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Posts Tagged ‘tissue characterisation’


The importance of spatially-localized and quantified image interpretation in cancer management

Writer & reporter: Dror Nir, PhD

I became involved in the development of quantified imaging-based tissue characterization more than a decade ago. From the start, it was clear to me that what clinicians needs will not be answered by just identifying whether a certain organ harbors cancer. If imaging devices are to play a significant role in future medicine, as a complementary source of information to bio-markers and gene sequencing the minimum value expected of them is accurate directing of biopsy needles and treatment tools to the malignant locations in the organ.  Therefore, the design goal of the first Prostate-HistoScanning (“PHS”) version I went into the trouble of characterizing localized volume of tissue at the level of approximately 0.1cc (1x1x1 mm). Thanks to that, the imaging-interpretation overlay of PHS localizes the suspicious lesions with accuracy of 5mm within the prostate gland; Detection, localisation and characterisation of prostate cancer by prostate HistoScanning(™).

I then started a more ambitious research aiming to explore the feasibility of identifying sub-structures within the cancer lesion itself. The preliminary results of this exploration were so promising that it surprised not only the clinicians I was working with but also myself. It seems, that using quality ultrasound, one can find Imaging-Biomarkers that allows differentiation of inside structures of a cancerous lesions. Unfortunately, for everyone involved in this work, including me, this scientific effort was interrupted by financial constrains before reaching maturity.

My short introduction was made to explain why I find the publication below important enough to post and bring to your attention.

I hope for your agreement on the matter.

Quantitative Imaging in Cancer Evolution and Ecology

Robert A. Gatenby, MD, Olya Grove, PhD and Robert J. Gillies, PhD

From the Departments of Radiology and Cancer Imaging and Metabolism, Moffitt Cancer Center, 12902 Magnolia Dr, Tampa, FL 33612. Address correspondence to  R.A.G. (e-mail: Robert.Gatenby@Moffitt.org).

Abstract

Cancer therapy, even when highly targeted, typically fails because of the remarkable capacity of malignant cells to evolve effective adaptations. These evolutionary dynamics are both a cause and a consequence of cancer system heterogeneity at many scales, ranging from genetic properties of individual cells to large-scale imaging features. Tumors of the same organ and cell type can have remarkably diverse appearances in different patients. Furthermore, even within a single tumor, marked variations in imaging features, such as necrosis or contrast enhancement, are common. Similar spatial variations recently have been reported in genetic profiles. Radiologic heterogeneity within tumors is usually governed by variations in blood flow, whereas genetic heterogeneity is typically ascribed to random mutations. However, evolution within tumors, as in all living systems, is subject to Darwinian principles; thus, it is governed by predictable and reproducible interactions between environmental selection forces and cell phenotype (not genotype). This link between regional variations in environmental properties and cellular adaptive strategies may permit clinical imaging to be used to assess and monitor intratumoral evolution in individual patients. This approach is enabled by new methods that extract, report, and analyze quantitative, reproducible, and mineable clinical imaging data. However, most current quantitative metrics lack spatialness, expressing quantitative radiologic features as a single value for a region of interest encompassing the whole tumor. In contrast, spatially explicit image analysis recognizes that tumors are heterogeneous but not well mixed and defines regionally distinct habitats, some of which appear to harbor tumor populations that are more aggressive and less treatable than others. By identifying regional variations in key environmental selection forces and evidence of cellular adaptation, clinical imaging can enable us to define intratumoral Darwinian dynamics before and during therapy. Advances in image analysis will place clinical imaging in an increasingly central role in the development of evolution-based patient-specific cancer therapy.

© RSNA, 2013

 

Introduction

Cancers are heterogeneous across a wide range of temporal and spatial scales. Morphologic heterogeneity between and within cancers is readily apparent in clinical imaging, and subjective descriptors of these differences, such as necrotic, spiculated, and enhancing, are common in the radiology lexicon. In the past several years, radiology research has increasingly focused on quantifying these imaging variations in an effort to understand their clinical and biologic implications (1,2). In parallel, technical advances now permit extensive molecular characterization of tumor cells in individual patients. This has led to increasing emphasis on personalized cancer therapy, in which treatment is based on the presence of specific molecular targets (3). However, recent studies (4,5) have shown that multiple genetic subpopulations coexist within cancers, reflecting extensive intratumoral somatic evolution. This heterogeneity is a clear barrier to therapy based on molecular targets, since the identified targets do not always represent the entire population of tumor cells in a patient (6,7). It is ironic that cancer, a disease extensively and primarily analyzed genetically, is also the most genetically flexible of all diseases and, therefore, least amenable to such an approach.

Genetic variations in tumors are typically ascribed to a mutator phenotype that generates new clones, some of which expand into large populations (8). However, although identification of genotypes is of substantial interest, it is insufficient for complete characterization of tumor dynamics because evolution is governed by the interactions of environmental selection forces with the phenotypic, not genotypic, properties of populations as shown, for example, by evolutionary convergence to identical phenotypes among cave fish even when they are from different species (911). This connection between tissue selection forces and cellular properties has the potential to provide a strong bridge between medical imaging and the cellular and molecular properties of cancers.

We postulate that differences within tumors at different spatial scales (ie, at the radiologic, cellular, and molecular [genetic] levels) are related. Tumor characteristics observable at clinical imaging reflect molecular-, cellular-, and tissue-level dynamics; thus, they may be useful in understanding the underlying evolving biology in individual patients. A challenge is that such mapping across spatial and temporal scales requires not only objective reproducible metrics for imaging features but also a theoretical construct that bridges those scales (Fig 1).

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Figure 1a: Computed tomographic (CT) scan of right upper lobe lung cancer in a 50-year-old woman.

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Figure 1b: Isoattenuation map shows regional heterogeneity at the tissue scale (measured in centimeters).

 cd

Figure 1c & 1d: (c, d)Whole-slide digital images (original magnification, ×3) of a histologic slice of the same tumor at the mesoscopic scale (measured in millimeters) (c) coupled with a masked image of regional morphologic differences showing spatial heterogeneity (d). 

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Figure 1e: Subsegment of the whole slide image shows the microscopic scale (measured in micrometers) (original magnification, ×50).

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Figure 1f: Pattern recognition masked image shows regional heterogeneity. In a, the CT image of non–small cell lung cancer can be analyzed to display gradients of attenuation, which reveals heterogeneous and spatially distinct environments (b). Histologic images in the same patient (c, e) reveal heterogeneities in tissue structure and density on the same scale as seen in the CT images. These images can be analyzed at much higher definition to identify differences in morphologies of individual cells (3), and these analyses reveal clusters of cells with similar morphologic features (d, f). An important goal of radiomics is to bridge radiologic data with cellular and molecular characteristics observed microscopically.

To promote the development and implementation of quantitative imaging methods, protocols, and software tools, the National Cancer Institute has established the Quantitative Imaging Network. One goal of this program is to identify reproducible quantifiable imaging features of tumors that will permit data mining and explicit examination of links between the imaging findings and the underlying molecular and cellular characteristics of the tumors. In the quest for more personalized cancer treatments, these quantitative radiologic features potentially represent nondestructive temporally and spatially variable predictive and prognostic biomarkers that readily can be obtained in each patient before, during, and after therapy.

Quantitative imaging requires computational technologies that can be used to reliably extract mineable data from radiographic images. This feature information can then be correlated with molecular and cellular properties by using bioinformatics methods. Most existing methods are agnostic and focus on statistical descriptions of existing data, without presupposing the existence of specific relationships. Although this is a valid approach, a more profound understanding of quantitative imaging information may be obtained with a theoretical hypothesis-driven framework. Such models use links between observable tumor characteristics and microenvironmental selection factors to make testable predictions about emergent phenotypes. One such theoretical framework is the developing paradigm of cancer as an ecologic and evolutionary process.

For decades, landscape ecologists have studied the effects of heterogeneity in physical features on interactions between populations of organisms and their environments, often by using observation and quantification of images at various scales (1214). We propose that analytic models of this type can easily be applied to radiologic studies of cancer to uncover underlying molecular, cellular, and microenvironmental drivers of tumor behavior and specifically, tumor adaptations and responses to therapy (15).

In this article, we review recent developments in quantitative imaging metrics and discuss how they correlate with underlying genetic data and clinical outcomes. We then introduce the concept of using ecology and evolutionary models for spatially explicit image analysis as an exciting potential avenue of investigation.

 

Quantitative Imaging and Radiomics

In patients with cancer, quantitative measurements are commonly limited to measurement of tumor size with one-dimensional (Response Evaluation Criteria in Solid Tumors [or RECIST]) or two-dimensional (World Health Organization) long-axis measurements (16). These measures do not reflect the complexity of tumor morphology or behavior, and in many cases, changes in these measures are not predictive of therapeutic benefit (17). In contrast, radiomics (18) is a high-throughput process in which a large number of shape, edge, and texture imaging features are extracted, quantified, and stored in databases in an objective, reproducible, and mineable form (Figs 12). Once transformed into a quantitative form, radiologic tumor properties can be linked to underlying genetic alterations (the field is called radiogenomics) (1921) and to medical outcomes (2227). Researchers are currently working to develop both a standardized lexicon to describe tumor features (28,29) and a standard method to convert these descriptors into quantitative mineable data (30,31) (Fig 3).

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Figure 2: Contrast-enhanced CT scans show non–small cell lung cancer (left) and corresponding cluster map (right). Subregions within the tumor are identified by clustering pixels based on the attenuation of pixels and their cumulative standard deviation across the region. While the entire region of interest of the tumor, lacking the spatial information, yields a weighted mean attenuation of 859.5 HU with a large and skewed standard deviation of 243.64 HU, the identified subregions have vastly different statistics. Mean attenuation was 438.9 HU ± 45 in the blue subregion, 210.91 HU ± 79 in the yellow subregion, and 1077.6 HU ± 18 in the red subregion.

 

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Figure 3: Chart shows the five processes in radiomics.

Several recent articles underscore the potential power of feature analysis. After manually extracting more than 100 CT image features, Segal and colleagues found that a subset of 14 features predicted 80% of the gene expression pattern in patients with hepatocellular carcinoma (21). A similar extraction of features from contrast agent–enhanced magnetic resonance (MR) images of glioblastoma was used to predict immunohistochemically identified protein expression patterns (22). Other radiomic features, such as texture, can be used to predict response to therapy in patients with renal cancer (32) and prognosis in those with metastatic colon cancer (33).

These pioneering studies were relatively small because the image analysis was performed manually, and the studies were consequently underpowered. Thus, recent work in radiomics has focused on technical developments that permit automated extraction of image features with the potential for high throughput. Such methods, which rely heavily on novel machine learning algorithms, can more completely cover the range of quantitative features that can describe tumor heterogeneity, such as texture, shape, or margin gradients or, importantly, different environments, or niches, within the tumors.

Generally speaking, texture in a biomedical image is quantified by identifying repeating patterns. Texture analyses fall into two broad categories based on the concepts of first- and second-order spatial statistics. First-order statistics are computed by using individual pixel values, and no relationships between neighboring pixels are assumed or evaluated. Texture analysis methods based on first-order statistics usually involve calculating cumulative statistics of pixel values and their histograms across the region of interest. Second-order statistics, on the other hand, are used to evaluate the likelihood of observing spatially correlated pixels (34). Hence, second-order texture analyses focus on the detection and quantification of nonrandom distributions of pixels throughout the region of interest.

The technical developments that permit second-order texture analysis in tumors by using regional enhancement patterns on dynamic contrast-enhanced MR images were reviewed recently (35). One such technique that is used to measure heterogeneity of contrast enhancement uses the Factor Analysis of Medical Image Sequences (or FAMIS) algorithm, which divides tumors into regions based on their patterns of enhancement (36). Factor Analysis of Medical Image Sequences–based analyses yielded better prognostic information when compared with region of interest–based methods in numerous cancer types (1921,3739), and they were a precursor to the Food and Drug Administration–approved three-time-point method (40). A number of additional promising methods have been developed. Rose and colleagues showed that a structured fractal-based approach to texture analysis improved differentiation between low- and high-grade brain cancers by orders of magnitude (41). Ahmed and colleagues used gray level co-occurrence matrix analyses of dynamic contrast-enhanced images to distinguish benign from malignant breast masses with high diagnostic accuracy (area under the receiver operating characteristic curve, 0.92) (26). Others have shown that Minkowski functional structured methods that convolve images with differently kernelled masks can be used to distinguish subtle differences in contrast enhancement patterns and can enable significant differentiation between treatment groups (42).

It is not surprising that analyses of heterogeneity in enhancement patterns can improve diagnosis and prognosis, as this heterogeneity is fundamentally based on perfusion deficits, which generate significant microenvironmental selection pressures. However, texture analysis is not limited to enhancement patterns. For example, measures of heterogeneity in diffusion-weighted MR images can reveal differences in cellular density in tumors, which can be matched to histologic findings (43). Measures of heterogeneity in T1- and T2-weighted images can be used to distinguish benign from malignant soft-tissue masses (23). CT-based texture features have been shown to be highly significant independent predictors of survival in patients with non–small cell lung cancer (24).

Texture analyses can also be applied to positron emission tomographic (PET) data, where they can provide information about metabolic heterogeneity (25,26). In a recent study, Nair and colleagues identified 14 quantitative PET imaging features that correlated with gene expression (19). This led to an association of metagene clusters to imaging features and yielded prognostic models with hazard ratios near 6. In a study of esophageal cancer, in which 38 quantitative features describing fluorodeoxyglucose uptake were extracted, measures of metabolic heterogeneity at baseline enabled prediction of response with significantly higher sensitivity than any whole region of interest standardized uptake value measurement (22). It is also notable that these extensive texture-based features are generally more reproducible than simple measures of the standardized uptake value (27), which can be highly variable in a clinical setting (44).

 

Spatially Explicit Analysis of Tumor Heterogeneity

Although radiomic analyses have shown high prognostic power, they are not inherently spatially explicit. Quantitative border, shape, and texture features are typically generated over a region of interest that comprises the entire tumor (45). This approach implicitly assumes that tumors are heterogeneous but well mixed. However, spatially explicit subregions of cancers are readily apparent on contrast-enhanced MR or CT images, as perfusion can vary markedly within the tumor, even over short distances, with changes in tumor cell density and necrosis.

An example is shown in Figure 2, which shows a contrast-enhanced CT scan of non–small cell lung cancer. Note that there are many subregions within this tumor that can be identified with attenuation gradient (attenuation per centimeter) edge detection algorithms. Each subregion has a characteristic quantitative attenuation, with a narrow standard deviation, whereas the mean attenuation over the entire region of interest is a weighted average of the values across all subregions, with a correspondingly large and skewed distribution. We contend that these subregions represent distinct habitats within the tumor, each with a distinct set of environmental selection forces.

These observations, along with the recent identification of regional variations in the genetic properties of tumor cells, indicate the need to abandon the conceptual model of cancers as bounded organlike structures. Rather than a single self-organized system, cancers represent a patchwork of habitats, each with a unique set of environmental selection forces and cellular evolution strategies. For example, regions of the tumor that are poorly perfused can be populated by only those cells that are well adapted to low-oxygen, low-glucose, and high-acid environmental conditions. Such adaptive responses to regional heterogeneity result in microenvironmental selection and hence, emergence of genetic variations within tumors. The concept of adaptive response is an important departure from the traditional view that genetic heterogeneity is the product of increased random mutations, which implies that molecular heterogeneity is fundamentally unpredictable and, therefore, chaotic. The Darwinian model proposes that genetic heterogeneity is the result of a predictable and reproducible selection of successful adaptive strategies to local microenvironmental conditions.

Current cross-sectional imaging modalities can be used to identify regional variations in selection forces by using contrast-enhanced, cell density–based, or metabolic features. Clinical imaging can also be used to identify evidence of cellular adaptation. For example, if a region of low perfusion on a contrast-enhanced study is necrotic, then an adaptive population is absent or minimal. However, if the poorly perfused area is cellular, then there is presumptive evidence of an adapted proliferating population. While the specific genetic properties of this population cannot be determined, the phenotype of the adaptive strategy is predictable since the environmental conditions are more or less known. Thus, standard medical images can be used to infer specific emergent phenotypes and, with ongoing research, these phenotypes can be associated with underlying genetic changes.

This area of investigation will likely be challenging. As noted earlier, the most obvious spatially heterogeneous imaging feature in tumors is perfusion heterogeneity on contrast-enhanced CT or MR images. It generally has been assumed that the links between contrast enhancement, blood flow, perfusion, and tumor cell characteristics are straightforward. That is, tumor regions with decreased blood flow will exhibit low perfusion, low cell density, and high necrosis. In reality, however, the dynamics are actually much more complex. As shown in Figure 4, when using multiple superimposed sequences from MR imaging of malignant gliomas, regions of tumor that are poorly perfused on contrast-enhanced T1-weighted images may exhibit areas of low or high water content on T2-weighted images and low or high diffusion on diffusion-weighted images. Thus, high or low cell densities can coexist in poorly perfused volumes, creating perfusion-diffusion mismatches. Regions with poor perfusion with high cell density are of particular clinical interest because they represent a cell population that is apparently adapted to microenvironmental conditions associated with poor perfusion. The associated hypoxia, acidosis, and nutrient deprivation select for cells that are resistant to apoptosis and thus are likely to be resistant to therapy (46,47).

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Figure 4: Left: Contrast-enhanced T1 image from subject TCGA-02-0034 in The Cancer Genome Atlas–Glioblastoma Multiforme repository of MR volumes of glioblastoma multiforme cases. Right: Spatial distribution of MR imaging–defined habitats within the tumor. The blue region (low T1 postgadolinium, low fluid-attenuated inversion recovery) is particularly notable because it presumably represents a habitat with low blood flow but high cell density, indicating a population presumably adapted to hypoxic acidic conditions.

Furthermore, other selection forces not related to perfusion are likely to be present within tumors. For example, evolutionary models suggest that cancer cells, even in stable microenvironments, tend to speciate into “engineers” that maximize tumor cell growth by promoting angiogenesis and “pioneers” that proliferate by invading normal issue and co-opting the blood supply. These invasive tumor phenotypes can exist only at the tumor edge, where movement into a normal tissue microenvironment can be rewarded by increased proliferation. This evolutionary dynamic may contribute to distinct differences between the tumor edges and the tumor cores, which frequently can be seen at analysis of cross-sectional images (Fig 5).

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Figure 5a: CT images obtained with conventional entropy filtering in two patients with non–small cell lung cancer with no apparent textural differences show similar entropy values across all sections. 

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Figure 5b: Contour plots obtained after the CT scans were convolved with the entropy filter. Further subdividing each section in the tumor stack into tumor edge and core regions (dotted black contour) reveals varying textural behavior across sections. Two distinct patterns have emerged, and preliminary analysis shows that the change of mean entropy value between core and edge regions correlates negatively with survival.

Interpretation of the subsegmentation of tumors will require computational models to understand and predict the complex nonlinear dynamics that lead to heterogeneous combinations of radiographic features. We have exploited ecologic methods and models to investigate regional variations in cancer environmental and cellular properties that lead to specific imaging characteristics. Conceptually, this approach assumes that regional variations in tumors can be viewed as a coalition of distinct ecologic communities or habitats of cells in which the environment is governed, at least to first order, by variations in vascular density and blood flow. The environmental conditions that result from alterations in blood flow, such as hypoxia, acidosis, immune response, growth factors, and glucose, represent evolutionary selection forces that give rise to local-regional phenotypic adaptations. Phenotypic alterations can result from epigenetic, genetic, or chromosomal rearrangements, and these in turn will affect prognosis and response to therapy. Changes in habitats or the relative abundance of specific ecologic communities over time and in response to therapy may be a valuable metric with which to measure treatment efficacy and emergence of resistant populations.

 

Emerging Strategies for Tumor Habitat Characterization

A method for converting images to spatially explicit tumor habitats is shown in Figure 4. Here, three-dimensional MR imaging data sets from a glioblastoma are segmented. Each voxel in the tumor is defined by a scale that includes its image intensity in different sequences. In this case, the imaging sets are from (a) a contrast-enhanced T1 sequence, (b) a fast spin-echo T2 sequence, and (c) a fluid-attenuated inversion-recovery (or FLAIR) sequence. Voxels in each sequence can be defined as high or low based on their value compared with the mean signal value. By using just two sequences, a contrast-enhanced T1 sequence and a fluid-attenuated inversion-recovery sequence, we can define four habitats: high or low postgadolinium T1 divided into high or low fluid-attenuated inversion recovery. When these voxel habitats are projected into the tumor volume, we find they cluster into spatially distinct regions. These habitats can be evaluated both in terms of their relative contributions to the total tumor volume and in terms of their interactions with each other, based on the imaging characteristics at the interfaces between regions. Similar spatially explicit analysis can be performed with CT scans (Fig 5).

Analysis of spatial patterns in cross-sectional images will ultimately require methods that bridge spatial scales from microns to millimeters. One possible method is a general class of numeric tools that is already widely used in terrestrial and marine ecology research to link species occurrence or abundance with environmental parameters. Species distribution models (4851) are used to gain ecologic and evolutionary insights and to predict distributions of species or morphs across landscapes, sometimes extrapolating in space and time. They can easily be used to link the environmental selection forces in MR imaging-defined habitats to the evolutionary dynamics of cancer cells.

Summary

Imaging can have an enormous role in the development and implementation of patient-specific therapies in cancer. The achievement of this goal will require new methods that expand and ultimately replace the current subjective qualitative assessments of tumor characteristics. The need for quantitative imaging has been clearly recognized by the National Cancer Institute and has resulted in formation of the Quantitative Imaging Network. A critical objective of this imaging consortium is to use objective, reproducible, and quantitative feature metrics extracted from clinical images to develop patient-specific imaging-based prognostic models and personalized cancer therapies.

It is increasingly clear that tumors are not homogeneous organlike systems. Rather, they contain regional coalitions of ecologic communities that consist of evolving cancer, stroma, and immune cell populations. The clinical consequence of such niche variations is that spatial and temporal variations of tumor phenotypes will inevitably evolve and present substantial challenges to targeted therapies. Hence, future research in cancer imaging will likely focus on spatially explicit analysis of tumor regions.

Clinical imaging can readily characterize regional variations in blood flow, cell density, and necrosis. When viewed in a Darwinian evolutionary context, these features reflect regional variations in environmental selection forces and can, at least in principle, be used to predict the likely adaptive strategies of the local cancer population. Hence, analyses of radiologic data can be used to inform evolutionary models and then can be mapped to regional population dynamics. Ecologic and evolutionary principles may provide a theoretical framework to link imaging to the cellular and molecular features of cancer cells and ultimately lead to a more comprehensive understanding of specific cancer biology in individual patients.

 

Essentials

  • • Marked heterogeneity in genetic properties of different cells in the same tumor is typical and reflects ongoing intratumoral evolution.
  • • Evolution within tumors is governed by Darwinian dynamics, with identifiable environmental selection forces that interact with phenotypic (not genotypic) properties of tumor cells in a predictable and reproducible manner; clinical imaging is uniquely suited to measure temporal and spatial heterogeneity within tumors that is both a cause and a consequence of this evolution.
  • • Subjective radiologic descriptors of cancers are inadequate to capture this heterogeneity and must be replaced by quantitative metrics that enable statistical comparisons between features describing intratumoral heterogeneity and clinical outcomes and molecular properties.
  • • Spatially explicit mapping of tumor regions, for example by superimposing multiple imaging sequences, may permit patient-specific characterization of intratumoral evolution and ecology, leading to patient- and tumor-specific therapies.
  • • We summarize current information on quantitative analysis of radiologic images and propose future quantitative imaging must become spatially explicit to identify intratumoral habitats before and during therapy.

Disclosures of Conflicts of Interest: R.A.G. No relevant conflicts of interest to disclose. O.G. No relevant conflicts of interest to disclose.R.J.G. No relevant conflicts of interest to disclose.

 

Acknowledgments

The authors thank Mark Lloyd, MS; Joel Brown, PhD; Dmitry Goldgoff, PhD; and Larry Hall, PhD, for their input to image analysis and for their lively and informative discussions.

Footnotes

  • Received December 18, 2012; revision requested February 5, 2013; revision received March 11; accepted April 9; final version accepted April 29.
  • Funding: This research was supported by the National Institutes of Health (grants U54CA143970-01, U01CA143062; R01CA077575, andR01CA170595).

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Personalized Medicine: Clinical Aspiration of Microarrays

Reporter, Writer: Stephen J. Williams, Ph.D.

 In this month’s Science, Mike May (at http://www.sciencemag.org/site/products/lst_20130215.xhtml) describes some of the challenges and successes in introducing microarray analysis to the clinical setting.  Traditionally used for investigational research, microarray is now being developed, customized and used for biomarker analysis, prognostic and predictive value, in a disease-specific manner.

Challenges in data interpretation

      In an interview with Seth Crosby, director of the Genome Technology Access Center at Washington University School of Medicine in St. Louis, “the biggest challenge” in moving microarray to the clinical setting is data interpretation.  The current technology makes it possible to evaluate expression of thousands of genes from a patient’s sample however as Crosby describes is assigning clinical relevance to the data.  For example Crosby explains that Washington University had validated a panel of 45 oncology genes by next generation sequencing and are using these genes to develop diagnostic tests to screen patient tumors for the purpose of determining a personalized therapeutic strategy. Seth Crosby noted it took “hundreds of Ph.D. and M.D. hours” to sift through the hundreds of papers to determine which genes were relevant to a specific cancer type. However, he notes, that once we better understand which changes in the patient’s genome are related to a specific disease we will be able to narrow down the list and be able to produce both economical and more disease-relevant microarrays.

Is this aberration pathogenic or not?

     Microarrays are becoming an invaluable tool in cytogenetics, as eluded by Andy Last, executive vice president of the genetic analysis business unit at Affymetrix.  Certain diseases like Down syndrome have well characterized chromosomal alterations like additions or deletions of parts or entire chromosomes.  According to Affymetrix, the most common use of microarrays is for determining copy number variation.  However according to James Clough, vice president of clinical and genomic services at Oxford Gene Technology, given the hundreds of syndromes associated with chromosomal rearrangements, the challenge will be to determine if a small chromosomal aberration has pathologic significance, given that microarray affords much higher diagnostic yield and speed of analysis than traditional microscopic techniques.  To address this challenge, Oxford Gene Technologies, PerkinElmer, Affymetrix, and Agilent all have custom designed microarrays to evaluate disease specific copy number and SNP (single nucleotide polymorphism) microarrays.  For example PerkinElmer designed OncoChip™ to evaluate copy number variation in more than 1.800 cancer genes.  Agilent makes microarrays that evaluates both copy number variation such as its CGH (comparative genomic hybridization) plus SNP microarrays.  Patricia Barco, product manager for cytogenetics at Agilent, notes these arrays can be used in prenatal and postnatal research and cancer, and “can be customized from more than 28 million probes in our library”.

Custom Tools and Software to Handle the Onslaught of Big Data

     There is a need for FDA approved diagnostic tools based on microarrays. Pathwork Diagnostic’s has one such tool (the Pathwork Tissue of Origin test), which uses 2,000 transcript markers and a proprietary computational algorithm to determine from expression analysis, the tissue of origin of a patient’s tumor.  Pathwork also provides a fast, custom turn-around analytical service for pathologists who encounter difficult to interpret samples.  Illumina provides the Infinium HumanCore BeadChip family of microarrays, which can determine genetic variations for purposes of biological tissue banking.  This system uses a set of over 300,000 SNP probes plus 240,000 exome-based markers.

     Tools have also been developed to validate microarray results.  A common validation strategy is the use of quantitative real-time PCR to verify the expression changes seen on the microarray.  Life Technologies developed the TaqMan OpenArray Real Time PCR plates, which have 3,072 wells and can be custom-formatted using their library of eight million validated TaqMan assays.

Making Sense of the Big Data: Bridging the Knowledge Gap using Bioinformatics

          The use of microarray has spurned industries devoted to developing the bioinformatics software to analyze the massive amounts of data and provide clinical significance.  For example companies such as Expression Analysis use their bioinformatics software to provide pathway analysis for microarray data in order to translate the data into the biology.  Using such strategies can also validate the design of microarrays for various diseases.

Foundation Medicine, Inc., a molecular information company, provides cancer genomics test solutions. It offers FoundationOne, an informative genomic profile to identify a patient’s individual molecular alterations and match them with relevant targeted therapies and clinical trials. The company’s product enables physicians to recommend treatment options for patients based on the molecular subtype of their cancer.

The Canadian Bioinformatics Workshops series recently offered a course on using bioinformatic approaches to analyze clinical data generated from microarray approaches (http://bioinformatics.ca/workshops/2012/bioinformatics-cancer-genomics-bicg).   The course objectives are described below:

Course Objectives

Cancer research has rapidly embraced high throughput technologies into its research, using various microarray, tissue array, and next generation sequencing platforms. The result has been a rapid increase in cancer data output and data types. Now more than ever, having the bioinformatic skills and knowledge of available bioinformatic resources specific to cancer is critical. The CBW will host a 5-day workshop covering the key bioinformatics concepts and tools required to analyze cancer genomic data sets. Participants will gain experience in genomic data visualization tools which will be applied throughout the development of the skills required to analyze cancer -omic data for gene expression, genome rearrangement, somatic mutations and copy number variation. The workshop will conclude with analyzing and conducting pathway analysis on the resultant cancer gene list and integration of clinical data.

Successful Examples of Clinical Ventures Integrating Bioinformatics in Cancer Treatment Decision –Making

The University of Pavia, Italy developed a fully integrated oncology bioinformatics workflow as described on their website and at the ESMO 2012 Congress meeting:

http://abstracts.webges.com/viewing/view.php?congress=esmo2012&congress_id=370&publication_id=2530

ESMO

ONCO-I2B2 PROJECT: A BIOINFORMATICS TOOL INTEGRATING –OMICS AND CLINICAL DATA TO SUPPORT TRANSLATIONAL RESEARCH

Abstract:

2530

Congress:

ESMO 2012

Type:

Abstract

Topic:

Translational research

Authors:

A. Zambelli, D. Segagni, V. Tibollo, A. Dagliati, A. Malovini, V. Fotia, S. Manera, R. Bellazzi; Pavia/IT

  • Body

The ONCO-i2b2 project, supported by the University of Pavia and the Fondazione Salvatore Maugeri (FSM), aims at supporting translational research in oncology and exploits the software solutions implemented by the Informatics for Integrating Biology and the Bedside (i2b2) research centre, an initiative funded by the NIH Roadmap National Centres for Biomedical Computing. The ONCO-i2b2 software is designed to integrate the i2b2 infrastructure with the FSM hospital information system and the Bruno Boerci Biobank, in order to provide well-characterized cancer specimens along with an accurate patients clinical data-base. The i2b2 infrastructure provides a web-based access to all the electronic medical records of cancer patients, and allow researchers analyzing the vast amount of biological and clinical information, relying on a user-friendly interface. Data coming from multiple sources are integrated and jointly queried.

In 2011 at AIOM Meeting we reported the preliminary experience of the ONCO-i2b2 project, now we’re able to present the up and running platform and the extended data set. Currently, more than 4400 specimens are stored and more than 600 of breast cancer patients give the consent for the use of specimens in the context of clinical research, in addition, more than 5000 histological reports are stored in order to integrate clinical data.

Within the ONCO-i2b2 project is possible to query and merge data regarding:

• Anonymous patient personal data;

• Diagnosis and therapy ICD9-CM subset from the hospital information system;

• Histological data (tumour SNOMED and TNM codes) and receptor profile testing (Her2, Ki67) from anatomic pathology database;

• Specimen molecular characteristics (DNA, RNA, blood, plasma and cancer tissues) from the Bruno Boerci Biobank management system.

The research infrastructure will be completed by the development of new set of components designed to enhance the ability of an i2b2 hive to utilize data generated by NGS technology, providing a mechanism to apply custom genomic annotations. The translational tool created at FSM is a concrete example regarding how the integration of different information from heterogeneous sources could bring scientific research closer to understand the nature of disease itself and to create novel diagnostics through handy interfaces.

Disclosure

All authors have declared no conflicts of interest.

NCI has under-taken a similar effort under the Recovery Act (the full text of the latest report is taken from their website http://www.cancer.gov/aboutnci/recovery/recoveryfunding/investmentreports/bioinformatics:

Cancer Bioinformatics: Recovery Act Investment Report

November 2009

Public Health Burden of Cancer

Cancer is the second leading cause of death in the United States after heart disease. In 2009, it is estimated that nearly 1.5 million new cases of invasive cancer will be diagnosed in this country and more than 560,000 people will die of the disease.

To learn more, visit:

Cancer Bioinformatics Program Overview

Over the past five years, NCI’s Center for Biomedical Informatics and Information Technology (CBIIT) has led the effort to develop and deploy the cancer Biomedical Informatics Grid® (caBIG) in partnership with the broader cancer community.  The caBIG network is designed to enable the integration and exchange of data among researchers in the laboratory and the clinic, simplify collaboration, and realize the potential of information-based (personalized) medicine in improving patient outcomes. caBIG has connected major components of the cancer community, including NCI-designated Cancer Centers, participating institutions of the NCI Community Cancer Centers Program (NCCCP), and numerous large-scale scientific endeavors, as well as basic, translational, and clinical researchers at public and private institutions across the United States and around the world.  Beyond cancer research, caBIG capabilities—infrastructure, standards, and tools—provide a prototype for linking other disease communities and catalyzing a new 21st-century biomedical ecosystem that unifies research and care. ARRA funding will allow NCI to accelerate the ongoing development of the Cancer Knowledge Cloud and Oncology Electronic Health Records (EHRs) initiatives, thereby providing for continued job creation in the areas of biomedical informatics development and application as well as healthcare delivery.

The caBIG Cancer Knowledge Cloud: Extending the Research Infrastructure

The Cancer Knowledge Cloud is a virtual biomedical capability that utilizes caBIG tools, infrastructure, and security frameworks to integrate distributed individual and organizational data, software applications, and computational capacity throughout the broad cancer research and treatment community. The Cancer Knowledge Cloud connects, integrates, and facilitates sharing of the diverse primary data generated through basic and clinical research and care delivery to enable personalized medicine. The cloud includes information generated through large-scale research projects such as The Cancer Genome Atlas (TCGA), the cancer Human Biobank (caHUB) tissue acquisition network, the NCI Functional Biology Consortium, the NCI Patient Characterization Center, and the NCI Preclinical Development Pipeline, academic and industry counterparts to these projects, and clinical observations (from entities such as the NCCCP) captured in oncology-extended Electronic Health Records.  Through the use of the caBIG Data Sharing and Security Framework, the Cloud will support appropriate sharing of information, supporting in silico hypothesis generation and testing, and enabling a learning healthcare system.

A caBIG-Based Rapid-Learning Healthcare System: Incorporating Oncology-Extended Electronic Healthcare Records (EHRs)

The 21st-century Cancer Knowledge Cloud will connect individuals, organizations, institutions, and their associated information within an information technology-enabled cycle of discovery, development, and clinical care—the paradigm of a rapid-learning healthcare system. This will transform these disconnected sectors into a system that is personalized, preventive, pre-emptive, and patient-participatory.  To be realized, this model requires the adoption of standards-based EHRs. Presently, however, no certified oncology-based EHR exists, and fewer than 3 percent of oncologists with outpatient-based practices utilize EHRs. caBIG has recently established a collaboration with the American Society of Clinical Oncology (ASCO) to develop an oncology-specific EHR (caEHR) specification based on open standards already in use in the oncology community that will utilize caBIG standards for interoperability. NCI will implement an open-source version of this specification to validate the specification and to provide a free alternative to sites that choose not to purchase a commercial system. The launch customer for the caEHR will be NCCCP participating sites. NCI will work with appropriate entities to provide a mechanism for certifying that caEHR implementations are consistent with the NCI/ASCO specification.

Bards Cancer Institute has another clinical bioinformatics program to support their clinical efforts:

Clinical Bioinformatics Program in Oncology at Barts Cancer Institute at Barts and the London School of Medicine

http://www.bci.qmul.ac.uk/cancer-bioinformatics

BCI HomeCancer Bioinformatics

Bards

Why we focus on Cancer Bioinformatics

Bioinformatics is a new interdisciplinary area involving biological, statistical and computational sciences. Bioinformatics will enable cancer researchers not only to manage, analyze, mine and understand the currently accumulated, valuable, high-throughput data, but also to integrate these in their current research programs. The need for bioinformatics will become ever more important as new technologies increase the already exponential rate at which cancer data are generated.

What we do

  • We work alongside clinical and basic scientists to support the cancer projects within BCI.  This is an ideal partnership between scientific experts, who know the research questions that will be relevant from a cancer biologist or clinician’s perspective, and bioinformatics experts, who know how to develop the proposed methods to provide answers.
  • We also conduct independent bioinformatics research, focusing on the development of computational and integrative methods, algorithms, databases and tools to tackle the analysis of the high volumes of cancer data.
  • We also are actively involved in the development of bioinformatics educational courses at BCI. Our courses offer a unique opportunity for biologists to gain a basic understanding in the use of bioinformatics methods to access and harness large complicated high-throughput data and uncover meaningful information that could be used to understand molecular mechanisms and develop novel targeted therapeutics/diagnostic tools.

Developing Criteria for Genomic Profiling in Lung Cancer:

A Report from U.S. Cancer Centers

In a report by Pao et. al., a group of clinicians organized a meeting to standardize some protocols for the integration of microarray and genomic data from lung cancer patients into the clinical setting.[1]  There has been ample evidence that adenocarcinomas could be classified into “clinically relevant molecular subsets” based on distinct genomic changes.  For example EGFR (epidermal growth factor receptor) exon 19 deletions and exon 21 point mutations predict sensitivity to tyrosine kinase inhibitors (TKIs) like gefitinib, whereas exon 20 insertions predict primary resistance[2].

However, as the authors note, “mutational profiling has not been widely accepted or adopted into practice in thoracic oncology”.  

     Therefore, a multi-institutional workshop was held in 2009 among participants from Massachusetts General Hospital (MGH) Cancer Center, Memorial Sloan-Kettering Cancer Center (MSKCC), the Dana-Farber/Bingham & Women’s Cancer Center (DF/BWCC), the M.D. Anderson Cancer Center (VICC), and the Vanderbilt-Ingram Cancer Center (VICC) to discuss their institutes molecular profiling programs with emphasis on:

·         Organization/workflow

·         Mutation detection technologies

·         Clinical protocols and reporting

·         Patient consent

In addition to the aforementioned challenges, the panel discussed further issues for developing improved science-driven criteria for determining targeted therapies including:

1)      Including pathologists into criteria development as pathology departments are usually the main repositories for specimens

2)      Developing integrated informatics systems

3)      Standardizing new target validation methodology across cancer centers

 References

1.            Pao W, Kris MG, Iafrate AJ, Ladanyi M, Janne PA, Wistuba, II, Miake-Lye R, Herbst RS, Carbone DP, Johnson BE et al: Integration of molecular profiling into the lung cancer clinic. Clinical cancer research : an official journal of the American Association for Cancer Research 2009, 15(17):5317-5322.

2.            Wu JY, Wu SG, Yang CH, Gow CH, Chang YL, Yu CJ, Shih JY, Yang PC: Lung cancer with epidermal growth factor receptor exon 20 mutations is associated with poor gefitinib treatment response. Clinical cancer research : an official journal of the American Association for Cancer Research 2008, 14(15):4877-4882.

Other posts on this website on Cancer and Genomics include:

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Imaging-biomarkers is Imaging-based tissue characterization

Author – Writer: Dror Nir, PhD

For everyone who is skeptical about the future role of imaging-based tissue chracterisation in the management of cancer, the following “Statement paper” ESR statement on the stepwise development of imaging biomarkers published online: 9 February 2013, by the European Society of Radiology (ESR), should provide substantial reassurance that this kind of technology will become a must! In support of this claim I quote the following information:

The European Society of Radiology and its related European Institute for Biomedical Imaging Research (EIBIR) should have a relevant role in coordinating future developments of biomarkers and in the assessment and validation of imaging biomarkers as surrogate end points.

Acknowledgements

This paper was kindly prepared by the ESR Subcommittee on Imaging Biomarkers (Chairperson: Bernard Van Beers. Research Committee Chairperson: Luis Martí-Bonmatí. Members: Marco Essig, Thomas Helbich, Celso Matos, Wiro Niessen, Anwar Padhani, Harriet C. Thoeny, Siegfried Trattnig, Jean-Paul Vallée. Co-opted members: Peter Brader, Nicolas Grenier) on behalf of the European Society of Radiology (ESR) and with the help of Sabrina Doblas, INSERM U773, Paris, France.

It was approved by the ESR Executive Council in December 2012..

According to ESR: “There is increasing interest in developing the quantitative imaging of biomarkers in personalised medicine”. In this perspective, “Biomarkers” are tissue properties that can be quantitatively and reproducibly measured by imaging devices. One example for a major unmet need, which I found to be most interesting is the imaging-based detection of tumor invasiveness.

Quoting from the paper: ” Biomarkers are defined as “characteristics that are objectively measured and evaluated as indicators of normal biological processes, pathological processes, or pharmaceutical responses to a therapeutic intervention” [1]. Broadly, biomarkers fall into two categories: bio-specimen biomarkers, including molecular biomarkers and genetic biomarkers, and bio-signal biomarkers or imaging biomarkers. Bio-specimen biomarkers are obtained by removing a sample from a patient. Examples of these molecular biomarkers are genes and proteins detected from fluids or tissue samples. Bio-signal biomarkers remove no material from the patient, but rather detect and analyse an electromagnetic, photonic or acoustic signal emitted by the patient [2]. These imaging biomarkers have the advantage of being non-invasive, spatially resolved and repeatable [3]. They are of particular interest if they can overcome the limitations of the established histological “gold standards”. Indeed, invasive reference examinations, such as biopsy, can be inconclusive, are non-representative of the whole tissue (which is a tremendous limitation when assessing malignant tumours, which are known to be heterogeneous) and possess non-negligible levels of mortality and morbidity.

Genetic biomarkers indicate whether a disease may occur, but they are usually inefficient to assess the presence and stage of a disease. Similar to molecular biomarkers, imaging biomarkers can be used for early detection of diseases, staging and grading, and predicting or assessing the response to treatment [3]. Accordingly, because of their relative lower cost compared with imaging, molecular biomarkers may be more appropriate for disease screening and early detection than imaging biomarkers. With their high sensitivity, molecular biomarkers could also detect subclinical stages of disease before any morphological or functional change is detectable on imaging. In contrast, imaging biomarkers are often more useful than molecular biomarkers for disease staging, and also grading and for assessing tumour response, because localised information is crucial.

The main messages ESR wishes to deliver in this paper are that:

• Using imaging-biomarkers to streamline drug discovery and disease progression will drive a huge advancement in healthcare.

• The clinical qualification and validation of imaging biomarkers technology pose challenges, mainly in establishing the accuracy and reproducibility of such techniques. In that respect, agreements on standards and evaluation methods (e.g. clinical studies design) is imperative.

• There should be high motivation to pursue the development of imaging-biomarkers as the “clinical value of new biomarkers is of the highest priority in terms of patient management, assessing risk factors and disease prognosis.”

The paper deals to a great extent with the requirements on accuracy, reproducibility, standardization and quality control from the process of developing imaging-biomarkers:

Accuracy: Before being routinely used in the clinic, imaging biomarkers must be validated. Determining the accuracy implies calculating the sensitivity and specificity of the biomarker when compared with a biological process, such as tumour necrosis, which can be assessed at histopathological examination… [69]  [10, 11]

Reproducibility: Repeatability (measurements at short intervals on the same subjects using the same equipment in the same centres) and reproducibility (measurements at short intervals on the same subjects using different facilities in the same and different centres) studies must be conducted for image acquisition and image analysis…. Reproducibility studies are now very often included in scientific papers, as advised by the “standards for reporting of diagnostic accuracy” (STARD) criteria and should ideally include Bland-Altman plots and results of coefficients of repeatability [1617].

Standardisation: Standardisation relates to the establishment of norms or requirements about technical aspects. In the development of imaging biomarkers, two main aspects should be considered: Standardisation of image acquisition and Standardisation of image analysis…  [18] [1921]  [22] [27, 28] [3133]

Quality control: Adequate phantoms could be used to validate, on a day-to-day basis, that the biomarker stays robust and to avoid any drift in the machine, acquisition or processing protocol….  [34] [3035] [36] [37] [23].

The proposed development workflow:

“Similar to new drugs, the development of biomarkers has to pass along a pipeline going from discovery, through verification in different laboratories, validation and qualification before they can be used in clinical routine. Validation includes the determination of the accuracy and the precision (reproducibility) of the biomarker and standardisation concerns both acquisition and analysis. Qualification, defined as a “graded, fit-for-purpose evidentiary process linking a biomarker with biological processes and clinical end-points”, is a validation process in large cohorts of patients involving multiple centres, similar to phase III clinical trials, to obtain regulatory approval as surrogate endpoints [4]. A more extensive path to biomarker development has been reported [5]. The first step is the proof of concept, which defines any specific change relevant to the disease that can be studied using the available imaging and computational techniques. The relationship between this change and the presence, grading and response to treatment of the disease constitutes the proof of mechanism. The images needed to extract the biomarker must be appropriate (in terms of resolution, signal and contrast behaviour). Preparation of images relates to improving the data before the analysis (such as segmentation, filtering, interpolation or registration). The analysis and modelling of the signal by computational numerical adjustment of a mathematical model allow extracting the needed information (such as structural, physical, chemical, biological and functional properties). After this voxel-by-voxel computation, the spatial distribution of the biomarker can be depicted by parametric images, defined as derived secondary images which pixels represent the distribution values of a given parameter. Multivariate parametric images obtained by statistical modelling of the relevant parameters allow the reduction of data and a clear definition of the defined disease target. The abnormal values should be defined and measured through histogram analysis. A pilot test on a small sample of subjects, with and without the disease, has to be performed to validate the process—also called proof of principle—and to evaluate the influence of potential variations related to age, sex or any other source of biases. Finally, proofs of efficacy and effectiveness on larger and well-defined series of patients will show the ability of a biomarker to measure the clinical endpoint (Fig. 1).

Steps for the development of imaging biomarkers (adapted from [5])

Steps for the development of imaging biomarkers (adapted from [5])

The authors admit that the requirement posed on development of imaging-biomarkers represents a huge challenge and they try to offer ideas, mainly taken from the “MRI experience” to overcome certain hurdles. There is one important point on which they do not discuss: the definition of appropriate reference test. It is my own experience, based on many study protocols I developed in the past decade, that without reaching an agreement on that point, the development of imaging-biomarkers will just move in circles. Note, that today’s most “acceptable” reference test is histopathology, which everyone admits (as well mentioned in this paper); suffers many limitations. When it comes to validating imaging-biomarkers, the need to accurately match imaging products with histopathology is an additional major hurdle.

This is why, I see as a necessary step, to develop “real-time” imaging based tissue characterization combined with in-situ imaging-based histology.

 

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Many feedbacks to my last post reflected radiologists’ perception of ultrasound as a low-tech, unreliable imaging device.

Ultrasounds most manifested limitation by radiologists is that its performance is too-much user-dependent. This opinion finds support in numerous clinical studies concluding that ultrasound-based assessment of a cancer patient varies with the operator.

How come that an imaging technology that is not only  low-cost, simple to operate and risk-free to the patient, but has also gained a leading position in certain domain, like obstetrics,  is perceived as the underdog when it comes  to cancer assessment? Could it be because of its positioning as a “multi-purpose” system, which requires only very basic training?

If indeed this is the case, it doesn’t require “rocket-science” to turn it around. It only needs designing dedicated ultrasound machines who offer a comprehensive solution to one specific clinical need. Using such machines will require highly skilled operators who will enjoy a superior workflow, reporting tools and proven clinical guidelines.

The unsatisfactory reality of mammography-based breast cancer screening, as evident by epidemiology data and expert-panels’ reports, opens the opportunity to transform ultrasound into a winner in the niche-market of breast cancer screening and diagnosis. It’s a significant market that justifies the investment in ultrasound systems dedicated to detection and characterisation of breast cancer lesions.

No doubt, that the ability to provide accurate and standardized interpretation of such ultrasound systems’ scans is a pre-requisite. Ultrasound-based tissue characterisation is a must for any application aiming at standardized image interpretation. A sample out-of present ultrasound-based technologies aiming at providing some level of tissue-characterisation are listed below. Recent clinical studies show promising results using these technologies. It is worth watching carefully to see if any of those could be part of a future ultrasound-based solution to breast cancer screening.

Solid Breast Lesions: Clinical Experience with US-guided Diffuse Optical Tomography Combined with Conventional US

Results: Of the 136 biopsied lesions, 54 were carcinomas and 82 were benign. The average total hemoglobin concentration in the malignant group was 223.3 μmol/L ± 55.8 (standard deviation), and the average hemoglobin concentration in the benign group was 122.5 μmol/L ± 80.6 (P = .005). When the maximum hemoglobin concentration of 137.8 μmol/L was used as the threshold value, the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of DOT with US localization were 96.3%, 65.9%, 65.0%, 96.4%, and 76.5%, respectively. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of conventional US were 96.3%, 92.6%, 89.7%, 97.4%, and 93.4%, respectively. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of conventional US combined with DOT were 100%, 93.9%, 91.5%, 100%, and 96.3%, respectively.

Conclusion: US-guided DOT combined with conventional US improves accuracy compared with DOT alone.

Breast Lesions: Quantitative Elastography with Supersonic Shear Imaging—Preliminary Results

 

 

Results: All breast lesions were detected at Supersonic Shear Imaging. Malignant lesions exhibited a mean elasticity value of 146.6 kPa ± 40.05 (standard deviation), whereas benign ones had an elasticity value of 45.3 kPa ± 41.1 (P < .001). Complicated cysts were differentiated from solid lesions because they had elasticity values of 0 kPa (no signal was retrieved from liquid areas).

Conclusion: Supersonic Shear Imaging provides quantitative elasticity measurements, thus adding complementary information that potentially could help in breast lesion characterization with B-mode US.

 Distinguishing Benign from Malignant Masses at Breast US: Combined US Elastography and Color Doppler US—Influence on Radiologist Accuracy

Results: The Az of B-mode US, US elastography, and Doppler US (average, 0.844; range, 0.797–0.876) was greater than that of B-mode US alone (average, 0.771; range, 0.738–0.798) for all readers (P = .001 for readers 1, 2, and 3; P < .001 for reader 4; P = .002 for reader 5). When both elastography and Doppler scores were negative, leading to strict downgrading, the specificity increased for all readers from an average of 25.3% (75.4 of 298; range, 6.4%–40.9%) to 34.0% (101.2 of 298; range, 26.5%–48.7%) (P < .001 for readers 1, 2, 4, and 5; P = .016 for reader 3) without a significant change in sensitivity.

Conclusion: Combined use of US elastography and color Doppler US increases both the accuracy in distinguishing benign from malignant masses and the specificity in decision-making for biopsy recommendation at B-mode US.

Evaluation of breast lesions by contrast enhanced ultrasound: Qualitative and quantitative analysis

A 57-year-old woman with a no-palpable lesion in the outer upper quadrant of left breast. (a) Gray scale image show an indistinct, hypo-echoic lesion. (b) Contrast enhanced image obtained 35 s after contrast agent injection showing a homogeneously and hyper-enhanced lesion. (c) Micro flow image obtained 38 s after contrast agent injection showing the enhanced mass with several radial vessels (arrow). (d) The time-intensity curve analysis show the peak intensity is 145.69 (intensity/1000), time to peak is 15.08 s, ascending slope is 8.98, descending slope is 1.03, the area under the curve is 7783.34. Pathologic analyses show this is an invasive ductal carcinoma.

Results: Histopathologic analysis of the 91 lesions revealed 44 benign and 47 malignant. For qualitative analysis, benign and malignant lesions differ significantly in enhancement patterns (p < 0.05). Malignant lesions more often showed heterogeneous and centripetal enhancement, whereas benign lesions mainly showed homogeneous and centrifugal enhancement. The detectable rate of peripheral radial or penetrating vessels was significantly higher in malignant lesions than in benign ones (p < 0.001). For quantitative analysis, malignant lesions showed significantly higher (p = 0.031) and faster enhancement (p = 0.025) than benign ones, and its time to peak was significantly shorter (p = 0.002). The areas under the ROC curve for qualitative, quantitative and combined analysis were 0.910 (Az1), 0.768 (Az2) and 0.926(Az3) respectively. The values of Az1 and Az3 were significantly higher than that for Az2 (p = 0.024 and p = 0.008, respectively). But there was no significant difference between the values of Az1 and Az3 (p = 0.625).

Conclusions: The diagnostic performance of qualitative and combined analysis was significantly higher than that for quantitative analysis. Although quantitative analysis has the potential to differentiate benign from malignant lesions, it has not yet improved the final diagnostic accuracy.

 Breast HistoScanning: the development of a novel technique to improve tissue characterization during breast ultrasound

Results: In 17 normal testing volumes, 3% of isolated voxels were classified as abnormal. In 15 abnormal testing volumes, the subclassifiers differentiated between malignant and benign tissue. BHS in benign tissue showed <1% abnormal voxels in cyst, hamartoma, papilloma and benign fibrosis. The fibroadenomas differed showing <5% and <24% abnormal voxels. Abnormal voxels in cancers increased with the volume of cancer at pathology.

Conclusions: HistoScanning reliably discriminated normal from abnormal tissue and could distinguish between benign and malignant lesions.

Written by: Dror Nir, PhD

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Automated Breast Ultrasound System (‘ABUS’) for full breast scanning: The beginning of structuring a solution for an acute need!

Writer: Dror Nir, PhD

GE Healthcare announced this week the acquisition of U-Systems, Inc. U-systems has developed the first and only Automated Breast Ultrasound System (ABUS) on the market – somo•v®, to receive FDA approval as an adjunct to mammography screening for breast cancer of; “asymptomatic women, with greater than 50 percent dense breast tissue and no prior breast interventions.”

somo•v® screen shot, showing mass in upper-outer quadrant of the left breast. Image courtesy of U-Systems.

I became aware of somo•v® already in 2004, when Prof. André Grivegnée, head of the breast screening unit at Jules Bordet – European oncology center in Brussels, Belgium, invited me to participate in a technology assessment of U-Systems’ somo•v® product. On that occasion, I also shared with U-System’s developers the idea of incorporating tissue characterisation into their product, an idea which they did not take on board. There is nothing more vivid to fully understand the meaning of this acquisition for breast cancer screening then the following quote from AuntMinnie’s report “GE taps interest in ABUS with U-Systems acquisition”:  “You know you’re onto something when the big boys come calling. GE Healthcare today announced its acquisition of automated breast ultrasound (ABUS) developer U-Systems, a move that highlights the rapid evolution of ABUS from a niche technology into a promising adjunct to screening mammography. “ First savvy: The reality of medical device startups is that it doesn’t matter how real and large is the need for your technology. Until one of the big boys will adopt it, it is prone to be considered as niche technology. I discussed the potential role of ABUS in future breast screening in my recent posts: Closing the Mammography gap; Introducing smart-imaging into radiologists’ daily practice.  As noted, in recent years, several ABUS systems were developed. An intriguing question is; why did GE choose to buy the somo•v® and not one of the other systems? Why now and not 2 or 3 years ago? The answer must have to do with the fact that in September 2012, somo•v® became the first ABUS system to receive premarket approval (PMA) for its application to use the system in a breast cancer screening environment. Until then, somo·v was indicated for use as an adjunct to mammography for B-mode ultrasonic imaging of a patient’s breast when used with an automatic scanning linear array transducer or a handheld transducer. The PMA has extended somo·v’s Indication For Use (IFU) allowing a claim that it increases breast cancer detection in a certain patients population. Second savvy: Having a PMA approval for a compelling indication for use, in a significant enough patient group, will dramatically increase “big boys” interest in your product. From the information available on the FDA site, one can get an insight into U-System’s regulatory strategy. They were smart enough to be satisfied with achieving a small step; increasing the detection rate of mammography-based screening. Therefore, the same radiologist who read the mammograms also read the ultrasound image. This increases the probability that your device’s sensitivity will not be worse than that of mammography. U-Systems did not try to go all the way to become an alternative to mammography. A claim that would significantly increase the complexity of the required clinical study; e.g. will require comparison of cancer detection-rates between modalities by independent, blinded-readers. Therefore, “the device is not intended to be used as a replacement for screening mammography”.   Third savvy: The most expensive component, in time and money, in a regulatory pathway are the clinical studies. A cost-effective regulatory strategy is linked to good understanding of the market segmentation. Identifying what kind of IFU differentiates your products from its competition in a large enough niche-market is key. It will also lead to the simplest clinical-study design possible. As an entrepreneur, I cannot help congratulating U-Systems’ team for pulling through continuous hurdles to reach the point all medical device startups are hoping for. They certainly picked up the right item to focus their efforts on: i.e. PMA approval for breast cancer screening. Finally, I will reiterate my vision that embedding real-time tissue characterization in an ultrasound system, capable of performing fast and standardized full breast scanning is: a. Technologically achievable; and b. in the long-term, will be an excellent alternative to mammography for breast cancer screening. Additional readings: Two studies related to  somo•v® will be discussed at the 2012 RSNA meeting: “ A study led by Dr. Rachel Brem of George Washington University Medical Center: ABUS plus mammography finds cancer early in women with dense tissue  Brem’s study found that ABUS enabled detection of early-stage cancers in women with dense breasts, giving healthcare providers time to start early treatment. In all, 88% of cancers found by ABUS alone in a group of 15,000 women were grade 1 or 2.” “A study presented by Maryellen Giger, PhD, of the University of Chicago: ABUS boosts mammography’s performance  this study results showthat adding ABUS to mammography for women with dense breast tissue improved sensitivity by 23.3 percentage points, from 38.8% for mammography alone to 63.1% for mammography plus ABUS.” As I mentioned already, there are other ultrasound modalities out there, some are ABUS and some are not. All are adjunct to mammography screening. Related studies will also be presented during that same meeting.

UPDATE (04-Aug-2013)

Here below is a recent publication on  the use of ABUS for better detection of breast cancer in patients presented with mammographically dense breast.

Improved breast cancer detection in asymptomatic women using 3D-automated breast ultrasound in mammographically dense breasts

  • Breast Cancer Research Institute, Nova Southeastern University College of Medicine, 5732 Canton Cove, Winter Springs, FL 32708, USA

Abstract

Automated breast ultrasound (ABUS)was performed in 3418 asymptomatic women with mammographically dense breasts. The addition of ABUS to mammography in women with greater than 50% breast density resulted in the detection of 12.3 per 1,000 breast cancers, compared to 4.6 per 1,000 by mammography alone. The mean tumor size was 14.3 mm and overall attributable risk of breast cancer was 19.92 (95% confidence level, 16.75 – 23.61) in our screened population. These preliminary results may justify the cost-benefit of implementing the judicious us of ABUS in conjunction with mammography in the dense breast screening population.

Keywords

  • Breast ultrasound;
  • 3-dimensional sonography;
  • Breast screening;
  • Dense breast;
  • Breast cancer;
  • Cancer detection

1. Introduction

Mammographic density as an independent risk factor for developing breast cancer has been documented since the 1970’s [1]. The appearance of breast tissue is variable among women. The appearance of density on mammography is the result of the relative proportion of breast stroma, which is less radiolucent compared to fat, accounting for increased breast density. Wolfe classified breast density as an independent risk factor for breast cancer in women [2] and [3]. Approximately 70 to 80% of breast cancers occur in women with no major predictors [4][5] and [6]. Population-based screening for early detection of breast cancer is therefore the primary strategy for reducing breast cancer mortality. Mammography has been used as the standard imaging method for breast cancer screening, with reduction in breast cancer mortality [7]. Breast density significantly reduces the ability to visualize cancers on mammography. The number of missed cancers is substantially increased in mammographically dense breasts, where the sensitivity is reported as low as 30 to 48%. [8]; and the odds of developing breast cancer 17.8 times higher [9]. Hand held ultrasound (HHUS) has been used to optimize the detection of cancers in mammographically dense breasts, but is limited due to technical factors, such as breast size, considerable user variability and reproducibility, technical skill, and time constraints, precluding HHUS as an effective screening modality for breast cancer [10][11] and [12]. Kelly described the use of 3D-automated breast ultrasound (ABUS) as an adjunct to mammography in the evaluation of non-palpable breast cancers in asymptomatic women. ABUS with mammography resulted in an increase in diagnostic yield from 3.6 per 1,000 with mammography alone, to 7.2 per 1,000 by adding ABUS, resulting in a mammography miss rate of 3.6 per 1,000 [13]. However, one of the limitations of the study was that it did not isolate dense breasts as an independent risk factor for developing breast cancer, where the detection rate should be expected to be higher. ABUS is FDA-approved in the United States for screening of women with dense breast parenchyma [14]. The purpose of this study was to demonstrate that ABUS increases the detection of non-palpable breast cancers in mammographically dense breasts when used as an adjunct diagnostic modality in asymptomatic women. This resulted in the subsequent detection of cancers missed by mammography of smaller size and stage, justifying the basis for the judicious use of implementing ABUS in conjunction with mammography in the dense breast screening population. The tabulated data was extrapolated based on known mammography screening utilization to show a cost-benefit of additional ABUS as a population based screening method.

2. Methods

2.1. Selection of participants

This study and the use of patient electronic health records were approved by an ethics committee appointed by the institute Board of Directors. The study design included two study groups, the control and test groups, in successive years. Each group was followed prospectively for 1 year. The control group consisted of women screened by digital mammography alone and stratified for breast density based on a Wolf classification of 50% or greater breast density (defined as the ‘mammographically dense breast’ for the purpose of this study). The second group consisted of women initially screening by digital mammography as having mammographically dense breasts, followed by automated breast ultrasound (ABUS). Each group was carefully selected on the basis of breast density and having no major pre-existing predictors of breast cancer, such personal or family history of breast cancer, or BRCA gene positive. In addition, the test group patients were not included in the screening group so as to eliminate impact on the results of the test group patients. The control group consisting of 4076 asymptomatic women designated as Wolf classification of 50% or greater breast density underwent stand-alone screening digital mammography between January 2009 and December 2009 using digital mammography (Selenia, Hologic Inc., Bedford, MA USA). The sensitivity, specificity, positive predictive value, and negative predictive value for biopsy recommendation were determined, in addition to data collection regarding the size and stage of cancers missed by mammography. The test group, consisting of 3418 asymptomatic women designated as Wolf classification of 50% or greater breast density, underwent stand-alone screening digital mammography between January 2010 and May 2011 using digital mammography (Selenia, Hologic Inc., Bedford, MA USA). This was followed by automated whole breast ultrasound (Somo-V. U-Systems, Sunnyvale, CA USA). The mammography-alone results were not used as control results in order to eliminate potential bias introduced by ABUS results on the mammography interpretations. In addition, mammography results were interpreted independently from ABUS results so as not to introduce bias. The sensitivity, specificity, positive predictive value, and negative predictive value for biopsy recommendation were determined, in addition to derived statistical data regarding the relative risk, and odds ratio for developing breast cancer.

2.2. Assessment of mammographic density

Mammographic density was assessed independently by radiologists on a dedicated mammography viewing workstation equipped with 5-Megapixel resolution. The radiologists were FDA-qualified in mammography, with at least 10 years experience in breast ultrasound, 24 months of which included ABUS. Two radiologists interpreted both the mammography and ABUS examinations under identical viewing conditions of 5-Megapixel resolution. The mammograms and ABUS studies were double read by two radiologists, with final consensus determination for each case. Mammograms were evaluated according to one of five categories of density (0%, 1 to 24%, 25 to 49%, 50 to 74%, and 75 to 100%) and only mammograms with breast density of 50% or greater were included in the control and test study groups.

2.3. 3D-Automated breast ultrasound evaluation

3D-Automated Breast Ultrasound (ABUS) is a computer-based system for evaluating the whole breast. The whole breast ultrasound system (Somo-V, U-Systems, Sunnyvale, CA USA) was used in combination with a 6 to 14 MHz broadband mechanical transducer attached to a rigid compression plate and arm, producing over 300 images per image acquisition obtained as coronal sweeps from the skin to the chest wall. The mechanical arm controls transducer speed and position, while a trained ultrasound technologist maintains appropriate contact pressure and vertical orientation to the skin. Interpretation and reporting time for an experienced radiologist is approximately 10 minutes per examination. The radiologist has cine functionality to simultaneously view breast images in the coronal, sagittal, and axial imaging planes.

2.4. Data collection

ABUS scan data was collected for location and size of breast masses and recorded in a radial or clock orientation consistent with American College of Radiology reporting lexicon. Studies were reported according to the American College of Radiology Breast Imaging Reporting and Data System (BI-RADS) six-point scale (0=incomplete, needs additional assessment; 1=normal; 2=benign; 3=probably benign; 4=suspicious; 5=highly suggestive of malignancy) [15] and [16]. For BI-RADS scores of 1, 2, and 3 on ABUS, patients were followed prospectively for 1 year to exclude cancers missed on both mammography and ABUS. For BI-RADS scores of 4 and 5, stereotactic hand held ultrasound (HHUS) biopsy was performed using 14 gauge or larger percutaneous biopsy. HHUS was employed because ABUS is presently not equipped with biopsy capability. If a benign non-high risk lesion was diagnosed, such as simple breast cysts, no further tissue sampling was performed. All non-cystic lesions were biopsied. Cystic lesions were identified as anechoic, thin walled lesions with posterior acoustic enhancement. All pathology proven breast malignancies were further staged using contrast volumetric/whole breast MR imaging (1.5T HDe Version 15.0/M4 with VIBRANT software, GE Medical Systems, Waukesha, WI USA.) with computer assisted detection (CADStream software, Merge Healthcare, Belleview WA USA). A final pathological stage was assigned by the pathologists in the usual manner in accordance with the American Joint Committee on Cancer (AJCC) TNM system guidelines. The pathologists were blinded to patient participation in the study and the method of cancer detection.

2.5. Statistical analysis

Calculations were made of the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), relative risk, odds risk, and attributable risk of breast cancer using MedCal version 12.2.1 software. Exact 95% confidence intervals (CI) were calculated for diagnostic yield. Statistical methods involved the Chi-square test statistic, which was used to compare the number of cancers detected by ABUS, based on the size of cancer. P-values of less than .05 were considered to indicate statistical significance. Attributable risk (AR) was calculated according to the following formula: AR=(RR − 1)Pc ÷ RR, where RR denotes relative risk of greater than 50%, and Pc prevalence of density of greater than 50% in case patients[17][18] and [19].

3. Results

Comparable interobserver diagnostic reliability (Kappa value of 0.98) was observed with mammography and ABUS examinations. In the control group (N=4076), the median age of participants with breast cancer (N=19) at the time of biopsy was 54 years, distributed as follows: 26% (5 out of 19) cancers occurred in women younger than age 50; 63% (12 out of 19) in women 50 to 69 years; and 11% (2 out of 19) over the age of 70 years. All cancers (N=19) were biopsy proven invasive ductal carcinoma. The sensitivity and specificity of stand-alone digital mammography were 76.00% (95% CI: 54.87% – 90.58%) and 98.2% (95% CI: 97.76% – 98.59%). The positive predictive value was 20.43% (95% CI: 12.78% – 30.05%) with a breast cancer prevalence rate of 0.60% (95% CI: 12.78% – 30.05%). The cancer detection rate was 4.6 per 1,000, with mean tumor size detected by mammography (N=19) of 21.3 mm. The average size of missed breast cancer (N=6) was 22.3 mm. The node positivity rate was 5% (1 of 19 cases). In the ABUS study group (N=3418), the median age of participants with breast cancer (N=42) at the time of biopsy was 57 years, distributed as follows: 17% (7 out of 42) cancers occurred in women younger than age 50; 64% (27 out of 42) in women 50 to 69 years; and 19% (8 out of 42) over the age of 70 years. The sensitivity and specificity of ABUS were 97.67% (95% CI: 87.67% – 99.61%) and 99.70%, (95% CI=99.46% – 99.86%), respectively, in mammographically dense breasts. The positive predictive value of ABUS was 80.77% (95% CI=67.46% – 90.36%), with a breast cancer prevalence rate of 1.25% (95% CI: 0.91% – 1.69%). The odds ratio of breast cancer in mammographically dense breasts determined by ABUS was 2.65 (95% CI: 1.54 – 4.57; P=0.0004). The cancer detection rate was 12.3 per 1,000. A 2.6-fold increase in cancer detection rate was observed between ABUS added to digital screening mammography compared to stand-alone digital screening mammography. Invasive breast cancer accounted for 81% (42 out of 52) solid breast masses detected by ABUS, of which 93% (39 out of 42) were invasive ductal carcinomas, and 7% (3 out of 42) were invasive lobular carcinomas. The mean tumor size detected by ABUS in patients with breast cancer (N=42) was 14.3 mm, distributed as follows: Stage 1A disease accounted for 83% (35 out of 42) of cases; 12% were Stage 2A (5 out of 42), and 5% were Stage 3A (2 out of 42). Stage 3A disease was associated with multifocal disease in both cases, one of which also was Level 1 axillary lymph node positive. The node positivity rate was 2% (1 in 42) of cases. The false positive rate of ABUS was 19.3%, with a negative predictive value of 99.97% (95% CI 99.83% – 100.00%). The pathologies associated with false positive results (N=10) were fibroadenomas and atypical epithelial neoplasms. We also used our data to extrapolate the theoretical cost-benefit of ABUS screening applied to a large screening population in the United States. Our analysis relied on the following assumptions: (1) Global Centers for Medicare and Medicaid reimbursement rate of breast ultrasound of $71 [20]; and (2) Estimated mean doubling time of a missed cancer of 250 days at the 95th percentile [21] and [22]. According to previously cited cancer kinetics models, a missed breast cancer should be clinically evident within 9 months[23]. When we considered the mean breast cancer size in our positive test subject group, 14.3 mm (N=42), we extrapolated a theoretical missed cancer size of 29.2 mm at 9 months in mammographically dense breasts, representative of Stage 2 or greater disease. In control subjects, a mean breast cancer size of 22.3 mm was consistent with stage 2 breast cancer. Incremental treatment cost assumptions, based on the global Centers for Medicare and Medicaid reimbursement rate between Stage 1 and Stage 2 breast cancer, were $24,002 and $34,469, respectively, for a cost differential of $10,467 [24]. Accordingly, the aggregate costs of screening 3418 ABUS patients in this study were $239,260, compared to the estimated aggregate costs of additional treatment in 26 potentially missed cancers (based on previously noted theoretical assumptions) of $275,557 based on a cancer miss rate of 0.77% (or 7.7 per 1,000).

4. Discussion

Table 1 shows the clinical indications for ordering an ABUS examination. Table 2 shows the distribution of breast cancer size according to age in the control and test study groups. The test group showed no statistical difference between size of the cancer and patient age at presentation. A significant increase in tumor size in the over 70 patients in control subjects was attributed to the more advanced tumor stage at presentation.Table 3 shows that stand-alone digital mammography was less sensitive than ABUS in breast cancer detection, with a 4-fold increase in positive predictive value of ABUS compared to stand-alone mammography in dense breasts. Our results showed that mammographic density of 50% or more was associated with an increased risk of breast cancer and resulted in a significant miss rate in asymptomatic women. Table 4 shows a statistically significant age-related attributable risk of developing breast cancer for mammographic density of 50% or greater. These observations are consistent with other studies which have shown an increased risk of breast cancer in dense breasts following negative mammography screening [2],[3][8] and [9]. We observed that breast cancer risk was highest in patients over age 70, where increased breast density was associated with an attributable risk of 29.6 (95% CI, 21.5 – 40.8). Fig. 1 shows box plots comparing case patients and control subjects according to age, with tumor sizes shown as a function of the odds ratio, relative risk, and attributable risk for each age category.

Table 1. Clinical criteria for ABUS screening
• As a supplement to mammography, screening for occult cancers in certain populations of women (such as those with dense fibroglandular breasts and/or with elevated risk of breast cancer);
• Imaging evaluation of non-palpable masses in women under 30 years of age who are not at high risk for development of breast cancer, and in lactating and pregnant women; and
• BI-RADS (American College of Radiology Breast Imaging Reporting and Data System) scoring classification class III, heterogeneously dense, with 50% to 74% or 75% to 100% breast density on mammography, without palpable mass.
Table 2. Breast cancer size according to method detection

T2

Table 3. Detection of breast cancer according to method
t3 

Table 4. Risk of breast cancer according to method detection

t4
  1-s2.0-S0899707112002872-gr1

Fig. 1. Breast Cancer Staging and Risk Assessment by Screening Method Detection. Box plots comparing case patients and control subjects according to age (boxes A through D). Tumor sizes are shown as a function of the odds ratio, relative risk, and attributable risk for each age category. Bars represent the highest and lowest observed values with respect to individual variables (individually labeled with arrows).

 

Our study also showed that 3D-Automated Breast Ultrasound (ABUS) was an effective screening modality in mammographically dense breasts. Our extrapolated data suggest a breast cancer miss rate of 7.7 per 1,000 in mammographically dense breasts in asymptomatic women, which is higher compared to the cancer miss rate of 3.6 per 1,000 reported by Kelly using ABUS [13]. We attribute the increased breast cancer miss rate due to breast density, which was isolated as the principal risk factor in our study. Other studies have shown that the attributable risk of breast cancer for a mammographic density of 50% or greater was 40% for all cancers detected less than 12 months after a negative screening mammogram, and as high as 50% in women less than the age of 50. This marked increase in the risk of breast cancer associated with mammographic density of 50% or greater up to 12 months following screening directly reflects cancers that were present at the time of screening but went undetected due to masking by dense breast parenchyma [25],[26][27][28] and [29]. In the final analysis, there is the issue of the theoretical cost-benefit of adding ABUS screening to mammography in an otherwise healthy population. The importance of screening mammographically dense breasts with ABUS has particular relevance based on the small size and early stage of breast cancers. Our study showed a mean tumor size of 14.3 mm, representing stage 1 disease, which was present in 81% of patients. From our data, we derived theoretical population-based costs as a basis for the cost-benefit of ABUS in the United States population. Our study compared the incremental costs of screening versus the costs of added treatment related to a change in the staging of missed cancers from Stage 1 to Stage 2. The costs of additional treatment outweighed the costs of screening by $32,808, which calculated to $9.60 added healthcare cost per patient in the 3418 participants in the study. In the United States, 48 million mammograms were performed annually, with a reported estimated miss rate of 10% [30]. When comparing control versus test patients, our study suggests a theoretical miss rate of 7.7 cancers per 1,000 mammograms, or 0.77%, which is considerably lower than the reported missed rate of 10%. Based on these theoretical assumptions, annual added ABUS screening of the entire U.S. population would cost $3.40-billion. However, in actual practice, ABUS would be used only in the mammographically dense breast, which would potentially reduce the screening costs by at least a factor of 0.8, bringing the cost closer to $2.72-billion. By contrast, the incremental costs of added treatment associated with stage 2 compared to stage 1 breast cancer in the U.S. population would be $3.82-billion, assuming a conservative cost basis of $10,467 per patient.. The cost-benefit of early detection of stage 1 disease results in a theoretical per capital annual cost savings of $22.75 per screened patient in the U.S. population, according to our model. However, we have no actual or derived data to support improved breast cancer mortality with the addition of ABUS as a universal screening modality. This is one of the major limitations of our study because actuarial analyses used to justify screening modalities are typically based on mortality statistics. With respect to five year survival statistics between stage 1 and stage 2 breast cancers, of 98% and 80%, respectively, one could construe the potential for a theoretical quality-of-life benefit based on judicious ABUS screening. Another limitation of our study is the relatively small screening population used in our study, emphasizing the need for continued research in order to validate ABUS as a viable and cost-effective population-based screening modality, which should be stratified for other risk factors for breast cancer, such as: personal or family history of breast cancer, BRCA genetic results, environmental factors (late parity, previous exposure to ionizing radiation, exogenous estrogen, smoking, and alcohol use), early menarche/late menopause, and ethnic/racial differences. At most imaging centers, mammography is the only screening method for breast cancer detection. Our study corroborates with the data derived from other studies that the principal mechanism for breast cancer in dense breast parenchyma is not rapid growth, but rather, the masking of coincident cancers that are missed on screening mammograms [9]. These findings further suggest that the addition of mammographic screening in patients with dense breast parenchyma is likely not to increase diagnostic yield in the detection of breast cancers. Therefore, emphasis should be placed on alternative imaging techniques for such women. To conclude, our study of a small representative dense breast screening population showed that the addition of ABUS was more effective than digital mammography alone. This study provides a platform for using ABUS as cost-effective approach to breast cancer detection in the judicious screening of asymptomatic women with excessive mammographic density, in whom the greatest risk is between screening mammography examinations.

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    • Breast cancer screening with ultrasonography
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    • Combined screening with ultrasound and mammography versus mammography alone in women at elevated risk of breast cancer
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Corresponding author. Breast Cancer Research Institute, Nova Southeastern University College of Medicine, 5732 Canton Cove, Winter Springs, FL 32708, USA. Tel.: 1 407 699 7787.

Copyright © 2013 Elsevier Inc. All rights reserved.

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The Incentive for “Imaging based cancer patient’ management”


 Writer: Dror Nir, PhD

It is generally agreed by radiologists and oncologists that in order to provide a comprehensive work-flow that complies with the principles of personalized medicine, future cancer patients’ management will heavily rely on “smart imaging” applications. These could be accompanied by highly sensitive and specific bio-markers, which are expected to be delivered by pharmaceutical companies in the upcoming decade. In the context of this post, smart imaging refers to imaging systems that are enhanced with tissue characterization and computerized image interpretation applications. It is expected that such systems will enable gathering of comprehensive clinical information on cancer tumors, such as location, size and rate of growth.

What is the main incentive for promoting cancer patients’ management based on smart imaging? 

It promises to enable personalized cancer patient management by providing the medical practitioner with a non-invasive and non-destructive tool to detect, stage and follow up cancer tumors in a standardized and reproducible manner. Furthermore, applying smart imaging that provides valuable disease-related information throughout the management pathway of cancer patient will eventually result in reducing the growing burden of health-care costs related to cancer patients’ treatment.

Let’s briefly review the segments that are common to all cancer patients’ pathway: screening, treatment and costs.

 

Screening for cancer: It is well known that one of the important factors in cancer treatment success is the specific disease staging. Often this is dependent on when the patient is diagnosed as a cancer patient. In order to detect cancer as early as possible, i.e. before any symptoms appear, leaders in cancer patients’ management came up with the idea of screening. To date, two screening programs are the most spoken of: the “officially approved and budgeted” breast cancer screening; and the unofficial, but still extremely costly, prostate cancer screening. After 20 years of practice, both are causing serious controversies:

In trend analysis of WHO mortality data base [1], the authors, Autier P, Boniol M, Gavin A and Vatten LJ, argue that breast cancer mortality in neighboring European countries with different levels of screening but similar access to treatment is the same: “The contrast between the time differences in implementation of mammography screening and the similarity in reductions in mortality between the country pairs suggest that screening did not play a direct part in the reductions in breast cancer mortality”.

In prostate cancer mortality at 11 years of follow-up [2],  the authors,Schröder FH et. al. argue regarding prostate cancer patients’ overdiagnosis and overtreatment: “To prevent one death from prostate cancer at 11 years of follow-up, 1055 men would need to be invited for screening and 37 cancers would need to be detected”.

The lobbying campaign (see picture below)  that AdmeTech (http://www.admetech.org/) is conducting in order to raise the USA administration’s awareness and get funding to improve prostate cancer treatment is a tribute to patients’ and practitioners’ frustration.

 

 

 

Treatment: Current state of the art in oncology is characterized by a shift in  the decision-making process from an evidence-based guidelines approach toward personalized medicine. Information gathered from large clinical trials with regard to individual biological cancer characteristics leads to a more comprehensive understanding of cancer.

Quoting from the National cancer institute (http://www.cancer.gov/) website: “Advances accrued over the past decade of cancer research have fundamentally changed the conversations that Americans can have about cancer. Although many still think of a single disease affecting different parts of the body, research tells us through new tools and technologies, massive computing power, and new insights from other fields that cancer is, in fact, a collection of many diseases whose ultimate number, causes, and treatment represent a challenging biomedical puzzle. Yet cancer’s complexity also provides a range of opportunities to confront its many incarnations”.

Personalized medicine, whether it uses cytostatics, hormones, growth inhibitors, monoclonal antibodies, and loco-regional medical devices, proves more efficient, less toxic, less expensive, and creates new opportunities for cancer patients and health care providers, including the medical industry.

To date, at least 50 types of systemic oncological treatments can be offered with much more quality and efficiency through patient selection and treatment outcome prediction.

Figure taken from presentation given by Prof. Jaak Janssens at the INTERVENTIONAL ONCOLOGY SOCIETY meeting held in Brussels in October 2011

For oncologists, recent technological developments in medical imaging-guided tissue acquisition technology (biopsy) create opportunities to provide representative fresh biological materials in a large enough quantity for all kinds of diagnostic tests.

 

Health-care economics: We are living in an era where life expectancy is increasing while national treasuries are over their limits in supporting health care costs. In the USA, of the nation’s 10 most expensive medical conditions, cancer has the highest cost per person. The total cost of treating cancer in the U.S. rose from about $95.5 billion in 2000 to $124.6 billion in 2010, the National Cancer Institute (www.camcer.gov) estimates. The true sum is probably higher as this estimate is based on average costs from 2001-2006, before many expensive treatments came out; quoting from www.usatoday.com : “new drugs often cost $100,000 or more a year. Patients are being put on them sooner in the course of their illness and for a longer time, sometimes for the rest of their lives.”

With such high costs at stake, solutions to reduce the overall cost of cancer patients’ management should be considered. My experience is that introducing smart imaging applications into routine use could contribute to significant savings in the overall cost of cancer patients’ management, by enabling personalized treatment choice and timely monitoring of tumors’ response to treatment.

 

 References

  1. 1.      BMJ. 2011 Jul 28;343:d4411. doi: 10.1136/bmj.d4411
  2. 2.      (N Engl J Med. 2012 Mar 15;366(11):981-90):

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