Department of Medicine JOURNAL CLUB Dr. Awadhesh Kr. Sharma
Peroxisome Proliferator Activated Receptor Gamma Agonists : Their Role as Vasoprotective Agents in Diabetes
Florian Blaschke, MD, Evren MD, Willa A, MD
Airway smooth muscle as a Target for Asthma therapy
Julian Solway, M.D. and Charles G. Irvin, Ph.D.
The evolving role of MRI in the detection and evaluation of breast cancer
Robert A, Smith Ph.D.
Peroxisome Proliferator Activated Receptor Gamma Agonists : Their Role as Vasoprotective Agents in Diabetes Florian Blaschke, MD, Evren MD, Willa A, MD Department of Endocrinology, University of California The incidence of type 2 diabetes is increasing dramatically in Western industrialized societies because of increasing obesity, sedentary lifestyles and an aging population. Diabetes mellitus is associated with an increased risk of developing atherosclerotic vascular disorders (including coronary, cerebrovascular, and peripheral artery disease) and cardiovascular disease accounts for upto 80% of premature excess mortality in diabetic patients. Consequently, both type 1 and type 2 diabetes are considered a coronary artery disease (CAD) risk equivalent.
Metabolic syndrome, a constellation of metabolic alterations associated with obesity, sedentary lifestyle, and ethnic background, is a major risk factor for subsequent development of type 2 diabetes and CAD, and is defined by the National Cholesterol Education Program Adult Treatment Panel III as three or more of the following five conditions:
Fasting hyperglycemia ( 110 mg/dl)
Hypertension ( 130/85 mmHg)
Hypertriglyceridemia ( 150 mg/dl)
Reduced high density lipoprotein (HDL : men< 40 mg/dl, women < 50 mg/dl)
Increased waist circumference (men > 102 cm : women > 88 cm)
Insulin resistance, defined as a defect in the ability of insulin to derive glucose into its major target tissue, skeletal muscle, is usually a component of the metabolic syndrome. It is key factor in the pathogenesis of type 2 diabetes and a cofactor in the development of dyslipidemia, hypertension, and atherosclerosis. Insulin resistance is present in more than 90% of people with type 2 diabetes and predates the development of hyperglycemia by many years. Other components of the metabolic syndrome (ie, hypertension, hypertriglyceridemia, and decreased HDL) are themselves CAD risk factors and hyperglycemia further contributes to vascular damage. Whether or not hyperinsulinemia and insulin resistance directly contribute to vascular damage is controversial and under active investigation.
The pathogenesis of CAD in diabetes is multifactorial. Metabolic changes, oxidative stress and glycoxidation, endothelial dysfunction, inflammation, and a diabetes associated prothrombotic state all play a role in the cardiovascular complications of diabetes. For example, current evidence suggests a pivotal role for inflammation in all phases of atherosclerosis, from the formation of fatty streaks to subsequent rupture of the lesions and acute coronary syndromes. This concept is supported by epidemiological and clinical studies where systemic inflammatory markers such as C–reactive protein (CRP), interleukin-6 (IL-6), and serum amyloid A, have been shown to be strong predictors of cardiovascular complications in various settings. In addition to the potential use of inflammatory biomarkers as risk predictors for cardiovascular events, they might serve as targets for pharmacologic therapy.
Diabetes mellitus is also associated with poor outcomes after vascular occlusion, compared with the nondiabetic population. Plaque composition is known to determine the risk of plaque disruption and thrombosis, which is the main cause of acute coronary syndrome. Plaques prone to rupture are characterized by decreased collagen and vascular smooth muscle cells (VSMCs) in their cap and shoulder regions, and a rich inflammatory infiltrate. Atherosclerotic lesions of type 2 diabetic patients reveal greater macrophage infiltration, larger lipid cores and decreased VSMC content than lesions from non diabetic patients. Thus, type 2 diabetes is associated not only with accelerated and premature coronary atherosclerosis, but also with an increased vulnerability for plaque rupture and thrombosis.
The United Kingdom Prospective Diabetes Study demonstrated that intensive blood glucose control with insulin or sulfonylurea in type 2 diabetic subjects had only a limited effect on the incidence of cardiovascular events indicating the necessity of new treatment strategies to reduce cardiovascular morbidity and mortality associated with this syndrome. Thiazolidinediones and peroxisome proliferator activated receptors Thiazolidinediones (TZDs), a class of insulin sensitizing agents that act as ligands for the nuclear receptor peroxisome proliferator activated receptor gamma (PPAR- ), are used frequently in the treatment of patients who have type 2 diabetes. These drugs reduce peripheral insulin resistance, characteristically found in type 2 diabetic patients, by increasing insulin dependent glucose disposal and reducing hepatic glucose output.
The first clinically used TZD, Troglitazone was withdrawn from the market because of rare, but serious hepatotoxicity. Rosiglitazone and pioglitazone, the two TZDs currently available are not associated with any hepatotoxicity and are used widely for treatment of type 2 diabetes. In addition to their effects on carbohydrate metabolism, TZDs have beneficial effects on plasma lipids. Both pioglitazone and rosiglitazone increase serum levels of HDL and pioglitazone also markedly reduces plasma triglyceride levels. In addition in numerous studies, TZDs and non TZD PPAR- ligands have been found to attenuate atherosclerotic lesion formation in animal models and reduce inflammatory gene expression in vascular cells in vitro.
Role of peroxisome proliferator activated receptor gamma in adipose tissue Adipose tissue is an endocrine organ that releases proinflammatory factors that promote vascular damage and atherosclerosis. Tumor necrosis factor alpha (TNF- ) inhibits insulin signaling, thereby contributing to insulin resistance and activates multiple proinflammatory pathways. Leptin, produced by adipose tissue, can alter insulin action and has been recognized recently to be an important mediator of obesity related hypertension. In contrast, visceral adipose tissue increases are associated with decreased plasma adiponectin, a protein recently shown to have significant antidiabetic and anti-atherogenic functions. Taken together, these observations indicate that the adipocyte plays a central role in the relationship between obesity, diabetes and CAD.
PPAR- , the molecular target of the TZD ligands, is expressed at high levels in adipose tissue, and is a central regulator of adipocyte gene expression and differentiation. Retroviral mediated expression of PPAR- stimulated adipose differentiation of cultured fibroblasts and several studies have demonstrated that PPAR- expression is necessary and sufficient to promote adipocyte cell differentiation in vivo and in vitro. Although the mechanisms underlying the insulin sensitizing effects of TZDs are complex and not understood completely, adipose tissue is known to be an important target of TZDs. Activation of PPAR- in insulin resistant animals or humans results in an increase in the sensitivity of the liver to insulin mediated suppression of hepatic glucose production and the skeletal muscle to insulin mediated glucose uptake. These in vivo effects on insulin signaling are caused by the combined actions of PPAR- ligands on adipose tissue, liver and skeletal muscle.
PPAR- ligands profoundly alter gene expression in adipose tissue. Resistin and TNF- expression, both of which induce insulin resistance, are reduced by PPAR- ligands, suggesting that the insulin sensitizing effects of PPAR- agonists are related to their anti-inflammatory properties. In addition, expression and secretion of adiponectin, a protein produced exclusively by the adipocyte, is increased by PPAR- agonists both in vivo and in vitro. Altering pro and anti-inflammatory protein secretion from adipose tissue thus appears to be an important mechanisms whereby TZDs improve insulin sensitivity in distant organs, and exert vasoprotective effects. These data suggest that adipose tissue may be the primary target of PPAR- ligands, resulting in improved insulin sensitivity in liver and muscle.
However, in recent studies, PPAR- ligands were found to improve insulin sensitivity in several different mouse models lacking adipose tissue, indicating a beneficial effect outside the adipose tissue. Consistent with these observations, mice deficient in skeletal muscle or liver PPAR- expression have severe whole body insulin resistance. Hevener and colleagues postulated that selective deletion of PPAR- in skeletal muscle caused insulin resistance in muscle, followed by impaired insulin action in adipose tissue and liver. In contrast, Norris and colleagues found that in mice with muscle specific deletion of PPAR- , insulin sensitivity in skeletal muscle was normal, but was impaired in the liver. Many of the differences in the mouse studies may depend on strain differences.
Role of peroxisome proliferator activated receptor gamma in inflammation and atherosclerosis In addition to adipose tissue, liver and skeletal muscle, PPAR- is expressed in VSMCs, endothelial cells, macrophages and T cells, where it plays an important role in regulating inflammatory responses. PPAR- specific ligands inhibit the production of a host of inflammatory cytokines, such as TNF- , IL-1- and IL-6 in monocytes, inducible nitric oxide synthtase, endothelin –1 and interferon inducible protein 10 (IP-10) in endothelial cells. Moreover, PPAR- agonists have been shown to decrease the expression of the adhesive, proinflammatory molecule.
In various studies, PPAR- ligands have been shown to decrease atherosclerotic lesion formation in genetically prone mouse models. This effect occurs in insulin sensitive and insulin resistant models with or without diabetes. Female mice demonstrate proportionally less attenuation of atherosclerosis upon PPAR- ligand treatment than male mice, indicating that additional factors such as hormonal status may affect the outcome. PPAR- ligands also inhibited angiotensin II (Ang II) accelerated atherosclerosis in mice without effects on lipid profile, glucose, or blood pressure. The attenuation of Ang II-accelerated artherosclerosis correlated with a downregulation of the proinflammatory transcription factor early growth response gene 1 (Egr-1) and several of its target genes, indicating that inhibition of inflammation plays a crucial role for the antiatherosclerotic effect of PPAR- ligands.
Ang II is known to be a major proatherogenic factor that induces inflammation in the vessel wall and stimulates proliferation and migration of VSMCs and monocytes. Previous studies have shown that PPAR- ligands modulate Ang II signaling both at the receptor level and downstream of the Ang II type 1 receptor (AT(1)-R). PPAR- activators have been found to downregulate AT(1)-R expression in VSMC and block AT(1)-R mediated mitogen activated protein kinase activation, which is crucial for VSMC proliferation and migration.
Results from the first TZD cardiovascular outcome trial, Prospective Pioglitazone Clinical Trial in Macrovascular Events (PROactive), were published recently. In this prospective double blind, randomized placebo-controlled, secondary prevention study, pioglitazone treatment was found to reduce the composite of all cause mortality, nonfatal myocardial infarction, and stroke in type 2 diabetic subjects. Clinical trials examining shorter term surrogate end points for atherosclerosis have revealed that TZD treatment improves measures of carotid intimal medial thickness. TZDs may also improve endothelial reactivity. The author’s group recently demonstrated that rosiglitazone treatment improved positron emission tomography assessed myocardial blood flow responses test, which is largely endothelial dependent.
In addition, various studies have shown that treatment of subjects with type 2 diabetes with TZDs reduced inflammatory surrogate parameters of atherosclerosis, such as CRP, TNF- serum amyloid A and plasminogen activator inhibitor type 1 (PAI-1), while increasing adiponectin. Although these effects where observed as early as 2 weeks after treatment. TZDs exhibit maximal glucose lowering effects 8 to 12 weeks after treatment. Sato and colleagues observed that pioglitazone treatment reduced CRP levels in both responders and nonresponders with respect to its antidiabetic effect. These findings suggest that the effect of TZDs on the biomarkers of cardiovascular risk may be independent of their antidiabetic actions. Previous data indicate that throughout the spectrum of insulin resistance from the metabolic syndrome to type 2 diabetes PAI-1 levels are increased.
Because PAI-1 promotes clot formation in plasma and various studies have demonstrated an association between circulating PAI-1 levels and cardiovascular events, a TZD mediated decrease in PAI-1 might play an important role in reducing the incidence of CAD and its complications in this population. Role of peroxisome proliferator activated receptor gamma in restenosis VSMC activation, migration and proliferation not only play decisive roles in the development of atherosclerosis, but are also the primary pathophysiologic mechanism for the failure of procedures used to treat occlusive proliferative atherosclerotic diseases, such as postangioplasty restenosis, transplant vasculopathy, and vein bypass graft failure.
Patients who have diabetes are at increased risk not only for the development of CAD, but also have an elevated risk of developing postangioplasty restenosis compared with individuals who do not have diabetes. In response to vascular injury endothelial cells. VSMCs and macrophages secrete cytokines and growth factors that perpetuate the vasculoproliferative response. PPAR- ligands have been shown to inhibit proliferation and migration of VSMCs in vivo. The antiproliferative activity of PPAR- ligands appears to result from their ability to inhibit retinoblastoma protein (Rb) phosphorylation by modulating the expression of several key cell cycle regulators that control G 1 S phase progression. Inhibition of VSMC growth and migration by PPAR- ligands in vitro turns into an in vivo alteration of neointima formation.
In animal models of restenosis, TZDs have been shown to inhibit intimal hyperplasia after mechanical injury in both insulin sensitive and insulin resistant animals. Moreover, early clinical trials of subjects with type 2 diabetes have demonstrated that both pioglitazone and rosiglitazone have a potent inhibitory effect of neointimal tissue formation after coronary stent implantation. Summary Obesity and diabetes mellitus, significant risk factors for the development of CAD, are becoming a global epidemic. Currently, CAD is the leading cause of death. Despite significant improvements in the management of diabetes, type 2 diabetes mellitus remains a risk equivalent for CAD. A type 2 diabetic patients has the same risk of a future cardiovascular event as a nondiabetic individual who has had a prior myocardial infarction.
New treatment strategies are needed urgently to reduce diabetes associated cardiovascular morbidity and mortality. TZDs have demonstrated some cardiovascular benefits in early trials, and theoretically may improve cardiovascular disease risk through several mechanisms. PPAR- ligands have been shown to attenuate inflammatory responses, which have been shown to be associated with both insulin resistance and atherosclerosis. Inhibition of VSMC proliferation and migration, fundamental processes involved in atherosclerosis and restenosis, may contribute further to the potential cardiovascular benefit of these ligands. Although current TZD PPAR- ligands may have significant potential benefits in the treatment of type 2 diabetes, these must be offset against potentially serious side effects. In clinical trials, both pioglitazone and rosiglitazone have been associated with fluid retention, hemodilution, weight gain, and congestive heart failure (CHF).
The observed, normally modest weight gain is explained by fluid retention, increased adipogenesis and a net flux of fatty acids into adipose tissue. However, these side effects were more apparent when TZDs were used in combination with insulin, and appeared to correlated with drug dosage. For example, rosiglitazone (4 to 8 mg/d) added to insulin therapy resulted in CHF rates of 2% and 3% respectively compared with a rate of 1% in the group treated with insulin alone. Thus, according to American Heart Association and American Diabetes Association guidelines, TZDs should not be used in patients who have NHYA class III and IV CHF. Another potential concern is the possibility that TZDs may promote tumorigenesis or tumor growth, because PPAR- ligands have been shown to increase the frequency and size of colon tumors in mice. However, PPAR- agonists have also been shown to cause a significant reduction in the growth of human cancer cell lines.
Extrapolation of the evidence of carcinogenesis from rodents to humans is an uncertain process, and further studies are necessary. The vascular effects of TZDs and their beneficial activity against multiple proinflammatory and prothrombotic factors provide a compelling rationale for conducting cardiovascular outcomes trials with these oral antidiabetic agents. In clinical studies, TZD treatment has been found to decrease carotid intimal medial wall thickness in type 2 diabetic subjects at 3 and 6 month end points. In addition, clinical trials have shown that after coronary stent implantation, type 2 diabetics who received TZDs had a significant reduction in restenosis, compared with a control group who received equal glucose lowering therapy with other agents. Results from the first TZD cardiovascular outcome trial.
Proactive, demonstrated that pioglitazone reduced the risk of all cause mortality myocardial infarction (excluding silent myocardial infarction), and stroke in subjects with type 2 diabetes. The cardiovascular outcomes trials RECORD (Rosiglitazone Evaluation for Cardiac Outcomes and Regulation of Glycemia in Diabetes) and BARI-2D (Bypass Angioplasty Revascularization Investigation in Type 2 Diabetes), using rosiglitazone, will help to determine whether the vascular and metabolic effects of PPAR- ligands can protect persons with type 2 diabetes from the increased artherothrombolic risk associated with that disease.
Airway smooth muscle as a Target for Asthma therapy Julian Solway, M.D. and Charles G. Irvin, Ph.D. Department of Medicine, University of Chicago The precise role of airway smooth muscle in the pathogenesis of asthma remains uncertain. The contraction of airway smooth muscle certainly causes acute narrowing of the airway and airflow obstruction in asthma, and smooth muscle mass in increased in asthmatic airways.
However, whether airway smooth muscle generates sufficient force in vivo to account for the excessive airway obstruction that characterizes asthma is unknown. Abnormalities in the dynamics of contraction in the capacity of smooth muscle to maintain shortening in the face of load fluctuations imposed by tidal breathing or in the capacity to relax represent other important mechanisms by which airway smooth muscle might contribute to airway narrowing in asthma. Beyond these mechanical effects, airway smooth muscle probably contributes to inflammation of the airway by secreting cytokines, modifying the tissue matrix, binding migratory inflammatory cells or all three. Whatever its role in asthma may be, it seems clear that airway smooth muscle could not contribute to asthma pathogenesis if it were absent.
In this issue of the Journal, Cox and colleagues report a clinical benefit of a novel approach to asthma therapy – bronchial thermoplasty. In this procedure, during three separate treatment visits, radiofrequency current is applied to the walls of the central airways through a brochoscopically placed probe. Studies in animals and humans have shown that such treatment reduces the airway smooth muscle mass but causes epithelial damage that resolves over time. In patients with moderately severe asthma, bronchial thermoplasty reduced airway responsiveness to an inhaled constrictor and modestly increased flow rates – effects that persisted for at least a year.
The study by Cox and colleagues extends those findings by showing improvements in symptoms and quality of life and by reducing the use of rescue medication in subjects with moderate or severe asthma during periods when long acting 2 -adrenergic agonists were withdrawn. That these effects occurred without significant increases in the forced expiratory volume in 1 second or a reduction in airway hyperresponsiveness suggests either that smooth muscle mediated airway constriction beyond the central airways accessible on bronchoscopy is clinically important or that mechanisms independent of airway smooth muscle, such as airway closure, contribute to airflow obstruction in subjects with asthma.
The mechanism underlying the effect of bronchial thermoplasty in asthma has not been fully, established and might include changes other than the loss of airway muscle. For example conceivably, bronchial thermoplasty alters properties of airway epithelium, mucus glands, nerves, or blood vessels or modifies the character of airway inflammation in such a way that asthma related symptoms are reduced as a result of either alterations in airway sensation or a genuine reduction in steady or episodic airway narrowing. What seems certain, however, is that bronchial thermoplasty reduces the smooth muscle mass in the airway wall. This well documented effect, together with the beneficial clinical effects suggested in the report by Cox and colleagues and in previous studies, highlights the potential usefulness of targeting airway smooth muscle in the treatment of asthma.
Indeed, a number of current treatments already, exert some beneficial effects by acting on airway smooth muscle. Inhaled 2 -agonists often relax airway smooth muscle and can enhance the nuclear entry of glucocorticoids, thereby potentiating their anti-inflammatory effect. Glucocorticoids inhibit the proliferation and migration or airway myocytes and suppress their expression of a number of proinflammatory cytokines. Anti-IgE antibody might also modulate the function of airway smooth muscle, since the low affinity IgE receptor is expressed on airway smooth muscle and sensitization with IgE increases its force generation, impairs relaxation, and stimulates cytokine production. Furthermore, exposure to serum from persons with atopy increases the velocity of contraction of human bronchial rings, this increased velocity is thought to enhance the shortening of airway smooth muscle and to confer resistance to the relengthening of the muscle induced by force fluctuations. Perhaps anti-IgE antibody also prevents these phenomena.
Bronchial thermoplasty represents a novel approach to targeting airway smooth muscle, but it ablates airway myocytes only in bronchi 3 mm or larger in diameter, which can be treated directly. For this reason, and because of the considerable effort involved (three separate bronchoscopic procedures, each with a small but significant risk of complications), notable adverse effects (in the short term, at least) and likely expense, bronchial thermoplasty will probably need further refinement if it is to emerge as a widely applicable, practical treatment for moderate or severe asthma. Nonetheless, the results reported by Cox and colleagues suggest that we should now contemplate other approaches to targeting airway smooth muscle that might prove to be less invasive, more practical and more amenable to application throughout the airways.
Among the approaches envisioned is the possibility of ridding the airways of smooth muscle by stimulating apoptosis of airway myocytes. Alternatively, since many of the genes encoding smooth muscle contractile apparatus proteins require a common, relatively muscle specific transcription factor (serum response factor) for transcriptional activation, it might be possible to antagonize the activity of the serum response factor and in that way shut down expression of the contractile apparatus. Depletion of contractile proteins should prevent smooth muscle mediated airway constriction and thus might prevent the occurrence of acute asthma attacks.
Another approach to preventing contraction might be to attack the integrity of contractile filaments (e.g. destroying actin filaments by activating cofilin, an actin binding protein that depolymerizes filamentous actin) or to block the linking of contractile myofilaments to focal adhesions at the cell surface, thereby preventing the transmission of the contractile force generated within each myocyte to the surrounding tissue. Finally, ways might be discovered to magnify the antiobstructive effect of tidal breathing, in which fluctuations in the tidal force transmitted through parenchyma- airway interactions relengthen shortened airway smooth muscle even during continued contractile stimulation. An airway that cannot remain constricted for long cannot cause prolonged airflow obstruction.
In medicine, pioneering approaches have often been replaced by other approaches with similar goals but better means of implementation. Vagotomy, for example, which was performed to reduce acid secretion in peptic ulcer disease, has been replaced by treatment with H 2 receptor antagonists and proton pump inhibitors, which also reduce acid secretion. We expect that bronchial thermoplasty may refined to become more effective and more practically applicable, but we also hope that the lessons it has already taught will prompt the development of other novel approaches that target the contribution of airway smooth muscle to the pathogenesis of asthma.
The evolving role of MRI in the detection and evaluation of breast cancer Robert A, Smith Ph.D. American Cancer Society, Atlanta The age adjusted rate of death from breast cancer in the United States was 24% lower in 2003 than it was in 1989. A decline that has been attributed principally to both the role of mammography in detecting early stage tumors and improvements in therapy. Indeed, early diagnosis and therapy have been the cornerstone of efforts to control breast cancer, since a readily accessible preventive strategy for women with an average risk has been elusive. Prevention is clearly the preferable strategy for controlling cancer, but for the foreseeable future, the control of breast cancer will depend mostly on early detection, careful diagnostic evaluation and therapy.
The introduction and widespread use of mammography for the early detection of breast cancer is one of the most important recent achievements in the control of cancer. Mammography is the study of breast using X-ray. The actual test is called a Mammogram. There are two types of mammograms – a screening mammogram is ordered for women who have no problems with their breasts. It consists of two x-ray views of each breast. A diagnostic mammogram is for evaluation of new woman with breast cancer treated with lumpectomy.
The prognostic value of detecting breast cancer while it is still localized to the breast exceeds what can be achieved with therapy when breast cancer is advanced and over the past decade the trend toward a more favorable stage at diagnosis has played a major role in the reduction of the rate of death due to breast cancer. Although the association is difficult to measure, it is likely that ultrasonography, magnetic resonance imaging (MRI) and digital mammography also improve the outcome when they are used as a substitute for women in whom conventional mammographic screening has not been useful. For example, digital mammography has recently been shown to be a more effective imaging tool in younger women and in women with heterogeneously or extremely dense breasts. It is well established that conventional film mammography does not identify all breast cancer and those other imaging methods can detects tumors that are occult on mammography or can provide more information about findings that were inconclusive with conventional imaging.
Once breast cancer has been detected, the importance of thorough and accurate breast imaging is paramount, because multicentric breast cancer may preclude breast conserving strategies, and the detection of a synchronous, contralateral primary tumor may affect choices regarding surgery and reconstruction. The risk of local recurrence is a dark cloud that hangs over patients with newly diagnosed breast cancer and longer term survivors, despite reassurances that multicentric or multifocal disease that may present, but not visible, can effectively treated by whole breast irradiation and adjuvant therapy. Even with this reassurance, it is likely that most women would prefer the detection of such mammographically invisible lesions so that they could be factored into decision making with regard to treatment. For this reason, a growing proportion of patients with newly diagnosed breast cancer are undergoing further evaluation with MRI.
In this issue of the Journal, Lehman and colleagues report the results of their study of the effectiveness of MRI in the detection of cancer in the contralateral breast after negative clinical and mammographic findings in women with newly diagnosed breast cancer. Among 969 study participants, MRI of the contralateral breast was performed within 60 days after the diagnosis of unilateral breast cancer and within 90 days after clinical and mammographic breast examination. Among 33 patients in whom breast tumors were diagnosed in the contralateral breast during the 12 months follow up period, 30 tumors (invasive tumors in 18 women and ductal carcinoma in situ in 12) were detected by means of MRI. Thus, the additional diagnostic yield of MRI was 3.1% after negative findings on mammographic and clinical breast examination, with 91% sensitivity and 88% specificity.
As Lehman and colleagues note, the very high negative predictive value of MRI can be reassuring to women whose concern about the presence of undetected disease leads them to seek prophylactic mastectomy of the contralateral breast. The authors also note the advantage of treating synchronous cancers simultaneously, thus avoiding another round of therapy at a later time when the tumour in the contralateral breast would be detected by means of conventional imaging or on the basis of symptoms. There may be arguments that the added sensitivity of MRI of the contralateral breast comes at high cost in terms of false positive results and overdiagnosis due to the high rate of detection of ductal carcinoma in situ. Nevertheless, the false positive rate and the predictive value of a positive test are in an acceptable range, and there is little persuasive evidence that most cases of ductal carcinoma in situ are not progressive.
Therefore, there is a value in detecting and treating malignant tumors in the contralateral breast that were not identified by means of mammography and clinical breast examination. The responsible use of MRI for the evaluation of the breast is focused primarily on patients with a high probability of breast cancer, and it includes screening in women who are known or likely carriers of a BRCA1 and BRCA2 mutation. The American College of Radiology’s practice guideline for the performance of breast MRI outlines 12 clinical applications of MRI in the evaluation of breast disease. Coincident with this issue of the Journal, the American Cancer Society is publishing new recommendations for breast cancer screening in women at high risk for breast cancer.
In the 2003 update to its guidelines for breast cancer screening, the American Cancer Society stated that women at increased risk for breast cancer might benefit from the earlier initiation of screening, shorter screening intervals, or the addition of screening methods such as breast ultrasound or MRI. On the basis of newer evidence, as well as requests from clinicians for greater guidance in the use of breast MRI, the guidelines now recommends annual breast cancer screening by means of MRI for women with approximately 20% or greater life time risk of breast cancer, according to risk models that are largely dependent on a strong family history of breast or ovarian cancer. Annual MRI screening is also recommended for women who have undergone radiotherapy to the chest for Hodgkin’s disease.
The updated guideline also states that there is insufficient evidence to make a recommendation for or against MRI screening in women with a personal history of breast cancer, carcinoma in situ, or atypical hyperplasia or in women with extremely dense breasts. This year, the American College of Radiology is likely to initiate a voluntary accreditation program for breast MRI that is similar to its current programs for mammography and breast ultrasonography.