Disclosure Breast cancer is the most common cancer and the second most common cause of death from cancer in women. Because of the high frequency of the disease and the esthetic and symbolic value invested in the breast, breast cancer has always been a source of severe distress to patients and their families. For the same reasons, breast cancer research has increased dramatically during the last 2 decades, resulting in extraordinary progress in our understanding of the disease and in new, more efficient and less toxic treatments. Furthermore, the diffusion of knowledge, the medical advancements, and the increased public awareness have led to earlier diagnosis at stages usually amenable to complete resection and potential cure of the disease. This article addresses the etiology, pathophysiology, clinical presentation, diagnosis, surgical and medical treatment, prognosis, and future directions of breast cancer. For excellent patient education resources, visit eMedicine's Cancer and Tumors Center, Women's Health Center, and Imaging Center. Also, see eMedicine's patient education articles Breast Cancer, Mastectomy, Breast Lumps and Pain, Breast Self-Exam, Mammogram, and Ovarian Cancer. Problem: Over the past few decades, breast cancer management has undergone significant changes characterized by less aggressive approaches to diagnosis and treatment. Mammogram and ultrasound or stereotactic biopsies have supplanted clinical diagnosis and surgical biopsy for the diagnosis; breast-conserving surgery (BCS) and sentinel lymph node biopsy (SLNB) have successfully replaced the more aggressive radical mastectomy (RM) and axillary lymph node dissection (ALND). These changes are the results of a century-long experience whereby different models for the disease have been proposed and tested. RM, introduced by Halsted at the end of the last century, was based on the centrifugal model of tumor spread, according to which cancer spread starts locally then moves to the lymphatics and only then invades distant organs. Despite increasingly radical procedures, most patients relapsed with systemic disease. New paradigms appeared to palliate the deficiency of this model. Both the systemic and the spectrum models acknowledge the role of the blood stream in tumor dissemination independent of lymphatic invasion, but they differ in their explication of the relationship between tumor size and distant metastases. The systemic model considers breast cancer a systemic disease from its inception, while the spectrum model views breast cancer as a progressive disease in which invasion and metastases are a function of tumor growth and biological transformation. In addition, this model acknowledges that the disease may manifest over a spectrum of biological behaviors, with tumors that are metastatic from the beginning and others that may reach large sizes without dissemination. Modern trials comparing different forms of locoregional control for patients at the same stage of disease show that variations in local treatment do not result in differences in long-term survival, validating the first premise of these models regarding the inadequacy of local approaches to control the disease in the absence of systemic therapy. In addition, screening mammography results in early detection of breast cancer (average size 1.4 cm vs 2.2 cm for tumors clinically detected) and is associated with a 25% decrease in the mortality rate for breast cancer, thus lending credibility to the spectrum model. This model stresses the importance of both local and systemic treatment. ALND remains one of the mainstays of breast cancer management because clinical, imaging, or biological methods are insufficient to reliably define nodal status, the most reliable predictor of final outcome. Furthermore, ALND allows local control of the disease and may also improve survival. However, the extent of axillary dissection is still debated. Knowing that the procedure has risks of chronic morbidity in terms of arm mobility and lymphedema, the question is not a trivial one. Results from several prospective studies show that 10 nodes or more should be removed and found negative before declaring the axilla stage N0. This involves a level I dissection and, usually, a level II dissection. Early detection of breast cancer in the screening mammogram era has raised the question of whether extensive axillary dissection could be replaced by more limited procedures or SLNB. Less invasive techniques, such as positron emission tomography scan and endoscopic axillary clearance, are being evaluated for staging and local treatment. The indications for postoperative radiation therapy (RT) are being redefined for small estrogen-positive tumors, particularly in postmenopausal women. Immediate reconstruction after mastectomy became an accepted practice that proved to be safe and compatible with early detection of recurrence. Because breast cancer is being detected at increasingly smaller sizes, plastic surgery will likely play a larger role in the initial treatment of breast cancer. Frequency: The American Cancer Society estimated that 211,240 new cases of breast cancer (32.1% of all cancers in women) would be diagnosed in 2005 in the United States, making breast cancer the most-diagnosed cancer in women. Male breast cancer is a rare disease and 1690 cases were expected for 2005 in the US. The true incidence rates of breast cancer have been stable from 1987-1996 after a constant increase since 1979 (increase of 1% per year from 1979-1982; 4% per y from 1982-1987). The lack of decline of breast cancer incidence in the 1990s contrasts with a slight decline (decline of 1.3% per y from 1992-1997) of the incidence rate of cancer for all sites. Up to 40,870 cases of breast cancer-related deaths were expected for 2005 in the US. Based on cancer cases diagnosed from 1995-1997, the probability of developing invasive cancer is 0.44% (1 in 225) for women younger than 39 years, 4.15% (1 in 24) for women aged 40-59 years, and 7.02% (1 in 14) for women aged 60-79 years. The estimated lifetime probability of developing breast cancer is 12.83% (~1 in 8). The likelihood of developing breast cancer is higher in white women than in women of any other racial or ethnic group. Although the death rate from breast cancer has decreased an average of 2.2% per year from 1990-1997, the recorded number of deaths from breast cancer has remained stable, at approximately 43,000 per year. Deaths dropped to 41,737 in 1998 after reaching the highest number, 43,844, in 1995. Among women aged 20-59 years, breast cancer is the leading cause of death from cancer. However, lung cancer remains the leading cause of death from cancer in women aged 60 years or older. Etiology: Breast cancer is a heterogeneous disease with no single characterized cause. Epidemiological studies have identified many risk factors that increase the chance for a woman to develop breast cancer:
Genetic factors As with other cancers, breast cancer is the result of multiple genetic changes or mutations. Early mutations may be inherited (eg, mutations of breast stem cells) or acquired (eg, somatic mutations due to ionizing radiation, chemical carcinogens, or oxidative damage). Estrogens, by their proliferation-promoting effect on the breast epithelium later, increase the chance of DNA replication errors leading to carcinogenic mutations. Indeed, the common denominator to many of these risk factors is their effect on the level and duration of exposure to endogenous estrogenic stimulation. Early menarche, regular ovulation, and late menopause increase lifetime exposure to estrogens in premenopausal women, while obesity and hormone replacement therapy increase estrogen levels in postmenopausal women. Conversely, late menarche, anovulation, and early menopause (spontaneous or induced) are protective, owing to their effect on lowering the level or shortening the duration of estrogenic exposure. Lactation and premenopausal obesity are associated with lower estrogen levels as a result of anovulation. For unknown reasons, pregnancy decreases breast tissue susceptibility to somatic mutations; thus, the earlier the first pregnancy, the shorter the susceptibility period. Hereditary breast cancers have been thought to represent a small proportion (5-10%) of all breast cancers. However, based on new data derived from the comparison of identical and nonidentical twins, up to 27% of breast cancers may be attributed to inherited factors. The mutated genes BRCA1 and BRCA2 are responsible for approximately 30-40% of inherited breast cancers. The prevalence of BRCA1 in the general population is 0.1%, compared with 20% in the Ashkenazi Jewish population. The gene is encountered in 3% of the unselected breast cancer population and in 70% of women with inherited early-onset breast cancer. Up to 50-87% of women carrying a mutated BRCA1 gene develop breast cancer during their lifetime. Risks for ovarian and prostate cancers are also increased in carriers of this mutation. BRCA2 mutations are identified in 10-20% of families at high risk for breast and ovarian cancers and in only 2.7% of women with early-onset breast cancer. The lifetime risk of developing breast cancer in female carriers is 25-30%. BRCA2 is also a risk factor for male breast cancer; carriers have a lifetime risk of 6% for developing the cancer. BRCA2 mutations are associated with other types of cancers, such as prostate, pancreatic, fallopian tube, bladder, non-Hodgkin lymphoma, and basal cell carcinoma. Li-Fraumeni syndrome, characterized by a mutation of TP53, is associated with multiple cancers, including the SBLLA syndrome (sarcoma, breast and brain tumors, leukemia, laryngeal and lung cancer). Cancer susceptibility is transmitted by an autosomal dominant pattern, with penetrance approximating 90% by age 70 years. Li-Fraumeni syndrome is identified in 1% of women with early-onset breast cancer. Bilateral breast cancer is noted in up to 25% of patients. Cowden disease is a rare genetic syndrome associated with papillomatosis of the lips and oral mucosa, multiple facial trichilemmomas, and acral keratosis. The prevalence rate of breast cancer in women with this disease is 29%. Benign mammary abnormalities (eg, fibroadenomas, fibrocystic lesions, ductal epithelial hyperplasia, nipple malformations) are also more common. Other rare genetic disorders, such as Peutz-Jeghers and Muir-Torre syndromes, are associated with an increased risk of breast cancer. Pathophysiology: In a normal state, cells proliferate in response to external proliferation-promoting signals to fulfill a function such as replacing lost cells or repairing injured tissues. Once the goal has been reached, a set of proliferation-repressing signals is activated. These signals allow the cells to exit the proliferation cycle (cell cycle) by returning to the dormant state (G0), by differentiating, or by dying (apoptosis). Each of these functions is carried out by a complex system of interacting proteins. Constitutive expression by mutation or another genetic change of any component of the proliferation-promoting system may result in uncontrolled proliferation. The constitutively expressed component is called an oncogene. Conversely, the loss by mutation or deletion of a proliferation-repressing gene results in an inability to stop the cell cycle and, thereby, continuous proliferation, possibly leading to cancer. The lost gene is called a tumor suppressor gene. Likewise, constitutive expression of antiapoptotic genes may result in immortalization of the cell, paving the way for further genetic changes and eventually cancer formation. Loss of proapoptotic genes may lead to similar results. Thus, autonomous proliferation and immortality shared by all cancers are the final result of successive genetic changes, which may be different from one cancer to another. Breast cancer is not an exception in that regard. It is the result of multiple genetic changes that are different from those of other malignancies and that confer to this cancer its characteristic phenotype. Cell-cycle deregulation in breast cancer Estrogen and progesterone induce cyclin D1 and c-myc expression. Although both sex hormones provide directionality by shifting the CDKI p21 from CDK2 to CDK4, progesterone promotes maturation by inducing p27, while only estrogen allows multiple cycles. Recent studies have reported common amplification of cyclin D1 (a third of breast cancers), inactivation of p16, and mutation of TP53 in breast cancer. c-myc overexpression is one of the most common genetic alterations encountered in persons with breast cancer (a third of patients). Depending on the availability of its different partners, it may result in proliferation and chromosomal instability (Myc-Max) or differentiation (Myc-Mad), probably by sequestering Myc and reducing its availability. Amplification of the c-myc gene is associated with a poor prognosis and a high S-phase. Estrogen receptor (ER)–positive breast cancer cells undergo apoptosis after withdrawal of estrogen, suggesting that this hormone functions not only as a mitogen but also as a survival factor. The antiapoptotic factor Bcl-2 is commonly overexpressed in ER-positive breast cancers. ER negativity is observed in a third of primary breast cancers and a third of recurrences of ER-positive primaries. The ER gene is usually intact with no identifiable deletions or mutations. Although the exact mechanism of this lack of expression is not known, hypermethylation used normally by the genome to silence certain genes is a possible explanation. Methylation of cytosine-rich areas (called CpG islands) of the ER-gene promoter region has been described in the majority of ER-negative breast cancers and in a small fraction of ER-positive breast cancers. Demethylation of these areas with specific agents (eg, 5-azacytidine) restores ER expression and its function in vitro. A progesterone receptor (PR) is present in approximately 50% of all ER-positive tumors. Its presence depends on the expression of functional ER, which explains its absence in almost all ER-negative breast cancers. The mitogenic effect of progesterone in breast cancer may depend on the induction of local growth hormone production in the hyperplastic mammary epithelium. However, high doses of progestins have proven inhibitory effects on breast cancer growth mediated by the down-regulation of G1-phase CDKs and cyclin D1 leading to cell differentiation. Regarding adhesion-dependent cell regulation, the transmembrane glycoproteins, ie, epithelial cadherins (E-cadherins), mediate with their extracellular domain cell-to-cell interactions, thus stabilizing the cell in the epithelial tissue. Their intracellular domain interacts with and controls the transcription factors B-catenins. A mutation or the absence of E-cadherins results in cell detachment, increased motility and invasiveness, and release of B-catenins, which up-regulates c-myc expression. Expression of E-cadherins is down-regulated in breast cancer. Another family of adhesion molecules, the integrins, is involved in cell-to-matrix interactions. Integrins signal through the Fak-Src pathway, which activates PI3K and AKT, resulting in enhanced survival, proliferation, and motility. The main components of this pathway (Fak, PI3K, and AKT) are inhibited by PTEN (ie, phosphatase on chromosome 10 gene product, mutated in Cowden disease), which results in the suppression of survival and apoptosis. The epidermal growth factor (EGF) receptor family plays a critical role in mammary tumorigenesis. Other than the EGF receptor itself, 3 other members of this family have been described, including c-erb-B2 (HER2, HER2/neu), c-erb-B3, and c-erb-B4; the latter is called a kinase-dead receptor because it does not carry a kinase function on the cytoplasmic domain of the receptor, which is in contrast to the other members of the family. These receptors interact with many ligands, including EGF, transforming growth factor (TGF)–alpha, hergulin (or Neu differentiation factor), heparin-binding EGF-like growth factor, beta-cellulin, and epiregulin. Upon binding of a ligand with its cognate receptor, a homodimerization or heterodimerization process occurs, followed by autophosphorylation of the intracellular domain and activation of the intrinsic catalytic domain. Transmission of the signal is operated via phosphorylation of adaptor proteins (GRB2-SOS, Shc, IRS-1/2, STAT) docked or recruited to the cytoplasmic domain of the receptor, followed by activation of the RAS-GTP protein, then 1 of 3 pathways to the nucleus (ie, Raf/MEK/ERK-1/2, MEKK1/MEK4/7/JNK, PI3K/AKT/GSK). Transmission of the signal from adaptor proteins to the nucleus without mediation by RAS is possible through Fak/Src or Rho/Rac/CDC42 pathways. In addition, phospholipase C-gamma is activated by direct interaction with the phosphorylated c-erb-B-2; however, its intracellular pathway is not fully known. The final result is the induction of transcription factors (ie, Myc, NF-kB, ATF, Ets, AP-1, EIK, SRF) that drive the cell cycle by up-regulating cyclins and inhibiting CDKIs and proapoptotic signals. Once the biological message has been executed, the complex ligand receptor is internalized and destroyed in the lysosomes. The pattern of heterodimerization, the intracellular pathway used, and the rate of internalization and destruction of the receptor depend on the specific ligand bound to the receptor. Although c-erb-B2 does not have a specific ligand, its role in the signal transmission from the epidermal growth factor receptor is crucial. Cell lines lacking c-erb-B2 are resistant to the tumorigenic effect of EGF, while those with a kinase-deficient or carboxyl terminal–truncated EGF receptor with intact c-erb-B2 can still execute all the functions of the wild type. The discovery of the role of HER2 in breast cancer was one of the landmarks in breast cancer research in the last 2 decades. HER2 is overexpressed in 20-30% of breast cancers. Tumor cells overexpressing HER2/neu may have up to 2 million copies of the receptor on their surface compared with 20,000-50,000 copies in normal breast epithelial cells. Because of this abundance of HER2/neu, many heterodimers contain HER2/neu, resulting in potent intracellular signaling and malignant growth. Despite persistent controversy regarding certain aspects of its biology, prognostic value, and methods of evaluation, HER2 overexpression or amplification is generally accepted to be correlated with a high histologic grade, the absence of hormone receptor expression, aneuploidy, a high proliferation index, tumor size, and a poor clinical outcome. Its role as a predictor of response to chemotherapy and hormonal therapy (HT) is not clearly defined. Certain clinical studies using tamoxifen showed not only a lack of response, but also a detrimental effect in the group of patients overexpressing HER2. Retrospectively reviewed chemotherapy data showed longer disease-free survival and overall survival in HER2 overexpressors who received high doses of doxorubicin-containing chemotherapy compared with HER2-negative patients. Available data concerning the interaction between cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) chemotherapy and HER2 overexpression are inconclusive and do not allow the formation of final conclusions. Taxanes seem to have high efficacy in patients overexpressing HER2 (relative risk, 65%) compared with the HER2-negative group (relative risk, 35%). The IGF family consists of IGF-1, IGF-2, IGF receptor-1, IGF receptor-2, and IGF-binding proteins. The members of this family play an important role in normal mammary development and tumorigenesis. Both IGF-1 and IGF-2 bind to IGF receptor-1, whose strong mutagenic effect is synergistic with estrogen. In breast cancer, IGF receptor-1 and IGF-1 and IGF-2 are overexpressed in epithelial cells and stromal cells, respectively. Paradoxically, this overexpression correlates with a good prognosis, perhaps reflecting simple hormone dependence or association. IGF receptor-2 plays a tumor-suppressing role by down-regulating IGF-2. The TGF-beta family consists of 3 TGF-beta and 2 interdependent serine-threonine kinase receptors. In normal mammary epithelial cells, TGF-beta blocks the expression of cyclin A, an S-phase–promoting protein and (to a lesser degree) cyclins D and E involved in the G1 phase and induces the expression of the CDKI p15, which results in cell-cycle arrest and, potentially, apoptosis. This explains its role in postlactational mammary gland regression. Expression of TGF-beta in breast cancer is increased and seems to correlate with disease progression rather than tumor suppression. Mutation of TGF-beta receptors (type I and II) or any of the downstream molecules (Smad4) involved in intracellular signal transduction renders breast cancer cells resistant to its suppressive effects. However, its role in promoting angiogenesis and invasion and in suppressing the immune system becomes advantageous for the cancer cells, which acquire a proliferative advantage by losing sensitivity to TGF-beta and developing a way to escape the host immunosurveillance. Mutated BRCA1 and BRCA2, breast cancer susceptibility genes, are proven risk factors for breast cancer. More than 500 mutations have been described in the BRCA1 gene (band 17q21), and 250 have been described in the BRCA2 gene (band 13q12-13). The mutations occurring at either end of the BRCA1 gene are associated with more aggressive tumors; those occurring at the 5` extremity are associated with breast and ovarian cancers, while those closer to the 3` end are associated with only breast cancer. The biological function of the BRCA1 gene product is not well known. Accumulated evidence suggests that BRCA1 is a nuclear protein involved in other genes' expression, in cell cycle progression, and in the response to DNA damage. DNA damage results in activation and interaction of BRCA1, BRCA2, RAD51, and TP53 with subsequent expression of p21, which leads to a cell cycle pause until the damage is repaired. The mutation or absence of BRCA1 results in failure to repair the damaged DNA, and the cell cycle continues to accumulate further mutations, eventually leading to tumorigenesis. BRCA2 seems to play a role similar to that of BRCA1 in the cell cycle, other genes' expression, and DNA damage repair. Clinical: In the past, the great majority of patients presented with a painless palpable mass. Although more than 80% of palpable masses are benign, the decision to observe such lesions should be made only after careful clinical, mammographic, and pathologic workup. Cystic lesions identified clinically or on ultrasound images should be explored using fine-needle aspiration (FNA) biopsy. Nonbloody fluid and complete resolution of the cyst confirm its benign nature. If the fluid is bloody or the cyst does not resolve after aspiration or has a complex appearance on the ultrasound image, a biopsy is indicated. Other symptoms, such as breast pain or deformity, nipple discharge, and erythema or skin ulceration, occasionally occur. Patients with Paget disease present with a long-standing eczematoid rash of the nipple-areola complex, itching, tenderness, burning, and occasional bloody discharge from the nipple. Skin dimpling, the result of shortening or retraction of the Cooper ligaments induced by the tumor, does not have prognostic value, while the ominous peau d'orange sign reflects the invasion of the subdermal lymphatic plexus and portends a shortened survival. Symptoms related to distant metastases, such as bone pain, dyspnea, or meningitic syndrome, are encountered in some cases. In current practice, increasing numbers of breast cancers are mammographically diagnosed in the preclinical stage. Screening mammography has resulted in earlier diagnosis of breast cancer, which has translated in recent years into a 25% improvement in the mortality rate related to breast cancer. Mammographic signs suggestive of cancer include architectural distortions, microcalcifications, or masses. These changes require further evaluation using diagnostic mammograms with or without ultrasound. Biopsies are indicated if these changes are confirmed. Features helpful in the evaluation of palpable breast masses are as follows:
Nipple discharge may be spontaneous or induced, unilateral or bilateral, and have different colors and textures. If the discharge is associated with one or more of the suggestive features, further investigation is necessary. Clinical characteristics of nipple discharges are as follows:
Ductal carcinoma in situ Mastectomy has been the criterion standard for many years, with significantly low local recurrence and mortality rates (0.75% and 1.7%, respectively). The idea of using BCS has gained acceptance after good success in women with invasive disease. When BCS is used, RT is often a part of the treatment plan because the prevalence of ipsilateral noninvasive breast cancer was reduced from 13.4% to 8.2% and, for invasive cancer, from 13.4% to 3.9%, after using RT (National Surgical Adjuvant Breast Project [NSABP] B-17). Because most of the tumors in this study were smaller than 1 cm, a wise plan is to continue offering mastectomy to (1) patients with extensive multicentricity, (2) those with multifocality, and (3) those in whom negative margins cannot be obtained with wide excision. Axillary node dissection or adjuvant chemotherapy has no role in the treatment of this disease. Patients with early-stage invasive breast cancer (TNM stage I and II) may benefit from BCS. BCS should be offered to patients with small tumors and adequate breast size. Family history, tumor location, and the presence of pathologically or clinically involved axillary lymph nodes are not contraindications to such a surgery. Absolute contraindications are 2 or more primary tumors in separate quadrants, previous RT to the breast, persistent positive margins, and pregnancy. An extensive intraductal component within the index lesion and the surrounding tissue is not associated with a high risk of recurrence as long as clear margins can be achieved. For Paget disease, mastectomy should be performed in patients with a tumor located beyond the central portion of the breast, while BCS may be considered in patients with disease limited to the retroareolar area, with excision of the nipple-areolar complex and complete excision of the mammographic abnormalities with a 2-cm cone of the retroareolar tissue. If surgical margins are negative, RT should complete the treatment; otherwise, mastectomy is the treatment of choice. Indications for mastectomy include patient preference, an inability to achieve clean margins without unacceptable deformation of the remaining breast tissue, multiple primary tumors, previous chest wall irradiation, pregnancy, and severe collagen vascular diseases (eg, lupus), which are considered absolute contraindications to BCS. Simple mastectomy is used in the treatment of ductal carcinoma in situ (DCIS), after lumpectomy or axillary dissection with or without radiation, if the specimen shows positive margins, in frail patients in whom an axillary dissection is contraindicated, and as a prophylactic measure. Modified RM is performed in the presence of contraindications to BCS or as a patient preference. ALND remains the standard of care in the management of invasive carcinoma of the breast. ALND is not indicated in carcinoma in situ, unless the presence of an invasive component is strongly suggested. SLNB has recently emerged as a credible alternative to ALND, with comparable, if not better, staging results and much less morbidity. In expert hands, SLNB identifies the sentinel lymph node (SLN) in 85-98% of patients and correctly stages the axilla in more than 95% of patients, with a false-negative rate of less than 5%. The combined use of technetium colloid and blue dye techniques increases the detection rate of the SLN. SLNB is usually offered to patients with early-stage breast cancer (stage I or II) who have no gross axillary lymph node involvement. SLNB is contraindicated in patients with clinically palpable axillary lymphadenopathy, multifocal disease, or locally advanced lesions. Patients with positive SLNB findings should undergo level I and II ALND. Because of the slow learning curve for this new procedure, the American Society of Breast Surgeons considers that an individual surgeon should perform at least 20 SLNB procedures with ALND to minimize the risk of false-negative results.
Relevant Anatomy: The breasts are between the second and sixth ribs and are composed of breast tissue, skin, and subcutaneous tissue. The breast tissue is composed of parenchyma and stroma. The parenchyma is composed of 15-25 lobes, and each lobe contains 20-40 lobules. Each lobule consists of 10-100 alveoli. Fifteen to 25 lactiferous ducts provide separate drainage to the corresponding lobes. Before opening at the nipple, these ducts become dilated, forming the lactiferous sinuses. The breast tissue is enveloped superficially by the superficial pectoral fascia and deeply by the deep pectoral fascia, with the 2 layers connected by fibrous bands called Cooper suspensory ligaments. The lymphatic drainage of the breast is unidirectional, from the superficial to the deep lymphatic plexus. The lymph then flows centrifugally to the regional lymph nodes after traveling through the lymphatic vessels of the lactiferous ducts. Ninety-seven percent of this flow is collected in the axillary lymph nodes, while only 3% goes to the internal mammary nodes. Axillary lymph nodes are divided into apical lymph nodes, interpectoral (Rotter) lymph nodes, axillary vein lymph nodes, central lymph nodes, scapular lymph nodes, and external mammary lymph nodes. An arbitrary method divides these lymph nodes into 3 levels relative to their relationship with the pectoralis minor muscle. Lateral to the lateral border of this muscle lie the level I lymph nodes, and medial to it lie the level III lymph nodes. Level II lymph nodes are located between and behind the muscle. Several structures, including vessels and muscles with their nerve supply, are related to the breasts and should be preserved during mastectomy or axillary node dissection. The pectoralis minor muscle and the lateral portion of the pectoralis major muscle are innervated by the medial pectoral nerve. Preservation of this nerve is particularly important to prevent atrophy of the pectoral muscles if a submuscular implant reconstruction is planned. Additionally, the serratus anterior muscle is innervated by the long thoracic nerve of Bell, whose preservation is crucial to prevent winging of the scapula. Resection of the thoracodorsal nerve supplying the latissimus dorsi muscle should be avoided whenever possible, although resection does not result in any cosmetic or functional sequelae. Exposure of the axillary artery and brachial plexus should be avoided. Also, injury to certain sensory branches of the brachial plexus that occasionally pass superficially to the axillary vein may result in arm numbness extending to the wrist. Injury to the intercostobrachial nerve results in numbness over the triceps area. It can be identified by its large size (2 mm) and its location near the axillary vein. Occasionally, this nerve is composed of multiple, thin branches that cannot be preserved. In this case, the nerve should be sectioned with the knife to prevent postoperative causalgia related to the use of electrocautery. Contraindications:
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In situ carcinoma In situ carcinoma is characteristically contained within the epithelium, with the basement membrane intact, and no signs of invasion. Many features distinguish lobular carcinoma in situ (LCIS) from DCIS. LCIS arises from the terminal duct lobular apparatus and shows a rather diffuse distribution throughout the breast, without evidence of a palpable mass. DCIS originates from the major lactiferous ducts and tends to be a localized disease frequently associated with a palpable mass. This explains the high incidence of synchronous involvement in the contralateral breast (bilaterality) or in other quadrants of the same breast (multicentricity) in LCIS (90-100%) compared with DCIS (10-15%), suggesting that complete surgical resection of DCIS is not only possible but also desirable, particularly if the index lesion manifests as a palpable mass. Conversely, locoregional modalities, such as surgery or RT, have no role in the treatment of LCIS except for prophylactic bilateral mastectomy. DCIS originates by proliferation of the ductal luminal cells, which form protrusions into the lumen (papillary DCIS). These become more coalescent, leaving a few empty, rounded spaces (cribriform DCIS). When the lumen is filled with proliferating cells, it becomes completely obliterated (solid DCIS). Central areas of these ducts undergo necrosis because of the ischemic microenvironment (comedo DCIS), with secondary deposition of calcium responsible for the appearance of microcalcifications, a typical radiographic feature of this disease. DCIS is probably a continuum of successive steps of the same process, with increasing malignant potential as the disease progresses from papillary to comedo forms. Indeed, cells in the earliest stages are well differentiated with no atypia or mitoses, while cells in advanced stages become more anaplastic with frequent mitotic figures. From a practical standpoint, dividing DCIS into 2 categories, comedo-type and non–comedo-type, is helpful. Both DCIS and LCIS occasionally may be difficult to differentiate from atypical hyperplasia (eg, atypical ductal hyperplasia, atypical lobular hyperplasia), which is a benign change of the mammary gland preceding the in situ disease. The characteristics of comedo and noncomedo (ie, cribriform, micropapillary, papillary, solid) DCIS are as follows:
Invasive ductal carcinoma develops in 30-50% of patients with DCIS over a 10-year period, usually in the same quadrant where the DCIS was found. In contrast, only 10-37% of patients with LCIS develop invasive carcinoma, mostly of the ductal variety and with equal frequency in both breasts. Therefore, DCIS may be considered a true precancerous process, while LCIS is only a marker of increased risk for cancer. Infiltrating ductal carcinoma with productive fibrosis (scirrhous, simplex, not otherwise specified) represents approximately 80% of ductal carcinoma of the breast cases, with the highest prevalence associated with perimenopause or early postmenopause. Typically, the mass is solitary, firm, and nontender with poorly defined borders. Heterogeneity is a characteristic feature of the malignant cells, which are arranged in single rows, producing the so-called Indian filing. Typical sites of metastases are bone, lung, and liver. Lobular carcinoma Invasive lobular carcinoma is the second most common histologic type after ductal carcinoma, accounting for 5-10% of all breast cancers. It is associated with a high rate of multifocality and bilaterality. LCIS is identified in 70-80% of cases. It may manifest as a palpable mass clinically and mammographically indistinguishable from ductal carcinoma, except that the extent of the tumor is often underestimated in lobular carcinoma. Typical lobular carcinoma is composed of small, homogenous cells that invade the stroma in a single-file pattern. Signet-ring cells may be observed. Their stromal desmoplastic reaction is mild or absent. While ERs and PRs are expressed in the majority of tumors, HER2/neu overexpression and TP53 mutation are rare. Tumor behavior is characterized by more common bone metastases and less frequent lung, liver, and brain metastases than ductal carcinoma. Metastases to the leptomeninges, peritoneum, retroperitoneum, GI tract, and reproductive system seem to be more common in lobular carcinoma compared with ductal carcinoma. Patients with the classic form of lobular carcinoma share the same prognosis as those who have ductal carcinoma, patients with the tubulolobular variant fare slightly better, and those with the signet-cell variant fare significantly worse than average. Medullary carcinoma is relatively uncommon (5-7%) and occurs in younger persons. It manifests as a bulky palpable mass, with axillary lymphadenopathy in 40% of patients. Microscopically, the tumor has a syncytial growth pattern, without tubuloglandular differentiation in 75% of the tumor, mixed with intense lymphoplasmacytic infiltrate and, in most cases, associated with reactive lymphadenopathy. Nuclei are large and pleomorphic (grade 2 or 3). DCIS may be observed in the neighboring normal tissues, although there is no increased risk of bilaterality or multicentricity. ER, PR, and HER2/neu are usually negative and TP53 is commonly mutated. The prognosis of patients with this type is usually very good. Mucinous carcinoma is another uncommon histologic type of invasive breast cancer (<5%). It is more common in the seventh decade of life and manifests clinically as a palpable mass or mammographically (with increasing frequency) as a poorly defined tumor with rare calcification. Its histologic hallmark is the presence of mucin production occupying more than 90% of the tumor in pure mucinous forms and variable percentages in the mixed forms. The cells are clustered in small islets dispersed in a pool of mucin. DCIS is often present in the vicinity of the tumor. ERs and PRs are positive in 90% and 68% of cases, respectively. HER2/neu overexpression is extremely rare. Patients with pure mucinous carcinoma have a better prognosis than those with mixed forms or other breast cancers of no special type. Inflammatory breast cancer is diagnosed clinically based on the association of edema, erythema, and skin ridging (peau d'orange). Although subdermal lymphatic and vascular invasion is nearly constant, it is not a mandatory criterion for diagnosis. The mass is not palpable in most cases. Molecularly, ERs and PRs are negative, HER2/neu is overexpressed, TP53 is commonly mutated, and the thymidine-labeling index is frequently high. Inflammatory carcinoma is an aggressive but fortunately rare disease, with a sudden onset and a rapidly progressive course. It is uniformly fatal if not treated with multimodality therapy. It should be differentiated from benign cellulitis by the characteristic absence of polymorphonuclear leukocytes in the involved area and from locally advanced breast cancer with a secondary inflammatory component, which has a more indolent course and is often responsive to HT. Nipple Paget disease of the breast is a relatively rare entity comprising approximately 1% of all breast cancer cases, with the highest incidence in the seventh decade of life. However, pathologic evidence of the disease can be observed in 2-5% of mastectomy specimens. Approximately half the patients present with an underlying mass, which is an invasive cancer in 93% and a DCIS in 7%. In patients with no mass upon presentation, invasive cancer is present in approximately 40% and DCIS in approximately 60%. Histologically, the disease is localized to the epithelium of the nipple-areola complex and the characteristic cells, or Paget cells, are contained within the basement membrane. Paget cells are large, pale cells with prominent nuclei and large nucleoli, dispersed between the keratinocytes as single or clusters of cells. Other Tubular carcinoma is an uncommon type with limited metastatic potential and a very good prognosis. The average size of pure tubular carcinomas is smaller than 1 cm, and they are associated with axillary metastases in approximately 15% of cases. Mammographically detected tumors (60-70%) tend to be smaller and less frequently associated with nodal metastases than clinically detected tumors. Characteristic features of this type include a single layer of epithelial cells with low-grade nuclei and apical cytoplasmic "snoutings" arranged in well-formed tubules and glands. Tubular elements comprise more than 90% of pure tubular carcinomas and different proportions of mixed tubular tumors. DCIS is associated with most of these tumors. ERs and PRs are positive in 70-100% and 60-83%, respectively. HER2/neu overexpression and TP53 mutation are very uncommon in this type. Papillary carcinoma is rare (<1% of breast cancers), occurring mainly in postmenopausal women. Histologically, the tumor is circumscribed with cells arranged in delicate or blunt papillae. Nuclei are of intermediate grade. Occasionally, extracellular mucin production can be observed. ERs and PRs are positive in approximately 100% and 80% of cases, respectively. Lymphatic vessel invasion occurs in a third of the cases; however, axillary lymph node enlargement can be related to benign reactive changes in a significant number of cases. This type has a good prognosis. The papillae in the micropapillary type lack the lymphvascular core. This type is associated with lower ER and PR positivity and a higher percentage of HER2/neu overexpression, which explain its worse prognosis. TNM definitions
Medical therapy: Treatment of in situ diseaseDuctal carcinoma in situ Approximately 85% of DCIS is detected mammographically, and this represents 20-30% of mammographically detected breast cancer. The risk of developing invasive cancer is approximately 40% in the ipsilateral breast and 5% in the contralateral breast. Regardless of the initial treatment modality, 50% of recurrences are invasive carcinoma. Mastectomy cures 98-99% of all types of DCIS, with a recurrence rate of only 1-2%. Most recently, lumpectomy with RT was shown to yield local recurrence rates of 7-13.4%, compared with 26.8-43% for local excision alone. Furthermore, the addition of tamoxifen resulted in a 44% decrease of invasive breast cancer in the ipsilateral breast and a 52% decrease of invasive breast cancer in the contralateral breast. Predictors of recurrence in patients undergoing BCS for DCIS are as follows:
Lobular carcinoma in situ This lesion is usually an incidental finding in breast biopsy specimens. LCIS is not a cancer; it is an indicator for increased risk for breast cancer. This risk is estimated at 1-1.5% per year and 20-30% over a lifetime. Of invasive carcinoma developing in this setting, 50% is ductal carcinoma; the other 50% is lobular carcinoma. Patients may be observed or offered participation in a chemoprevention trial. Bilateral simple mastectomy with immediate reconstruction is the recommended surgery should the patient elect a radical treatment. Chemotherapy and RT have no role in the treatment of this lesion. Treatment of invasive diseaseModern treatment of breast cancer is based on a multimodality approach combining surgery, chemotherapy, HT, and RT. Treatment is tailored for an individual patient based on tumor size, axillary lymph node involvement, ER and PR status (the most important variables identified by many historical studies), histologic tumor type, standardized pathologic grade, and menopausal status. The 2000 US National Institutes of Health Consensus Conference updated adjuvant therapy guidelines for breast cancer. Adjuvant hormonal therapy Adjuvant HT is indicated only in the presence of hormone receptors (ER and/or PR) on cancer tissue assessed using IHC. Adjuvant tamoxifen has shown a 50% decrease in the risk of breast cancer recurrence and a 28% decrease in breast cancer mortality, while ovarian ablation produced benefits similar to certain chemotherapies (20-25%) in this population. In 2 cooperative trials (NSABP 23, Intergroup trial 0102), the addition of tamoxifen to chemotherapy was not associated with improvement in disease-free survival and overall survival in patients with ER-negative tumors and was even detrimental in premenopausal patients with ER-negative tumors. Therefore, HT is indicated only in case of ER and/or PR positivity, regardless of age, menopausal status, lymph node status, or tumor size. The goal of HT in breast cancer is to induce an estrogen deprivation state at the tumor level. This may be achieved by (1) receptor blockade using one of the selective estrogen receptor modulators, such as tamoxifen or toremifene; (2) suppression of estrogen synthesis by aromatase inhibitors (eg, anastrozole, letrozole, exemestane) in postmenopausal women or by luteinizing hormone-releasing hormone analogues (eg, goserelin) in premenopausal women; or (3) ovarian ablation by surgical oophorectomy or external beam radiation therapy in premenopausal women. Tamoxifen has been the most common form of adjuvant HT used to date. It can be used both in pre and post menopausal women. However, the recent publication of the results of many large aromatase inhibitor (AI) trials (ATAC, BIG 1-98, examestene trial) has shown that AIs are superior to tamoxifen as adjuvant HT in postmenopausal women. Anastrozole and letrozol are approved for use in first line hormonal therapy for HR-positive postmenopausal women and examestene is approved for use sequentially after 2-3 years of tamoxifen. When tamoxifen is chosen, administer 20 mg/d for 5 years. In asymptomatic women, no special screening procedures (eg, transvaginal ultrasound, endometrial biopsies) for endometrial cancer are recommended. The dose of anastrozole is 1 mg a day, of letrozol 2.5 mg and of examestene 25 mg a day. The Early Breast Cancer Trialists' Collaborative Group's overview analysis suggests that ovarian ablation is effective as adjuvant HT for premenopausal receptor-positive breast cancer patients regardless of nodal status. Premenopausal patients who receive chemotherapy and maintain their ovarian function may benefit from ovarian ablation. If the patient is younger than 50 years and there is a question about her ovarian function, FSH/LH and estradiol should be checked to document her menopausal status. Adjuvant chemotherapy Combination chemotherapy is superior to single agents in the adjuvant setting. The body of knowledge about adjuvant chemotherapy for breast cancer has benefited from the serial updates of the Oxford Overview analysis and from other large randomized trials, which have shown slight but statistically significant superiority of anthracycline-containing regimens over traditional CMF. Adjuvant chemotherapy results in an approximately 25% decrease of breast cancer mortality. However, the determination of the anthracycline-containing regimen of choice is still under investigation. For the doses and schedules of the most common regimens used in breast cancer see Table 2. Doxorubicin (Adriamycin) and cyclophosphamide (AC) has a threshold effect; thus, doses greater than 60 mg/m2 and 600 mg/m2, respectively, are of no additional benefit. The results of 3 large US trials (NSABP B22 and B25, Cancer and Leukemia Group B 9344) did not support any role for dose intensification of the AC combination. However, 2 other studies, one French (French Adjuvant Study Group -05) and the other Canadian, showed that when epirubicin was escalated in the fluorouracil-epirubicin-cyclophosphamide (FEC) combination, disease-free survival and overall survival were significantly improved in operable breast cancer with positive axillary lymph nodes. High-dose chemotherapy with stem cell or bone marrow support did not prove superior to standard chemotherapy and is best reserved for clinical trials. Results from two trials (Cancer and Leukemia Group B 9344 and NSABP-B28) exploring the role of taxanes in the adjuvant setting were encouraging. CALGB-9344 had a 3x2 factorial design with patients randomized to receive doxorubicin at 60, 75, or 90 mg/m2 followed by paclitaxel at 175 mg/m2 or no additional therapy. NSABP-B28 had similar design except that the dose of doxorubicin was not escalated and the dose of paclitaxel was 225 mg/m2. From the first trial it was established unequivocally that doxorubicin dose escalation does not improve outcome while the addition of paclitaxel results in small but statistically significant improvement of both the risk of relapse and the risk of death. In NSABP-B28, relapse free survival was significantly improved by the addition of paclitaxel while the data about survival are not available yet. In patients with node-negative, early-stage disease (stages I, IIA, and IIB), chemotherapy is not indicated if the tumor is smaller than 0.5 cm, regardless of the histologic subtype. In persons with invasive ductal and lobular carcinomas, tumors measuring 0.6-1 cm require chemotherapy only if they were associated with unfavorable features (eg, angiolymphatic invasion, high S-phase, high nuclear grade, high histologic grade), while all tumors larger than 1 cm require adjuvant chemotherapy alone (hormone-receptor negative) or in combination with tamoxifen (hormone-receptor positive). In patients with other histologic types (ie, tubular, colloid, medullary, adenoid), chemotherapy is indicated only for tumors larger than 3 cm. It may be considered in those from 1-2.9 cm, and it is not indicated for tumors smaller than 1 cm. In patients with node-positive, early-stage disease, adjuvant chemotherapy with or without adjuvant HT is the mainstay of treatment. Anthracycline-containing chemotherapy, such as doxorubicin (Adriamycin) (60 mg/m2) and cyclophosphamide (600 mg/m2), administered for 4 cycles is the treatment of choice. Many oncologists consider this treatment insufficient and opt for 2 more cycles of the same treatment or 2-4 cycles of paclitaxel (175 mg/m2). In persons with advanced-stage disease (stage IIIA and IIIB), the same regimen of AC for 4 cycles followed by at least 2 more cycles of the same treatment or 4 cycles of a taxane is recommended after surgical treatment. Neoadjuvant chemotherapy may be offered to patients with this stage. The role of neoadjuvant chemotherapy is being intensively investigated. The NSABP B-18 trial compared the effect of preoperative AC for 4 cycles to the same regimen postoperatively in subjects with early-stage breast cancer. Pathologic node-negativity of 60% and BCS of 68% could be achieved in the preoperative AC group compared with 42% and 60%, respectively, in the postoperative AC group. Five-year disease-free survival and overall survival rates for those who achieved pathologic complete response were 84% and 87% compared with 72% and 78%, respectively, in patients who had residual disease. Based on these encouraging results, NSABP started its B-27 trial to address the question related to the role of 4 cycles of preoperative or postoperative docetaxel added to 4 AC cycles. The use of preoperative docetaxel almost doubled the pathologically confirmed complete remission rate compared with the AC arm (25.6% vs 13.7%). Because the role of neoadjuvant therapy is not fully established, participation in clinical trials should be encouraged. In ER- and/or PR-positive tumors, neoadjuvant tamoxifen or letrozole may achieve the same magnitude of response as chemotherapy but with longer time to response. Although the neoadjuvant approach does not seem to prolong survival, its theoretical advantages include downstaging the tumor, in vivo testing of the chemosensitivity of the tumor, and allowing BCS. The treatment of metastatic disease is mainly medical. In postmenopausal patients with ER- and/or PR-positive tumors, the use of tamoxifen or an aromatase inhibitor (eg, anastrozole, letrozole, exemestane) is the standard of care for bone disease and limited visceral disease. In many cases, at least a partial response can be achieved. Patients who progress on first-line HT may still respond to second- or third-line HT, aromatase inhibitors, and megestrol acetate, respectively. ER down-regulators are a promising new class of HT agents that may have some efficacy if the previous treatments fail. In premenopausal women with ER- and/or PR-positive breast cancer, ovarian ablation and tamoxifen are the mainstays of treatment. Ovarian ablation can be achieved by medical (eg, luteinizing hormone-releasing hormone analogues such as goserelin, leuprolide, buserelin, and triptorelin), surgical (ie, bilateral oophorectomy), or RT methods. Chemotherapy is indicated for patients with advanced visceral disease (visceral crisis) and those with hormone-refractory or hormone-insensitive tumors. The goals of chemotherapy in this setting are palliative and include control of symptoms, control of disease progression, and prolongation of life. The best response rates are obtained with first-line therapy and combination regimens. However, regardless of the response rates achieved with these therapies (including high-dose chemotherapy with autologous stem cell support), survival is not affected in most cases. In 2001, Slamon and Pegram reported a survival advantage for the combination of chemotherapy and trastuzumab over chemotherapy alone in women with HER2-positive metastatic breast cancer. Table 1. Single-Agent Chemotherapy for Metastatic Breast Cancer
Predictors of poor response to chemotherapy in patients with metastatic breast cancer are poor performance status, multiple and/or visceral sites of disease, short disease-free intervals, and failure to respond to prior chemotherapy. Because the goals of chemotherapy in patients with metastatic breast cancer are palliative, many authorities recommend the sequential use of single chemotherapeutic agents rather than combinations in order to limit toxicity. Taxanes, anthracyclines, oral fluoropyrimidines, vinorelbine, and gemcitabine are the most effective drugs used in this setting. Trastuzumab, a monoclonal antibody directed against the extracellular domain of the HER2/neu receptor, has shown significant antitumor activity in patients with metastatic breast cancer overexpressing HER2/neu. Response rates of 30-35% have been observed in patients with metastatic breast cancer who are receiving single-agent trastuzumab as a first-line therapy. The relative risk of death was decreased by 20% with a median follow-up of 30 months when trastuzumab was used in combination with chemotherapy. However, when combined with doxorubicin, a significant increase in cardiotoxicity was noted. For this reason, the current recommendation is to avoid trastuzumab in combination with or after doxorubicin. The mechanism of action of trastuzumab is still debated. Trastuzumab induces down-regulation of HER2/neu and prevents its heterodimerization, reestablishing breast cancer cell sensitivity to HT and chemotherapy. As a result of this down-regulation, p27 is induced, resulting in cell-cycle arrest in the G1 phase. Furthermore, trastuzumab binds to the receptor at a site wher | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
