Breast Cancer: An Overview for the Primary Care Physician, Part I
Breast Cancer: An Overview for the Primary Care Physician, Part I
Author: Mark A. Marinella, MD, FACP, CNSP, Dayton Physicians, LLC, Hematology-Oncology, Assistant Clinical Professor of Medicine, Wright State University School of Medicine, Dayton, OH.
Peer Reviewer: Sharon Lum, MD, FACS, Assistant Professor, Department of Surgery, Division of Surgical Oncology, Loma Linda University School of Medicine, Loma Linda, CA.
Although breast cancer may not be the most common cancer in women, the diagnosis or even the suspicion is a cause of great distress. Primary care physicians play a pivotal role in their female patients' care by providing the proper risk assessment, encouraging women to get the regular screening, and providing patients with the appropriate referral to definitive treatment. The PCP must be attentive to the enormous emotional stress that the disease can cause in both the patient and family. Awareness of the current epidemiological features and clinical options available today for patients will enable the PCP to be the best advocate for these patients so that they will not become frustrated by the vagaries of sometimes conflicting advice from specialists. This two-part series on breast cancer offers a concise and practical guide to a disease that can be both physically challenging and emotional draining for our patients.
-The Editor
Introduction
Breast cancer is the most common non-cutaneous malignancy affecting women worldwide, accounting for approximately 30% of all female cancers.1 The American Cancer Society estimated that 184,450 new cases of breast cancer would be diagnosed in the United States in 2008, with 40,930 deaths.2 Indeed, breast cancer is second only to lung cancer as a cause of cancer death in the United States, and is responsible for 15% of cancer deaths in women.2 Although the overall incidence of breast cancer has increased in a steady fashion over the past few decades, mortality is slowly declining, most likely reflecting advances in early detection and more efficacious therapies.2,3 This mortality decrease is reflected in a growing number of breast cancer survivors, with approximately two million currently alive in the United States.1 Since breast cancer affects one in eight women during an expected life span of 80 years, it remains a commonly encountered disease for physicians of many specialties, especially those involved in primary care. The goal of this review is to present an overview of breast cancer diagnosis and management in a manner relevant to primary care providers.
Epidemiology and Risk Factors
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The precise cause of most breast cancers in the average woman remains unknown, although numerous risk factors for disease initiation and progression have been established. (See Table 1.) Unalterable risk factors include gender, age, race, and family history. Breast cancer overwhelmingly affects women by a ratio of 100:1, with only 400 annual deaths occurring in men. The incidence of breast cancer increases with advancing age, with most cases occurring in post-menopausal women. Breast cancer is rare in women younger than age 30, with only 0.8% of cases involving this age group.1,2 Racial differences in breast cancer incidence exist, with the disease being more prevalent overall in post-menopausal whites. Breast cancer is less common in Asian and Hispanic women residing in the United States and is rare in the Native American population.2 Additionally, rates of breast cancer are slightly higher in women of higher socioeconomic status, possibly resulting from delayed first childbirth. Family history is another unmodifiable factor in the pathogenesis of breast cancer, but it is quite heterogeneous in the role it plays in the increased risk among various families. Overall, the relative risk (RR) in a woman with a first-degree relative diagnosed with breast cancer is approximately 1.7, with an RR of 3 if that relative was pre-menopausal, 1.5 if post-menopausal, and 5 if the relative had bilateral breast cancer.1 Hereditary breast cancer syndromes account for less than 10% of cases and will be discussed in greater detail below.
A personal history of proliferative breast disease, especially atypical ductal or lobular hyperplasia, or prior breast biopsy for benign disease variably increases risk two- to five-fold. A personal history of invasive breast cancer increases annual risk by 1%.1-3 A prolonged cumulative exposure to endogenous estrogens accounts for the increased risk in women with early menarche, late menopause, nulliparity, and late first pregnancy.4 Multiparity, early first pregnancy, and lactation may modestly decrease risk, likely reflecting periods of estrogen suppression.4,5 Radiation to the chest wall for Hodgkin's disease before the age of 20-25 years markedly increases the risk of breast cancer and has important screening implications.6 Breast cancer is the most common solid tumor complicating thoracic radiotherapy for Hodgkin's disease, affecting 35% of women by 40 years of age.7 Obesity may elevate risk by 50% in post-menopausal women by altering endogenous estrogen production.4,5 Conversely, a lower body mass index, weight loss, and moderate exercise are believed to decrease risk modestly.8-10 Dietary factors such as excess alcohol ingestion (> 1 beverage daily), red meat consumption, and low intake of fresh fruits and vegetables have been variably demonstrated to increase risk to a modest degree.1,4,11,12 Recently, data on the protective effect of vitamin D against breast neoplasia have been reported, with a risk reduction of 50% in patients with plasma vitamin D levels > 50 ng/dL compared to levels < 13 ng/dL.13 Although further research is ongoing, proposed anti-cancer mechanisms of vitamin D include inhibition of cell proliferation, induction of apoptosis and differentiation, and decreased formation of tumoral blood vessels (angiogenesis).14 Increased mammographic density of breast tissue also has been shown to increase risk of interval breast cancers, possibly by making mammographic detection more difficult.15
Estrogen plays a central and complex role in breast carcinogenesis, resulting in tumor initiation and progression not only due to the parent estrogen, but also to genotoxic metabolites.4 Exogenous estrogen compounds have been utilized for years for a variety of indications including birth control, alleviation of post-menopausal symptoms, and prevention of cardiovascular disease and osteoporosis. Increasing levels of plasma estrogen have been associated with an increased risk of breast cancer in various epidemiologic studies.1 However, usage of estrogen therapy declined substantially following publication of the Women's Health Initiative (WHI) study. This study consisted of 16,000 healthy women and demonstrated that hormone replacement therapy (HRT) with pharmaceutical doses of estrogen and progesterone increased the risk of invasive breast carcinoma by 26% compared to placebo.16 Additionally, the WHI revealed an increased risk of stroke, cardiovascular disease, and venous thrombosis. Estrogen-only preparations, however, were associated with a decreased relative risk of breast cancer in the WHI. As a result of these data, HRT use has declined substantially in the United States.17 Although consumption of early formulations (pre-1975) of higher-dose estrogen-containing oral contraceptive pills (OCPs) has been associated with increased breast cancer risk,18 newer formulations are not associated with a significantly increased risk of breast cancer.19
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Several genetic syndromes, most commonly involving mutations of the breast cancer (BRCA) genes 1 and 2, are associated with a marked elevation in breast cancer risk. Although defined genetic syndromes account for only 5-10% of all breast cancers, the young age at presentation, lifelong risk, and often dramatic presentation make it important for all primary care physicians to have a basic understanding of these disorders. (See Table 2.) The BRCA 1 and BRCA 2 genes are tumor suppressor genes located on chromosomes 17 and 13, respectively. Approximately 2% of asymptomatic Ashkenazi Jewish women and 12% of those with breast cancer carry a mutation of BRCA 1 or BRCA 2.20 The presence of a mutation involving BRCA 1 or 2 increases a woman's lifetime risk of breast cancer to approximately 56-85%; the risk of ovarian cancer is significantly increased as well, though to a lesser degree.21,22 In addition to breast cancer, the presence of a BRCA 2 mutation is associated with an increased risk of melanoma, pancreatic cancer, prostate cancer, and male breast cancer.1 Prophylactic bilateral mastectomy reduces the risk of breast cancer in patients with either BRCA mutation by approximately 90%.23 Prophylactic oophorectomy decreases the risk of ovarian cancer by 95% and breast cancer by 50% if performed prior to 40 years of age.24
Less common causes of genetic breast cancers include mutations in the PTEN, CHEK 2, and ATM genes. Germline mutation of the tumor suppressor gene p53, known as "the guardian of the genome," is associated with the autosomal dominant Li-Fraumeni syndrome, characterized by early-onset breast cancer, often in conjunction with sarcoma, glioma, leukemia, adrenal carcinoma, and other solid tumors.25
Pathogenesis and Histologic Types of Breast Cancer
Initiation and sustained growth of breast cancer cells is multifactorial, dependent not only upon estrogen and estrogenic metabolites, but also catechol metabolites, up-regulation of cell cycle regulator cyclin D1, and the presence of gene mutations such as p53, bcl-2,and c-myc.26 A variety of additional factors stimulate tumor cell growth as well as proliferation of peri-tumoral stroma and endothelial cells, which are important for tumor structural support and blood supply, respectively. The overexpression of the epidermal growth factor receptor HER2/neu, inhibits cell apoptosis and confers a more aggressive phenotype and growth advantage and is present in approximately 20% of breast cancers.27 As will be discussed in a subsequent section, the monoclonal antibody trastuzumab targets the HER2/neu receptor and has revolutionized the treatment of breast cancer. Angiogenesis is a vital component of tumor cell growth, since tumors outgrow their local blood supply and die of hypoxia once a tumor diameter of > 1 mm is reached. Circulating vascular endothelial growth factor (VEGF) is a trophic substance that initiates and sustains endothelial proliferation and migration within various solid neoplasms, including breast cancer.28 The monoclonal antibody bevacizumab targets circulating VEGF and has been effective in treating patients with cancers of the breast, lung, and colon.
The majority of breast cancers (85-90%) originate from ductal epithelium and may progress through a relatively orderly sequence of benign proliferative changes, atypical hyperplasia, ductal carcinoma in situ (DCIS), and, finally, invasive ductal carcinoma. The time course of development of invasive ductal cancer is variable and complex but likely relates to gradual acquisition of "genetic hits" that ultimately result in an aggressive, invasive phenotype. Some of these "hits" include chromosomal loss/gain, cellular damage from genotoxic estrogenic metabolites, loss of tumor suppressor genes, upregulation of HER2/neu, gain-of-function mutations such as c-myc, and loss of cellular apoptosis from bcl-2 expression.29,30 The histologic definition of DCIS is the presence of cancerous ductal epithelium contained within basement membrane, with no evidence of breast parenchymal invasion. The presence of DCIS is a non-obligate precursor to invasive ductal carcinoma, with gain-of-function gene mutations felt to mark the transition from DCIS into an invasive phenotype.30 Calcification of DCIS lesions is common and is responsible for detection of this lesion on screening mammography. However, DCIS occasionally can manifest as a palpable breast lesion or bloody nipple discharge.
Lobular carcinoma in situ (LCIS) is purely a histologic entity without any mammographic abnormalities and is characterized by distention of the lobular breast unit with proliferative epithelium containing bland nuclei. Diagnosis of LCIS most often is made at breast biopsy for another condition in premenopausal women and often is multicentric and bilateral.31 The mere histologic presence of LCIS does not mandate treatment as is the case with DCIS, but rather serves as a marker for an increased risk of future invasive carcinoma. Rosen et al.32 followed a cohort of 84 patients with untreated LCIS who had 24-year follow-up data available and noted the subsequent development of invasive cancer in 29 patients, 9 of which were contralateral and 7 of which were bilateral. The key importance for primary care physicians in regard to LCIS is recognition of the substantial risk of future invasive breast cancer.
Invasive ductal carcinoma accounts for 85-90% and invasive lobular carcinoma for 5-10% of cases of invasive breast cancers. Ductal cancers typically are characterized by irregularly dispersed malignant glandular epithelium within a surrounding desmoplastic stroma. Lobular cancers are characterized by single-filing or "Indian-file" of malignant cells in a linear pattern. Uncommonly encountered histologic types of invasive carcinomas include mucinous, medullary, papillary, tubular, and adenoid cystic carcinomas.31 Breast lymphomas, sarcomas, and metastatic tumors may occur on occasion but will not be discussed further.
Histologic assessment of invasive ductal cancer includes tumor grading by the pathologist according to the degree of tubule formation, nuclear pleomorphism, and number of mitoses. High-grade cancers are associated with a poor prognosis, as is the presence of lymphovascular and neural invasion.1,31 Pathologic assessment of the tumor also includes analysis for the presence of estrogen receptor (ER), progesterone receptor (PR) by immunohistochemical (IHC) staining, and HER2/neu by IHC and/or fluorescent in situ hybridization (FISH). Histologic examination of resected lymph nodes by hematoxylin and eosin staining is routine, but IHC is being studied as a more sensitive and possible predictor of recurrence and metastasis.1
Recently, investigators have identified subclasses of breast cancer cells characterized by CD44 expression and lack of CD24 expression (CD44+/CD24-) that possess a high invasive and metastatic ability when injected into immunodeficient mice.34 This research has resulted in the development of genomic tumoral profiling to identify an invasive 186 gene signature that predicted metastasis-free and overall survival in breast cancer patients.34 Development of a 21-gene assay performed on paraffin-embedded tumor tissue of ER-positive tumors to predict recurrence risk and benefit of adjuvant chemotherapy has gained acceptance into pathologic risk assessment for many patients.35 Extraction of RNA from paraffin-embedded tumor specimens and performance of real-time polymerase chain reaction (PCR) is utilized to identify a variety of genes associated with cell proliferation, invasion, estrogen, and HER2.36 Although a detailed discussion is beyond the scope of this review, higher expression of favorable genes (ER group) predicts a lower risk of recurrence, and higher expression of unfavorable genes (proliferation group, invasion group, and HER2) predicts a higher risk of recurrence. Many oncologists have been applying this genomic test (Oncotype DX®) to assist in determining the benefit of chemotherapy in patients with ER-positive, node-negative breast cancer.37 Other genomic microarray assays, such as Mammaprint®, are available commercially.
Chemoprevention
Prevention of invasive breast cancer in high-risk women is an important facet in providing primary care to patients with a strong family history or multiple risk factors that result in at least a 1.67% risk of breast cancer based on the Gail model, a logistic regression equation that estimates the absolute likelihood that a woman will develop breast cancer over a specific time period. The National Surgical Adjuvant Breast and Bowel Project (NSABP) Breast Cancer Prevention Trial (P-1) randomized 13,388 high-risk women to either 5 years of the first generation selective estrogen receptor modulator (SERM) tamoxifen or to placebo and revealed a 49% reduction of invasive breast cancer at 7 years with tamoxifen 20 mg daily across all analyzed age groups.38 Additionally, tamoxifen decreased the risk of non-invasive breast cancer by 50% and by 56% in patients with a history of LCIS and by 86% in those with a history of atypical hyperplasia.38 The P-1 trial as well as a meta-analysis of tamoxifen for breast cancer prevention showed a decreased risk of breast cancer, but no decline in mortality.38,39 Adverse risks in these reports included a slight increased risk of thromboembolism, hot flushes, vaginal complaints, and stage I endometrial cancer.
Raloxifene (Evista®) is a second-generation SERM with estrogen antagonistic properties similar to tamoxifen but with less agonism on the endometrium. Raloxifene originally was approved for prevention of post-menopausal osteoporosis. The MORE (Multiple Outcomes of Raloxifene Evaluation) study was a randomized trial of raloxifene versus placebo in 7,705 postmenopausal women with osteoporosis that revealed as a secondary endpoint a 72% reduction in the incidence of breast cancer at four years.40 In this trial, the risk of vertebral fracture was reduced by 30% without an increase in cases of endometrial cancer among participants; however, the relative risk of venous thromboembolism was 3.1 compared to placebo.40 Following the MORE study, the CORE trial (Continuing Outcomes Relevant to Evista) was completed to evaluate the efficacy of an additional four years of raloxifene in the prevention of invasive breast cancer. This trial showed a 59% risk reduction in the development of invasive breast cancer from an additional four years of therapy; no new safety concerns were noted.41 Another important prevention study was the NSABP P-2 STAR (Study of Tamoxifen and Raloxifene) trial, which was a prospective, randomized, double blind, multi-institution, North American study consisting of 19,747 postmenopausal women (mean age 59 years) randomized to tamoxifen (20 mg/daily) or raloxifene (60 mg/daily).42 The incidence of invasive breast cancer was identical with both drugs (163 with tamoxifen and 168 with raloxifene, risk ratio 1.02), leading the authors to conclude that raloxifene is an acceptable agent for chemoprevention in higher-risk postmenopausal women.42 Non-invasive breast cancers were not prevented, however, with raloxifene. There were fewer cases of uterine cancer, cataracts, and venous thromboembolism in the raloxifene cohort, but there was no difference between groups with regard to stroke, ischemic cardiac disease, fractures, other cancers, or mortality. Finally, although the aromatase inhibitors (AIs, to be discussed in a subsequent section) have been shown to be effective at preventing events in the adjuvant setting, trials are ongoing to investigate their use in chemoprevention.4
Symptoms and Signs
Although most cases of breast cancer are diagnosed with screening mammography, many women come to medical attention with symptoms or signs of localized or advanced disease discovered on self-examination or by a medical professional. Asymptomatic cancers may be discovered by a palpable lump or fullness in the breast or axilla by self breast examination or by physician examination. A palpable breast mass may represent DCIS or invasive ductal or lobular carcinoma.43 Symptoms and signs of DCIS also may include mastalgia or bloody nipple discharge. Patients with larger tumors may present with skin changes or nipple deformity. Special mention of inflammatory breast cancer (IBC) will be made due to potential misdiagnosis as mastitis, cellulitis, or herpetic zoster. Inflammatory breast cancer is a clinical diagnosis that often presents as rapid-onset breast pain, erythema, and warmth. Physical examination often reveals skin thickening and a finding known as peau d'orange, in which the epidermis resembles the skin of an orange or grapefruit. Pathologically, IBC is characterized by the presence of invasive cancer cells plugging dermal lymphatic vessels.31 Recognition of IBC is vital because aggressive and immediate treatment is necessary due to the rapid progression and poor prognosis of this type of breast cancer. Metastatic breast cancer (MBC) may present with symptoms of headache, bone pain, dyspnea, and abdominal pain in cases of brain, skeletal, lung, and liver involvement, respectively.44 Signs of MBC include focal neurologic deficits, bone tenderness, evidence of pleural effusion (e.g., dullness to percussion), or hepatomegaly.31,34 Rarely, rare paraneoplastic syndromes causing neurologic symptoms (e.g, cerebellar dysfunction) may be the initial manifestation of breast cancer.
Breast Cancer Screening
Screening is defined as detection of subclinical disease in asymptomatic individuals. Although an in-depth review of the pitfalls and controversies regarding cancer screening is beyond the scope of this review, a brief discussion of breast cancer screening and potential risks and benefits will be presented. Many pitfalls to screening asymptomatic populations for disease include imperfections in design, analysis, and interpretation of screening clinical trials, including lead-time and length biases.45,46 For a screening test to be useful to the practicing physician, three requirements should be met: the test must detect cancer earlier than routine methods such as clinical or self-examination; there must be evidence that therapy initiated at an earlier stage of disease will result in improved outcome, typically disease-specific morbidity or mortality; and, there must be evidence of a total health benefit, especially in older patients as it pertains to the issue of disease-specific versus all-cause mortality.47 Fortunately, strong evidence exists for screening mammography at decreasing mortality by 20-35% in patients in the 50-69 year old age group.48 Patients in the 40-50 year old age group have a lower mortality benefit from screening mammography but still enjoy a modest reduction in breast cancer mortality.47,49 Screening mammography generally should begin at age 40 in the average-risk woman, and at approximately age 25 in patients with BRCA mutations, with the goal of detecting cancer before it becomes symptomatic or spreads to axillary lymph nodes.4 The American College of Radiology (ACR) has established that a successful mammography practice should diagnose more than 50% of breast cancers as stage 0 (DCIS) or stage I (< 2 cm tumor with negative lymph nodes).50
Screening mammography consists of two views of both breasts: the craniocaudal view and the medial lateral oblique (MLO) view. While screening mammography possesses an overall favorable track record, it detects only 85-90% of breast cancers.51 A false-negative mammogram usually is defined as a negative mammogram obtained within the year before a histologic diagnosis of breast cancer.4 Many factors affect the sensitivity of screening mammography in an individual woman, most commonly the presence of large amounts of dense fibroglandular tissue.4 Indeed, the sensitivity of screening mammography increases with advancing age due to the increased amount of fatty breast tissue.52 Another factor affecting breast density and mammographic sensitivity is the phase of the menstrual cycle, with sensitivity being highest during the first two weeks (the follicular phase) of the cycle.53 For women with greater than 75% of fibroglandular breast tissue, screening breast magnetic resonance imaging (MRI) should be considered since it is not limited by breast density. Patients with known or suspected BRCA mutations also may benefit from screening MRI, with reported sensitivities of 77-100%.54
Film screen mammography is the most widely used screening modality throughout the country; however, digital mammography is gaining popularity, especially among larger centers. The advantages of digital mammography are yet to be fully elucidated, but this method seems to be more sensitive at cancer detection in women with dense breasts, mainly from the ability to manipulate image contrast during radiologist interpretation, thereby enhancing the visibility of smaller lesions.55 Recently, computer-aided detection (CAD) systems have been approved for screening and diagnostic mammography. The CAD method serves as a "second reader," pointing out suspicious areas for the interpreting radiologist.56 A recent study noted a 7.6% increase in screening mammographic cancer detection with CAD.57 Finally, image interpretation by more experienced radiologists seems to increase sensitivity of screening mammography.58
Although ultrasound is useful for further evaluation of suspicious lesions found on diagnostic mammography, its utility for screening remains to be defined because of high false-positive detection rates and significant inter-operator variability.4 Similarly, screening MRI should be limited to high-risk women such as those with BRCA mutations, very dense breast tissue, or a strong family history of breast cancer.4,25 Although sensitivity of MRI is excellent, the appearance of malignant and benign lesions may overlap. Consequently, specificity is not optimal, especially in patients with a low pre-test probability of breast cancer, such as the average-risk woman.59 In fact, false-positive screening MRI can lead to unnecessary evaluations, biopsies, and undue patient stress and anxiety. Plain film or digital mammography remains the preferred imaging technique for breast cancer screening in the general population.
Diagnostic Imaging
Women with suspicious screening mammograms are called back for diagnostic mammography and, occasionally, ultrasonography of the affected breast. The presence of palpable lesions, skin changes, or nipple discharge also should prompt diagnostic mammography. Views in addition to the craniocaudal and MLO views include magnification and spot compression views to better focus on the abnormality.4 The mammographic abnormality with the highest likelihood of malignancy is a mass lesion with varying degrees of calcification. The presence of a mass lesion harboring calcifications is malignant in 29% of cases.59 Various types of mammographic calcifications exist, but most malignant lesions contain linear, branching, non-uniform, and clustered calcifications.25 Spiculated and pleomorphic calcifications are worrisome for malignancy, DCIS, and invasive cancer, as well. Conversely, benign calcifications often are large, round, and have smooth margins. The presence of a popcorn-like calcification is typical for a benign lesion, most often an involuting fibroadenoma.25,48 Other benign etiologies of breast parenchymal calcification include arteriosclerosis (following a vascular pattern), sclerosing adenosis, traumatic fat necrosis, and previous mastitis. Lobular neoplasia often manifests no mammographic abnormalities.
Diagnostic ultrasonography is a complementary procedure to mammography and is useful for distinguishing a solid mass from a cystic lesion, especially for lesions measuring > 1 cm. Accuracy of ultrasound for diagnosis of a cystic lesion is > 95% and permits simple needle aspiration, which is diagnostic if non-bloody fluid is aspirated.25 The typical appearance of a breast cyst is a well-demarcated circular lesion with a smooth margin, echo-free center, and acoustic shadowing.60 Malignant lesions typically are solid, with varying degrees of increased echogenecity and may reveal increased vascular flow due to hypervascularity.
Diagnostic MRI usually is not indicated in staging most cases of newly diagnosed breast cancer but may aid in more accurate assessment of the breast lesion, chest wall invasion, or axillary node involvement.4,25 Malignant lesions typically reveal rapid gadolinium enhancement and washout, with the converse being typical for benign tumors.44 Contralateral breast cancers were noted in 3.1% of patients in a recent study of women with newly diagnosed breast cancer and no clinical or mammographic evidence of contralateral breast cancer who underwent breast MRI.61 In this study, sensitivity of MRI for the contralateral breast was 91%, specificity 88%, and the negative predictive value was 99%.61 Although MRI is very sensitive and is very accurate at virtually excluding malignancy if negative, limited specificity and no data showing improved overall survival in the typical patient limits its usefulness in most patients.4 Evolving imaging technologies such as positron emission mammography (PEM), a breast-imaging modality similar to PET scan, are being studied to increase breast cancer detection and diagnosis.
Histologic Diagnosis of Breast Cancer
As with all types of cancer, an accurate histologic diagnosis of breast cancer is vital for optimal staging and treatment planning. Core needle biopsy (CNB) is the standard modality for tissue diagnosis and is superior to aspiration cytology, which does not provide tissue architecture, and for differentiation between in situ and invasive cancers. A tru-cut type needle loaded on a gun-like device easily can obtain tissue via ultrasonographic, stereotactic, or MRI localization.62 A vacuum device typically is utilized for securing a core biopsy from a non-palpable or deep lesion. Concordance of CNB with surgical specimens was 97% in one study with use of a large-bore needle.25 Similarly, false-negative rates of CNB have been reported as low as 2%.63 Another biopsy technique reserved for non-palpable mammographic lesions and for patients who cannot undergo or tolerate needle biopsy is wire-localized excisional biopsy performed under mammographic guidance. Success of this technique is dependent upon accurate deployment of the wire or needle, ensuring it is placed into the area to be excised. After resection, mammographic imaging of the specimen is performed to ensure that the tissue contains all of the lesion and/or suspicious calcifications.25 As noted above, the biopsy specimen should be examined by an experienced pathologist; approximately 85% of cases are of ductal origin. Determination of tumor grade (e.g., well, moderately, or poorly differentiated) has important treatment and prognostic implications.1,2,4,25 Assessment for the expression of ER and PR receptors as well as HER2/neu is vital for preoperative treatment planning, especially if preoperative chemotherapy or hormone therapy (e.g., neoadjuvant treatment) is planned.
Staging Evaluation
Accurate staging is vital for providing optimal treatment recommendations and prognostic information. Tumor size and presence of lymph node metastasis are well-established predictors of overall survival in breast cancer patients. Indeed, survival is inversely proportional to tumor size and the number of lymph nodes involved by tumor.64 Staging evaluation can be divided into preoperative, or clinical staging, and post-operative staging based on pathologic assessment of surgical specimens.1,4,25 Although an in-depth discussion on staging techniques is beyond the scope of this review and typically not in the purview of primary care medicine, some salient features will be discussed. The tumor (T), node (N), metastasis (M), or TNM staging system established by the American Joint Committee on Cancer (AJCC), is the most widely adopted staging system for breast cancer and most other solid tumors (Table 3).25 Basic clinical staging of breast cancer relies on physical examination and imaging modalities to determine approximate breast cancer size, number of involved axillary lymph nodes, and presence of systemic metastases. Following surgical resection, more accurate assessment of tumor size and exact number of positive lymph nodes, if axillary dissection is performed, can be determined and forms the platform for the therapeutic prescription by the medical oncologist.
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Although a scrutinous staging evaluation is performed by the medical oncologist or surgeon, the primary care provider should have a basic understanding of breast cancer stages in order to appreciate indications for therapy and to facilitate discussion with subspecialists and patients about their general care. Basic clinical staging includes assessment of tumor size by physical examination and imaging procedures: T1 lesions are < 2 cm in greatest dimension; T2 lesions are > 2 cm but < 5 cm in greatest dimension; T3 tumors are > 5 cm in greatest dimension; and T4 tumors involve the chest wall and/or skin.1 Defining a definitive T stage relies upon accurate pathologic measurement of the resected specimen and is important since increased T stage is inversely proportional to disease-free and overall survival.25 Similarly, nodal staging is more accurately assessed on surgical specimens, where the pathologist can determine the total number of positive lymph nodes removed at axillary dissection, if performed: N1 and N2 status are defined by the presence of metastasis in 1-3 and 4-9 axillary nodes, respectively. The presence of N3 disease signifies metastasis in > 10 nodes or infra- or supraclavicular lymph nodes. Preoperative axillary staging includes a thorough examination of the axillary and clavicular nodal basins. A simple nodal staging approach for the primary care physician is as follows: N1 involvement is characterized by movable ipsilateral axillary nodes; N2 by fixed or matted ipsilateral axillary nodes; and N3 by palpable adenopathy within ipsilateral supra- or infraclavicular nodes.1 The absence of metastasis is designated M0, and any distant metastasis is designated M1. Table 3 displays a simplified version of the TNM system for breast cancer.
Extensive preoperative or postoperative staging to assess for distant metastasis generally is not indicated for localized disease, especially when the primary tumor is < 2 cm and there is no evidence of lymph node metastasis. Basic chemistry studies and a complete blood count are reasonable in patients with stage I and II disease, especially in the absence of lymph node involvement, as yield for extensive imaging and tumor marker studies is very low and not cost-effective.1,65 Exceptions may include those tumors with triple-negative marker studies, high-grade histology, and/or lymphovascular and perineural invasion by cancer cells. With large tumors (> 5 cm) and N2 or N3 disease, the risk of distant metastasis increases. Reasonable staging in this patient population includes chest imaging and directed imaging studies in cases of liver function abnormalities (computed tomography of the liver and abdomen), headache or neurologic findings (MRI of the brain), and bone pain (technetium bone scanning). Similarly, routine use of positron emission tomography (PET) 18-fluorodeoxyglucose (FDG) scans for staging of asymptomatic, low-stage patients is not suggested, and is utilized if conventional imaging is equivocal in symptomatic patients. If imaging suggests possible metastatic disease that would change treatment aim from potential cure to palliation, biopsy of suspected metastatic sites should be considered. Breast cancer tumor markers such as CA 27-29 are not diagnostic of breast cancer, and normal values should not preclude histologic diagnosis. Measurement of these markers primarily is utilized in following response to therapy in the metastatic setting, although their use is not without controversy and is not recommended in the absence of symptoms.1
Lymph node status with regard to the presence or absence of metastatic disease is a powerful prognostic factor in patients with breast cancer.66,67 Accurate determination of nodal involvement and assessment of the total number of positive nodes is a vital aspect of accurate staging.68 Historically, axillary lymph node dissection (ALND) was the diagnostic modality of choice but often left patients with significant morbidity, including chronic lymphedema, pain, and functional impairment of the upper extremity due to damage of lymphatics, nerves, and soft tissue, respectively. Unfortunately, these complications often occurred in patients without histologic evidence of axillary metastasis.
To decrease the morbidity of ALND, the sentinel lymph node biopsy (SLNB) technique has evolved to decrease unnecessary ALND procedures in those patients who would not derive benefit.69 Although patients with palpable or radiographic evidence of axillary lymphadenopathy generally should undergo ALND at the time of surgery, those patients with a clinically negative axilla benefit most from avoidance of unnecessary dissection. Briefly, the rationale behind SLNB pertains to the pattern of lymphatic drainage and is based upon the expected step-wise lymphatic flow pattern within the three Berg node levels. The first nodes to receive breast lymph flow within the Berg level I nodal basin are known as the sentinel nodes. These nodes form the basis of the SLNB procedure in which isosulfan blue dye is injected around the nipple, dermal, or peri-tumoral area and observed for the appearance of blue dye staining the nodes though a small axillary incision.70 Identification of the sentinel node with blue dye is possible in up to 93% of patients, and increased accuracy may be obtained with additional injection of the radioisotope 99Tc sulfur colloid and detection of the node with a handheld intra-operative gamma probe.25,70,71 The sentinel node is resected, and if the touch prep, frozen section, or intraoperative molecular assay shows malignant cells, an immediate ALND typically is performed during the initial surgery. A delayed ALND may be necessary if definitive pathologic assessment reveals metastatic carcinoma. Patients with no histologic evidence of tumor within the sentinel nodes can be spared ALND with its attendant morbidity due to the high sensitivity and specificity of SLNB.72 Although SLNB is not generally indicated in patients with DCIS, if total mastectomy is performed, SLNB is recommended in case an occult invasive malignancy is identified post-operatively, as SLNB requires an intact breast.25
Principles of Breast Cancer Treatment
The goal of this section is to provide primary care providers with a general overview of the sentinel features of multidisciplinary breast cancer management. The field of breast cancer medicine has evolved substantially over the last two decades from radical mastectomy and CMF chemotherapy (cyclophosphamide, methotrexate, florouracil) to breast-conservation surgery, less toxic radiotherapy approaches, and an increased armamentarium of chemotherapeutic, hormonal, and biologic agents. Indeed, tailoring drug therapy to the patient's tumor by targeting not only the ER/PR and HER2/neu receptors, but also by evolving technologies such as DNR microarray studies, holds promise for designing the most effective regimens for each patient and avoiding chemotherapy in cases where it would not be beneficial. Table 4 displays various medical professionals frequently involved with breast cancer patients and the various roles they play during diagnosis, treatment, and follow-up.
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Surgical Management
Surgery is the cornerstone of management for patients with localized breast cancer. Historically, modified radical mastectomy was performed in most patients with stage I or II disease and consisted of removal of the breast and an ALND. This procedure resulted in the overtreatment of many women with the morbidity of chronic lymphedema and its attendant complications such as arm swelling, pain, impaired range of motion, and recurrent cellulitis. However, during the latter part of the 20th century, several authors demonstrated equivalent survival rates for patients undergoing breast conservation surgery (BCS) compared to mastectomy.73,74 The technique of BCS entails lumpectomy followed by whole breast radiation therapy (WBRT). With regard to DCIS, a breast-conserving approach is indicated in most women, except in cases of diffuse breast involvement or patient preference. Veronisi et al.74 demonstrated identical breast cancer death rates at 20-year follow-up in 701 women with T1 stage breast cancer randomized to mastectomy versus BCS who received adjuvant CMF chemotherapy (24.3% vs 26.1%). Fisher et al.73 reported a randomized trial of 1851 women with localized disease who underwent lumpectomy with or without radiation versus total mastectomy and noted a marked reduction in local recurrence rates in lumpectomy patients who received adjuvant radiotherapy (14.3% vs 39.2%, p < 0.001). There were no differences, however, among the three cohorts with regard to overall survival, demonstrating therapeutic equivalence of BCS compared to mastectomy in patients with non-locally advanced breast cancer.73 Additionally, Fisher et al.75 compared 1079 women treated with radical mastectomy, total mastectomy without ALND but with postoperative radiotherapy, and total mastectomy plus ALND only if the nodes became positive.75 This trial showed no benefit of radical mastectomy compared to the other groups with regard to disease-free and overall survival.75 As a result of these trials and others, the majority of women with localized breast cancer and DCIS currently are treated with BCS and spared the psychologic and physical morbidity of mastectomy procedures. Contraindications to BCS, however, include large tumor-to-breast size ratio, previous chest wall irradiation, active collagen vascular disease with skin involvement, pregnancy, persistently positive surgical resection margins, and diffuse or widespread mammographic calcifications.65
Patients with large tumors (> 5 cm) and/or easily palpable axillary adenopathy are considered to have locally advanced breast cancer (LABC) and typically are not considered optimal candidates for BCS due to difficulty in obtaining adequate margins and preserving cosmesis.1,4 Patients with LABC are at significant risk for local as well as distant recurrence, and mastectomy has been the historical standard approach in this patient group. However, administration of pre-operative, or neoadjuvant, chemotherapy may result in tumor and/or nodal downstaging, thereby permitting an adequate oncologic BCS procedure.1,4,25,65 If axillary staging by clinical examination, ultrasound-guided needle biopsy, or SLNB is positive pre-chemotherapy, then an ALND should be performed at surgery; if not performed pre-operatively, then ALND should be considered at surgery for adequate axillary management. Randomized trials have not demonstrated any survival difference in women with LABC who received pre-operative or post-operative chemotherapy.1,44 Patients with inflammatory breast cancer are best treated with pre-operative chemotherapy, mastectomy, and post-operative radiation, as BCS results in an unacceptably high rate of local recurrence.25,76
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Although breast cancer may not be the most common cancer in women, the diagnosis or even the suspicion is a cause of great distress. Primary care physicians play a pivotal role in their female patients' care by providing the proper risk assessment, encouraging women to get the regular screening, and providing patients with the appropriate referral to definitive treatment.Subscribe Now for Access
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