Catherine M. Dang and M. William Audeh
Breast cancer is the most common malignancy in women throughout the world, and particularly in Westernized, developed countries. The relative roles of genetic, environmental, and lifestyle factors in explaining the high incidence of breast cancer in the modern world is a subject of much debate. However, it is clear that the complex biology of the human breast and its involvement in the reproductive cycle is also the basis for the increased susceptibility of this organ to malignant transformation.1
EPIDEMIOLOGY
Key Points
1. The most significant risk factors for breast cancer include increasing age and deleterious mutations in the BRCA1 and BRCA2 genes.
2. Reproductive factors that contribute to breast cancer risk are related to the length of estrogen and progesterone exposure.
3. The total number of ovulatory cycles promotes an increased estrogenic exposure that can modulate breast cancer risk.
Breast cancer remains the most common cancer diagnosed in women worldwide. In the United States, more than 209,060 new cases of breast cancer are expected in 2011.2 Despite the preponderance of epidemiologic studies examining risk factors and causes of breast cancer, only very few highly significant risk factors, such as increasing age and deleterious mutations in the BRCA genes, have been identified.3 Epidemiologic factors reproducibly associated with increased risk of breast cancer are shown in Table 15-1.4-6 Although increasing age is recognized as a universal risk factor for many cancers, including that of the breast, reproductive factors play a significant role in modulating breast cancer risk. The common thread appears to be the timing and length of exposure to estrogen and progesterone, and the age at which a pregnancy is first carried to term, leading to differentiation of the breast epithelium, lactation, and eventual involution. Furthermore, breast density, as measured on mammography, appears to be an anatomical surrogate for the glandular and potentially proliferative cellular content of the breast and is increasingly recognized as an additional marker of risk.7 In addition, a growing body of evidence supports the cancer-promoting effect of increasing length of exposure of the breast tissue to estrogen and progestin as a result of the use of postmenopausal hormone replacement therapy (HRT).8 The use of as little as 2 years of postmenopausal HRT yields an increased risk.9
Table 15-1 Risk Factors for Breast Cancer
Beyond purposeful exposure to postmenopausal HRT, however, there are the underlying changes in the lifestyle of women in Westernized, developed countries and societies that also affect hormonal factors.8,10 Women in such societies have on average earlier onset of menses, later and fewer full-term pregnancies, and a lesser likelihood of breast feeding than women in less developed societies, where the rates of breast cancer are much lower. The overall result of these factors is to dramatically increase the total number of ovulatory cycles a woman may undergo in her lifetime. Although this increased estrogen effect has been primarily attributed to lifestyle and reproductive history, worldwide environmental exposure to estrogenic compounds is of increasing concern, with potential sources being dietary phytoestrogens, xenobiotic pesticides, and plastic-related exposures to estrogenic substances such as dioxin and bisphenol-A.11,12
Efforts to identify genetic factors associated with breast cancer risk have succeeded in identifying very likely all highly penetrant, but relatively rare genes, which are associated with positive family history of cancer13 (Table 15-2). These genes are all involved in DNA damage detection and repair and, when mutated, confer extremely high lifetime risks of breast (and other) cancers. Of all the identified high-penetrance genes associated with breast cancer, the BRCA1 and BRCA2 genes account for as much as 5% or 10% of all breast cancers, with the lifetime risk of breast cancer in mutation carriers ranging from 55% to 87%.14,15
Table 15-2 Germ-line Genes Associated With Increased Risk of Breast Cancer
The search for genetic factors which may affect the risk of breast cancer in women without a family history has involved genome-wide association studies, seeking genetic markers and polymorphisms.16 These studies have yielded a growing list of common genetic variants and polymorphisms that exert their effect by modest functional changes, rather than loss of function through mutation. The strongest candidate for a “universal” breast cancer risk factor is fibroblast growth factor receptor 2 (FGFR2),16,17 in which single nucleotide polymorphisms (SNPs) have been associated with risk of breast cancer. However, as this and the 6 other major risk-associated SNPs were identified from unselected populations in genome-wide searches, no gene–environment or gene–gene interactions have been defined, and no functional biologic associations have been proposed. Therefore, attempts to combine these 7 SNPs with traditional epidemiologic risk factors, as developed in the Gail model, have failed to show any additional predictive power with the addition of this level of genetic information.18
The pathogenesis of breast cancer is complex. The evolutionary function of the breast in all mammals is primarily to provide nourishment to newly born offspring. Therefore, breast development and differentiation to provide this function in the female is limited to the reproductive years; it is not required to begin until puberty and is no longer required after menopause. As a result, the breast tissue is minimally formed during embryogenesis, with a single epithelial ectodermal bud, and grows postnatally but without differentiation in keeping with body size. Breast tissue then enters a phase of rapid proliferation and ductal branching with puberty.1 The development of the breasts under the influence of pituitary and ovarian hormones at the onset of puberty is a so-called invasive process, in which branching morphogenesis by the epithelial ductal tree spreads through the mammary fat pad. The tips of the branching structure are the terminal end buds (TEBs), in which highly proliferative cells drive growth and expansion through the stroma. This process is driven by molecular pathways involved in the so-called epithelial-mesenchymal transition, similar to those seen in embryogenesis, as well as those frequently identified in aggressive invasive malignancies19 (Figure 15-1). Molecular pathways involving epidermal growth factor, insulin-like growth factor, src kinase, hepatocyte growth factor/scatter factor, Wnt, transforming growth factor β, and matrix metalloproteinases, among others, are integral to the biology of the developing breast and may explain why they are often upregulated in breast cancers and provide active targets for cancer therapy.20 In addition, many of the cells of the breast TEB possess stem-cell properties and may represent the vehicle by which mammary stem cells, thought by many to be the origin of breast cancer, spread and populate the breast tissue.21,22
FIGURE 15-1. Similarities between breast development and invasive breast cancer.
From puberty until first pregnancy, the breast epithelial ductal structure is made up of 15 to 20 lactiferous ducts ending in a terminal duct containing from 6 to 11 ductules, forming the terminal duct lobular unit (TDLU)23 (Figure 15-2). This initial lobular unit is the least differentiated in postpubertal, nulliparous women; has the highest proliferative rate as measured by Ki-67; and has been termed Lob 1.24 Nearly all epithelial malignancies of the breast are thought to arise from the Lob 1 TDLU. In order to perform the function for which the breast has evolved, namely to produce milk after a full-term pregnancy, the lobular units must remain poised to rapidly proliferate in response to the hormones of pregnancy, first from the pituitary and ovaries, and later from the placenta and fetus itself. Until this occurs, the cells of the breast epithelium must remain in a state of undifferentiated plasticity, which carries with it the risk of malignant transformation.
FIGURE 15-2. The terminal duct lobular unit. (Reproduced, with permission, from World Cancer Research Fund and American Institute for Cancer Research.10)
In animal models, these undifferentiated lobules have been found to be most susceptible to carcinogen-esis, with susceptibility diminishing and DNA-repair proficiency increasing, with the differentiated state induced by pregnancy. With pregnancy, the Lob 1 structure is induced to differentiate and branch to a level of approximately 65 to 90 ductules per TDLU, known as Lob 3, and during lactation, Lob 4. The majority of TDLUs in the breasts of women who have undergone full-term pregnancy before age 30 years are Lob 3, whereas those of nulliparous or late pregnancy women remain primarily Lob 1. Although the classification of lobules as Lob 1 or 3 is based on histology and morphology, the genomic signature underlying these phenotypes has recently been studied and may provide insights into the differing susceptibility to malignant transformation and the observed protective effects of early pregnancy.25,26 The genomic signature induced by the first full-term pregnancy remains detectable in the breast epithelium after menopause and is characterized by more than 200 genes that have either been up- or downregulated and involve functions of DNA repair, carcinogen metabolism, and regulation of apoptosis, among others. The analysis of the genomic pathways that may affect breast cancer development could allow the identification of factors that may be used to identify women at increased risk, interventions to reduce risk, and new targets for therapy of established cancer. Indeed, the management of breast cancer, perhaps more than any other solid tumor, has been dramatically changed by the introduction of genomic and molecular information into the clinic.27
DIAGNOSIS
Key Points
1. The Gail model can predict breast cancer risk in women older than 35 years and includes reproductive history, history of prior breast biopsies, history of hormone use, and family history.
2. Abnormal mammogram findings that are often associated with malignancy include masses, clustered calcifications, architectural distortion, asymmetric density, skin thickening, and abnormal axillary lymph nodes.
3. The American Congress of Obstetrics and Gynecology recommends screening mammography every 1 to 2 years in women between the ages of 40 and 49 years and annually for women 50 years of age and older.
4. Breast imaging for screening and diagnosis may include mammography, ultrasound, and/or magnetic resonance imaging (MRI).
Traditionally, the diagnosis of breast cancer and related diseases was based primarily on history and physical examination. A detailed reproductive history (age at menarche, childbearing, breastfeeding, age at menopause); history of previous breast surgeries or biopsies, particularly biopsies showing atypia or lobular carcinoma in situ (LCIS); history of medication and hormone use; and family history of breast and ovarian cancer are particularly important components of the initial history. These factors form the basis of the Gail model, which may be used to predict breast cancer risk in women older than 35 years.28 Additionally, the patient should be asked about breast symptoms, including pain, tenderness, mass, nipple discharge and retraction, changes in size or contour of the breast, and changes in the skin of the breasts. In patients in whom a cancer diagnosis has been confirmed or is suspected, systemic complaints of weight loss, fatigue, abdominal pain, bone pain, and neurologic symptoms should also be elicited.
Physical examination usually begins with visual inspection with the patient sitting upright. Asymmetries; skin changes such as erythema, edema, ulceration, or thickening; nipple retraction or excoriation (a sign of Paget disease); and skin dimpling should be noted. Having the patient raise the arms overhead may exaggerate subtle skin dimpling or nipple retraction. Next, examination of the regional lymph node basins (supraclavicular, infraclavicular, cervical, and axillary) is performed to detect enlarged and/or firm lymph nodes. Finally, the breasts are systematically examined with the patient supine and the ipsilateral arm raised above the head. Aside from distinct masses, more vague asymmetrically dense areas and any nipple discharge should be noted and characterized by color and whether it is emanating from a single or multiple ductal orifices. Nipple fluid that is bloody, spontaneous, and arises from a single ductal orifice is more likely to be related to underlying malignancy than nipple discharge that is bilateral, nonspontaneous, and non-bloody. Although malignancy must be excluded, intraductal papillomas, which are generally benign, are the most common cause of spontaneous, bloody nipple discharge. Milky nipple discharge, or galactorrhea, in a nonpregnant or nonlactating woman may be sign of a pituitary prolactinoma or hypothyroidism. Thyroid function tests and prolactin levels should be evaluated in this instance. Hemoccult testing can be performed on nipple fluid if it seems bloody, although this is not strictly necessary. Of potentially greater value is preparation of smears of nipple fluid for cytologic analysis, which can identify atypical or even malignant epithelial cells in nipple fluid.29
Breast imaging is preferably performed before biopsy of any physical exam finding and for screening purposes in asymptomatic women. Since its introduction in the 1930s, mammography, in which the breast is compressed and x-ray images are obtained, has become the standard modality for breast imaging. Screening mammography, which images each breast in 2 views, is performed in asymptomatic women.30 Diagnostic mammography, in which magnification and/or additional views of the breast are obtained, is usually performed in patients with breast symptoms, physical examination findings, lesions detected by screening mammography, and for short-interval follow-up of probably benign findings detected on prior mammograms.31 Mammography is effective as a screening tool because cancers are often denser radiographically than the surrounding normal glandular breast tissue, which in turn is denser than fatty breast tissue. Premenopausal women, especially women younger than 30 years, may have very dense glandular breast tissue, which severely limits the sensitivity of mammography. Generally, the glandular breast tissue atrophies and is replaced by fatty tissue as a woman ages, especially after menopause. Consequently, the breasts become less dense mammographically and the sensitivity of mammography for cancer detection increases with age.
Mammogram reports generally specify whether the breasts are fatty, heterogeneously dense, dense, or extremely dense. Abnormal mammogram findings that are often associated with malignancy include masses, clustered calcifications (≥ 5 calcifications in 
area), architectural distortion, asymmetric density, skin thickening, and abnormal axillary lymph nodes. Specifically, masses are noted to be suspicious for malignancy if the margins are obscured, ill-defined, or spiculated (irregular) (Figure 15-3), and calcifications are noted to be indeterminate or more likely to be malignant if they are amorphous or pleomorphic (heterogeneous) in shape and linear or branching in orientation (Figure 15-4). To standardize the reporting of mammograms and other breast imaging modalities, radiologic findings in the breast are rated using the Breast Imaging Reporting and Data System (BIRADS) developed by the American College of Radiology (Table 15-3). The positive predictive value of a lesion identified as being suspicious on mammography is estimated to be between 10% and 40%. Thus the vast majority of mammographically detected lesions are benign. Breastfeeding and pregnancy are relative contraindications to the use of mammography.32
Table 15-3 Breast Imaging Reporting and Data System (BI-RADS) Categories and Recommendations
FIGURE 15-3. Mammogram images (A, B) indicate an irregular mass in the upper outer left breast. Ultrasound of the left breast (C) shows this to be a solid, hypoechoic mass with very irregular borders and confirms its suspicious nature. The mass was subsequently biopsied and demonstrated to be an invasive ductal carcinoma.
FIGURE 15-4. Mammogram images indicate a suspicious cluster of microcalcifications, which were subsequently biopsied and demonstrated to be associated with ductal carcinoma in situ.
Current recommendations for annual screening mammography are controversial. Screening mammography is performed in asymptomatic women because, theoretically, screen-detected cancers will be smaller, associated with better prognosis, and require less radical treatment than cancers detected by physical examination. The Health Insurance Plan (HIP) of Greater New York study was the first randomized controlled trial to demonstrate a survival benefit with the use of screening mammography. The trial followed a cohort of women aged 40 to 64 years who were randomly assigned to either undergo 3 annual screening mammograms versus no mammography. After 18 years of follow-up, women ages 40 to 49 and 50 to 59 years at enrollment who had undergone screening mammography had a 25% reduction in breast cancer-related mortality.33 Subsequently, 7 other prospective, randomized trials worldwide have demonstrated that screening mammography decreases the risk of death from breast cancer.32 However, the age of mammogram screening, screening interval, and method varied in these trials, and the benefit of mammogram screening in average-risk women between the ages of 40 and 49 years is highly debated. Proponents for mammo-gram screening in women 40 to 49 years argue that breast cancer is the leading cause of death in this population; this population accounts for 20% of all breast cancer–related deaths and 34% of years of life lost to breast cancer; and breast cancers in younger women tend to be more aggressive. Arguments against routine annual screening mammograms in this younger age group include the following: only 16% of breast cancers occur in women under the age of 50 years, there is a decreased sensitivity of screening mammography in this age group, and there are significant psychological and physical harms associated with the relatively high false-positive rate of biopsies and unnecessary imaging tests associated with screen-detected lesions.32,34 Furthermore, in 2009, the US Preventative Services Task Force (USPSTF) dramatically changed their recommendation for screening mammography to biennially (every 2 years) for women between the ages of 50 and 74 years. They recommended against screening mammography for all women ages 40 to 49 years, with the disclaimer that the decision to begin screening mammography before the age of 50 years should be made on an individualized basis. The USPSTF acknowledged that the relative risk reduction of screening mammography was similar in the 40 to 49 and 50 to 59 year age groups (15% and 14%, respectively). However, they argued that the absolute benefit is less in women 40 to 49 years of age because of the lower incidence of breast cancer in this age group. The USPSTF also noted that there are insufficient data to recommend for or against mammogram screening in women 75 years of age and older. However, The American Cancer Society, with support from the American College of Surgeons, continues to recommend annual screening mammography in addition to clinical breast examination in women aged 40 years and older and note that women ages 20 to 39 years of age should undergo clinical breast examination every 3 years.35,36 The American Congress of Obstetrics and Gynecology, meanwhile, recommends screening mammography every 1 to 2 years in women between the ages of 40 and 49 years and annually for women 50 years of age and older.37 Women with family history of premenopausal breast cancer in first-degree relatives (ie, mother, sister) may choose to begin annual mammogram screening 10 years before the age at diagnosis of the affected relative, but no later than age 40 years.35
Advances in mammographic technology including digital mammography and computer-aided diagnosis (CAD) systems may improve the efficacy of screening mammography. Full-field digital mammography captures digital images of the breasts that can be manipulated and processed to optimize image quality while minimizing radiation exposure. The average radiation dose to the breast with digital mammography is approximately 22% less than with film screen mammography.38 The Digital Mammographic Imaging Screening Trial, a retrospective, multicenter trial conducted at 33 academic medical centers by the American College of Radiology Imaging Network (ACRIN) demonstrated that the sensitivity of digital mammography for cancer detection (59%) is greater than that of film mammography (27%) in pre- or perimenopausal women younger than 50 years with dense breasts, although this did not apply to other subgroups, particularly older women with fatty breasts.39 With CAD, digital or digitized mammogram images are subjected to computer analysis after initial radiologist interpretation of the films. The computer software may highlight additional lesions for the radiologist to review and make the final determination regarding whether the lesion is real or artifact and the nature of the lesion. No prospective randomized, controlled trials of CAD exist, although multiple retrospective and cohort studies have demonstrated some improvement in sensitivity (range, 1.7%-19.5% increased sensitivity) along with decreased specificity and increased recall rate for additional imaging with the use of CAD.40
Ultrasound is an important adjunct to mammography in evaluation of the breasts. It can help distinguish cystic from solid lesions and further characterize solid lesions as being probably benign or suspicious in nature (Figure 15-3). Unlike mammography, ultrasound is usually performed in a targeted fashion for diagnostic purposes rather than for breast cancer screening. Breast ultrasound is commonly used to evaluate palpable masses or lesions, mammographic abnormalities, and nipple discharge and is also used to guide percutaneous needle biopsies and cyst aspirations and localize nonpalpable lesions for surgical excision; it is also used for intra-operative assessment of margins at surgery.41 Advantages of ultrasound include no exposure to ionizing radiation, patient comfort, and anatomic evaluation of the breast. Ultrasound, however, is operator dependent and can be time-consuming. Because of the limited sensitivity of mammography in women with denser breasts, screening whole-breast ultrasound in conjunction with screening mammography is currently being investigated in the prospective, multicenter ACRIN 6666 trial of a high-risk cohort of 2637 women. Initial results of the first round of screening with both mammography and ultrasound indicate that the addition of ultrasound screening detected an additional 4.2 (95% confidence interval, 1.1-7.2) cancers per 1000 women at high risk for breast cancer, but also increased the false-positive biopsy rate.42
MRI is now also commonly used to evaluate the breasts. Dynamic contrast-enhanced MRI to evaluate the breast parenchyma employs intravenous gadolinium, which is contraindicated in patients with renal insufficiency and during pregnancy. MRI relies on angiogenesis and the abnormal microvasculature surrounding tumors to detect cancers. Both the degree of contrast enhancement and the perfusion pattern or kinetics of a lesion, along with lesion morphology, are taken into consideration to distinguish between suspicious and benign lesions43 (Figure 15-5). Although it does not replace mammography, MRI has a number of advantages over mammography: no exposure to ionizing radiation, no limitations due to breast density, better spatial localization, and assessment of the extent of lesions.32 Furthermore, the sensitivity of MRI for detection of invasive breast cancer, ranging from 91% to 100% in the literature, is far greater than that of mammography and ultrasound, although the specificity of MRI is certainly no better and perhaps worse (as low as 30%) than that of mammography and ultrasound. The sensitivity of MRI for detection of ductal carcinoma in situ (DCIS) is especially low and is also lower for intermediate-grade DCIS.43 Diagnostic breast MRI is frequently performed for the following reasons: to define the extent of the index lesion, to identify of otherwise occult ipsilateral or contralateral breast lesions, and to evaluate response to neoadjuvant chemotherapy.44 In women diagnosed with breast cancer, meta-analysis of observational studies indicates that preoperative MRI identifies otherwise occult (not detected by physical examination, mammography, or ultrasound) cancer foci in the ipsilateral breast in 16% of cases and in the contralateral breast in 4% of cases. Accordingly, preoperative MRI changes surgical management in 11.3% of cases, generally resulting in more extensive surgical resection than originally planned, and has been linked to increased rates of mastectomy in women with early-stage breast cancer.45 However, use of MRI preoperatively has not been shown to decrease rates of reoperation after lumpectomy to achieve adequate surgical margins in the randomized, prospective Comparative Effectiveness of MRI in Breast Cancer (COMICE) trial.46 Furthermore, to date, there are no randomized prospective trials that demonstrate that preoperative MRI use improves breast cancer survival or reduces recurrence.45 In summary, routine use of preoperative MRI in women newly diagnosed with breast cancer remains controversial.
FIGURE 15-5. Dynamic contrast-enhanced MRI of an enhancing, irregular mass that has a “washout” perfusion pattern of enhancement, indicative of malignancy.
Screening breast MRI in high-risk, asymptomatic populations, by contrast, is routinely performed. The American Cancer Society and American College of Surgeons recommends annual screening breast MRI be performed in the following populations at high risk for developing breast cancer: (1) women with deleterious BRCA1 or BRCA2 gene mutations and first-degree relatives of BRCA carriers who themselves have not undergone genetic testing; (2) women estimated to have at least 20% lifetime risk of breast cancer; (3) women who have undergone chest wall radiation therapy (eg, Hodgkin disease treatment) between the ages of 10 and 30 years; and (4) women with p53 gene mutations (Li-Fraumeni syndrome, Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome) and their first-degree relatives. Currently, there is insufficient evidence to support the use of routine screening MRI in women who are at moderately increased risk for breast cancer (15%-20% lifetime risk), including those with a personal history of breast cancer, history of biopsy showing atypia or lobular carcinoma in situ (LCIS), or extremely dense breasts.35
After breast imaging, tissue diagnosis is obtained either with an open surgical biopsy or preferably via minimally invasive, percutaneous needle biopsy. Surgical biopsy, both excisional and incisional, is generally performed in the outpatient setting. Surgical biopsy of nonpalpable lesions detected by mammography, ultrasound, or MRI requires preoperative placement of a wire (or needle) by radiology under local anesthesia to guide surgical excision. Intraoperative specimen radiograph or ultrasound should be performed to confirm complete excision of these nonpalpable lesions. Because 70% to 80% of all biopsies yield benign results, surgical incisions should be made as cosmetically as possible, generally along the Langer lines of skin tension, which are oriented concentric with the nipple. Incisions in the cleavage area (upper inner quadrants) should be avoided if possible.47 Surgical biopsy, however, is more costly and has the potential for greater disfigurement, morbidity, and loss of productivity for the patient. Additionally, patients whose cancer diagnosis is made by surgical biopsy will frequently need at least one other surgery for definitive treatment of their cancer.48
A number of options for percutaneous biopsy exist. Fine-needle aspiration (FNA) biopsy is inexpensive and easy to perform in the office setting with a 10-or 20-mL syringe and 22- or 25-gauge needle. Local anesthetic can be used to anesthetize the skin if desired. While pulling back on the syringe to generate suction, the needle is moved back and forth at different angles within the lesion of interest to dislodge cells, which are then aspirated into the syringe. Slides can then be made with the aspirated material, which are sent in fixative for review by a qualified cytopathologist. The accuracy of FNA approaches 80%, but false-negative rates remain as high as 15%-20%, and in some cases, there is insufficient material for analysis. FNA can identify malignant cells but cannot distinguish between in situ and invasive carcinoma. FNA can also be used to completely aspirate cystic lesions. Core (cutting) needle biopsy can be performed on any palpable lesion and on nonpalpable lesions with ultrasound, MRI, and mammogram (stereotactic core needle biopsy) guidance. Because core needle devices are larger (18 to 7 gauge), the skin and surrounding tissue should be well anesthetized with local anesthetic before making the small skin incision required to accommodate introduction of the biopsy needle into the breast.47 Using a larger-gauge needle and vacuum assistance decreases the potential for sampling error. A radiopaque tissue marker (clip) is generally placed at the time of biopsy to facilitate subsequent lesion identification and confirm sampling of benign lesions on follow-up imaging. Core needle biopsy provides an accurate tissue diagnosis in approximately 98% of cases. The potential for sampling error, however, exists with any needle biopsy technique, and surgical excision is still recommended after benign core needle biopsy results if the pathology findings are discordant with the imaging impression, atypical ductal or lobular hyperplasia (discussed later), LCIS, papillary lesion, or radial scar. When surgical excision is performed subsequent to core needle biopsy showing atypical ductal hyperplasia, for example, 10% to 20% of cases will be found to have DCIS or invasive cancer. Also as a result of sampling error, surgery performed for DCIS may occasionally yield invasive cancer.44,48
PATHOLOGY
Key Points
1. The majority of breast cancers are classified as invasive ductal carcinoma and invasive lobular carcinoma.
2. The critical proteins resulting from underlying genomic abnormalities in breast cancer include Ki67, estrogen receptor (ER), progesterone receptor (PR), and HER2; presence or absence of these proteins correlates with clinical outcome and affects adjuvant therapy.
3. Lobular carcinoma in situ (LCIS) is associated with increased risk of both ipsilateral and contralateral breast cancer.
Breast cancer is a clinically heterogeneous and diverse disease, and morphology-based histopathology has attempted to classify breast cancer into categories that would predict clinical and biologic behavior, with limited success.49The true basis of the pathology that produces the clinically recognizable entity of “breast cancer” is to be found at the level of the genome: genetic changes inherited and acquired in the course of carcinogenesis, passed on through cell division to daughter cells, involving multiple molecular networks and pathways that have promoted the survival of the malignant clone and produce the phenotype of breast cancer.50
Traditional histopathology identifies the phenotypic effects of the underlying molecular and genetic lesions. Immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH) identify the presence and amount of specific proteins expressed as a result of the underlying genomic abnormalities associated with malignancy of the breast. The critical proteins include Ki67, a general marker of proliferation51; nuclear and cytoplasmic receptors for estrogen and progesterone, ER and PR52; and the cell surface signaling molecule HER2.53 This gene expression profiling of breast cancers yields the beginnings of a molecular “taxonomy” of breast cancer that has added considerable insight to the previously identified but clinically heterogeneous histopathologically defined subtypes. Standard management guidelines for breast cancer at the present time are based on traditional histopathology and IHC—the tissue, cellular, and protein level of analysis.49
The current morphologic classification of invasive epithelial cancers of the breast cancer recognizes at least 18 distinct histologic types (Table 15-4), although the majority of all breast cancers (50%-80%) are classified in this system as invasive ductal carcinoma, not otherwise specified (IDC-NOS).49 This places the burden of identifying clinically meaningful subtypes at the molecular level, by IHC and genomic measures. Therefore, within invasive ductal (Figure 15-6) and invasive lobular (Figure 15-7), an additional 5% to 15%, subsets are more usefully defined by ER, PR, and HER2 expression through IHC. HER2-positive cancers represent approximately 20% of all breast cancers, ER negative/PR negative/HER2 negative (triple negative) cancers approximately 15%, with the remaining being ER positive/PR positive and ER positive/PR negative.
Table 15-4 Histopathologic Subtypes of Epithelial Breast Cancer
|
Invasive ductal carcinomas (not otherwise specified) |
|
Carcinoma with osteoclast-like giant cells |
|
Invasive lobular carcinomas |
|
Pure tubular carcinoma |
|
Invasive cribriform carcinoma |
|
Medullary carcinomas |
|
Mucinous carcinoma |
|
Neuroendocrine tumors |
|
Invasive papillary carcinoma |
|
Invasive micropapillary carcinoma |
|
Apocrine carcinoma |
|
Metaplastic carcinoma |
|
Lipid-rich carcinoma |
|
Secretory carcinoma |
|
Oncocytic carcinoma |
|
Adenoid cystic carcinoma |
|
Acinic-cell carcinoma |
|
Glycogen-rich clear-cell carcinoma |
|
Sebaceous carcinoma |
FIGURE 15-6. Invasive ductal carcinoma. (Image contributed by Dr. Shika Bose, Cedars-Sinai Department of Pathology.)
FIGURE 15-7. Invasive lobular carcinoma. (Image contributed by Dr. Shika Bose, Cedars-Sinai Department of Pathology.)
Histopathology also assigns the tumor grade though morphologic features, which correlate with the degree of differentiation of the tumor. This is subject to considerable interobserver variation; although efforts have been made to diminish this variability, with the introduction of descriptive morphology assigning numerical weights to specific features (eg, the Nottingham and Bloom-Richardson grading systems), analysis of grade at the genomic level again suggests the superiority of molecular analysis to light microscopy.54,55 A Genomic Grade Index (GGI), based on 97 genes representing several genomic pathways, including cell cycle and proliferation, proved capable of predicting response to therapy more accurately than traditional grading, with a high degree of reproducibility.
Noninvasive but malignant disease of the breast (so-called premalignant states) has been increasingly detected with improvements in breast imaging.56,57 Proliferative breast disease involves a continuum of increasing genomic and histologic pathology, with enhanced proliferation and/or diminished apoptosis being among the earliest of biologic changes.58 In addition, the associated risk of subsequent invasive cancer also increases along this continuum.59,60Currently, data suggest that noninvasive breast cancer may be a marker as well as a non-obligate precursor to invasive disease.61
Intraductal proliferative lesions are categorized into 3 groups: usual ductal hyperplasia (UDH), atypical ductal hyperplasia (ADH) (Figure 15-8), and ductal carcinoma in situ (DCIS) (Figure 15-9). The risk of subsequent invasive cancer associated with these lesions is approximately 1.5-fold with UDH, 4- to 5-fold with ADH, and 8- to 10-fold with DCIS.58 Lobular intraepithelial neoplasia (LIN) provides the lobular counterpart, with a similar continuum of pathology from atypical lobular hyperplasia to LCIS (Figure 15-10). The subsequent risk of invasive breast cancer, either ductal or lobular, is approximately 8.7%. Unique to LIN is the increased risk of both ipsilateral and contralateral breast cancer, with each breast carrying a risk of more than 4%, supporting the concept of such pathology as a marker of increased susceptibility to lobular neoplasia throughout the breast epithelium.
FIGURE 15-8. Atypical ductal hyperplasia. (Image contributed by Dr. Shika Bose, Cedars-Sinai Department of Pathology.)
FIGURE 15-9. Ductal carcinoma in situ. (Image contributed by Dr. Shika Bose, Cedars-Sinai Department of Pathology.)
FIGURE 15-10. Lobular carcinoma in situ. (Image contributed by Dr. Shika Bose, Cedars-Sinai Department of Pathology.)
Two additional pathologic entities warrant further mention. Paget disease of the breast is not considered a distinct histopathologic subtype, but is rather an in situ neoplasm in the squamous epithelium of the nipple and is clinically identified as an eczematoid or crusting lesion.62 Although treated as a noninvasive form of breast cancer with local surgical excision, its true significance is as a marker of malignancy elsewhere in the breast. Paget disease may be associated with underlying DCIS or invasive cancer, with the majority of these invasive cancers being ER negative and of high grade. Phyllodes tumor of the breast63 is another rare entity, less than 1% of all breast neoplasms, and is thought to be of fibroepithelial origin and mimics the shape of leaves, hence the term phylloides from the Greek word for “leaf.” The challenge with such tumors is to recognize the benign versus the malignant form, for which no specific molecular biomarkers have been established. It is most often seen in young women as a rapidly enlarging lesion and is also treated with wide local excision.63
Breast cancers are staged using the American Joint Committee on Cancer (AJCC) TNM staging classification (Table 15-5).
TREATMENT
Key Points
1. Modified radical mastectomy with axillary lymph-adenectomy is the surgical treatment of choice for women who have large cancers with clinically apparent axillary lymph node involvement at the time of diagnosis.
2. Smaller cancers with clinically negative lymph node involvement may be treated conservatively with lumpectomy and sentinel lymph node dissection followed by radiation.
3. Expression of ER, PR, and HER2 in breast cancers allows for administration of targeted anti-estrogen and anti-HER2 therapy.
Surgery/Radiation Therapy
Breast cancer treatment is based on the clinical and pathologic stage of the cancer at the time of diagnosis. Treatment usually involves multiple modalities, including surgery, radiation therapy, chemotherapy, and endocrine therapy.
Surgical treatment of breast cancer continues to evolve. In the 1890s, William Halsted propagated the idea of the radical mastectomy in which the breast and overlying teardrop-shaped skin paddle was resected en bloc with the pectoralis major and minor muscles and axillary and supraclavicular lymph nodes. Skin grafts were routinely used to cover the large skin defect. Drains were placed temporarily after mastectomy to allow the skin flaps to adhere to the underlying chest wall. The radical mastectomy quickly achieved widespread acceptance because it conferred significantly improved survival and lower local recurrence rates when compared with the lesser operations being performed at the time. Most breast cancers in this era were also large and locally advanced at diagnosis. A number of developments in the latter half of the 20th century led to the adoption of less radical operations for breast cancer, including modified radical mastectomy and simple mastectomy. Introduced in the 1960s, mammography allowed identification of smaller, earlier-stage breast cancers. Cobalt beam radiation therapy became available in the 1960s, only to be replaced in the 1970s by linear accelerators, which are primarily used to deliver radiation therapy today. Finally, the fact that breast cancer is potentially a systemic disease and the development of adjuvant chemotherapy led to the demise of the radical mastectomy, which is now generally performed only for locally advanced cancers.64
Modified radical mastectomy, in which a skin ellipse encompassing the nipple-areola complex is resected in continuity with the underlying breast tissue and level I and II axillary lymph nodes (nodes lateral to the lateral border of the pectoralis minor muscle and nodes located beneath the pectoralis minor, respectively), became the standard surgical treatment for breast cancer beginning in the 1970s. As opposed to a radical mastectomy, the pectoralis muscles and level III nodes (medial to pectoralis minor muscle) are left intact, and skin flaps are reapproximated primarily in a modified radical mastectomy. Two randomized, prospective trials conducted in the 1970s compared overall survival and locoregional recurrence rates in women treated with radical mastectomy versus modified radical mastectomy. Both trials demonstrated no difference in overall survival or locoregional recurrence rates for women with stage I and II disease.65,66 Currently, modified radical mastectomy is the surgical treatment of choice for women who have large cancers with clinically apparent axillary lymph node involvement at the time of diagnosis.
Table 15-5 AJCC TNM Staging Classification for Breast Cancer
Taking the trend toward less aggressive surgery further, breast conservation was demonstrated to be a viable alternative to modified radical mastectomy in women with early-stage breast cancer in the late 1970s and early 1980s. The National Surgical Adjuvant Breast and Bowel Project (NSABP) B-06 trial randomized women with tumors less than 4 cm in size and clinically negative lymph nodes (stages I and II) to one of 3 treatment arms: modified radical mastectomy, lumpectomy with axillary lymph node dissection (levels I and II), and lumpectomy with axillary lymph node dissection plus adjuvant whole-breast external-beam radiation therapy (50 Gy). After more than 20 years of follow-up, NSABP B-06 demonstrated that overall survival and disease-free survival were equivalent in each of the treatment arms. Although local and regional (axillary) recurrence was lowest in the group who underwent modified radical mastectomy, the addition of radiation therapy decreased the local recurrence rate from 39.2% for those who underwent lumpectomy and axillary node dissection alone to 14.3% in those treated with lumpectomy, axillary node dissection, and radiation therapy.67 Five other randomized, prospective trials, including the Milan I trial, Institute Gustave-Roussy trial, National Cancer Institute trial, European Organization for Research and Treatment of Cancer (EORTC) 10801 trial, and Danish Breast Cancer Group trial, also confirmed the lack of a survival benefit for mastectomy over breast-conserving surgery.68-72 In summary, most women with early-stage breast cancers are candidates for breast-conserving therapy. Absolute contraindications to breast conservation include pregnancy, multicentric (cancer in ≥ 2 quadrants of the breast) disease, history of prior radiation therapy to the breasts or inability to tolerate radiation therapy, and persistently positive surgical margins. Furthermore, relative contraindications to breast conservation include tumor volume to breast volume ratio that would preclude acceptable cosmesis, large area of multifocal (cancers all in same quadrant of the breast) disease, and history of collagen vascular disorder.73
The surgical approach to the axilla has also become less radical because standard axillary lymph node dissection places the patient at risk for significant morbidity, including lymphedema (15%-20% incidence), neurovascular injury such as a winged scapula deformity, limited range of shoulder motion, acute pain and discomfort (drains are usually placed after standard axillary dissection), and chronic pain syndromes.74 The NSABP B-04 trial randomized women with clinically negative lymph nodes to 1 of 3 treatments: radical mastectomy, total (simple) mastectomy in which only skin and breast tissue are removed alone, or total mastectomy plus radiation (50 Gy) to the chest wall and axilla. Women with clinically positive lymph nodes at enrollment were randomized to either radical mastectomy or total mastectomy with axillary radiation. Adjuvant chemotherapy was not given, and women who initially were treated with total mastectomy alone and later developed clinical evidence of axillary lymph node involvement underwent delayed axillary lymph node dissection. After 25 years of follow-up, in the node-negative group, there was no statistically significant difference in overall survival or disease-free survival in the 3 treatment groups. Although overall survival was lower in the clinically node-positive patients, there was also no difference between the 2 treatment subgroups with positive nodes: radical mastectomy versus total mastectomy with radiation.75
With the knowledge that the timing and mode of treatment of the axillary lymph nodes does not affect survival, the NSABP B-32 trial was conducted to compare standard axillary lymph node dissection with sentinel lymph node dissection in women with invasive breast cancers and clinically negative axillae. Sentinel lymph node dissection, which is based on the premise that tumors have specific lymphatic drainage patterns, was first demonstrated to be effective in the staging and treatment of malignant melanoma. To identify the sentinel lymph node(s), vital blue dye (methylene blue or isosulfan blue) and/or technetium-radiolabeled sulfur colloid is injected either into the breast at the site of the tumor or into the subareolar Sappey plexus of lymphatics or intradermally. Either through a separate axillary incision or mastectomy incision, the clavi-pectoral fascia is then divided and the axilla carefully inspected, and lymph nodes that are blue and/or radioactive, as measured with a hand-held gamma probe, are resected. If no sentinel nodes can be identified, standard axillary lymph node dissection should be performed. Intraoperative frozen section analysis of the sentinel lymph node(s) can be performed, but this adds additional time and cost to the operation. Lymphoscintigraphy can also be performed preoperatively to facilitate identification of the sentinel lymph node. At most institutions, sentinel lymph nodes are subjected to histologic analysis with both conventional hematoxylin and eosin staining and immunohistochemical staining. A number of studies have shown that the combined use of blue dye and radioisotope may yield a slightly lower false-negative rate than blue dye alone, although both techniques confer equivalent rates of sentinel lymph node identification.76 Completion axillary lymph node dissection is then performed only in the event that lymph node metastases are identified in the sentinel lymph node(s).
In the NSABP B-32 trial, women with clinically node-negative, invasive breast cancer were randomly assigned to either sentinel lymph node dissection followed by immediate completion axillary lymph node dissection or sentinel lymph node dissection alone. Patients in the latter group underwent delayed completion axillary dissection only if histologic analysis identified metastases in the sentinel lymph nodes. Both blue dye and radioisotope were used to identify sentinel nodes. Sentinel lymph nodes were successfully identified in 97.2%, and the overall accuracy was 97.1% with a false-negative rate of 9.8%.77 Overall morbidity, including lymphedema (14% standard axillary dissection vs. 8% sentinel lymph node dissection), was lower in the group who underwent sentinel lymph node dissection alone.78 Since the study completed enrollment in 1994, the primary end points of survival and recurrence have yet to be reported, although sentinel lymph node dissection is now the preferred method of axillary staging in women with invasive breast cancer and clinically negative lymph nodes.44
Consistent with the concern for improved cosmesis in women undergoing prophylactic surgery and breast cancer treatment, skin-sparing and nipple-sparing mastectomy are also being performed in many centers nationwide. In a skin-sparing mastectomy, the nipple and areola are resected along with the breast, but as much of the native skin envelope as possible is preserved to facilitate immediate breast reconstruction. Initially, the oncologic safety of this approach was questioned. A recent meta-analysis of 9 retrospective, observational studies demonstrated that that there appears to be no significant difference in local recurrence rates between women who underwent skin-sparing mastectomies for cancer (range, 3.8%-10%) and those who had non–skin-sparing mastectomies (range, 1.7%-11.5%). Complication rates, including flap necrosis, were similar between the 2 groups.79 Nipple-sparing mastectomy preserves the entire skin envelope, including the dermis and epidermis of the nipple, and can be performed via circumareolar, transareolar, transnipple, or inframam-mary incisions. To minimize residual breast tissue, the major ducts leading to the nipple should be excised and sent for biopsy separately to confirm the abscess of malignancy. Among the small number of published retrospective studies, local recurrence rates after nipple-sparing mastectomy range from 1% to 28%, although it was noted that recurrences most frequently occurred in the skin flap overlying the site of the primary tumor rather than in the retained nipple. Because the major blood supply to the nipple normally courses through the breast parenchyma deep to the nipple, viability of the nipple is a concern with nipple-sparing mastectomy. Necrosis of the retained nipple reportedly occurs in 2% to 20% of cases.80 Optimal patient selection for nipple-sparing mastectomy is critical to the success of the operation, and generally nipple-sparing mastectomy should be reserved for women with small to moderate breast volume and mild to moderate breast ptosis who are undergoing prophylactic surgery or surgery for cancers that are smaller, peripherally located, and not multicentric.
Breast reconstruction after mastectomy can be performed either immediately after mastectomy or in a delayed fashion. Reconstruction is an important part of breast cancer treatment because it can restore the patient’s body image and improve quality of life. Most women who undergo mastectomy can be safely offered breast reconstruction. For the vast majority of women who do not undergo nipple-sparing mastectomy, reconstruction initially involves creation of a new breast mound followed by creation of a new nipple and areola. Approximately 70% of reconstructive breast surgery involves implant-based reconstruction, in which a breast implant is placed posterior to the skin and pectoralis major and serratus anterior muscles (Figure 15-11). This is most frequently achieved initially by placing a tissue expander at the time of the mastectomy, followed by serial addition of saline to the tissue expander over a period of weeks to months, and finally exchange of the tissue expander for a breast implant (silicone or saline). Less frequently, a submuscular implant is placed at the time of mastectomy, although radiated cadaveric human skin is often incorporated to create an adequate muscular pocket for the implant.
FIGURE 15-11. A. Reconstructed breast with implants after bilateral skin-sparing mastectomy. B. Tattoo of the reconstructed nipple and areola after skin-sparing mastectomy and implant reconstruction. (Image contributed by Dr. R. Kendrick Slate.)
Alternatively, a number of autogenous tissue-based options for reconstruction exist. The most commonly used autogenous reconstruction is the transverse rectus abdominis muscle (TRAM) flap, in which excess skin, fat, and a portion of the rectus abdominis muscle are resected and either rotated or transposed freely on a superior epigastric vascular pedicle into the mastectomy defect. A low transverse abdominal incision is left at the donor site. Patients who undergo TRAM reconstructions may be prone to develop abdominal wall hernias. The deep inferior epigastric perforator (DIEP) flap is similar to the TRAM flap in that excess skin and fat from the infraumbilical abdominal wall is harvested, although the rectus abdominis muscles are preserved in a DIEP flap. DIEP flaps rely on microvascular anastomosis and are technically more difficult to perform. A hybrid option for breast reconstruction is the latissimus dorsi myocutaneous flap, in which skin, fat, and a portion of the back muscle is rotated on the thoracodorsal vascular pedicle anteriorly to fill the mastectomy defect. Frequently an implant is also placed posterior to the flap to provide more volume to the reconstruction.81
Radiation therapy is an integral part of breast cancer treatment, especially in women who desire breast conservation. The NSABP-06 trial demonstrated the importance of adjuvant radiation therapy in decreasing local and regional recurrences in women undergoing lumpectomy for early-stage breast cancer. Most commonly, external-beam whole-breast radiation therapy using tangential photon fields generated by a linear accelerator (to limit exposure to the underlying heart and lungs) is used. Typically in the United States, a total dose of 50 Gy is delivered in 25 to 28 daily fractions, 5 days per week, for a total of 5 to 7 weeks, to the entire breast or chest wall. The boundaries of the radiation field include the inferior clavicular head superiorly, midline medially, 2 cm below the inframammary fold inferiorly, and mid- to posterior axillary line laterally. In women who opt for breast conservation with lumpectomy, an additional 10- to 15-Gy “boost” dose is generally delivered to the lumpectomy cavity to further reduce the risk of local failure. Radiation fields may be expanded to include the entire axilla, intramammary, and/or supraclavicular lymph node basins in women who are deemed to be at high risk for regional recurrence in these areas due to the extent of regional lymph node involvement.82 Hypofractionated whole-breast radiation therapy in which larger treatment fractions are delivered over a shorter period of time (3 weeks) is also being used more commonly as concerns about the potential adverse effects on cosmesis and local recurrence in select patient populations have been disproved.83 External-beam radiation therapy to the chest wall after mastectomy and chemotherapy is also recommended for women with T3 or T4 lesions, tumor invading skin or chest wall, and ≥ 4 axillary lymph nodes with metastatic cancer.84
Chemotherapy/Endocrine Therapy/Targeted Therapy
In stages I to III breast cancers, where cure is achievable, systemic therapy is used to eradicate micrometa-static disease; in the case of neoadjuvant therapy, it is used to reduce the tumor burden before surgery. The efficacy of adjuvant chemotherapy of breast cancer has been established for more than 25 years, whereas hormonal therapy, in the form of surgically or medically induced menopause, has been recognized as early as the 19th century. Depending on the type of breast cancer, modern adjuvant systemic therapy now includes cytotoxic chemotherapy and targeted therapy directed against estrogen (estrogen production or the ER) and against the human epidermal growth factor receptor 2 (HER2). The routine molecular profiling of breast cancer allowing stratification into biologically and therapeutically distinct subsets has improved the therapeutic index of systemic therapy, allowing for increased survival rates with fewer patients receiving toxic therapy when predicted to be ineffective.85,86 Regimens for therapy are also determined by stage of disease and level of risk of micrometastatic disease, allowing for shorter courses and fewer drugs in stage I, low-risk disease versus aggressive, dose-dense, and extended regimens for high-risk patients, particularly those with multiple axillary nodes involved (stage IIB and III).87
Chemotherapy
Systemic adjuvant chemotherapy for breast cancer is accomplished with a variety of regimens, with first-, second-, and third-generation regimens increasing in aggressiveness and effectiveness.87 All regimens use some combination of an alkylating agent (usually cyclophosphamide), a taxane (either paclitaxel or docetaxel), and/or an anthracycline (either doxorubicin or epirubicin). For ER-positive disease, anti-estrogen therapy is given after chemotherapy, usually for a total of 5 years, whereas for HER2-positive breast cancer, therapy with a monoclonal antibody, trastuzumab, directed at the HER2 receptor is given concurrently with chemotherapy, as well as after chemotherapy, usually for a total of 12 months.
First-generation chemotherapy regimens include modestly toxic combinations such as cyclophosphamide, methotrexate, and fluorouracil for 6 cycles and doxorubicin plus cyclophosphamide (AC) or docetaxel plus cyclophosphamide (TC) for 4 cycles and are appropriate for patients with stage I and low-risk stage II disease. Second-generation regimens include fluorouracil, epirubicin, and cyclophosphamide for 6 cycles; cyclophosphamide, doxorubicin, and fluorouracil for 6 cycles; and standard AC/T: AC for 4 cycles followed by a taxane for 4 cycles, given every 21 days, or weekly paclitaxel for 12 weeks. Second-generation regimens are thought to have somewhat superior efficacy to first-generation regimens, with an approximately 20% improvement in survival, but with longer duration of therapy and increased toxicity. Third-generation regimens include TAC (with all 3 agents given concurrently rather than in sequence as in AC/T), and AC/T given at 2-week intervals rather than 3 (so-called dose-dense AC/T) and are thought to provide an additional 20% improvement in survival over second-generation regiments for high-risk subsets, but with considerable increase in toxicity and a requirement for active growth factor support. The decision regarding which regimen to select is based on stage of disease, prognostic factors such as grade, and the ability of the patient to tolerate therapy as a result of comorbidities such as underlying cardiac, hepatic, and renal function. In addition, the incremental benefit of chemotherapy in prolonging overall survival is contingent on the expected actuarial survival of the individual, such that 2 women with breast cancer similar in stage and prognostic features may receive different therapies if one has no comorbidities and the other has significant health issues other than breast cancer that are expected to affect her overall survival.
The rapid increase in the molecular understanding of breast cancer, and the observation of molecularly defined subsets with distinct biologic behavior, has revealed differing cellular pathways that are up- or downregulated depending on tumor type. This body of information, however, has not been fully integrated into standard clinical decision making for breast cancer chemotherapy; it may serve to guide, in some cases, the decision regarding whether chemotherapy should be used at all.88 The commercially available 70-gene and 21-gene profiles use differing sets of genes, whose expression levels predict the likelihood of metastases and/or the likelihood of response to anti-estrogen therapy and chemotherapy.
Targeted Therapy: Anti-Estrogen
All breast cancers expressing ER in greater than 1% of tumor cells are expected to benefit from the use of anti-estrogen therapy.89 The role of the PR in predicting the degree of benefit remains controversial, and it is thought that the absence of PR predicts less benefit; it is also possible that the rare tumors classified as ER negative but PR positive may represent technical errors in processing, rather than a true subset.52 The degree of benefit of anti-estrogen therapy may be predicted in breast cancer by examining the expression levels of 16 genes,88 with 5 additional reference genes making up a 21-gene profile. Three levels of benefit are identified based on gene expression: a low-risk profile indicating extreme sensitivity to anti-estrogen therapy and no incremental benefit predicted from the addition of standard chemotherapy; a high-risk profile indicating significantly less sensitivity to anti-estrogen therapy than anticipated despite the presence of ER, but with a commensurately increased sensitivity and benefit from cytotoxic chemotherapy; and an intermediate-risk group, in which the reciprocal trends of sensitivity to anti-estrogen and chemotherapy vary as a continuous variable. A large cooperative group trial designed to determine the optimal therapy for patients in the intermediate category is currently underway.90
Targeted therapy directed against estrogen in the premenopausal woman with intact ovarian function is limited to blockade of estrogen binding to the ER by the drug tamoxifen. The pituitary-ovarian axis is often disrupted by tamoxifen, with estrogen “deficiency” sensed by the pituitary, resulting in an increase in luteinizing hormone and follicle-stimulating hormone, which in turn induces increased ovarian production of estrogen. Estrogen levels in women taking tamoxifen may be extremely elevated as result of this feedback mechanism. Tamoxifen acts as an antagonist to estrogen in the breast, but may have agonist effects in the uterus and elsewhere, such that not all women experience menopausal sequelae or become amenorrheic on the drug.
In the postmenopausal woman with no ovarian function, the preferred anti-estrogen therapy is the reduction of non-ovarian estrogen production through the use of inhibitors of the enzyme aromatase, found throughout the body in various tissues, including the breast itself. Aromatase inhibitors (AI) such as anastrazole, letrozole, and exemestane have been proven superior to tamoxifen in several large clinical trials, and, like tamoxifen, are given for a period of 5 years.89 Longer use of AIs has not been documented as yet to be of benefit, although the use of 5 years of AI after an initial 5 years of tamoxifen does add a small incremental benefit to disease-free survival. Due to the profound reduction in estrogen caused by inhibition of aroma-tase, menopausal symptoms may be exacerbated, and accelerated loss of bone density may occur. This latter effect warrants the yearly assessment of bone mineral density, calcium, and vitamin D supplementation and often therapy to prevent or treat osteoporosis.
Targeted Therapy: Anti-HER2 Therapy
Overexpression of the HER2 receptor and excessive signaling through this pathway is an important driver of growth and angiogenesis in breast cancer cells. Until the advent of HER2-directed therapy, HER2 positivity identified the worst prognosis subset of breast cancer. However, a monoclonal antibody binding to HER2, trastuzumab, has proven effective in the metastatic setting, in combination with chemotherapy, and in the adjuvant setting; in some cases, use of trastuzumab doubled the survival seen with chemotherapy alone.91 The addition of trastuzumab to adjuvant chemotherapy for HER2-positive breast cancer is now the standard of care. Additional methods of targeting HER2 function, as with the small molecule tyrosine kinase inhibitor lapatinib, are undergoing testing in clinical trials at this time.
Special Situations
Ductal carcinoma in situ (DCIS), which accounts for approximately 20% to 25% of all newly diagnosed breast cancers, is treated slightly differently than invasive breast cancer. Overall prognosis for DCIS is good: 10-year overall survival for women with DCIS is 96%-98%. DCIS is most frequently asymptomatic at presentation and detected mammographically as suspicious microcalcifications. In some cases, DCIS may be a precursor lesion to invasive breast cancer. Consequently, treatment of DCIS is geared to preventing progression to invasive breast cancer. After mastectomy for DCIS, the risk of local recurrence is 1%.60 With lumpectomy for DCIS, the risk of local recurrence was 26.8% in the NSABP B-17 trial. The addition of external-beam whole-breast radiation therapy to lumpectomy decreased this local recurrence risk to 12.1%. Furthermore, half of the local recurrences were invasive breast cancers. Although radiation therapy may play an important role in decreasing local recurrence in women undergoing lumpectomy for DCIS, there may be some patients treated with lumpectomy for DCIS in whom radiation therapy can be safely omitted. Specifically, it may be plausible to omit radiation therapy in older women with smaller areas of low-grade DCIS and wide surgical margins, as summarized by the University of Southern California/Van Nuys Prognostic Index.92 In most cases of DCIS, sentinel lymph node biopsy/axillary staging is not necessary because the risk of lymph node metastasis associated with surgically excised DCIS is only approximately 5%. However, when mastectomy is performed for DCIS, sentinel node biopsy should be considered due to the possibility of subsequent identification of invasive cancer in the mastectomy specimen. Tamoxifen is also recommended for women with DCIS that is positive immunohistochemically for ER.60
SURVIVAL AND PROGNOSIS
Key Points
1. The majority of early-stage breast cancers are curable, and prognosis is related to ER, PR, and HER2 status.
2. Breast cancers that do not express ER, PR, or HER2 (triple-negative disease) have a greater risk of relapse, usually within 5 years.
3. Breast cancers that are positive for ER may recur as late as 10 to 25 years after primary diagnosis.
Breast cancer is detected at earlier stages then ever before in the United States, due to heightened public awareness and generally widespread access to mammography34; the majority of patients are now diagnosed with highly curable stage 0 to stage II disease. The ability to reliably document the “cure” of breast cancer in an affected individual with early-stage disease varies by the type of breast cancer due to the observation that the likelihood of relapse varies over time by ER, PR, and HER2 status.89 Basal or triple-negative and HER2-positive breast cancers are characterized by rapid proliferative rates and early risk of relapse, primarily within the first 5 years of diagnosis. ER-positive breast cancer, on the other hand, may relapse as late as 10 to 25 years after diagnosis,93 with clear proof of genetic relatedness of the relapsing cancer to the original primary tumor.94 Breast cancer is also a highly chemo-responsive tumor relative to other solid tumors, such that the average 5-year survival rate of patients with metastatic disease is at least 20%95 and may extend for a decade or more in the case of breast cancer metastatic to bone only. In addition to the heterogeneous clinical behavior of breast cancer subtypes, the collection of survival statistics lags well behind the incorporation of new therapies into the standard of care, causing widely cited summaries of survival by stage, as in Table 15-6,95 to be of limited value in assessing the prognosis of an individual patient. Specific predictions through computer-based clinical subset data or genomic profiling96 appear to be far more accurate.
Table 15-6 Five-Year Survival by Stage of Breast Cancer
MANAGEMENT OF RECURRENT DISEASE
Key Points
1. Recurrent breast cancer is managed primarily with chemotherapy and agents targeting known expression of ER and HER2.
2. Novel targeted agents, such as trastuzumab and olaparib, have demonstrated significant activity in certain subsets of recurrent breast cancer.
The management of recurrent breast cancer is dictated by the molecular biomarkers known to drive breast tumor growth. Therefore, estrogen-driven tumors expressing ER and PR are preferentially treated with anti-estrogen therapy typically involving tamoxifen and aromatase inhibitors, as well as the selective down-modulator of ER, fulvestrant.97 For HER2-positive disease, the anti-HER2 antibody trastuzumab is combined with chemotherapy such as taxanes, and on progression, alternative HER2 targeting with the tyrosine kinase inhibitor lapatinib, in combination with the fluorouracil pro-drug capecitabine, is employed.98 More recently, however, dual targeted therapy of molecular targets has been studied, for example, by combining lapatinib and trastuzumab (dual HER2 targeting)99 and lapatinib and an aromatase inhibitor (HER2 and ER targeting).100
Recognition of the role of DNA repair proficiency in response to chemotherapy in recurrent disease has led to the use of therapy directed at specific subsets of breast cancer in which DNA repair deficiency is suspected, as in the triple-negative breast cancer, or confirmed, as in BRCA-mutated breast cancer. In triple-negative breast cancer, the high rate of genomic instability suggested a potential sensitivity to agents that would further disable DNA repair, such as inhibitors of poly (ADP ribose) polymerase (PARP), an essential component of single-strand, base excision repair.101 When combined with carboplatin and gemcitabine in a phase II study, the PARP inhibitor iniparib achieved a tripling of response rate and prolongation of survival in metastatic triple-negative breast cancer over chemotherapy alone. In an even more compelling proof of the concept of targeting DNA repair deficiency, in BRCA-mutated breast cancer known to be deficient in homologous double-strand repair, the use of the PARP inhibitor olaparib alone, without chemotherapy, produced a greater than 40% response rate in heavily pretreated BRCA-mutated cancers.102 This approach, using a genetically targeted therapy that takes advantage of the presence of an intrinsic sensitivity within the cancer cell, has been dubbed “synthetic lethality” and has been applied with similar success to BRCA- mutated ovarian cancer as well.103
For the vast majority of patients with recurrent breast cancer, the choice of therapy is limited to the use of single-agent chemotherapy, with the goal being to maintain control of disease while striving to maintain quality of life. With the advent of targeted therapies with generally lesser toxicity, appearing to show synergy with chemotherapy and in some cases superiority, this goal is increasingly achievable with the additional promise of prolonged survival. As in all cases of advanced cancer, the best therapeutic choice is likely to be a clinical trial.
SPECIAL MANAGEMENT PROBLEMS
Approximately 5% of breast cancers in the United states occur in carriers of BRCA gene mutations. For BRCA gene mutation carriers, the lifetime breast cancer risk is estimated to be between 26% and 85%. Breast cancers in women with BRCA1 gene mutations are more likely to occur at younger ages and be higher grade and ER negative. Although commonly used screening protocols have not been prospectively validated, heightened surveillance is generally recommended for this high-risk population. The National Comprehensive Cancer Network recommends annual screening mammography, annual screening breast MRI, and clinical breast examination every 6 months beginning at the age of 25 years. Prophylactic bilateral salpingo-oophorectomy in BRCA carriers not only reduces the risk of gynecologic malignancies, but also significantly reduces the BRCA-associated breast cancer risk. Prophylactic mastectomy furthermore reduces breast cancer risk by more than 90%.104 The prognosis in terms of survival and local recurrence of BRCA-associated breast cancers, however, remains the same, stage for stage, as that of similar cancers in women who are not BRCA carriers. BRCA carriers who develop breast cancer, however, are more likely to develop contralateral and new primary ipsilateral breast cancers at a rate of approximately 3% per year.105Consequently, bilateral mastectomy is often recommended for BRCA carriers who develop breast cancer.
Breast cancer diagnosed during pregnancy also provides special challenges in terms of diagnosis, staging, and treatment. Although traditionally a diagnosis of breast cancer during pregnancy was associated with worse prognosis, it now appears that this is largely due to the more advanced stage at the time of diagnosis of cancer in women who are pregnant. Expeditious and appropriate therapy, therefore, may result in survival comparable to that of nonpregnant women with breast cancer. In pregnant women, clinical breast examination is less sensitive as a result of glandular hyperplasia and increased density of the breasts. Mammography and other forms of ionizing radiation, furthermore, should generally be avoided in pregnancy. Although MRI itself is safe in pregnancy, gadolinium, the contrast agent used for breast MRIs, does cross the placenta and has not yet been studied in pregnancy. Breast ultrasound is the only safe imaging modality in pregnant women. Breast cancer treatment during pregnancy largely depends the gestational age of the fetus when the cancer is diagnosed. In the first trimester, most pregnant women with breast cancer will be recommended to undergo modified radical mastectomy because adjuvant radiation therapy, which should ideally be started within 8 weeks of successful lumpectomy, cannot be safely given until at least the second trimester. Axillary lymph node dissection, rather than sentinel node biopsy, is performed in pregnancy because the blue dyes and radioactive isotopes used to identify the sentinel lymph nodes have not been demonstrated to be safe for the developing fetus. Chemotherapy should be avoided in the first trimester and stopped at least 3 weeks before anticipated delivery of the baby to allow time for recovery of immune function. Tamoxifen and other estrogen receptor modulators may have teratogenic effects and should not be given during pregnancy. For women diagnosed with stage III or IV breast cancer during the first trimester of pregnancy, termination of the pregnancy should be considered.106
Unlike the far more common epithelial breast cancers, treatment of phyllodes tumors, regardless of whether they are classified as being benign or malignant, is wide local excision to at least 1-cm margins because of the propensity for even benign phyllodes tumors to recur locally. At times, mastectomy may be required to achieve the desired surgical margins. Axillary lymph node dissection is not routinely performed because lymph node metastases with phyllodes tumors are rare, and the role of chemotherapy and radiation therapy has not been established in the management of phyllodes tumors.107
FUTURE DIRECTIONS
The therapy of breast cancer has evolved dramatically in the past 30 years. For the management of local disease, this era has been marked by the steadily diminishing extent of surgery on the breast, with lumpectomy replacing mastectomy in many cases, and in the axilla, with sentinel lymph node sampling replacing full axillary dissection for many women. In radiation oncology, new technology has allowed a reduction in the extent of radiation therapy both to the breast and surrounding normal tissues, with a resulting decrease in toxicity to normal structures. In the use of systemic adjuvant therapy to control the risk of micrometastatic disease, in combination with definitive local therapy, molecular analysis and genomic profiling of breast cancers have allowed the avoidance of unnecessary chemotherapy and the identification of patients for whom specific chemotherapies may be remarkably effective. The use of less toxic, targeted therapy directed against the intrinsic biology of breast cancer has led to large, incremental increases in rates of cure and diminished reliance on chemotherapy. In the metastatic setting, the growing understanding of the unique and heterogeneous biology of breast cancer, characterized at the level of the genome, transcriptome, and proteome, has created an explosion of new molecular targets and potential therapies directed against these targets. The future of breast cancer is at the molecular and genomic level; a new generation of clinical trials has incorporated this level of definition of breast cancer into the design of studies involving the rational combination of targeted agents to enhance efficacy and reduce resistance. This approach relies on the biologic knowledge derived from the laboratory and applied to the clinic. For example, the knowledge that resistance to HER2-directed therapy with trastuzumab occurs through the activation of the PI3-kinase/AKT survival pathway leads to trials with trastuzumab and inhibitors of the PI3-kinase pathway108; knowledge that therapy-resistant ER-positive breast cancer increasingly acquires an epithelial to mesenchymal transition (EMT)-like profile leads to the combination of src-inhibitors with ER blockade109,110; knowledge that fibroblast growth factor receptor polymorphisms increase risk of breast cancer and that fibroblast growth factor receptor genes are amplified in subsets of breast cancer leads to trials of agents targeting this pathway.111 Adding to this expanding molecular world is the discovery of microRNA; this represents untranslated regulatory genetic material with diagnostic, prognostic, and ultimately therapeutic potential in breast cancer.112 By examining, understanding, and now defining breast cancer by the disease-causing pathology at the level of the genome, new insights are gained and opportunities revealed for both improvements in cancer therapy and the advancement of cancer biology.
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