Showing papers in "Breast disease in 1998"

Mammographic densities and breast cancer risk

Abstract: Variations between individuals in the radiographic appearance, or mammographic pattern, of the female breast arise because of differences in the relative amounts and X-ray attenuation characteristics of fat and connective and epithelial tissue. Studies using quantitative methods of assessment have consistently shown these variations to be strongly related to risk of breast cancer. Individuals with extensive areas of radiologically dense breast tissue on the mammogram have been found to have a risk of breast cancer that is four to six times higher than women with little or no density. In this paper, we propose a model for the relationship of mammographic densities to risk of breast cancer. We propose that the risk of breast cancer associated with mammographically dense breast tissue is due to the combined effects of two processes: cell proliferation (mitogenesis), induced by growth factors and sex hormones and influenced by reproductive risk factors for breast cancer; and damage to the DNA of dividing cells (mutagenesis) by mutagens generated by lipid peroxidation. We review the evidence that each of these processes is associated with mammographic densities and propose further work that we believe should be done to clarify these relationships.

Medical applications of diffraction enhanced imaging.

Abstract: We have developed a new X-ray imaging technique, diffraction enhanced imaging (DEI), which can be used to independently visualize the refraction and absorption of an object. The images are almost completely scatter-free, allowing enhanced contrast of objects that develop small angle scattering. The combination of these properties has resulted in images of mammography phantoms and tissues that have dramatically improved contrast over standard imaging techniques. This technique potentially is applicable to mammography and other fields of medical X-ray imaging and to radiology in general, as well as possible use in nondestructive testing and X-ray computed tomography. Images of various tissues and materials are presented to demonstrate the wide applicability of this technique to medical and biological imaging.

Digital breast imaging: tomosynthesis and digital subtraction mammography.

Abstract: Advances in the computer technology and the introduction of new digital imaging detectors offer the potential for digital image acquisition and several new mammography techniques, such as tomosynthesis and digital subtraction mammography. Tomosynthesis is a method of obtaining tomographic images of a breast. In tomosynthesis, any number of tomographic planes may be reconstructed from a set of images obtained as the X-ray source is moved in an arc above the breast. By shifting and adding the information obtained at different source positions, any plane of the breast can be brought into a sharp focus, while structures outside this selected plane are blurred. This may lead to improved lesion detection, especially in dense breast tissue. Thus, tomosynthesis may play a role in improving breast cancer screening and lesion characterization. Digital subtraction mammography is a method of breast angiography. It is performed by obtaining a digital radiographic image before, and one or more digital radiographic images after the injection of a contrast agent such as iodine. The pre- and post-contrast images are subtracted, resulting in an image of the vascular structures in the breast. Because breast cancer lesions have increased vascularity, digital subtraction mammography may play an important role in improving lesion detection, characterizing lesions, monitoring response to therapy, and determining lesion extent. Thus, both of these new digital techniques have the potential to address the major limitation of conventional mammography, namely the difficulty in detecting cancer in radiographically dense breasts.

Perspective on BRCA1.

Abstract: In a very real sense, the search for a breast cancer susceptibility gene reflects the rapid evolution of molecular genetics as a field and the power of molecular technology to accelerate the pace of discovery. This search began with the study of blood proteins through biochemical analysis; the number of loci accessible was limited, and very few consistent results were obtained (1). Then came recombinant DNA technology. The number of available markers, and the information they provide, has grown rapidly over the years. The same is true for the development of new, high-throughput genotyping methods and associated informatics systems and statistical methods, making gene mapping more feasible. For BRCA1, it took five years and 183 markers to identify the chromosomal location as 17q21 (2). It took an additional four years before BRCA1 was cloned (3). In contrast, BRCA2 was localized to chromosome 13q12-13 two months before the cloning of BRCA1 was reported; less than two years later, BRCA2 was cloned (4,5). Characterization of these two genes is still underway, in part, because of unanticipated complexity. This complexity plays out at multiple levels, including the relationship between phenotype and genotype within and between the populations studied, biological function(s), and social consequences. The reviews presented in this issue reflect the breadth of impact that the discovery of the BRCA genes has had on science, medicine, and law. As with most great discoveries, the identification of BRCA1 has forced us to question the fundamentals of our belief systems: what is a mutation, what is a tumor suppressor, what is righteous, and what is ethical?

Yeast-based assays for detection and characterization of mutations in BRCA1.

Abstract: Germ-line mutations in BRCA1 account for the majority of families with breast and ovarian cancer predisposition. BRCA1 encodes a 1,863 amino acid protein with no ascribed function. Due to its size and the fact that mutations are evenly scattered along the sequence, screening for mutations is particularly challenging. Here we review recently published yeast-based assays that may form the basis of an alternative diagnostic test for BRCA1. Although individually limited, these assays may, when combined, become a useful method to screen for cancer predisposing mutations. In any event, the yeast-based assays could complement results from direct sequencing providing functional information about unique mutations.

Genetic testing for the BRCA1 gene and the need for protection from discrimination: an evolving legislative and social issue.

Abstract: Genetic testing for the BRCA1 gene is available commercially and clinically. The information gained from this test impacts not only on the individual tested, but on family members as well. The test can offer an individual and their family the opportunity to gain valuable information about their risks of developing certain forms of inherited breast cancer and other inherited cancers. In addition to its emotional and psychological impact, this information is associated with significant social and economic issues. This includes the potential for denial, loss, or increased rates for health insurance as well as denial and loss of employment based on genetic test information. The risk for such discrimination can lead to fear of seeking testing and can discourage participation in and potential benefit from prevention, screening, and treatment programs. Therefore, misuse of this information carries significant risk for the individual being tested and for their family members. It is imperative that the potential benefits of genetic testing and genetic information be afforded to all without this risk and fear. In addition to protecting all individuals from genetic discrimination, there is a need to protect the confidentiality of genetic information and an individual's right to privacy. This article discusses protection currently available through legislation at the federal and state level, focusing on the experience in North Carolina in developing and passing a genetic antidiscrimination bill. Although progress has been made, troublesome issues still remain.

Perspective from the Department of Defense Breast Cancer Research Program.

Abstract: The Department of Defense (DOD), Breast Cancer Research Program (BCRP) was established in 1993. Since its inception, Congress has appropriated more than 878 million dollars for the BCRP, a unique public-private partnership between the DOD, consumer advocacy, and scientific communities which has funded approximately 1,800 breast cancer research grants. Through this partnership, the BCRP designed a model program for consumer involvement in scientific peer review. This paper describes the BCRP's approach to the processes of recruitment, selection, and preparation of consumers for this expanded role. Further, factors critical to program implementation, such as effective program management, ongoing process improvement, strong program leadership, and allocation of resources, that led to the BCRP's success in developing the previously undefined role of breast cancer survivors as members of scientific peer review panels are discussed. The BCRP demonstrates the feasibility and unique contributions of consumers in scientific peer review and provides a critical foundation for future efforts to ensure consumer involvement in scientific research programs.

Informed Consent for BRCA1 and BRCA2 Testing

Abstract: While the cloning of BRCA1 and BRCA2 in 1994 and 1995 engendered great enthusiasm from cancer patients, their families and physicians, concerns about potential problems faced by those undergoing genetic testing were also evident. Although much can be learned from previous research on informed consent for testing and research for predictive genetic testing in diseases other than cancer, there are some specific issues related to cancer that make the questions more pressing, more difficult, and of larger social concern. Organizations such as the National Advisory Council for Human Genome Research, the American Society for Human Genetics, the American Society of Clinical Oncology and the Task Force for Genetic Testing have presented recommendations about informed consent for cancer susceptibility testing. However, many unanswered questions remain concerning the informed consent process. This review provides background on informed consent, summarizes studies that have been conducted in the area of genetic testing, with a focus on testing for BRCA1 and BRCA2, and details recommendations for achieving informed consent for genetic testing for cancer susceptibility and research on cancer genetics.

Bringing down the barriers to mammography: A review of current research and interventions

Abstract: Although mammography screening is effective in reducing breast cancer mortality, major challenges still remain in increasing rates of initial mammography and in improving subsequent adherence to mammography screening. Behavioral science theories offer insights into the potential for individual, organizational, community, and population-level interventions to address these challenges. In this review, we draw on social ecological approaches to health promotion to suggest a conceptual framework for such interventions. After discussing theories of who is and is not screened regularly, and why, we consider selected barriers to mammography and corresponding interventions to overcome them. We conclude with an illustration of the North Carolina Breast Cancer Screening Program (NC-BCSP), a series of interventions informed by the social ecological perspective.

Rationale for annual screening mammography for women ages 40-49 years.

Abstract: Proof of the benefit for mammographic screening of women ages 40-49 years is now available. Randomized controlled trials (RCTs) conducted in Gothenburg and Malmo, Sweden have shown statistically significant breast cancer mortality reductions of 36% and 45% respectively. A meta-analysis of all five Swedish trials has found a statistically significant mortality reduction of 29% for woman in this age group. Substantially greater reductions in mortality would likely have resulted if women in these trials had been screened annually. Because the benefits are substantial, and the risks from screening are relatively small and acceptable, screening mammography beginning at age 40 is now recommended by the American Cancer Society, as well as the National Cancer Institute.

Development of functional electron paramagnetic resonance imaging.

Abstract: The potential use of electron paramagnetic resonance imaging (EPRI) to obtain physiological information noninvasively is reviewed EPR, a spectroscopic technique similar to nuclear magnetic resonance (NMR), is useful in detecting and characterizing free radical species The ability to obtain information about tissue redox and oxygen status using nontoxic free radical spin probes is presented The capability to encode this information spatially using magnetic field gradients, similar to magnetic resonance imaging (MRI), gives this technique the ability to overlay functional information of tissue with anatomic information The noninvasive and quantitative nature of EPRI makes it a potentially useful technique for obtaining physiological information from tumors The requirements for the magnetic field strengths are approximately 600 times lower than that for proton MRI at an identical frequency, making this a low-cost diagnostic tool

The Potential for Hall Effect Breast Imaging

Abstract: Hall effect imaging is a noninvasive imaging method that combines ultrasound with a strong magnetic field to investigate the electrical properties of tissue. Although technical development is at an early stage, its value for detecting or characterizing pathologies in the breast and other organs is promising. In vitro studies in the past showed that tissue electrical properties are closely related to its physiology and morphology. Hall effect imaging may become a new tool to study these electrical properties in the body and potentially provide unique diagnostic information.

Positron Emission Tomography (PET): an update on applications in breast cancer.

Abstract: Positron Emission Tomography (PET) is an imaging method which detects alterations in tumor physiology and displays them in an anatomically precise manner. Historically, the method has been a research tool, but it is being increasingly applied to clinical imaging problems. PET, using the glucose analog 18-F-fluoro-2-deoxy-D-glucose (FDG), has been applied most widely and shows promise in detecting primary cancers, characterizing breast masses, staging for axillary metastases, evaluating for systemic metastases, and following response to therapy. This review summarizes the current status of this technique, which is in rapid evolution as new tracers and new imaging cameras become available.

Screening mammography for women in their forties.

Abstract: Nonrandomized screening studies and some analyses of randomized data are subject to enormous biases. Many such analyses have the goal of showing that screening mammography is beneficial. They masquerade as science but are extreme examples of lying with statistics. Randomized trials have provided mixed results concerning whether screening reduces breast cancer mortality. Estimates from these trials are subject to a great deal more variability than traditional meta-analyses belie. A blanket recommendation for the screening of women in their forties is inappropriate, and it is a disservice to these women. Regular screening mammography of women in this age group is not an imperative health measure. If it is beneficial, its benefits are limited: taking the results of the randomized trials at face value, regular screening adds about five days in life expectancy per woman. In addition, screening has many significant risks. Those who are most concerned about their health will probably discount the risks and choose regular screening, and reasonably SO, Others will eschew screening, also reasonably SO.

Augmented reality applied to ultrasound-guided breast cyst aspiration.

Abstract: Etta D. Pisano , Henry Fuchs, Andrei State, Mark A. Livingston, Gentaro Hirota, William F. Garrett and Mary C. Whitton a Departments of Radiology, The University of North Carolina { Chapel Hill School of Medicine and College of Arts and Sciences, Chapel Hill, NC, USA b Computers Science, The University of North Carolina { Chapel Hill School of Medicine and College of Arts and Sciences, Chapel Hill, NC, USA

Characterization of Brca1 deficient mice.

Abstract: BRCA1 is a nuclear phosphoprotein that is expressed in a cell cycle regulated manner in virtually all normal dividing cells. Inheritance of a mutated copy of the BRCA1 gene increases a woman's risk for developing breast and ovarian cancer (1-3). Since the tumors that arise in these individuals consistently fail to express the wild-type allele, BRCA1 is believed to encode a tumor suppressor. Loss of the remaining functional BRCA1 allele, therefore, is one of the steps leading to neoplastic transformation of some types of epithelial cells. The isolation of the murine homologue of the human BRCA1 gene opened up the possibility of using a powerful genetic approach to study the role of this gene in both normal development and tumor formation. This genetic approach involves in vitro manipulation of the genome of embryonic stem (ES) cells, stable tissue culture cell lines derived from mouse blastocysts. After introducing mutations into the murine homologue of the BRCA1 gene Brca1 in these cell lines, four groups have generated mouse lines carrying the same mutations (4-7). Surprisingly, mice carrying a single mutant Brca1 allele do not display the increased risk for breast tumors seen in humans carrying similar mutations. However, while loss of BRCA1 appears to be a one of the many events involved in tumorgenesis in humans, these mouse lines demonstrate that gene expression is essential for development; as homozygosity for each of the Brca1 mutations results in postimplantation embryonic lethality. The survival of Brca1 deficient embryos is extended by one or two days in the absence of p53 and p21 (7,8).

BRCA1 in special populations.

Abstract: A restricted number of mutant BRCA1 alleles are present at high frequency in the Ashkenazi Jewish population: 185delAG and 5382insC and, perhaps, 188del11 These mutations have provided a means to re-estimate the penetrance function of an abnormal BRCA1 allele to be in the range of 50-60% for breast cancer, and 8-16% for ovarian cancer Moreover, there was an increased rate of prostate, but not colorectal, cancers in BRCA1 carriers Further studies in the Ashkenazi population may provide one approach to identifying the environmental or genetic cofactors that modify the impact of an abnormal BRCA1 gene

Assessing the benefits of testing for breast cancer susceptibility genes: a decision analysis.

Abstract: Tests for the presence of mutations of genes BRCA1 and BRCA2 are increasingly available. Genetic testing creates dilemmas for women and men who regard themselves to be at high risk for breast cancer. Who will benefit from genetic testing? What is the benefit? Does testing improve quality of life? An important consideration in addressing these questions is the woman's chance of carrying a mutation at BRCA1 or BRCA2. Also important are the effectiveness and cost of the testing procedure, the availability of prophylactic interventions, the effectiveness and negative aspects of interventions, the impact of testing on other family members, and the impact of testing on the woman's ability to obtain insurance coverage. In this article we review the development of a statistical model for predicting whether a woman is a carrier of a BRCA1 or a BRCA2 mutation. We also show how this calculation can be used to assess the benefit of testing, and we quantify the size of the benefit in terms of its improvement on quality-adjusted life years (QALYs).

Gene therapy for breast and ovarian cancer with BRCA1.

Abstract: As an initial step toward gene therapy for ovarian cancer, we conducted a Phase 1 trial to assess the pharmacokinetics and toxicity of intraperitoneal BRCA1sv retroviral vector therapy. Gene transfer and expression were documented by PCR, southern blot, RT-PCR and nuclease protection assays. Pharmacokinetics were assessed by PCR and southern blots detecting vector DNA, and toxicity was evaluated by clinical exam and fluid analysis. Three of twelve patients developed an acute sterile peritonitis which spontaneously resolved within 48 hours. Plasma and peritoneal antibodies to the retroviral envelope protein were detected only in patients treated with the highest dose levels but not in others, despite repeat dosing for an interval of up to four months. Eight patients showed stable disease for 4 to 16 weeks. Three patients showed tumor reduction with diminished miliary tumor implants at reoperation (two patients) and radiographic shrinkage of measurable disease (one patient). Ovarian cancer may provide an imporant model for retroviral gene therapy studies due to vector stability, minimal antibody response, and access to tumor by intraperitoneal therapy.

Screening mammography in an integrated health care system: the Kaiser permanente experience.

Abstract: In this paper, we describe the attributes of a comprehensive approach to breast cancer screening possible in an integrated health care system. We define an integrated health care system as one in which comprehensive preventive and medical care is provided to a defined population, by a defined panel of providers, and in which this care can be tracked using automated electronic data systems. Guided by the Pathways Conceptual Framework, it is possible to identify and systematically address (through research and interventions) the multiple predisposing, enabling, and reinforcing factors at the individual and organizational level associated with each step along the screening process. This framework is helpful as both a planning and an evaluation tool, in identifying places in the screening and follow-up process that could benefit from concerted quality improvement efforts and in guiding an evaluation of those efforts. We describe examples from research and organizational programmatic efforts, and use the framework to point to additional areas for further investigation and potential organizational intervention. These examples use a variety of research methods, impact the breast cancer screening pathway in different places, and therefore show how it is possible to approach the broad issue of reduction of breast cancer mortality from multiple perspectives. Integrated health care systems, unlike more traditional academic settings, are well suited to supporting this full spectrum of research while also providing the context for its application.

New approaches to BRCA1 mutation detection.

Abstract: The development of technologies to identify quickly, efficiently, and inexpensively all possible heterozygous mutations and sequence variants in patient samples will play a crucial role in the future of medical genetics. In addition to the continued refinement of more established mutation detection protocols, several innovative methodologies recently have emerged with the potential to increase sample throughput as well as decrease the cost of mutational analysis. The allelic heterogeneity of BRCA1 mutations serves as an example of the considerable technical challenge in developing diagnostic tests for all possible sequence variants in large genes. We describe recent advances in methologies that have previously been or could be readily adapted for use in BRCA1 mutation detection. Special emphasis is placed on the use of high density oligonucleotide arrays (DNA chips) as tools for detecting sequence variations in BRCA1.

Percutaneous breast biopsy for nonpalpable lesions.

Abstract: Increasingly, biopsies for suspected breast abnormalities are conducted by percutaneous needle extraction of core samples rather than by standard surgical excision or fine-needle aspiration (FNA) of cellular material. Core-needle biopsies are highly accurate and have many advantages over surgical excisions, including reduction of the morbidity and cost of breast disease diagnosis. Limitations include differentiating atypical ductal hyperplasia from ductal carcinoma in situ. Equipment and technique for stereotactic and ultrasound-guided core breast biopsy are discussed. Appropriate indications for core-needle biopsy, excisional biopsy after needle localization, and FNA are provided. Appropriate management after core-needle biopsy includes the establishment of concordance of histologic results with the level of suspicion of the mammographic findings to prevent false-negative core biopsies. A recommendation for return to regular mammographic screening, short-interval (6-month) mammographic follow-up, or repeat core or surgical appearance depends on this correlation.