal cells.
During pregnancy the lobular units proliferate maximally and only rarely return to normal in the postpartum period. As pregnancy proceeds, colostrum is formed from fluid accumulation and desquamation of epithelial cells. Colostrum is then released in the immediate postpartum period. In the postmenopausal years, the loss of hormonal stimulation results in a decrease in the number of lobular units and atrophy of the remaining ones. The connective tissue also becomes less cellular with an increased fat content. The dynamic changes that occur in the breast at different phases can result in a spectrum of benign breast disorders with histologic features that range from cystic and fibrous changes to ductal, lobular, and stromal proliferation. It is important to realize that anatomic changes associated with normal hormonal fluctuations during a menstrual cycle do not occur to the same degree in all areas of the breast. This accounts for the asymmetric palpatory findings in the normal breast, which is often lumpy.
Screening Procedures
The aim of breast cancer screening is to detect breast cancer at the earliest possible stage, when effective treatments confer the greatest chances for long-term survival. There are three commonly used screening modalities for breast cancer and these are often used concurrently: mammography, clinical breast examination, and breast self examination. A main endpoint in assessing the benefit from screening is whether it decreases cancer-related mortality.
The role of screening mammography in reducing mortality from breast cancer and the age at which to start and stop screening have been a source of much debate over the years. Eight randomized controlled trials of breast cancer screening as well as several cohort and case-control studies have been conducted. A meta-analysis of 13 studies, including the eight randomized controlled screening trials, showed an overall 25% reduction in breast cancer mortality for the women who underwent screening compared with those who did not ([randomized risk] RR 0.75, 95% [confidence interval CI, 0.68 to 0.83) (4).
A re-analysis of published reports by the Cochrane Institute stirred considerable controversy in 2001 when the authors suggested that mammography is of no value for women of any age. They deemed that only two trials were methodologically sound and found no benefit from screening mammography in these trials (5,6). However there have been rebuttals of this analysis, and more recent updates of the trials appear to show that screening mammography does decrease mortality from breast cancer (7, 8, 9, 10, 11). The impact of news media coverage of this controversy was examined in a recent article (12).
At this time there is strong consensus among the major American medical societies that routine screening mammography, with or without clinical breast examination, should be offered to women age 50 years and older. There is less agreement on screening women age 40 to 49 years and little data on which to base recommendations for screening women older than 74 years.
The American Cancer Society, American College of Radiology, American Medical Association, the American College of Obstetrics and Gynecology, and the National Cancer Institute (NCI) all recommend routine screening starting at age 40 (13, 14, 15, 16). This recommendation is also supported by the U.S. Preventive Services Task Force (17).
The Canadian Task Force on the Periodic Health Examination and the American College of Physicians recommend starting screening mammography at the age of 50 years (18).
In 1997, the National Institutes of Health (NIH) held a consensus conference on breast cancer screening in women age 40 to 49 years. It was concluded that there were not enough data to recommend routine mammographic screening for women in that age group, and that each woman should decide individually about screening after discussion with her health care provider. Nevertheless, the NCI recommends screening every 1 to 2 years for women 40 to 49 years of age.
The disagreement on the benefit of mammography for women age 40 to 49 years stems in part from the length of followup time needed to show a reduction in breast cancer mortality among screened women. At 11 to 16 years of followup, the Canadian National Breast Screening study in women in their forties continues to fail to show a reduction in breast cancer mortality among screened women (18). However a meta-analysis performed by the U.S. Preventive Services Task Force shows a relative risk of breast cancer mortality of 0.85 for screened women younger than 50 after 14 years of observation (9). The number of women needed to be screened to prevent one death from breast cancer was 1,792. This compares with the need to screen 838 women older than 50 years to prevent a breast cancer-related death (9). Most of the cancers found in women who begin screening in their forties are not discovered until the women are in their fifties. Some authors have suggested in the past that the incremental benefit of starting screening at 40 years of age is not worth exposing women to the emotional and physical harms of screening for an extra decade. The possibility that, for most women, the outcome would have been the same had they started screening after 50 years of age has been raised. Another concern is the lower test specificity in young women, who often have dense breasts, complicating interpretation. This leads to a much higher benign-to-malignant biopsy ratio than that found in older women. For women 40 to 49 years old or their clinicians who are considering delaying the initiation of screening, Gail and Rimer have provided risk-based
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recommendations that may help the primary caregiver in the counseling process and in the selection of patients who might best be served by screening mammography (19).
Whatever decision the primary caregiver makes about the usefulness of screening mammography in young women, it is important to discuss the benefits and the risks of screening with all women about to start screening. A woman needs to understand her likely experience when she goes for testing, particularly if it is her first mammogram. Patients should know that mammography may be uncomfortable because of the need for breast compression in order to obtain a good image quality. The communication plan following mammography should be worked out ahead of time to minimize the anxiety of waiting for a telephone call, although breast cancer screening centers now increasingly offer immediate film interpretation. This allows the radiologist to order additional mammographic views or breast ultrasound at the same visit, thereby lowering the recall rate and possibly patient anxiety. Young women in particular should understand the poor specificity of mammography and the high likelihood of a recommendation for intervention (biopsy or early followup), especially with the first mammogram. The patient should know that if she receives that recommendation, the chance of benign or no disease far outweighs the chance of cancer. In the United States, additional evaluation is recommended in about 11% of cases, of which 90% are ultimately proved to be benign conditions (20). False-positive mammograms can result in a heightened state of anxiety about breast cancer that can last several months (21).
There is a paucity of data to guide the recommendation on what age to stop screening, as few women older than 70 years old were enrolled in screening trials. Although the incidence of breast cancer increases with age, the benefit of screening mammography in the elderly may be offset by increasing comorbidities and reduced life expectancy. For example, detecting a clinically occult, slow growing breast cancer in an 85-year-old woman with heart failure and a short life expectancy is likely to be more harmful than beneficial. However it is reasonable to continue screening women older than 70 years if their life expectancy is not compromised by comorbid disease. Biennial mammography beyond age 65 years has been shown to be cost-effective by the U.S. preventive Task Force (22).
The independent role of clinical breast examination (CBE) in decreasing mortality from breast cancer is less well defined, but CBE is an important component of screening, as 10% to 15% of palpable breast cancers are not visualized by mammography. Breast self-examination (BSE) is often advocated, but there is no evidence that it is effective as a screening modality and it may increase the chance of having a breast biopsy for benign disease (17,23). BSE should not substitute for mammography and a CBE. However, if a woman wishes to perform BSE, she should be taught the proper technique and be instructed on how to differentiate normal breast tissue from suspicious breast lumps.
Several new screening procedures are under review but are not currently recommended for population screening. These include digital mammography, computer-assisted detection, and magnetic resonance imaging (MRI). Digital mammography is costlier than conventional mammography, but was recently found to be significantly better at detecting breast cancer in young women, premenopausal and perimenopausal women, and women with dense breasts (24). Studies have shown that breast MRI has an increased sensitivity but a reduced specificity compared with mammography. Women with breast cancer gene 1 (BRCA 1) or breast cancer gene 2 (BRCA 2) mutations have a significant lifetime risk for developing breast cancer and may benefit from breast MRI screening (25,26). However, this is an expensive screening modality and at this point it is unknown if it improves survival rates.
Clinical Characteristics of Common Diseases of the Breast
Benign Tumors
Breast complaints are common in primary care practice and the vast majority of these complaints are related to benign conditions. It is important to have a clear understanding of the clinical features of benign conditions and to evaluate and follow the patient in order to avoid failing to diagnose breast cancer.
The patient may be asymptomatic or present with breast pain, nonbreast pain, focal or diffuse breast lumps, or nipple discharge. Most benign breast diseases are related to the hormonal changes that occur during the three main reproductive periods. Histologically confirmed benign breast conditions may be associated with no increased risk versus a small or moderate increase in risk for subsequent development of breast cancer (27).
Fibroadenoma
Fibroadenoma is the most common cause of a unilateral discrete mass in the 15- to 35-year-old age group, with a peak incidence from 20 to 25 years of age. In 10% to 15% of cases, there are multiple tumors. These are benign tumors that contain both epithelial and stromal components, and usually remain static at 1 to 2 cm in size. The etiology of these tumors is unknown, but a hormonal relationship is postulated as the tumors can grow significantly during pregnancy, persist during the reproductive years, and regress in the postmenopausal years.
The patient with a fibroadenoma usually reports a breast mass but denies pain, nipple discharge, or other breast changes. On physical examination, the lesion is usually firm but not rock-hard; it is smooth and well
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circumscribed, nontender, and easily moveable. It often rolls about in the breast, mimicking a very large marble. Mammography reveals a discrete, round, well-circums-cribed lesion. New or enlarging lesions need to be distinguished from cancer. Many believe that fibroadenomas also have a characteristic ultrasonographic appearance. There is some controversy about the optimal management of these lesions. Most surgeons recommend obtaining a core biopsy or fine-needle aspiration (FNA) to establish the diagnosis histologically. If the diagnosis is confirmed, close followup with CBE and imaging to assess for stability is accepted clinical practice, especially in women under 25 years. Close followup is important because of the rare possibility of simultaneous lobular carcinoma or progression to cystosarcoma phyllodes. Excisional biopsy is often recommended for women older than 25 years.
Phyllodes Tumor
Phyllodes tumor is a unique sarcomatous tumor of the breast that may arise from fibroadenoma. The mean age of presentation ranges between 44 and 50 years. Rapid growth of a breast mass is often reported. The mass is usually well-circumscribed, with a rubbery and lobulated consistency, and can be quite large at presentation. Histologically, phyllodes tumors differ from fibroadenomas in that the stromal elements have increased cellularity, pleomorphism, nuclear atypia, and mitotic figures. The tumors are classified as benign, borderline malignant, or malignant based on histological features. The malignancy rate is 20% to 30%, and approximately one third to one half of these will metastasize, primarily in a hematogenous fashion, with lung involvement the most frequent site. However, the overall metastatic rate for all phyllodes tumors is less than 5%. The current surgical practice is to perform a wide local excision with adequate clear margins. Mastectomy may be necessary for larger tumors and for repeated local recurrences (28).
Intraductal Papilloma
Intraductal papillomas often present with serosanguineous, spontaneous, recurrent, or persistent nipple discharge from a single duct. These small tumors are not palpable, but their location can usually be determined by applying pressure on various quadrants of the areolocutaneous margin and noting which quadrant produces the discharge. An intraductal papillary cancer is a possibility that must be excluded by excising a small, pie-shaped segment in the area producing the discharge.
Fibrocystic Disease
Fibrocystic changes of the breast are common and occur to some extent in most women. These changes consist of an increased number of cysts or fibrous tissue in a normal breast and are considered a normal variant. Fibrocystic disease is diagnosed when fibrocystic changes are associated with symptoms such as of breast pain, nipple discharge, or breast lumpiness. A hormonal basis is thought to be at play, and the pain is often more prominent just before the onset of menses. On physical examination the breast feels lumpy, with bilateral, diffuse, tender, easily movable ill-defined masses, usually in the upper outer quadrant of the breasts. Breast cysts can sometimes enlarge acutely and cause sudden and severe localized pain. The subareolar ducts may be dilated and spontaneous discharge of thick, gray-green fluid is common. Histologically, cyst and ductal ectasia is noted.
Because of clinical and sometimes radiological uncertainty, many patients undergo at least one biopsy to rule out cancer. Most lesions are benign; usually, the histology is either normal (70%) or shows only epithelial hyperplasia (25%). These findings are of little concern, as such patients are at low risk for development of breast cancer and do not require more vigilant followup than normal (29). In contrast, a report of hyperplasia with atypia (3% to 4% of benign biopsies) is significant, particularly if the mother or a sister of the patient has had breast cancer. In the absence of a positive family history, the finding of atypia increases the risk for breast cancer development fourfold, and in association with a positive family history this risk is increased almost 11-fold (29). These patients require careful followup, with annual mammogram and biannual physical examinations, and in selected cases, even prophylactic bilateral mastectomies may be considered, especially if the woman has a mutation of the BRCA 1 or BRCA 2 gene (30).
Premature Hyperplasia
A concentric unilateral swelling can occur beneath the nipple before puberty in girls. This commonly occurs between the ages of 7 and 9 years. The lump can be 1 to 2 cm in diameter and is usually nontender. Within a year, a contralateral lump appears and often both lumps remain static until puberty. Since a biopsy is functionally equivalent to a mastectomy in a child, it is contraindicated.
Gynecomastia
Among men with breast masses, the differential diagnosis includes gynecomastia (see Chapter 85) and male breast cancer. The latter is rare, accounting for approximately 1% of all breast cancers. Although gynecomastia has many causes, it has a characteristic presentation. Gynecomastia appears as a breast mass beneath the areola that is usually slightly tender and easily movable. It is never associated with ulceration or nipple retraction. If gynecomastia is ruled out, a breast mass in a male should be examined by biopsy.
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Cancer
The widespread use of screening mammography has changed the presentation of breast cancer, with increasing detection of smaller nonpalpable lesions. Sometimes a breast lump is found by the patient or is detected by the primary caregiver during a routine examination. The classical clinical finding that raises suspicion for breast cancer is the presence of a single, often painless, hard fixed lesion measuring more than 2 cm. There may be associated subtle skin dimpling or nipple retraction. Approximately 15% of cases are locally advanced at presentation. These are associated with more significant skin dimpling with peau d’orange appearance, erythema, altered venous pattern, matted fixed axillary nodes, or a mass fixed to the chest wall.
Evaluation of a Breast Mass
History: Risk Factors and Symptoms
The chance of a woman developing cancer increases with age (1). Most women who present with a breast lump will need additional testing, although most lumps will ultimately prove to be benign lesions. The evaluation starts with a careful history and physical examination. The history should elicit information on the location of the lump, how it was detected, how long it has been present, any associated complaints, whether it waxes and wanes at different times in the menstrual cycle, and if it has changed in size. The reproductive history, use of oral contraceptives or hormone replacement therapy, alcohol use, previous history of breast biopsy, and family history of breast cancer are also important components of the history.
Women are becoming increasingly sensitive to the possibility of developing breast cancer and are more aware of factors that may modulate their risk (Table 105.1). Genetic testing for breast cancer susceptibility genes (BRCA 1 and BRCA 2) has now become commercially available. Women with worrisome family histories, those who have developed breast cancer before age 40, and women of Ashkenazi Jewish descent may be candidates for such testing. These women should be referred to a specialized risk assessment clinic, usually located in an academic center, where a genetic counselor is involved in the evaluation. Counseling is provided on the risks and benefits, limitations and potential insurance implications of genetic testing. Guidelines for such testing have been published by the American Society of Clinical Oncology (31).
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TABLE 105.1 Risk Factors for Carcinoma of the Breast |
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Most breast cancers are sporadic and genetic testing is not recommended in these instances. Women tend to overestimate their breast cancer risk, and also may not realize that their risk of dying from breast cancer is one third of their chance of developing the disease. It falls on the primary caregiver to guide the patient in understanding her own risk and to counsel her as to whether her risk may justify a request for genetic testing. There are well established risk factors for breast cancer (32). For an average woman increasing age confers the highest relative risk for breast cancer. In ascertaining a woman's risk, the menstrual and reproductive history is also important. Early menarche and late menopause are associated with a slightly increased risk for development of breast cancer, whereas menopause before 35 years of age (normal or surgical) reduces the risk. The risk of breast cancer is increased in nulliparous women, whereas a full-term pregnancy before age 18 years offers some protection. It appears unlikely that the use of oral contraceptives changes a woman's risk of breast cancer (see Chapter 100), but postmenopausal estrogen replacement therapy may increase the risk by 30% (see Chapter 106). The occurrence of breast cancer in a first-degree relative (sister or mother) increases a woman's probability of developing cancer two- to fourfold. A second degree-relative with breast cancer increases the risk to a lower extent. A personal history of a breast biopsy showing atypical hyperplasia also increases the risk fourfold (29). The other major risk factor besides family history is a personal history of breast cancer, which increases the risk of contralateral breast cancer fivefold (33).
Two risk-prediction models are widely available and can be used to assess a woman's personal level of breast cancer risk. The Gail model developed for the NCI is available at http://www.bcra.nci.nih.gov/brc/q1.htm. This tool was used to select patients for the Breast Cancer Prevention trial discussed later in this chapter. The revised Gail model incorporates information about race. The limitations of this tool stem from not including information about second-and third-degree relatives, thereby making it unreliable for patients with a strong family history of breast cancer. For such women, the risk assessment tool developed by Claus (34) is more appropriate.
The patient should be questioned about the presence of other symptoms (e.g., pain, discharge) related to a breast mass, the duration of those symptoms if present, and whether the discovery of the mass or onset of the other symptoms was associated with changes in the menses, injury to the breast, pregnancy, or changes in medication.
After the presence of a mass, nipple discharge is the second most common sign of breast cancer. Nonlactational
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nipple discharge can be unilateral or bilateral, spontaneous or evoked only by pressure and massage, and persistent or recurrent. If the discharge is associated with a mass on physical examination, the mass should be the primary concern. Nipple discharge in women older than 50 years of age must be viewed with more suspicion than in younger women, regardless of its presentation. Discharge evoked only by trauma, massage, or pressure has no clinical importance. Spontaneous, recurrent, or persistent discharge from one or two ducts not associated with a mass requires surgical exploration of the duct to differentiate benign papilloma from intraductal papillary carcinoma. Either is possible in the absence of a presenting mass, and the character of the discharge is not helpful (see Chapters 81 and 101 for a discussion of galactorrhea).
Physical Examination
The patient should be seated undressed to the waist on an examining table. Inspection and palpation of the supraclavicular and axillary lymph nodes should be performed. Inspection and palpation of the nipples, areolae, and breasts are done next. While the patient is sitting, the arm on the side being examined can be raised by the clinician to allow palpation high into the axilla. The examination should then be repeated with the patient in the supine position with her arm raised over her head so that the breast flattens on the chest wall. If the clinician cannot appreciate a mass noted by the patient, it is important to allow the patient sufficient time to find the lesion herself rather than to dismiss the complaint. If both the patient and the clinician cannot locate the mass, the patient should be reassured that benign fibrous masses often disappear spontaneously, as do menstrual-related cysts.
Initial Management
The three most common masses found in the breast are fibroadenoma, fibrocystic changes, and carcinoma. Each of these common lesions has a peak incidence at different ages, but there is considerable overlap. Because of this overlap and the inability of the clinician to make a diagnosis with certainty from history, physical examination, or radiographic studies, a biopsy usually is the only definitive test to rule out carcinoma. Breast lumps are either felt by the patient or her physician, or may be nonpalpable, picked up by screening mammography. The evaluation of palpable and nonpalpable lumps may differ.
Age Younger Than 35 Years
Diagnostic mammography is not routinely ordered for women younger than 35 years who present with a breast lump, because their breasts are often too dense for the mammograms to provide additional useful information. However, if the patient has large breasts that are difficult to examine, persistent symptoms, or a strong family history of breast cancer, mammography should be considered. For such patients digital mammograms have been shown recently to be superior to standard mammography in detecting breast cancer (24). A discrete mass that feels cystic may be watched through one or two menstrual cycles. Breast ultrasound can establish whether a mass is solid or cystic. A cystic mass could be aspirated and if the fluid is not bloody, no additional workup is needed. The patient should be checked again after a few weeks to ensure that the cyst has not recurred. A surgical consultation is recommended if the cyst recurs, if the fluid is bloody or if the mass is solid. An easily movable, nontender, smooth, marble-like mass in a woman younger than 30 years of age is most likely a fibroadenoma.
Age 1 Years and Over
The evaluation usually starts with mammography. It is important to remember that a persistent mass that is not seen on mammography should not be ignored, since 10% to 15% of palpable breast cancers present with lesions that are not seen on mammography (16). A breast ultrasound may also be obtained at the same time to evaluate whether the mass is solid or cystic. The next step in the evaluation depends on the local facilities and expertise. A suspicious lump needs to be worked up fully to avoid missing a breast cancer. This could involve a fine needle aspiration of the mass, an ultrasound-guided core biopsy or an excisional biopsy.
FNA for cytology, or an ultrasound-guided core biopsy are often performed first because they are easier and less traumatic than an open biopsy. If cancer is documented, then the surgical approach can be discussed and planned with the patient. A preoperative consultation with a medical oncologist may be suggested by the surgeon, if the patient is a candidate for neoadjuvant (prior to surgery) chemotherapy or hormonal therapy. At times, an excisional biopsy is performed as the initial diagnostic procedure, but more often it is done when the FNA or the core biopsy is negative for cancer. In such situations, the definitive surgical management of the breast cancer may be delayed until the final pathology report is available. In special circumstances, a plan could be outlined with the patient based on the possibility that the intra-operative frozen sections reveal cancer.
Needle Aspiration of a Palpable Mass
In the past, aspiration was limited to nodules thought to be cystic, with sonography used to help distinguish cystic from solid lesions. More recently, aspiration by the surgeon of solid lesions to obtain material for cytologic examination has allowed the diagnosis of carcinoma to be made from the office and perhaps can spare some patients a surgical biopsy. In the case of a cystic lesion, if the mass
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does not completely disappear, if the fluid is bloody, or the mass rapidly recurs, an open biopsy is necessary. Cytologic examination of the fluid is usually of little use and need not be done routinely, unless the fluid is bloody. If the lesion disappears completely without recurrence, routine followup is sufficient. If the results of cytology obtained by needle aspiration of a solid lesion are negative, formal biopsy usually is required, because false-negative findings are common.
Surgical Biopsy
The referring practitioner should inform the patient not only of the need for surgical consultation but also why it is needed and that a biopsy may be recommended by the surgeon. The patient should be encouraged to ask questions. The consultation is stressful, and the patient is more likely to absorb information from her personal caregiver. Additionally, the patient needs support from her personal caregiver and the reassurance of continued involvement in her care should a biopsy reveal cancer.
Preparation
Most biopsies can be done on an outpatient basis in an ambulatory surgery unit. Either local anesthesia with intravenous sedation (preferred) or general anesthesia can be used. The patient should not eat or drink after midnight on the night before the biopsy.
Operation
A 2.5- to 5.0-cm incision is used to allow an adequate biopsy that is cosmetically satisfactory. The incision site is selected very carefully to minimize the potential for disfigurement should cancer be found and should breast-conserving therapy be chosen subsequently. It should be explained to the patient that, in addition to a possible residual mass, a ridge of tissue secondary to sutures and scar often remains after the operation. Removal of a large mass might necessitate a small drain, which is withdrawn in the office 1 or 2 days after the biopsy.
Stereotactic Biopsy
If the mass is palpable, then the tissue of concern is easily located and biopsied. As noted previously, biopsies increasingly are being obtained for mammographic lesions found in the absence of a palpable mass. Stereotactic biopsy using imaging to guide an automatic biopsy gun equipped with a core biopsy needle is the preferred approach. In experienced hands, adequate tissue can be obtained almost 100% of the time with this technique, with a diagnostic sensitivity of 95% or better (35,36). Stereotactic biopsy greatly simplifies the diagnostic process and may allow a preliminary diagnosis to be made on the day of the procedure. It is often the first step in the evaluation of suspicious microcalcifications identified on the mammogram. After the procedure, a specimen radiograph is done to ensure that the microcalcifications have been sampled. Several weeks after the biopsy, the patient should have a mammogram to confirm that the suspicious area is no longer present. However, there are a few caveats. Because radiographic stereotactic biopsy shifts the diagnostic procedure from the surgeon to the radiologist, it must be made clear to all who is responsible for reporting the final results to the patient and arranging appropriate followup, whether it is the primary caregiver or the radiologist.
All areas of the breast may not be accessible to stereotactic biopsies; for example, deep or very superficial lesions are not. Such lesions are better approached by surgery with needle localization. Under mammographic guidance, a radiologist places thin needles or hooks into the breast, with the tips resting within 1 cm of the suspicious area on the mammogram. Methylene blue or some other color marker is then injected into the breast to mark the abnormal area noted on the mammogram. The patient then proceeds to the ambulatory surgery unit, where the surgeon excises the stained area. If the mammographic abnormality contains microcalcifications, radiography of the biopsy specimen is used to ensure that they have been removed with the biopsy specimen. A negative result from a stereotactic core biopsy usually entails a subsequent surgical biopsy to ensure that the result was not falsely negative. The primary practitioner needs to work with the surgeon and radiologist so that the patient undergoes the minimal number of procedures.
Followup
Ecchymoses or hematoma (5% of patients) and wound infection (1% to 2% of patients) are the main complications of breast biopsy. A large hematoma may require evacuation, but this usually can be done in the office. Exercise and strenuous activities should be avoided for 7 to 10 days after a breast biopsy to guard against late bleeding. The long-term sequelae of breast biopsy are minimal; chronic scar formation may cause some difficulty with followup examinations and interpretation of mammograms. Detailed descriptions of the biopsy site should be noted in the patient's chart by caregivers on followup, and details of the biopsy should be conveyed to radiologists reading future mammograms.
Followup Management of a Benign Breast Mass
Fibroadenoma
If a fibroadenoma is excised, the patient should have routine followup as defined by her risk factors for carcinoma and age. The patient should be reassured that there is no increased risk of malignancy because of the fibroadenoma.
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Fibrocystic Disease
If the epithelium is normal on histologic examination, no special followup is necessary for the patient with a benign biopsy. Even if proliferative epithelial changes are noted, the increased risk is so minimal (less than twofold) that the patient should be reassured and no special followup is warranted. Only the finding of atypia, especially in a patient with a history of breast cancer in a sibling or mother, requires special consideration. Without such a family history, monthly self-examinations of the breasts, a physical examination twice yearly, and an annual mammogram should suffice. If a woman has at least a 40% lifetime risk of developing breast cancer, then bilateral prophylactic mastectomies have been shown to improve survival by at least 3 years (30). Subcutaneous mastectomy with implants should not be considered as a compromise, because the 15% to 20% of the breast that is left behind with this procedure remains at risk.
As mentioned earlier, the pain associated with fibrocystic changes is often ameliorated once a cancer has been excluded. If pain continues, the patient should be advised to wear a brassiere both day and night. A number of pharmacologic and dietary strategies are said to be effective in the management of painful fibrocystic changes (e.g., vitamin E, primrose oil, avoidance of caffeine and nicotine), usually without adequate supporting evidence. However, danazol, a weak androgenic steroid, has been shown to decrease pain and nodularity in up to 70% of patients with fibrocystic changes when used in dosages of 100 to 400 mg/day for 4 to 6 months (37). Side effects increase with the higher doses, the most common being weight gain, acne, hirsutism and amenorrhea. Tamoxifen (discussed later), 20 mg/day, is equally effective (38); its major side effects are hot flushes and vaginal discharge.
Cancer
If the biopsy reveals carcinoma, consultation with a medical oncologist and radiation oncologist should be considered. The treatment of breast cancer is complex, rapidly changing, and involves the coordinated efforts of the surgeon, radiation oncologist, medical oncologist, and primary practitioner. The primary caregiver may not be knowledgeable in all of the details of treatment, but it is important to understand the general concepts discussed here because the patient will look to her caregiver for support and clarification as she struggles with difficult treatment decisions.
Staging
Several clinical staging systems have been devised for breast cancer, but none facilitates the management of individual patients. It is perhaps simplest to divide tumors into three main groups: clearly resectable tumors (not fixed to the chest wall and not associated with fixed, matted axillary nodes), locally advanced tumors (fixed to the chest wall or associated with the presence of matted axillary nodes or inflammatory skin changes, but without signs of metastasis), and metastatic tumors.
In the absence of symptoms or physical findings, patients with resectable tumors require minimal further studies consisting of a chest radiograph, routine blood analyses (including liver function tests and determination of the serum calcium concentration), and, if not done before the biopsy, a mammogram to look for contralateral disease or multicentric lesions. Additionally, the patient's history should be retaken to ensure that there are no musculoskeletal complaints suggestive of bony metastases. If there are, bone scanning and local radiographs of the symptomatic region should be obtained. Generally, liver and bone scans should not be obtained routinely in patients with good prognoses, such as those having small tumors and uninvolved axillary lymph nodes. In the absence of symptoms, physical findings, or abnormal serum chemistries, these studies are more likely to produce confusing false positive results than to disclose unexpected metastases. Imaging might be considered for a patient who has a high risk for metastatic disease and whose treatment plan would be greatly altered in the presence of metastatic disease. An example would be a patient with more than three positive lymph nodes who is being considered for postlumpectomy radiotherapy, since one might not proceed with radiation if distant metastases were documented.
Surgery
Radical mastectomy, for years the standard procedure, is no longer performed. The modified radical mastectomy (removal of the breast and the ipsilateral axillary lymph nodes), which preserves the pectoral muscles, is of equal efficacy but is less disfiguring, allows easier reconstruction, and only occasionally leads to clinically significant arm edema.
A modified radical mastectomy requires general anesthesia and a short period of hospitalization, usually overnight. Most patients are ambulatory and eating normally within 24 hours after the operation. Occasionally, a patient is discharged with a drain, which is removed at the time of followup. Serous fluid may accumulate under the skin flap even after the drain is removed and may require aspiration in the office. In the early postoperative period, the patient may be inconvenienced by arm and shoulder discomfort, but usually she can use the arm normally within 2 to 3 weeks. Some patients experience shoulder and arm pain for a much more extensive period; it is important for these patients to continue arm exercises as prescribed by the
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surgeon. In 10% of patients who undergo a modified radical mastectomy, lymphedema of the ipsilateral upper extremity develops. Swelling is usually minimal in the morning and increases during the day. Typically, the degree of swelling gradually becomes worse over several years. Management includes the following:
It is most important to be sensitive to cosmetic and emotional needs of the patient after what most patients consider disfiguring surgery. Most hospitals have image recovery programs, such as the American Cancer Society Reach for Recovery program, or have someone who can assist in this regard. The patient should be referred for evaluation in the perioperative period. Within 3 to 6 weeks after the operation, most patients can be fitted with a breast form if skin healing is complete.
Breast reconstruction after mastectomy should be discussed with the patient before the surgery to allow referral to a plastic surgeon beforeher scheduled mastectomy. The patient then can decide which of several reconstruction procedures she prefers. A common technique of breast reconstruction involves implantation of a tissue expander that is gradually inflated over several weeks to effect sufficient stretching of the chest tissues to allow the later insertion of an implant after removal of the expander. Use of autologous tissue is gaining in popularity. A transverse rectus abdominis myocutaneous (TRAM) flap or a latissimus dorsi flap is most commonly used. Careful discussion of all the options with the plastic surgeon is critical for the patient's satisfaction with the surgical result. Reconstruction can be done at the time of mastectomy or later as a second operation. The timing of reconstruction depends on the discussions that the patient has with the breast and plastic surgeons involved in her care. Immediate reconstruction has the advantage of avoiding a second operation and allows the patient the psychological benefit of awakening with some resemblance to her premastectomy appearance. A nipple complex, if desired, can be reconstructed or represented as a tattoo. A poor prognosis or the planned use of postoperative radiotherapy should not serve as contraindications to immediate reconstruction.
Lumpectomy and Radiation Therapy
Radiotherapy alone as treatment for primary breast cancer has not been studied systematically. For patients with resectable primary tumors ≤4 cm in diameter, the National Surgical Adjuvant Breast Project has established that, at 20 years of followup, distant disease-free and overall survival are similar after either modified radical mastectomy or lumpectomy with axillary lymph node dissection followed by breast irradiation (39). Radiation therapy decreased the risk of recurrence in the same breast from 39% to 13% over the same period of followup (39). For larger lesions, the information is not as well established. Breast conservation may result in a poorer cosmetic result, if the tumor to breast ratio is large, or if it is close to the nipple complex. However, breast conservation surgery has been made possible for more women by the increasing use of neoadjuvant chemotherapy or hormonal therapy to shrink the tumor preoperatively (40,41). If a tumor is close to or involves the nipple complex, a better cosmetic result may be achieved after mastectomy and reconstruction than after lumpectomy and radiotherapy.
Radiation therapy after lumpectomy reduces the local recurrence rate, but does not impact the overall survival. The patient should be informed of the risk of recurrent breast cancer in the irradiated breast, not only at the lum-pectomy site, but also elsewhere in the breast, and should be encouraged to continue with surveillance followup. If the patient suffers a local relapse after breast-conserving therapy, a salvage mastectomy can be performed and the patient can survive as long as patients initially treated with a modified radical mastectomy (39,42). In most reported series, the incidence of local recurrence is about 20%, with recurrence occurring up to two decades after lumpectomy. In contrast, the local recurrence rate after
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mastectomy is 2% to 9%, with recurrence usually in the first 5 years (43,44). Among patients choosing lumpectomy and radiotherapy, more than 80% are satisfied with the cosmetic results. The treatment is accompanied by minimal, if any, postoperative breast lymphedema or impaired wound healing. The irradiated breast atrophies over a number of months and may remain tender during this period. For some patients, reduction mammoplasty of the opposite breast may need to be considered.
In summary, the patient should have the surgical choices outlined for her, and be informed of the benefits and disadvantages of the treatment options. She should be given the option of discussing neoadjuvant chemotherapy or hormonal therapy if there is doubt about the ability to perform breast conservation surgery, or if she has locally advanced disease.
Intraductal Carcinoma
With the increased use of mammography, up to 20% of all new breast cancers are noninvasive intraductal lesions (45). The optimal treatment for these lesions has not been defined precisely. Mastectomy is curative 99% of the time, but it is probably an overly aggressive treatment. However, a simple lumpectomy may not be sufficient. The National Surgical Adjuvant Breast Project study compared breast irradiation versus no irradiation after local excision for patients with small (<2.5 cm), intraductal (noninvasive) carcinoma (46). The study concluded that omission of breast irradiation after local excision for intraductal cancer is unacceptable because of a 16% rate of relapse at or near the biopsy site. Approximately half of these recurrences were invasive, and radiotherapy appeared to reduce their incidence by 70%. This conclusion is not universally accepted. It is unclear to what degree radiotherapy prevented or merely delayed local recurrences. Other, albeit nonrandomized, studies, suggest that, with careful patient selection, a practitioner can identify women who may not need irradiation after removal of an intraductal lesion. The following features are associated with a better prognosis: (a) a completely excised, well-differentiated tumor without comedonecrosis; (b) a tumor smaller than 2.5 cm in diameter; (c) a tumor found incidentally or detected by mammographic microcalcifications; or (d) a tumor that occurs in an older woman. The recurrence rate in such cases can be as low as 3% (47). Many believe that patients whose tumors have these characteristics can be cured by simple excision without irradiation (48). Clinical trials are ongoing to define more clearly the selection criteria to identify those patients who may not require radiotherapy.
Multimodality Treatment
Patients with locally advanced, unresectable disease, or with inflammatory disease should be considered for treatment with initial systemic chemotherapy followed by surgery, if sufficient tumor reduction occurs, or by local irradiation with or without further chemotherapy. For a select group, such an approach may allow long-term survival. Other patients who should be considered for preoperative therapy are those who desire breast conserving therapy but have tumors too large for such as option. Several cycles of chemotherapy—or, for older, less fit patients with estrogen receptor–positive tumors, a short course of an oral antiestrogen or an aromatase inhibitor—induces sufficient tumor regression to allow lumpectomy with negative margins. The aromatase inhibitors anastrozole and letrozole are associated with a higher rate of breast conservation than is tamoxifen, with 44% and 45% of patients who would have otherwise required a mastectomy becoming eligible for lumpectomy (49,50).
Prognosis, Further Therapy, and Followup
Prognosis
Current estimates of survival are based mainly on tumor size, on whether the tumor is wholly intraductal (noninvasive), and on the results of axillary node sampling. The cure rate with mastectomy approaches 100% for women whose tumor consists only of intraductal carcinoma. Axillary node involvement occurs in fewer than 3% of these patients, so node resection provides little further information and may be omitted.
A special case is lobular carcinoma in situ (LCIS). This diagnosis is viewed more accurately as a risk factor for breast cancer in a manner similar to the finding of hyperplasia with atypia on a biopsy. Although there continues to be some disagreement among experts about how significant a risk factor LCIS is, a reasonable estimate is that a woman with a finding of LCIS has a 15% to 30% lifetime risk of developing invasive cancer, or approximately 0.5% to 1% risk of cancer per year. It is important to realize that this risk applies to both breasts. Recommendations vary for LCIS, but most oncologists recommend close mammographic follow-up, with prophylactic bilateral mastectomies reserved for women who are psychologically unable to deal with their increased risk of breast cancer. Such women should be considered for preventive therapy with tamoxifen (see Prevention).
For women with invasive cancer, the status of the axillary lymph nodes is the best indicator of prognosis. Overall survival at 10 years is approximately 65% with no node involvement, 37% with one to three positive nodes, and 13% with four or more nodes involved (51,52). The size of the tumor is also important. Patients with tumors larger than 5 cm do somewhat worse, especially if there are positive nodes. Patients with tumors smaller than 1.0 cm, especially
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if less than 0.5 cm, with uninvolved nodes do better. Within these subgroups, patients whose tumor is rich in estrogen receptors and/or progesterone receptors may do better than those whose tumor lacks significant receptor content (53). However, estrogen and progesterone receptor content is more properly considered as a predictor for response to hormonal treatments rather than as a prognostic indicator. The need to determine more accurately the prognosis of individual patients is important, because prognostic category is the basis for patient selection for adjuvant therapy after treatment of the primary tumor. Patients whose tumor appears well-differentiated to the pathologist tend to survive better than those whose tumor appears poorly differentiated. The pathology report usually includes a description of the size of the tumor, the degree of differentiation of the cancer cells, a marker of proliferation such as the Ki-67 index, the estrogen, progesterone, and Her-2/Neu oncogene expression status, as well as the number of positive lymph nodes. All of these are taken into consideration when deciding which adjuvant therapy the patient should be offered.
From this discussion it is clear that axillary dissection serves mainly to obtain prognostic information and may not directly improve a patient's survival. Unfortunately, it is the disruption of the lymphatic drainage of the arm and nerve damage from this operation that result in the long-term sequelae of arm swelling, arm and shoulder pain, and hypoesthesia or hyperesthesia. In attempts to minimize this operation, techniques have been developed to identify intraoperatively the axillary lymph nodes to which a particular woman's breast cancer would first metastasize. Injection of the tumor with a radioactive colloid and/or dye (methylene blue) with diffusion of the tracer to the axilla allows the surgeon to identify the lymph nodes that initially drain the tumor. Removal and pathologic examination of these nodes can predict whether the remaining nodes will be involved with breast cancer. If the sentinel nodes prove negative, then the chance that no other nodes are involved is greater than 95% and the patient can be spared a formal axillary dissection with its consequences (54). The American Society of Clinical Oncology has recently published guidelines for the use of sentinel lymph node biopsy in early stage breast cancer (55). This technique is not recommended for >5 cm tumors, for locally advanced or inflammatory breast cancer, in the presence of clinically suspicious axillary nodal enlargement, or if the axilla has been operated on in the past.
The primary caregiver needs to be mindful of two aspects of the sentinel node approach. First, there is a necessary learning curve for this procedure. In inexperienced hands, the rate of false-negative findings may be as high as 30%. A minimum of 20 sentinel lymph node biopsy procedures in combination with axillary lymph node dissection or with mentoring is required to minimize the risk of false-negative results (55). Second, the limited number of nodes presented to the pathologist (one to three) allows them to be examined in detail. Not only are thinner slices produced, but also the pathology department has the ability to stain the slides with antibodies to the cytokeratin of breast cancer cells. These detailed procedures greatly increase the sensitivity of the examination. Microscopic nests of tumor cells that would not be found by a routine dissection can now be detected, thus upstaging the disease in approximately 10% of patients. There is controversy about whether a node containing a few tumor cells discoverable only through such detailed scrutiny should be considered positive or negative when making a decision concerning adjuvant therapy (56). Completion of axillary lymph node dissection is recommended if the sentinel lymph node is positive for cancer, as approximately 50% of the patients will have additional positive lymph nodes (55).
Adjuvant Therapy
Adjuvant systemic therapy decreases the annual predicted death rate by approximately 30% (57). Therefore, the absolute degree of benefit from adjuvant therapy increases as the predicted prognosis worsens and, conversely, may be clinically insignificant in a woman whose cure rate with primary treatment alone is high. For example, a woman with one to three positive nodes has a 50% chance of recurrence. Therefore, adjuvant therapy reduces the risk of recurrence by (50% × 30%), or 15%. However, a woman with a tumor smaller than 1.0 cm and no positive nodes has a cure rate of more than 90%. In this case, adjuvant therapy would decrease the risk of recurrence by 3% at most. Most oncologists would urge adjuvant therapy in the former case but may be more reserved in the latter case. It should be noted that in surveys, women have stated that they would accept the short-term side effects of adjuvant chemotherapy for as little as a 1% improved probability of survival. Consequently, almost all patients, particularly those with poor prognoses, should have the benefits of further treatment with chemotherapy, hormonal therapy, and radiotherapy presented to them by the medical or radiation oncologist (see Chapter 10).
Currently, patients are selected for various adjuvant therapies based on the number of axillary nodes involved, their menopausal status, and the estrogen and progesterone receptor status of the tumor. Her-2/neu positivity, either by immunohistochemical staining (3+ intensity), or amplification of the gene on fluorescent in situ hybridization (FISH), has just recently become an important factor to consider as well. Two large adjuvant chemotherapy clinical trials have shown that addition of trastuzumab, a monoclonal antibody against the extracellular domain of Her-2, to chemotherapy significantly improves outcomes in Her-2 positive early breast cancer (58,59). These
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reports have caused considerable excitement and have been hailed as a revolutionary development in the treatment of breast cancer (60). Systemic chemotherapy is recommended to almost all women with metastases to axillary nodes. For patients who opt for lumpectomy and radiotherapy, results seem to be better if the chemotherapy is delivered between the lumpectomy and the breast irradiation (61). For premenopausal women, a major shift in the paradigm for guiding the selection of adjuvant therapy has been the realization that both premenopausal and postmenopausal women accrue the same benefit from tamoxifen, an estrogen receptor modulator. It is now standard to treat premenopausal women whose tumors are receptor positive with tamoxifen after chemotherapy or with tamoxifen alone in selected patients with good prognoses. Additionally, because the most recent meta-analysis of adjuvant therapies suggested that oophorectomy is as effective as chemotherapy in premenopausal patients with receptor-positive tumors, there is renewed interest in medical oophorectomy using luteinizing hormone-releasing hormone (LHRH) agonists combined with tamoxifen or an aromatase inhibitor (62). Similarly, use of tamoxifen or an aromatase inhibitor is recommended for most postmenopausal women if their tumors are either estrogen or progesterone receptor positive. Recent trials have shown that the aromatase inhibitors anastrozole, letrozole, and exemestane play an important role and should be incorporated in the planning of adjuvant hormonal therapy (63). The postmenopausal patient with positive nodes whose tumor is estrogen receptor–positive may obtain a small increase in survival by the addition of chemotherapy to tamoxifen (57). Whether such treatment is warranted, given the additional toxicity, is for the individual patient to decide. Postmenopausal patients whose tumors lack estrogen receptors can benefit from chemotherapy, especially if their axillary nodes contain tumor. Patients diagnosed with only ductal carcinoma in situ should also be considered for tamoxifen, especially if the ductal carcinoma in situ (DCIS) is estrogen receptor positive. A clinical trial demonstrated a 44% to 52% decrease in the incidence of invasive breast cancer in the ipsilateral and contralateral breasts when tamoxifen was employed along with radiation (64). However, at this time, there is no survival advantage with adjuvant tamoxifen for DCIS.
Several adjuvant chemotherapeutic regimens are available, each differing in side effects and duration of treatment. In discussing the potential benefit of adjuvant therapy, it is important to present the data to the patient in terms of the absolute, rather than the relative benefit of therapy. A useful tool is the Adjuvant! program (http://www.adjuvant_online.com), which incorporates the tumor characteristics and the patient's general health status in providing estimates of the absolute benefit from chemotherapy, hormonal therapy, or combined therapy. It is also important to explain to the patient that adjuvant therapy does not assure that the tumor will not recur, but when selected appropriately, may decrease the chance of such recur-rences.
Postmastectomy radiotherapy should be considered for all women with node-positive disease. Studies have shown not only a decreased local recurrence rate in women receiving postoperative radiotherapy but also an increased survival rate (65,66). Although these results are still controversial for women with fewer than four positive nodes, an NCI consensus conference recommended postmastectomy radiotherapy for women with four or more positive nodes (67). Radiation therapy should also be considered for women with tumors larger than 5 cm, even if the lymph nodes are negative for cancer.
There are uncommon long-term side effects of adjuvant therapy that must be recognized by the patient and the primary caregiver. Chemotherapy can cause premature menopause and a slight increase in the incidence of second neoplasms, mainly hematologic. Radiotherapy can lead to darkened skin, pulmonary damage, or later solid neoplasms (but not breast cancer in the unaffected breast). In 20% of patients, tamoxifen causes bothersome hot flushes that, if severe, can sometimes be ameliorated with one of the selective serotonin reuptake inhibitors (68,69). There is an increased incidence of endometrial carcinoma in women treated with tamoxifen (annual rate, 1.7 per 1000, or an approximately two and half-fold increased risk [70]. Therefore, all women taking tamoxifen should have annual gynecologic examinations and should be instructed to report any spotting. More detailed followup, such as uterine sonography, is unwarranted. The rate of cataract development is also slightly higher, so periodic eye examinations are also recommended (70). Tamoxifen also increases the risk of pulmonary embolism and deep vein thrombosis, with risk ratios of 3.0 and 1.6 respectively, relative to women who do not receive the drug (70). Tamoxifen does seem to decrease the risk of developing cancer in the unaffected breast, and it may have a bone-preserving effect in postmenopausal women. In contrast, aromatase inhibitors do not appear to increase the risk of vascular complications or endometrial cancer. They are however, associated with increased musculoskeletal complaints and a higher risk for osteopenia, osteoporosis, and osteoporotic fractures (71,72).
The selection criteria for adjuvant systemic therapy are constantly being re-examined as new information is obtained. Refining the criteria for benefit from chemotherapy is important as many women may be receiving chemotherapy unnecessarily because of a low personal risk of recurrence. For patients with node-negative, estrogen receptor–positive breast cancer, the likelihood of breast cancer recurrence can now be refined with the commercial
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availability of a 21-gene reverse transcriptase polymerase chain reaction (RT-PCR) assay that can be ordered on paraffin-embedded tumor tissue. A recurrence score is provided and this predicts the patient's individual chances of distant recurrence if treated with tamoxifen alone (73). The test is expensive and as yet is not covered by many insurance carriers.
Followup
The patient with breast cancer has a fivefold greater risk of developing cancer in the other breast (33). Consequently, she should be screened with routine mammography and physical examinations, as would any woman with moderately increased risk. Patients choosing lumpectomy and radiotherapy should have a biannual mammogram initially and careful examination of the irradiated breast every 3 months to look for a local, potentially curable recurrence. Patients who have had a mastectomy should have the scar examined at regular intervals, because 10% of patients with recurrences in the scar may be cured with local resection followed by radiotherapy.
At present there is little evidence to support the concept that the asymptomatic patient benefits by the early diagnosis and treatment of systemic metastases (74). No studies have demonstrated that monitoring of patients with radiography, liver function tests, or breast cancer markers at regular intervals improves survival or minimizes the morbidity of a relapse. This probably is true because there is no curative salvage therapy. If these studies are normal, they serve to reassure the patient. However, if they are abnormal, they often initiate a series of difficult management issues that mainly provoke uncertainty in the caregiver and anxiety in the patient without clear benefit to either. Therefore, followup plans can be individualized. Most women, when apprised of the lack of benefit from detailed laboratory and imaging followup, are comfortable doing without these studies.
Prevention
A large trial in the United States examined the use of tamoxifen for 5 years in women who were without known breast cancer but were considered to be at higher risk for development of the disease (70). The cohort receiving tamoxifen had a 50% odds reduction of developing breast cancer. This cohort also acquired a two-to-threefold increased risk for development of a deep vein thrombosis or uterine carcinoma. The tumors that were prevented were receptor-positive, suggesting that the effect may have been more related to early treatment than to prevention. Despite these results, many women at high risk are not receiving tamoxifen. One reason is that the absolute number of breast cancers prevented in the treated group was quite small. Additionally, two smaller European studies failed to confirm the American findings (75,76). Because a trial examining the effect of another estrogen receptor modulator, raloxifene, on osteoporosis saw a reduction in breast cancers in the treated group (77), a clinical trial is being conducted in the United States examining the effect of tamoxifen or raloxifene on breast cancer development. The primary caregiver needs to keep abreast of this field and to be aware of the results as they become available. The current recommendation would be to discuss preventive therapy using tamoxifen with any woman younger than 60 years of age who has a 1.67 or greater risk of developing breast cancer as determined by the Gail tool (http://www.bcra.nci.nih.gov/brc/q1.htm), as well as any woman who is older than 60 years of age or who has LCIS (see Prognosis).
Breast Cancer in the Elderly
Fifty percent of all new breast cancers occur in women 65 years of age or older. In the year 2020, it is estimated that 20% of the U.S. population will be that old (78). In patients older than 68 years of age with breast cancer, 60% of the tumors are node negative and at least 58% are estrogen receptor positive (79). Several studies have shown that older women are less likely than younger women to receive postoperative radiation or adjuvant systemic therapy (80,81). In healthier older women, such undertreatment may lead to poorer outcomes.
A major factor related to the ultimate benefits of adjuvant chemotherapy in older women is the effect of comorbidity on survival. Women with breast cancer who have three or more comorbid illnesses have a 20-fold increased risk of dying from a cause other than breast cancer when compared with women who have no comorbid conditions, even after adjustment for disease stage, type of therapy, race, and social and behavioral factors (82).
It is clear that the benefits of adjuvant therapy decrease with increasing age and comorbidity. The effect of adjuvant treatment on overall life expectancy is small for the oldest patients. Provided they are in good health and have a life expectancy of at least 5 years, women in their eighties who have estrogen receptor–positive, high-risk node-negative, or node-positive tumors should be considered for adjuvant hormonal therapy with tamoxifen or an aromatase inhibitor. Chemotherapy is unlikely to benefit these patients unless they are in excellent health and have high-risk, estrogen receptor–negative, node-positive tumors. The greatest dilemma is for women in their seventies. Comorbidity and risk of metastases must be carefully considered in each of these cases before final recommendations about treatment are made.
Older patients are clearly underrepresented in cancer clinical trials (83). Efforts are now underway to overcome this deficiency, with increasing focus on breast cancer research in older women.
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Specific References*
For annotated General References and resources related to this chapter, visit http://www.hopkinsbayview.org/PAMreferences.
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