Acronyms and Glossary

ACRONYMS

AHRQ Agency for Healthcare Research and Quality

ASCO American Society of Clinical Oncology

ASR Analyte-specific reagent

C-Path Critical Path Institute

CDC Centers for Disease Control and Prevention

CEA Cost-effectiveness analysis

CED Coverage under Evidence Development

CLIA Clinical Laboratory Improvement Amendments

CMS Centers for Medicare & Medicaid Services

CPI Consumer Price Index

CPT Current procedural terminology

CPTAC Clinical Proteomic Technologies Initiative for Cancer

DARPA Defense Advanced Research Projects Agency

DHHS Department of Health and Human Services

EDRN Early Detection Research Network

EGFR Epidermal growth factor receptor

ER Estrogen receptor

FDA Food and Drug Administration

FDG-PET fluorodeoxyglucose positron emission tomography

FNIH Foundation of the National Institutes of Health

FTC Federal Trade Commission



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Cancer Biomarkers: The Promises and Challenges of Improving Detection and Treatment Acronyms and Glossary ACRONYMS AHRQ Agency for Healthcare Research and Quality ASCO American Society of Clinical Oncology ASR Analyte-specific reagent C-Path Critical Path Institute CDC Centers for Disease Control and Prevention CEA Cost-effectiveness analysis CED Coverage under Evidence Development CLIA Clinical Laboratory Improvement Amendments CMS Centers for Medicare & Medicaid Services CPI Consumer Price Index CPT Current procedural terminology CPTAC Clinical Proteomic Technologies Initiative for Cancer DARPA Defense Advanced Research Projects Agency DHHS Department of Health and Human Services EDRN Early Detection Research Network EGFR Epidermal growth factor receptor ER Estrogen receptor FDA Food and Drug Administration FDG-PET fluorodeoxyglucose positron emission tomography FNIH Foundation of the National Institutes of Health FTC Federal Trade Commission

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Cancer Biomarkers: The Promises and Challenges of Improving Detection and Treatment HIPAA Health Insurance Portability and Accountability Act IOM Institute of Medicine IP Intellectual property IRB Institutional Review Board IVDMIA In Vitro Diagnostic Multivariate Index Assay MIAME Minimum Information About a Microarray Experiment MMRC Multiple Myeloma Research Consortium NBN National Biospecimen Network NCI National Cancer Institute NICE U.K. National Institute for Clinical Excellence NIH National Institutes of Health NIST National Institute of Standards and Technology NLA National limitation amount OBQI Oncology Biomarker Qualification Initiative PBRC Pharmaceutical Biomedical Research Consortium PET Positron emission tomography PMA Premarket approval PPP Public–private partnerships PSA Prostate-specific antigen PSI Protein Structure Initiative SACGT Secretary’s Advisory Committee on Genetic Testing SEMATECH Semiconductor Manufacturing Technology SNP Single nucleotide polymorphism TRWG Translational Research Working Group TSC The SNP Consortium USPSTF U.S. Preventive Services Task Force GLOSSARY Allele—any one of a series of two or more different genes that occupy the same position (locus) on a chromosome. Amplification—a process by which specific genetic material is increased. For some cancers, the number of copies of specific genes is higher than normal. These genes are said to be amplified. Analyte-specific reagent (ASR)—antibodies, both polyclonal and monoclonal, specific receptor proteins, ligands, nucleic acid sequences, and similar reagents, which through specific binding or chemical reaction with substances in a specimen are intended to be used in a diagnos-

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Cancer Biomarkers: The Promises and Challenges of Improving Detection and Treatment tic application for identification and quantification of an individual chemical substance or ligand in biological specimens. Analytical validity—the accuracy of a test in detecting the specific entity that it was designed to detect. This accuracy does not imply any clinical significance, such as diagnosis. Bias—the systematic but unintentional erroneous association of some characteristic with a group in a way that distorts a comparison with another group. Biorepository—a collection of biological samples, such as tissue, that can be used for research. BRCA—a gene that when mutated increases a woman’s risk of developing breast cancer. Two BRCA genes have been identified and are known as BRCA1 and BRCA2. Cetuximab—a monoclonal antibody drug used to treat advanced or metastatic cancer of the colon and rectum, usually in combination with chemotherapy or irinotecan, another cancer drug. It is currently being used in research trials for treatment of head and neck cancers. Clinical endpoint—a characteristic or variable that reflects how a patient feels, functions, or survives in response to an intervention. Clinical trial—a formal study carried out according to a prospectively defined protocol that is intended to discover or verify the safety and effectiveness of procedures or interventions in humans. Clinical utility—the clinical and psychological benefits and risks of positive and negative results of a given technique or test. Clinical validity—the accuracy of a test for a specific clinical purpose, such as diagnosing or predicting risk for a disorder. Comparative genomic hybridization—a technique for detecting the gain or loss of genetic material in tumor cells. Computed tomography (CT)—a special radiographic technique that uses a computer to assimilate multiple X-ray images into a two-dimensional, cross-sectional image, which also can be reconstructed into a three-dimensional image. This can reveal many soft tissue structures not shown by conventional radiography. Conditional coverage—a policy by which insurers agree to preliminarily cover new tests with the proviso that data would be collected in conjunction with the use of the test, to assess the clinical utility and value of the test, and to create better evidence. Data collected during conditional coverage assessments are used in later decisions regarding full coverage and may be used for research purposes afterward.

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Cancer Biomarkers: The Promises and Challenges of Improving Detection and Treatment Coverage with evidence development (CED)—a CMS program whereby prospective data collection on a product is required for national Medicare coverage (see Conditional coverage). A product that has an insufficient evidence base for CMS coverage determination could be evaluated through CED. Current Procedural Terminology—a listing of descriptive terms and identifying codes for reporting medical services and procedures, designed to standardize the terminology used for medical, surgical, and diagnostic services. CPT codes were first developed by the American Medical Association and are updated by the CPT Editorial Panel. CYP450—the gene that codes for the drug-metabolizing enzyme cytochrome P450. Variants in this gene can alter the enzyme’s ability to metabolize certain drugs. Defense Advanced Research Projects Agency (DARPA)—the central research and development organization for the Department of Defense, it has focused on research projects that have high risk but also potential for high payoff if successful. De novo classification—a Food and Drug Administration classification of a device or diagnostic that is not equivalent to a legally marketed product. Deletion—the loss of genetic material. Some cancers are triggered by the deletion of key genes, portions of genes, or their regulatory sequences. Diagnostic—the investigative tools and techniques used in biological studies or to identify or determine the presence of a disease or other condition. In this report, “diagnostic” is often used synonymously with “biomarker test.” These terms refer to any laboratory-based test that can be used in drug discovery and development as well as in patient care and clinical decision making. Epidermal growth factor receptor (EGFR)—a receptor that is overproduced in several solid tumors, including breast and lung cancers. Its overproduction is linked to a poorer prognosis because it enables cell proliferation, migration, and the development of blood vessels. Several new drugs recently approved by the Food and Drug Administration specifically target EGFR. Flow cytometry—a technique for identifying and sorting cells and their components (such as DNA) by staining with fluorescent dyes and detecting the fluorescence, usually by laser beam illumination.

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Cancer Biomarkers: The Promises and Challenges of Improving Detection and Treatment Genome—an organism’s entire complement of DNA, which determines its genetic makeup. Genomics—the study of all of the nucleotide sequences, including structural genes, regulatory sequences, and noncoding DNA segments, in the chromosomes of an organism or tissue sample. One example of the application of genomics in oncology is the use of microarray or other techniques to uncover the genetic “fingerprint” of a tissue sample. This genetic fingerprint is the pattern that stems from the variable expression of different genes in normal and cancer tissues. Genotype—the genetic makeup of an organism or cell. Health Insurance Portability and Accountability Act (HIPAA)—an act passed in 1996 that includes privacy and security regulations regarding disclosure and use of medical information. Herceptin—see Human epidermal growth factor receptor 2. High-density expression arrays—microarrays with so many probes that they can detect the expression of hundreds of thousands of genes, as opposed to low-density expression arrays, which can detect a much smaller number. High-throughput technology—any approach using robotics, automated machines, and computers to process many samples at once. Homebrew test—diagnostic tests that are custom made in individual laboratories by combining several reagents in a specified protocol. All testing of a homebrew diagnostic is done within the laboratory that developed it. The Food and Drug Administration regulates commercial tests through a premarket approval (PMA) or premarket notification (510[k]) review process. In contrast, it does not regulate homebrew tests, except to the extent that they use analyte-specific reagents. Clearance or approval of the test itself is not required. Human epidermal growth factor receptor 2 (HER2)—a growth factor receptor that is used as a breast cancer biomarker for prognosis and treatment with the drug trastuzumab (Herceptin), which targets the protein. The HER2 protein is overexpressed in approximately 25 percent of breast cancer patients, due to amplification of the gene. Human Genome Project—a 13-year project coordinated by the U.S. Department of Energy and the National Institutes of Health and completed in 2003. The project completed its goal of sequencing the genome and mapping all 20,000–25,000 genes in human DNA two years earlier than anticipated, due to technological advances.

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Cancer Biomarkers: The Promises and Challenges of Improving Detection and Treatment Imatinib—A small molecule compound originally developed for treating chronic myelogenous leukemia and gastrointestinal stromal tumors, imatinib (STI571, Gleevec) is a selective tyrosine kinase inhibitor that binds to the ATP-binding pocket and blocks the tyrosine kinase activities of Abl, c-kit, and PDGFR. Liquid chromatography—a process in which a chemical mixture carried by a liquid is separated into its components due to the different rates at which these components travel through a stationary phase. Loss of heterozygosity—loss of one allele at a specific position on a chromosome. Magnetic resonance imaging (MRI)—method by which images are created by recording signals generated from the excitation (the gain and loss of energy) of such elements as the hydrogen of water in tissue when placed in a powerful magnetic field and pulsed with radio frequencies. Mass spectrometry—a method for separating ionized molecular particles according to mass by applying a combination of electrical and magnetic fields to deflect ions passing in a beam through the instrument. Messenger RNA (mRNA) expression profiling—the use of microarrays or other technology to quantify all the different mRNAs transcribed from the various protein-encoding genes in a sample. (Messenger RNA carries the information from the DNA genetic code to areas in the cytoplasm of the cell in which proteins are made.) Metabolomics—the systematic study of the unique chemical fingerprints that specific cellular processes leave behind, that is, small-molecule metabolites. Microarray—a high-throughput biological assay in which different probes are deposited on a chip surface (glass or silicon) in a miniature arrangement. DNA microarrays are the most commonly used. Off-label use—using a drug that either has not been approved by the Food and Drug Administration or has not been approved for the purpose for which it is being used. Overfitting—a false pattern that is found between large numbers of possible predictors and an outcome due to high complexity and “noise” in the data. Overfitting leads to erroneous conclusions about the data. This can be identified by checking the reproducibility in a separate, independent group of individuals. Pathway biomarker—a biomarker that can be detected in one or several key steps along a biochemical pathway that may be perturbed in cancer

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Cancer Biomarkers: The Promises and Challenges of Improving Detection and Treatment cells. Because of their broad applicability, pathway biomarkers may be useful in assessing the effectiveness of multiple drugs in different types of cancers. Pharmacodynamics—the study of the biochemical and physiological effects of drugs, the mechanisms of drug action, and the relationship between drug concentration and effect. Pharmacodynamics is the study of what a drug does to the body, as opposed to pharmacokinetics, which is the study of what a body does to a drug. Pharmacogenomics—a biotechnological science that combines the techniques of medicine, pharmacology, and genomics to determine the effects of genetic differences in patients on the metabolism and hence the potential toxicity or efficacy of drugs. Pharmacokinetics—the study of the time course of substances, such as drugs, in an organism. Pharmacokinetics is used to determine how long a drug remains in the body. Phase I trial—clinical trial in a small number of patients in which the toxicity and dosing of an intervention are assessed. Phase II trial—clinical trial in which the safety and preliminary efficacy of an intervention are assessed in patients. Phase III trial—large-scale clinical trial in which the safety and efficacy of an intervention are assessed in a large number of patients. The Food and Drug Administration generally requires new drugs to be tested in phase III trials before they can be put on the market. Phenotype—the physical traits of an individual. Phosphorylated proteins—proteins to which a phosphate group has been attached. The excessive growth that typifies cancer is often thought to be prompted by the phosphorylation of growth-signaling proteins called tyrosine kinases. Such phosphorylation activates these enzymes which then phosphorylate other molecules. Polyacrylamide gel electrophoresis (two-dimensional)—a technique used to separate molecules out of a solution based on their charge, isoelectric point, mass, and size. One-dimensional electrophoresis, in contrast, has fewer molecule-distinguishing capabilities, as it only separates molecules out of a solution on the basis of their charge and size. Polymerase chain reaction (PCR)—a technique for duplicating genetic sequences in vitro by as many as a billion times. This technique enables the detection of relatively scarce genetic material. Polymorphism—existence of a gene in several allelic forms.

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Cancer Biomarkers: The Promises and Challenges of Improving Detection and Treatment Positive predictive value—the probability that an individual with a positive test has, or will develop, a particular disease, or characteristic, that the test is designed to detect. It is a measure of the ratio of true positives to (false + true positives). Positron emission tomography (PET)—a highly sensitive technique that uses radioactive probes to image in vivo tumors, receptors, enzymes, DNA replication, gene expression, antibodies, hormones, drugs, and other compounds and processes. Premarket approval (PMA)—a Food and Drug Administration approval for a new test or device that enables it to be marketed for clinical use. To receive this approval, the manufacturer of the product must submit clinical data showing the product is safe and effective for its intended use. Premarket notification or 510(k)—a Food and Drug Administration review process that enables a new test or device to be marketed for clinical use. This review process requires manufacturers to submit data showing the accuracy and precision of their product, as well as, in some cases, its analytical sensitivity and specificity. Manufacturers also have to provide documentation supporting the claim that their product is substantially equivalent to one already on the market. This review does not typically consider the clinical safety and effectiveness of the product. Proficiency testing—laboratories performing nonwaived tests must enroll laboratory personnel in tests specific to the subspecialty relevant to the tests they will be evaluating. The Clinical Laboratory Improvement Act requires proficiency testing of personnel at least once every two years. Protein chip—a piece of glass or other surface on which different protein probes have been affixed at separate locations in an ordered manner. The probes are often antibodies to specific proteins. The protein chip identifies the amounts and types of proteins present in a sample via fluorescence-based imaging. Proteomics—the study of the structure, function, and interactions of the proteins produced by the genes of a particular cell, tissue, or organism. The application of proteomics in oncology may involve mass spectroscopy, two-dimensional polyacrylamide gel electrophoresis, protein chips, and other techniques to uncover the protein “fingerprint” of a tissue sample. This protein fingerprint is the pattern that stems from the various amounts and types of all the proteins in the sample.

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Cancer Biomarkers: The Promises and Challenges of Improving Detection and Treatment PSA test—a blood test that detects prostate-specific antigen. The PSA test was approved by the Food and Drug Administration in 1985 for prostate cancer recurrence, but it is now widely used as a screening test for prostate cancer. Qualification—the evidentiary process of linking an assay with biological and clinical endpoints that is dependent on the intended application. Quality-adjusted life-year (QALY) index—an index that combines measures of quality of life with length of life. Sample bias—see Bias. Sensitivity (analytical)—the lowest concentration that can be distinguished from background noise. This concentration is termed an assay’s detection limit. Sensitivity (clinical)—a measure of how often a test correctly identifies patients with a specific diagnosis. It is calculated as the number of true-positive results divided by the number of true-positive plus false-negative results. Single-molecule sequencing—also called nanopore sequencing, is a method for sequencing DNA that involves passing the DNA through small pores about 1 nanometer in diameter. The size of the pore ensures that the DNA is forced through the hole as a long string, one base at a time. The base (i.e., adenine, guanine, cytosine, or thymine) is identified by the characteristic obstruction it creates in the pore, which is detected electrically. Single-molecule sequencing can be a more sensitive technique for identifying relatively rare genetic strands in a sample, without the need for replicating them with a polymerase chain reaction. Single nucleotide polymorphism (SNP)—a variant DNA sequence in which the purine or pyrimidine base (e.g., cytosine) of a single nucleotide has been replaced by another such base (e.g., thymine). SNP microarray—a type of microarray used to identify genetic changes linked to specific cancers. Specificity (analytical)—how well an assay detects only a specific substance and does not detect closely related substances. Specificity (clinical)—a measure of how often a test correctly identifies the proportion of persons without a specific diagnosis. It is calculated as the number of true-negative results divided by the number of true negative plus false-positive results. Surface-enhanced laser desorption/ionization (SELDI)—a technique that uses chemical or antibody probes to bind to specific proteins in a

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Cancer Biomarkers: The Promises and Challenges of Improving Detection and Treatment sample. The bound proteins are then vaporized with a laser and ionized for analysis in a mass spectrometer. Patterns of the masses of the various proteins in a sample, rather than actual protein identifications, are produced by SELDI analysis. These mass spectral patterns are used to differentiate patient samples from one another, such as to distinguish diseased from normal samples. Surrogate endpoint—a biomarker that is intended to substitute for a clinical endpoint in a therapeutic clinical trial and is expected to predict clinical benefit (or harm or lack of benefit or harm) based on epidemiologic, therapeutic, pathophysiologic, or other scientific evidence. Trastuzumab—see HER2. Validation—the process of assessing the assay or measurement performance characteristics.