Armando E. Giuliano
Essential tools for the practicing gynecologist are an understanding of benign and malignant breast diseases, the ability to detect and diagnose breast cancer, and an appreciation of the various treatment options for the breast cancer patient. In this chapter, benign conditions that can masquerade as malignancy, as well as the diagnosis and management of in situ and invasive breast cancers, are discussed.
Breast malignancies are usually asymptomatic and are discovered only by physical examination or screening mammography. Any physical findings on a routine breast examination must be recorded in the medical record for future reference.
For the breast and nodal examination, the patient should be examined in both the upright and supine positions. Examination should begin with inspection of the breasts with the patient seated comfortably, arms relaxed at her sides. Differences in symmetry or contour of the breasts should be noted, as well as any skin changes such as edema or erythema. Skin dimpling or nipple retraction may become apparent by having the patient raise her arms above her head then press her hands on her hips (Fig. 16.1). Next, the cervical, supraclavicular and axillary areas should be palpated for enlarged nodes. With the patient still seated, each breast is examined by using the nondominant hand to support the breast while palpating with the dominant hand using the flat portion of the fingers rather than the tips. The upper outer quadrant of the breast up to the clavicle, the axillary tail of Spence, and the axilla are palpated for possible masses. The nipples should also be assessed for nipple discharge.
The patient is then asked to lie down and raise one arm over her head while keeping the other arm at her side. The breast examination commences on the side with the raised arm. Once again, the breast is systematically palpated from the clavicle to the costal margin. The manner in which the breast is examined is not as important as consistency and diligence; it is important to choose one method that allows for examination of the entire breast that can be repeated methodically. One technique that many clinicians use is to palpate the breast in enlarging concentric circles. Placement of a pillow or towel beneath the scapula to elevate the side examined is important for women with large, pendulous breasts, which tend to fall laterally, making palpation of the lateral breast challenging.
Figure 16.1 Retraction of the skin of the lower, outer quadrant seen only on raising the arm. A small carcinoma was palpable.
The major features in a breast examination to be identified are nodularity, tenderness, and dominant masses. Any abnormalities should be documented by identifying the area of concern as the position on the face of a clock and its distance from the nipple, e.g., a right breast lesion at 10 o'clock, 5 cm from the nipple is located in the upper outer quadrant. Many patients, particularly young, premenopausal women, have nodular breast parenchyma. Nodularity is frequently diffuse although it tends to be more prevalent in the upper outer quadrants where there is more breast tissue. Nodules are small, indistinct, and similar in size. Conversely, breast cancers tend to present as nontender, firm masses with unclear margins, often feeling distinct from the surrounding nodularity. Malignant masses may also be fixed to the chest wall (underlying fascia) or to the skin. However, not all breast cancers possess these characteristics so any dominant mass in the breast requires further evaluation.
Around the time of menses, many women have increased nodularity and engorgement of the breast, which occasionally obscures an underlying lesion. If a patient presents to the physician with concern about a mass that she has palpated and the physician cannot confirm the patient's finding due to engorgement of the breasts, the examination should be repeated after the patient's menstrual period. Further imaging such as mammography or ultrasonography is also a useful adjunct in cases where the patient has palpated a mass, yet the clinician is unable to confirm the patient's finding.
Although there is no evidence to date that breast self-examination (BSE) leads to a decreased mortality rate by diagnosing breast cancers at an early stage, its utilization is still advocated by many organizations (1,2). It is viewed as a surveillance tool for women to heighten awareness of the normal composition of the breast, as well as to detect changes that may occur. BSE can be useful in detecting interval cancers between screenings. It is important to note that BSE should not be used in isolation; it supplements screening by clinical breast examination (CBE) and mammography.
It is advocated by the American Cancer Society (ACS) as well as the National Comprehensive Cancer Network (NCCN) that BSE begin early, at age 20 years. Starting BSE at an early age allows women to familiarize themselves with the composition of their breasts, increases awareness of breast cancer surveillance, and establishes a good habit for when they are older. Women should report any changes to their physicians. As part of the ACS guidelines for the Early Detection of Breast Cancer, clinical breast examination should be performed every 3 years starting at age 20, with the option of monthly BSE also starting at age 20. Premenopausal women may find that monthly examinations are most informative during the week after their menses. There are complex reasons why many women do not perform BSE, but reassurance and patient education may encourage women to overcome psychological barriers. In women who have been treated for breast cancer, BSE can also be used as a supplemental method to aid in detecting recurrence.
Like clinical breast examination, the breast self-examination should begin with visual inspection. A woman should inspect her breasts while standing or sitting before a mirror, looking for asymmetry, nipple retraction or skin dimpling. Skin dimpling is highlighted by elevation of the arms over the head or by pressing the hands against the hips and performing a “squeezing” motion (to contract the chest muscles). While standing or sitting, she should carefully palpate her breasts using the finger pads of the opposite hand with first light pressure then with increasing firmness. This may be performed while showering with soapy hands to increase the sensitivity of palpation. Finally, she should lie down and again palpate each quadrant of the breast extending into the axilla. A good resource for instructions on BSE can be found on the Susan G. Komen for the Cure Web site(http://cms.komen.org/komen/index.htm).
The two most common and important imaging techniques for the early detection of malignancy are mammography and ultrasonography. Recently magnetic resonance imaging (MRI) has been incorporated as a screening tool in subsets of women at higher risk of breast cancer, as well as a diagnostic tool in certain clinical situations.
Screening of asymptomatic women for breast cancer has been shown to reduce the death rate by 20% to 30%, most likely due to earlier detection. Half of the reduction seen in breast cancer deaths in the United States has been attributed to screening mammography (3).
Several randomized controlled trials (RCTs) support the use of mammography for breast cancer screening in women older than 50 years of age. Controversy regarding the benefit of screening women aged 40 to 49 years was primarily due to the lack of RCTs designed specifically to evaluate the efficacy of screening in that particular age group. However, when data regarding screening in women aged 40 to 49 years were pooled together from the various RCTs and analyzed in a meta-analysis, there was a significant reduction of 18% in the breast cancer mortality rate for this group of women (4). In addition, the Swedish Two-Country Trial demonstrated a 23% reduction in mortality rate for this group of women with screening mammography with 18 years of follow-up (5). Furthermore, a UK study has shown a survival benefit in younger women equivalent to that seen in women over 50 years (6).
Currently, the American Cancer Society as well as the National Cancer Institute recommends that annual screening begin at age 40 for women at normal risk (7). Additional screening recommendations exist for women at increased risk of breast cancer; these recommendations include more frequent clinical breast examination, initiation of screening at ages younger than 40, and using other modalities as adjuncts to mammography including ultrasound and MRI. There is no established upper age limit for breast cancer screening.
Mammography is the best method of detection for a nonpalpable breast cancer but occasionally misses some palpable and nonpalpable or ultrasonographically detected malignancies. Mammography should not be used in isolation. Neither the technology of mammography nor its interpretation by radiologists is infallible. The basis of any screening program or work-up of breast abnormalities is the physical examination. Mammography and CBE complement one another; it is recommended that women undergo CBEs around the time of their regularly scheduled annual mammograms (8). Patients should be cautioned that breast compression can be uncomfortable and that steady compression of the breast is necessary to obtain good images.
In addition to mammography used as a screening tool, there are circumstances in which bilateral mammography is mandatory:
Mammography, either used as a screening tool or used in the diagnostic work-up of a breast mass, can detect microcalcifications, breast densities, and architectural distortions (Fig. 16.2). To standardize the reporting of mammographic findings, the American College of Radiology developed the Breast-Imaging Reporting and Data System (BI-RADS) classification(9). There are six categories (1,2,3,4,5,6) for classifying findings, with category 0 representing an incomplete assessment with the need for additional studies (Table 16.1). Additional imaging recommendations may include magnification, spot compression, and ultrasonography. A patient may have a screening mammogram that shows a questionable abnormality, while spot compression views may indicate the finding is completely normal; this would fall into category 1 “negative.”
Figure 16.2 Bilateral film screen mammograms showing typical carcinoma in each breast, illustrating the importance of bilateral mammography in the workup of a clinically apparent mass.
Table 16.1 Mammographic Interpretations and the Breast Imaging Reporting and Data System Classification with Recommendations
Microcalcifications are the most frequent mammographic abnormalities necessitating biopsy. The evaluation of microcalcifications includes review of their size, number, location, distribution, and morphology. Microcalcifications that tend to be benign are smooth, round, solid, or lucent-centered spheres. Tubular or rod-shaped calcifications are often associated with ectatic ducts. If further analysis is required, magnification and spot compression views are the primary techniques used. Calcifications that are classified as benign do not require histologic confirmation. Of concern, are calcifications that vary in size and shape. The majority of calcifications in breast cancers form in the intraductal portion of the breast and are small and irregular with varying levels of maturation or density.
The most common signs of breast cancer seen on mammography are:
These “common signs” can also be seen with benign lesions, leading to a false-positive mammography rate of 15% to 20% (10). For example, clusters of microcalcifications are also seen with benign processes such as hyperplasia, adenosis, fibroadenomas, and ductal papillomas. However, for accurate diagnosis, a stereotactic core or excisional biopsy may be required. Mammography misses approximately 10% to 15% of cancers. It has a low sensitivity for the detection of cancers in dense breasts, and infiltrating lobular cancers (11). False-negative mammograms occur particularly in young women with dense breast parenchyma and little fat (11). If there are suspicious findings on clinical examination, biopsy of the breast must be performed regardless of the mammographic findings; this will be discussed in more detail below (12).
Digital mammography (DM) was developed to address some of the limitations of film mammography (13). Its advantages include speed and higher contrast resolution, which in theory is better for detecting densities and masses in dense tissue. The image contrast can be manipulated to aid in the evaluation of dense breasts, which have low contrast. The advantage of film mammography (FM) is spatial resolution, which is better for detecting calcifications. Digital mammography also delivers a smaller dose of radiation than that of FM. However, given that the dose of radiation from FM is so low, the differences in radiation doses is of minor significance.
Results from previous trials have not demonstrated a significant difference in accuracy in breast cancer detection between digital and conventional mammography; however, these studies were limited by sample size. The Digital Mammographic Imaging Screening Trial (DMIST) was designed to assess the performance of digital versus film mammography. The study involved 49,500 female volunteers undergoing both conventional screening mammography and digital mammography. Subset analyses indicated that in women under age 50, as well as in women with dense breasts, digital mammography may be more accurate in detecting breast cancer (14). Because digital images can be stored electronically, many facilities plan to transition to DM in the future. At this time however, many centers still use conventional FM. Even though DM may be of benefit in certain subgroups of women, women should not forego annual screening mammograms if DM is not available to them.
Breast ultrasonography (US) is a popular imaging technique that is primarily used as an adjunctive tool and not as a screening modality. Currently, there is an American College of Radiology Imaging Network Trial in progress to assess the screening capabilities of breast US, but current clinical practices utilize US with accompanying mammography (15).
Although studies are examining the use of ultrasound for screening, currently there is no role for surveying the entire breast using ultrasound; the main use of ultrasound is to focus on an area of concern identified as abnormal by mammography or clinical examination. Ultrasonography can determine whether a lesion is present, or whether a clinical breast examination finding is within the spectrum of normal parenchyma, such as a prominent fat lobule. If a lesion does exist, US can be used to further characterize the finding.
There are clinical indications for the use of US as the primary imaging modality. These include evaluating palpable findings in young patients (teens and early 20s); pregnant women; and women presenting with erythematous, tender breasts (15). In the latter category, the diagnostic dilemma is between infection and inflammatory breast cancer; US allows for an initial evaluation of the breast when the breast is too tender for mammographic compression. Other uses for US are in the evaluation of axillary lymph nodes in breast cancer patients; post-operative examination of fluid collections (seroma, hematoma); and as an aid in interventional procedures such as in needle aspiration or biopsy and the preoperative localization of nonpalpable lesions.
Ultrasonography is 95% to 100% accurate in differentiating solid masses from cysts. It can aid in the evaluation of a benign-appearing, nonpalpable density identified by mammography. If such a lesion proves to be a simple cyst, no further workup is necessary if the patient is asymptomatic. There are certain criteria that must be met for a cyst to be classified as “simple,” thus falling into the category of BI-RADS 2: benign finding. These criteria are: (i) anechoic; (ii) well-circumscribed round or oval mass with posterior enhancement; and (iii) thin bilateral edge shadows (16).
Magnetic Resonance Imaging
Magnetic resonance imaging (MRI) produces detailed cross-sectional images of tissues and structures utilizing magnetic fields. The use of screening and diagnostic MRI is gaining more recognition as an adjunct to mammography in specific clinical scenarios. However, as with mammography and other screening tools, MRI has associated false-negative rates depending on the specific clinical application. In studies evaluating MRI, the specificity of MRI is significantly lower than that of mammography, resulting in an increased recall and biopsy rate, due to the enhancement of benign lesions such as fat necrosis, fibroadenomas, and fibrocystic changes (17).
As the technology of MRI has become more sophisticated with dedicated breast MRI coils, contrast agents, and protocols (17), breast MRI is increasingly being used in the clinical setting. MRI is a useful tool in the setting of equivocal mammographic or ultrasonic findings, particularly in patients with dense breasts, post-lumpectomy scarring, a strong suspicion of infiltrating lobular carcinoma, scattered calcifications suggestive of extensive ductal carcinoma in situ (DCIS) or extensive intraductal cancer, bloody nipple discharge, or silicone implants (11).
In women who have an occult primary breast cancer presenting as axillary adenopathy, mammography is limited in its ability to identify the primary breast cancer. There is evidence that MRI can identify occult breast lesions, allowing for more accurate staging and the possibility of breast conserving surgery (18,19). Clinical studies have shown that MRI can be beneficial in monitoring the response to neoadjuvant chemotherapy (20) as well as determining the extent of disease in a breast cancer patient for staging purposes and for contralateral breast cancer screening (21). MRI is also used as an adjunct to mammography in high-risk women (22) (Table 16.2).
Table 16.2 Recommendations for Breast MRI Screening as Adjunct to Mammography
Benign Breast Conditions
Fibrocystic disease is one of the most common breast problems seen in clinical practice. The term “disease” is misleading and “change” or “condition” is a preferable, more accurate description. Fibrocystic change/condition (FCC) constitutes a spectrum of clinical signs, symptoms and histologic features. In a woman with FCC symptoms, an important part of the evaluation is to exclude malignancy, because the diagnosis of FCC is otherwise of little clinical significance (23).
Symptoms and Signs FCC is thought to be hormonally related because it appears primarily in women between the ages of 30 and 50 years, subsides after menopause, and can fluctuate with menstrual cycles. Women may present with multiple, tender, palpable masses; usually the breasts are most tender and the masses largest just before the menses, with signs and symptoms abating after menstruation. It is estimated that 60% of women have clinical findings compatible with the diagnosis of FCC (23). FCC involves changes of both the stromal (fatty and fibrous tissue that give the breast support and shape) and glandular tissues (lobules and ducts).
Evaluation Malignancy must be excluded in the evaluation of a woman with probable FCC. Often on physical examination, the breasts are diffusely nodular, with areas of increased density, mainly in the upper, outer quadrants, with no dominant masses. A mammogram should be performed, with possible ultrasound if there is concern about the presence of a mass on physical examination. A repeat physical examination after the next menstrual cycle is often valuable to document resolution of questionable areas. In the case of a dominant mass, a breast biopsy, preferably needle biopsy or aspiration cytology, is recommended to rule out malignancy. Large cysts may be aspirated if symptomatic.
Clear, watery, straw-colored, or greenish nipple discharge in patients with FCC should be tested for blood by means of a standard guaiac or Hemoccult test. If the discharge is from multiple ducts, bilateral and nonbloody, most likely the discharge is benign. Copious discharge may be a sign of malignancy.
Pathology The histologic features of FCC are variable (23). Changes such as fibrosis, cyst formation, hyperplasia (overgrowth of the cells that line the ducts), adenosis (enlargement of breast lobules), and sclerosing adenosis can be seen microscopically. One or more of these histologic features can be found in 50% to 60% of asymptomatic women (23). In the case of epithelial hyperplasia, it is important to distinguish between usual and atypical hyperplasia. Atypical hyperplasia is associated with an increased risk of breast cancer in the future(see below).
Cancer and Fibrocystic Disease
The conclusion that there is an association between FCC and cancer was originally drawn because FCC and malignancy were commonly found together in the same breast (24). However, because 50% to 60% of women have FCC and one in every eight women has breast cancer in her lifetime, it is not surprising that these two entities frequently coexist.
Not all women with FCC are at an increased risk for cancer. Those with histologic features such as fibrosis, cysts, apocrine metaplasia, and mild hyperplasia are at no increased risk of developing breast cancer (25,26). Histologic features such as sclerosing adenosis and solid or papillary hyperplasia increase the risk slightly (1.5-2 times). Women who have atypical hyperplasia, either lobular or ductal, have 5 times the average risk.
An intraductal papilloma is a benign lesion that can cause serous, serosanguinous, or bloody nipple discharge (27). It is the most common etiology of bloody nipple discharge without an associated mass. True polyps of epithelial-lined breast ducts, intraductal papillomas are often solitary and found in the subareolar location, arising in a major duct close to the nipple. Intraductal papillomas are most frequently observed in women aged 30 to 50 years, and typically are not palpable because they are rarely larger than 5 mm. Compression of the breast close to the nipple in the affected quadrant often produces discharge from the affected duct. Because malignancies may also present with bloody nipple discharge, mammography should be performed to rule out other abnormalities in the breast. Biopsy is usually necessary to rule out malignancy.
Fiber optic ductoscopy is an endoscopic technique that has been developed over the past 15 years for evaluating bloody nipple discharge; it allows direct visualization of the ductal system of the breast through a nipple orifice. For diagnosis of nipple discharge, fiber optic ductoscopy demonstrated 88% sensitivity, 77% specificity, 83% positive predictive value, and 82% negative predictive value (28). However, this technique is not widely used in clinical practice due to limited expertise, high cost, and poor reproducibility.
In addition to ductoscopy, ductal lavage is another screening procedure for women with nipple discharge. Ductal lavage involves irrigation of the duct with saline and cytologic evaluation of the irrigant. Cytologic analysis of ductal lavage alone has a positive predictive value of 72% and a negative predictive value of 50% but when combined with fiber optic ductoscopy, the positive predictive value increases to 86% and the negative predictive value increases to 87% (28). There are limitations to the utilization of this technique including patient discomfort, low cytologic yield, and limited accuracy
Treatment Local excision of the draining duct is the treatment of choice. This can be performed using local anesthesia through a circumareolar incision by reflecting the nipple away from the breast tissue. A lacrimal probe can be used to assist in locating the offending duct. If it is not possible to identify the duct, total ductal excision of the subareolar duct can be performed through the same incision. The subsequent risk of invasive breast cancer is increased with the presence of atypical hyperplasia in a papilloma, with an increased risk similar to that of proliferative disease with atypia (29). Papillomas may have malignant epithelium either in situ or invasive (30).
Fibroadenomas are the most common benign breast mass in women (23). They are noncancerous growths composed of epithelial and stromal elements. They rarely occur after menopause, but occasionally calcified fibroadenomas are found in postmenopausal women. It is believed that they are influenced by estrogenic stimulation (23).
Symptoms and Signs Clinically, a young patient usually notices a mass while showering or dressing. Most masses are 1 to 3 cm in diameter, but they can grow to an extremely large size (i.e., the giant fibroadenoma). On physical examination, they are firm, rubbery, smooth, and freely mobile. Fibroadenomas may be multiple. On mammography, they may appear as circumscribed oval or round masses. Occasionally, coarse calcifications can be seen within a fibroadenoma. On ultrasonography, they characteristically appear as circumscribed, homogeneous, hypoechoic oval masses with occasional lobulations and are wider rather than tall. On MRI, they typically appear as smooth masses with high signal intensity on T2-weighted images.
Although the risk of cancer in a fibroadenoma is extremely low, some clinicians choose to biopsy (with FNA, core needle, or excisional biopsy) any solid mass in patients older than 30 years for definitive diagnosis. A lesion that is benign on ultrasonography and mammography is benign more than 99% of the time. Some clinicians will omit biopsies in younger women with lesions characteristic of fibroadenomas, and will follow these patients with serial ultrasonography (23).
Complex fibroadenomas are fibroadenomas that contain cysts, sclerosing adenosis, papillary apocrine changes, or epithelial calcifications. In a clinical follow-up study by Dupont et al. (31), complex fibroadenomas were shown to be associated with a slightly increased risk of breast cancer. Patients who have simple fibroadenomas without complex histologic features are at no increased risk for development of invasive cancer.
Treatment Although complete excision under local anesthesia can treat the lesion and confirm the absence of malignancy, excision is not often necessary. A fibroadenoma diagnosed by clinical examination, imaging, and needle biopsy may be followed if the lesion remains stable. If a fibroadenoma increases in size, it should be excised. Also, excision is generally recommended for fibroadenomas that are greater than 2 cm or 3 cm to rule out phyllodes tumor. Fibroadenomas may diminish in size or even totally resolve particularly in younger women, and therefore excision can be avoided (32).
Benign Phyllodes Tumor
Phyllodes tumors are fibroepithelial breast tumors characterized by stromal overgrowth and hypercellularity combined with an epithelial component, grossly forming a leaflike structure. Clinically, phyllodes tumors tend to occur in women aged 35 to 55 years, and comprise less than 1% of breast tumors (33). These lesions usually appear as isolated masses that are difficult to distinguish from fibroadenomas (34). Size is not a diagnostic criterion, although phyllodes tumors tend to be larger than fibroadenomas, often with a history of rapid growth. Both appear as well circumscribed, oval or lobulated masses with round borders on mammography and ultrasonography. There are no good clinical or radiographic criteria by which to distinguish a phyllodes tumor from a fibroadenoma (33,34).
Pathology Phyllodes tumors are classified as benign, borderline, or malignant based on the histologic criteria first described in 1978 by Pietruszka and Barnes (35). These histologic criteria are based on features such as the number of mitoses, pushing or infiltrative tumor margins, degree of stromal overgrowth, and degree of stromal cellular atypia, which are all used in combination to distinguish between the benign and malignant spectrum (36). Even with histologic criteria, definitive distinction between fibroadenoma, benign phyllodes tumor, and malignant phyllodes tumor can be very difficult and the correlation of histologic grade to clinical behavior and outcome has been challenging. Even “benign” phyllodes tumors tend to recur locally particularly if the tumor is simply enucleated. Malignant phyllodes tumors have a higher local recurrence rate but also can metastasize, usually to the lungs (36,37); for this reason, these tumors were originally called cystosarcoma phyllodes. Axillary lymph node metastases are extremely unusual despite the large size of some phyllodes tumors that are classified as “malignant.”
Treatment Due to the high propensity for local recurrence, the treatment of phyllodes tumors should consist of a wide, local excision (36,37,38). Large tumors not amenable to breast conservation and malignant tumors with particularly infiltrative margins may require total mastectomy without axillary node dissection; however, mastectomy should be avoided whenever possible. These malignant tumors are rarely multicentric and rarely metastasize to lymph nodes. Typically, a phyllodes tumor is discovered by histologic examination after a patient undergoes an excisional biopsy of a mass believed to be a fibroadenoma. When the pathologic diagnosis is phyllodes tumor, a complete reexcision of the area should be undertaken so that the prior biopsy site and any residual tumor are excised. There is no role for adjuvant therapy, either radiation therapy or chemotherapy.
Breast cancer is the most common cancer in women under the age of 60 and is second only to lung cancer as the leading cause of cancer deaths in women. It accounts for 26% of all new cancer cases in women. In 2009 in the United States, an estimated 192,370 new cases of invasive breast cancer and 62,280 cases of ductal carcinoma in situ (DCIS) will be diagnosed in women, with approximately 40,170 deaths (39). The overall lifetime risk for development of breast cancer in women in the United States is one in eight or 12.5% (39).
During the past 50 years, there has been a significant increase in the incidence of breast cancer in the United States. This correlates with the increased use of screening mammography (40). Breast cancer incidence rates increased after 1980, but decreased by 3.5% per year from 2001 to 2004 probably due to declining use of hormonal replacement therapy (HRT) by postmenopausal women, as well as delays in diagnosis due to a decrease in mammographic utilization (41).
The mortality rate has dropped slightly, thought to be due in part to mammographic screening and improvements in systemic therapy (3). Screening mammography has also resulted in a decrease in the size of breast cancer at diagnosis, with close to one-third of cancers being 1 cm or less in diameter (42). Not surprisingly, nodal involvement has decreased and the proportion of DCIS cases has increased. It is predicted that in the next decade, these trends will continue.
One of the fundamental steps in determining a patient's risk for breast cancer is to obtain a detailed history. This allows the physician to plan preventive and diagnostic strategies, as well as to educate the patient about breast cancer. Intrinsic and extrinsic factors both contribute to increasing a woman's risk. Intrinsic characteristics include genetic and familial elements, age, endogenous hormonal exposures, and benign breast lesions with high-risk histologies. Extrinsic characteristics include environmental exposures, diet, and exogenous hormonal exposures.
The risk of developing breast cancer increases steadily with age. Breast cancer is rare before the age of 25 years, accounting for less than 1% of all cases of breast cancer. After the age of 30 years, there is a sharp increase in the incidence, with a small plateau between the ages of 45 and 50 years, which points to the involvement of hormonal factors (43). From 1996 to 2000, the incidence of breast cancer in the U.S. for women aged 30 to 34 years was 25 per 100,000, 198 per 100,000 for women aged 45 to 49 years, and for women aged 70 to 74, the incidence was 476 per 100,000 (44).
Prior History of Breast Cancer
One of the strongest single risk factors for the development of a breast cancer is the previous diagnosis of a contralateral breast cancer. The risk of subsequent contralateral breast cancer in a patient with unilateral breast cancer has been reported to range from 0.5% to 1% per year (45,46,47,48). Young age (45,46,48) and lobular histology (46,47,48) were found to be associated with a greater likelihood of contralateral breast cancer; adjuvant chemotherapy significantly decreased the rate (47,48). In patients diagnosed with unilateral breast cancer, breast MRI has been shown to detect clinically and mammographically occult contralateral cancers in 3.1% of cases at the time of diagnosis (21).
A family history of breast cancer increases a patient's overall relative risk (49). However, the risk is not significantly increased for women with first-degree relatives (mother, sister) with post-menopausal breast cancers, whereas women whose mothers or sisters had bilateral premenopausal breast cancer have a high likelihood of acquiring the disease. If the patient's mother or sister had unilateral premenopausal breast cancer, the likelihood of the patient developing breast cancer is approximately 30%. If a woman has several first-degree relatives with breast cancer, the risk increases. The risk of breast cancer is substantially increased if there is a genetic component.
Inherited Syndromes of Breast Cancer
The majority of breast cancers occur sporadically without a recognizable genetic association, with only approximately 5% to 10% attributed to breast cancer susceptibility genes (50). Two breast cancer susceptibility genes, BRCA1 mapped to chromosome 17q21, and BRCA2 on chromosome 13q12-13, are high penetrance tumor suppressor genes inherited in an autosomaldominant fashion (51,52). Mutations in these genes account for only about 15% of all familial breast cancers, suggesting that other breast cancer susceptibility genes may exist. (53).
The estimated lifetime risk of breast cancer for women who have BRCA1 genetic mutations ranges from 36% to as high as 87%, with a pooled estimate of 65% (54,55,56). The cumulative risk of ovarian cancer in BRCA1 carriers has been reported to be between 27% and 45% (56,57,58). Estimates for the risk of developing a contralateral breast cancer are 60% (58). An increased risk also exists for the development of additional cancers such as colon, pancreatic, uterine, and cervical cancers (57,58). Breast cancers that occur in women with BRCA1 mutations are mostly estrogen-receptor (ER) negative (up to 90%) and of high nuclear grade. Lifetime estimated risk for BRCA2 mutation carriers is 45% to 84% for breast cancer and 10% to 20% for ovarian cancer (49). BRCA2 mutations are also associated with a 6% lifetime risk for male breast cancer.
The prevalence of BRCA1 and BRCA2 in the general population is unknown but is estimated to be less than 0.12% and 0.044%, respectively (53). In Ashkenazi Jewish women, the prevalence of these mutations is as high as 2% (59). In women diagnosed with breast cancer before the age of 32, the incidence of BRCA1 or BRCA2 mutations is approximately 12% and in Ashkenazi women diagnosed with breast cancer before age 40, the incidence is 20% (60,61). Both BRCA1 and BRCA2 are very large genes with numerous possible mutations. This accounts for the highly variable risks for the development of breast, ovarian, and other cancers (62).
There are other hereditary syndromes associated with breast cancer with mostly autosomal dominant transmission, such as Li-Fraumeni, Cowden's disease, Muir-Torre, a variant of hereditary nonpolyposis colon cancer (HNPCC), ataxia-telangiectasia (autosomal recessive), and Peutz-Jeghers syndromes. Each syndrome is associated with an abnormal gene responsible for producing a recognized phenotype. In clinical practice, these syndromes contribute to only a small fraction of hereditary breast cancers; however, it is important that clinicians recognize when patients should be considered candidates for genetic testing.
In 1996, the American Society of Clinical Oncology issued a statement regarding genetic testing for cancer susceptibility with an update released in 2003 (63,64). The guidelines are summarized in Table 16.3.
Table 16.3 American Society of Clinical Oncology: Genetic Testing for Cancer Susceptibility Guidelines*
The American Society of Breast Surgeons issued a statement in 2006 defining patients at high risk for breast cancer. Persons in this high-risk population are patients with early onset breast cancer (before age 50), two primary breast cancers, a family history of early onset breast cancer, a previously identified BRCA1/BRCA2 mutation in the family, a personal or family history of ovarian cancer, or Ashkenazi Jewish heritage (http://www.breastsurgeons.org/brca.shtml). Patients included in this group are at a 10% or greater risk of harboring aBRCA1 or BRCA2 mutation, which is the traditional cutoff for testing.
Reproductive and Hormonal Factors
A number of studies have shown a relationship between early menarche, late menopause, and breast cancer. (65,66,67). It is thought that lifetime exposure to endogenous estrogen plays a promotional role in the development of breast cancer. Women with breast cancer begin menses at a younger median age, (67) and the longer a woman's reproductive phase, the higher the risk for development of breast cancer (65). There is no clear association between the risk of breast cancer and duration of menses or menstrual irregularity. Studies of the effect of lactation on the incidence of breast cancer have been inconclusive but childbearing definitely has an effect on breast cancer risk (66). Women who have never been pregnant have an increased risk of breast cancer compared to women who are parous; additionally, late age at first birth also increases the risk of breast cancer (66).
There have been conflicting reports concerning the effect of oral contraceptives on breast cancer incidence. A large meta-analysis of 54 epidemiologic studies found convincing evidence that there was a small increased relative risk of breast cancer for women currently using oral contraceptives and for up to 10 years after stopping use (68). Because breast cancer incidence rises steeply with age, the estimated excess number of cancers diagnosed increased with increasing age at last use. After 10 or more years from cessation of oral contraceptives, there was no excess risk. Additionally, breast cancers in women who had used oral contraceptives tended to be less advanced clinically and localized to the breast. No risk factors, such as reproductive history or family history of breast cancer, changed the results after current usage had been taken into account. Similarly, the duration of use, age at first use, and the dose and type of hormone had little additional effect on breast cancer risk.
The association between breast cancer and hormonal replacement therapy (HRT) in post-menopausal women has been investigated in two large randomized trials. In the Women's Health Initiative (WHI) study, investigators demonstrated that women randomized to combination HRT, had a significantly increased incidence of breast cancer, stroke, and pulmonary embolus compared with those randomized to a placebo (69). HRT significantly decreased the incidence of colorectal cancer and femoral neck fractures. The trial was stopped early after it became apparent that the risks outweighed the benefits. The risk of breast cancer has been shown to be greater for combination versus estrogen-only HRT.However, the WHI demonstrated that women receiving estrogen-only HRT after hysterectomy were at an increased risk for stroke (70). The Million Women Study in the United Kingdom recruited 1,084,110 women and also demonstrated that current use of HRT was associated with an increased risk of breast cancer (71).
Soon after the report of the Women's Health Initiative, the use of HRT in the United States decreased by 38% with approximately 20 million fewer prescriptions written in 2003 than 2002 (72). Analysis of data from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) registries indicate that the age-adjusted incidence rate of breast cancer in women fell by 6.7% in 2003. This decrease in breast cancer incidence seems to be temporally related to the drop in HRT by post-menopausal women (73).
In counseling women with complaints of post-menopausal symptoms, the decision to initiate combination HRT must be individualized. For some patients, the improved quality of life and protection against fractures outweigh the potential risks. The individual risk of breast cancer in a particular postmenopausal patient should be considered before initiating HRT. If HRT is to be prescribed, low dosage formulations should be used with the understanding that the risk for harm will likely increase with prolonged use, and the survival benefit will diminish over time. For women at high risk for fractures, bisphosphonates are a suitable alternative. Any post-menopausal women on HRT should be aware of the increased risks of breast cancer and should be counseled to be particularly diligent regarding breast cancer awareness and screening.
Diet, Obesity, and Exercise
Earlier studies linked marked differences in the incidence of breast cancer among women in different geographic areas to high-fat diets in particular, and to obesity in general (74). Current epidemiologic studies have linked obesity and increasing BMI to an increased risk in post-menopausal breast cancer, but have not been able to demonstrate the same increased risk in premenopausal breast cancer (75,76). Regarding diet and breast cancer, the majority of epidemiologic studies are case-control studies and cohort studies. Few randomized control trials have been conducted and are problematic because the randomized dietary plan has to be adhered to for a many years. One large pooled analysis of seven cohort studies including 337,819 women found no evidence of a positive association between fat intake and risk of breast cancer when those in the highest quintile of total fat intake were compared with those in the lowest quintile (77). In the same study, the type of fat intake and cholesterol also had no positive association with an increased risk. Similarly, a recent, large randomized controlled trial involving 40 U.S. clinical centers from the Women's Health Initiative followed 48,835 postmenopausal women for 8 years who were randomly assigned to a dietary modification group or control group (78). The dietary modifications included 5 servings of fruits and vegetables, 6 servings of grains and total fat to 20% of energy requirements daily. The results surprisingly showed that a low-fat diet did not prevent a statistically significant reduction in invasive breast cancer risk. However, results were confounded by relatively few women meeting the low-fat dietary target (only 14.4% at year 6). Future studies were encouraged because it may take years for the benefits of a low-fat diet to be manifested.
One large prospective study in the United States of 90,655 premenopausal women found no association between fiber intake and the risk of breast cancer, whereas a study in the United Kingdom of 35,792 women demonstrated a reduced risk of breast cancer for premenopausal women who consumed >30 gram of fiber day as compared to those who consumed <20 g/day (79,80). Studies of dietary carotenoids, vitamins A, C, and E, as measured by intake of fruits and vegetables, have also been conflicting. One large prospective cohort study involving 83,234 women in the Nurses' Health Study showed that premenopausal women who consumed more than five or more servings of fruits and vegetables had a modestly lower risk of breast cancer than those who had less than two servings per day (81). These findings are in contrast to a large prospective study of 285,526 women, which showed no significant association between fruit or vegetable intake and reduction in breast cancer risk (82). Similarly, a large pooled analysis of cohort studies involving 351,825 women showed no significant association between increased fruit and vegetable consumption and reduced breast cancer risk (83). It has been postulated that selected nutrients have an effect on DNA repair and metabolic detoxification by virtue of their antioxidant properties (84).
Exercise has been shown to reduce the risk of postmenopausal breast cancer in a large systematic review (85). A recent study of 64,777 women from the Nurses' Health Study Cohort II evaluated premenopausal exercise habits and showed that the most active women (running 3.25 hours or walking 13 hours per week) had a 23% reduction in the risk for premenopausal breast cancer (86). A large systematic review also supports the decreased risk of breast cancer with exercise: 62 studies were evaluated with the conclusion that increased physical activity led to an overall risk reduction for breast cancer of 25% with a dose-dependent effect noted in 28 of the studies (87). This reduction in risk was seen in both premenopausal and postmenopausal women.
Regular alcohol consumption has been linked to an increased risk of breast cancer. A large pooled analysis of seven prospective case-control studies from the United States (Nurses' Health Study, Iowa Women's Health Study, New York State Cohort); Canada (CNBSS); Sweden (Sweden Mammography Cohort); and the Netherlands (Netherlands Cohort Study) was conducted. With 322,647 women and up to 11 years of follow-up, this pooled study found a linear increase in the relative risk of breast cancer from 9% in women with a daily alcohol consumption of 10 g/day (approximately one drink per day) to 41% in women who consumed 60 g/day (approximately five drinks per day) compared with nondrinkers (88).The type of alcoholic beverage was not shown to be of significance.
Prior radiation exposure, particularly to the thoracic area, has been shown to increase the risk of breast cancer. A study of Canadian women who received radiation from fluoroscopic examinations during the treatment of tuberculosis demonstrated that the risk of breast cancer associated with radiation was related to the age of exposure (89). The risk was highest for women who were exposed at ages 10-14. Similarly, Japanese women who survived the atomic bomb had an increased risk of breast cancer, and that risk was greatest for women who were exposed as children (90). Regarding the risk of breast cancer from radiation used for therapy, multiple studies demonstrate an increased risk for women who underwent treatment for Hodgkin's disease (HD) (91,92,93,94). Survivors of Hodgkin's disease have an increased risk of breast cancer from radiation exposure that is primarily age-related, with the highest risk associated with treatment at ages 10 to 20 years. In addition, the increased risk has been shown to have a late manifestation with a median time from treatment to breast cancer of 15 years.
The majority of breast tumors are found in the upper, outer quadrant, where there is more breast tissue, although breast cancer may occur anywhere in the breast. Breast cancer is often discovered by the patient when she feels a painless mass. Less commonly, a physician discovers a mass during a routine breast examination. The findings on mammography may suggest that a palpable lesion is malignant. On the other hand, screening mammography may detect an abnormality without a palpable tumor. Rarely, the patient may present with an axillary mass and no obvious carcinoma in the breast.
A breast mass in a woman of any age must be approached as a possible carcinoma. Physical examination alone is inaccurate in evaluating palpable masses. At times, the only clue to an underlying malignancy may be a subtle finding of an area of thickening amid normal nodularity. Obvious clues to malignancy include nipple retraction, skin dimpling, involved nodes, or ulceration, but these are late signs and, fortunately, are not common at presentation.
After obtaining the history and physical examination, the “triple test” should be utilized to evaluate a palpable mass. Triple test refers to the combination of physical examination, breast imaging (usually mammogram +/- ultrasound), and pathologic diagnosis employing cytology by means of fine-needle aspiration (FNA), or histology by means of coreneedle biopsy or excisional biopsy. The diagnostic accuracy is approximately 100% when all three are concordant (95,96). Indications for an excisional biopsy include cytologic or histologic atypia on needle biopsy, any discordance between any of the three modalities, or the patient's desire to eliminate a source for concern. Algorithms for the evaluation of breast masses in premenopausal and postmenopausal women are presented in Figs. 16.3 and 16.4. The American Cancer Society reports that 80% of breast biopsies are benign (http://www.cancer.org).
Fine-Needle Aspiration Cytologic Testing
Fine-needle aspiration is performed with a 20- or 22-gauge needle. The technique has a high diagnostic accuracy, with a 10% to 15% false-negative rate and a rare but persistent falsepositive rate often in association with epithelial proliferative lesions such as ductal or lobular hyperplasia (97,98).
Fine-needle aspiration can aid a clinician in discussing alternatives with a patient if a mass appears to be malignant on physical examination and/or breast imaging. A negative FNA cytologic diagnosis is usually discordant with other modalities and frequently must be followed with excisional biopsy. An FNA cytologic diagnosis of a fibroadenoma (without atypia) in a young woman can be used to safely follow the mass.
Core-Needle Biopsy Core-needle biopsy (CNB) is a less invasive procedure than open biopsy to obtain tissue for accurate histopathologic diagnosis of palpable or nonpalpable mammographic or ultrasonographic lesions. It utilizes an 11- to 14-gauge needle to obtain specimens; abnormal architecture and invasion can be identified in these tissue samples which can provide more information than FNA and may be evaluated for specific tumor markers such as estrogen receptor (ER), progesterone receptor (PR), or HER-2/neu.Indications for CNB are the same as for open biopsy and may be performed handheld for palpable masses. Suspicious nonpalpable lesions seen on mammography or ultrasonography should be biopsied using an image-guided core biopsy technique (99,100).
Figure 16.3 Schematic evaluation of breast masses in premenopausal women. 1 complex mass—a cystic mass with a solid component that may be malignant. 2 complicated cyst—usually multiple simple cysts or cysts with septations.
Figure 16.4 Schematic evaluation of breast masses in postmenopausal women.
A number of studies have shown sensitivity and specificity ranging from of 85% to 100% for image-guided CNB for diagnosing breast cancer. The sensitivity and negative predictive values of CNB are less for mammographic calcifications (.84 and .94, respectively) than for the diagnosis of masses (.96 and .99 respectively) (99,100). When CNB is used to sample microcalcifications, radiography must be performed of the specimen to ensure the calcifications are present in the tissue removed. A microclip is placed after CNB to indicate the biopsied area and a post-biopsy mammogram is obtained. CNB usually does not result in architectural distortion, which may alter the interpretation of future mammograms.
Certain technical issues may not allow CNB to be employed, such as very superficial or posterior lesions. Mammographic lesions in a very small breast are usually not amenable to stereotactic core biopsy, and silicone implants can make CNB more challenging. Depending on the location of the lesion in relation to the implant, open biopsy is sometimes recommended to avoid implant rupture. If a lesion is detectable on ultrasound, CNB using ultrasound guidance is simpler and less expensive than stereotactic CNB and does not require special equipment. Vacuum-assisted devices with CNB allow for multiple samples to be obtained without withdrawing and reinserting the needle.
Open Biopsy A minority of patients require surgical biopsy if the lesion is not amenable to CNB, the sample is inadequate, or the pathologic results are equivocal. Likewise, follow-up open biopsy is indicated if benign diagnoses of a radial scar or atypical ductal hyperplasia are made after CNB because of the coexistence of malignancy in 20% to 30% of cases (99). As mentioned above, the biopsy results must correlate with the clinical and mammographic results. Any discordance requires an additional biopsy, either repeat CNB, or more commonly surgical biopsy.
Image-Guided Open-Biopsy Nonpalpable lesions detected by a mammogram or ultrasound that are not amenable to CNB require open biopsy after pre-operative localization by imaging. This requires the collaborative effort of the surgeon and the radiologist and entails the placement of a needle or specialized wire into the area of the suspected abnormality in the breast parenchyma. To further assist in localization, many radiologists also inject a biologic dye. The surgeon then reviews the films and localizes the abnormality with respect to the tip of the wire or needle and plans his/her operation accordingly.
Open biopsy can usually be performed in the outpatient setting with the aid of intravenous (IV) sedation and local anesthesia. The following steps are undertaken:
Two-Step Approach The two-step approach involves the initial biopsy, either by needle or open procedures, followed by subsequent definitive treatment. Women who are diagnosed with breast cancer on biopsy can discuss the various treatment options and seek out additional consultations, if desirable, before undergoing definitive treatment. For most patients, being engaged in the planning of therapy is an important psychological aspect in the healing process.
Pathology and Natural History
Breast cancer constitutes a heterogeneous group of histopathologic lesions (101). Regardless of the histologic type, most breast cancers arise in the terminal duct lobular unit. The most widely used classification of invasive breast cancers, that of the World Health Organization, recognizes invasive carcinoma as “ductal” and “lobular.” This classification scheme is based on cytologic features and growth patterns of the invasive tumor cells, with the distinction between lobular and intraductal carcinoma based on the histologic appearance rather than the site of origin.
Breast cancer may be either invasive (infiltrating ductal carcinoma, infiltrating lobular carcinoma) which indicates invasion into the breast stroma with the potential for lymph node and distant metastases or in situ (ductal carcinoma in situ [DCIS] or lobular carcinoma in situ [LCIS]) which indicates the inability to spread to other sites.
The most common histologic diagnosis of invasive breast carcinoma is infiltrating ductal carcinoma. This histologic type accounts for 60% to 70% of the breast cancers in the United States (102). This diagnosis is actually a diagnosis by default because this tumor type is defined as a type of cancer that does not fall into any of the other categories of invasive mammary carcinoma (101) as recognized by defined histologic features (mucinous, tubular, medullary). Mammographically, it is often characterized by a stellate appearance with microcalcifications. The classic macroscopic appearance of infiltrating ductal carcinoma is a firm, often rock-hard mass that has gritty, chalky streaks within the substance of the tumor. This consistency is due to the fibrotic response of the surrounding stroma, not the neoplastic cells. Microscopically, the appearance is highly heterogeneous with regard to growth pattern, cytologic features, mitotic activity, and extent of in situ component.
The second most common histologic diagnosis of invasive breast carcinoma is infiltrating lobular carcinoma (ILC), which comprises 5% to 10% of breast cancers (102,103). It may present as a mammographic abnormality or palpable mass, as with invasive ductal carcinoma, but the extent of disease may be underestimated by the physical or radiographic findings (103). Invasive lobular carcinoma often presents as multicentric disease in the ipsilateral breast with coexistent LCIS in approximately 5% to 15% of cases (104,105). The incidence of contralateral breast cancer in ILC patients is about 20% (103). Macroscopically, some invasive lobular carcinomas may appear as firm, gray-white masses similar to invasive ductal cancers, or some may only have a rubbery consistency of the breast tissue. Microscopically, invasive lobular cancer is characterized by small, uniform neoplastic cells infiltrating the stroma in a single-file pattern (101) with little or no desmoplastic stromal reaction.
Other types of invasive breast carcinoma are far less common and are subtypes of infiltrating ductal carcinoma. Medullary carcinoma accounts for approximately 2% to 5% of breast carcinomas and may be a slow-growing, less aggressive malignancy than the usual infiltrating ductal carcinoma (101,102,106). These tumors are often well circumscribed grossly with a dense lymphocytic infiltrate microscopically. Tubular carcinoma is a well-differentiated breast cancer with limited metastatic potential and an excellent prognosis, occurring in about 1% of breast cancers (102,106,107). Mucinous (colloid) carcinoma accounts for fewer than 5% of all breast cancers and is associated with a favorable prognosis (102,106,107). Grossly, the tumors are well circumscribed and may have areas that appear mucinous or gelatinous. Microscopically, small clusters or sheets of tumor cells are dispersed in pools of extracellular mucin (101). Papillary carcinoma is used to describe a predominantly noninvasive ductal carcinoma; invasive papillary carcinomas are rare, accounting for approximately 1% of breast cancers (102,107). An extremely rare form of breast cancer is adenoid cystic carcinoma, which is similar histologically to the salivary gland tumor (108). They often present as a palpable mass with no clinico-radiological features. These cancers metastasize late and tend to be well differentiated.
The tumor growth rate of a breast cancer varies widely among patients and at different stages of the disease. Many mathematical models have been devised based on the natural history of breast cancer, assumptions of tumor growth rate, the probability of detecting a tumor of a given size, and the rate of clinical surfacing (109). Doubling time of breast cancer has been estimated to range from several weeks for rapidly growing tumors to months for slowly growing ones. Based on seminal studies, the mean doubling time for mammary carcinomas has been estimated to be 5.4 months with a standard deviation of 4 months (110). To give an example for clinical application, if it is assumed that the doubling time is 100 days, the doubling time is constant (which is not often the case), and the tumor originated from one cell, it would take 8 years to result in a 1-cm tumor (111) (Fig. 16.5). One primary concern is that during the time in which the tumor is growing before being clinically apparent, tumor cells may be circulating through the body.
On account of the long preclinical tumor growth phase and the early metastastic rate of some infiltrating carcinomas, many clinicians view breast cancer as a systemic disease at the time of diagnosis. This pessimistic view is not justified. A more realistic approach is to view breast cancer as a two-compartment disease: one consists of the primary breast tumor with its possible local and regional extension, and the other consists of the systemic metastases with their life-threatening consequences.
Biology of Breast Cancer
The biology of breast cancer is highly variable. Some view breast cancer as a local disease that progresses in a predictable manner to develop distant metastases over time, known as the “Halstedian” theory, named after the prominent surgeon who popularized the radical mastectomy. With this view, aggressive local control is necessary for survival. Others view breast cancer as a “systemic” disease, with distant metastases present before a patient is diagnosed.
Figure 16.5 Growth rate of breast cancer, indicating long preclinical phase. (From Gullino PM. Natural history of breast cancer: progression from hyperplasia to neoplasia as predicted by angiogenesis. Cancer 1977;39:2699. Copyright 1977 American Cancer Society. Reprinted by permission of Wiley-Liss, Inc., a subsidiary of John Wiley & Sons, Inc.)
With the systemic view, it is thought that some tumors have the ability to metastasize and others do not; the emphasis is on systemic therapy with the belief that local recurrences are treated as they develop and have no bearing on the development of future distant disease or on survival. Another theory, known as the “spectrum theory,” is a synthesis of the two views: breast cancer is a heterogeneous disease with some cancers that remain local throughout their course at one end of the spectrum while others are systemic from the outset at the other end (112). With this view, unless initial local control is sufficient, some tumors will gain the ability to disseminate to distant sites. However, it is acknowledged that if there is a high likelihood that a tumor has disseminated at the time of diagnosis, local control will have little overall impact.
After the diagnosis of breast cancer has been confirmed either by cytology or histology, the clinical stage of the disease should be determined. Clinical staging involves findings on physical examination, with incorporation of information gained from imaging. The American Joint Committee on Cancer (AJCC) uses the TNM (tumor-nodes-metastases) system,presented in Tables 16.4 and 16.5 (113). The advantage of this system is its use both preoperatively for clinical staging as well as postoperatively for pathologic staging. In the most recent AJCC staging revision, new areas are incorporated regarding evaluation of the axilla and prognostic factors: the number of positive axillary nodes; the method used for detection (clinical examination or sentinel node biopsy); and the presence of micrometastatic disease.
Table 16.4 TNM (Tumor-Nodes-Metastases) System for Staging of Breast Cancer
Table 16.5 TNM (Tumor-Nodes-Metastases) Stage Grouping of Breast Cancer
The initial stage of the disease dictates the extent of the preoperative workup (114). According to the National Comprehensive Cancer Network, for most patients with TNM stage I or II disease (small tumors, no palpable lymph nodes, and no symptoms of metastases), the preoperative evaluation should consist of: (http://www.nccn.org).
A routine bone scan, abdominal CT scan (to evaluate the liver), and chest CT imaging are not necessary unless symptoms or abnormal blood chemistry suggest bone, liver, or pulmonary metastases. Chest CT imaging should be included for any patient presenting with clinical stage III or IV disease. Although the NCCN guidelines for clinical stage III workup recommends a bone scan or abdominal CT scan only if dictated by symptoms or laboratory values, most physicians will obtain these studies in patients with locally advanced breast cancer. Patients with clinical stage IV disease should have both a bone scan and abdominal CT scan; if metastases are evident on imaging or there is obvious bone marrow dysfunction, most physicians will recommend a bone marrow biopsy for confirmation of bony metastatic disease. Routine bone marrow biopsy is viewed by some to be an important prognostic test for staging breast cancer patients that may supplant axillary dissection (115).
Positron emission tomography (PET) uses a glucose analog tracer, fluorodeoxyglucose (FDG), which is taken up by cells in proportion to the rate of glucose metabolism (116); malignant cells have increased glucose uptake in comparison to normal tissue. As of November 2004, the Centers for Medicare and Medicaid Services approved coverage for FDG-PET scanning in breast cancer for the following indications: (i) staging patients with distant metastasis; (ii) restaging patients with locoregional recurrence; or (iii) monitoring response to therapy in women with either metastasis or locally advanced breast cancer when a change in treatment is planned. Currently, FDG-PET should be used as an adjunct to standard imaging modalities. At this time, FDG-PET is not recommended for axillary staging in patients with an initial diagnosis of breast cancer because research studies have produced mixed results and FDG-PET cannot detect small metastases (i.e., <1 cm) (116,117,118,119).
Treatment of Breast Cancer
The traditional treatment of breast cancer was primarily surgical but has evolved over the years to a multidisciplinary approach, requiring the collaborative effort of surgeons, pathologists, radiologists, oncologists, and others.
The modern era of breast surgery began with Halsted and the development of the radical mastectomy, based on his understanding of breast cancer as a locally infiltrative process that spread primarily via the lymphatics (120). The radical mastectomy involved resection of the entire breast with overlying skin, the underlying pectoral muscles, and the axillary lymph nodes in continuity 121 (Fig. 16.6). However, this initial operation was designed to treat patients with palpable axillary lymph nodes and locally advanced disease. Although effective in local control of the tumor, this surgery failed to cure many patients, most likely because of their advanced stage at presentation.
Figure 16.6 Defects after mastectomy (A) radical mastectomy (B) modified radical mastectomy.
During the 20th century, more extensive variations of the radical mastectomy were adopted in order to remove more regional tissue. Some of the variations included supraclavicular dissection (122) and supraclavicular, internal mammary, and mediastinal lymph node dissections, with resulting higher morbidity and mortality rates (123). The extended radical mastectomy, first described by Urban (124) added an en bloc internal mammary node dissection to the standard operation. This surgery did not improve survival rates but increased morbidity.
The modified radical mastectomy (MRM) was gradually adopted as the operative treatment for invasive breast cancer when it was recognized that mortality after treatment was due to systemic dissemination of neoplastic cells before surgery rather than inadequate resection. In addition, MRM is functionally and cosmetically superior to more radical mastectomies. The MRM is similar to the radical mastectomy with complete removal of the breast and axillary nodes; however, there is less removal of the skin with no need for skin grafting, and the pectoralis muscles are preserved (Fig. 16.6B). The main advantage of the MRM is a better functional and cosmetic result.
Total or simple mastectomy is the removal of the entire breast, nipple, and areolar complex with preservation of the pectoralis muscles and axillary lymph nodes. Usually included in the specimen are the low-lying lymph nodes in the upper, outer portion of the breast and low axilla.
To refute the Halstedian concept that aggressive local control was necessary in the treatment of invasive breast cancer, the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-04 study was a randomized trial comparing the Halsted mastectomy to less extensive surgery, with or without radiation therapy. In this trial, patients with clinically negative axillary nodes were randomly assigned to a radical mastectomy, total mastectomy with postoperative irradiation, or total mastectomy with delayed dissection if positive nodes developed. Patients with clinically positive axillary nodes were randomly assigned to radical mastectomy or total mastectomy with postoperative irradiation. After 25-year follow-up, there was no significant difference among the three groups of women with negative nodes or between the two groups of women with positive nodes with respect to disease-free survival, distant-disease free survival, or overall survival (125). Therefore, the radical mastectomy was shown to have no advantage over total mastectomy in terms of local control or overall survival; in addition, the removal of lymph nodes was shown to have no effect on survival.
Breast-conserving surgery developed from the same desires as did the modified radical mastectomy: defining the extent of surgery required to treat invasive breast cancer without compromising outcome. One of the major goals of breast-conserving surgery is to preserve the cosmetic appearance of the breast. Radiation therapy without surgical treatment was shown to result in high local failure rates (126). Two pivotal prospective randomized trials compared standard surgery to a combination of less extensive surgery with or without radiation. In the Milan study, patients were randomly assigned to either (i) the standard Halsted radical mastectomy or (ii) quadrantectomy, axillary lymph node dissection (ALND), and postoperative radiation (127,128). Patients with tumors less than or equal to 2 cm with clinically negative axillary nodes (T1N0M0) were eligible for this trial; the two groups (total of 701 women) were comparable (age, tumor size, menopausal status, nodal involvement) (128). After 20 years of follow-up, there was no statistical significant difference between the two groups regarding contralateral breast cancer, second primary cancer, distant metastases, or overall survival (Table 16.6) (128); however there was a statistical difference of chest wall recurrences of 8.8% in the BCS group versus 2.3% in the radical mastectomy group.
Table 16.6 Halsted Radical Mastectomy Versus Breast-Conserving Surgery: Results of 20-Year Follow-Up
Figure 16.7 Appearance after lumpectomy, axillary dissection, and radiation therapy.
The NSABP conducted a similar trial, B-06 (129). Patients with tumors less than or equal to 4 cm either without palpable nodes or with palpable nonfixed axillary lymph nodes (i.e., stage I or II: T1 or T2, and N0 or N1) were eligible. Patients were assigned randomly to (i) the modified radical mastectomy (MRM); (ii) lumpectomy (segmental mastectomy) and ALND; or (iii) lumpectomy, ALND, and postoperative radiation therapy (Fig. 16.7). Tumor-free specimen margins were required to maintain eligibility. A total of 1,851 women were randomized among the three treatment arms, and the groups were comparable. After 20-years of follow-up, the NSABP B-06 trial provides clear evidence that the combined lumpectomy, ALND, and postoperative radiation therapy is as effective as the modified radical mastectomy for the management of patients with early stage breast cancer (130). Although there was no significant difference in overall survival among the three treatment arms, there were significant differences in local control. The in-breast recurrence rate for patients randomized to lumpectomy and radiation therapy was 14.3% versus 39.2% for patients randomized to lumpectomy alone. This trial also established the safety of breast-conserving surgery for early-stage breast cancer and showed the importance of postoperative radiation to reduce the risk of in-breast recurrences. The results of these trials led to a National Institute of Health (NIH) Consensus Conference in 1991 endorsing breast-conserving surgery as the preferred treatment for earlystage breast cancer (131).
Axillary Lymph Node Staging
Axillary nodal involvement remains the most significant prognostic factor for recurrence and survival for patients with early-stage breast cancer. Dissection of the axillary nodal basin provides excellent regional control if metastases are present, accurate prognostic information, and allows appropriate management decisions regarding additional therapy.
As part of breast-conserving surgery, the axillary dissection preferably is performed through a separate incision in the axilla. For accurate staging and the prevention of axillary recurrences in early-stage breast cancer, an NIH Consensus Development Conference concluded that removal of level I and II nodes should be routine (131). The three levels of nodes in the axilla are based on their relationship to the pectoralis minor muscle. Level I and II axillary dissection involves removal of all the fatty and lymph node-bearing tissue lateral and posterior to the medial border of the pectoralis minor muscle. It is very rare for so-called “skip metastases” to be present in the higher levels of the axilla without involvement of the lower levels (132). If palpable nodes are encountered medial to the pectoralis minor (level III) during surgery, a complete dissection involving all three levels should be performed, usually necessitating transection of the pectoralis minor muscle.
Although axillary nodal dissection is accurate for staging, there are known morbidities associated with the procedure such as paresthesias, wound complications, and lymphedema. The latter occurs in approximately 10% to 20% of patients. Since the advent of mammography, breast cancer size and positive nodal involvement at diagnosis have been diminishing. Only 30% of breast cancer patients have involved axillary nodes detected by standard pathologic techniques (42). This has led some authorities to question the value of routine ALND in patients with early stage breast cancer (42).
The technique of sentinel lymph node biopsy (SNB), a minimally invasive procedure, is based on the observation that specific areas drain via lymphatic channels to one or two primary nodes before involving other lymph nodes within a nodal basin. By injecting radioisotope and/or blue dye into the region of the tumor or under the areola and performing a limited axillary dissection, these primary or sentinel nodes can be identified either by visual inspection or by the use of a hand-held gamma counter. Only these sentinel nodes are removed and analyzed using routine hematoxylin and eosin (H&E) staining and/or immunohistochemistry (IHC) to identify small foci of metastases. When the H&E-stained slides are negative, most institutions perform IHC.
Studies have shown that if the sentinel node is free of tumor histopathologically, the rest of the axillary nodes are theoretically free of tumor, thereby avoiding the need for a complete ALND (133,134,135). In experienced hands the false-negative rate is low and can be nearly 0% with proper patient selection and adherence to technical detail (134). If the sentinel node is positive for metastases, then the standard treatment is to undergo complete axillary dissection of levels I and II.
In 2005, the American Society of Clinical Oncology (ASCO) published guideline recommendations for SNB in early-stage breast cancer (136). These guidelines were based on 69 studies in which SNB was compared to ALND. There was sufficient evidence to show that a negative sentinel lymph node (SLN) was predictive of negative axillary nodes for the panel to recommend the use of SNB in early-stage breast cancer patients with clinically negative nodes, provided the procedure was performed by an experienced team. The panel also recommended that suspicious palpable nodes found during dissection should be submitted as SLNs. Also advised was a completion ALND for any patient with SLN metastases including micrometastasis (>0.2 mm to <2.0 mm).
The panel also gave recommendations regarding the use of SNB in certain clinical circumstances. Regarding cases involving DCIS, the panel recommended SNB for mastectomy patients with DCIS, in DCIS with microinvasion, or in cases with DCIS larger than 5 cm. Although DCIS is noninvasive in nature, in 10% to 20% of patients diagnosed with DCIS by core biopsy, invasive disease will subsequently be found upon excision due to a sampling error (137). If invasion is discovered after a mastectomy, the opportunity to stage the axilla with SLND will be lost. Other special clinical circumstances in which SNB is recommended are (i) in elderly patients; (ii) obese patients; (iii) male patients;(iv) multicentric tumors; and (v) after prior excisional biopsy. Scenarios in which SNB is not recommended include (i) patients with a clinically positive axilla (N1); (ii) pregnant patients; (iii) prior axillary surgery; (iv) inflammatory breast cancer; (v) after preoperative systemic therapy; and (vi) in patients with tumors larger than 5 cm.
There is increasing evidence supporting the use of SNB in some of these circumstances. There are limited reports of the safe use of radioisotopes in pregnant patients (138,139). However, a recent review concluded that SNB should not be offered to pregnant patients under 30 weeks' gestation (140).
Regarding the technical aspects of the procedure, the panel supports the Guidelines for Performance of Sentinel Lymphadenectomy for Breast Cancer developed by the American Society of Breast Surgeons (ASBS) (http://www.breastsurgeons.org/officialstmts/sentinel.shtml). The ASBS maintains that a SLN identification rate of 85% and a false-negative rate of 5% or less are necessary in order to abandon axillary dissection. The ASBS also recommends that surgeons perform a minimum of 20 SNB cases followed by completion ALND, or have proper mentoring, before relying on the procedure to avoid ALND. The ASCO panel points out that the lowest false-negative rates in general were obtained with the combined methods of isotope and blue dye, but do not believe that ASCO should present separate guidelines for the technical performance of the procedure.
Adjuvant Radiation Therapy
Adjuvant radiation after breast-conserving procedures is essential for the achievement of recurrence rates equivalent to those obtained with mastectomy. Radiation therapy, when combined with radical surgery, improves local control, but overall survival rates are not affected (129,130,141). In B-06, the in-breast recurrence rate for patients randomized to lumpectomy and radiation therapy was 14.3% versus 39.2% for patients randomized to lumpectomy alone.
Although overall survival rates were not different between patients who were treated with BCS and those treated with more extensive mastectomies, as shown in B-06 and the Milan Group study, some small randomized trials have shown small but clinically relevant differences in survival. Pooled analyses of multiple trials, or meta-analyses, can often provide enough statistical power to detect these small differences. In 2005, the Early Breast Cancer Trialists' Collaborative Group (EBCTCG) presented the findings from 78 randomized clinical trials evaluating the extent of surgery and the use of radiation (142). This large meta-analysis investigated the effect of local recurrence on breast cancer mortality by analyzing data on 42,000 women, divided into groups based on a 5-year local recurrence risk, whether the risk was <10% or exceeded 10%. This study was able to show that improved local control with radiotherapy at 5 years resulted in significant improvement in breast cancer survival at 15 years: For every four local recurrences that could be avoided over 15 years, one breast cancer death would be avoided. Local treatments to improve local control had the greatest effects in the patients who were at greatest risk for local recurrence.
Postoperative radiation therapy is recommended as part of BCS to reduce local recurrence rates; however, there are also indications for its use in post-mastectomy patients who are at higher risk for locoregional failure. Studies, some included in the EBCTCG overview analysis, have shown that the risk of locoregional failure is reduced and diseasespecific survival is improved by post-mastectomy radiotherapy (PMRT) (111, 143,144,145). A literature review recommended post-mastectomy radiation for women with greater than 4 positive nodes and women with tumors greater than 5 cm in diameter (146). The review concluded that there was insufficient evidence at this time for post mastectomy radiation for patients with high-risk, node-negative disease, including premenopausal women with tumors greater than 2 cm in diameter, evidence of vascular invasion, invasion of the skin or pectoral fascia, or close/positive margins.
Clinical trials evaluating breast-conserving surgery and intraoperative radiation therapy (IORT) for localized breast cancer are ongoing (147). The rationale for IORT is based on the desire to minimize length of treatment and the finding that 85% of recurrent breast cancer is confined to the same quadrant of breast as the primary tumor. The use of IORT requires wide mobilization of the breast tissue and can prolong operative times. Whether the therapeutic effect of IORT is equivalent to traditional whole breast radiation therapy remains to be determined.
Accelerated Partial Breast Irradiation (APBI) The observation that most recurrences after breast-conserving surgery occur in close proximity to the surgical site led to investigation into the delivery of radiation therapy only to the lumpectomy cavity and the immediately adjacent tissue over a shortened period of time, referred to as accelerated partial-breast irradiation (148,149). Results from studies using interstitial catheter brachytherapy to deliver APBI have shown good local tumor control rates, but the technique can be cumbersome and difficult to learn. The MammoSite balloon catheter was developed as a single catheter delivery device that allows a shorter period of radiation treatment, usually 5 days instead of 5 to 6 weeks, as an alternative to external beam radiation or seed brachytherapy. The balloon catheter is placed in the lumpectomy cavity and filled with saline/contrast. Before treatment is initiated, the position of the balloon is checked to ensure adequate conformity to the lumpectomy cavity. The radiation source is advanced into the catheter and radiation therapy is delivered twice a day for five days. The radiation source is removed between treatments. After completion of therapy, the balloon catheter is removed.
The ASBS recommendations for eligibility criteria are age greater than 45, invasive ductal carcinoma or DCIS, tumor size of 3 cm or less, negative microscopic surgical margins and negative nodal status (http://www.breastsurgeons.org.apbi.shtml). Additional factors to be considered for MammoSite use are adequate skin-spacing (usually 7 mm) and catheter conformity to surgical cavity. Early results have been promising with 5-year local recurrence rates comparable to those achieved with conventional whole-breast radiation, with decreased toxicity and good to excellent cosmetic results in the majority of patients (150,151). Randomized studies currently in progress will determine the role of accelerated partial breast irradiation.
Adjuvant Systemic Therapy
Patients may have clinically undetectable systemic micrometastases during primary surgery that are responsible for later recurrences, as evidenced by the lower survival rates for women with metastatic nodal disease. The objective of systemic adjuvant therapy is to control microscopic disease, reduce the risk of recurrence and improve long-term survival.
The results of many well-designed, randomized trials support the use of adjuvant systemic therapy, with reductions demonstrated in recurrence rates and breast cancer mortality.These reductions are most evident when data from various trials are pooled together and analyzed, such as in The Early Breast Cancer Trialists' Collaborative Group (EBCTCG) overview (152).
Adjuvant Systemic Chemotherapy
In the 2005 EBCTCG overview, meta-analyses were initiated on 194 randomized trials of adjuvant chemotherapy or hormonal therapy that began in 1995. Many of the trials involvedanthracycline-based combinations, cyclophosphamide, methotrexate, and 5-fluorouracil, (CMF) tamoxifen, or ovarian suppression. None of the trials involved the newer agents such as taxanes, raloxifene, trastuzumab, or aromatase inhibitors.
There was a significant reduction in the annual breast cancer death rate for patients allocated to a 6-month regimen of anthracycline-based polychemotherapy (primarilydoxorubicin or epirubicin), which was independent of the use of tamoxifen, nodal status, estrogen-receptor (ER) status, or other tumor characteristics. The benefits were greater in younger women, with reductions in annual breast cancer death rates of 38% for women diagnosed under the age of 50 and 20% for women aged 50-69 years. The anthracyclineregimens were also more effective than the CMF regimens, with moderate, but highly significant reductions in the annual recurrence rate of 11% (p = 0.001) and annual breast cancer death rate of 16% (p <0.00001). Four cycles of doxorubicin and cyclophosphamide (AC) have been shown to have an equivalent disease-free survival and overall survival to six months of traditional CMF in two NSABP trials (B-15 and B-23) (153,154).
Newer chemotherapeutic agents have emerged as effective adjuvant systemic therapies for breast cancer, most notably, members of the taxane family, including paclitaxel (Taxol) and docetaxel (Taxotere). The taxanes have been shown to have good activity in patients with metastatic breast cancer and are not cross-resistant to anthracyclines. For these reasons, the NSABP B-28 trial and other similar large, randomized trials have been conducted to evaluate the efficacy of the taxanes. Results from NASBP B-28 demonstrated that the addition of paclitaxel after AC resulted in a significant improvement in disease-free survival, but not overall survival (155). By contrast, both disease-free and overall survival rates were improved in node-positive patients who were randomized to receive AC in combination with sequential paclitaxel compared with AC alone in a large, cooperative, randomized study (156). Early results from studies suggest that the combination of docetaxel and cyclophosphamide (TC) is associated with a superior disease-free survival than AC for patients with stage I-III breast cancer (157). Dose-dense regimens, in which chemotherapeutic agents are given every 2 weeks with granulocyte colony-stimulating factor support rather than every 3 weeks, have also been shown to improve clinical outcomes significantly (158). These studies demonstrate that taxanes are valuable components of adjuvant chemotherapy for patients with early-stage breast cancer.
Amplification of the HER-2/neu gene, a member of the tyrosine-kinase pathway family, or overexpression of the HER-2/neu protein occurs in approximately 15% to 25% of breast cancers and is associated with aggressive tumor behavior (159). Trastuzumab (Herceptin) is a humanized monoclonal antibody against the HER-2/neu growth factor receptor which has been shown to have clinical activity in women with metastatic HER-2/neu positive breast cancer (160). The Herceptin Adjuvant (HERA) Trial is a large international, intergroup study to investigate whether the administration of trastuzumab is effective as adjuvant therapy for HER-2/neu positive breast cancer after surgical treatment and completion of chemotherapy (161). Interim analysis at one year indicated a significant reduction in disease-free survival events by almost half (48%, p <0.0001) with an absolute benefit in disease-free survival of 8.4% at two years. At two-year analysis, a significant survival benefit was seen with a 34% reduction in the risk of death with trastuzumab therapy given for one year(162).
The available data from the EBCTCG overview support chemotherapy as adjuvant treatment for early breast cancer (152). However, some women will only derive a small benefit from such a regimen at the cost of excessive morbidity. A number of prognostic factors are used to predict the risk of future recurrence or death from breast cancer, factors including patient age, tumor size, number of involved axillary nodes, and HER-2-neu status (discussed below). One validated computer-based model (Adjuvant! Online; http://www.adjuvantonline.com) is available to the clinician to estimate 10-year disease-free and overall survival incorporating the abovementioned prognostic factors in addition to patient comorbidity and tumor grade; HER-2/neu status is not included. The estimates for recurrence and death vary based on various treatment options from no additional therapy to the most aggressive form of polychemotherapy.
Although chemotherapy has been shown to benefit women with node-negative, estrogen-receptor-positive disease in large clinical trials such as NSABP B-14 and B-20 trials (163,164), there are many patients who would not derive much additional benefit from adjuvant chemotherapy and would in fact be over treated.
Two gene-based approaches are also available to the clinician to aid in determining those most likely to benefit from additional chemotherapy. One such tool is a 21-gene assay using reverse transcription polymerase chain reaction on RNA isolated from paraffin-embedded breast cancer tissue (OncotypeDx) (165). This tool is able to quantify the 10-year risk of recurrence in tamoxifen-treated patients with node-negative, estrogen-receptor positive disease. Women are given a recurrence score and stratified according to risk levels: low, intermediate and high. Another microarray-based tool analyzes a 70-gene expression profile from frozen breast tissue to predict those early-stage breast cancer patients who are more likely to develop distant recurrence (Mammaprint) (166).
Adjuvant Hormone Therapy
In the EBCTCG overview, the effects of hormonal therapy for early breast cancer on recurrence and 15-year survival were investigated (152). For women with estrogen-receptor (ER) positive disease, adjuvant tamoxifen given for 5 years reduced the annual breast cancer rate by 31% independent of patient age, use of chemotherapy, or other tumor characteristics. Tamoxifen therapy for 5 years was significantly more effective than only 1 or 2 years of therapy. Among women with ER-positive disease who were allocated to 5 years of tamoxifen, there was a 41% reduction in the annual recurrence rate. Most of the effect on recurrence was seen during the first 5 years; however, most of the effect on breast cancer mortality was seen after this time period.
For years, tamoxifen was the gold standard of hormonal therapy for patients with breast cancer. Aromatase inhibitors (AI) were first studied in the metastatic setting for postmenopausal women with hormone-receptor positive disease (122,167). These agents act to markedly reduce the circulating estrogen levels in postmenopausal women. In 1996, a randomized double-blind multicenter trial was initiated to investigate the efficacy of the AI, anastrozole (Arimidex) in the adjuvant setting. The trial known as Arimidex, Tamoxifen, Alone or in Combination (ATAC) compared tamoxifen with Arimidex alone and in combination with tamoxifen as adjuvant endocrine therapy for postmenopausal patients with operable, invasive, early stage (stage I and II) breast cancer. Results of the ATAC trial demonstrated Arimidex to be better tolerated and more effective in improving disease-free survival and time to recurrence than tamoxifen after median follow-up of 100 months (168). There was a yearly increased fracture episode rate with anastrozole over tamoxifen(2.93% versus 1.90%, respectively), but this effect did not continue after therapy was completed. None of the known associated risks of tamoxifen, thromboembolism, endometrial cancer, or vaginal bleeding, were seen with anastrazole.
Other aromatase inhibitors, such as letrozole (Femara), and exemestane (Aromasin), are additional alternatives for postmenopausal patients with hormone-sensitive breast cancer. In 2004, ASCO published a status report on the use of aromatase inhibitors as adjuvant therapy (169). Based on the results of multiple large randomized trials, the ASCO practice guidelines recommend incorporating aromatase inhibitors into adjuvant regimens. AIs are also recommended as initial treatment for women intolerant of tamoxifen. Conversely, women intolerant of AIs should receive tamoxifen. Additionally, women with hormone receptor-negative tumors should not receive adjuvant hormonal therapy.
Endocrine therapy in combination with chemotherapy further increases the relative benefits. Anthracycline-based chemotherapy reduces 15-year mortality rates for women with ER-positive disease (the most common form of breast cancer). The 2005 meta-analysis demonstrated that 5 years of tamoxifen after anthracycline-based chemotherapy further reduced the 15-year mortality rates; for patients with ER-positive disease and age less than 50, the final mortality reduction was almost 60% and for patients aged 50-69, the reduction in mortality was almost cut in half (152). The authors suggested that the effects might even have been stronger had there been full compliance with the allocated treatments.
Table 16.7 Prognostic Factors in Node-Negative Breast Cancers
In practice, oncologists are using systemic adjuvant therapy for most patients with earlystage breast cancer >1 cm and patients with nodal disease. Factors that determine the patient's risk of recurrence are tumor size, ER and PR status, HER-2/neu status, nuclear grade, histologic type, and proliferative rate (170,171,172). Other biochemical and biologic factors such as ploidy, S-phase fraction, and cathepsin D levels appear to have some prognostic significance (Table 16.7), especially in node-negative patients (170). The NCCN guidelines recommend considering OncotypeDx testing in cases of tumors 0.6 cm to 1.0 cm with unfavorable features and in certain cases of tumors >1 cm. OncotypeDx testing is best used in patients who would receive questionable benefit from the addition of chemotherapy. In patients with large tumors or tumors with aggressive features, such as HER-2/neu over-expression, the decision to offer adjuvant chemotherapy is obvious without the need for further testing. Patients with nodal disease should be considered for adjuvant chemotherapy. Most patients with tumors larger than 0.5 cm (or larger than 1 cm in the cases of tubular or mucinous tumors) and positive ER status should be offered hormonal therapy. Table 16.7 summarizes these prognostic factors and their effect on recurrence (170,171,172).
To aid in the discussion with patients regarding the use of adjuvant therapy, risk reductions in breast cancer mortality should be translated into absolute benefits by calculating the number of deaths avoided per 100 women (173). For instance, if the 10-year risk of death from breast cancer is 10%, and if adjuvant chemotherapy reduces the mortality rate by 30%, the absolute increase in the number of patients alive will be three per one hundred treated. On the other hand, if the 10-year risk of death is 50%, the same proportional reduction in mortality would mean 15 extra lives saved.
The current recommendations for adjuvant chemotherapy and hormonal therapy in breast cancer can be summarized as follows (Table 16.8):
Table 16.8 Summary of Adjuvant Systemic Therapy for Women With Breast Cancer
In spite of all of the evidence, the decision for adjuvant therapy resides with a well-educated and well-informed patient.
Although the natural history of breast cancer can involve metastases to any organ, 85% of women with metastatic breast cancer have involvement of bone, lungs, or liver (174), with bone as the most common site. Bone metastases can give rise to pathologic fractures and/or hypercalcemia.
Treatment for metastatic disease may include surgery (if locally recurrent disease), chemotherapy, hormonal therapy, and radiation treatment if indicated. There are therapeutic regimens specific to each site of metastases. Work-up for metastatic disease is also tailored to specific complaints. If any one site is involved, metastases in other organs are highly likely which requires careful detailed work-up. The initial work-up for patients presenting with recurrent or stage IV disease should include liver function tests, chest imaging, bone scan, x-rays of symptomatic bones, biopsy documentation of first recurrence if possible, and possible CT scan/PET imaging and/or MRI. Whether a patient received prior chemotherapy or endocrine therapy also determines future treatment options. For patients with systemic recurrence of breast cancer, cure is no longer possible and the goal of treatment is to prolong survival without jeopardizing quality of life.
The treatment algorithm and various therapeutic options in metastatic breast disease are complex; to discuss them in any great detail is beyond the scope of this chapter, however, a few notable therapies will be addressed.
According to the NCCN guidelines for recurrent or metastatic breast cancer, patients are initially stratified according to the presence or absence of bony metastases. The two subsets of patients are then further stratified by HER-2/neu and hormone receptor status. Women with bone metastasis, especially with lytic lesions, should be offered a bisphosphonate with calcium and vitamin D. The use of bisphosphonates in this setting has no impact on overall survival but is of value in that it provides supportive care (175).
Metastatic disease may respond to hormonal manipulation. The latter may involve ovarian ablative surgery, radiation, (not frequently used), chemical ablation, drugs that block synthesis of hormones, or drugs that block hormonal receptor sites (176). The usual course of metastatic disease is progression after initial response to hormonal therapy, indicating the drug is no longer effective. Sequential therapy using other drugs is instituted in a stepwise fashion with responses typically diminishing with each new line of therapy. Even patients with ER/PR negative disease who have metastasis limited to bone or soft tissue may be considered for a trial of endocrine therapy, but the response rate is extremely low. Women with bulky, progressive visceral metastases should receive initial cytotoxic chemotherapy, not hormonal therapy even if ER-positive.
In premenopausal patients, who progress on tamoxifen, the preferred second-line therapy is oophorectomy, radiation, or chemical ovarian ablation using a luteinizing hormonereleasing hormone (LHRH) agonist, such as goserelin (Zoladex). The combination of tamoxifen and goserelin has been shown in a meta-analysis of four randomized trials to provide a significant survival and progression-free benefit, with a 30% reduction in the risk of an event with the combined therapy (177). Premenopausal women with ER-positive disease who have undergone ovarian ablation/suppression should be treated following postmenopausal guidelines.
Many postmenopausal women with hormone-receptor positive breast cancer benefit from sequential endocrine therapies. There are several aromatase inhibitors that are effective and well tolerated in metastatic disease, such as anastrozole (Arimidex), letrozole (Femara) or exemestane (Aromasin). Fulvestrant (Faslodex) is a new estrogen receptor antagonist that down-regulates the ER and has none of the estrogen agonist effects of tamoxifen (i.e., endometrial proliferation). It is indicated for postmenopausal patients with metastatic breast cancer previously treated with an antiestrogen, who progress on therapy. Fulvestrant appears to be at least as effective as anastrozole for the second-line treatment of patients with metastatic breast cancer (178).
Patients who have HER-2/neu positive metastatic disease may benefit from treatment with trastuzumab as a single agent or lapatinib (Tykerb) in combination with capecitabine (Xeloda), an oral form of 5-FU (179). Lapatinib, also an oral agent, is a tyrosine kinase inhibitor of HER-2/neu and epidermal growth factor receptor. In a phase III open-label trial,the combination of lapatinib plus capecitabine was superior to capecitabine alone in women with HER-2-positive metastatic breast cancer that had progressed after therapies including trastuzumab, anthracycline and a taxane (179). Time to progression was increased by 50% in patients receiving combination therapy, with median time to progression of 8.4 months compared to 4.4 months with capecitabine alone.
Other Breast Diseases
Preinvasive (In Situ) Breast Carcinoma
Both lobular and ductal carcinomas may be confined by the basement membrane of the ducts or lobules. These preinvasive cancers by definition do not invade the surrounding tissue and, in theory, lack the ability to spread. The goal of treatment for pure in situ disease is preventing invasive disease from occurring or diagnosing developing invasive disease that is localized to the breast. If microinvasion or invasion is found on pathologic review, re-excision, or mastectomy, then the patient should be treated appropriately for invasive disease.
Lobular Carcinoma In Situ (LCIS) LCIS is typically an incidental finding at biopsy for a mass, or mammographic abnormality unrelated to the LCIS. The true incidence of LCIS is unknown due to the lack of clinical and mammographic signs. Most cases occur in premenopausal women. It is viewed as a marker of increased risk for breast cancer, not limited to the side involved with LCIS. Most subsequent cancers that develop are invasive ductal carcinomas, with infiltrating lobular carcinomas representing the minority. The risk of developing invasive cancer is approximately 1% annually, a risk which indefinitely persists (136,137).
Biopsy-proven LCIS is usually managed after biopsy with surveillance by careful observation, clinical breast examination bi-annually, and yearly mammography and possibly breast MRI. Patients should be informed that they have a higher risk for development of invasive breast cancer, and bilateral prophylactic mastectomy should be considered in certain cases such as in women with strong family histories of breast cancer or women with a BRCA 1/2 mutation.
Tamoxifen is approved by the Food and Drug Administration (FDA) as a chemopreventive in women with LCIS. In the NSABP P-1 Study, women at an increased risk for breast cancer were given tamoxifen as a chemopreventive agent for 5 years. Women with LCIS who took tamoxifen had over a 50% reduction in the occurrence of invasive cancer compared to women in the placebo group. Women who are found to have LCIS on biopsy should be counseled regarding chemoprevention (see below) (180).
Ductal Carcinoma In Situ Ductal carcinoma in situ typically occurs in postmenopausal women. The incidence of ductal carcinoma in situ has increased by a factor of 10 in two decades since the implementation of mammography as a screening tool (181). The incidence has increased from approximately 5,000 cases annually in the 1980s to more than 50,000 cases annually currently (39). Mammographically, DCIS typically appears as a cluster of branched or Y-shaped microcalcifications, although it sometimes presents as a palpable mass. DCIS is characterized by a clonal proliferation of malignant epithelial cells that do not invade beyond the basement membrane.
Unlike patients with LCIS, 30% to 60% of patients with DCIS will develop invasive cancer in the same breast when treated with excisional biopsy alone (182). Axillary metastases occur in fewer than 5% of patients. The occurrence of metastases indicates that an invasive component has been missed on biopsy. Approximately 15% to 20% of patients with DCIS diagnosed with initial core-needle biopsy will be upstaged during excision due to the discovery of infiltrating ductal carcinoma (137).
For years the standard treatment for DCIS was total mastectomy. Currently, most women in the United States with ductal carcinoma in situ are treated with breast-conserving surgery owing to the shift toward this approach for invasive cancer (181). However, there have been no randomized trials comparing mastectomy with breast-conserving surgery for DCIS.
The NSABP B-17 randomized trial compared lumpectomy with or without postoperative radiation for DCIS. After 8 years of follow-up, the overall recurrence rate for either DCIS or invasive carcinoma in the ipsilateral breast was reduced by more than half, from 26.8% to 12.1% in the patients who received radiation (183). The benefit of radiation was greatest for recurrent invasive carcinoma, with an 8-year reduction from 13.4% to 3.9%. The benefit of radiation was seen with all patient subgroups, including those with small nonpalpable tumors detected by mammography.
The NSABP-24 randomized clinical trial evaluated adjuvant tamoxifen therapy in addition to lumpectomy and radiation. The trial involved 1,800 women with DCIS who were randomly assigned to lumpectomy and radiation therapy, followed by 5 years of tamoxifen or placebo. After 7 years of follow-up, the addition of tamoxifen significantly reduced the rate of all breast cancer events (ipsilateral and contralateral, in situ and invasive) by 39%, from 16% in the placebo group to 10% in the tamoxifen group (p = 0.0003) (184).
Paget's disease of the breast, first described in 1874, is a rare manifestation of breast cancer with associated nipple changes similar to eczema, with itching and ulceration (185). Characteristic large cells with irregular nuclei, called Paget's cells, invade the nipple and surrounding areola. There is debate as to the origin of Paget's cells: either the cells originate from underlying carcinoma in the breast and then migrate into the major ducts of the nippleareolar complex, or the cells originate in the epidermis. Initially there may be no visible changes with invasion of the nipple. Patients often notice a nipple discharge, a combination of serum and blood from the involved ducts. Paget's disease is often mistaken for a dermatitis, which can lead to a delay in diagnosis.
The underlying malignancy determines the overall prognosis for patients with Paget's disease. Paget's associated with DCIS alone has a very favorable prognosis, whereas those cases with infiltrating ductal carcinoma and involved lymph nodes do poorly.
Traditional treatment has been total mastectomy and lymph node dissection, although breastconserving surgery is being performed at some institutions. Results of studies of breastconserving surgery have generally been translated to the treatment of Paget's disease with underlying DCIS only. One small study treated patients with Paget's disease presenting without a palpable mass or radiographic abnormality with segmentectomy of the nipple-areolar complex followed by radiotherapy. The local control rate at 10 and 15 years was 87%, with a cause-specific survival of 97% (186). Another single institutional study showed breast-conserving surgery in Paget's cases to be equivalent to mastectomy regarding recurrence-specific, diseasespecific, and overall survival with proper patient selection (187).
Inflammatory breast carcinoma (IBC) is a rare but aggressive form of breast cancer, characterized by the rapid onset of inflammation of the breast with accompanying redness, warmth and edema. The differential diagnosis includes mastitis and cellulitis of the breast. The distinguishing pathologic finding associated with IBC is metastatic invasion of the dermal and subdermal lymphatics. However, the diagnosis of IBC is primarily clinical and absence of lymphatic invasion does not exclude the diagnosis. Mammographically, the breast shows skin thickening with an infiltrative process. Often there is no detectable palpable mass because the tumor, which is often very poorly differentiated, infiltrates through the breast with ill-defined margins. According to the AJCC staging guidelines, 6th edition, (113) (Tables 16.4 and 16.5), even if no mass is apparent, IBC by definition is classified a T4d lesion (the primary tumor size). Then, depending on the degree of nodal involvement and presence of distant metastasis, patients with IBC are staged as stage IIIb, IIIc, or IV.
The initial step in management is a skin biopsy with excision of a small portion of underlying tissue, followed by complete staging with diagnostic labs, bilateral mammograms (± ultrasound), bone scan, CT imaging, and optional breast MRI. Primary surgical treatment in the face of inflammatory carcinoma is associated with high local failure rates and survival is not improved. The treatment of IBC involves a combined-modality approach using chemotherapy, radiation therapy, and at times surgery. If a good response is achieved with induction chemotherapy, one of the combined-modality options includes a modified radical mastectomy with postoperative radiation therapy to the chest wall, internal mammary nodes, and supraclavicular nodes, followed by additional chemotherapy (188). If there is no response to induction chemotherapy, mastectomy is not recommended. Despite the improvements in IBC treatment, the prognosis for patients with IBC remains poor.
Approximately 25% of breast cancer cases occur in premenopausal women (189). For premenopausal women diagnosed with breast cancer, counseling regarding future childbearing is important. Infertility can be a significant problem for those patients treated with adjuvant systemic chemotherapy and endocrine therapy. In premenopausal patients, the rates of amenorrhea may be as high as 40% to 70% (190). Even if amenorrhea resolves and patients resume menstrual cycles, many cancer survivors have limited ovarian reserve with significantly reduced ability to become pregnant (191).
It is important to discuss fertility preservation for patients, if desired by the patient. In the recommendations set forth by ASCO, the only option not considered experimental is to undergo a cycle of ovarian stimulation, oocyte retrieval, and creation of embryos for cryopreservation and subsequent in vitro fertilization before starting chemotherapy (192). Another option, not as successful as in vitro fertilization, but which is rapidly gaining popularity, is cyropreservation of oocytes. For breast cancer survivors, there can be concern about the risk of recurrence due to the high levels of circulating hormones during a subsequent pregnancy. Epidemiologic data have not found a detrimental effect of subsequent pregnancy after treatment of breast cancer, even if conception takes place six months after therapy (193).
The most reliable predictor of survival for patients with breast cancer is the stage of disease at the time of diagnosis. Based on recent data collected on women diagnosed with breast cancer from 1995 to 1998 from the American College of Surgeons National Cancer Data Base, the 5-year survival rates for stage I disease is almost 100%. For patients with stage IIA disease, prognosis is favorable with a 5-year survival rate of 92%, and 82% for those with stage IIB disease. As the level of nodal involvement increases and/or tumor size increases, the survival rates are lower. Patients with stage IIIA breast cancer have a 5-year survival rate of 67%, stage IIIB 54% and those with distant metastasis, stage IV, have a 20% 5-year survival rate.
As primary components of staging, two significant prognostic indicators are the presence or absence of axillary nodal involvement and tumor size (170,171). Histologic subtype is also a prognostic factor; certain subtypes of breast cancer have more favorable prognosis, such as tubular or mucinous (106,107). Nuclear grade, lymphovascular invasion, younger age at diagnosis, and proliferation indices such as mitotic index, S-phase fraction, Ki-67 have all been shown to be of prognostic significance in breast cancer (170,171,194,195,196,197).
The presence of estrogen and progesterone receptors (ER/PR-positive) may indicate less aggressive disease, although these factors are more predictive than prognostic. The main utility of these factors is in determining which patients should receive hormonal therapy. Her-2/neu oncogene amplification is associated with more aggressive disease, and its presence in an invasive breast cancer indicates that trastuzumab therapy would be of benefit.
In an NSABP trial of adjuvant tamoxifen for breast cancer, tamoxifen was found to decrease the incidence of contralateral breast cancers as a secondary end point (198). As a consequence, the NSABP conducted a randomized, controlled trial, the Breast Cancer Prevention Trial (BCPT), which investigated the efficacy of tamoxifen as a chemopreventive agent in women who were at high risk for breast cancer based on their risk profile. With over 13,000 women enrolled, the group of women who received tamoxifen for 5 years experienced a 50% reduction in both noninvasive and invasive breast cancers compared with those women taking a placebo (199). Offsetting these benefits were a 2- to 3-fold increase in the risk of endometrial cancer as well as increased risk of deep venous thrombosis, particularly in postmenopausal women.
Raloxifene, a second-generation selective estrogen receptor modulator, has been used for the prevention of osteoporosis in postmenopausal women. It exhibits antiestrogenic properties in the breast and possibly in the endometrium, as well as protective, estrogenic properties in the bone. Secondary endpoints from studies of raloxifene demonstrated its ability to reduce the risk of invasive breast cancer. This led to the development of the multicenter, randomized, doubleblind trial named Study of Tamoxifen and Raloxifene (STAR)NSABP P-2 to directly compare the effectiveness of raloxifene with that of tamoxifen in postmenopausal women who are at increased risk for developing breast cancer (200,201).Initial results show that raloxifene is as effective as tamoxifen in reducing the risk of invasive breast cancer and has a lower risk of thromboembolic events and cataracts (202).